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.

# 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 *The Lancet 2026* Articles 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 Julio Rosenstock*, Daisuke Yabe, David Cox, Jianghao Li, Max Denning, Wen-Shuo Wu, Rong Liu, Youna Zhao, for the ACHIEVE-3 Investigators† Summary Background Orforglipron is a novel non-peptide (GLP-1) receptor agonist designed for daily oral administration Published Online without food or water restrictions. This study aimed to compare the ecacy and safety of orforglipron with oral February 26, 2026 https://doi.org/10.1016/ semaglutide in individuals with type 2 diabetes inadequately controlled with metformin. S0140-6736(26)00202-3 See Online/Comment Methods In this 52-week, randomised, open-label, active-controlled, multicentre, multinational, phase 3 study, we https://doi.org/10.1016/ enrolled adults (≥18 years) with type 2 diabetes inadequately controlled with metformin (≥1500 mg per day), glycated S0140-6736(26)00360-0 haemoglobin (HbA₁) between 7·0% and 10·5% (53–91 mmol/mol), and BMI at least 25 kg/m² from 131 medical *Formally affiliated with Velocity c research centres and hospitals in Argentina, China, Japan, Mexico, and the USA. Participants were randomly assigned Clinical Research, under which (1:1:1:1) to orforglipron (12 mg or 36 mg) or semaglutide (7 mg or 14 mg); all groups had an up to 4-week lead-in the current study was conducted period and 52-week treatment period, with the drugs administered orally once per day. The primary objective of the †Members listed in the appendix (pp 2−4) study was to assess non-inferiority of orforglipron 36 mg versus semaglutide 14 mg and orforglipron 12 mg versus Division of Endocrinology, semaglutide 7 mg for mean change at week 52 from baseline in HbA₁ (with a non-inferiority margin of 0·3%) in the c University of Texas, intention-to-treat population. Hierarchical analysis for superiority was prespecified after attainment of non-inferiority. Southwestern Medical Center, The treatment regimen estimand, based on data from all randomly assigned participants regardless of intercurrent Dallas, TX, USA events, was the primary estimand; the ecacy estimand was considered supportive. The safety endpoints used data (J Rosenstock MD); Department of Diabetes, Endocrinology and from all participants who received at least one dose of the study drug. This trial was registered on ClinicalTrials.gov Nutrition, Kyoto University (NCT06045221) and is completed. Graduate School of Medicine, Kyoto, Japan (D Yabe MD); Findings From Sept 22, 2023, to Aug 22, 2025, 1698 participants were recruited and randomly assigned to orforglipron Yutaka Seino Distinguished Center for Diabetes Research, (n=424 on 12 mg and n=423 on 36 mg) or semaglutide (n=426 on 7 mg and n=425 on 14 mg). For the treatment Kansai Electric Power Medical regimen estimand, mean changes at week 52 from a baseline HbA₁ of 8·3% were –1·71% (SE 0·07) with orforglipron Research Institute, Kyoto, c 12 mg, –1·91% (0·08) with orforglipron 36 mg, –1·23% (0·05) with semaglutide 7 mg, and –1·47% (0·06) with Japan (D Yabe MD); Center for semaglutide 14 mg. Estimated treatment dierences were –0·48% (95% CI –0·65 to –0·31; p<0·0001) for orforglipron One Medicine Innovative Translational Research, Gifu 12 mg versus semaglutide 7 mg; –0·44% (–0·62 to –0·26; p<0·0001) for orforglipron 36 mg versus semaglutide University Institute for 14 mg; –0·24% (95% CI –0·41 to –0·072; p=0·0050) for orforglipron 12 mg versus semaglutide 14 mg; and –0·68% Advanced Studies, Gifu, Japan (–0·85 to –0·50; p<0·0001) for orforglipron 36 mg versus semaglutide 7 mg. The primary objective of non-inferiority (D Yabe MD); Eli Lilly and was met and both orforglipron doses showed superiority to both semaglutide doses, including orforglipron 12 mg Company, Indianapolis, IN, USA (J Li PhD, M Denning MD, versus semaglutide 14 mg. The most frequent adverse events were gastrointestinal events (orforglipron: 249 [59%] W-S Wu MD, R Liu PhD, of 424 on 12 mg and 245 [58%] of 423 on 36 mg; semaglutide: 157 [37%] of 426 on 7 mg and 193 [45%] of 425 on D Cox PhD, Y Zhao PhD) 14 mg), most of which were mild to moderate in severity. More participants in the orforglipron groups (37 [9%] on Correspondence to: 12 mg and 41 [10%] on 36 mg) discontinued study treatment due to adverse events than in the semaglutide groups Dr Julio Rosenstock, Division of (19 (4%) on 7 mg and 21 (5%) on 14 mg), and mean increase in pulse rate was greater in the orforglipron groups Endocrinology, University of Texas, Southwestern Medical (12 mg 3·7 bpm; 36 mg 4·7 bpm) than in the semaglutide groups (7 mg 1·0 bpm; 14 mg 1·5 bpm). Four deaths Center, Dallas, TX 75390, USA occurred during the study: one in the orforglipron 12 mg group, one in the orforglipron 36 mg group, and two in the juliorosenstock@ semaglutide 7 mg group. dallasdiabetes.com See Online for appendix Interpretation In individuals with type 2 diabetes inadequately controlled with metformin, orforglipron 12 mg and 36 mg was non-inferior and superior to semaglutide 7 mg and 14 mg with respect to the mean change in HbA₁ from c baseline to 52 weeks. Although the safety profiles of both orforglipron and semaglutide were generally consistent with the GLP-1 receptor agonist class, the incidence of gastrointestinal