Educational information only. Not medical advice.

Research Memos

Orforglipron vs semaglutide

ACHIEVE-3 directly compared oral orforglipron capsules with oral semaglutide tablets in adults with type 2 diabetes taking metformin. Orforglipron lowered average blood glucose more. More participants reported stomach or intestinal adverse events or stopped treatment because of adverse events, and the average pulse increase was larger with orforglipron. The results concern the trial formulations and strengths; weight-management products need separate context.

Research reviewed October 15, 2026. Educational information only.

The same receptor, with different oral formulations

Orforglipron and semaglutide activate the receptor for glucagon-like peptide-1, or GLP-1, a hormone involved in appetite and blood-glucose regulation. Activating this receptor helps the pancreas release insulin when blood glucose is high and can reduce food intake. Orforglipron is a nonpeptide small molecule; semaglutide is a modified peptide. Their chemistry and formulation affect how an oral product reaches the bloodstream.

Both medicines now have oral products in the United States. Semaglutide also has injectable products, with their own indications and evidence. The useful direct comparison comes from ACHIEVE-3: a trial of oral preparations in adults whose type 2 diabetes remained inadequately controlled with metformin. The Foundayo label and oral semaglutide label explain the product-specific pharmacology.

The main differences

How much did blood glucose fall?

ACHIEVE-3 followed metformin-treated adults with type 2 diabetes for 52 weeks. Average starting HbA1c was 8.3%. HbA1c reflects glucose exposure over preceding weeks and months; the results below use the main analysis that included stopping and additional glucose-lowering treatment.

Orforglipron

HbA1c fell by 1.71 percentage points with the 12-mg trial capsule and 1.91 points with the 36-mg capsule. Both groups had greater average reductions than both semaglutide groups under the prespecified tests.

Sources

Semaglutide

HbA1c fell by 1.23 percentage points with the 7-mg oral tablet and 1.47 points with the 14-mg oral tablet. The comparison concerns these tablets and strengths.

Sources

How much weight did participants lose?

These 52-week estimates come from the sponsor’s results table for the main treatment-regimen analysis of ACHIEVE-3. They describe the same diabetes population and oral trial treatments as the glucose comparison.

Orforglipron

Average weight loss was 6.1% with the 12-mg trial capsule and 8.2% with the 36-mg capsule. The often-quoted 6.7% and 9.2% estimates instead assume continued treatment without additional glucose-lowering medication.

Sources

Semaglutide

Average weight loss was 3.9% with the 7-mg oral tablet and 5.3% with the 14-mg oral tablet. Injectable semaglutide and the Wegovy tablet were not tested in this comparison.

Sources

How common were stomach or intestinal adverse events?

The trial was open-label: participants knew their assignment. These are participants with at least one gastrointestinal adverse event over 52 weeks, most of which were mild or moderate.

Orforglipron

Events were reported by 249 of 424 participants (59%) with the 12-mg trial capsule and 245 of 423 (58%) with the 36-mg capsule.

Sources

Semaglutide

Events were reported by 157 of 426 participants (37%) with the 7-mg oral tablet and 193 of 425 (45%) with the 14-mg oral tablet.

Sources

How often did adverse events lead people to stop treatment?

These ACHIEVE-3 results concern stopping study treatment because of an adverse event. They do not count all reasons for stopping, and the events were not limited to digestive symptoms.

Orforglipron

37 of 424 participants (9%) stopped at the 12-mg trial capsule strength and 41 of 423 (10%) at 36 mg.

Sources

Semaglutide

19 of 426 participants (4%) stopped at the 7-mg oral tablet strength and 21 of 425 (5%) at 14 mg.

Sources

How do the trial formulations relate to current products?

The product and formulation matter. These distinctions explain the evidence and are not instructions for selecting or changing a medicine. U.S. labels were checked on October 15, 2026.

Orforglipron

ACHIEVE-3 used capsules. A separate blood-exposure study linked its 12-mg and 36-mg capsules to specified 9-mg and 17.2-mg tablets. The U.S. Foundayo label covers adult weight management and permits use with or without food.

Sources

Semaglutide

ACHIEVE-3 used 7-mg and 14-mg oral diabetes tablets. Current oral diabetes products have fasting and timing requirements. Wegovy tablets and weekly injections have separate weight-management evidence and were not ACHIEVE-3 comparators.

