Study finder

The question: How much did body weight change?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Trial semaglutide formulation

Who or what was studied: Adults with overweight or obesity, without diabetes; both groups received lifestyle intervention

Compared with: Placebo plus lifestyle intervention

Follow-up: 68 weeks

What changed: Mean weight change was -14.9% with semaglutide and -2.4% with placebo; adjusted difference -12.4 percentage points (95% CI -13.4 to -11.5).

What the result means: The semaglutide group lost substantially more weight on average in this trial. A group average does not predict one person's result.

What this cannot answer: Defined participants and formulation; does not test an online vial, a salt form or a blend.

Harms reported: Nausea and diarrhea were common. Gastrointestinal events led to treatment discontinuation in 4.5% versus 0.8%.

Funding: Novo Nordisk

Source access: Original abstract retrieved through indexed PubMed; direct page returned incomplete HTML; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 1961 — randomized

Citation: Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF, STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. The New England journal of medicine. 2021;384(11):989–1002. doi:10.1056/NEJMoa2032183. PMID:33567185.

Source type: Journal paper

Study/cohort key: NCT03548935

Analysis: Estimated mean, treatment-policy estimand, regardless of discontinuation or rescue intervention

DOI: 10.1056/NEJMoa2032183

PMID: 33567185

Registration: NCT03548935

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did cardiovascular death, nonfatal heart attack or stroke become less frequent?

How the study was done: Randomized, double-blind, placebo-controlled, event-driven

What was tested: Trial semaglutide formulation

Who or what was studied: Adults aged 45 or older with established cardiovascular disease and no diabetes; body mass index (BMI), a measure of weight relative to height, was at least 27 kg/m².

Compared with: Placebo

Follow-up: Mean follow-up 39.8 months

What changed: Researchers randomized 17,604 adults with established cardiovascular disease and overweight or obesity, without diabetes, to weekly semaglutide injections under the skin or placebo. Over a mean 39.8 months, cardiovascular death, nonfatal heart attack or nonfatal stroke occurred in 569 of 8,803 semaglutide recipients (6.5%) and 701 of 8,801 placebo recipients (8.0%). The risk comparison favored semaglutide (hazard ratio 0.80; 95% confidence interval 0.72–0.90).

What the result means: The study measured cardiovascular events, not only a weight or blood-test change. The difference was 1.5 percentage points in the observed event proportions.

What this cannot answer: Established disease population; the composite result is not proof of a reduction in every component or in everyone without cardiovascular disease.

Harms reported: Adverse events caused permanent trial-product discontinuation in 16.6% versus 8.2%.

Funding: Novo Nordisk

Source access: Indexed original PubMed abstract; journal full text returned 403; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 17604 — randomized

Citation: Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, Hardt-Lindberg S, Hovingh GK, Kahn SE, Kushner RF, Lingvay I, Oral TK, Michelsen MM, Plutzky J, Tornøe CW, Ryan DH, SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. The New England journal of medicine. 2023;389(24):2221–2232. doi:10.1056/NEJMoa2307563. PMID:37952131.

Source type: Journal paper

Study/cohort key: NCT03574597

DOI: 10.1056/NEJMoa2307563

PMID: 37952131

Registration: NCT03574597

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did major kidney disease events or kidney/cardiovascular death become less frequent?

How the study was done: Randomized, placebo-controlled

What was tested: Trial semaglutide formulation

Who or what was studied: Adults with type 2 diabetes who met the trial’s criteria for chronic kidney disease

Compared with: Placebo

Follow-up: Median 3.4 years; stopped after a planned interim analysis

What changed: Researchers randomly assigned 3,533 adults with type 2 diabetes and chronic kidney disease to weekly semaglutide injections under the skin or placebo, then followed them for a median 3.4 years. The combined outcome counted kidney failure, a fall of at least 50% in estimated kidney filtration, or death from kidney or cardiovascular causes. It occurred in 331 of 1,767 semaglutide recipients and 410 of 1,766 placebo recipients. The risk comparison favored semaglutide (hazard ratio 0.76; 95% CI 0.66 to 0.88). The trial stopped after a planned interim analysis.

What the result means: The trial found fewer events in its combined kidney-and-death outcome with semaglutide.

What this cannot answer: The composite includes cardiovascular death. It is not a general kidney-protection result for healthy people or every route.

Harms reported: Serious adverse events were reported in 49.6% versus 53.8%.

Funding: Novo Nordisk

Source access: Indexed original PubMed abstract; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 3533 — randomized

Citation: Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, Baeres FMM, Idorn T, Bosch-Traberg H, Lausvig NL, Pratley R, FLOW Trial Committees and Investigators. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. The New England journal of medicine. 2024;391(2):109–121. doi:10.1056/NEJMoa2403347. PMID:38785209.

Source type: Journal paper

Study/cohort key: NCT03819153

DOI: 10.1056/NEJMoa2403347

PMID: 38785209

Registration: NCT03819153

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Was the earlier weight change maintained after withdrawal?

How the study was done: Exploratory off-treatment follow-up of a selected trial subset

What was tested: Prior trial semaglutide exposure; treatment and lifestyle support withdrawn

Who or what was studied: A selected group of 327 adults without diabetes who had overweight or obesity and completed the 68-week STEP 1 treatment phase, followed for a further year after treatment and structured lifestyle support stopped.

Compared with: Prior placebo group

Follow-up: One year after semaglutide or placebo and structured lifestyle support stopped at week 68; the final assessment was at week 120 from the original starting measurement.

What changed: Researchers followed a selected 327-person subset of STEP 1 participants for a year after semaglutide or placebo and structured lifestyle support stopped at week 68. The former semaglutide group had lost an average 17.3% of starting weight during treatment, then regained 11.6 percentage points by week 120; average weight remained 5.6% below the original starting level. Former placebo recipients regained 1.9 percentage points after a 2.0% loss, ending 0.1% below starting weight. These were exploratory observations in selected trial completers, with both medication and lifestyle support withdrawn.

What the result means: Much of the earlier weight loss returned on average, but the group had not returned completely to its starting weight.

What this cannot answer: Selected completers, exploratory analysis, and lifestyle support stopped too; not a new randomized stopping trial or proof that everyone regains all weight.

Harms reported: Not fully extracted in this extension record.

Funding: Novo Nordisk study programme; full funding statement not extracted

Source access: Indexed original PubMed abstract; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Prior subcutaneous exposure

Sample: 327 — extension analysis

Citation: Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, Lingvay I, McGowan BM, Oral TK, Rosenstock J, Wadden TA, Wharton S, Yokote K, Kushner RF, STEP 1 Study Group. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes, obesity & metabolism. 2022;24(8):1553–1564. doi:10.1111/dom.14725. PMID:35441470.

Source type: Journal paper

Study/cohort key: NCT03548935

DOI: 10.1111/dom.14725

PMID: 35441470

Registration: NCT03548935

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did prespecified kidney events fall with the oral formulation?

How the study was done: Prespecified kidney analysis of a double-blind randomized trial

What was tested: Trial oral semaglutide formulation

Who or what was studied: Type 2 diabetes with cardiovascular disease and/or kidney disease; mostly preserved baseline kidney filtration

Compared with: Placebo

Follow-up: Follow-up 47.5 months

What changed: Five-point kidney/cardiovascular-death composite: 8.4% versus 9.0%; hazard ratio 0.91 (95% CI 0.80 to 1.05), P=0.19. Filtration declined more slowly with semaglutide.

What the result means: A kidney-function trend improved, but the combined kidney-event result was not statistically significant.

What this cannot answer: Different route, population and endpoint from FLOW; neither interchangeable nor evidence that all semaglutide kidney findings are negative.

Harms reported: Serious adverse-event rates were similar.

Source access: Indexed original PubMed abstract; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: oral

Sample: 9650 — participants in analysis

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Mann JFE, Marx N, Deanfield JE, Emerson SS, Inzucchi SE, McGuire DK, Mulvagh SL, Pop-Busui R, Poulter NR, Engelmann MDM, Hovingh GK, Belmar N, Idorn T, Jeppesen OK, Birkenfeld AL, Amod A, Mankovsky B, Desouza C, Gorgojo-Martinez JJ, Arechavaleta R, Tu ST, Buse JB, SOUL Study Group*. Impact of Oral Semaglutide on Kidney Outcomes in People With Type 2 Diabetes: Results From the SOUL Randomized Trial. Diabetes care. 2026;49(2):257–265. doi:10.2337/dc25-1080. PMID:41380027.

Source type: Journal paper

Study/cohort key: NCT03914326

DOI: 10.2337/dc25-1080

PMID: 41380027

Registration: NCT03914326

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did liver inflammation and fibrosis improve on biopsy?

How the study was done: Planned interim analysis of randomized, double-blind, placebo-controlled phase 3 trial

What was tested: Trial semaglutide formulation

Who or what was studied: People with metabolic fatty-liver disease with inflammation (MASH) and liver scarring at stages 2 or 3, confirmed by tissue samples

Compared with: Placebo

Follow-up: 72-week interim analysis; longer trial continues

What changed: At a planned 72-week analysis, researchers examined the first 800 of 1,197 participants randomized in an ongoing trial of weekly semaglutide injections under the skin or placebo. Participants had MASH, a metabolic fatty-liver disease with inflammation, and moderate or advanced scarring (fibrosis stage 2 or 3). Liver tissue samples (biopsies) met the trial’s criteria for resolution of the inflammatory liver disease without worsening scarring in 62.9% of semaglutide recipients and 34.3% of placebo recipients. Scarring improved without worsening the inflammatory disease in 36.8% of semaglutide recipients and 22.4% of placebo recipients. These are interim changes in liver tissue; the trial continues to assess longer-term outcomes.

What the result means: More participants reached the defined biopsy improvements. That is more specific than saying the liver was cured.

What this cannot answer: Interim tissue endpoints do not yet establish the long-term liver-complication result.

Harms reported: Gastrointestinal events were more common with semaglutide.

Funding: Novo Nordisk

Source access: Indexed original PubMed abstract; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 800 — First 800 analyzed of 1197 randomized

Citation: Sanyal AJ, Newsome PN, Kliers I, Østergaard LH, Long MT, Kjær MS, Cali AMG, Bugianesi E, Rinella ME, Roden M, Ratziu V, ESSENCE Study Group. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. The New England journal of medicine. 2025;392(21):2089–2099. doi:10.1056/NEJMoa2413258. PMID:40305708.

Source type: Journal paper

Study/cohort key: NCT04822181

DOI: 10.1056/NEJMoa2413258

PMID: 40305708

Registration: NCT04822181

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How much did body weight change?

How the study was done: Randomized, double-blind, placebo-controlled phase 3 trial

What was tested: Trial tirzepatide formulation

Who or what was studied: Adults without diabetes whose body mass index (BMI), a measure of weight relative to height, was at least 30 kg/m², or at least 27 kg/m² with a weight-related complication.

Compared with: Placebo

Follow-up: 72 weeks

What changed: Researchers randomized 2,539 adults without diabetes who had obesity, or overweight with a weight-related complication, to weekly tirzepatide injections under the skin or placebo for 72 weeks. Average weight reductions were 15.0%, 19.5% and 20.9% in the three tirzepatide groups, compared with 3.1% with placebo. These estimates included outcomes after treatment stopped (the treatment-regimen analysis). The percentages are averages within groups assigned different study doses; individual responses varied.

What the result means: The trial found substantial weight reduction across its tirzepatide groups.

What this cannot answer: Results depend on assigned trial exposure, follow-up and population. These percentages are not a head-to-head comparison with another trial.

Harms reported: Mostly mild-to-moderate gastrointestinal events; adverse-event discontinuation 4.3%, 7.1% and 6.2%, versus 2.6%.

Funding: Eli Lilly

Source access: Indexed original PubMed abstract; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 2539 — randomized

Citation: Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A, SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. The New England journal of medicine. 2022;387(3):205–216. doi:10.1056/NEJMoa2206038. PMID:35658024.

Source type: Journal paper

Study/cohort key: NCT04184622

DOI: 10.1056/NEJMoa2206038

PMID: 35658024

Registration: NCT04184622

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Which trial group had the greater average weight reduction?

How the study was done: Randomized, open-label, active-controlled phase 3b trial

What was tested: Trial tirzepatide and semaglutide formulations at tolerated protocol exposures

Who or what was studied: Adults with obesity, without type 2 diabetes

Compared with: Semaglutide

Follow-up: 72 weeks

What changed: Least-squares mean weight change: tirzepatide -20.2% (95% CI -21.4 to -19.1), semaglutide -13.7% (-14.9 to -12.6), P<0.001.

What the result means: Tirzepatide produced greater average weight reduction in this direct comparison.

What this cannot answer: Open-label trial; defined tolerated exposures and population. Does not rank every formulation, indication or individual treatment choice.

Harms reported: Gastrointestinal events were most common in both groups, usually mild or moderate.

Funding: Eli Lilly

Source access: Indexed original PubMed abstract; direct page incomplete; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 751 — 751 randomized; 750 received at least one dose and were included in efficacy and safety analyses (374 tirzepatide and 376 semaglutide).

Citation: Aronne LJ, Horn DB, le Roux CW, Ho W, Falcon BL, Gomez Valderas E, Das S, Lee CJ, Glass LC, Senyucel C, Dunn JP, SURMOUNT-5 Trial Investigators. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. The New England journal of medicine. 2025;393(1):26–36. doi:10.1056/NEJMoa2416394. PMID:40353578.

Source type: Journal paper

Study/cohort key: NCT05822830

Analysis: Modified treatment-regimen estimand; ANCOVA least-squares means. Assesses effects regardless of premature discontinuation or other obesity medications, with prespecified handling of crossover to the comparator and weight-reduction surgery.

DOI: 10.1056/NEJMoa2416394

PMID: 40353578

Registration: NCT05822830

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did breathing interruptions during sleep become less frequent?

How the study was done: Two randomized, double-blind, placebo-controlled phase 3 trial populations

What was tested: Trial tirzepatide formulation

Who or what was studied: Adults with obesity and moderate to severe obstructive sleep apnea, in which breathing repeatedly stops or becomes too shallow during sleep. One trial enrolled people not using positive-airway-pressure breathing treatment; the other enrolled people already using it.

Compared with: Placebo

Follow-up: 52 weeks

What changed: Two 52-week trials randomized 469 adults with obesity and moderate to severe obstructive sleep apnea to weekly tirzepatide injections under the skin or placebo. One trial enrolled people not using positive-airway-pressure breathing treatment; the other enrolled people already using it. Sleep tests counted breathing pauses or unusually shallow breaths per hour, called the apnea–hypopnea index (AHI). Tirzepatide reduced that count by 20.0 more events per hour than placebo in the first trial (95% confidence interval 14.2–25.8 fewer) and by 23.8 more in the second (17.9–29.6 fewer).

What the result means: The sleep tests recorded fewer breathing events with tirzepatide.

What this cannot answer: Obesity-related obstructive sleep apnea; not every sleep problem or a reason to abandon PAP.

Harms reported: Gastrointestinal events were most frequent, mostly mild or moderate.

Funding: Eli Lilly

Source access: Indexed original result and design abstracts; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 469 — 234 and 235 in the two trial populations, confirmed in original design paper PMID 38547961

Citation: Malhotra A, Grunstein RR, Fietze I, Weaver TE, Redline S, Azarbarzin A, Sands SA, Schwab RJ, Dunn JP, Chakladar S, Bunck MC, Bednarik J, SURMOUNT-OSA Investigators. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. The New England journal of medicine. 2024;391(13):1193–1205. doi:10.1056/NEJMoa2404881. PMID:38912654.

Source type: Journal paper

Study/cohort key: NCT05412004

DOI: 10.1056/NEJMoa2404881

PMID: 38912654

Registration: NCT05412004

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did cardiovascular death or worsening heart failure become less frequent?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Trial tirzepatide formulation

Who or what was studied: Heart failure with preserved ejection fraction and obesity

Compared with: Placebo

Follow-up: Median follow-up 104 weeks; health-status outcome at 52 weeks

What changed: Composite events: 9.9% versus 15.3%; hazard ratio 0.62 (95% CI 0.41 to 0.95). Health-status score difference was 6.9 points (95% CI 3.3 to 10.6).

What the result means: Fewer combined events and better reported health status were observed.

What this cannot answer: Cardiovascular death alone was not reduced; few deaths and wide uncertainty. Composite benefit must not become a mortality claim.

Harms reported: Adverse-event discontinuation 6.3% versus 1.4%.

Funding: Eli Lilly

Source access: Indexed original PubMed abstract; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 731 — randomized

Citation: Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V, Ge J, Weerakkody GJ, Ou Y, Bunck MC, Hurt KC, Murakami M, Borlaug BA, SUMMIT Trial Study Group. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. The New England journal of medicine. 2025;392(5):427–437. doi:10.1056/NEJMoa2410027. PMID:39555826.

Source type: Journal paper

Study/cohort key: NCT04847557

DOI: 10.1056/NEJMoa2410027

PMID: 39555826

Registration: NCT04847557

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did tirzepatide prevent cardiovascular events at least as well as dulaglutide in people with type 2 diabetes?

How the study was done: Randomized, double-blind, active-comparator noninferiority trial

What was tested: Trial tirzepatide formulation

Who or what was studied: People with type 2 diabetes and cardiovascular disease caused by plaque buildup in the arteries (atherosclerosis)

Compared with: Dulaglutide

Follow-up: The current Mounjaro label reports a median 210.1 weeks of follow-up for SURPASS-CVOT. The original paper’s accessible abstract does not give its own follow-up summary.

What changed: Researchers compared weekly injections under the skin of tirzepatide and dulaglutide in people with type 2 diabetes and cardiovascular disease caused by plaque buildup in the arteries (atherosclerosis). Of 13,299 randomized participants, 134 were excluded for not meeting entry criteria, leaving 13,165 in the analysis. Cardiovascular death, heart attack or stroke occurred in 12.2% with tirzepatide and 13.1% with dulaglutide (hazard ratio 0.92; 95.3% CI 0.83 to 1.01). This met the trial’s criterion for ruling out an unacceptably worse outcome with tirzepatide (noninferiority P=0.003). The observed difference did not establish that tirzepatide prevented more of these events than dulaglutide (superiority P=0.09).

What the result means: It met the trial's noninferiority test; it did not establish superiority on the primary cardiovascular endpoint.

What this cannot answer: An active comparator already known to reduce events; no placebo arm. Do not describe the result as proven cardiovascular superiority.

Harms reported: Overall adverse-event incidence appeared similar, with more gastrointestinal adverse events in the tirzepatide group; detailed full-report extraction remains incomplete.

Funding: Eli Lilly

Source access: Indexed original PubMed abstract excerpt; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 13299 — randomized; modified intention-to-treat 13165 after 134 inclusion-criteria exclusions

Citation: Nicholls SJ, Pavo I, Bhatt DL, Buse JB, Del Prato S, Kahn SE, Lincoff AM, McGuire DK, Miller D, Nauck MA, Nishiyama H, Nissen SE, Sattar N, Weerakkody G, Wiese RJ, Zinman B, Zoungas S, Basile J, Davies MJ, Giorgino F, Kellerer M, Ji L, Varkonyi T, Menon V, Broder JC, Herschtal A, D'Alessio D, SURPASS-CVOT Investigators. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. The New England journal of medicine. 2025;393(24):2409–2420. doi:10.1056/NEJMoa2505928. PMID:41406444.

Additional source: Eli Lilly and Company. MOUNJARO (tirzepatide injection) prescribing information. Revised August 2026; DailyMed updated August 27, 2026. Section 14.6: SURPASS-CVOT median follow-up 210.1 weeks.

Source type: Journal paper

Study/cohort key: SURPASS-CVOT

DOI: 10.1056/NEJMoa2505928

PMID: 41406444

Registration: NCT04255433

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How much did body weight change with cagrilintide alone?

How the study was done: Randomized dose-finding trial; masked active-versus-placebo, not between different active treatments

What was tested: Trial cagrilintide formulation

Who or what was studied: Overweight or obesity without diabetes

Compared with: Pooled placebo; liraglutide active comparator

Follow-up: 26-week treatment plus six-week follow-up

What changed: Weight reductions ranged 6.0% to 10.8% across cagrilintide groups versus 3.0% with placebo, using the trial-product analysis assuming adherence.

What the result means: Cagrilintide alone produced a weight-loss signal before the larger combination programme.

What this cannot answer: Shorter dose-finding trial. The adherence analysis differs from an analysis regardless of adherence; do not copy CagriSema results into this record.

Harms reported: Gastrointestinal events in 41%-63% versus 32%; nausea 20%-47% versus 18%.

Funding: Novo Nordisk

Source access: Indexed original PubMed abstract; direct page incomplete; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 706 — randomized total

Citation: Lau DCW, Erichsen L, Francisco AM, Satylganova A, le Roux CW, McGowan B, Pedersen SD, Pietiläinen KH, Rubino D, Batterham RL. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet (London, England). 2021;398(10317):2160–2172. doi:10.1016/S0140-6736(21)01751-7. PMID:34798060.

Source type: Journal paper

Study/cohort key: NCT03856047

DOI: 10.1016/S0140-6736(21)01751-7

PMID: 34798060

Registration: NCT03856047

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did adding cagrilintide to semaglutide improve blood-glucose control and weight more than either treatment alone?

How the study was done: Randomized, double-blind, active-controlled phase 2

What was tested: Co-administered trial cagrilintide and semaglutide; separate monotherapy arms

Who or what was studied: Adults with type 2 diabetes taking metformin, with or without an SGLT2 inhibitor, another type of blood-glucose-lowering medicine. Their body mass index (BMI), a measure of weight relative to height, was at least 27 kg/m².

Compared with: Semaglutide or cagrilintide alone

Follow-up: 32 weeks

What changed: In a 32-week trial, 92 adults with type 2 diabetes received weekly injections under the skin of cagrilintide plus semaglutide, semaglutide alone or cagrilintide alone. Average weight fell 15.6% with the combination, 5.1% with semaglutide and 8.1% with cagrilintide. HbA1c, a blood test reflecting glucose exposure over preceding months, fell 2.2 percentage points with the combination, 1.8 with semaglutide and 0.9 with cagrilintide. HbA1c fell 0.4 percentage points more with the combination than with semaglutide, but the comparison remained uncertain (estimated difference in HbA1c change −0.4 points; 95% confidence interval −0.8 to 0.0; P=0.075).

What the result means: The combination produced greater average weight loss than either ingredient alone. Its observed added reduction in the blood-glucose marker was too uncertain to establish an advantage over semaglutide in this small trial.

What this cannot answer: Small, short trial; combination is distinct from each monotherapy.

Harms reported: Mostly mild/moderate gastrointestinal events; no level 2 or 3 hypoglycemia reported.

Funding: Novo Nordisk

Source access: Original PubMed abstract and indexed author manuscript from University of Leicester repository; preserves existing stable study ID.

Route or setting: subcutaneous

Sample: 92 — 31 combination, 31 semaglutide, 30 cagrilintide

Citation: Frias JP, Deenadayalan S, Erichsen L, Knop FK, Lingvay I, Macura S, Mathieu C, Pedersen SD, Davies M. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet (London, England). 2023;402(10403):720–730. doi:10.1016/S0140-6736(23)01163-7. PMID:37364590.

Source type: Journal paper

Study/cohort key: NCT04982575

Analysis: Trial-product estimand: full analysis population and on-treatment observation period for the reported weight and HbA1c estimates.

DOI: 10.1016/S0140-6736(23)01163-7

PMID: 37364590

Registration: NCT04982575

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How much did weight change with the combination?

How the study was done: Randomized, double-blind, placebo- and active-controlled phase 3a

What was tested: Trial cagrilintide-semaglutide combination and separate individual-agent arms

Who or what was studied: Adults without diabetes whose body mass index (BMI), a measure of weight relative to height, was at least 30 kg/m², or at least 27 kg/m² with an obesity-related complication. All groups received lifestyle support.

Compared with: Placebo and separate monotherapies

Follow-up: 68 weeks

What changed: At week 68, average weight fell 20.4% with cagrilintide–semaglutide and 3.0% with placebo. The adjusted difference was −17.3 percentage points (95% CI −18.1 to −16.6), using an analysis that includes results after treatment stopped or another weight-loss intervention began.

What the result means: This directly tests the clinical combination rather than attributing its result to an ingredient alone.

What this cannot answer: Adherence-assuming estimates differ; subsequent BP paper is the same cohort.

Harms reported: Gastrointestinal events in 79.6% versus 39.9% placebo, mostly transient mild/moderate.

Funding: Novo Nordisk

Source access: Original indexed PubMed abstract; preserves existing stable study ID

Route or setting: subcutaneous

Sample: 3417 — 2,108 combination, 302 semaglutide, 302 cagrilintide, 705 placebo

Citation: Garvey WT, Blüher M, Osorto Contreras CK, Davies MJ, Winning Lehmann E, Pietiläinen KH, Rubino D, Sbraccia P, Wadden T, Zeuthen N, Wilding JPH, REDEFINE 1 Study Group. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. The New England journal of medicine. 2025;393(7):635–647. doi:10.1056/NEJMoa2502081. PMID:40544433.

Source type: Journal paper

Study/cohort key: NCT05567796

Analysis: The analysis estimates effects regardless of whether participants stopped assigned treatment or received another weight-loss intervention (the treatment-policy estimand).

DOI: 10.1056/NEJMoa2502081

PMID: 40544433

Registration: NCT05567796

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How much did weight change in participants with diabetes?

How the study was done: Randomized, double-blind, placebo-controlled phase 3a

What was tested: Trial cagrilintide-semaglutide combination

Who or what was studied: Type 2 diabetes, BMI at least 27 and HbA1c 7–10%; lifestyle intervention

Compared with: Placebo

Follow-up: 68 weeks

What changed: At week 68, average weight fell 13.7% with cagrilintide–semaglutide and 3.4% with placebo. The adjusted difference was −10.4 percentage points (95% CI −11.2 to −9.5), using an analysis that includes results after treatment stopped or another weight-loss intervention began.

What the result means: The combination improved average weight in a separate diabetes cohort.

What this cannot answer: No ingredient-alone arms; between-study differences do not isolate the effect of having diabetes.

Harms reported: Gastrointestinal events 72.5% versus 34.4%, mostly transient mild/moderate.

Funding: Novo Nordisk

Source access: Original indexed PubMed abstract; preserves existing stable study ID

Route or setting: subcutaneous

Sample: 1206 — 904 combination, 302 placebo

Citation: Davies MJ, Bajaj HS, Broholm C, Eliasen A, Garvey WT, le Roux CW, Lingvay I, Lyndgaard CB, Rosenstock J, Pedersen SD, REDEFINE 2 Study Group. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. The New England journal of medicine. 2025;393(7):648–659. doi:10.1056/NEJMoa2502082. PMID:40544432.