events, discontinuations due to adverse events, and mean increase in pulse rate were higher with orforglipron than oral semaglutide. Funding Eli Lilly. Copyright © 2026 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies. www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 1 Articles Research in context Evidence before this study Added value of this study GLP-1 receptor agonists have become a cornerstone in the ACHIEVE-3 is a multicentre, open-label, international, management of type 2 diabetes, primarily due to their efficacy in randomised, active-controlled phase 3 trial to directly compare improving glycaemic control and weight reduction. On orforglipron (12 mg or 36 mg) with oral semaglutide (7 or Nov 20, 2025, we searched PubMed with the search terms 14 mg) in adults with type 2 diabetes inadequately controlled “glucagon-like peptide-1 receptor agonist”, AND “oral”, AND with metformin. The findings show that orforglipron was non- “type 2 diabetes”, AND “overweight” and limited our search to inferior and superior to semaglutide for HbA reduction. c clinical trials, with no date or language restrictions. Most Orforglipron 12 mg was significantly better than semaglutide approved GLP-1 receptor agonists are peptide-based and require 7 mg and orforglipron 36 mg was significantly better than both subcutaneous administration, with oral semaglutide, semaglutide 7 mg and 14 mg for achieving glycaemic targets co-formulated with an absorption enhancer, and robust weight reduction. Additionally, orforglipron 12 mg sodium N-(8-[2-hydroxybenzoyl]amino) caprylate, being the was superior to semaglutide 14 mg for HbA change from c only oral option. Oral semaglutide has restrictions on food and baseline and the proportion of participants achieving HbA of 1c fluid intake to improve bioavailability. Phase 2 clinical trials less than 7·0% and 6·5% or less. The frequency of gastro- showed that orforglipron, a non-peptide, orally available, small intestinal adverse events and treatment discontinuation due to molecule GLP-1 receptor agonist, could achieve dose-dependent gastrointestinal adverse events, and the increase from baseline reductions in glycated haemoglobin (HbA ) and bodyweight over in pulse rate, were higher in orforglipron groups than 1c 26 weeks. In addition to type 2 diabetes and an ongoing semaglutide groups. The overall safety profiles of both cardiovascular outcomes trial, orforglipron is under development orforglipron and semaglutide were overall consistent with the for obesity (NCT05869903 and NCT05872620), obstructive GLP-1 receptor agonist class. sleep apnoea (NCT06649045), stress urinary incontinence Implications of all the available evidence (NCT07202884), and peripheral artery disease (NCT07223593). Together with previous research, the results of the ACHIEVE-3 ACHIEVE-1, the first phase 3 clinical trial of orforglipron, showed study suggest that orforglipron represents an important clinically meaningful efficacy for reduction in HbA and 1c advancement in the oral treatment landscape for type 2 diabetes. bodyweight and safety consistent with the GLP-1 receptor Its efficacy, safety, tolerability, and simple dosing could address agonist class in individuals with early type 2 diabetes inadequately important barriers associated with current incretin-based controlled with diet and exercise alone. In individuals with type 2 therapies, offering a new highly efficacious and safe option for diabetes and obesity or overweight (ATTAIN-2), orforglipron was individuals seeking effective glycaemic and weight control superior for HbA and weight reduction than placebo. For 1c without the use of injections or administration restrictions. individuals or health-care providers considering initiating an oral GLP-1 receptor agonist, there is no evidence on the comparative efficacy and safety of orforglipron versus oral semaglutide. Introduction benefits of peptide-based GLP-1 receptor agonists, without GLP-1 receptor agonists have gained increasing the need for injections, would allow further tailoring of prominence in the management of type 2 diabetes due to therapy to meet individual preferences of patients and their pleiotropic benefits, including glycaemic control, prescribers. weight reduction, and cardiorenal risk reduction.1–3 These Oral semaglutide is a peptide-based GLP-1 receptor therapies act by stimulating insulin secretion and agonist co-formulated with an absorption enhancer, suppressing glucagon secretion, both in a glucose- sodium N-(8-[2-hydroxybenzoyl]amino) caprylate. Due to dependent manner, decreasing appetite, and reducing the low bioavailability of this formulation (~1–2%),11 to bodyweight. Additionally, observed benefits include achieve therapeutic concentrations, administration must reductions in blood pressure,4 reductions in visceral occur in a fasted state in the morning, with no more than adiposity,5 and improvements in lipid profiles,6 120 mL of water, and at least 30 min before food, particularly diabetic dyslipidaemia.7 beverages, or other oral medication.12,13 Oral semaglutide Most GLP-1 receptor agonists are peptide-based, with a is currently the only orally administered GLP-1 receptor large molecular weight.8 Consequently, these therapies are agonist approved for the management of type 2 diabetes, currently administered via subcutaneous injection to with additional