Sources

What ACHIEVE-3 actually compared

Rosenstock and colleagues randomly assigned 1,698 adults at 131 centers in five countries to four groups. Participants had type 2 diabetes, an HbA1c of 7.0–10.5% despite metformin, and a body mass index of at least 25 kg/m². Body mass index relates weight to height. HbA1c measures the proportion of hemoglobin carrying glucose and reflects blood-glucose exposure over preceding weeks and months.

The 52-week treatment period compared once-daily orforglipron trial capsules at 12 mg (424 people) or 36 mg (423 people) with oral semaglutide tablets at 7 mg (426 people) or 14 mg (425 people). Those amounts identify the research treatments. Participants and investigators knew the assigned medicine. The trial was funded by Eli Lilly, and several authors were company employees and shareholders.

The main analysis estimated the effect of assignment to each treatment, including what happened after treatment interruptions or stopping and after additional glucose-lowering medication was started. The paper calls this the treatment-regimen estimand. A separate supportive analysis estimated outcomes if participants continued their assigned treatment without additional glucose-lowering medication. These analyses answer different questions and can give different averages.

Blood glucose fell more with the tested orforglipron capsules

Starting from an average HbA1c of 8.3%, the main analysis estimated falls of 1.71 percentage points with orforglipron 12 mg and 1.91 points with orforglipron 36 mg. The corresponding falls were 1.23 points with semaglutide 7 mg and 1.47 points with semaglutide 14 mg. A fall from 8% to 7% is one percentage point.

The additional reduction was 0.48 percentage points for orforglipron 12 mg versus semaglutide 7 mg (95% confidence interval 0.31–0.65), and 0.44 points for orforglipron 36 mg versus semaglutide 14 mg (0.26–0.62). The initial non-inferiority test ruled out losing more than 0.3 percentage points of HbA1c reduction against the paired semaglutide group. The prespecified testing then asked whether orforglipron lowered HbA1c more. Both orforglipron groups met the superiority criteria against both semaglutide groups.

These findings establish a difference in average glucose lowering under the ACHIEVE-3 protocol. HbA1c is useful for assessing glucose control, but the difference by itself does not measure how often participants later had heart attacks, strokes or other diabetes complications.

Weight changed in the same diabetes trial

The sponsor’s dated report of the trial results provides the weight estimates for both analyses. In the main treatment-regimen analysis, average weight loss at 52 weeks was 6.1% with orforglipron 12 mg and 8.2% with orforglipron 36 mg, compared with 3.9% with semaglutide 7 mg and 5.3% with semaglutide 14 mg. These estimates allow for stopping or additional glucose-lowering treatment, consistent with the main glucose results above.

Larger orforglipron weight-loss estimates often quoted from this trial—6.7% and 9.2%—come from the supportive analysis that assumed continued treatment without additional glucose-lowering medication. All these results concern adults with type 2 diabetes receiving metformin and the four oral treatments tested. The trial did not compare orforglipron with a semaglutide injection or the Wegovy weight-management tablet.

Digestive symptoms, treatment stopping and pulse

Stomach or intestinal adverse events were reported by 249 of 424 people (59%) assigned to orforglipron 12 mg and 245 of 423 (58%) assigned to 36 mg. With semaglutide, the counts were 157 of 426 (37%) at 7 mg and 193 of 425 (45%) at 14 mg. Most of these events were mild or moderate. Because participants knew which treatment they received, expectations could have affected reporting of symptoms.

Adverse events led 37 people (9%) in the orforglipron 12-mg group and 41 (10%) in the 36-mg group to stop study treatment. The counts were 19 (4%) with semaglutide 7 mg and 21 (5%) with 14 mg. These are stopping rates attributed to adverse events, rather than rates of stopping for any reason or rates attributed only to digestive symptoms.

Average pulse increased by 3.7 beats per minute with orforglipron 12 mg and 4.7 beats per minute with 36 mg. It increased by 1.0 beat per minute with semaglutide 7 mg and 1.5 beats per minute with 14 mg. The primary report therefore describes a larger glucose reduction alongside a greater burden of digestive events, adverse-event-related stopping and pulse increase. A 52-week study of this size cannot settle uncommon or long-term safety differences.