Source type: Journal paper

Study/cohort key: NCT05394519

Analysis: The analysis estimates effects regardless of whether participants stopped assigned treatment or received another weight-loss intervention (the treatment-policy estimand).

DOI: 10.1056/NEJMoa2502082

PMID: 40544432

Registration: NCT05394519

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did visceral fat change and was that change maintained?

How the study was done: Randomized, double-blind, placebo-controlled efficacy phase and rerandomized extension

What was tested: Trial tesamorelin formulation, GHRH(1-44) analogue

Who or what was studied: HIV treated with antiretroviral therapy and excess abdominal fat

Compared with: Placebo; continuation-versus-withdrawal extension

Follow-up: Six-month primary phase, 12 months total

What changed: At six months visceral fat fell 10.9% versus 0.6%. Continued-treatment group had about 18% reduction at 12 months; early gains were lost after switching to placebo.

What the result means: The main result concerns fat around abdominal organs, not every type of body fat.

What this cannot answer: HIV-associated body-composition question; neither general weight-loss nor bodybuilding trial.

Harms reported: IGF-I rose; abstract reported no change in glucose measures. Full adverse-event extraction pending.

Source access: Indexed original PubMed abstract; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 404 — trial participants

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Falutz J, Potvin D, Mamputu JC, Assaad H, Zoltowska M, Michaud SE, Berger D, Somero M, Moyle G, Brown S, Martorell C, Turner R, Grinspoon S. Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension. Journal of acquired immune deficiency syndromes (1999). 2010;53(3):311–322. doi:10.1097/QAI.0b013e3181cbdaff. PMID:20101189.

Source type: Journal paper

Study/cohort key: tesamorelin-phase3-second-trial

DOI: 10.1097/QAI.0b013e3181cbdaff

PMID: 20101189

Registration: NCT00435136, NCT00608023

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did visceral fat and liver fat change?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Trial tesamorelin formulation

Who or what was studied: Antiretroviral-treated HIV and abdominal fat accumulation

Compared with: Placebo

Follow-up: Six months

What changed: Visceral-fat treatment difference -42 cm² (95% CI -71 to -14); net liver lipid-to-water percentage difference -2.9 percentage points.

What the result means: The study found changes in imaging measures of abdominal and liver fat.

What this cannot answer: Small preliminary study; imaging change is not proof of fewer future liver complications or benefit in people without HIV.

Harms reported: Fasting glucose rose early at two weeks; group differences were not significant at six months.

Source access: Indexed original PubMed abstract; PMC full text challenged; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 50 — randomized; 48 received study drug

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Stanley TL, Feldpausch MN, Oh J, Branch KL, Lee H, Torriani M, Grinspoon SK. Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial. JAMA. 2014 Jul 23-30;312(4):380–389. doi:10.1001/jama.2014.8334. PMID:25038357.

Source type: Journal paper

Study/cohort key: NCT01263717

DOI: 10.1001/jama.2014.8334

PMID: 25038357

Registration: NCT01263717

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did liver fat change?

How the study was done: Randomized, double-blind, multicentre, placebo-controlled

What was tested: Trial tesamorelin formulation

Who or what was studied: HIV with hepatic fat fraction at least 5%

Compared with: Placebo

Follow-up: 12-month blinded phase plus six-month open-label phase

What changed: Absolute hepatic-fat-fraction treatment effect -4.1 percentage points (95% CI -7.6 to -0.7); corresponding relative reduction 37%.

What the result means: Absolute and relative percentages describe the same result differently; they are not interchangeable.

What this cannot answer: Small specific population. Long-term histology and liver-event benefit require further study.

Harms reported: More localized injection-site complaints; glucose and HbA1c changes did not differ at 12 months.

Funding: NIH and NIAID

Source access: Indexed original abstract; PMC browser challenge prevented full-text extraction; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: subcutaneous

Sample: 61 — enrolled; 30 received each intervention

Citation: Stanley TL, Fourman LT, Feldpausch MN, Purdy J, Zheng I, Pan CS, Aepfelbacher J, Buckless C, Tsao A, Kellogg A, Branch K, Lee H, Liu CY, Corey KE, Chung RT, Torriani M, Kleiner DE, Hadigan CM, Grinspoon SK. Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial. The lancet. HIV. 2019;6(12):e821–e830. doi:10.1016/S2352-3018(19)30338-8. PMID:31611038.

Source type: Journal paper

Study/cohort key: NCT02196831

DOI: 10.1016/S2352-3018(19)30338-8

PMID: 31611038

Registration: NCT02196831

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did collagen synthesis change?

How the study was done: Fibroblast culture experiment

What was tested: GHK complexed with copper(II)

Who or what was studied: Cultured fibroblasts; exact donor details not extracted

Compared with: Culture control details need full text

What changed: GHK-Cu stimulated collagen synthesis in culture without an increase in cell number.

What the result means: This helps explain the interest in matrix biology. It measures a cellular process rather than a visible change in human skin.

What this cannot answer: Culture concentrations and collagen production cannot become a wrinkle-reduction or injectable efficacy claim.

Harms reported: Clinical harms not assessed by this design.

Source access: Indexed original PubMed abstract; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Added to cell culture

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Maquart FX, Pickart L, Laurent M, Gillery P, Monboisse JC, Borel JP. Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. FEBS letters. 1988;238(2):343–346. doi:10.1016/0014-5793(88)80509-x. PMID:3169264.

Source type: Journal paper

Study/cohort key: maquart-fibroblast-1988

DOI: 10.1016/0014-5793(88)80509-x

PMID: 3169264

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did connective-tissue material accumulate differently?

How the study was done: Rat implanted wound-chamber experiment

What was tested: GHK-Cu

Who or what was studied: Rats

Compared with: Saline and control tripeptide

What changed: Higher collagen and other matrix contents were reported alongside collagen messenger-RNA changes.

What the result means: A chamber makes tissue accumulation measurable. It does not reproduce all the events involved in a person recovering from injury.

What this cannot answer: Does not test wrinkles, human wound outcomes or commercial creams/injectables.

Harms reported: Clinical harms not assessed by this design.

Source access: Original journal abstract; full methods not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Experimental wound-chamber delivery

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Maquart FX, Bellon G, Chaqour B, Wegrowski J, Patt LM, Trachy RE, Monboisse JC, Chastang F, Birembaut P, Gillery P. In vivo stimulation of connective tissue accumulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ in rat experimental wounds. The Journal of clinical investigation. 1993;92(5):2368–2376. doi:10.1172/JCI116842. PMID:8227353.

Source type: Journal paper

Study/cohort key: maquart-rat-wound-1993

DOI: 10.1172/JCI116842

PMID: 8227353

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did redness, wrinkles or perceived skin quality improve more?

How the study was done: Randomized post-procedure regimen comparison with blinded evaluators

What was tested: Skincare regimen containing GHK-Cu

Who or what was studied: Patients after circumoral CO2 laser resurfacing

Compared with: Post-procedure regimen without GHK-Cu

Follow-up: 12 weeks

What changed: No significant group difference in objective redness, wrinkles or skin quality. Patient-rated skin quality favored GHK-Cu (P=0.04).

What the result means: Measured appearance and patient perception did not tell the same story.

What this cannot answer: Very small, specific post-laser setting. The objective null is not proof about every cosmetic formula; the questionnaire does not prove regeneration.

Harms reported: Detailed adverse-event extraction pending.

Source access: Indexed original PubMed abstract; direct page incomplete; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: topical

Sample: 13 — completed; initial enrollment not extracted

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Miller TR, Wagner JD, Baack BR, Eisbach KJ. Effects of topical copper tripeptide complex on CO2 laser-resurfaced skin. Archives of facial plastic surgery. 2006;8(4):252–259. doi:10.1001/archfaci.8.4.252. PMID:16847171.

Source type: Journal paper

Study/cohort key: miller-laser-skin-2006

DOI: 10.1001/archfaci.8.4.252

PMID: 16847171

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did collagen expression respond to the combination?

How the study was done: Human dermal fibroblast experiments and ex-vivo skin testing

What was tested: GHK-Cu plus different hyaluronic-acid forms and ratios

Who or what was studied: Human-derived cells and skin samples, not treated participants

Compared with: Combination screening; exact factorial controls need full text

What changed: Selected combination increased collagen-IV measures in cell and ex-vivo testing; reported changes differed substantially between the two systems.

What the result means: This is formulation research. Human-derived skin outside a person is not a clinical skincare trial.

What this cannot answer: Cannot validate every copper-peptide serum or generalize laboratory synergy into human anti-aging benefits.

Harms reported: Clinical safety not assessed.

Source access: Indexed original PubMed abstract and affiliation/reference record; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Laboratory exposure of cells and tissue

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Jiang F, Wu Y, Liu Z, Hong M, Huang Y. Synergy of GHK-Cu and hyaluronic acid on collagen IV upregulation via fibroblast and ex-vivo skin tests. Journal of cosmetic dermatology. 2023;22(9):2598–2604. doi:10.1111/jocd.15763. PMID:37062921.

Source type: Journal paper

Study/cohort key: jiang-ghk-ha-2023

DOI: 10.1111/jocd.15763

PMID: 37062921

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did eyebrow hair count and diameter change?

How the study was done: Reported randomized, double-blind, vehicle-controlled split-face study

What was tested: Serum described as 2% GHK-Cu; exact speciation/formulation not verified

Who or what was studied: 18 healthy participants aged 18-40

Compared with: The serum base without GHK-Cu on the opposite eyebrow

Follow-up: 12 weeks

What changed: Abstract reports better hair count, diameter, photographs and satisfaction on the GHK-Cu side; numerical between-side effect size and confidence interval not given.

What the result means: The treated eyebrow had better reported hair measurements, but this 18-person report does not establish a benefit for scalp hair loss or whole-body repair.

What this cannot answer: Proceedings-format source; full report, protocol, registration, statistics and publication-review process need appraisal. Sparse reporting cannot establish general safety.

Harms reported: No serious effects or allergic reactions reported in this small sample.

Source access: Original publisher abstract; PDF link opened a viewer without extractable text; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: topical

Sample: 18 — participants in report

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Bo SL, Nararatwanchai T, Supornpun N, Poomarapan K, Thaploka S. The Efficacy of 2% Copper Peptide (GHK-Cu) Serum for Eyebrow Hypotrichosis: A Randomized, Double-Blind, Vehicle-Controlled, Split-Face Comparative Study. Procedia of Multidisciplinary Research. 2026;4(5). Published May 22, 2026.

Source type: Conference report · preliminary

Study/cohort key: bo-eyebrow-2026

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did lifespan and stress-related readouts change?

How the study was done: Caenorhabditis elegans lifespan and pathway experiment

What was tested: GHK-Cu

Who or what was studied: Laboratory nematodes

Compared with: Control and pathway details require full text

What changed: Reported longer worm lifespan, stress resistance and mitochondrial/pathway changes.

What the result means: The result extends the research questions beyond skin, but it is a worm finding.

What this cannot answer: Not evidence that GHK-Cu makes people live longer or improves human cognition.

Harms reported: Human safety not assessed.

Source access: Indexed original PubMed abstract; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Experimental organism exposure; exact method not extracted

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Wen H, Zhao K, Luo X, Pu J, Li Y, Dou Y, He J, Nie X, Ke Y, Zhou W. The GHK-Cu delays aging in Caenorhabditis elegans via coordinated regulation of mitochondrial function and activation of DAF-16/SKN-1 pathways. Biogerontology. 2026;27(3). doi:10.1007/s10522-026-10444-x. PMID:42084774.

Source type: Journal paper

Study/cohort key: wen-worm-aging-2026

DOI: 10.1007/s10522-026-10444-x

PMID: 42084774

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did BPC-157 change the movement and survival of rat tendon cells in laboratory dishes?

How the study was done: Rat tendon explant and fibroblast experiments

What was tested: Synthetic BPC-157 peptide in rat Achilles tendon explants and fibroblasts

Who or what was studied: Connective-tissue cells and pieces of tissue removed from rat Achilles tendons and grown in laboratory dishes; the tissue pieces are called explants.

Compared with: Cultures with and without BPC-157

Follow-up: The accessible abstract does not give a complete timing schedule for the separate tissue and cell experiments.

What changed: Researchers grew tissue pieces and connective-tissue cells from rat Achilles tendons with or without BPC-157. More cells grew out from the treated tissue pieces, and treated cells moved and spread more readily across culture surfaces. Cells exposed to hydrogen peroxide, which causes oxidative stress, survived better with BPC-157. The peptide did not directly increase cell multiplication in the proliferation test. These were removed-tissue and cell experiments, with no human injury-recovery outcome.

What the result means: The experiment helps explain why tendon biology attracts interest. It measured cell behavior rather than recovery after a human injury.

What this cannot answer: No human clinical endpoint; pathway changes are not proof of tissue repair in people.

Harms reported: Detailed safety extraction pending; this record is not a safety assessment

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Exposure of cultured tendon cells and explants

Not yet extracted for this card: Funding, Sample size. The original source may report these details.

Citation: Chang CH, Tsai WC, Lin MS, Hsu YH, Pang JH. The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. Journal of applied physiology (Bethesda, Md. : 1985). 2011;110(3):774–780. doi:10.1152/japplphysiol.00945.2010. PMID:21030672.

Source type: Journal paper

Study/cohort key: original-21030672

DOI: 10.1152/japplphysiol.00945.2010

PMID: 21030672

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did BPC-157 change how rat tendon cells responded to growth hormone?

How the study was done: Rat tendon fibroblast culture experiment

What was tested: BPC-157 pretreatment; subsequent growth-hormone exposure in rat tendon fibroblasts

Who or what was studied: Connective-tissue cells (fibroblasts) isolated from the Achilles tendons of male Sprague-Dawley rats and grown in laboratory dishes.

Compared with: Cells receiving no BPC-157 were compared with cells exposed to BPC-157; subsequent experiments also compared responses to added growth hormone.

Follow-up: Growth-hormone receptors were measured after 1, 2 and 3 days of BPC-157 exposure; subsequent hormone-response tests had their own observation times.

What changed: Researchers exposed connective-tissue cells from male rat Achilles tendons to BPC-157 or no peptide. Over one to three days, treated cells produced more growth-hormone receptor RNA and protein. Adding growth hormone to cells previously exposed to BPC-157 increased cell multiplication and activated JAK2, a protein that relays the growth-hormone receptor’s signal within the cell. This is a response in cultured tendon cells; it does not show that BPC-157 raises circulating growth hormone or improves human injury recovery.

What the result means: A receptor change is a possible mechanism, not evidence that a person becomes stronger or recovers faster.

What this cannot answer: Cell culture and a second experimental hormone exposure; clinical effects not measured.

Harms reported: Detailed safety extraction pending; this record is not a safety assessment

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Exposure of cultured tendon fibroblasts

Not yet extracted for this card: Funding, Sample size. The original source may report these details.

Citation: Chang CH, Tsai WC, Hsu YH, Pang JH. Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules (Basel, Switzerland). 2014;19(11):19066–19077. doi:10.3390/molecules191119066. PMID:25415472.

Source type: Journal paper

Study/cohort key: original-25415472

DOI: 10.3390/molecules191119066

PMID: 25415472

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Healing measurements after rat Achilles transection

How the study was done: Controlled rat tendon-transection experiment

What was tested: BPC-157 in saline, tested in surgically transected rat Achilles tendons

Who or what was studied: Rats with surgically transected Achilles tendons

Compared with: Saline control

Follow-up: Assessments through day 14

What changed: Reported better mechanical failure-load, functional and tissue-structure measurements than saline controls.

What the result means: This study went beyond a cell marker and measured a tendon in an animal injury model.

What this cannot answer: A surgical rat model does not establish a human tendon-healing effect.

Harms reported: Detailed safety extraction pending; this record is not a safety assessment

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Intraperitoneal exposure in the rat experiment

Not yet extracted for this card: Funding, Sample size. The original source may report these details.

Citation: Staresinic M, Sebecic B, Patrlj L, Jadrijevic S, Suknaic S, Perovic D, Aralica G, Zarkovic N, Borovic S, Srdjak M, Hajdarevic K, Kopljar M, Batelja L, Boban-Blagaic A, Turcic I, Anic T, Seiwerth S, Sikiric P. Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth. Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 2003;21(6):976–983. doi:10.1016/S0736-0266(03)00110-4. PMID:14554208.

Source type: Journal paper

Study/cohort key: original-14554208

DOI: 10.1016/S0736-0266(03)00110-4

PMID: 14554208

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: What knee-pain changes did patients report after BPC-157, alone or with TB4, in this small clinic series?

How the study was done: Retrospective chart review and telephone survey

What was tested: BPC-157 alone in 12 reached participants; distinct four-person combination subgroup described as BPC-157 plus thymosin-beta-4

Who or what was studied: People treated for knee pain in one clinic: 17 charts were reviewed and 16 patients answered the follow-up call. Twelve respondents had received BPC-157 alone and four had received BPC-157 plus the material called thymosin-beta-4 (TB4) in the report.

Compared with: No untreated or placebo comparison

Follow-up: Variable follow-up, most 6–12 months

What changed: Researchers reviewed 17 knee-pain treatment records and reached 16 patients by phone, most 6–12 months after injection into the knee. Eleven of 12 respondents given BPC-157 alone reported pain improvement. Three of four respondents given BPC-157 with the material called TB4 in the report also reported improvement, for 14 of 16 overall. There was no untreated or placebo group, and no standardized measurement of function, stiffness or daily activities. The reports therefore cannot show how much improvement was caused by treatment or demonstrate cartilage or tendon repair.

What the result means: The symptom reports are worth tracking, but the study did not demonstrate structural tendon or cartilage healing.

What this cannot answer: No randomized comparison, standardized functional assessment or imaging-confirmed repair; the combination was not the same intervention.

Harms reported: Detailed safety extraction pending; this record is not a safety assessment

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Intra-articular clinical exposure

Sample: 17 — 17 charts reviewed, 16 reached by telephone: 12 single-agent and 4 combination recipients

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Lee E, Padgett B. Intra-Articular Injection of BPC 157 for Multiple Types of Knee Pain. Alternative therapies in health and medicine. 2021;27(4):8–13. PMID:34324435.

Source type: Journal paper

Study/cohort key: original-34324435

PMID: 34324435

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: What bladder-symptom changes did women report after BPC-157 in this uncontrolled pilot?

How the study was done: Uncontrolled clinical pilot

What was tested: Compounded BPC-157 used in the studied bladder procedure

Who or what was studied: Twelve women aged 39–76 with persistent bladder pain and urinary symptoms (interstitial cystitis/bladder pain syndrome) that had not responded to pentosan polysulfate.

Compared with: No randomized placebo comparison

Follow-up: The accessible abstract describes one treatment procedure but does not state when the symptom questionnaire was completed.

What changed: Twelve women with bladder pain syndrome that had not responded to pentosan polysulfate received compounded BPC-157 injections around inflamed areas of the bladder during cystoscopy, an examination with a small camera. On a symptom-response questionnaire, 10 women reported complete symptom resolution and two reported about 80% improvement. No adverse events were reported. There was no randomized placebo comparison, and the accessible abstract does not state the questionnaire’s follow-up time. These reports cannot establish the treatment’s effect or lasting safety.

What the result means: These results concern bladder symptoms in a small selected group, not general tissue recovery.

What this cannot answer: No placebo comparison; questionnaire outcomes and a small selected sample cannot establish causation or general safety.

Harms reported: No adverse events reported in this small pilot; uncommon or delayed harms cannot be excluded

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Bladder-wall clinical exposure during cystoscopy

Sample: 12 — 12 enrolled women; no randomized comparator

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Lee E, Walker C, Ayadi B. Effect of BPC-157 on Symptoms in Patients with Interstitial Cystitis: A Pilot Study. Alternative therapies in health and medicine. 2024;30(10):12–17. PMID:39325560.

Source type: Journal paper

Study/cohort key: original-39325560

PMID: 39325560

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could cells take up KPV, and did it reduce inflammation in cell cultures and mouse colons?

How the study was done: Cell signaling/uptake experiments and two mouse colitis models

What was tested: KPV (Lys-Pro-Val) in human-derived cell lines and induced mouse colitis models

Who or what was studied: Human-derived intestinal-lining cell lines (Caco2-BBE and HT29-Cl.19A), a human immune T-cell line (Jurkat), and separate mice with chemically induced colon inflammation using DSS or TNBS.

Compared with: Stimulated cell cultures with or without KPV; mice with chemically induced colon inflammation with or without KPV added to drinking water.

Follow-up: Mouse colon inflammation was assessed 8 days after the start of DSS exposure or 48 hours after TNBS administration; the separate cell experiments used their own observation times.

What changed: Researchers tested KPV in human-derived intestinal-lining and immune-cell cultures, then separately in mice with chemically induced colon inflammation. In cells, uptake through the PepT1 peptide transporter accompanied lower inflammatory signaling and lower release of inflammation-promoting proteins. Mice receiving KPV in drinking water had less colon inflammation than mice exposed to the same injury chemicals without KPV. Tissue examination and inflammatory gene measurements supported the result; these experiments did not test treatment of inflammatory bowel disease in people.

What the result means: The paper connects a cellular transport mechanism with findings in animal gut models.

What this cannot answer: Human-derived cell lines are not human participants; induced mouse colitis differs from clinical inflammatory bowel disease.

Harms reported: Detailed safety extraction pending; this record is not a safety assessment

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Cell-culture exposure and oral exposure in mice

Not yet extracted for this card: Funding, Sample size. The original source may report these details.

Citation: Dalmasso G, Charrier-Hisamuddin L, Nguyen HT, Yan Y, Sitaraman S, Merlin D. PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation. Gastroenterology. 2008;134(1):166–178. doi:10.1053/j.gastro.2007.10.026. PMID:18061177.

Source type: Journal paper

Study/cohort key: original-18061177

DOI: 10.1053/j.gastro.2007.10.026

PMID: 18061177

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did KPV help mice recover from chemically induced or immune-cell-driven colon inflammation?

How the study was done: Two murine colitis-model experiments

What was tested: KPV, alpha-MSH(11–13), in chemically induced and immune-cell-transfer mouse colitis

Who or what was studied: Mice with colon inflammation caused by the chemical DSS or by transfer of immune cells selected for high CD45RB expression; an additional DSS experiment used mice with a nonfunctional melanocortin-1 receptor (MC1R).

Compared with: See original paper; complete controls not extracted

Follow-up: The accessible abstract does not give the observation periods for the separate mouse colon-inflammation experiments.

What changed: Researchers tested KPV in two mouse models of colon inflammation, one caused by the chemical DSS and the other by transferred immune cells. In the DSS model, KPV-treated mice recovered weight earlier and more strongly, had fewer inflammatory cells in colon tissue and had lower activity of myeloperoxidase, a marker associated with inflammatory cells. Mice in the immune-cell-transfer model also regained weight and had less inflammatory change in colon tissue. In the separate DSS experiment in mice with a nonfunctional melanocortin-1 receptor, all KPV-treated animals survived. The accessible abstract gives neither group sizes nor a full timing schedule, so it cannot establish the size or durability of these effects.

What the result means: A separate experiment adds biological context to the earlier gut findings.

What this cannot answer: Preclinical endpoints; a controlled human clinical benefit is not established by these experiments.

Harms reported: Detailed safety extraction pending; this record is not a safety assessment

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Not extracted

Not yet extracted for this card: Funding, Sample size. The original source may report these details.

Citation: Kannengiesser K, Maaser C, Heidemann J, Luegering A, Ross M, Brzoska T, Bohm M, Luger TA, Domschke W, Kucharzik T. Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease. Inflammatory bowel diseases. 2008;14(3):324–331. doi:10.1002/ibd.20334. PMID:18092346.

Source type: Journal paper

Study/cohort key: original-18092346

DOI: 10.1002/ibd.20334

PMID: 18092346

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did coating KPV-carrying nanoparticles with hyaluronic acid improve delivery and reduce mouse colon inflammation?

How the study was done: Cell delivery experiments and mouse colitis model

What was tested: KPV in hyaluronic-acid-functionalized nanoparticles and hydrogel

Who or what was studied: Cultured intestinal-lining cells and macrophages, an immune-cell type, plus separate mice with chemically induced colon inflammation.

Compared with: KPV-loaded nanoparticles with or without the hyaluronic-acid coating, both delivered in chitosan/alginate hydrogel; the study also included other laboratory and mouse controls.

Follow-up: The complete timing schedule for the separate cell, delivery and mouse experiments was not established in this source review.

What changed: Researchers enclosed KPV in tiny polymer particles, coated them with hyaluronic acid and embedded them in a chitosan/alginate hydrogel for oral delivery. In separate cell and mouse experiments, the coating improved delivery to intestinal-lining cells and macrophages. Mice with chemically induced colon inflammation had less damage to the colon lining and lower amounts of the inflammatory protein TNF-α with the coated-particle preparation than with uncoated KPV particles in hydrogel. The tested intervention included the particles, coating and hydrogel, so this result cannot be assigned to plain KPV alone.

What the result means: The formulation was part of the intervention. This is not a test of plain KPV sold under any label.

What this cannot answer: Specialized carrier, hydrogel and animal model; neither a standard KPV formulation nor a human efficacy trial.

Harms reported: Detailed safety extraction pending; this record is not a safety assessment

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Oral nanoparticle/hydrogel exposure in mice; cell tests

Not yet extracted for this card: Funding, Sample size. The original source may report these details.

Citation: Xiao B, Xu Z, Viennois E, Zhang Y, Zhang Z, Zhang M, Han MK, Kang Y, Merlin D. Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis. Molecular therapy : the journal of the American Society of Gene Therapy. 2017;25(7):1628–1640. doi:10.1016/j.ymthe.2016.11.020. PMID:28143741.

Source type: Journal paper

Study/cohort key: original-28143741

DOI: 10.1016/j.ymthe.2016.11.020

PMID: 28143741

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could a laboratory method detect the TB-500 fragment and its breakdown products in horse blood and urine?

How the study was done: Mass-spectrometry method development with equine samples

What was tested: N-acetyl-LKKTETQ fragment

Who or what was studied: Laboratory metabolic systems and samples from treated horses

Compared with: See original paper; complete controls not extracted

Follow-up: Samples were collected after a single TB-500 administration in horses; the accessible abstract does not state the full collection window.

What changed: The preparation contained N-acetylated LKKTETQ; the method detected that fragment and metabolites in urine and plasma.

What the result means: This establishes what was analyzed and how it could be detected. It is not a recovery trial.

What this cannot answer: Detection is not evidence of clinical benefit; full-length thymosin beta-4 is a different material.

Harms reported: Detailed safety extraction pending; this record is not a safety assessment

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Laboratory metabolism and equine sample analysis; administration route not extracted

Not yet extracted for this card: Funding, Sample size. The original source may report these details.