indications for risk reductions in allow absorption, avoid proteolytic degradation in the cardiovascular and chronic kidney diseases.14–16 gastrointestinal tract, and minimise the eect of first-pass Orforglipron is a non-peptide (small molecule), partial metabolism. However, some individuals are hesitant to GLP-1 receptor agonist biased towards G-protein activation initiate injectable therapies, which can delay timely versus β-arrestin recruitment, with pharmacokinetic treatment initiation and intensification.9,10 An oral non- characteristics favourable for once per day oral dosing peptide GLP-1 receptor agonist with the physiological without dietary restrictions.8 Orforglipron is under 2 www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 Articles investigation for several potential indications, including Randomisation and masking treatment of type 2 diabetes and obesity.17,18 In the 40-week Participants were randomly assigned (1:1:1:1) to receive phase 3 ACHIEVE-1 study, under the treatment regimen either orforglipron (escalated up to doses of 12 mg or estimand, orforglipron as a monotherapy reduced HbA₁ 36 mg) or oral semaglutide (escalated up to doses of 7 mg c by up to 1·5% (1·1% treatment dierence vs placebo) from or 14 mg) through an interactive web-response system a mean overall baseline of 8·0% and reduced bodyweight and stratified by country and HbA₁ (≤8·0% or >8·0%) at c by up to 7·6% (5·9% treatment dierence vs placebo) from visit 1. Treatment assignment was open label; however, a mean overall baseline of 90·2 kg in people with early all investigators (including those assessing data), type 2 diabetes inadequately controlled with diet and participants, and the sponsor were masked to the exercise.19 randomly assigned dose of orforglipron. Orforglipron There are no published randomised controlled trials capsules were manufactured visually indistinguishable addressing the comparative ecacy and safety of oral and packaged in identical bottles, distinguished only by a GLP-1 receptor agonist therapies. We aim to address this unique package number to support masked dispensing evidence gap by investigating the non-inferiority and at clinical sites. superiority of orforglipron (12 mg and 36 mg) compared with oral semaglutide (7 mg and 14 mg) in participants Procedures with type 2 diabetes who had inadequate glycaemic The study period included a screening and lead-in period control with metformin monotherapy. of up to 4 weeks, a 52-week treatment period, and a safety follow-up period of 2–5 weeks. Genetic sex (male or Methods female), race, and ethnicity were collected based on Study design and participants participant self-report. This 52-week, open-label, randomised, active comparator Participants receiving orforglipron started with 1 mg controlled, parallel-arm, non-inferiority, phase 3 study daily, increasing every 4 weeks until reaching their (ACHIEVE-3) was done in 131 medical research centres randomly assigned dose of 12 mg or 36 mg. Those and hospitals in Argentina, China, Japan, Mexico, and receiving semaglutide began with 3 mg daily, taken at the USA. least 30 min before the first food, drink, or other oral Key inclusion criteria were being aged 18 years or older medications of the day with up to 4 ounces (120 mL) of with type 2 diabetes inadequately controlled with plain water, and had increasing doses every 4 weeks until metformin at a dose of at least 1500 mg per day, with reaching their randomly assigned dose of 7 mg or 14 mg HbA₁ of 7·0% (53 mmol/mol) to 10·5% (91 mmol/mol), (appendix p 21). Initiation of new glucose-lowering c a BMI of 25 kg/m² or more, and a stable bodyweight medications was allowed according to specific criteria for (≤5% bodyweight gain or loss) during the 3 months rescue therapy for severe persistent hyperglycaemia before screening. (appendix pp 8–9). Other GLP-1 receptor agonists, DPP4 Key exclusion criteria were a history of severe inhibitors, or other incretin-based therapies were not hypoglycaemia within 6 months of screening, type 1 allowed. In case of intolerable gastrointestinal symptoms, diabetes, current or planned treatment for diabetic participants were advised to have smaller meals, use retinopathy and/or macular oedema, estimated symptomatic medications and, if needed, temporarily glomerular filtration rate of less than 45 mL per min per interrupt use of the study drug for up to two consecutive 1·73 m², New York Health Association Functional doses for orforglipron or up to seven consecutive doses Classification IV congestive heart failure, a family or for semaglutide (equivalent to one half-life). If intolerable personal history of medullary thyroid carcinoma or gastrointestinal symptoms persisted, de-escalation of the multiple endocrine neoplasia syndrome type 2, any liver study drug to the previous lower dose for at least 8 weeks disease (except metabolic dysfunction-associated steatotic could be considered for participants taking orforglipron liver disease), AST and/or ALT concentrations more than 6 mg and more or semaglutide 14 mg. Only one dose 5 times upper limit of normal, and a history of chronic or de-escalation and re-escalation attempt was permitted acute pancreatitis. A complete list of eligibility criteria is during the study. All participants continued on stable available in the appendix (pp 5–8). metformin as a