How the trial relates to current products

The orforglipron capsule strengths in ACHIEVE-3 differ from the marketed Foundayo tablet strengths. In a separate 429-person formulation study, specified capsules and tablets produced sufficiently similar blood concentrations over 24 hours and peak concentrations to meet the study’s bioequivalence criteria. The 12-mg capsule was paired with a 9-mg tablet and the 36-mg capsule with a 17.2-mg tablet. This allows results from the tested capsules to inform understanding of the corresponding tablets. The trial strengths are not instructions for choosing or changing treatment.

The U.S. Foundayo label checked for this article covers reducing excess weight and maintaining weight reduction in adults with obesity, or adults with overweight and a weight-related condition, alongside diet and activity measures. It does not list a separate indication for treating diabetes. Its instructions permit use with or without food. The current U.S. oral semaglutide label covers diabetes glucose control and reduction of cardiovascular death, nonfatal heart attack or nonfatal stroke in adults with type 2 diabetes at high cardiovascular risk. It includes Rybelsus and Ozempic tablets, which are not interchangeable milligram for milligram, and describes fasting and timing requirements for absorption.

Semaglutide’s Wegovy label includes weight-management tablets and weekly injections. These are distinct from the 7-mg and 14-mg oral diabetes treatments in ACHIEVE-3. Separate weight-management evidence includes ATTAIN-1 for orforglipron, which enrolled adults without diabetes and used placebo as the comparator. Comparing percentages from separate obesity trials would also compare different populations and protocols.

What remains outside the direct comparison

A September 2026 sponsor report comparing orforglipron with oral semaglutide 25 mg combined information from ACHIEVE-3 and a separate semaglutide trial. It was an indirect comparison: participants were not randomly assigned between those two treatments within a shared trial. Its interpretation depends on how well differences between the trial populations and protocols were accounted for. Neither analysis establishes which current formulation produces better weight or cardiovascular outcomes in every population.

The Foundayo and oral semaglutide prescribing information also address pancreatic inflammation, severe digestive reactions, kidney injury associated with fluid loss, and low blood glucose, especially alongside insulin or medicines that stimulate insulin release. Both have boxed warnings concerning thyroid C-cell tumor risk and contraindications for a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. The relevance of GLP-1-related rodent thyroid tumors to people remains uncertain. Pregnancy, interactions with other medicines and the individual’s medical history require their own assessment; average trial results cannot resolve them.

Frequently asked questions

Did ACHIEVE-3 compare orforglipron with semaglutide injections?

ACHIEVE-3 compared oral preparations: orforglipron trial capsules at 12 mg or 36 mg and semaglutide tablets at 7 mg or 14 mg. Injectable semaglutide and the Wegovy weight-management tablet were not tested in that trial.

Why do reports quote different glucose and weight reductions from the same trial?

The main treatment-regimen analysis estimates the effect of assignment to treatment even when people stop or need additional glucose-lowering medication. The supportive efficacy analysis estimates what would happen if participants continued treatment without additional glucose-lowering medication. For example, the 36-mg orforglipron capsule’s average weight loss was 8.2% in the main analysis and 9.2% in the supportive analysis. Each estimate needs its analysis identified.

Was orforglipron easier to tolerate because it is a nonpeptide pill?

The direct trial found more stomach or intestinal adverse events with orforglipron, and more participants stopped because of adverse events. Mean pulse increases were also larger. Chemical structure and convenient administration do not establish easier clinical tolerability.

Are the trial capsule strengths the same as current Foundayo tablet strengths?

A separate formulation study demonstrated sufficiently similar blood exposure at specified pairs, including 12-mg capsules with 9-mg tablets and 36-mg capsules with 17.2-mg tablets. The study supports those manufactured formulations; it is not a general conversion rule or a treatment-switching instruction.

Is the newer comparison with semaglutide 25 mg another head-to-head trial?

The sponsor’s September 2026 report describes an indirect comparison using data from ACHIEVE-3 and the separate PIONEER PLUS trial. It did not randomly assign people between orforglipron and semaglutide 25 mg within one shared trial. This article’s direct results refer to ACHIEVE-3’s 7-mg and 14-mg semaglutide groups.

Does the glucose result show which medicine prevents more heart attacks or strokes?

The HbA1c result measures average glucose lowering over 52 weeks. It does not establish a difference in heart attacks or strokes between the two medicines. Oral semaglutide has a separate U.S. cardiovascular-risk-reduction indication for adults with type 2 diabetes at high cardiovascular risk; that label claim comes from evidence beyond this direct glucose comparison.