Citation: Ho EN, Kwok WH, Lau MY, Wong AS, Wan TS, Lam KK, Schiff PJ, Stewart BD. Doping control analysis of TB-500, a synthetic version of an active region of thymosin β₄, in equine urine and plasma by liquid chromatography-mass spectrometry. Journal of chromatography. A. 2012;1265:57–69. doi:10.1016/j.chroma.2012.09.043. PMID:23084823.

Source type: Journal paper

Study/cohort key: original-23084823

DOI: 10.1016/j.chroma.2012.09.043

PMID: 23084823

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did TB-500 or its breakdown products help cultured connective-tissue cells close a scratch?

How the study was done: Analytical metabolism work and fibroblast scratch assay

What was tested: Ac-LKKTETQ and defined metabolites

Who or what was studied: In-vitro systems, rat urine and cultured fibroblasts

Compared with: Control in fibroblast assay

Follow-up: A breakdown product, Ac-LKK, remained detectable in rat urine through 72 hours after TB-500 administration. The accessible abstract does not give the timing of the separate cell-scratch experiment.

What changed: Researchers measured breakdown of TB-500, the acetylated fragment Ac-LKKTETQ, in human serum, laboratory enzyme systems and urine from treated rats. They separately tested the parent peptide and metabolites in cultured connective-tissue cells using a scratch assay, which measures closure of a gap in a cell layer. Only the metabolite Ac-LKKTE significantly improved gap closure compared with the assay control; the parent TB-500 did not establish that effect in this test. Ac-LKK, a different metabolite, was detectable in rat urine through 72 hours. Neither assay measured recovery from an injury in people.

What the result means: The parent and its breakdown products did not behave identically. That matters when interpreting broad recovery claims.

What this cannot answer: A scratch assay does not reproduce human wound healing; analytical work and clinical benefit are different questions.

Harms reported: No cytotoxicity found in tested culture conditions; human safety was not assessed

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Laboratory exposure and rat sample analysis; administration route not extracted

Not yet extracted for this card: Funding, Sample size. The original source may report these details.

Citation: Rahaman KA, Muresan AR, Min H, Son J, Han HS, Kang MJ, Kwon OS. Simultaneous quantification of TB-500 and its metabolites in in-vitro experiments and rats by UHPLC-Q-Exactive orbitrap MS/MS and their screening by wound healing activities in-vitro. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. 2024;1235:124033. doi:10.1016/j.jchromb.2024.124033. PMID:38382158.

Source type: Journal paper

Study/cohort key: original-38382158

DOI: 10.1016/j.jchromb.2024.124033

PMID: 38382158

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How did body weight change at the primary week-24 and secondary week-48 endpoints?

How the study was done: Randomized, double-blind, placebo-controlled phase 2 trial

What was tested: Trial retatrutide formulation

Who or what was studied: Adults without diabetes whose body mass index (BMI), a measure of weight relative to height, was at least 30 kg/m², or 27 to less than 30 kg/m² with at least one weight-related condition.

Compared with: Placebo

Follow-up: 48 weeks

What changed: Researchers randomized 338 adults without diabetes who had obesity, or overweight with a weight-related condition, to weekly retatrutide injections under the skin or placebo. At the primary 24-week assessment, estimated average weight reductions were 7.2%, 12.9%, 17.3% and 17.5% across the 1-, 4-, 8- and 12-mg study-dose groups, compared with 1.6% with placebo. At the secondary 48-week assessment, reductions were 8.7%, 17.1%, 22.8% and 24.2% in those retatrutide groups, compared with 2.1% with placebo. The 4- and 8-mg results each pooled different starting-dose groups. These averages estimate weight change if participants continued the assigned treatment as planned, an analysis called the efficacy estimand.

What the result means: The phase 2 trial found larger average weight reductions with retatrutide. The often-quoted 24.2% is one group at the secondary 48-week time point, not the primary 24-week result or a placebo-adjusted difference.

What this cannot answer: Four pooled assignment groups summarize six active arms. Primary and secondary time points and least-squares group estimates remain distinct; no direct comparison with another molecule.

Harms reported: Gastrointestinal events were most common, mostly mild/moderate; heart-rate increases peaked at week 24 and declined thereafter.

Funding: Eli Lilly

Source access: Indexed original PubMed abstract and NEJM result section read; full supplements not fully extracted

Route or setting: Subcutaneous exposure in the clinical trial

Sample: 338 — 338 enrolled in randomized phase 2 trial

Citation: Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML, Retatrutide Phase 2 Obesity Trial Investigators. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. The New England journal of medicine. 2023;389(6):514–526. doi:10.1056/NEJMoa2301972. PMID:37366315.

Source type: Journal paper

Study/cohort key: original-37366315

Analysis: Efficacy estimand: hypothetical mean effect if treatment was administered as intended. MMRM least-squares mean percentage changes; primary 24 weeks, secondary 48 weeks. Four pooled assignment groups summarize six active arms.

DOI: 10.1056/NEJMoa2301972

PMID: 37366315

Registration: NCT04881760

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: TRIUMPH-1 phase 3 obesity results

How the study was done: Randomized, double-blind, placebo-controlled phase 3 trial

What was tested: Trial retatrutide formulation

Who or what was studied: Adults with obesity without diabetes

Compared with: Placebo

Follow-up: 80 weeks

What changed: Mean weight reductions at week 80 were 17.6%, 23.7% and 25.0% across assigned retatrutide groups, versus 3.9% with placebo.

What the result means: The programme now includes phase 3 results. A published trial and regulatory approval remain different things.

What this cannot answer: Abstract-level extraction; full text/supplements and the apparent sleep-apnea subgroup sign issue remain unreviewed, so that subgroup number is not reproduced.

Harms reported: Gastrointestinal events were the most common adverse events; detailed full-report safety rates and uncommon harms not fully extracted.

Funding: Eli Lilly

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Subcutaneous exposure in the clinical trial

Sample: 2339 — Randomized

Citation: Jastreboff AM, Kaplan LM, Davies MJ, Wilding JPH, Ahmad NN, Murray M, Du Y, Makarova N, Giblin K, Schloot NC, Wang Y, TRIUMPH-1 Investigators. Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. The New England journal of medicine. 2026. doi:10.1056/NEJMoa2604169. PMID:42814954.

Source type: Journal paper

Study/cohort key: NCT05929066

Analysis: Treatment-regimen intention-to-treat

DOI: 10.1056/NEJMoa2604169

PMID: 42814954

Registration: NCT05929066

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: TRIUMPH-2 in obesity and type 2 diabetes

How the study was done: Randomized, double-blind, placebo-controlled phase 3 trial

What was tested: Trial retatrutide formulation

Who or what was studied: Adults with obesity and type 2 diabetes

Compared with: Placebo

Follow-up: 80 weeks

What changed: Treatment-regimen mean weight changes at week 80 were -11.9%, -16.8% and -18.8% across assigned retatrutide groups, versus -5.1% with placebo.

What the result means: Diabetes status and trial analysis matter when comparing these results with an obesity trial that excluded diabetes.

What this cannot answer: No active-drug comparator; outcomes concern the studied formulation and population.

Harms reported: Gastrointestinal events were more common with retatrutide; hypotension and dysesthesia were also more frequent. Full uncommon-harm and withdrawal details not extracted.

Funding: Eli Lilly

Source access: Original indexed PubMed abstract checked; full text and supplements not extracted; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: Subcutaneous exposure in the clinical trial

Sample: 1152 — Randomized

Citation: Bellido V, le Roux CW, Ekinci EI, Bjornstad P, Frias JP, Giblin K, Eyde S, Park SY, Ferro J, Johnson C, Taylor A. Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial. Lancet (London, England). 2026;408(10563):1455–1472. doi:10.1016/S0140-6736(26)01861-1. PMID:42810372.

Source type: Journal paper

Study/cohort key: NCT05929079

DOI: 10.1016/S0140-6736(26)01861-1

PMID: 42810372

Registration: NCT05929079

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did ulcer size decrease more?

How the study was done: Randomized, evaluator-blinded

What was tested: 0.4% copper-tripeptide cream; publisher discussion identifies glycine, L-histidine and L-lysine. Exact speciation not extracted.

Who or what was studied: Venous stasis ulcers

Compared with: The cream base without copper tripeptide, and a separate 1% silver sulfadiazine cream group

Follow-up: Not reported in the source sections checked

What changed: The trial did not establish greater ulcer-size reduction with copper-tripeptide cream than with the cream base without peptide. Silver sulfadiazine reduced ulcer size more than either. The abstract does not give the numerical differences or their uncertainty.

What the result means: This trial did not establish that adding copper tripeptide improved ulcer-size reduction over the cream base.

What this cannot answer: A formulation-specific wound trial, not an equivalence test, cosmetic trial or injectable study.

Harms reported: Detailed harms not extracted

Source access: Original PubMed abstract plus accessible publisher Results, Discussion and Acknowledgements snippets; complete methods and supplements not reviewed; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: topical

Sample: 93 — randomized; 90 safety-evaluable after 3 immediate dropouts; 86 completed/evaluable

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Bishop JB, Phillips LG, Mustoe TA, VanderZee AJ, Wiersema L, Roach DE, Heggers JP, Hill DP, Taylor EL, Robson MC. A prospective randomized evaluator-blinded trial of two potential wound healing agents for the treatment of venous stasis ulcers. Journal of vascular surgery. 1992;16(2):251–257. doi:10.1067/mva.1992.37086. PMID:1495150.

Source type: Journal paper

Study/cohort key: bishop-venous-ulcer-1992

DOI: 10.1067/mva.1992.37086

PMID: 1495150

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did measured wrinkle depth and volume change?

How the study was done: Double-blind split-face study; comparison-group allocation randomized, treatment side fixed

What was tested: GHK-Cu lipid-nanocarrier serum; concentration not reported in checked clinical methods

Who or what was studied: Women aged 40-65

Compared with: Vehicle lacking both GHK-Cu and nanocarrier; separate commercial-serum comparison

Follow-up: 8 weeks

What changed: In the comparison with a serum lacking both GHK-Cu and its nanocarrier, average wrinkle volume fell 24.1% from baseline on the test-serum side and 15.0% on the other side. Statistical models favored the test serum for volume and depth. The depth comparison with a separate commercial serum was uncertain (P=0.0577).

What the result means: The tested formula improved measured wrinkles; ingredient and carrier effects cannot be separated.

What this cannot answer: Small, short study with fixed treatment side. Reported 55.8% intergroup improvement is not baseline wrinkle reduction.

Harms reported: One participant withdrew after skin reactions on both sides

Funding: Snowberry New Zealand and Callaghan Innovation

Source access: Original publisher full text, including clinical methods, Tables 2-3 and disclosure; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: topical

Sample: 40 — 40 women enrolled and 39 completed: 20 compared the test serum with serum lacking GHK-Cu and its nanocarrier on the opposite facial side; 19 used the commercial comparator

Citation: Badenhorst T, Svirskis D, Merrilees M, Bolke L, Wu Z. Effects of GHK-Cu on MMP and TIMP Expression, Collagen and Elastin Production, and Facial Wrinkle Parameters. Journal of Aging Science. 2016;4(3):166. DOI: 10.4172/2329-8847.1000166.

Source type: Journal paper

Study/cohort key: badenhorst-wrinkle-2016

DOI: 10.4172/2329-8847.1000166

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did plantar-ulcer closure differ?

How the study was done: Multicenter, randomized, evaluator-blinded, placebo-controlled

What was tested: Gel containing glycyl-L-histidyl-L-lysine:copper complex; concentration, speciation and complete formulation not reported in the abstract checked

Who or what was studied: Diabetic neuropathic ulcers; reported positive results concern plantar ulcers

Compared with: The gel base without copper tripeptide; both groups also received standardized wound care

Follow-up: Not reported in the source checked

What changed: For plantar ulcers, the abstract reports a median reduction in ulcer area of 98.5% with the copper-tripeptide gel versus 60.8% with the gel base (P<0.05), plus other favorable closure measurements. These percentages describe area reduction, not the proportion of patients whose ulcers healed. The abstract does not report the denominator, assessment time or confidence interval.

What the result means: The gel improved reported plantar-ulcer closure measures within the trial's wound-care programme.

What this cannot answer: Do not interpret percentage area closure as the percentage of patients healed, or transfer this result to cosmetic products or injections.

Harms reported: Abstract reports fewer ulcer infections in a specified immediate-post-debridement subset; broader adverse-event reporting not extracted

Funding: Not reported in the source checked

Source access: Original PubMed abstract only; full text and subgroup methods not reviewed; re-read 2026-10-12 from original indexed abstract/journal record, with prior extraction gaps retained

Route or setting: topical

Not yet extracted for this card: Sample size. The original source may report these details.

Citation: Mulder GD, Patt LM, Sanders L, Rosenstock J, Altman MI, Hanley ME, Duncan GW. Enhanced healing of ulcers in patients with diabetes by topical treatment with glycyl-l-histidyl-l-lysine copper. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. 1994;2(4):259–269. doi:10.1046/j.1524-475X.1994.20406.x. PMID:17147644.

Source type: Journal paper

Study/cohort key: mulder-diabetic-neuropathic-ulcer-1994

DOI: 10.1046/j.1524-475X.1994.20406.x

PMID: 17147644

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did the single peptide activate all three target receptors?

How the study was done: Receptor signaling and binding characterization in a translational discovery report

What was tested: LY3437943 (retatrutide); defined receptor-expressing cell systems

Who or what was studied: Laboratory cells carrying human GIP, GLP-1 or glucagon receptors. The same paper separately reports obese-mouse experiments and an early human single-dose study.

Compared with: Native receptor ligands and other studied agonists

Follow-up: The accessible abstract does not give a timing schedule for the selected receptor-cell experiments; its separate human study reported weight observations through day 43.

What changed: The original work demonstrated agonist activity at human GIP, GLP-1 and glucagon receptors and characterized a single peptide with an albumin-binding modification.

What the result means: Triple agonism describes receptor activity of one molecule; it is not three hormones mixed together.

What this cannot answer: Cell receptor activity and mouse energy-expenditure findings do not isolate the clinical contribution of each receptor.

Harms reported: Selected cell characterization is not a clinical safety assessment.

Funding: Eli Lilly; authors reported employee/stockholder relationships

Source access: Original journal indexed full-report sections read; selected receptor findings only, not a new extraction of the report's phase 1 trial

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Sample size. The original source may report these details.

Citation: Coskun T, Urva S, Roell WC, et al. (2022). LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metabolism 34(9):1234–1247.e9. DOI: 10.1016/j.cmet.2022.07.013.

Source type: Journal paper

Study/cohort key: report-doi-10.1016-j.cmet.2022.07.013

DOI: 10.1016/j.cmet.2022.07.013

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How did retatrutide change the blood-glucose marker HbA1c at 24 weeks, and when was weight assessed?

How the study was done: Randomized, double-blind, double-dummy, placebo- and active-controlled phase 2 trial

What was tested: Trial retatrutide formulation; separate placebo and dulaglutide arms

Who or what was studied: Adults aged 18–75 with type 2 diabetes using diet and exercise alone or stable metformin. HbA1c, a blood test reflecting glucose exposure over preceding months, was 7.0%–10.5%; body mass index, a measure of weight relative to height, was 25–50 kg/m².

Compared with: Placebo and studied dulaglutide formulation

Follow-up: 36 weeks of treatment; the primary blood-glucose-marker assessment was at week 24.

What changed: Researchers randomized 281 adults with type 2 diabetes to weekly injections under the skin of retatrutide, placebo or dulaglutide, an established diabetes medicine; 275 participants entered the efficacy analysis after six inadvertent enrollments were excluded. At week 24, HbA1c, a blood test reflecting glucose exposure over preceding months, fell by an average 0.43–2.02 percentage points across six retatrutide groups, compared with 0.01 with placebo and 1.41 with dulaglutide. All retatrutide groups except the lowest studied dose, 0.5 mg, lowered HbA1c significantly more than placebo. The 8-mg group with slower dose escalation and the 12-mg group also lowered it significantly more than dulaglutide. Weight change was a separate secondary outcome at week 36.

What the result means: This trial directly studied glucose control in type 2 diabetes. It did not infer that benefit from an obesity population without diabetes.

What this cannot answer: Short phase 2 trial; active comparator was a defined diabetes formulation, not a comparison with every available diabetes/obesity treatment.

Harms reported: Mild/moderate gastrointestinal events in 35% of retatrutide recipients overall, 13% placebo and 35% dulaglutide; no severe hypoglycemia or deaths reported.

Funding: Eli Lilly

Source access: Original indexed PubMed abstract read, including allocation and analysis denominators; full text/supplements not fully extracted

Route or setting: Not extracted from the accessible source

Sample: 281 — Randomized and safety analysis; 275 efficacy participants after six inadvertently enrolled exclusions

Citation: Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z, Coskun T. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet (London, England). 2023;402(10401):529–544. doi:10.1016/S0140-6736(23)01053-X. PMID:37385280.

Source type: Journal paper

Study/cohort key: NCT04867785

DOI: 10.1016/S0140-6736(23)01053-X

PMID: 37385280

Registration: NCT04867785

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How did molecular modification address persistence and fibrillation?

How the study was done: Comparative molecular and pharmacological characterization

What was tested: Cagrilintide (AM833/NN0174-0833) and studied amylin analogues

Who or what was studied: Chemical, stability and receptor characterization systems

Compared with: Native amylin and other characterized analogues

What changed: The original report characterized a lipidated long-acting analogue with modifications addressing stability and aggregation tendency, supporting selection of cagrilintide for clinical development.

What the result means: Molecular identity, stability and receptor activity help explain why the analogue differs from native amylin.

What this cannot answer: Molecular development does not demonstrate clinical weight loss or validate a differently formulated material.

Harms reported: Not a clinical adverse-event comparison.

Source access: Original indexed abstract and ACS development/structure sections read; no procedural preparation details reproduced

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Kruse T, Hansen JL, Dahl K, Schäffer L, Sensfuss U, Poulsen C, Schlein M, Hansen AMK, Jeppesen CB, Dornonville de la Cour C, Clausen TR, Johansson E, Fulle S, Skyggebjerg RB, Raun K. Development of Cagrilintide, a Long-Acting Amylin Analogue. Journal of medicinal chemistry. 2021;64(15):11183–11194. doi:10.1021/acs.jmedchem.1c00565. PMID:34288673.

Source type: Journal paper

Study/cohort key: report-pmid-34288673

DOI: 10.1021/acs.jmedchem.1c00565

PMID: 34288673

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How did cagrilintide engage its receptor complexes?

How the study was done: Comparative structural and receptor-dynamics investigation

What was tested: Cagrilintide bound to active Gs-coupled AMY1R, AMY2R, AMY3R and calcitonin receptor complexes

Who or what was studied: Receptor complexes in structural and dynamic characterization systems

Compared with: Previously characterized amylin/calcitonin-family peptide structures

What changed: Structures showed an amylin-like binding mode with distinctive conformational dynamics at amylin and calcitonin receptors.

What the result means: Its pharmacology includes both amylin-receptor complexes and the calcitonin receptor.

What this cannot answer: A binding structure does not establish the relative clinical contribution of each receptor or a patient outcome.

Harms reported: Clinical harms not assessed by the selected structural work.

Source access: Original indexed PubMed abstract read; complete structural dataset not independently reanalyzed

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Cao J, Belousoff MJ, Johnson RM, Keov P, Mariam Z, Deganutti G, Christopoulos G, Hick CA, Reedtz-Runge S, Glendorf T, Ballarín-González B, Raun K, Bayly-Jones C, Wootten D, Sexton PM. Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors. Nature communications. 2025;16(1):3389. doi:10.1038/s41467-025-58680-y. PMID:40204768.

Source type: Journal paper

Study/cohort key: report-pmid-40204768

DOI: 10.1038/s41467-025-58680-y

PMID: 40204768

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did measured exposure vary consistently with renal or hepatic impairment?

How the study was done: Two single-exposure pharmacokinetic comparisons by organ-function category

What was tested: Trial cagrilintide formulation in two separate pharmacokinetic studies

Who or what was studied: Adults grouped by normal, mild, moderate or severe renal function in one study and hepatic function in another

Compared with: Normal-function group within each study

Follow-up: Exposure measurements through day 36 in the renal study and day 39 in the hepatic study

What changed: Total exposure and other pharmacokinetic measures were broadly similar across categories, without a consistent impairment-related pattern. Renal exposure ratios versus normal ranged 1.18–1.23; hepatic ratios 0.99–1.11, with uncertainty intervals reported in the original.

What the result means: These studies asked how the tested formulation moves through the body, rather than whether weight or clinical disease outcomes improved.

What this cannot answer: Small category samples and limited exposure/follow-up; not long-term safety or efficacy in every organ-disease population.

Harms reported: Treatment-emergent events affected 11 renal-study and 9 hepatic-study participants; no serious treatment-emergent events, event-related withdrawals or deaths reported.

Source access: Original indexed PubMed abstract read; separate study denominators and registry IDs retained

Route or setting: Not extracted from the accessible source

Sample: 65 — 33 renal-study participants and 32 hepatic-study participants; separate studies, not one randomized cohort

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Nielsen MJF, Becker NP, Duus HHH, Kirkeby K, Kupčová V, Lauenborg BW, Low B, Svolgaard O, Witten L. Renal or Hepatic Impairment Does Not Affect Pharmacokinetics, Safety, or Tolerability of Subcutaneous Cagrilintide. Clinical pharmacokinetics. 2026;65(7):1087–1099. doi:10.1007/s40262-026-01654-0. PMID:42228334.

Source type: Journal paper

Study/cohort key: NCT04209049+NCT05564104

DOI: 10.1007/s40262-026-01654-0

PMID: 42228334

Registration: NCT04209049, NCT05564104

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did CT-measured visceral adipose tissue change?

How the study was done: Randomized, placebo-controlled clinical trial

What was tested: Trial tesamorelin formulation

Who or what was studied: People with HIV and abdominal-fat accumulation during antiretroviral therapy; 86% men

Compared with: Placebo

Follow-up: 26 weeks

What changed: Visceral adipose tissue decreased 15.2% with tesamorelin and increased 5.0% with placebo; P<0.001. IGF-1 rose 81.0% with tesamorelin versus a 5.0% decline with placebo.

What the result means: A specific abdominal-fat compartment changed in the studied HIV population; this is not a general weight-loss trial.

What this cannot answer: HIV-related body-composition setting and 26-week follow-up; not long-term cardiovascular-event or liver-event prevention.

Harms reported: Overall adverse events did not differ significantly, but more tesamorelin participants withdrew because of an adverse event; no significant group differences in glycemic measures.

Source access: Original indexed PubMed abstract and NEJM report/participant-flow figure read

Route or setting: Not extracted from the accessible source

Sample: 412 — Randomized; 275 tesamorelin and 137 placebo assigned

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Falutz J, Allas S, Blot K, Potvin D, Kotler D, Somero M, Berger D, Brown S, Richmond G, Fessel J, Turner R, Grinspoon S. Metabolic effects of a growth hormone-releasing factor in patients with HIV. The New England journal of medicine. 2007;357(23):2359–2370. doi:10.1056/NEJMoa072375. PMID:18057338.

Source type: Journal paper

Study/cohort key: NCT00123253

DOI: 10.1056/NEJMoa072375

PMID: 18057338

Registration: NCT00123253

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did visceral and subcutaneous abdominal fat change similarly?

How the study was done: Randomized, double-blind, placebo-controlled trial

What was tested: Trial tesamorelin formulation

Who or what was studied: 60 adults with abdominal obesity and reduced stimulated GH secretion; HIV and diabetes excluded

Compared with: Placebo

Follow-up: 12 months

What changed: Visceral-fat treatment effect −35 cm² (95% CI −58 to −12), P=0.003. Abdominal subcutaneous-fat effect −10 cm² (95% CI −32 to +13), P=0.40; BMI unchanged. Carotid-wall thickness and several risk markers also improved.

What the result means: The trial found a selective abdominal-fat effect in a narrow non-HIV population; cardiovascular risk markers were not cardiovascular events.

What this cannot answer: 60 selected adults with low stimulated GH; diabetes and several chronic illnesses excluded. No cardiovascular-event endpoint and no general weight-loss indication inference.

Harms reported: Abstract reported no serious events or group adverse-event difference; full report notes two discontinuations for persistently elevated IGF-1. Larger studies needed for safety.

Funding: NIH grants plus partial research funding and study drug from Theratechnologies

Source access: Original indexed abstract and PMC full-text eligibility, discussion, IGF-1 safety, funding and registry sections read

Route or setting: Not extracted from the accessible source

Sample: 60 — Trial participants; selected endocrine phenotype, not general obesity

Citation: Makimura H, Feldpausch MN, Rope AM, Hemphill LC, Torriani M, Lee H, Grinspoon SK. Metabolic effects of a growth hormone-releasing factor in obese subjects with reduced growth hormone secretion: a randomized controlled trial. The Journal of clinical endocrinology and metabolism. 2012;97(12):4769–4779. doi:10.1210/jc.2012-2794. PMID:23015655.

Source type: Journal paper

Study/cohort key: NCT00675506

DOI: 10.1210/jc.2012-2794

PMID: 23015655

Registration: NCT00675506

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did weight change more with liraglutide?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of liraglutide

Who or what was studied: Adults without type 2 diabetes, BMI at least 30 or at least 27 with dyslipidemia or hypertension; lifestyle support in both groups

Compared with: Placebo

Follow-up: 56 weeks

What changed: Mean loss was 8.4 kg with liraglutide and 2.8 kg with placebo; 63.2% versus 27.1% lost at least 5% of starting weight.

What the result means: The defined weight-management population lost more weight on average with liraglutide.

What this cannot answer: Diabetes was excluded; this does not test cardiovascular events or durability after withdrawal.

Harms reported: Nausea and diarrhea were frequent; serious events occurred in 6.2% versus 5.0%.

Funding: Novo Nordisk

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 3731 — Randomized: 2,487 liraglutide and 1,244 placebo

Citation: Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DC, le Roux CW, Violante Ortiz R, Jensen CB, Wilding JP, SCALE Obesity and Prediabetes NN8022-1839 Study Group. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. The New England journal of medicine. 2015;373(1):11–22. doi:10.1056/NEJMoa1411892. PMID:26132939.

Source type: Journal paper

Study/cohort key: NCT01272219

DOI: 10.1056/NEJMoa1411892

PMID: 26132939

Registration: NCT01272219

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did type 2 diabetes develop less often while on treatment?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of liraglutide

Who or what was studied: Adults with prediabetes and obesity or qualifying overweight from the SCALE programme

Compared with: Placebo

Follow-up: 160 weeks

What changed: Diagnoses occurred in 26/1,472 versus 46/738; time-to-onset hazard ratio 0.21 (95% CI 0.13–0.34). Mean weight change was -6.1% versus -1.9%.

What the result means: Fewer people were diagnosed during observed treatment, with substantial follow-up loss.

What this cannot answer: Only 50% completed; withdrawn participants were not followed after discontinuation. Same parent cohort as the 56-week report.