background glucose-lowering medication The trial was registered on ClinicalTrials.gov throughout the study, except for those with safety (NCT06045221) and is complete. The trial protocol was concerns. approved by local institutional review boards at all Participants who prematurely discontinued the trial participating sites (appendix p 14). The trial was done in treatment were encouraged to stay in the study and accordance with the principles of the Declaration of complete the scheduled visits and assessments. Helsinki and the Good Clinical Practice guidelines of the Ophthalmological evaluation of fundus photographs International Council for Harmonisation. All participants for diabetic retinopathy or macular oedema (taken by an provided written informed consent. The statistical ophthalmologist or optometrist or at the local clinic) was analysis plan is available with the protocol in the done for all participants at baseline and week 52, with an appendix. additional assessment at week 24 for those found to have www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 3 Articles any degree of diabetic retinopathy at baseline. Further infarction, hospitalisation for unstable angina or heart details of fundus photography assessments are provided failure, coronary interventions, and cerebrovascular in the appendix (pp 9–10). events), and potential pancreatitis cases were reviewed by Clinic visits occurred every 4 weeks for the first an independent external adjudication committee. 24 weeks, followed by visits at weeks 32, 40, and 52. Details of the schedule of ecacy and safety assessments Statistical analysis are provided in the protocol available at the end of the We estimated that 1576 participants would provide at least appendix. 90% power to assess the non-inferiority of orforglipron 36 mg to semaglutide 14 mg and of orforglipron 12 mg to Outcomes semaglutide 7 mg at the two-sided 0·025 significance level The primary endpoint was the change in HbA₁ (0·05 overall α split between comparisons) with a c concentration from baseline to week 52. The key two-sample t test based on the primary endpoint secondary endpoints assessed at week 52 were the (ie, change from baseline in HbA₁ at week 52), with a c proportion of participants with an HbA₁ concentration non-inferiority margin of 0·3%, a common SD of 1·2%, c of less than 7·0% (53 mmol/mol) and 6·5% or less and assuming no expected dierence between (48 mmol/mol), the percentage change from baseline in orforglipron 12 mg and semaglutide 7 mg or between bodyweight, and the absolute change from baseline in orforglipron 36 mg and semaglutide 14 mg under the bodyweight. Other secondary endpoints at week 52 were treatment regimen estimand. Additionally, the sample the proportion of participants with an HbA₁ size ensured 90% power to assess superiority of c concentration of less than 5·7% (39 mmol/mol), the orforglipron 36 mg over semaglutide 14 mg and of proportion with a weight loss of at least 5%, at least 10%, orforglipron 12 mg over semaglutide 7 mg, assuming a and at least 15%, the change from baseline in fasting 0·3% greater reduction in HbA₁. These assumptions also c serum glucose, the change from baseline in daily mean ensured the power for the ecacy estimand. We did 7-point self-monitored blood glucose, percentage change power calculations with nQuery (version 9.1.0.0). from baseline in lipid measures, and the change from We did ecacy analyses in all randomly assigned baseline in waist circumference, BMI, and systolic and participants. Two estimands were prespecified: the diastolic blood pressure. Patient-reported outcomes treatment regimen estimand and the ecacy estimand. collected during the study were Short Form–36 Health For each estimand, we applied a graphical testing Survey Version 2, EQ-5D-5L, Ability to Perform Physical procedure to control multiplicity, strongly controlling the Activities of Daily Living, Impact of Weight on Self- overall family-wise (type 1) error rate at 0·05 for the Perception, Impact of Weight on Quality of Life-Lite primary and key secondary endpoints, with an initial Clinical Trials Version, Diabetes Treatment Satisfaction α=0·025 equally allocated to each of the two primary Questionnaire—Status, Diabetes Treatment Satisfaction hypotheses: orforglipron 36 mg versus semaglutide 14 mg Questionnaire—Change, and Simplicity of Diabetes and orforglipron 12 mg versus semaglutide 7 mg (appendix Treatment Questionnaire. Only the Short Form–36 p 22). Inferences regarding treatment eects in this Article Health Survey Version 2 is reported here; other patient- pertain primarily to the treatment regimen estimand. reported outcomes will be published in a programme-level The treatment regimen estimand assessed the treatment health-outcomes-focused manuscript. eect between orforglipron and semaglutide, irrespective Safety endpoints were the number and incidence of of premature discontinuation or the use of additional serious adverse events, treatment-emergent adverse antihyperglycaemic medication (ie, in the intention-to- events, and discontinuations due to adverse events. treat population). We analysed continuous outcomes at Adverse events were coded with the Medical Dictionary week 52 with an ANCOVA model adjusted for baseline for Regulatory Activities and assessed for severity and value, country, and the stratification