Orforglipron — full profile · Selected studies

Semaglutide — full profile · Selected studies

Compare other compounds · Explore the guide previews

References

  1. Rosenstock J, Yabe D, Cox D, Li J, Denning M, Wu WS, Liu R, Zhao Y; ACHIEVE-3 Investigators. Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial. Lancet. 2026;407(10534):1147–1160. doi:10.1016/S0140-6736(26)00202-3.

    Complete original PubMed abstract and conflict-of-interest statement accessed October 15, 2026. Publisher full text could not be acquired; weight values are separately bound to the sponsor’s dated results table. Abstract Methods and Findings: population, 1,698 randomized, all four groups, main treatment-regimen analysis, HbA1c changes and confidence intervals, gastrointestinal counts, adverse-event discontinuations, pulse and funding. NCT06045221.

  2. Eli Lilly and Company. Lilly's oral GLP-1, orforglipron, delivered superior blood sugar control and weight loss compared to oral semaglutide in head-to-head type 2 diabetes trial published in The Lancet. Sponsor news release. February 26, 2026.

    Complete dated sponsor results report accessed October 15, 2026. This is a company report, not an independently acquired full journal article. ACHIEVE-3 Full Results table, change in weight: treatment-regimen row 3.9%, 5.3%, 6.1%, 8.2%; efficacy row 3.7%, 5.3%, 6.7%, 9.2%. Endnotes 2–3 define the analyses. Footnotes 1 and iv identify multiplicity limits.

  3. U.S. Food and Drug Administration. FOUNDAYO (orforglipron) tablets, for oral use. Prescribing information, revised July 2026. NDA 220934; Reference ID 5842935.

    Complete 26-page FDA PDF accessed October 15, 2026. The checked indication is explicitly U.S.-scoped. Boxed warning; sections 1–5, 7–8, 11–12 and 14; July 2026 revision on PDF page 1.

  4. Ma X, Li YG, Raha S, Sperry DC, Coutant DE, Bhattachar S. Pharmacokinetic Bioequivalence of Orforglipron Tablets and Capsules in Healthy Participants With Obesity or Overweight. Diabetes, Obesity and Metabolism. 2026;28(7):5803–5809. doi:10.1111/dom.70783.

    Original PubMed abstract accessed October 15, 2026; its methods and results support the limited formulation bridge used here. Abstract Materials and methods and Results: otherwise healthy adults with obesity or overweight, six specific pairs, seven days at each strength, steady-state 24-hour concentration area and peak, prespecified mixed-scaling criteria.

  5. Novo Nordisk. RYBELSUS and OZEMPIC (oral semaglutide) tablets: U.S. prescribing information. DailyMed. Current listing accessed October 15, 2026.

    Official DailyMed prescribing information accessed October 15, 2026. Sections 1, 2.1–2.4, 3–5, 11 and 12.1–12.3. Highlights explicitly state that Rybelsus and Ozempic tablets are not substitutable milligram for milligram.

  6. Novo Nordisk. WEGOVY (semaglutide) injection and tablets: U.S. prescribing information. DailyMed. Current listing accessed October 15, 2026.

    Official DailyMed prescribing information accessed October 15, 2026. Sections 1–3, 12.1–12.3 and 14.2; tablet and injection indications and different trial populations.

  7. Wharton S, Aronne LJ, Stefanski A, Alfaris NF, Ciudin A, Yokote K, Halpern B, Shukla AP, Zhou C, Macpherson L, Allen SE, Ahmad NN, Klise SR; ATTAIN-1 Trial Investigators. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment. New England Journal of Medicine. 2025;393(18):1796–1806. doi:10.1056/NEJMoa2511774.

    Original PubMed abstract checked during the independent Orforglipron profile review on October 15, 2026; retained here only for population and comparator context. Abstract Methods: adults with obesity without diabetes; randomized placebo-controlled 72-week design.

  8. Eli Lilly and Company. Lilly's Foundayo (orforglipron) 17.2 mg showed greater weight loss and A1C reduction than oral semaglutide 25 mg among adults with type 2 diabetes in a new indirect treatment comparison. Sponsor news release. September 29, 2026.

    Complete dated sponsor report accessed October 15, 2026. Conference analysis; a full independent journal report was not acquired. Opening paragraphs; description of ACHIEVE-3 and PIONEER PLUS; endnotes 2–5. The article uses only the comparison’s design and source studies.