Harms reported: Serious events in 15% versus 13% of randomized treated participants.

Funding: Novo Nordisk

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 2254 — Randomized prediabetes population: 1,505 liraglutide and 749 placebo; on-treatment diabetes counts use 1,472 and 738

Citation: le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DCW, Van Gaal L, Ortiz RV, Wilding JPH, Skjøth TV, Manning LS, Pi-Sunyer X, SCALE Obesity Prediabetes NN8022-1839 Study Group. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet (London, England). 2017;389(10077):1399–1409. doi:10.1016/S0140-6736(17)30069-7. PMID:28237263.

Source type: Journal paper

Study/cohort key: NCT01272219

DOI: 10.1016/S0140-6736(17)30069-7

PMID: 28237263

Registration: NCT01272219

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did cardiovascular death, nonfatal myocardial infarction or nonfatal stroke occur less often?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of liraglutide

Who or what was studied: Type 2 diabetes and high cardiovascular risk, added to usual care

Compared with: Placebo

Follow-up: Median follow-up 3.8 years

What changed: Composite events: 608/4,668 (13.0%) versus 694/4,672 (14.9%); hazard ratio 0.87 (95% CI 0.78–0.97). Heart-failure hospitalization was not significantly reduced.

What the result means: The combined cardiovascular outcome improved, but not every individual cardiovascular comparison was significant.

What this cannot answer: High-risk diabetes cohort; does not establish treatment of advanced reduced-ejection-fraction heart failure.

Harms reported: Gastrointestinal events were the most common reason for treatment discontinuation.

Funding: Novo Nordisk and NIH

Source access: Original PubMed abstract and indexed PMC/journal results

Route or setting: Not extracted from the accessible source

Sample: 9340 — Randomized: 4,668 liraglutide and 4,672 placebo

Citation: Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB, LEADER Steering Committee, LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine. 2016;375(4):311–322. doi:10.1056/NEJMoa1603827. PMID:27295427.

Source type: Journal paper

Study/cohort key: NCT01179048

DOI: 10.1056/NEJMoa1603827

PMID: 27295427

Registration: NCT01179048

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did liraglutide improve a hierarchical clinical-stability score?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of liraglutide

Who or what was studied: Recently hospitalized adults with established heart failure and reduced left ventricular ejection fraction; 59% had type 2 diabetes

Compared with: Placebo

Follow-up: 180-day primary assessment; adverse-event contact at about 210 days

What changed: The trial combined death, heart-failure readmission and a cardiac blood marker into one ranking of clinical stability. Liraglutide did not establish a better ranking than placebo: average ranks were 146 and 156, respectively (P=0.31).

What the result means: The study did not establish better clinical stability with liraglutide after a heart-failure hospitalization; the uncertain result is not proof that the treatments have identical effects.

What this cannot answer: Separate disease setting and endpoint from LEADER; small trial cannot characterize rare harms.

Harms reported: Heart-failure rehospitalization occurred in 63/154 (41%) versus 50/146 (34%); hazard ratio 1.30 (95% CI 0.89–1.88), P=0.17. The authors also described renal-function signals and raised safety concerns. These exploratory, nonsignificant findings do not establish a harm effect; the trial was not powered for safety comparisons.

Funding: NHLBI Heart Failure Clinical Research Network

Source access: Indexed original PMC results/methods and PubMed metadata

Route or setting: Not extracted from the accessible source

Sample: 300 — Randomized: 154 liraglutide and 146 placebo

Citation: Margulies KB, Hernandez AF, Redfield MM, Givertz MM, Oliveira GH, Cole R, Mann DL, Whellan DJ, Kiernan MS, Felker GM, McNulty SE, Anstrom KJ, Shah MR, Braunwald E, Cappola TP, NHLBI Heart Failure Clinical Research Network. Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2016;316(5):500–508. doi:10.1001/jama.2016.10260. PMID:27483064.

Source type: Journal paper

Study/cohort key: NCT01800968

DOI: 10.1001/jama.2016.10260

PMID: 27483064

Registration: NCT01800968

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did steatohepatitis resolve without worsening fibrosis?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of liraglutide

Who or what was studied: Overweight adults with biopsy-confirmed NASH, with or without diabetes, in four UK centres

Compared with: Placebo

Follow-up: 48 weeks

What changed: Resolution in 9/23 versus 2/22 participants with final biopsy; relative risk 4.3 (95% CI 1.0–17.7), P=0.019.

What the result means: More final biopsies met the defined inflammation-resolution endpoint.

What this cannot answer: Small sample with seven participants lacking end biopsy; not proof of preventing cirrhosis or liver death.

Harms reported: Gastrointestinal symptoms were more frequent; complete safety tables not extracted.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 52 — Randomized 26 per group; end-of-treatment biopsy results use 23 liraglutide and 22 placebo

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, Guo K, LEAN trial team, Abouda G, Aldersley MA, Stocken D, Gough SC, Tomlinson JW, Brown RM, Hübscher SG, Newsome PN. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet (London, England). 2016;387(10019):679–690. doi:10.1016/S0140-6736(15)00803-X. PMID:26608256.

Source type: Journal paper

Study/cohort key: original-26608256

DOI: 10.1016/S0140-6736(15)00803-X

PMID: 26608256

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did adding the amylin analogue improve HbA1c and weight?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of pramlintide

Who or what was studied: People with type 1 diabetes using insulin; mean baseline HbA1c 8.9%

Compared with: Placebo

Follow-up: 52 weeks

What changed: Selected active groups had HbA1c changes of -0.29 and -0.34 percentage points versus -0.04 with placebo; weight fell about 0.4 kg versus a 0.8-kg increase.

What the result means: Selected adjunctive-treatment groups had modest improvements in the glucose average and weight.

What this cannot answer: Multiple trial arms; reported effects should not be assigned to every exposure or treated as insulin replacement.

Harms reported: Transient mild-to-moderate nausea was common.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 651 — Randomized across placebo and several pramlintide groups; arm denominators not extracted

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, Weyer C, Kolterman OG. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabetic medicine : a journal of the British Diabetic Association. 2004;21(11):1204–1212. doi:10.1111/j.1464-5491.2004.01319.x. PMID:15498087.

Source type: Journal paper

Study/cohort key: original-15498087

DOI: 10.1111/j.1464-5491.2004.01319.x

PMID: 15498087

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Were glucose and weight effects sustained during adjunctive treatment?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of pramlintide

Who or what was studied: Insulin-treated type 2 diabetes, sometimes with metformin or sulfonylureas; mean baseline HbA1c 9.1%

Compared with: Placebo

Follow-up: 52 weeks

What changed: One active arm had HbA1c change -0.62 percentage points at week 52, significantly greater reduction than placebo; weight change -1.4 kg versus +0.7 kg.

What the result means: One studied adjunctive-treatment group improved glucose control while avoiding the placebo group's mean weight gain.

What this cannot answer: The absence of an overall hypoglycemia increase here does not cancel the product's boxed warning with insulin.

Harms reported: Nausea was common; no overall increase in severe hypoglycemia rate was reported in this trial.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 656 — Randomized; arm denominators not extracted

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, Weyer C, Kolterman OG. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes care. 2003;26(3):784–790. doi:10.2337/diacare.26.3.784. PMID:12610038.

Source type: Journal paper

Study/cohort key: original-12610038

DOI: 10.2337/diacare.26.3.784

PMID: 12610038

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did pramlintide add a glucose-average benefit during intensive insulin management?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of pramlintide

Who or what was studied: Type 1 diabetes using intensive insulin treatment; baseline HbA1c 8.1% in each group

Compared with: Placebo

Follow-up: 29 weeks

What changed: HbA1c fell approximately 0.5 percentage points in both groups. Post-meal glucose excursion and weight favored pramlintide; weight change -1.3 versus +1.2 kg.

What the result means: Post-meal and weight effects improved without an additional HbA1c difference.

What this cannot answer: Background insulin optimization is part of the intervention context, not a transferable self-management protocol.

Harms reported: Nausea affected 63% versus 36%, P<0.01. Severe hypoglycemia rates were 0.57±0.09 versus 0.30±0.06 events per patient-year, P<0.05; rates are not participant percentages.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 296 — Randomized

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Edelman S, Garg S, Frias J, Maggs D, Wang Y, Zhang B, Strobel S, Lutz K, Kolterman O. A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes care. 2006;29(10):2189–2195. doi:10.2337/dc06-0042. PMID:17003291.

Source type: Journal paper

Study/cohort key: original-17003291

DOI: 10.2337/dc06-0042

PMID: 17003291

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Was there an early weight-loss signal outside insulin-treated diabetes?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of pramlintide

Who or what was studied: Adults with obesity, with or without type 2 diabetes, not using insulin

Compared with: Placebo

Follow-up: 16 weeks

What changed: Among completers, placebo-corrected weight reduction was 3.7% (3.6 kg); active-group withdrawal 29% versus placebo 25%.

What the result means: An exploratory completer analysis found greater weight loss, with substantial withdrawals.

What this cannot answer: Completer effect is not an all-randomized estimate; short duration and different exposure from diabetes trials.

Harms reported: Mild transient nausea was the most common reported event.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 204 — Participants in randomized trial; completer denominator for headline weight estimate not extracted

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Aronne L, Fujioka K, Aroda V, Chen K, Halseth A, Kesty NC, Burns C, Lush CW, Weyer C. Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study. The Journal of clinical endocrinology and metabolism. 2007;92(8):2977–2983. doi:10.1210/jc.2006-2003. PMID:17504894.

Source type: Journal paper

Study/cohort key: original-17504894

DOI: 10.1210/jc.2006-2003

PMID: 17504894

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Were initial weight changes maintained in participants who continued?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of pramlintide

Who or what was studied: Adults with obesity receiving structured lifestyle intervention alongside pramlintide or placebo

Compared with: Placebo

Follow-up: Four-month double-blind trial plus eight-month selected single-blind extension

What changed: In the four-month evaluable population (n=270), mean losses ranged 3.8–6.1 kg across active groups versus 2.8 kg placebo. In the selected one-year evaluable population (n=146), most active groups maintained initial loss, while placebo regained it; one active group did not maintain the loss.

What the result means: Longer follow-up supports a maintenance signal in selected continuing participants, with variation between active groups.

What this cannot answer: Only selected evaluable participants entered the extension; not an independent randomization or an estimate for all 411 starters.

Harms reported: Complete adverse-event results not extracted.

Source access: Indexed original PMC abstract and PubMed registration metadata

Route or setting: Not extracted from the accessible source

Sample: 411 — Initially randomized; 270 evaluable at four months and 77% of those chose extension

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Smith SR, Aronne LJ, Burns CM, Kesty NC, Halseth AE, Weyer C. Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes care. 2008;31(9):1816–1823. doi:10.2337/dc08-0029. PMID:18753666.

Source type: Journal paper

Study/cohort key: NCT00112021

DOI: 10.2337/dc08-0029

PMID: 18753666

Registration: NCT00112021, NCT00189514

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did the engineered candidate combine glucagon and GLP-1 receptor activity with prolonged exposure?

How the study was done: Candidate discovery, receptor pharmacology and preclinical metabolic experiments

What was tested: Exact BI 456906/survodutide candidate in receptor assays and preclinical species

Who or what was studied: Receptor-expressing assay systems and preclinical animals

Compared with: Reference receptor agonists and experimental controls

Follow-up: Varied experiments; not pooled

What changed: BI 456906 activated both receptor systems and showed preclinical anti-obesity effects; modifications supported proteolytic stability and albumin binding.

What the result means: The original work established a plausible molecular design before clinical outcome testing.

What this cannot answer: Cell potency and preclinical metabolic effects do not quantify the contribution of either receptor in humans.

Harms reported: Not a human safety trial.

Funding: Boehringer Ingelheim

Source access: Indexed original PMC abstract and chemical-structure section

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Sample size. The original source may report these details.

Citation: Zimmermann T, Thomas L, Baader-Pagler T, Haebel P, Simon E, Reindl W, Bajrami B, Rist W, Uphues I, Drucker DJ, Klein H, Santhanam R, Hamprecht D, Neubauer H, Augustin R. BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. Molecular metabolism. 2022;66:101633. doi:10.1016/j.molmet.2022.101633. PMID:36356832.

Source type: Journal paper

Study/cohort key: original-36356832

DOI: 10.1016/j.molmet.2022.101633

PMID: 36356832

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did body weight fall, and how much treatment was completed?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of survodutide

Who or what was studied: Adults aged 18–75 with BMI at least 27, without diabetes, at 43 centres in 12 countries

Compared with: Placebo

Follow-up: 46 weeks

What changed: Planned-treatment mean weight changes at week 46 were -6.2%, -12.5%, -13.2% and -14.9% across four active arms versus -2.8% with placebo. Only 233/386 treated participants completed treatment.

What the result means: The trial showed a weight signal alongside substantial incomplete treatment.

What this cannot answer: High discontinuation and analysis differences limit interpretation of an unlabeled headline percentage.

Harms reported: Any adverse event: 281/309 (91%) pooled active versus 58/77 (75%) placebo; gastrointestinal events: 232/309 (75%) versus 32/77 (42%).

Funding: Boehringer Ingelheim

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 387 — Enrolled/randomized; 386 treated and 233 completed the 46-week treatment period

Citation: le Roux CW, Steen O, Lucas KJ, Startseva E, Unseld A, Hennige AM. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. The lancet. Diabetes & endocrinology. 2024;12(3):162–173. doi:10.1016/S2213-8587(23)00356-X. PMID:38330987.

Source type: Journal paper

Study/cohort key: NCT04667377

Analysis: Primary modified intention-to-treat analysis used assignment at randomization (planned treatment), with COVID-19-related discontinuation censoring. The sensitivity analysis used exposure received during maintenance (actual treatment) and on-treatment data.

DOI: 10.1016/S2213-8587(23)00356-X

PMID: 38330987

Registration: NCT04667377, EudraCT 2020-002479-37

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How much weight did adults without diabetes lose over 76 weeks?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of survodutide

Who or what was studied: Adults without diabetes, BMI at least 30 or at least 27 with an obesity-related complication; lifestyle counseling

Compared with: Placebo

Follow-up: 76 weeks

What changed: At week 76, average weight fell 12.2% and 13.0% in the two survodutide groups versus 5.4% with placebo. At least 5% weight loss occurred in 72.6%, 71.9% and 46.3%, respectively. The analysis includes results after early treatment stopping, use of obesity medicines prohibited by the protocol, or a longer period of dose escalation.

What the result means: Both survodutide groups had greater average loss under an analysis incorporating interruption and other specified events.

What this cannot answer: No active comparator; not evidence of cardiovascular benefit or the exact glucagon contribution.

Harms reported: Gastrointestinal events in 80.9% and 89.7% versus 47.9%; no deaths reported.

Funding: Boehringer Ingelheim

Source access: Indexed original PubMed/NEJM abstract; direct NEJM full text returned 403

Route or setting: Not extracted from the accessible source

Sample: 725 — Reported participants: 241 and 242 in two active groups, 242 placebo

Citation: le Roux CW, Wharton S, Startseva E, Kloer IM, Hussain SA, Unseld A, Bozkurt B, Ard JD, Bays HE, Bogdański P, Ekinci EI, Jastreboff AM, Ji L, Ogawa W, Pedersen SD, Pietiläinen KH, Sattar N, Seufert J, Stenlöf K, van Beek AP, Vangoitsenhoven R, Brueckmann M, Younes R, Kaplan LM, SYNCHRONIZE-1 Investigators. Survodutide Once Weekly for the Treatment of Adults with Obesity. The New England journal of medicine. 2026;395(8):776–787. doi:10.1056/NEJMoa2600751. PMID:42253238.

Source type: Journal paper

Study/cohort key: NCT06066515

Analysis: The analysis estimates results even when participants stopped treatment early, used obesity medicines prohibited by the protocol, or took longer to increase their dose (the treatment-regimen estimand).

DOI: 10.1056/NEJMoa2600751

PMID: 42253238

Registration: NCT06066515

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did weight and HbA1c improve in the diabetes population?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of survodutide

Who or what was studied: Adults with type 2 diabetes and BMI at least 27; baseline mean HbA1c 7.4%

Compared with: Placebo

Follow-up: 76 weeks

What changed: At week 76, average weight fell 8.2% and 9.8% in the two survodutide groups versus 3.9% with placebo. HbA1c fell 0.9 and 0.8 percentage points versus 0.2 with placebo.

What the result means: Weight and the glucose average improved in this separate diabetes cohort.

What this cannot answer: Different population from SYNCHRONIZE-1; no active comparator or measured long-term event benefit.

Harms reported: Gastrointestinal events in 182/250 (72.8%) and 195/251 (77.7%) versus 97/251 (38.6%), generally mild/moderate and transient.

Funding: Boehringer Ingelheim

Source access: Original indexed PubMed/NEJM and author-institution abstract; direct NEJM full text returned 403

Route or setting: Not extracted from the accessible source

Sample: 752 — Participants: 250 and 251 active, 251 placebo

Citation: Wharton S, le Roux CW, Startseva E, Kloer IM, Alhussein A, Hussain SA, Unseld A, Bozkurt B, Ard JD, Bays HE, Bogdański P, Butt JH, Ekinci EI, Jastreboff AM, Ji L, Schou M, Tinahones FJ, Kokkinos AD, Merkely B, Ogawa W, Pedersen SD, Pietiläinen KH, Quinn D, Sattar N, Seufert J, Stenlöf K, van Beek AP, Vangoitsenhoven R, Brueckmann M, Younes R, Kaplan LM, SYNCHRONIZE-2 Investigators. Survodutide Once Weekly in Adults with Obesity and Type 2 Diabetes. The New England journal of medicine. 2026. doi:10.1056/NEJMoa2607219. PMID:42820639.

Source type: Journal paper

Study/cohort key: NCT06066528

Analysis: The analysis estimates results even when participants stopped or interrupted treatment or used other obesity medicines (the treatment-regimen estimand).

DOI: 10.1056/NEJMoa2607219

PMID: 42820639

Registration: NCT06066528

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did MASH improve without worsening fibrosis?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of survodutide

Who or what was studied: Adults with biopsy-confirmed MASH and fibrosis stages F1–F3

Compared with: Placebo

Follow-up: 48 weeks

What changed: Primary biopsy response 47%, 62% and 43% across active groups versus 14% placebo. One-stage fibrosis improvement occurred in 34%, 36%, 34% and 22%, respectively.

What the result means: The defined MASH endpoint improved; fibrosis percentages describe a separate endpoint.

What this cannot answer: Histological improvement is not proof of preventing cirrhosis or liver-related death.

Harms reported: Nausea 66% versus 23%, diarrhea 49% versus 23%, vomiting 41% versus 4%; serious events 8% versus 7%.

Funding: Boehringer Ingelheim

Source access: Original indexed journal abstract and results

Route or setting: Not extracted from the accessible source

Sample: 293 — Randomly assigned participants who received at least one treatment; arm totals not extracted

Citation: Sanyal AJ, Bedossa P, Fraessdorf M, et al. (2024). A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. New England Journal of Medicine 391(4):311–319. DOI: 10.1056/NEJMoa2401755.

Source type: Journal paper

Study/cohort key: NCT04771273

DOI: 10.1056/nejmoa2401755

Registration: NCT04771273

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did weight and metabolic measures change, and what happened after treatment stopped?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of mazdutide

Who or what was studied: Chinese adults without diabetes, BMI at least 28 or qualifying overweight from BMI 24

Compared with: Placebo

Follow-up: 24 weeks plus 12-week off-treatment follow-up

What changed: Mean weight changes -6.7%, -10.4%, -11.3% versus +1.0%. Weight and some metabolic measures rebounded off treatment. Physical-function score changes were minimal.

What the result means: Weight fell more in active groups, while not every functional measure improved.

What this cannot answer: Body-composition results in 22 paired observations do not establish universal lean-mass preservation; local enrollment thresholds differ from other trials.

Harms reported: Diarrhea, nausea and upper respiratory infection were common.

Funding: Innovent Biologics

Source access: Original open-access journal abstract/results/methods

Route or setting: Not extracted from the accessible source

Sample: 248 — Randomized: 62, 63 and 61 active; 62 placebo. Paired body-composition subset n=22

Citation: Ji L, Jiang H, Cheng Z, Qiu W, Liao L, Zhang Y, Li X, Pang S, Zhang L, Chen L, Yang T, Li Y, Qu S, Wen J, Gu J, Deng H, Wang Y, Li L, Han-Zhang H, Ma Q, Qian L. A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity. Nature communications. 2023;14(1):8289. doi:10.1038/s41467-023-44067-4. PMID:38092790.

Source type: Journal paper

Study/cohort key: NCT04904913

DOI: 10.1038/s41467-023-44067-4

PMID: 38092790

Registration: NCT04904913

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How much weight did participants lose at weeks 32 and 48?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of mazdutide

Who or what was studied: Chinese adults aged 18–75 with BMI at least 28, or 24 to below 28 plus a weight-related condition

Compared with: Placebo

Follow-up: Week 32 primary outcomes; week 48 secondary follow-up

What changed: At the primary week-32 assessment, average weight fell 10.09% and 12.55% in the two mazdutide groups, while it rose 0.45% with placebo. At week 48, the reductions were 11.00% and 14.01%, versus a 0.30% increase with placebo. The analysis includes results after participants stopped treatment or started another obesity treatment.

What the result means: Both study groups lost more weight, and the primary and later timepoints differ.

What this cannot answer: Chinese cohort and local enrollment criteria; no direct comparison with other obesity medicines.

Harms reported: Mostly mild/moderate gastrointestinal events; adverse-event discontinuation 1.5%, 0.5% and 1.0% across the two active groups and placebo.

Funding: Innovent Biologics

Source access: Indexed original journal abstract

Route or setting: Not extracted from the accessible source

Sample: 610 — Randomized across two mazdutide groups and placebo; per-arm totals not extracted

Citation: Ji L, Jiang H, Bi Y, Li H, Tian J, Liu D, Zhao Y, Qiu W, Huang C, Chen L, Zhong S, Han J, Zhang Y, Lian Q, Yang P, Lv L, Gu J, Liu Z, Deng H, Wang Y, Li L, Pei L, Qian L, GLORY-1 Investigators. Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight. The New England journal of medicine. 2025;392(22):2215–2225. doi:10.1056/NEJMoa2411528. PMID:40421736.

Source type: Journal paper

Study/cohort key: NCT05607680

Analysis: The analysis estimates effects regardless of whether participants stopped assigned treatment or started another obesity treatment (the treatment-policy estimand).

DOI: 10.1056/NEJMoa2411528

PMID: 40421736

Registration: NCT05607680

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did glucose and weight improve despite combined glucagon activity?

How the study was done: Randomized, blinded mazdutide/placebo groups with an open-label active comparator

What was tested: Clinical trial formulation of mazdutide

Who or what was studied: Chinese adults with type 2 diabetes inadequately controlled by diet/exercise or stable metformin; baseline HbA1c 7.0–10.5%

Compared with: Placebo and open-label dulaglutide

Follow-up: 20 weeks

What changed: HbA1c changes ranged -1.41 to -1.67 percentage points versus +0.03 placebo and -1.35 dulaglutide; mazdutide weight reductions 4.1–7.1%.

What the result means: The engineered molecule improved net glucose control and weight relative to placebo.

What this cannot answer: Active comparator was open label; enrollment and treated denominators are different.

Harms reported: Gastrointestinal events were prominent; complete safety rates not extracted.

Funding: Innovent Biologics

Source access: Indexed original PMC/ADA results and methods

Route or setting: Not extracted from the accessible source

Sample: 252 — Enrolled; 250 treated: active groups 51,49,49; dulaglutide 50; placebo 51

Citation: Zhang B, Cheng Z, Chen J, Zhang X, Liu D, Jiang H, Ma G, Wang X, Gan S, Sun J, Jin P, Yi J, Shi B, Ma J, Ye S, Wang G, Ji L, Gu X, Yu T, An P, Deng H, Li H, Li L, Ma Q, Qian L, Yang W. Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial. Diabetes care. 2024;47(1):160–168. doi:10.2337/dc23-1287. PMID:37943529.

Source type: Journal paper

Study/cohort key: NCT04466904

DOI: 10.2337/dc23-1287

PMID: 37943529

Registration: NCT04466904

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did mazdutide monotherapy improve HbA1c?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of mazdutide

Who or what was studied: Chinese adults with type 2 diabetes inadequately controlled by diet/exercise alone; mean disease duration 1.9 years

Compared with: Placebo

Follow-up: 24-week primary comparison, followed by 24-week extended treatment

What changed: HbA1c changes -1.57 and -2.15 percentage points versus -0.14 placebo; body-weight changes -5.61% and -7.81% versus -1.26%.

What the result means: The primary glucose-average endpoint improved in this early-diabetes monotherapy setting.

What this cannot answer: Subscription abstract preview; full tables, detailed harms, registry and analysis details not extracted.

Harms reported: Diarrhea, reduced appetite and nausea were the most common reported events.

Funding: Innovent Biologics

Source access: Original journal abstract, funding and metadata; subscription preview

Route or setting: Not extracted from the accessible source

Sample: 320 — Randomized 1:1:1; arm totals not extracted

Citation: Zhu D, Zhao J, Cai H, et al. (2026; online 2025). Mazdutide versus placebo in Chinese adults with type 2 diabetes. Nature 652:174–180. DOI: 10.1038/s41586-025-10026-w.

Source type: Journal paper

Study/cohort key: doi-s41586-025-10026-w

DOI: 10.1038/s41586-025-10026-w

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How much weight did participants lose with the higher experimental amounts tested in this small trial?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of mazdutide

Who or what was studied: Adults with overweight or obesity without diabetes

Compared with: Placebo

Follow-up: 20 weeks

What changed: Mixed-model repeated-measures estimates at week 20: mean weight changes -20.0% and -21.0% in the two active cohorts versus -0.1% placebo, P<0.001.

What the result means: The two mazdutide groups lost an average of about one fifth of their weight over 20 weeks, but this phase 1 trial enrolled only 32 people and tested different amounts from the phase 3 GLORY-1 trial.

What this cannot answer: Very small phase 1 sample; not the same exposure or a replacement for the phase 3 GLORY-1 estimate.

Harms reported: No serious adverse events reported; most common events were mild/moderate gastrointestinal disorders.

Funding: Eli Lilly and Company

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 32 — Treated: two mazdutide cohorts of 12 each and 8 placebo participants

Citation: Bhattachar SN, Tham LS, Li Y, Chua L, Ng SX, Tang Y, Ibriga H, Ni W, Gurbuz S, Mather KJ, Thomas MK. Mazdutide reduces body weight in adults with overweight or obesity: A high-dose Phase 1 trial. Diabetes, obesity & metabolism. 2025;27(11):6460–6469. doi:10.1111/dom.70040. PMID:40832785.