factor (baseline HbA₁ c relationship to study treatment by the study investigators. ≤8·0% or >8·0), and interactions of treatment-by-baseline Diabetic retinopathy was monitored through and treatment-by-stratification factor, incorporating ophthalmological evaluation of fundus photographs. imputed data for missing values at baseline and missing Physical examinations, vital sign measurements, endpoints at week 52, as detailed in the statistical analysis electrocardiograms, and clinical laboratory assessments plan. The ecacy estimand was used to assess the were done as outlined in the protocol. Hepatic safety was treatment eect between orforglipron and semaglutide evaluated with liver function tests at every clinic visit. under the assumption that all the participants who were Hypoglycaemic episodes were recorded in the study randomly assigned continued to receive orforglipron or eDiary and reported as a serious adverse event if the semaglutide as assigned for 52 weeks without the use of event met the criteria for severe hypoglycaemia (altered additional glucose-lowering medications for more than mental or physical status requiring assistance from 14 days. For the ecacy estimand, we used a restricted another person to administer carbohydrates, glucagon, maximum likelihood-based mixed model (MMRM) for or other resuscitation measures). Additionally, deaths, repeated measures to analyse the continuous outcomes. major adverse cardiovascular events (eg, myocardial The MMRM included fixed eects for treatment, visit, 4 www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 Articles country, other strata, baseline value of the dependent continuous measures with MMRM or ANCOVA with variable, baseline-by-treatment-by-visit interaction, and relevant covariates. Analyses of safety endpoints were strata-by-treatment-by-visit interaction. Under both exploratory. No explicit imputations were done for safety estimands, we analysed binary ecacy outcomes with the measures. use of logistic regression; we addressed missing values No dedicated data monitoring committee was used. An through estimand-specific multiple imputation strategies, unmasked programme-level committee regularly with results combined according to Rubin’s rule.20 We did reviewed safety data from ACHIEVE-4, the longest prespecified subgroup analyses for the change from orforglipron study in participants with high cardiovascular baseline in HbA at week 52 by baseline HbA stratum risk. This committee could assess data from other studies, 1c 1c (≤8·0% and >8·0%). including ACHIEVE-3, if routine masked monitoring of We assessed safety endpoints with data from the safety adverse events by the sponsor identified a need, or if the population (all participants who were randomly assigned committee deemed this was warranted based on open- to a study intervention and received at least one dose of label review of ACHIEVE-4 data, but no such need arose the study intervention) during treatment and the safety during ACHIEVE-3 or other studies. follow-up period, regardless of adherence. Assessment of Statistical analyses were done with SAS (version 9.4) hypoglycaemia excluded events that occurred after and R (version 3.5 and later). initiation of any new antihyperglycaemic therapy. Additional details regarding the statistical analysis are Role of the funding source provided in the appendix (pp 10–13). The funder of the study designed and oversaw the The frequency and proportion of participants conduct of the trial. The investigators were responsible experiencing adverse events and serious adverse events for participant-level data collection and worked under were summarised descriptively. We used Fisher’s exact confidentiality agreements with the funder. The funder test for categorical comparisons and provide risk conducted site monitoring, study-level data collection dierences with 95% CIs. We analysed some prespecified and dataset creation, and data analysis. 2604 assessed for eligibility 906 ineligible 1 adverse event 18 withdrawals 5 physician decisions 3 lost to follow-up 8 other 871 screen failures 1698 randomly assigned 424 assigned to orforglipron 12 mg 423 assigned to orforglipron 36 mg 426 assigned to semaglutide 7 mg 425 assigned to semaglutide 14 mg 42 (10%) discontinued study 43 (10%) discontinued study 38 (9%) discontinued study 24 (6%) discontinued study 76 (18%) discontinued study drug 87 (21%) discontinued study drug 46 (11%) discontinued study drug 39 (9%) discontinued study drug 36 adverse event 41 adverse event 17 adverse event 21 adverse event 21 withdrawal by participant 28 withdrawal by participant 15 withdrawal by participant 10 withdrawal by participant 7 lost to follow-up 7 lost to follow-up 8 lost to follow-up 3 lost to follow-up 5 non-compliance with study 4 non-compliance with study 1 non-compliance with study 1 non-compliance with drug drug drug study drug 2 physician decisions 3 physician decisions 2 death 3 physician decisions 3 other 2 other 2 lack of efficacy 1 other 1 death 2 pregnancies 1 protocol deviation 1 protocol deviation 348 (82%) completed study treatment 336 (79%) completed study treatment 380 (89%) completed study treatment 386 (91%) completed study treatment 13 completed with rescue medication 10 completed with rescue medication 50 completed with rescue medication 24 completed with rescue medication 382 (90%) completed study 380 (90%) completed study 388 (91%) completed study 401 (94%) completed study Figure 1: Participant flowchart www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 5 Articles Results 12 mg; 41 [10%] on 36 mg) discontinued study treatment Between Sept 22, 2023, and Aug 22, 2025, we screened due to adverse events than in the semaglutide groups 2604 participants and 1698 participants were randomly (17 [4%] on 7 mg; 21 [5%] on 14 mg; appendix p 33). Fewer assigned to orforglipron 12 mg (n=424), orforglipron participants completed study treatment with rescue 36 mg (n=423), semaglutide 7 mg (n=426), or semaglutide therapy for severe persistent hyperglycaemia in 14 mg (n=425; figure 1). A total of 1551 (91%) participants orforglipron groups: 13 (3%) of 424 in the orforglipron completed the study. The demographics and clinical 12 mg group and 10 (2%) of 423 in the orforglipron 36 mg characteristics were similar between groups (table 1). The group compared with 50 (12%) of 426 in the semaglutide mean age of participants was 53·9 years (SD 11·1), 7 mg group and 24 (6%) of 425 in the semaglutide 14 mg 825 (48·6%) were female, 873 (51·4%) were male, mean group (figure 1). baseline duration of diabetes was 8·6 years (SD 6·5), Orforglipron met the primary objective of non- mean HbA₁ was 8·3% (SD 1·1), mean bodyweight was inferiority (margin 0·3%) and met the c 97·0 kg (22·3), and mean BMI was 35·1 kg/m² (7·1). multiplicity-controlled key secondary objective of There was more treatment discontinuation in superiority to semaglutide in mean change from baseline orforglipron groups (76 [18%] of 424 on 12 mg; 87 [21%] in HbA₁ at week 52 (figure 2A; appendix pp 29–30). For c of 423 on 36 mg) than semaglutide groups (46 [11%] the treatment regimen estimand, from a mean overall of 426 on 7 mg; 39 [9%] of 425 on 14 mg), with adverse baseline HbA₁ of 8·3%, the mean change in HbA₁ at c c events as the main reason (figure 1; appendix p 33). More week 52 for orforglipron 12 mg was –1·71% (SE 0·07), participants in the orforglipron groups (36 [8%] on for orforglipron 36 mg was –1·91% (0·08), for Orforglipron Orforglipron Semaglutide Semaglutide Overall 12 mg (n=424) 36 mg (n=423) 7 mg (n=426) 14 mg (n=425) (n=1698) Age, years 54·0 (11·3) 53·4 (11·4) 54·9 (11·2) 53·4 (10·5) 53·9 (11·1) Sex Female 195 (46%) 218 (52%) 206 (48%) 206 (48%) 825 (48·6%) Male 229 (54%) 205 (48%) 220 (52%) 219 (52%) 873 (51·4%) Race White 250/418 (60%) 259/415 (62%) 266/419 (63%) 254/420 (60%) 1029/1672 (61·5%) American Indian or Alaska Native 90/418 (22%) 79/415 (19%) 76/419 (18%) 89/420 (21%) 334/1672 (20·0%) Asian 50/418 (12%) 51/415 (12%) 52/419 (12%) 49/420 (12%) 202/1672 (12·1%) Black or African American 17/418 (4%) 16/415 (4%) 12/419 (3%) 20/420 (5%) 65/1672 (3·9%) Ethnicity Hispanic or Latino 304 (72%) 304 (72%) 316 (74%) 310 (73%) 1234 (72·7%) Not Hispanic or Latino 117 (28%) 117 (28%) 108 (25%) 113 (27%) 455 (26·8%) Diabetes duration, years 9·0 (7·1) 8·2 (5·8) 8·7 (6·3) 8·6 (6·9) 8·6 (6·5) HbA concentration c In % 8·3 (1·0) 8·3 (1·1) 8·3 (1·1) 8·3 (1·1) 8·3 (1·1) In mmol/mol 66·8 (11·5) 67·0 (12·1) 67·3 (11·9) 67·2 (12·3) 67·1 (12·0) ≤8·0% [n (%)] 202 (48%) 217 (51%) 199 (47%) 200 (47%) 818 (48·2%) >8·0% [n (%)] 222 (52%) 206 (49%) 227 (53%) 225 (53%) 880 (51·8%) Fasting serum glucose In mg/dL 169 (54) 167 (52) 170 (51) 172 (52) 169 (52) In mmol/L 9·4 (3·0) 9·3 (2·9) 9·4 (2·8) 9·6 (2·9) 9·4 (2·9) BMI, kg/m² 34·5 (7·1) 35·3 (7·2) 35·1 (7·0) 35·5 (7·1) 35·1 (7·1) Weight, kg 96·1 (22·2) 96·5 (21·9) 97·1 (22·6) 98·4 (22·6) 97·0 (22·3) Waist circumference, cm 111·4 (14·9) 112·3 (15·2) 112·3 (15·6) 113·4 (15·4) 112·3 (15·3) Mean estimated glomerular filtration rate, mL per min 90·4 (20·3) 92·4 (19·2) 88·9 (19·7) 90·5 (19·2) 90·6 (19·6) per 1·73 m² Blood pressure, mm Hg Systolic 129·6 (13·8) 129·1 (13·1) 129·5 (13·4) 128·8 (13·7) 129·2 (13·5) Diastolic 80·0 (9·2) 79·9 (8·3) 80·2 (9·1) 80·1 (8·9) 80·0 (8·9) Pulse rate, bpm 74·7 (10·0) 75·1 (10·1) 74·8 (10·3) 76·2 (10·0) 75·2 (10·1) Data are mean (SD) or n (%), unless otherwise indicated. This table includes all randomly assigned participants. Estimated glomerular filtration rate is calculated by use of the Chronic Kidney Disease Epidemiology cystatin-C equation. Table 1: Demographics and clinical characteristics of participants at baseline 6 www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 Articles semaglutide 7 mg was –1·23% (0·05), and for overall mean daily, pre-meal, and 2-h post-meal glucose semaglutide 14 mg was –1·47% (0·06; figure 2A; values at week 52 compared with both semaglutide appendix pp 29–30). Both orforglipron doses were non- doses, with both doses of orforglipron maintaining the inferior and also superior to both doses of semaglutide, mean glucose concentrations below 144 mg/dL with estimated treatment dierences ranging from –0·24 (8 mmol/L)21 at every timepoint measured throughout to –0·68 (figure 2A; appendix pp 29–30). Similar results the day (ecacy estimand; figure 2F). and identical inferences were obtained for the ecacy Both orforglipron groups had significant weight estimand (figure 2B; appendix pp 31–32). Participants reductions from baseline, starting from week 4 and assigned to orforglipron groups had greater dose-related continuing to week 52 (figure 3A, B). For the treatment mean improvements in HbA₁ than those assigned