Source type: Journal paper

Study/cohort key: NCT05623839

DOI: 10.1111/dom.70040

PMID: 40832785

Registration: NCT05623839

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did MRI-measured liver fat decrease?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of pemvidutide

Who or what was studied: Adults with BMI at least 28 and liver fat at least 10% by MRI-PDFF

Compared with: Placebo

Follow-up: 12 weeks

What changed: Relative reductions 46.6%, 68.5% and 57.1% in three active groups versus 4.4% placebo, all P<0.001.

What the result means: The trial found less liver fat on imaging, rather than a measured fibrosis-resolution outcome.

What this cannot answer: Imaging endpoint does not establish MASH or fibrosis resolution; parent cohort of the later extension.

Harms reported: Complete adverse-event table not extracted.

Funding: Altimmune

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 94 — Randomized and treated; 29% had type 2 diabetes

Citation: Harrison SA, Browne SK, Suschak JJ, Tomah S, Gutierrez JA, Yang J, Roberts MS, Harris MS. Effect of pemvidutide, a GLP-1/glucagon dual receptor agonist, on MASLD: A randomized, double-blind, placebo-controlled study. Journal of hepatology. 2025;82(1):7–17. doi:10.1016/j.jhep.2024.07.006. PMID:39002641.

Source type: Journal paper

Study/cohort key: NCT05006885

DOI: 10.1016/j.jhep.2024.07.006

PMID: 39002641

Registration: NCT05006885

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Were liver-fat changes maintained with longer observed treatment?

How the study was done: Double-blind extension at original treatment assignment; no new independent randomization

What was tested: Clinical trial formulation of pemvidutide

Who or what was studied: Selected MASLD parent-trial completers; 26.6% had type 2 diabetes

Compared with: Placebo

Follow-up: Additional 12 weeks; 24 weeks total from parent baseline

What changed: Relative liver-fat reductions 56.3%, 75.2% and 76.4% versus 14.0% placebo at total week 24, all P<0.001.

What the result means: Selected continuing participants retained a liver-fat response.

What this cannot answer: Selected-completer follow-up; do not add its participants to the parent trial as new people. No biopsy proof of fibrosis reversal.

Harms reported: Complete safety results not extracted.

Funding: Altimmune

Source access: Indexed original PubMed abstract/PMC methods; direct PMC open displayed browser check

Route or setting: Not extracted from the accessible source

Sample: 64 — Eligible extension participants selected from 83 completers of 94 treated in the parent trial; 66 consented

Citation: Browne SK, Suschak JJ, Tomah S, Gutierrez JA, Yang J, Georges B, Roberts MS, Harris MS. Safety and efficacy of 24 weeks of pemvidutide in metabolic dysfunction-associated steatotic liver disease: A randomized, controlled clinical trial. JHEP reports : innovation in hepatology. 2025;7(11):101483. doi:10.1016/j.jhepr.2025.101483. PMID:41113119.

Source type: Journal paper

Study/cohort key: NCT05006885

DOI: 10.1016/j.jhepr.2025.101483

PMID: 41113119

Registration: NCT05292911, NCT05006885

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did pemvidutide change weight in the obesity trial?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of pemvidutide

Who or what was studied: Adults without diabetes with obesity or BMI 27–29.9 plus an obesity-related condition

Compared with: Placebo

Follow-up: 48 weeks

What changed: Mean weight reductions 10.3%, 11.2% and 15.6% versus 2.2% placebo; all P<0.001.

What the result means: The original conference report describes a weight-loss signal across its active groups.

What this cannot answer: Conference abstract, with less detail than a full trial paper; analysis method and complete harms remain unextracted.

Harms reported: Full adverse-event and discontinuation tables not extracted from the conference source.

Funding: Altimmune

Source access: Original ADA conference abstract; no complete journal report acquired

Route or setting: Not extracted from the accessible source

Sample: 391 — Enrolled in randomized trial; arm totals not extracted

Citation: Aronne L, Harris MS, Roberts MS, et al. (2024). 262-OR: Pemvidutide, a GLP-1/Glucagon Dual Receptor Agonist, in Subjects with Overweight or Obesity—A 48-Week, Placebo-Controlled, Phase 2 (MOMENTUM) Trial. Diabetes 73(Supplement_1):262-OR. DOI: 10.2337/db24-262-OR.

Source type: Conference report · preliminary

Study/cohort key: MOMENTUM

DOI: 10.2337/db24-262-or

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Were both prespecified biopsy outcomes improved?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial formulation of pemvidutide

Who or what was studied: Adults with biopsy-confirmed MASH and liver fibrosis stage F2 or F3

Compared with: Placebo

Follow-up: 24-week reported analysis of a 48-week trial

What changed: MASH resolution without fibrosis worsening: 24/41 (58%) and 45/85 (52%) versus 18/86 (20%), both P<0.0001. Fibrosis improvement without MASH worsening: 33% and 36% versus 28%, P=0.59 and P=0.27.

What the result means: The inflammation-resolution outcome succeeded; the fibrosis co-primary endpoint did not at this timepoint.

What this cannot answer: Early biopsy analysis; numerical fibrosis differences are not statistically established efficacy.

Harms reported: Any events 78%, 81% versus 67%; adverse-event discontinuations 0/41, 1/85 and 2/86, mostly mild/moderate events.

Funding: Altimmune

Source access: Indexed original PubMed abstract; direct PubMed open returned 429

Route or setting: Not extracted from the accessible source

Sample: 212 — Randomized: 41 and 85 active, 86 placebo

Citation: Noureddin M, Harrison SA, Loomba R, Alkhouri N, Chalasani N, Sheikh MY, Tomah S, Gutierrez JA, Urbina S, Suschak JJ, Brown R, Odili O, Yang J, Keeton S, Neff G, Mena E, Roberts MS, Browne SK, Harris MS. Safety and efficacy of weekly pemvidutide versus placebo for metabolic dysfunction-associated steatohepatitis (IMPACT): 24-week results from a multicentre, randomised, double-blind, phase 2b study. Lancet (London, England). 2025;406(10520):2644–2655. doi:10.1016/S0140-6736(25)02114-2. PMID:41237796.

Source type: Journal paper

Study/cohort key: NCT05989711

DOI: 10.1016/S0140-6736(25)02114-2

PMID: 41237796

Registration: NCT05989711

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did blood pressure change, including in hypertension subgroups?

How the study was done: Secondary and post hoc analyses of the existing randomized phase 3a cohort

What was tested: Trial CagriSema combination from REDEFINE 1

Who or what was studied: REDEFINE 1 adults without diabetes who had overweight or obesity; 167 participants were classified as having resistant hypertension because they were taking at least three blood-pressure medicines at the start, including a medicine that removes extra salt and water (a diuretic)

Compared with: Placebo

Follow-up: 68 weeks

What changed: Researchers reanalyzed the existing 68-week REDEFINE 1 trial in adults without diabetes who had overweight or obesity. It randomized 3,417 participants, including 2,108 to CagriSema and 705 to placebo; all groups received lifestyle intervention. In an analysis estimating what would happen if trial treatment were taken as intended (the trial-product estimand), the upper blood-pressure number, systolic pressure, fell by 10.9 mmHg with CagriSema and 2.8 mmHg with placebo. The lower number, diastolic pressure, fell by 5.4 mmHg with CagriSema and 1.7 mmHg with placebo. At the start of the trial, 167 participants across all four trial groups were taking at least three blood-pressure medicines, including a medicine that removes extra salt and water (a diuretic). The study classified this subgroup as having resistant hypertension. A higher proportion of CagriSema recipients than placebo recipients in this subgroup reached the study’s blood-pressure target, but the comparison remained uncertain (odds ratio 1.7; 95% CI 0.7–4.4). This is an additional analysis of the same cohort, not another trial.

What the result means: Overall blood pressure improved; the small resistant-hypertension comparison retained uncertainty.

What this cannot answer: Same REDEFINE 1 participants, not another independent trial; BP change is not a cardiovascular event endpoint.

Harms reported: Not a new safety cohort; detailed subgroup harms not extracted.

Funding: Novo Nordisk trial programme; complete paper funding statement not extracted

Source access: Original indexed PubMed abstract and PMC report

Route or setting: Not extracted from the accessible source

Sample: 3417 — Parent randomization; comparison emphasizes 2,108 combination and 705 placebo, with endpoint-specific subsets

Citation: Verma S, Böttcher M, Brown P, Dicker D, Rubino D, Sbraccia P, Sharma AM, Smedegaard L, Sørrig R, Garvey WT. CagriSema Reduces Blood Pressure in Adults With Overweight or Obesity: REDEFINE 1. Hypertension (Dallas, Tex. : 1979). 2026;83(2):e26055. doi:10.1161/HYPERTENSIONAHA.125.26055. PMID:41328546.

Source type: Journal paper

Study/cohort key: NCT05567796

DOI: 10.1161/HYPERTENSIONAHA.125.26055

PMID: 41328546

Registration: NCT05567796

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did CagriSema meet the specified weight non-inferiority endpoint?

How the study was done: Open-label, active-controlled phase 3 trial; preliminary sponsor topline

What was tested: Protocol-specified clinical CagriSema combination versus protocol-specified tirzepatide

Who or what was studied: People with obesity and at least one other condition; mean (average) starting body weight 114.2 kg

Compared with: Tirzepatide

Follow-up: 84 weeks

What changed: Novo Nordisk’s preliminary announcement described an 84-week, open-label trial of 809 people with obesity and at least one other condition. Weekly injections under the skin compared CagriSema 2.4 mg/2.4 mg with tirzepatide 15 mg. Participants and investigators knew the treatment assignments. The analysis estimating effects regardless of treatment adherence (the treatment-regimen estimand) estimated weight loss of 20.2% with CagriSema and 23.6% with tirzepatide. The analysis assuming adherence (the efficacy estimand) estimated weight loss of 23.0% with CagriSema and 25.5% with tirzepatide. The trial did not meet its prespecified criterion for showing that CagriSema was not unacceptably worse than tirzepatide (noninferiority). The estimates show less weight loss with CagriSema, but the failed noninferiority test alone does not establish that a test planned in advance showed greater weight loss with tirzepatide (superiority). The announcement did not supply full confidence intervals or the trial’s threshold for an acceptably small difference in weight loss (the noninferiority margin).

What the result means: Both groups lost weight, while the prespecified comparison failed.

What this cannot answer: Sponsor report, not a journal paper; prespecified margin, full confidence intervals and complete safety tables not extracted. Failure of non-inferiority is not automatically a tested superiority result.

Harms reported: Sponsor described mostly mild/moderate gastrointestinal events; detailed denominators and tables not supplied.

Funding: Novo Nordisk

Source access: Official sponsor report acquired in full; no peer-reviewed trial paper acquired

Route or setting: Not extracted from the accessible source

Sample: 809 — Randomized per sponsor; arm totals not reported in acquired announcement

Citation: Novo Nordisk (23 February 2026). CagriSema demonstrated 23% weight loss in an open-label head-to-head REDEFINE 4 trial in people with obesity, the primary endpoint was not achieved. Company announcement.

Source type: Sponsor report · preliminary

Study/cohort key: REDEFINE-4

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did selected active groups improve sexual-function outcomes?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Trial subcutaneous bremelanotide formulation

Who or what was studied: Premenopausal women with HSDD, female sexual arousal disorder or both

Compared with: Placebo

Follow-up: 12 weeks

What changed: Pooled selected active groups had satisfying-event changes +0.7 versus +0.2 per month, P=0.0180; function and distress scores also favored active treatment.

What the result means: An exploratory trial found benefit on several patient-reported measures in a broader diagnostic population.

What this cannot answer: Pooled active-group comparison and broader eligibility differ from the pivotal trials.

Harms reported: Full adverse-event rates not extracted.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 397 — Randomized across placebo and three active groups; reported efficacy comparison pools two active groups

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Clayton AH, Althof SE, Kingsberg S, DeRogatis LR, Kroll R, Goldstein I, Kaminetsky J, Spana C, Lucas J, Jordan R, Portman DJ. Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial. Women's health (London, England). 2016;12(3):325–337. doi:10.2217/whe-2016-0018. PMID:27181790.

Source type: Journal paper

Study/cohort key: NCT01382719

DOI: 10.2217/whe-2016-0018

PMID: 27181790

Registration: NCT01382719

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did desire and distress improve, and did satisfying-event counts increase?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Clinical trial subcutaneous bremelanotide formulation

Who or what was studied: Premenopausal women with acquired, generalized HSDD; selected eligibility and medication exclusions

Compared with: Placebo

Follow-up: 24 weeks

What changed: Integrated placebo-adjusted changes +0.35 on desire and -0.33 on distress, both P<0.001. Prespecified satisfying-event count comparison was null, integrated P=0.630.

What the result means: Symptom scores improved while the specified event-count endpoint did not.

What this cannot answer: Two cohorts in one publication; post hoc satisfying-event proportions do not replace the null count endpoint.

Harms reported: Nausea occurred in 40.0% versus 1.3% across the two trials. Withdrawal for any reason was 41.9% versus 16.0% in study 301 and 43.8% versus 28.4% in study 302. Flushing and headache were more frequent.

Funding: Palatin Technologies and AMAG Pharmaceuticals

Source access: Original indexed PMC methods/results and metadata

Route or setting: Not extracted from the accessible source

Sample: 1267 — Combined randomization in two trials; 1,247 safety and 1,202 modified-intention-to-treat efficacy participants

Citation: Kingsberg SA, Clayton AH, Portman D, Williams LA, Krop J, Jordan R, Lucas J, Simon JA. Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Obstetrics and gynecology. 2019;134(5):899–908. doi:10.1097/AOG.0000000000003500. PMID:31599840.

Source type: Journal paper

Study/cohort key: RECONNECT-core

Analysis: Primary endpoints used last observation carried forward in the modified intention-to-treat population; missing outcomes and unequal withdrawal matter.

DOI: 10.1097/AOG.0000000000003500

PMID: 31599840

Registration: NCT02333071, NCT02338960

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: What happened during longer selected follow-up?

How the study was done: Open-label extension, no continuing placebo comparison

What was tested: Trial bremelanotide, including former placebo participants switching to active treatment

Who or what was studied: Selected premenopausal HSDD core-trial completers

Compared with: Baseline and prior core-trial assignment

Follow-up: 52 additional weeks after the core study

What changed: Reported desire/distress improvements persisted in continuing participants; only about 40% completed the extension.

What the result means: Longer observations came from a selected group with substantial attrition.

What this cannot answer: Same underlying trial cohorts, open label and highly selective completion; not new controlled efficacy evidence.

Harms reported: Adverse events contributed to discontinuation; common events included nausea, flushing and headache.

Funding: Palatin Technologies and AMAG Pharmaceuticals

Source access: Original indexed journal results and PubMed metadata

Route or setting: Not extracted from the accessible source

Sample: 684 — 856 core completers, 684 opted into extension and 272 completed the full extension

Citation: Simon JA, Kingsberg SA, Portman D, Williams LA, Krop J, Jordan R, Lucas J, Clayton AH. Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder. Obstetrics and gynecology. 2019;134(5):909–917. doi:10.1097/AOG.0000000000003514. PMID:31599847.

Source type: Journal paper

Study/cohort key: RECONNECT-core

DOI: 10.1097/AOG.0000000000003514

PMID: 31599847

Registration: NCT02333071, NCT02338960

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could kisspeptin-10 stimulate LH and alter pulse frequency?

How the study was done: Small controlled physiological dose-response and infusion experiments

What was tested: Synthetic kisspeptin-10 for monitored intravenous physiological experiments

Who or what was studied: Healthy male volunteers

Compared with: A control liquid without kisspeptin, plus hormone measurements before peptide administration

Follow-up: Acute sampling; selected infusion experiments up to 22.5 hours

What changed: Selected infusion experiment increased mean LH from 5.2 to 14.1 IU/L and pulse frequency from 0.7 to 1.0 pulses/hour in four men.

What the result means: The peptide changed short-term reproductive-hormone physiology.

What this cannot answer: Subgroups are not pooled into a unique sample denominator; no long-term fertility or symptom outcome.

Harms reported: Complete adverse-event data not extracted.

Source access: Indexed original PubMed abstract and PMC physiological results

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Funding, Sample size. The original source may report these details.

Citation: George JT, Veldhuis JD, Roseweir AK, Newton CL, Faccenda E, Millar RP, Anderson RA. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. The Journal of clinical endocrinology and metabolism. 2011;96(8):E1228–E1236. doi:10.1210/jc.2011-0089. PMID:21632807.

Source type: Journal paper

Study/cohort key: original-21632807

DOI: 10.1210/jc.2011-0089

PMID: 21632807

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did the shorter form stimulate gonadotropins in all tested settings?

How the study was done: Controlled small physiological experiments across forms and routes

What was tested: Synthetic kisspeptin-10; an intravenous kisspeptin-54 comparator in one female experiment

Who or what was studied: Healthy men and women studied in follicular or preovulatory menstrual phases

Compared with: Saline, menstrual phase and kisspeptin-54 in the specified experiment

Follow-up: Acute sampling windows of about 3–4 hours

What changed: Kisspeptin-10 increased LH/FSH in men and preovulatory women but not follicular-phase women under tested conditions; the KP54 comparison retained its distinct response.

What the result means: A shared receptor-binding region did not produce identical responses across hormonal contexts.

What this cannot answer: Recruited total is not each experiment's n; route- and phase-specific null findings are not universal nonresponse.

Harms reported: Heart rate, blood pressure and symptoms monitored; detailed harm outcomes not extracted.

Source access: Original indexed PMC abstract and participant/methods sections

Route or setting: Not extracted from the accessible source

Sample: 46 — Recruited 35 women and 11 men; experiments used 4–5 per subgroup, with repeated participants

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Jayasena CN, Nijher GM, Comninos AN, Abbara A, Januszewki A, Vaal ML, Sriskandarajah L, Murphy KG, Farzad Z, Ghatei MA, Bloom SR, Dhillo WS. The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans. The Journal of clinical endocrinology and metabolism. 2011;96(12):E1963–E1972. doi:10.1210/jc.2011-1408. PMID:21976724.

Source type: Journal paper

Study/cohort key: original-21976724

DOI: 10.1210/jc.2011-1408

PMID: 21976724

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could the upstream axis still respond in men with low testosterone?

How the study was done: Small proof-of-concept endocrine experiments; within-participant sampling

What was tested: Synthetic kisspeptin-10 in monitored intravenous physiological experiments

Who or what was studied: Men with type 2 diabetes and mild biochemical hypogonadism, plus age-matched healthy men

Compared with: Hormone measurements before peptide administration, a control liquid without kisspeptin, and healthy men

Follow-up: Acute experiment plus 11-hour infusion sampling

What changed: Acute LH increased in both groups. In four men with diabetes, testosterone rose from 8.5 to 11.4 nmol/L and LH pulse frequency from 0.6 to 0.9/hour.

What the result means: The reproductive axis responded during brief monitored exposure.

What this cannot answer: No sustained fertility, sexual-symptom or long-term treatment outcome; five diabetes participants are not twelve affected patients.

Harms reported: Detailed adverse-event data not extracted.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 12 — Five men with diabetes and seven healthy controls; infusion experiment used four diabetes participants

Not yet extracted for this card: Funding. The original source may report these details.

Citation: George JT, Veldhuis JD, Tena-Sempere M, Millar RP, Anderson RA. Exploring the pathophysiology of hypogonadism in men with type 2 diabetes: kisspeptin-10 stimulates serum testosterone and LH secretion in men with type 2 diabetes and mild biochemical hypogonadism. Clinical endocrinology. 2013;79(1):100–104. doi:10.1111/cen.12103. PMID:23153270.

Source type: Journal paper

Study/cohort key: original-23153270

DOI: 10.1111/cen.12103

PMID: 23153270

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could downstream kisspeptin signaling restore LH pulses?

How the study was done: Each participant had a sampling day with control liquid without kisspeptin, followed by a day with kisspeptin-10

What was tested: GMP synthetic kisspeptin-10 in intravenous physiology study

Who or what was studied: Reproductive-age patients with congenital hypogonadotropic hypogonadism from neurokinin B signaling defects

Compared with: The same participants on the preceding day, when they received control liquid without kisspeptin

Follow-up: Two consecutive 12-hour sampling days

What changed: LH pulses were restored in previously nonpulsatile participants; mean pulse frequency increased from about 0.1 to 0.5/hour, with sex-steroid/inhibin responses.

What the result means: A functioning downstream pathway could be stimulated in this specific genetic condition.

What this cannot answer: Four patients and surrogate endocrine outcomes; does not test KISS1R deficiency or demonstrate restored fertility.

Harms reported: No adverse events related to kisspeptin or the control liquid without kisspeptin were reported.

Source access: Original PMC methods, individual-patient table and results

Route or setting: Not extracted from the accessible source

Sample: 4 — Three men and one woman with biallelic TAC3 or TACR3 mutations

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Young J, George JT, Tello JA, Francou B, Bouligand J, Guiochon-Mantel A, Brailly-Tabard S, Anderson RA, Millar RP. Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications. Neuroendocrinology. 2013;97(2):193–202. doi:10.1159/000336376. PMID:22377698.

Source type: Journal paper

Study/cohort key: original-22377698

DOI: 10.1159/000336376

PMID: 22377698

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did repeated exposure sustain its initial hormone effect?

How the study was done: Randomized, double-blind, parallel physiological trial

What was tested: Synthetic kisspeptin-54 in monitored subcutaneous research formulation

Who or what was studied: Women with hypothalamic amenorrhea

Compared with: Saline

Follow-up: Two weeks

What changed: Initial LH and FSH increases diminished with continued exposure, demonstrating tachyphylaxis.

What the result means: An initial strong hormone response did not remain strong throughout repeated stimulation.

What this cannot answer: Small endocrine study; not long-term fertility efficacy or a general prediction for every menstrual context.

Harms reported: Complete clinical safety data not extracted.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 10 — Randomized: five active and five saline

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Jayasena CN, Nijher GM, Chaudhri OB, Murphy KG, Ranger A, Lim A, Patel D, Mehta A, Todd C, Ramachandran R, Salem V, Stamp GW, Donaldson M, Ghatei MA, Bloom SR, Dhillo WS. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. The Journal of clinical endocrinology and metabolism. 2009;94(11):4315–4323. doi:10.1210/jc.2009-0406. PMID:19820030.

Source type: Journal paper

Study/cohort key: original-19820030

DOI: 10.1210/jc.2009-0406

PMID: 19820030

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could kisspeptin-54 trigger mature oocyte retrieval?

How the study was done: Adaptive dose-finding clinical proof of concept; no established-trigger efficacy comparator

What was tested: GMP kisspeptin-54 as final oocyte-maturation trigger within IVF care

Who or what was studied: Women undergoing specialist IVF with prior ovarian stimulation at a single UK centre

Compared with: Different assigned peptide groups, not an established trigger

Follow-up: One IVF cycle; pregnancy assessments after embryo transfer

What changed: Mature oocytes obtained in 51/53 women; fertilized embryos and pregnancies followed in a subset.

What the result means: The research demonstrated feasibility of a specific step within IVF.

What this cannot answer: Not a head-to-head live-birth superiority trial; egg, embryo-transfer and pregnancy denominators differ.

Harms reported: Complete adverse-event extraction limited; specialist monitoring and cancellation decisions formed part of the study context.

Funding: MRC, Wellcome Trust and NIHR

Source access: Indexed original PMC results and JCI original PDF; JCI HTML extract included an unrelated vignette

Route or setting: Not extracted from the accessible source

Sample: 53 — Treated women; 49 proceeded to embryo transfer

Citation: Jayasena CN, Abbara A, Comninos AN, Nijher GMK, Christopoulos G, Narayanaswamy S, Izzi-Engbeaya C, Sridharan M, Mason AJ, Warwick J, Ashby D, Ghatei MA, Bloom SR, Carby A, Trew GH, Dhillo WS. Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. Journal of Clinical Investigation. 2014;124(8):3667–3677. DOI: 10.1172/JCI75730.

Source type: Journal paper

Study/cohort key: doi-jci75730

DOI: 10.1172/jci75730

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could mature oocytes be obtained without frequent clinically significant OHSS in this cohort?

How the study was done: Open-label randomized phase 2 dose-finding trial

What was tested: GMP kisspeptin-54 trigger within specialist IVF care

Who or what was studied: Women at high risk of OHSS undergoing IVF at one UK centre

Compared with: Other assigned kisspeptin-54 groups; no standard-trigger control

Follow-up: One IVF cycle with early/late OHSS and pregnancy follow-up

What changed: Mature oocytes obtained in 57/60; no moderate, severe or critical OHSS was observed.

What the result means: A high-risk cohort showed maturation with a limited number of observed complications.

What this cannot answer: Sixty participants cannot exclude uncommon OHSS; no standard-trigger comparison establishing relative safety.

Harms reported: Three mild early OHSS cases and one mild late OHSS case were reported.

Source access: Indexed original PMC abstract/results

Route or setting: Not extracted from the accessible source

Sample: 60 — Treated women across four assigned groups

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Abbara A, Jayasena CN, Christopoulos G, Narayanaswamy S, Izzi-Engbeaya C, Nijher GMK, Comninos AN, Peters D, Buckley A, Ratnasabapathy R, Prague JK, Salim R, Lavery SA, Bloom SR, Szigeti M, Ashby DA, Trew GH, Dhillo WS. Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy. Journal of Clinical Endocrinology and Metabolism. 2015;100(9):3322–3331. DOI: 10.1210/jc.2015-2332.

Source type: Journal paper

Study/cohort key: doi-jc2015-2332

DOI: 10.1210/jc.2015-2332

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did additional exposure improve mature-oocyte yield?

How the study was done: Randomized, blinded, placebo-controlled phase 2 comparison after shared initial trigger

What was tested: Kisspeptin-54 additional trigger exposure within specialist IVF care

Who or what was studied: Women aged 18–34 at high OHSS risk, at a single UK IVF centre

Compared with: Saline after initial kisspeptin-54 trigger

Follow-up: One IVF cycle, OHSS and pregnancy follow-up

What changed: At least 60% oocyte yield in 22/31 (71.0%) with additional kisspeptin-54 versus 14/31 (45.2%) with saline; absolute difference 25.8 percentage points (95% CI 2.1–49.5), P=0.042.

What the result means: More women reached the specified egg-yield threshold with additional exposure.

What this cannot answer: Not peptide versus no peptide, nor powered proof of live-birth superiority or OHSS elimination.

Harms reported: One moderate early OHSS in the saline/additional-placebo group and one mild late OHSS in the active-additional group; one unexplained second-trimester miscarriage in the former group.