to regimen estimand, from a mean overall baseline c semaglutide groups, beginning at week 4 (the earliest bodyweight of 97·0 kg, mean percentage bodyweight timepoint measured) and continuing for 52 weeks changes to week 52 were –6·1% (SE 0·4) with orforglipron (figure 2A, B). The final mean HbA₁ at end of treatment 12 mg, –8·2% (0·4) with orforglipron 36 mg, –3·9% (0·3) c was 6·4% (SE 0·06) in the orforglipron 12 mg group, with semaglutide 7 mg, and –5·3% (0·3) with 6·1% (0·05) in the orforglipron 36 mg group, 7·2% semaglutide 14 mg (figure 3A; appendix pp 29–30). With (0·06) in the semaglutide 7 mg group, and 6·8% (0·06) the exception of orforglipron 12 mg versus semaglutide in the semaglutide 14 mg group (ecacy estimand; 14 mg, for which the comparison was not significant appendix p 23). (estimated treatment dierence –0·8; 95% CI –1·7 to 0·2), Compared with semaglutide, both orforglipron groups orforglipron treatment was superior to semaglutide for had a significantly higher proportion of participants who weight loss with estimated treatment dierences reached HbA₁ target values of less than 7·0% (307 [72%] of –2·3% (95% CI –3·2 to –1·3; p<0·0001) with c of 424 on orforglipron 12 mg and 321 [76%] of 423 on orforglipron 12 mg versus semaglutide 7 mg, –4·3% orforglipron 36 mg vs 228 [54%] of 426 on semaglutide (–5·3 to –3·3; p<0·0001) with orforglipron 36 mg versus 7 mg and 270 [64%] of 425 on semaglutide 14 mg), 6·5% or semaglutide 7 mg, and –2·8% (–3·9 to –1·9; p<0·0001) less (266 [63%] on orforglipron 12 mg and 287 [68%] on with orforglipron 36 mg versus semaglutide 14 mg orforglipron 36 mg vs 162 [38%] on semaglutide 7 mg (figure 3A; appendix pp 29–30). Results for mean change and 204 [48%] on semaglutide 14 mg), and less than 5·7% from baseline in bodyweight (kg) are presented in the (91 [21%] on orforglipron 12 mg and 133 [31%] on appendix (pp 25, 29–30). Both orforglipron doses were orforglipron 36 mg vs 31 [7%] on semaglutide 7 mg and 50 superior to both doses of semaglutide in terms of mean [12%] on semaglutide 14 mg) at week 52 for treatment percent change in bodyweight for the ecacy estimand regimen estimand (figure 2C; appendix pp 29–30). Of (figure 3B; appendix pp 31–32). Mean reductions in those who had HbA₁ of less than 5·7%, all (100%) bodyweight and percentage bodyweight with orforglipron c 91 participants in the orforglipron 12 mg group, 130 (98%) were dose dependent (figure 3B; appendix p 25). Greater of 133 in the orforglipron 36 mg group, and 30 (97%) of 31 proportions of participants treated with orforglipron in the semaglutide 7 mg group, and all (100%) 50 in the than those treated with semaglutide had reductions in semaglutide 14 mg group did so without level 2 or 3 bodyweight of 5% or more (orforglipron 250 [59%] on hypoglycaemia. Similar significantly higher proportions 12 mg and 295 [69%] on 36 mg vs semaglutide 157 [37%] of participants on orforglipron achieving HbA₁ targets on 7 mg and 208 [49%] on 14 mg), 10% or more c were observed for the ecacy estimand (figure 2D). (orforglipron 119 [28%] on 12 mg and 185 [44%] on 36 mg In a prespecified subgroup analysis, the change from vs semaglutide 56 [13%] on 7 mg and 88 [21%] on 14 mg), baseline in HbA₁ favoured orforglipron compared with and 15% or more (orforglipron 51 [12%] on 12 mg and 100 c both doses of semaglutide in each baseline HbA₁ [23%] on 36 mg vs semaglutide 21 [5%] on 7 mg and c subgroup. Participants with baseline HbA₁ of more 27 [6%] on 14 mg; ecacy estimand; figure 3C; c than 8·0% had larger reductions in HbA₁ appendix 31–32). Mean reduction in waist circumference c (orforglipron –2·1% [SE 0·1] on 12 mg and –2·6% [0·1] and BMI was larger in participants treated with on 36 mg vs semaglutide –1·7% [0·08] on 7 mg and –2·0% orforglipron 36 mg than all other groups (figure 3D; [0·09] on 14 mg) than those with a baseline HbA₁ appendix p 26). c of 8·0% or less (orforglipron –1·2% [SE 0·06] on 12 mg At week 52, for the ecacy estimand, there were and –1·2% [0·1] on 36 mg vs semaglutide 0·7% [0·07] on improvements from baseline in non-HDL cholesterol, 7 mg and –0·9% [0·07] on 14 mg; appendix p 24). triglycerides, VLDL cholesterol, total cholesterol, and Fasting serum glucose decreased from baseline to HDL cholesterol in most treatment groups (figure 3E; week 52 with greater reductions observed with appendix p 34). Mean systolic blood pressure decreased orforglipron than semaglutide beginning at week 4 and over the course of the study in all groups, with greater continuing to week 52 (ecacy estimand; figure 2E). decreases with orforglipron 12 mg and 36 mg than with Based on participant self-monitored blood glucose semaglutide 7 mg and 14 mg (figure 3F). No clinically profiles, treatment with both orforglipron doses was relevant dierences were observed in mean change from associated with a greater reduction from baseline in baseline in diastolic blood pressure across the www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 7 Articles –0·5 –1·0 –1·5 –2·0 –2·5 –100 Orforglipron Orforglipron Semaglutide Semaglutide 12 mg 36 mg 7 mg 14 mg 8 www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 )%( enilesab morf egnahc AbH c1 A HbA1c change from base line (mmol/mol) B 0 0 –5·5 –10·9 –1·23 –16·4 –1 –1·47 –1·71 –21·9 –1·91 ETD –0·68 (95% CI –0·85 to –0·50) –27·3 p<0·0001 ETD –0·44 (95% CI –0·62 to –0·26) –2 