Source access: Indexed original PMC abstract, results and adverse-event sections

Route or setting: Not extracted from the accessible source

Sample: 62 — Randomized 31 additional kisspeptin-54 and 31 saline; all received initial kisspeptin trigger

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Abbara A, Clarke S, Islam R, Prague JK, Comninos AN, Narayanaswamy S, Papadopoulou D, Roberts R, Izzi-Engbeaya C, Ratnasabapathy R, Nesbitt A, Vimalesvaran S, Salim R, Lavery SA, Bloom SR, Huson L, Trew GH, Dhillo WS. A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial. Human reproduction (Oxford, England). 2017;32(9):1915–1924. doi:10.1093/humrep/dex253. PMID:28854728.

Source type: Journal paper

Study/cohort key: original-28854728

DOI: 10.1093/humrep/dex253

PMID: 28854728

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did the peptide alter brain responses to sexual and attraction stimuli?

How the study was done: Double-masked, placebo-controlled two-way crossover

What was tested: Synthetic kisspeptin-54 intravenous research formulation

Who or what was studied: Premenopausal women with hypoactive sexual desire disorder in a UK university study

Compared with: Placebo

Follow-up: 75-minute experimental exposure at each visit

What changed: Task-related activation/deactivation patterns differed from placebo; some responses correlated with baseline distress and sexual-aversion measures.

What the result means: Brain processing changed during a brief laboratory experiment.

What this cannot answer: Acute imaging and psychometric endpoints, selected completers; not durable desire-disorder treatment efficacy.

Harms reported: Complete adverse-event data not extracted.

Source access: Indexed original PMC abstract/methods and PubMed metadata

Route or setting: Not extracted from the accessible source

Sample: 40 — Randomized; 32 completed both crossover visits and were analyzed

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Thurston L, Hunjan T, Ertl N, Wall MB, Mills EG, Suladze S, Patel B, Alexander EC, Muzi B, Bassett PA, Rabiner EA, Bech P, Goldmeier D, Abbara A, Comninos AN, Dhillo WS. Effects of Kisspeptin Administration in Women With Hypoactive Sexual Desire Disorder: A Randomized Clinical Trial. JAMA network open. 2022;5(10):e2236131. doi:10.1001/jamanetworkopen.2022.36131. PMID:36287566.

Source type: Journal paper

Study/cohort key: original-36287566

DOI: 10.1001/jamanetworkopen.2022.36131

PMID: 36287566

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did brain and physiological responses to sexual stimuli change?

How the study was done: Randomized, double-blind, placebo-controlled crossover

What was tested: Synthetic kisspeptin-54 intravenous research formulation

Who or what was studied: Men with hypoactive sexual desire disorder in a UK university study

Compared with: Placebo

Follow-up: Acute laboratory exposure at two visits

What changed: Kisspeptin modulated task-related brain activity and increased penile tumescence during sexual stimuli compared with placebo.

What the result means: A short experiment detected neural and physiological responses.

What this cannot answer: Physiological response during stimuli does not establish months-long symptom benefit or repeat-use safety.

Harms reported: Complete adverse-event results not extracted.

Funding: MRC and NIHR

Source access: Indexed original PubMed abstract and PMC methods/funding

Route or setting: Not extracted from the accessible source

Sample: 37 — Randomized; 32 completed both crossover visits

Citation: Mills EG, Ertl N, Wall MB, Thurston L, Yang L, Suladze S, Hunjan T, Phylactou M, Patel B, Muzi B, Ettehad D, Bassett PA, Howard J, Rabiner EA, Bech P, Abbara A, Goldmeier D, Comninos AN, Dhillo WS. Effects of Kisspeptin on Sexual Brain Processing and Penile Tumescence in Men With Hypoactive Sexual Desire Disorder: A Randomized Clinical Trial. JAMA network open. 2023;6(2):e2254313. doi:10.1001/jamanetworkopen.2022.54313. PMID:36735255.

Source type: Journal paper

Study/cohort key: original-36735255

DOI: 10.1001/jamanetworkopen.2022.54313

PMID: 36735255

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did specified cumulative pain-free sunlight exposure improve?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Controlled-release clinical afamelanotide implant

Who or what was studied: Adults with biochemically confirmed EPP, excluding clinically significant organ dysfunction and specified skin disease

Compared with: Placebo

Follow-up: 180 days US; 270 days EU

What changed: Participants with afamelanotide recorded more pain-free time in sunlight than those with placebo: US medians were 69.4 versus 40.8 hours (P=0.04), and EU medians were 6.0 versus 0.8 hours (P=0.005). Phototoxic reaction counts were lower with afamelanotide in the EU trial. The US counts were 46 versus 43, which did not establish a difference (P=0.60).

What the result means: Both trials found more pain-free time in sunlight with afamelanotide. A reduction in phototoxic reaction counts was established in the EU trial but remained uncertain in the US trial.

What this cannot answer: Two cohorts with different diary definitions and observation periods; pain-free hours are not directly interchangeable or proof of correcting EPP.

Harms reported: Mostly mild events; serious events were not judged related. Pigmentation and implant-site changes occurred.

Funding: Clinuvel Pharmaceuticals and others

Source access: Original indexed journal/PMC results; direct PubMed open returned 429

Route or setting: Not extracted from the accessible source

Sample: 168 — Two separate randomized cohorts: 94 US and 74 EU; 167 received implants

Citation: Langendonk JG, Balwani M, Anderson KE, Bonkovsky HL, Anstey AV, Bissell DM, Bloomer J, Edwards C, Neumann NJ, Parker C, Phillips JD, Lim HW, Hamzavi I, Deybach JC, Kauppinen R, Rhodes LE, Frank J, Murphy GM, Karstens FPJ, Sijbrands EJG, de Rooij FWM, Lebwohl M, Naik H, Goding CR, Wilson JHP, Desnick RJ. Afamelanotide for Erythropoietic Protoporphyria. The New England journal of medicine. 2015;373(1):48–59. doi:10.1056/NEJMoa1411481. PMID:26132941.

Source type: Journal paper

Study/cohort key: EPP-CUV039-and-CUV029

DOI: 10.1056/NEJMoa1411481

PMID: 26132941

Registration: NCT01605136, NCT00979745

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: What was the longer-term treatment experience?

How the study was done: Longitudinal observational study

What was tested: Clinical afamelanotide implants in compassionate/special-access care

Who or what was studied: EPP patients in Rome and Zurich

Compared with: Pretreatment condition-specific quality of life; no randomized concurrent comparator

Follow-up: Up to eight years, 2006–2014 observations

What changed: EPP-specific quality-of-life scores rose from about 31% to 74% of the scale maximum and remained higher during observed follow-up.

What the result means: Patients reported better quality of life over prolonged treatment experience.

What this cannot answer: Observational and selected treatment access; cannot isolate all causal effects or exclude uncommon harms.

Harms reported: Attributed events were mainly minor, including nausea; other reasons such as pregnancy or financial constraints contributed to discontinuation.

Funding: None reported in acquired original journal funding statement

Source access: Original journal summary/funding and full PubMed abstract

Route or setting: Not extracted from the accessible source

Sample: 115 — Ambulatory treated patients, with 1,023 implants over differing follow-up durations

Citation: Biolcati G, Marchesini E, Sorge F, Barbieri L, Schneider-Yin X, Minder EI. Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria. The British journal of dermatology. 2015;172(6):1601–1612. doi:10.1111/bjd.13598. PMID:25494545.

Source type: Journal paper

Study/cohort key: original-25494545

DOI: 10.1111/bjd.13598

PMID: 25494545

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: What did longer routine-care follow-up report?

How the study was done: Multicentre observational postauthorization registry analysis

What was tested: Clinical afamelanotide implant in approved-product care

Who or what was studied: Adults with EPP enrolled at four German specialist centres

Compared with: Matched pretreatment quality-of-life assessments; no untreated comparator in this analysis

Follow-up: Enrollment and follow-up from November 2016 to June 2021; variable individual duration

What changed: Condition-specific quality of life improved; 182/200 (91.0%) continued treatment at cutoff.

What the result means: The registry adds experience beyond short trials, with varying follow-up and paired samples.

What this cannot answer: Event occurrence and investigator attribution differ; no randomized comparator or uniform six-year follow-up for all 200.

Harms reported: 174/200 had any treatment-emergent event; 108/200 had an event judged related. Serious events 36/200; serious related events 4/200.

Funding: Complete funding statement not extracted; company coauthors disclosed

Source access: Indexed original PMC full-text methods, registry dates and safety table

Route or setting: Not extracted from the accessible source

Sample: 200 — Treated enrolled registry participants; outcome-specific paired subsets vary

Citation: Homey B, Schelonke K, Schlegel CM, Bruch-Gerharz D, Weller K, Kiefer L, Stölzel U, Staubach-Renz P, Wegner J, Keller-Melchior R, Walker G, Bochno M, Bilbao P. German Cohort Observational Study to Investigate the Short- and Long-Term Safety and Clinical Effectiveness of Afamelanotide 16 mg (SCENESSE) in Patients With Erythropoietic Protoporphyria (EPP). Photodermatology, photoimmunology & photomedicine. 2025;41(2):e13012. doi:10.1111/phpp.13012. PMID:40082741.

Source type: Journal paper

Study/cohort key: EUPAS13004

DOI: 10.1111/phpp.13012

PMID: 40082741

Registration: EUPAS13004

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did adding the implant improve repigmentation?

How the study was done: Randomized multicentre add-on trial

What was tested: Afamelanotide implant added to narrowband UV-B phototherapy

Who or what was studied: Adults with nonsegmental vitiligo affecting 15–50% of body surface, Fitzpatrick skin types III–VI

Compared with: Narrowband UV-B alone

Follow-up: Reported repigmentation endpoint at day 168

What changed: Repigmentation 48.64% (95% CI 39.49–57.80) versus 33.26% (24.18–42.33) at day 168. Early skin-type III subgroup comparisons were not significant.

What the result means: The combined strategy improved average repigmentation, with population and subgroup limits.

What this cannot answer: Combination trial, not peptide monotherapy; restricted disease and skin-type population.

Harms reported: Erythema in both groups; minor infections and nausea in the combination group.

Source access: Indexed original JAMA abstract/results; direct PubMed open returned incomplete HTML

Route or setting: Not extracted from the accessible source

Sample: 55 — Randomized: 28 combination and 27 narrowband UV-B alone

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Lim HW, Grimes PE, Agbai O, Hamzavi I, Henderson M, Haddican M, Linkner RV, Lebwohl M. Afamelanotide and narrowband UV-B phototherapy for the treatment of vitiligo: a randomized multicenter trial. JAMA dermatology. 2015;151(1):42–50. doi:10.1001/jamadermatol.2014.1875. PMID:25230094.

Source type: Journal paper

Study/cohort key: NCT01430195

DOI: 10.1001/jamadermatol.2014.1875

PMID: 25230094

Registration: NCT01430195

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did route affect systemic exposure and pigmentation?

How the study was done: Randomized route-comparison crossover pharmacokinetic experiment

What was tested: Purified melanotan-I/NDP-alpha-MSH peptide; not the controlled-release Scenesse implant

Who or what was studied: Healthy male volunteers

Compared with: Intravenous, subcutaneous and oral research formulations

Follow-up: Two-week exposure period with pigmentation observations to three weeks afterward

What changed: No detectable drug levels after oral exposure; intravenous and subcutaneous formulations produced pigmentation changes.

What the result means: The same peptide had different measured exposure across tested formulations.

What this cannot answer: Three-person formulation study; cannot inherit the clinical implant's full benefit and safety record or establish efficacy of another oral formulation.

Harms reported: Occasional gastrointestinal upset and facial flushing.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 3 — Three healthy male volunteers in randomized crossover

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Ugwu SO, Blanchard J, Dorr RT, Levine N, Brooks C, Hadley ME, Aickin M, Hruby VJ. Skin pigmentation and pharmacokinetics of melanotan-I in humans. Biopharmaceutics & drug disposition. 1997;18(3):259–269. doi:10.1002/(sici)1099-081x(199704)18:3<259::aid-bdd20>3.0.co;2-x. PMID:9113347.

Source type: Journal paper

Study/cohort key: original-9113347

DOI: 10.1002/(sici)1099-081x(199704)18:3<259::aid-bdd20>3.0.co;2-x

PMID: 9113347

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Was pigmentation activity observed in humans?

How the study was done: Single-blind alternating peptide/placebo phase 1 pilot

What was tested: Defined cyclic Melanotan II peptide in subcutaneous research formulation

Who or what was studied: Healthy adult men

Compared with: Saline

Follow-up: Two weeks with pigmentation assessment after exposure

What changed: Two participants showed increased pigmentation after the experiment; spontaneous erections and other systemic effects were also reported.

What the result means: The peptide produced effects in a very small human pilot.

What this cannot answer: Three people cannot characterize efficacy consistency or uncommon/long-term harms.

Harms reported: Nausea; one participant had grade II somnolence/fatigue at a studied higher exposure.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 3 — Three healthy male volunteers

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Dorr RT, Lines R, Levine N, Brooks C, Xiang L, Hruby VJ, Hadley ME. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life sciences. 1996;58(20):1777–1784. doi:10.1016/0024-3205(96)00160-9. PMID:8637402.

Source type: Journal paper

Study/cohort key: original-8637402

DOI: 10.1016/0024-3205(96)00160-9

PMID: 8637402

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did measured penile rigidity differ from placebo?

How the study was done: Double-blind, placebo-controlled crossover

What was tested: Defined Melanotan II subcutaneous research formulation

Who or what was studied: Men with erectile dysfunction and no identified organic cause

Compared with: Placebo

Follow-up: Six-hour observation per experimental exposure

What changed: Clinically apparent erections in 8/10; mean duration of tip rigidity over 80% was 38.0 versus 3.0 minutes, P=0.0045.

What the result means: The small experiment detected an acute erectile response.

What this cannot answer: Acute physiological endpoint, no long-term satisfaction or repeated-use safety. DOI not verified rather than copied from conflicting secondary metadata.

Harms reported: Nausea, yawning/stretching and reduced appetite were more frequent.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 10 — Ten men in crossover experiment

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Wessells H, Fuciarelli K, Hansen J, Hadley ME, Hruby VJ, Dorr R, Levine N. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. The Journal of urology. 1998;160(2):389–393. PMID:9679884.

Source type: Journal paper

Study/cohort key: original-9679884

PMID: 9679884

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did an acute response also occur in men with organic risk factors?

How the study was done: Double-blind, placebo-controlled crossover

What was tested: Defined Melanotan II subcutaneous research formulation

Who or what was studied: Men with erectile dysfunction and organic risk factors

Compared with: Placebo

Follow-up: Six-hour observation per experimental exposure

What changed: Mean duration of tip rigidity over 80% was 45.3 versus 1.9 minutes, P=0.047.

What the result means: The response was observed in another small clinical setting.

What this cannot answer: Participants and exposure counts are different denominators; not long-term efficacy or the same cohort as the earlier psychogenic study.

Harms reported: Nausea and other systemic effects require exposure-specific interpretation; complete table not extracted.

Source access: Indexed original PubMed abstract; direct PubMed open returned incomplete HTML

Route or setting: Not extracted from the accessible source

Sample: 10 — Ten crossover participants; some outcome counts refer to 19 active and 21 placebo exposures

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Wessells H, Gralnek D, Dorr R, Hruby VJ, Hadley ME, Levine N. Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction. Urology. 2000;56(4):641–646. doi:10.1016/s0090-4295(00)00680-4. PMID:11018622.

Source type: Journal paper

Study/cohort key: original-11018622

DOI: 10.1016/s0090-4295(00)00680-4

PMID: 11018622

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: What serious toxicity was reported?

How the study was done: Clinical poisoning case report with material analysis

What was tested: Patient's material identified as Melanotan II by mass spectrometry against reference standard

Who or what was studied: A 39-year-old man after use of internet-purchased material

Compared with: None

Follow-up: Acute presentation with three-day intensive-care course

What changed: Autonomic symptoms, rhabdomyolysis and kidney dysfunction occurred; creatine kinase peaked at 17,773 IU/L.

What the result means: A reported case documented severe illness with analytically identified material.

What this cannot answer: No incidence denominator; unusual exposure and potential clinical contributors mean the case cannot define typical risk.

Harms reported: Marked tachycardia, muscle breakdown and impaired kidney function.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Sample: 1 — Single patient case report

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Nelson ME, Bryant SM, Aks SE. Melanotan II injection resulting in systemic toxicity and rhabdomyolysis. Clinical toxicology (Philadelphia, Pa.). 2012;50(10):1169–1173. doi:10.3109/15563650.2012.740637. PMID:23121206.

Source type: Journal paper

Study/cohort key: original-23121206

DOI: 10.3109/15563650.2012.740637

PMID: 23121206

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did measured contents agree with the commercial declarations?

How the study was done: Validated laboratory identity, content and impurity analysis

What was tested: Vials sold as Melanotan II, compared with analytical reference

Who or what was studied: Commercial samples purchased from three online shops, no patients

Compared with: Reference material and declared contents

Follow-up: Laboratory sample analysis; not a clinical exposure study

What changed: Measured peptide amounts varied below the declared amount; samples from two shops had unknown impurities of 4.1–5.9%.

What the result means: A product label did not guarantee its measured contents.

What this cannot answer: Historical selected samples do not measure the contents of another vendor or all contemporary products.

Harms reported: Clinical toxicity not tested; impurity identity not established.

Source access: Indexed original PubMed abstract; complete tables and supplements not extracted

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Funding, Sample size. The original source may report these details.

Citation: Breindahl T, Evans-Brown M, Hindersson P, McVeigh J, Bellis M, Stensballe A, Kimergård A. Identification and characterization by LC-UV-MS/MS of melanotan II skin-tanning products sold illegally on the Internet. Drug testing and analysis. 2015;7(2):164–172. doi:10.1002/dta.1655. PMID:24771717.

Source type: Journal paper

Study/cohort key: original-24771717

DOI: 10.1002/dta.1655

PMID: 24771717

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did money transfers in a trust game change?

How the study was done: Randomized, blinded, placebo-controlled task experiment

What was tested: Syntocinon oxytocin nasal spray in controlled laboratory experiment

Who or what was studied: Healthy male university students

Compared with: Placebo

Follow-up: Single experimental session

What changed: Mean investor transfers were 9.6 versus 8.1 monetary units; maximal trust in 13/29 versus 6/29. A nonsocial risk task did not show the same difference.

What the result means: A particular laboratory social-risk task changed, not every measure of willingness to take risks.

What this cannot answer: Task-specific male student experiment; investor subgroup is not all 194 participants or an enduring relationship outcome.

Harms reported: Complete adverse-event data not extracted.

Funding: MacArthur Foundation, Cogito Foundation and Swiss National Science Foundation

Source access: Original author-university PDF, participant methods and Table 1; indexed journal abstract

Route or setting: Not extracted from the accessible source

Sample: 194 — Initial participants: 128 trust and 66 risk experiment; 16 excluded. Trust investor comparison 29 per group

Citation: Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature. 2005;435(7042):673–676. doi:10.1038/nature03701. PMID:15931222.

Source type: Journal paper

Study/cohort key: original-15931222

DOI: 10.1038/nature03701

PMID: 15931222

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Was the original trust effect reproduced under minimal social contact?

How the study was done: Registered-report double-blind, placebo-controlled replication

What was tested: Intranasal oxytocin in registered replication

Who or what was studied: Human participants in controlled trust-game experiments; detailed demographics not extracted

Compared with: Placebo

Follow-up: Acute task sessions; precise duration not extracted

What changed: No oxytocin effect in the minimal-social-contact condition. A post hoc low-disposition-to-trust result in the no-contact condition required confirmation.

What the result means: The planned replication did not support a general trust increase in the key tested condition.

What this cannot answer: Total n and detailed harm tables unavailable in acquired primary preview; exploratory subgroup does not replace the main null finding.

Source access: Original journal/PubMed abstract; full journal article behind subscription preview

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Harms reported, Funding, Sample size. The original source may report these details.

Citation: Declerck CH, Boone C, Pauwels L, Vogt B, Fehr E. A registered replication study on oxytocin and trust. Nature human behaviour. 2020;4(6):646–655. doi:10.1038/s41562-020-0878-x. PMID:32514040.

Source type: Journal paper

Study/cohort key: original-32514040

DOI: 10.1038/s41562-020-0878-x

PMID: 32514040

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did social scores improve when baseline neuropeptide measures were included?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Syntocinon oxytocin nasal formulation and matched placebo

Who or what was studied: Children aged 6–12 with autism spectrum disorder

Compared with: Placebo

Follow-up: Four weeks

What changed: Social Responsiveness Scale outcome favored oxytocin in the model incorporating baseline neuropeptide measures; lower baseline oxytocin also predicted improvement, without a significant treatment-by-baseline-oxytocin interaction.

What the result means: The small trial's reported benefit depended on the statistical model and did not validate a general treatment-selection blood test.

What this cannot answer: Small completer cohort and model dependence; not confirmed sustained benefit or a validated responder rule.

Harms reported: Adverse-event rates did not differ; no significant treatment-attributed changes in height, weight or vital signs.

Funding: Mosbacher/Yani Calmidis funds, Stanford support, Autism Speaks and NIMH support described in paper

Source access: Original indexed PMC results, participant table and model table

Route or setting: Not extracted from the accessible source

Sample: 32 — Completed trial: 14 oxytocin and 18 placebo

Citation: Parker KJ, Oztan O, Libove RA, Sumiyoshi RD, Jackson LP, Karhson DS, Summers JE, Hinman KE, Motonaga KS, Phillips JM, Carson DS, Garner JP, Hardan AY. Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(30):8119–8124. doi:10.1073/pnas.1705521114. PMID:28696286.

Source type: Journal paper

Study/cohort key: original-28696286

DOI: 10.1073/pnas.1705521114

PMID: 28696286

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did oxytocin add improvement in social functioning?

How the study was done: Randomized, double-blind, placebo-controlled

What was tested: Trial intranasal oxytocin formulation

Who or what was studied: Children and adolescents aged 3–17 with autism spectrum disorder

Compared with: Placebo

Follow-up: 24 weeks

What changed: Primary social-withdrawal score changed -3.7 versus -3.5; adjusted difference -0.2 (95% CI -1.5 to 1.0), P=0.61. Secondary outcomes generally did not differ.

What the result means: Both groups improved similarly, with no demonstrated additional effect of the peptide.

What this cannot answer: Specific developmental population/formulation; does not negate peripheral obstetric physiology or prove no effect in every possible context.

Harms reported: Adverse-event incidence and severity were similar between groups.

Funding: NIH investigator-initiated trial; no commercial involvement

Source access: Original indexed NEJM abstract and PMC methods

Route or setting: Not extracted from the accessible source

Sample: 290 — Randomized/treated: 146 active and 144 placebo; primary modified-ITT analysis 139 and 138

Citation: Sikich L, Kolevzon A, King BH, McDougle CJ, Sanders KB, Kim SJ, Spanos M, Chandrasekhar T, Trelles MDP, Rockhill CM, Palumbo ML, Witters Cundiff A, Montgomery A, Siper P, Minjarez M, Nowinski LA, Marler S, Shuffrey LC, Alderman C, Weissman J, Zappone B, Mullett JE, Crosson H, Hong N, Siecinski SK, Giamberardino SN, Luo S, She L, Bhapkar M, Dean R, Scheer A, Johnson JL, Gregory SG, Veenstra-VanderWeele J. Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder. The New England journal of medicine. 2021;385(16):1462–1473. doi:10.1056/NEJMoa2103583. PMID:34644471.

Source type: Journal paper

Study/cohort key: original-34644471

DOI: 10.1056/NEJMoa2103583

PMID: 34644471

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did nasal methods and peripheral exposure have the same brain-perfusion effects?

How the study was done: Double-blind, placebo-controlled, triple-dummy crossover

What was tested: Synthetic oxytocin via standard nasal spray, nasal nebulizer or intravenous research formulation

Who or what was studied: Healthy adult men

Compared with: Placebo and alternative oxytocin delivery routes

Follow-up: Four sessions with imaging through two hours after experimental exposure

What changed: Some amygdala/anterior-cingulate perfusion changes were shared with intravenous exposure and associated with plasma changes; other nasal effects differed and were not accounted for by plasma measures.

What the result means: The route and peripheral exposure influenced brain-imaging findings in different ways.

What this cannot answer: Small imaging study, not clinical efficacy. A 2022 correction fixed overestimated plasma AUC calculations; authors reported unchanged result patterns/conclusions. Correction notice: Corrects systematically overestimated plasma AUC calculations; the authors report unchanged patterns and conclusions after reanalysis. See https://www.nature.com/articles/s41467-022-29419-w

Harms reported: Complete adverse-event table not extracted.

Source access: Original journal methods/results; 2022 author correction read

Route or setting: Not extracted from the accessible source

Sample: 17 — Recruited; 16 completed all visits and were included in analyses

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Martins DA, Mazibuko N, Zelaya F, Vasilakopoulou S, Loveridge J, Oates A, Maltezos S, Mehta M, Wastling S, Howard M, McAlonan G, Murphy D, Williams SCR, Fotopoulou A, Schuschnig U, Paloyelis Y. Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans. Nature communications. 2020;11(1):1160. doi:10.1038/s41467-020-14845-5. PMID:32127545.

Source type: Journal paper

Study/cohort key: original-32127545

DOI: 10.1038/s41467-020-14845-5

PMID: 32127545

Checked: 2026-10-12. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Does a shared peptide segment preserve full-length actin binding?

How the study was done: Comparative biochemical experiment

What was tested: Full-length thymosin β4, oxidized thymosin β4 and distinct peptide fragments

Who or what was studied: Purified actin and peptide biochemical assays

Compared with: Full-length peptide versus fragments and related beta-thymosins

What changed: Full-length thymosin β4 bound actin monomers at a 1:1 ratio; the tested 13–43 and 24–43 fragments did not prevent polymerization.

What the result means: Having part of a parent peptide does not establish the parent's biochemical activity.

What this cannot answer: Purified-protein assay; the tested fragments are not a clinical TB-500 comparison.

Harms reported: Not assessed as a clinical safety study; harms reporting was not extracted.

Source access: Original journal abstract retrieved in indexed search; full text not acquired.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Hannappel E, Wartenberg F. Actin-sequestering ability of thymosin beta 4, thymosin beta 4 fragments, and thymosin beta 4-like peptides as assessed by the DNase I inhibition assay. Biological chemistry Hoppe-Seyler. 1993;374(2):117–122. doi:10.1515/bchm3.1993.374.1-6.117. PMID:8471179.

Source type: Journal paper

Study/cohort key: report-pmid-8471179

DOI: 10.1515/bchm3.1993.374.1-6.117

PMID: 8471179

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could topical full-length thymosin β4 accelerate venous-ulcer healing?

How the study was done: Phase 2 randomized, double-blind, placebo-controlled, dose-escalation trial

What was tested: Synthetic full-length thymosin β4 topical trial formulation

Who or what was studied: Patients with venous stasis ulcers at eight European sites

Compared with: Placebo formulation

Follow-up: Wound healing assessed through three months

What changed: The report described an exploratory healing signal in one formulation group, especially smaller or less severe wounds; the abstract did not supply a precise placebo-adjusted estimate.

What the result means: This was local treatment of a defined ulcer, with an exploratory result.

What this cannot answer: Small groups and exploratory subgroup findings; no tendon, muscle or systemic repair outcome.

Harms reported: Safety was described as acceptable and comparable with placebo; event counts were not extracted.

Source access: Original journal abstract retrieved in indexed search; full text not acquired.

Route or setting: Not extracted from the accessible source

Sample: 73 — Enrolled and randomized patients

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Guarnera G, DeRosa A, Camerini R, 8 European sites. The effect of thymosin treatment of venous ulcers. Annals of the New York Academy of Sciences. 2010;1194:207–212. doi:10.1111/j.1749-6632.2010.05490.x. PMID:20536470.

Source type: Journal paper

Study/cohort key: report-pmid-20536470

DOI: 10.1111/j.1749-6632.2010.05490.x

PMID: 20536470

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did ocular discomfort and corneal staining change?

How the study was done: Multicenter randomized, double-masked, vehicle-controlled phase 2 trial

What was tested: RGN-259 full-length thymosin β4 ophthalmic formulation

Who or what was studied: Nine patients with severe dry eye, including disease associated with graft-versus-host disease

Compared with: The eye-drop formulation without thymosin β4

Follow-up: 28-day treatment and 28-day follow-up

What changed: At day 56 the report described lower discomfort and total corneal staining in treated eyes.

What the result means: Treated eyes had less discomfort and less dye-visible corneal damage, but nine patients provide little precision and their two eyes can have related responses.

What this cannot answer: Eye-level reporting and very small patient groups limit precision and independence.

Harms reported: Reported as well tolerated; detailed adverse-event counts not extracted.

Source access: Original journal abstract retrieved in indexed search; full text not acquired.

Route or setting: Not extracted from the accessible source

Sample: 9 — Patients; 18 eyes were reported, not 18 independent people

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Sosne G, Dunn SP, Kim C. Thymosin β4 significantly improves signs and symptoms of severe dry eye in a phase 2 randomized trial. Cornea. 2015;34(5):491–496. doi:10.1097/ICO.0000000000000379. PMID:25826322.

Source type: Journal paper

Study/cohort key: report-pmid-25826322

DOI: 10.1097/ICO.0000000000000379

PMID: 25826322

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Were the two prespecified dry-eye endpoints better than control?

How the study was done: Single-center randomized, double-masked, vehicle-controlled phase 2 trial

What was tested: RGN-259 full-length thymosin β4 ophthalmic solution

Who or what was studied: Adults with moderate-to-severe dry eye meeting controlled-environment eligibility criteria

Compared with: The eye-drop formulation without thymosin β4

Follow-up: 28 days of treatment; visits across approximately 32 days

What changed: At the planned day-29 assessment, discomfort and lower-cornea staining scores were slightly higher with RGN-259 than with drops without peptide, an unfavorable numerical direction. Neither main comparison established a clear difference. Some secondary staining and discomfort measurements favored RGN-259.

What the result means: The trial did not establish benefit on its two planned main outcomes. Favorable secondary measurements need confirmation.

What this cannot answer: Single center, selected challenge population, multiple secondary endpoints.

Harms reported: The abstract says no adverse events occurred, but the detailed Results report ocular treatment-emergent events in 2/36 RGN-259 participants and 5/36 placebo participants. Two events were suspected to be treatment related, both with placebo. One participant withdrew with vomiting considered unrelated.

Source access: Indexed original abstract and publisher PDF text accessed; direct PMC open returned a browser challenge.

Route or setting: Not extracted from the accessible source

Sample: 72 — Randomized, 36 in each group

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Sosne G, Ousler GW. Thymosin beta 4 ophthalmic solution for dry eye: a randomized, placebo-controlled, Phase II clinical trial conducted using the controlled adverse environment (CAE™) model. Clinical ophthalmology (Auckland, N.Z.). 2015;9:877–884. doi:10.2147/OPTH.S80954. PMID:26056426.

Source type: Journal paper

Study/cohort key: NCT01387347

DOI: 10.2147/OPTH.S80954

PMID: 26056426

Registration: NCT01387347

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did persistent corneal epithelial defects completely heal?

How the study was done: Randomized, double-masked, placebo-controlled phase 3 trial, stopped early for slow recruitment

What was tested: RGN-259 full-length thymosin β4 ophthalmic trial formulation

Who or what was studied: Adults with stage 2 or 3 neurotrophic keratopathy and persistent corneal epithelial defects

Compared with: Placebo ophthalmic formulation

Follow-up: Four-week treatment; assessments through day 43

What changed: At day 29, 6/10 active versus 1/8 placebo subjects healed completely; P=0.0656.

What the result means: More participants healed completely with RGN-259 than with placebo at day 29, but the small, under-recruited trial left the size of the benefit uncertain (P=0.0656).

What this cannot answer: Under-recruited trial; a later favorable time point cannot replace its primary result.

Harms reported: Adverse events occurred in 4/10 active and 3/8 placebo participants, with 16 events in total. One event was considered treatment related; one nonocular serious event was considered unrelated. No event caused withdrawal.

Funding: ReGenTree involvement disclosed; full funding statement not extracted.

Source access: Original PMC full-text indexed results and study-design text accessed.

Route or setting: Not extracted from the accessible source

Sample: 18 — 10 active and 8 placebo subjects completed; planned enrollment was 46

Citation: Sosne G, Kleinman HK, Springs C, Gross RH, Sung J, Kang S. 0.1% RGN-259 (Thymosin ß4) Ophthalmic Solution Promotes Healing and Improves Comfort in Neurotrophic Keratopathy Patients in a Randomized, Placebo-Controlled, Double-Masked Phase III Clinical Trial. International journal of molecular sciences. 2022;24(1). doi:10.3390/ijms24010554. PMID:36613994.

Source type: Journal paper

Study/cohort key: report-pmid-36613994

DOI: 10.3390/ijms24010554

PMID: 36613994

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did synthetic GHK change cell survival and growth?

How the study was done: Comparative cell-culture study

What was tested: Synthetic glycyl-histidyl-lysine, without a preformed copper-complex designation

Who or what was studied: Hepatocytes from regenerating rat liver and cultured hepatoma cells

Compared with: Culture control; full comparator composition not extracted

What changed: The synthetic tripeptide prolonged normal hepatocyte survival and enhanced hepatoma-cell growth and labeled nucleic-acid precursor incorporation.

What the result means: The early finding concerns liver cells in culture, including tumor cells.

What this cannot answer: Medium metals were not excluded by the accessed abstract; this cannot isolate a permanently copper-free action or establish human skin repair.

Harms reported: Not assessed as a clinical safety study; harms reporting was not extracted.

Source access: Original publisher abstract accessed; PubMed entry has no abstract.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Pickart L, Thayer L, Thaler MM. A synthetic tripeptide which increases survival of normal liver cells, and stimulates growth in hepatoma cells. Biochemical and biophysical research communications. 1973;54(2):562–566. doi:10.1016/0006-291x(73)91459-9. PMID:4356974.

Source type: Journal paper

Study/cohort key: report-pmid-4356974

DOI: 10.1016/0006-291x(73)91459-9

PMID: 4356974

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could GHK modify copper availability to cultured cells?

How the study was done: Comparative structure-function and metal-uptake study

What was tested: GHK, metal complexes and structural analogues

Who or what was studied: Cultured hepatoma cells and biochemical metal-binding experiments

Compared with: Peptide/metal and structural comparisons; full groups not extracted

What changed: The paper reported copper(II) complex formation and enhanced metal uptake into cultured hepatoma cells.

What the result means: Metal binding can change how the nominal peptide acts in a culture system.

What this cannot answer: Supports a biochemical explanation, not a copper-free clinical effect or safe growth stimulation.

Harms reported: Not assessed as a clinical safety study; harms reporting was not extracted.

Source access: Original Nature indexed abstract accessed; later direct open failed at publisher authentication redirect.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Pickart L, Freedman JH, Loker WJ, Peisach J, Perkins CM, Stenkamp RE, Weinstein B. Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells. Nature. 1980;288(5792):715–717. doi:10.1038/288715a0. PMID:7453802.

Source type: Journal paper

Study/cohort key: report-pmid-7453802

DOI: 10.1038/288715a0

PMID: 7453802

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could GHK reverse a repair-related gene-expression pattern?

How the study was done: Observational regional transcriptomics followed by computational compound matching and ex-vivo cell experiments

What was tested: GHK tripeptide in human lung-fibroblast culture; tissue transcriptomics

Who or what was studied: Six severe-COPD explanted lungs and two unused donor lungs; cultured fibroblasts from former smokers with or without COPD

Compared with: Control cultures and TGFβ1; non-COPD fibroblasts

Follow-up: Cross-sectional tissue collection; culture duration varied and not extracted

What changed: GHK altered repair-associated gene expression and restored collagen-gel contraction by COPD-derived fibroblasts in culture.

What the result means: Cells regained a laboratory remodeling behavior; patients did not receive GHK.

What this cannot answer: A gene signature and gel contraction do not demonstrate restored lung function or clinical regeneration.

Harms reported: Clinical harms cannot be estimated from explanted tissue and cultures.

Source access: Original PMC full text accessed.

Route or setting: Not extracted from the accessible source

Sample: 8 — Lungs in discovery analysis; 64 regional samples, not 64 people; cell-experiment denominator not pooled

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Campbell JD, McDonough JE, Zeskind JE, Hackett TL, Pechkovsky DV, Brandsma CA, Suzuki M, Gosselink JV, Liu G, Alekseyev YO, Xiao J, Zhang X, Hayashi S, Cooper JD, Timens W, Postma DS, Knight DA, Lenburg ME, Hogg JC, Spira A. A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK. Genome medicine. 2012;4(8):67. doi:10.1186/gm367. PMID:22937864.

Source type: Journal paper

Study/cohort key: report-pmid-22937864

DOI: 10.1186/gm367

PMID: 22937864

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could a short EPO-derived peptide separate tissue protection from red-cell stimulation?

How the study was done: Comparative preclinical pharmacology

What was tested: Helix-B surface peptide corresponding to ARA-290/cibinetide; other distinct EPO-derived peptides

Who or what was studied: Cell systems and rodent injury models

Compared with: Preparations without the tested peptide, erythropoietin, and distinct peptide controls in separate experiments

What changed: The tested surface peptide produced tissue-protective effects without the erythropoietic activity of full-length EPO in the tested models.

What the result means: The experimental rationale was to separate two biological actions.

What this cannot answer: Multiple molecules and models; no universal tissue-repair or human safety conclusion.

Harms reported: Not assessed as a clinical safety study; harms reporting was not extracted.

Funding: Partial William Harvey Research Foundation support; several authors were Warren Pharmaceuticals employees.

Source access: Original PubMed abstract and PMC funding/disclosure text accessed.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Sample size. The original source may report these details.

Citation: Brines M, Patel NS, Villa P, Brines C, Mennini T, De Paola M, Erbayraktar Z, Erbayraktar S, Sepodes B, Thiemermann C, Ghezzi P, Yamin M, Hand CC, Xie QW, Coleman T, Cerami A. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(31):10925–10930. doi:10.1073/pnas.0805594105. PMID:18676614.

Source type: Journal paper

Study/cohort key: report-pmid-18676614

DOI: 10.1073/pnas.0805594105

PMID: 18676614

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did neuropathic symptoms improve beyond placebo?

How the study was done: Randomized, double-blind, placebo-controlled exploratory trial

What was tested: ARA-290 trial peptide

Who or what was studied: Patients with sarcoidosis and painful small-fiber-neuropathy symptoms

Compared with: Placebo

Follow-up: Four weeks

What changed: The small-fiber symptom score improved more with ARA-290; Brief Pain Inventory and fatigue scores improved similarly in both groups.

What the result means: One questionnaire favored treatment while general pain and fatigue measures did not separate.

What this cannot answer: Pilot size and short follow-up; questionnaire improvement is not proof of nerve regeneration.

Harms reported: No clinical or laboratory safety concern identified in this small study.

Source access: Original journal abstract retrieved in indexed search; full text not acquired.

Route or setting: Not extracted from the accessible source

Sample: 22 — 12 active and 10 placebo participants

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Heij L, Niesters M, Swartjes M, Hoitsma E, Drent M, Dunne A, Grutters JC, Vogels O, Brines M, Cerami A, Dahan A. Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Molecular medicine (Cambridge, Mass.). 2012;18(1):1430–1436. doi:10.2119/molmed.2012.00332. PMID:23168581.

Source type: Journal paper

Study/cohort key: report-pmid-23168581

DOI: 10.2119/molmed.2012.00332

PMID: 23168581

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did objective nerve measures and neuropathic symptoms improve?

How the study was done: Single-site double-blind, placebo-controlled trial

What was tested: ARA-290 trial peptide

Who or what was studied: Adults with longstanding sarcoidosis and painful small-nerve-fiber loss

Compared with: Placebo

Follow-up: 28-day treatment; 12-week follow-up

What changed: Corneal nerve-fiber area increased in the active group; epidermal nerve-fiber-density changes in the leg and thigh were not significant. Symptom measures also favored active treatment.

What the result means: A corneal imaging signal did not imply every sampled tissue regenerated.

What this cannot answer: Small cohort; two eyes were treated as independent samples for corneal analysis. A 2016 erratum corrected the corneal nerve-fiber-area algorithm and scaling; the original absolute area values should not be reused without that correction. Correction notice: The notice corrects the 2013 corneal area algorithm and normalization. It is a correction to the same cohort, not another trial. See https://link.springer.com/article/10.2119/molmed.2013.00122.erratum

Harms reported: No serious adverse event during treatment or follow-up; mild events were not judged likely drug-related.

Funding: Partial Dutch NIRM government grant; Araim employment and stock interests disclosed.

Source access: Original PMC full text accessed.

Route or setting: Not extracted from the accessible source

Sample: 38 — 21 active and 17 placebo participants

Citation: Dahan A, Dunne A, Swartjes M, Proto PL, Heij L, Vogels O, van Velzen M, Sarton E, Niesters M, Tannemaat MR, Cerami A, Brines M. ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Molecular medicine (Cambridge, Mass.). 2013;19(1):334–345. doi:10.2119/molmed.2013.00122. PMID:24136731.

Source type: Journal paper

Study/cohort key: NTR3575

DOI: 10.2119/molmed.2013.00122

PMID: 24136731

Registration: NTR3575, EudraCT 2012-001492-37

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did corneal nerve-fiber area improve, and did pain track it?

How the study was done: Randomized placebo-controlled phase 2b study with three active groups

What was tested: Cibinetide/ARA-290 clinical trial peptide

Who or what was studied: Sarcoidosis-associated small-nerve-fiber loss with neuropathic pain

Compared with: Placebo

Follow-up: 28 days

What changed: The middle active group improved corneal nerve-fiber area versus placebo by 697 μm² (95% CI 159 to 1236). The other active-group confidence intervals included zero; a pain subgroup comparison had P=0.157.

What the result means: Imaging improved in one group; a suggested pain benefit was statistically inconclusive.

What this cannot answer: Short surrogate-endpoint trial; correlation with walking does not establish a durable functional benefit.

Harms reported: Event counts not extracted from the accessed abstract.

Funding: Araim-affiliated authors disclosed; exact funding statement not extracted.

Source access: Original PubMed abstract accessed.

Route or setting: Not extracted from the accessible source

Sample: 64 — Randomized subjects across four groups

Citation: Culver DA, Dahan A, Bajorunas D, Jeziorska M, van Velzen M, Aarts LPHJ, Tavee J, Tannemaat MR, Dunne AN, Kirk RI, Petropoulos IN, Cerami A, Malik RA, Brines M. Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain. Investigative ophthalmology & visual science. 2017;58(6):BIO52–BIO60. doi:10.1167/iovs.16-21291. PMID:28475703.

Source type: Journal paper

Study/cohort key: NCT02039687

DOI: 10.1167/iovs.16-21291

PMID: 28475703

Registration: NCT02039687

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How did SS-31 interact with mitochondrial membrane chemistry?

How the study was done: Comparative biochemical membrane and respiration experiments

What was tested: SS-31/elamipretide and a distinct fluorescent SS-31 analogue used as a probe

Who or what was studied: Artificial lipid membranes, cytochrome-c complexes and isolated rat-kidney mitochondria

Compared with: Membranes without cardiolipin and preparations without peptide

What changed: SS-31 associated with cardiolipin-containing membranes and altered cytochrome-c-linked electron transfer and ATP production in isolated preparations.

What the result means: This explains a molecular target; it is not a clinical outcome.

What this cannot answer: Some localization experiments used a labeled analogue; isolated mitochondria cannot establish whole-person benefit.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Source access: Original PMC and publisher full-text results accessed.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. British journal of pharmacology. 2014;171(8):2017–2028. doi:10.1111/bph.12468. PMID:24134698.

Source type: Journal paper

Study/cohort key: report-pmid-24134698

DOI: 10.1111/bph.12468

PMID: 24134698

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did the six-minute walking distance improve?

How the study was done: Randomized double-blind placebo-controlled crossover

What was tested: Elamipretide clinical trial formulation

Who or what was studied: Adults with genetically confirmed primary mitochondrial myopathy

Compared with: Placebo, within-participant comparison

Follow-up: Two four-week treatment periods separated by four-week washout

What changed: The difference was 19.8 m (95% CI −2.8 to 42.5; P=0.0833), not statistically significant.

What the result means: The small walking signal remained compatible with no benefit.

What this cannot answer: Short crossover; favorable patient-reported secondary outcomes cannot convert the primary endpoint into a positive result.

Harms reported: Injection-site reactions in 80%, mostly mild; no serious adverse events or deaths reported.

Funding: Stealth BioTherapeutics involvement and investigator financial relationships disclosed; full funding statement not extracted.

Source access: Original indexed PubMed abstract; direct page returned incomplete HTML.

Route or setting: Not extracted from the accessible source

Sample: 30 — Enrolled/randomized participants

Citation: Karaa A, Haas R, Goldstein A, Vockley J, Cohen BH. A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy. Journal of cachexia, sarcopenia and muscle. 2020;11(4):909–918. doi:10.1002/jcsm.12559. PMID:32096613.

Source type: Journal paper

Study/cohort key: MMPOWER-2

DOI: 10.1002/jcsm.12559

PMID: 32096613

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did walking distance and total fatigue improve?

How the study was done: Multinational randomized double-blind placebo-controlled phase 3

What was tested: Elamipretide clinical trial formulation

Who or what was studied: Genetically confirmed primary mitochondrial myopathy; mitochondrial and nuclear DNA causes

Compared with: Placebo

Follow-up: 24 weeks

What changed: Both primary endpoints were negative. Walking difference: −3.2 m (95% CI −18.7 to 12.3; P=0.69); total fatigue did not significantly differ.

What the result means: The larger trial did not establish functional or fatigue benefit in its overall population.

What this cannot answer: Post-hoc genotype findings require separate confirmation and do not overturn the overall result.

Harms reported: Adverse events occurred in 107/109 active versus 83/109 placebo participants, mostly mild or moderate and commonly injection-site reactions. Events led to discontinuation in 8/109 versus 2/109. Serious events occurred in 5/109 versus 3/109 and were not deemed treatment related.

Funding: Stealth BioTherapeutics

Source access: Original PMC full-text results accessed.

Route or setting: Not extracted from the accessible source

Sample: 218 — 109 randomized in each group

Citation: Karaa A, Bertini E, Carelli V, Cohen BH, Enns GM, Falk MJ, Goldstein A, Gorman GS, Haas R, Hirano M, Klopstock T, Koenig MK, Kornblum C, Lamperti C, Lehman A, Longo N, Molnar MJ, Parikh S, Phan H, Pitceathly RDS, Saneto R, Scaglia F, Servidei S, Tarnopolsky M, Toscano A, Van Hove JLK, Vissing J, Vockley J, Finman JS, Brown DA, Shiffer JA, Mancuso M, MMPOWER-3 Trial Investigators. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. Neurology. 2023;101(3):e238–e252. doi:10.1212/WNL.0000000000207402. PMID:37268435.

Source type: Journal paper

Study/cohort key: NCT03323749

DOI: 10.1212/WNL.0000000000207402

PMID: 37268435

Registration: NCT03323749

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did exercise capacity and fatigue improve in Barth syndrome?

How the study was done: Randomized double-blind placebo-controlled crossover followed by open-label extension

What was tested: Elamipretide clinical trial formulation

Who or what was studied: Male patients aged 12–35 with genetically confirmed Barth syndrome

Compared with: Placebo in crossover; own baseline in extension

Follow-up: Two 12-week periods with four-week washout; 36-week reported extension

What changed: During the blinded crossover, elamipretide did not establish better six-minute walking distance or fatigue scores than placebo. Walking and fatigue improved from participants’ own starting measurements during the later open-label extension, when everyone knew they were receiving treatment.

What the result means: The blinded comparison left benefit uncertain. Later improvement without a blinded control cannot establish the same treatment effect.

What this cannot answer: Very small sample; open-label results are exposed to expectation, maturation and retention effects.

Harms reported: Injection-site reactions were common; detailed rates not extracted from this journal record.

Funding: Stealth BioTherapeutics

Source access: Original indexed PubMed record plus FDA original trial-review confirmation.

Route or setting: Not extracted from the accessible source

Sample: 12 — Randomized; eight completed the reported 36-week extension

Citation: Reid Thompson W, Hornby B, Manuel R, Bradley E, Laux J, Carr J, Vernon HJ. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Genetics in medicine : official journal of the American College of Medical Genetics. 2021;23(3):471–478. doi:10.1038/s41436-020-01006-8. PMID:33077895.

Source type: Journal paper

Study/cohort key: TAZPOWER

DOI: 10.1038/s41436-020-01006-8

PMID: 33077895

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Were functional changes and tolerability sustained among continuers?

How the study was done: Open-label extension, no concurrent untreated arm

What was tested: Elamipretide trial formulation in continued open-label exposure

Who or what was studied: Barth syndrome participants from the earlier TAZPOWER trial

Compared with: Extension baseline

Follow-up: 168-week extension

What changed: The week-168 mean walk change was +96.1 m versus extension baseline (P=0.003); several other measures also improved.

What the result means: Continuing participants improved over time, without a randomized long-term comparison.

What this cannot answer: Same cohort as the 2021 report; not a second independent randomized trial.

Harms reported: Injection-site reactions were the most common adverse events.

Funding: Stealth BioTherapeutics involvement; complete funding statement not extracted.

Source access: Original indexed PubMed abstract and author-institution journal PDF accessed.

Route or setting: Not extracted from the accessible source

Sample: 10 — Ten entered extension; eight reached week 168

Citation: Thompson WR, Manuel R, Abbruscato A, Carr J, Campbell J, Hornby B, Vaz FM, Vernon HJ. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genetics in medicine : official journal of the American College of Medical Genetics. 2024;26(7):101138. doi:10.1016/j.gim.2024.101138. PMID:38602181.

Source type: Journal paper

Study/cohort key: TAZPOWER

DOI: 10.1016/j.gim.2024.101138

PMID: 38602181

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did a sustained virologic response become more frequent?

How the study was done: Multicenter randomized double-blind placebo-controlled phase 3

What was tested: Thymosin α1 clinical trial peptide

Who or what was studied: Adults with HBV-DNA- and HBeAg-positive chronic hepatitis B

Compared with: Placebo

Follow-up: Six-month treatment and six-month follow-up

What changed: Complete response occurred in 7/49 versus 2/48 (P=0.084); the authors did not confirm efficacy.

What the result means: A numerical difference was insufficient to establish the trial's response benefit.

What this cannot answer: Disease-specific older trial and response definition; no basis for general immune enhancement.

Harms reported: Adverse-event details not extracted from abstract.

Source access: Original indexed PubMed abstract; direct open returned incomplete HTML.

Route or setting: Not extracted from the accessible source

Sample: 97 — 49 active and 48 placebo participants

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Mutchnick MG, Lindsay KL, Schiff ER, Cummings GD, Appelman HD, Peleman RR, Silva M, Roach KC, Simmons F, Milstein S, Gordon SC, Ehrinpreis MN. Thymosin alpha1 treatment of chronic hepatitis B: results of a phase III multicentre, randomized, double-blind and placebo-controlled study. Journal of viral hepatitis. 1999;6(5):397–403. doi:10.1046/j.1365-2893.1999.00181.x. PMID:10607256.

Source type: Journal paper

Study/cohort key: report-pmid-10607256

DOI: 10.1046/j.1365-2893.1999.00181.x

PMID: 10607256

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did adjunctive thymosin α1 reduce mortality?

How the study was done: Multicenter single-blind randomized controlled trial

What was tested: Thymosin α1 added to conventional care

Who or what was studied: Severe-sepsis ICU patients at six Chinese teaching hospitals

Compared with: Conventional care/control group

Follow-up: 28-day primary follow-up

What changed: Deaths occurred in 47/181 versus 63/180; RR 0.74 (95% CI 0.54 to 1.02), nonstratified P=0.062. A log-rank analysis had P=0.049; mHLA-DR changes favored treatment.

What the result means: The survival signal was borderline and depended on analysis; immune-marker improvement is separate.

What this cannot answer: Single blinding and different nominal mortality analyses; compare with the later larger TESTS trial.

Harms reported: No serious drug-related adverse event recorded.

Source access: Original PMC full-text abstract and participant-flow text accessed.

Route or setting: Not extracted from the accessible source

Sample: 361 — Analyzed after six consent withdrawals from 367 randomized; 181 active and 180 control

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Wu J, Zhou L, Liu J, Ma G, Kou Q, He Z, Chen J, Ou-Yang B, Chen M, Li Y, Wu X, Gu B, Chen L, Zou Z, Qiang X, Chen Y, Lin A, Zhang G, Guan X. The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial. Critical care (London, England). 2013;17(1):R8. doi:10.1186/cc11932. PMID:23327199.

Source type: Journal paper

Study/cohort key: NCT00711620

DOI: 10.1186/cc11932

PMID: 23327199

Registration: NCT00711620

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did adjunctive treatment reduce 28-day mortality?

How the study was done: Multicenter double-blind randomized placebo-controlled phase 3

What was tested: Thymosin α1 clinical trial product plus standard sepsis care

Who or what was studied: Adults with sepsis at 22 centers in China

Compared with: Placebo plus standard care

Follow-up: 28-day primary mortality; 90-day follow-up

What changed: Corrected deaths: 127/542 (23.4%) versus 132/547 (24.1%); HR 0.97 (95% CI 0.76 to 1.24; P=0.82).

What the result means: The large blinded trial did not demonstrate a mortality reduction.

What this cannot answer: Results apply to the overall sepsis population. Correction updated survival and some immune data; exploratory subgroups need confirmation. Correction notice: The notice updates survival analyses and immune data. The revised primary hazard ratio remains consistent with the trial's negative mortality conclusion. See https://www.bmj.com/content/389/bmj.r1098

Harms reported: Within 90 days, at least one adverse event occurred in 360/542 active versus 370/547 placebo participants; serious events occurred in 145/542 versus 160/547. No unexpected serious event related to thymosin α1 was reported. These are sepsis-cohort observations, not a universal safety conclusion.

Source access: Original PubMed abstract and corrected BMJ PDF indexed text, plus May correction, accessed.

Route or setting: Not extracted from the accessible source

Sample: 1106 — Randomized; modified intention-to-treat 1089 (542 active, 547 placebo)

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Wu J, Pei F, Zhou L, Li W, Sun R, Li Y, Wang Z, He Z, Zhang X, Jin X, Long Y, Cui W, Wang C, Chen E, Zeng J, Yan J, Lin Q, Zhou F, Huang L, Shang Y, Duan M, Zheng W, Zhu D, Kou Q, Zhang S, Liu Y, Yao C, Shang M, Peng S, Zhou Q, Cheng KK, Guan X, TESTS study collaborator group. The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial. BMJ (Clinical research ed.). 2025;388:e082583. doi:10.1136/bmj-2024-082583. PMID:39814420.

Source type: Journal paper

Study/cohort key: NCT02867267

DOI: 10.1136/bmj-2024-082583

PMID: 39814420

Registration: NCT02867267

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could one immune modulator promote both defense and tolerance?

How the study was done: Mechanistic comparative cell and animal experiments

What was tested: Thymosin α1 in immune-cell experiments

Who or what was studied: Human and murine dendritic-cell systems and preclinical immune models

Compared with: Untreated and pathway-specific controls; complete denominators not extracted

What changed: Thymosin α1 induced IDO-linked tryptophan catabolism, IL-10 and regulatory T-cell responses through TLR9/type-I-interferon-dependent signaling in the tested models.

What the result means: Immune regulation included restraining responses, rather than simply raising immune activity.

What this cannot answer: Mechanistic model results do not quantify clinical infection, mortality or autoimmune risk.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Source access: Original journal abstract and introduction accessed.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Romani L, Bistoni F, Perruccio K, Montagnoli C, Gaziano R, Bozza S, Bonifazi P, Bistoni G, Rasi G, Velardi A, Fallarino F, Garaci E, Puccetti P. Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance. Blood. 2006;108(7):2265–2274. DOI: 10.1182/blood-2006-02-004762.

Source type: Journal paper

Study/cohort key: report-doi-10-1182-blood-2006-02-004762

DOI: 10.1182/blood-2006-02-004762

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: How could thymosin α1 affect antigen-presenting-cell behavior?

How the study was done: Comparative mechanistic immune-cell and preclinical experiments

What was tested: Synthetic thymosin α1

Who or what was studied: Dendritic-cell systems and susceptible transplanted mice

Compared with: Control and pathway-deficient systems; group sizes not extracted

What changed: The peptide altered dendritic-cell maturation and IL-12-linked signaling, with related immune effects in mice.

What the result means: This supplies a cellular rationale for clinical questions.

What this cannot answer: Preclinical signaling is not proof of clinical immune enhancement; detailed pathogen methods are outside this library.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Source access: Original journal abstract accessed.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Romani L, Bistoni F, Gaziano R, Bozza S, Montagnoli C, Perruccio K, Pitzurra L, Bellocchio S, Velardi A, Rasi G, Di Francesco P, Garaci E. Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling. Blood. 2004;103(11):4232–4239. DOI: 10.1182/blood-2003-11-4036.

Source type: Journal paper

Study/cohort key: report-blood-2004-ta1-dc

DOI: 10.1182/blood-2003-11-4036

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Was zinc part of the active hormone?

How the study was done: Comparative biochemical experiment

What was tested: Natural/synthetic serum thymic factor (FTS) and zinc-bound thymulin

Who or what was studied: Biochemical metal-binding and cell-based rosette bioassays

Compared with: Metal-depleted FTS and metal-repleted preparations

What changed: Removing metal abolished measured activity; zinc restored it, with the strongest activation at a 1:1 metal:peptide ratio.

What the result means: Peptide amount and biologically active zinc-peptide complex are different measurements.

What this cannot answer: A functional assay defines activity in this system; it is not a clinical intervention study.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Source access: Original PMC abstract accessed.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Dardenne M, Pléau JM, Nabarra B, Lefrancier P, Derrien M, Choay J, Bach JF. Contribution of zinc and other metals to the biological activity of the serum thymic factor. Proceedings of the National Academy of Sciences of the United States of America. 1982;79(17):5370–5373. doi:10.1073/pnas.79.17.5370. PMID:6957870.

Source type: Journal paper

Study/cohort key: report-pmid-6957870

DOI: 10.1073/pnas.79.17.5370

PMID: 6957870

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could serum thymulin activity reflect mild zinc deficiency?

How the study was done: Small depletion/repletion and before-after biomarker study with laboratory serum testing

What was tested: Endogenous serum thymulin bioactivity; zinc intervention, not administered thymulin

Who or what was studied: Two dietary-depletion volunteers, six mildly zinc-deficient adults with sickle-cell anemia and six other mildly zinc-deficient adults

Compared with: Own prior/repleted state and serum before/after zinc addition

Follow-up: Repeated depletion/repletion observations; group-specific duration not fully extracted

What changed: Activity decreased despite normal plasma zinc and was restored by zinc repletion in people and in serum samples.

What the result means: The intervention tested zinc status and endogenous hormone activity.

What this cannot answer: Small heterogeneous groups; cannot establish clinical benefits of giving thymulin.

Harms reported: Thymulin intervention harms were not tested; zinc-study harms not extracted.

Source access: Original JCI/PubMed abstract and original PDF indexed text accessed.

Route or setting: Not extracted from the accessible source

Sample: 14 — 2+6+6 subjects across three groups, not a randomized thymulin trial

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Prasad AS, Meftah S, Abdallah J, Kaplan J, Brewer GJ, Bach JF, Dardenne M. Serum thymulin in human zinc deficiency. The Journal of clinical investigation. 1988;82(4):1202–1210. doi:10.1172/JCI113717. PMID:3262625.

Source type: Journal paper

Study/cohort key: report-pmid-3262625

DOI: 10.1172/JCI113717

PMID: 3262625

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did thymulin influence pituitary secretion?

How the study was done: Comparative ex-vivo endocrine signaling experiments

What was tested: Zinc-bound thymulin

Who or what was studied: Isolated rat anterior-pituitary tissue

Compared with: Control and cyclic-nucleotide pathway comparisons

What changed: ACTH release and cyclic nucleotide formation increased; growth-hormone release was unaffected, while prolactin release decreased in the tested conditions.

What the result means: Different hormones responded differently in isolated rat tissue.

What this cannot answer: Not evidence of hormone optimization or endocrine treatment in people.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Source access: Original PubMed abstract accessed.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Hadley AJ, Rantle CM, Buckingham JC. Thymulin stimulates corticotrophin release and cyclic nucleotide formation in the rat anterior pituitary gland. Neuroimmunomodulation. 1997;4(2):62–69. doi:10.1159/000097322. PMID:9483196.

Source type: Journal paper

Study/cohort key: report-pmid-9483196

DOI: 10.1159/000097322

PMID: 9483196

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did larazotide preserve tight-junction organization?

How the study was done: Comparative barrier-function experiments

What was tested: Larazotide acetate (AT-1001), distinct from permeability-inducing AT-1002

Who or what was studied: Caco-2 and IEC6 epithelial cultures and gluten-sensitive HLA-HCD4/DQ8 mice

Compared with: Stimulated cells/tissues without larazotide and unstimulated controls

What changed: Larazotide limited actin/ZO-1 redistribution and permeability changes in cell models and preserved intestinal tight-junction structure in the mouse model.

What the result means: Cell-layer leak measurements support a barrier mechanism.

What this cannot answer: Specific experimental disruptions; no proof of treating all causes of gastrointestinal symptoms.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Funding: Alba Therapeutics-affiliated authors; complete funding statement not extracted.

Source access: Original publisher abstract and selected full-text sections accessed.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Sample size. The original source may report these details.

Citation: Gopalakrishnan S, Durai M, Kitchens K, Tamiz AP, Somerville R, Ginski M, Paterson BM, Murray JA, Verdu EF, Alkan SS, Pandey NB. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides. 2012;35(1):86–94. doi:10.1016/j.peptides.2012.02.015. PMID:22401908.

Source type: Journal paper

Study/cohort key: report-doi-10-1016-j-peptides-2012-02-015

DOI: 10.1016/j.peptides.2012.02.015

PMID: 22401908

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could the peptide promote junction assembly, not only limit disassembly?

How the study was done: Comparative cell-layer junction-assembly experiments

What was tested: Larazotide acetate

Who or what was studied: MDCK and Caco-2 epithelial-cell cultures

Compared with: Control cultures without larazotide

What changed: Junctional protein distribution and actin rearrangement changed, with lower paracellular permeability in the tested models.

What the result means: The experiments measured cell-layer organization and passage between cells.

What this cannot answer: Renal/intestinal cell lines are not human clinical barrier-healing outcomes.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Funding: Alba Therapeutics-affiliated investigators; funding not fully extracted.

Source access: Original PubMed abstract accessed.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Sample size. The original source may report these details.

Citation: Gopalakrishnan S, Tripathi A, Tamiz AP, Alkan SS, Pandey NB. Larazotide acetate promotes tight junction assembly in epithelial cells. Peptides. 2012;35(1):95–101. doi:10.1016/j.peptides.2012.02.016. PMID:22401910.

Source type: Journal paper

Study/cohort key: report-pmid-22401910

DOI: 10.1016/j.peptides.2012.02.016

PMID: 22401910

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did the permeability endpoint and symptoms improve?

How the study was done: Randomized double-blind dose-ranging placebo-controlled trial

What was tested: Larazotide acetate clinical formulation

Who or what was studied: Diet-controlled celiac disease participants, with or without a study gluten challenge

Compared with: Placebo drug with gluten challenge; gluten-free control groups

Follow-up: 14 days

What changed: Lactulose/mannitol ratios were highly variable and did not significantly separate treatment from placebo; some lower active groups limited symptom worsening.

What the result means: The mechanistic clinical endpoint was inconclusive while some symptom results were encouraging.

What this cannot answer: Outpatient assay variability and small treatment groups; symptom change cannot establish mucosal protection.

Harms reported: No serious adverse events; headache and urinary tract infection were the common reported events.

Source access: Original indexed PubMed abstract; direct open returned incomplete HTML.

Route or setting: Not extracted from the accessible source

Sample: 86 — Randomly assigned participants

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Leffler DA, Kelly CP, Abdallah HZ, Colatrella AM, Harris LA, Leon F, Arterburn LA, Paterson BM, Lan ZH, Murray JA. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. The American journal of gastroenterology. 2012;107(10):1554–1562. doi:10.1038/ajg.2012.211. PMID:22825365.

Source type: Journal paper

Study/cohort key: report-pmid-22825365

DOI: 10.1038/ajg.2012.211

PMID: 22825365

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did permeability, symptoms and antibody responses change?

How the study was done: Exploratory double-blind randomized placebo-controlled trial

What was tested: Larazotide acetate clinical trial formulation

Who or what was studied: Diet-managed celiac disease patients undergoing a defined study gluten challenge

Compared with: Placebo plus the same challenge

Follow-up: Six-week challenge/treatment phase

What changed: No significant lactulose/mannitol-ratio difference. The lowest active group limited gastrointestinal symptoms (P=0.002); antibody rises were smaller across active groups.

What the result means: Symptoms and immune markers did not establish success on the permeability measure.

What this cannot answer: Exploratory outcome selection; the publication's 184 denominator should not be confused with a complete analyzed endpoint set.

Harms reported: Adverse-event rates were similar to placebo.

Funding: Alba Therapeutics involvement disclosed; full funding statement not extracted.

Source access: Original PubMed abstract, publisher and author-institution PDF text accessed.

Route or setting: Not extracted from the accessible source

Sample: 184 — Participants reported in the trial; publication notes 184 entered run-in

Citation: Kelly CP, Green PH, Murray JA, Dimarino A, Colatrella A, Leffler DA, Alexander T, Arsenescu R, Leon F, Jiang JG, Arterburn LA, Paterson BM, Fedorak RN, Larazotide Acetate Celiac Disease Study Group. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Alimentary pharmacology & therapeutics. 2013;37(2):252–262. doi:10.1111/apt.12147. PMID:23163616.

Source type: Journal paper

Study/cohort key: report-pmid-23163616

DOI: 10.1111/apt.12147

PMID: 23163616

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did persistent gastrointestinal symptoms improve?

How the study was done: Multicenter randomized double-blind placebo-controlled phase 2

What was tested: Larazotide acetate oral clinical trial formulation

Who or what was studied: Adults with ongoing celiac symptoms despite at least 12 months on a gluten-free diet, continued throughout the study

Compared with: Placebo while continuing the gluten-free diet

Follow-up: 12-week treatment with four-week run-in and run-out phases

What changed: The lowest active group improved the primary symptom score versus placebo (ANCOVA P=0.022); the two higher active groups did not.

What the result means: A symptom benefit in one group was not a uniform response across formulations/exposures.

What this cannot answer: Symptom endpoint; no demonstration that gluten can safely be eaten or that villous injury is prevented.

Harms reported: Safety was comparable with placebo in this trial.

Funding: Alba Therapeutics

Source access: Original PubMed abstract and journal full-text indexed sections accessed.

Route or setting: Not extracted from the accessible source

Sample: 342 — Randomized; modified intention-to-treat n=340

Citation: Leffler DA, Kelly CP, Green PH, Fedorak RN, DiMarino A, Perrow W, Rasmussen H, Wang C, Bercik P, Bachir NM, Murray JA. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology. 2015;148(7):1311–9.e6. doi:10.1053/j.gastro.2015.02.008. PMID:25683116.

Source type: Journal paper

Study/cohort key: NCT01396213

DOI: 10.1053/j.gastro.2015.02.008

PMID: 25683116

Registration: NCT01396213

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could a mitochondrial-region-encoded peptide influence metabolism?

How the study was done: Mechanistic cell experiments and controlled mouse interventions

What was tested: MOTS-c peptide and endogenous expression comparisons

Who or what was studied: Human cell systems and aged/high-fat-diet mouse models

Compared with: Cell and mouse controls without peptide exposure

Follow-up: Experiment-specific; no single pooled duration extracted

What changed: MOTS-c altered folate/purine-related metabolism and AMPK-linked signaling; treated mice were protected against diet- and age-related insulin resistance in the tested models.

What the result means: The metabolic intervention findings are preclinical.

What this cannot answer: Multiple cell/animal experiments, no human treatment trial; no pooled animal denominator.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Source access: Original PubMed abstract and PMC manuscript indexed text accessed.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Funding, Sample size. The original source may report these details.

Citation: Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell metabolism. 2015;21(3):443–454. doi:10.1016/j.cmet.2015.02.009. PMID:25738459.

Source type: Journal paper

Study/cohort key: report-pmid-25738459

DOI: 10.1016/j.cmet.2015.02.009

PMID: 25738459

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could MOTS-c communicate metabolic stress to nuclear gene regulation?

How the study was done: Comparative localization, gene-expression and stress-response experiments

What was tested: Endogenous/synthetic MOTS-c and assay-specific tracking material

Who or what was studied: Human-derived cultured cell systems

Compared with: Unstressed and pathway-control conditions

What changed: Metabolic stress was associated with nuclear MOTS-c localization and adaptive gene-expression changes in an AMPK-dependent manner.

What the result means: This is a cell-signaling observation, not an exercise or aging treatment result.

What this cannot answer: Localization and gene-expression readouts; variant/probe experiments are not identical to administering native peptide to people.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Source access: Original PMC indexed manuscript and author-institution PDF accessed.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Kim KH, Son JM, Benayoun BA, Lee C. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metabolism. 2018;28. DOI: 10.1016/j.cmet.2018.06.008.

Source type: Journal paper

Study/cohort key: report-doi-10-1016-j-cmet-2018-06-008

DOI: 10.1016/j.cmet.2018.06.008

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did systemic metabolic measurements change after peptide exposure?

How the study was done: Controlled short preclinical intervention with metabolomic analysis

What was tested: MOTS-c peptide

Who or what was studied: Diet-induced obese male mice, described by the authors as C57/6NJ, aged 17 weeks

Compared with: Water without MOTS-c

Follow-up: Three days

What changed: Blood glucose was lower after three days with MOTS-c, and selected groups of fat-related plasma metabolites changed. The study did not establish differences in body-weight change or food intake; insulin and leptin were numerically lower but uncertain.

What the result means: Blood metabolite changes provide a mechanistic clue; this is not a human diabetes trial.

What this cannot answer: Three-day mouse experiment; the metabolomic analysis used 12 of the 14 mice. Multiple exploratory metabolites and a lower blood-glucose measurement do not establish durable weight loss, directly measured insulin sensitivity or clinical benefit.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Source access: Original PMC abstract/results indexed text and FDA source-study description accessed.

Route or setting: Not extracted from the accessible source

Sample: 14 — 14 mice in the intervention, seven per group; 12 mice in the metabolomic analysis, six per group. These are outcome-specific denominators, not independent cohorts.

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Kim SJ, Miller B, Mehta HH, Xiao J, Wan J, Arpawong TE, Yen K, Cohen P. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiological Reports. 2019;7(13):e14171. DOI: 10.14814/phy2.14171.

Source type: Journal paper

Study/cohort key: report-doi-10-14814-phy2-14171

DOI: 10.14814/phy2.14171

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did the body's own MOTS-c measurements respond to exertion?

How the study was done: Within-person exercise-response biomarker study

What was tested: Endogenous muscle and circulating MOTS-c measurements; no peptide administered

Who or what was studied: Ten sedentary healthy young men, mean age 24.5 years

Compared with: Pre-exercise baseline

Follow-up: Acute exercise and four-hour recovery sampling

What changed: Muscle signal rose about 11.9-fold after exercise; circulating levels rose transiently and returned toward baseline by four hours.

What the result means: Exercise changed endogenous peptide measurements; the study did not test MOTS-c treatment in people.

What this cannot answer: Small male-only cohort and no untreated nonexercise arm; separate mouse interventions are different evidence.

Harms reported: Peptide intervention harms cannot be estimated because none was administered.

Source access: Original PMC manuscript indexed text and original journal PDF figure/results text accessed.

Route or setting: Not extracted from the accessible source

Sample: 10 — Human participants; separate mouse arms are not included in n

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, Graham NA, Benayoun BA, Merry TL, Lee C. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. 2021;12:470. DOI: 10.1038/s41467-020-20790-0.

Source type: Journal paper

Study/cohort key: Reynolds-2021-human-exercise

DOI: 10.1038/s41467-020-20790-0

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Were circulating measurements associated with obesity and insulin-resistance markers?

How the study was done: Cross-sectional case-control biomarker study

What was tested: Endogenous circulating MOTS-c measured with an immunoassay

Who or what was studied: Children aged 5–14 in Hubei, China: 40 with obesity and 57 controls

Compared with: Normal-BMI children and sex-specific subgroup comparisons

Follow-up: Single observational sampling period in 2017

What changed: Lower MOTS-c measurements and inverse metabolic-marker correlations were seen in the male cohort; female subgroup measurements did not significantly differ.

What the result means: Association in boys is not proof that low peptide caused obesity or that treatment reverses it.

What this cannot answer: Small female subgroup, one center, narrow ages and assay-specific values.

Harms reported: No administered MOTS-c; treatment harms were not studied.

Source access: Original PubMed abstract and publisher methods/results accessed.

Route or setting: Not extracted from the accessible source

Sample: 97 — 40 obesity and 57 control participants

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Du C, Zhang C, Wu W, Liang Y, Wang A, Wu S, Zhao Y, Hou L, Ning Q, Luo X. Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance. Pediatric diabetes. 2018. doi:10.1111/pedi.12685. PMID:29691953.

Source type: Journal paper

Study/cohort key: report-pmid-29691953

DOI: 10.1111/pedi.12685

PMID: 29691953

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could a short peptide protect cells against selected Alzheimer-related insults?

How the study was done: Functional screening followed by comparative cell-survival experiments

What was tested: Humanin expression and synthetic humanin with structure-function variants

Who or what was studied: Cultured neuronal-cell models exposed to Alzheimer-related cellular insults

Compared with: Stressed cells without effective humanin and distinct stressor/variant controls

What changed: Humanin reduced cell death from several Alzheimer-related insults but did not protect against all other tested causes of neuronal death.

What the result means: Protection was selective in culture, not evidence of treating Alzheimer's disease in people.

What this cannot answer: Variant and expression experiments have different exposures from a human intervention; no clinical cognitive outcome. A 2001 correction states that the discovery experiments did not prove natural peptide production or the genomic origin of the cDNA; the culture bioactivity finding is separate from that origin claim.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Source access: Original journal abstract accessed through indexed search; full text not acquired.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(11):6336–6341. doi:10.1073/pnas.101133498. PMID:11371646.

Source type: Journal paper

Study/cohort key: report-pmid-11371646

DOI: 10.1073/pnas.101133498

PMID: 11371646

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Could humanin interfere with a cell-death switch?

How the study was done: Mechanistic comparative binding and cell-death experiments

What was tested: Humanin and interaction-specific assay variants

Who or what was studied: Biochemical binding systems and cultured cells undergoing Bax-associated apoptosis

Compared with: Control proteins/peptides and cells without effective humanin interaction

What changed: Humanin interacted with Bax and inhibited its movement from cytosol to mitochondrial membranes.

What the result means: Preventing one step of apoptosis can improve survival of stressed cells in an assay.

What this cannot answer: Selective cell-death mechanism; no proof of safe long-term protection or disease reversal.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Funding: NIH and US Department of Defense support; no competing financial interests declared.

Source access: Original Nature abstract/funding and PubMed abstract accessed.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Sample size. The original source may report these details.

Citation: Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003;423(6938):456–461. doi:10.1038/nature01627. PMID:12732850.

Source type: Journal paper

Study/cohort key: report-pmid-12732850

DOI: 10.1038/nature01627

PMID: 12732850

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Which receptor components were necessary for the observed neuroprotection?

How the study was done: Mechanistic loss/gain-of-function receptor experiments

What was tested: Humanin and assay-specific control/variant peptides

Who or what was studied: Cultured neuronal cells and purified receptor-binding assays

Compared with: Control peptide and receptor-subunit manipulation controls

What changed: Binding and cell-survival responses required components involving CNTFRα, WSX-1 and gp130 in the tested systems.

What the result means: This mapped a possible cell-surface signaling route rather than a clinical outcome.

What this cannot answer: Receptor necessity in selected cultured cells does not establish a single universal humanin mechanism.

Harms reported: Clinical harms were not assessed or event details were not extracted.

Source access: Original PubMed and PMC indexed abstract accessed; direct PMC open returned a browser challenge.

Route or setting: Not extracted from the accessible source

Not yet extracted for this card: Follow-up, Funding, Sample size. The original source may report these details.

Citation: Hashimoto Y, Kurita M, Aiso S, Nishimoto I, Matsuoka M. Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130. Molecular biology of the cell. 2009;20(12):2864–2873. doi:10.1091/mbc.e09-02-0168. PMID:19386761.

Source type: Journal paper

Study/cohort key: report-pmid-19386761

DOI: 10.1091/mbc.e09-02-0168

PMID: 19386761

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Were endogenous humanin measurements associated with a familial longevity phenotype?

How the study was done: Cross-sectional biomarker comparison within a broader multispecies paper

What was tested: Measured endogenous circulating humanin; no administered peptide

Who or what was studied: Offspring of centenarians and age-matched controls in a longevity cohort

Compared with: Age-matched controls

Follow-up: Cross-sectional sampling

What changed: Circulating humanin was higher in the offspring group.

What the result means: A selected human biomarker association did not test whether humanin treatment extends life.

What this cannot answer: Small selected cohort; animal HNG intervention and transgenic experiments are distinct arms and materials.

Harms reported: No administered humanin in this comparison; intervention harms unmeasured.

Source access: Original PMC full-text results and figure caption accessed.

Route or setting: Not extracted from the accessible source

Sample: 37 — 18 offspring and 19 controls in this specific human comparison; other paper arms excluded

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Yen K, Mehta HH, Kim SJ, Lue Y, Hoang J, Guerrero N, Port J, Bi Q, Navarrete G, Brandhorst S, Lewis KN, Wan J, Swerdloff R, Mattison JA, Buffenstein R, Breton CV, Wang C, Longo V, Atzmon G, Wallace D, Barzilai N, Cohen P. The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan. Aging. 2020;12(12):11185–11199. doi:10.18632/aging.103534. PMID:32575074.

Source type: Journal paper

Study/cohort key: report-pmid-32575074

DOI: 10.18632/aging.103534

PMID: 32575074

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did humanin change similarly across aging-related diseases?

How the study was done: Cross-sectional biomarker case-control analysis

What was tested: Endogenous plasma humanin immunoassay; FGF21 and GDF15 measured separately

Who or what was studied: Older adults: centenarians' offspring, healthy controls, type 2 diabetes with or without complications, and Alzheimer's disease

Compared with: Healthy and disease-defined comparison groups

Follow-up: Cross-sectional sampling

What changed: Humanin was lower in the Alzheimer's group but not in the type 2 diabetes groups; healthy-aging measurements also varied with age.

What the result means: The biomarker did not show one universal disease pattern.

What this cannot answer: Disease association, assay and cohort context; no causal inference or replacement indication.

Harms reported: No humanin administered; treatment safety untested.

Source access: Original PMC full-text indexed results, original PubMed record and author-institution journal PDF accessed.

Route or setting: Not extracted from the accessible source

Sample: 569 — Plasma samples/subjects: 102 offspring, 92 controls, 162 diabetes without complications, 93 with complications, 120 Alzheimer participants

Not yet extracted for this card: Funding. The original source may report these details.

Citation: Conte M, Sabbatinelli J, Chiariello A, Martucci M, Santoro A, Monti D, Arcaro M, Galimberti D, Scarpini E, Bonfigli AR, Giuliani A, Olivieri F, Franceschi C, Salvioli S. Disease-specific plasma levels of mitokines FGF21, GDF15, and Humanin in type II diabetes and Alzheimer's disease in comparison with healthy aging. GeroScience. 2021;43(2):985–1001. doi:10.1007/s11357-020-00287-w. PMID:33131010.

Source type: Journal paper

Study/cohort key: report-pmid-33131010

DOI: 10.1007/s11357-020-00287-w

PMID: 33131010

Checked: 2026-10-11. Selected-source extraction; formal risk-of-bias and specialist review are not complete.

The question: Did AOD9604 change weight gain and insulin sensitivity?

How the study was done: Controlled preclinical metabolic intervention

What was tested: AOD9604, the tyrosine-modified hGH C-terminal analogue