p<0·0001 ETD –0·48 (95% CI –0·65 to –0·31) p<0·0001 ETD –0·24 (95% CI –0·41 to –0·07) p=0·0050 –3 )%( AbH ni enilesab morf egnahC c1 Change from baseline in HbA1c (mmol/mol) 0·0 –10·9 –1·11% –1·45% –1·91% –21·9 –2·16% Overall mean baseline HbA1c 8·3% –32·8 0 4 8 12162024 40 52 52* Time since randomisation (weeks) p<0·0001 p<0·0001 p<0·0001 p<0·0001 80 40 0 )%( tegrat AbH htiw stnapicitraP c1 C p=0·0002 p<0·0001 p<0·0001 p<0·0001 p=0·0080 p<0·0001 p<0·0001 p<0·0001 76 80 72 68 64 63 60 54 38 40 21 12 0 HbA1c <7·0% HbA1c ≤6·5% HbA1c <5·7% )%( tegrat AbH htiw stnapicitraP c1 D p<0·0001 p<0·0001 p<0·0001 p<0·0001 p<0·0001 p<0·0001 p<0·0001 p<0·0001 80 72 66 51 37 13 HbA1c <7·0% HbA1c ≤6·5% HbA1c <5·7% E –20 –40 –60 –80 )Ld/gm( GSF ni enilesab morf egnahC Change from baseline in FSG (mmol/L) F 0 250 –1·1 200 –29 mg/dL –40 mg/dL –2·2 –55 mg/dL –60 mg/dL –3·3 Overall mean baseline FSG 169 mg/dL –4·4 100 0 4 8 12 16 20 24 40 52 Time since randomisation (weeks) )ld/gm( esoculg doolb derotinom-fles tniop-7 Orforglipron 12 mg Semaglutide 7 mg Orforglipron 36 mg Semaglutide 14 mg Baseline <144 mg/dL Week 52 Morning pre m M e ( o a f r a l n s i t n i n g g ) h post me M al idday pr M e m idd ea a l y h post me E a v l ening p E re v m en e i a n l g h post meal Bedti me Articles orforglipron groups and semaglutide groups (appendix discontinued the study drug due to gastrointestinal p 28). adverse events was higher in orforglipron groups than Adverse events were reported by 317 (75%) of semaglutide groups (table 2). 424 participants receiving orforglipron 12 mg, 318 (75%) Clinically significant (level 2) hypoglycaemia (blood of 423 participants receiving orforglipron 36 mg, glucose <54 mg/dL [<3·0 mmol/L]) was reported in three 303 (71%) of 426 participants receiving semaglutide 7 mg, (1%) participants receiving orforglipron 12 mg, four (1%) and 308 (72%) of 425 participants receiving semaglutide receiving orforglipron 36 mg, two (<1%) receiving 14 mg (table 2). Permanent treatment discontinuations semaglutide 7 mg, and one (<1%) receiving semaglutide due to adverse events occurred in 37 (9%) of participants 14 mg; one case of severe hypoglycaemia was reported in receiving orforglipron 12 mg, 41 (10%) receiving a participant receiving orforglipron 36 mg (table 2). This orforglipron 36 mg, 19 (4%) receiving semaglutide 7 mg, participant reported skipping meals over the 3-day period and 21 (5%) receiving semaglutide 14 mg (table 2). preceding the hypoglycaemia event. The participant The frequency of serious adverse events was similar continued study treatment and did not report any between the orforglipron 12 mg and both semaglutide subsequent level 2 or severe hypoglycaemia events. No groups (table 2; appendix p 35). Although the overall participant discontinued the study drug due to hypo- frequency of serious adverse events was higher in the glycaemia. More participants assigned to semaglutide orforglipron 36 mg group than the other groups, about than to orforglipron required rescue therapy for half of the participants had these serious events before persistent severe hyperglycaemia during the study escalating to the 36 mg dose (table 2; appendix p 35). (table 2). There were four deaths overall: three deaths were Four cases of adjudication-confirmed acute pancreatitis adjudicated to a cardiovascular cause (one in the were reported: two in the orforglipron 12 mg group and orforglipron 12 mg group and two in semaglutide 7 mg two in the semaglutide 14 mg group (table 2). No cases of group) and one death in the orforglipron 36 mg group pancreatic cancer were reported. was adjudicated to non-cardiovascular cause (a No cases of medullary thyroid cancer were reported, malignancy; appendix p 36). and papillary thyroid cancer was reported in a participant The most frequent adverse events reported were in the orforglipron 12 mg group (<1%) and a participant gastrointestinal-related and occurred more frequently in the semaglutide 14 mg group (<1%). with orforglipron than semaglutide (table 2). Most Mean pulse rate increased in both participants assigned reports of nausea, diarrhoea, and vomiting in the orforglipron and those assigned semaglutide (appendix orforglipron groups were mild to moderate in severity p 28). At week 52, mean increases in pulse rate were (appendix p 37), occurred early in the study during the greater in the orforglipron groups (12 mg 3·7 bpm; dose escalation period, and diminished over time 36 mg 4·7 bpm) than the semaglutide groups (7 mg (appendix p 27). The proportion of participants who 1·0 bpm; 14 mg 1·5 bpm). Despite higher mean increases from baseline in pulse rate, the proportion of people with treatment-emergent tachycardia (pulse rate >100 bpm) or persistent tachycardia (pulse rate >100 bpm at two or Figure 2: HbA changes, proportion of participants meeting HbA targets, FSG, and 7-po 1c int self-monitored blood glucose profiles 1c more consecutive visits) was similar between orforglipron (A) Change from baseline in HbA at 52 weeks from ANCOVA with multiple and semaglutide, as were the incidences of adverse 1c imputation by treatment for missing HbA 1c data at 52 weeks (treatment events related to supraventricular tachyarrhythmias and regimen estimand). (B) Change from baseline in HbA over time. Data are 1c tachycardias (appendix p 38). A total of 19 (1·1%) of all observed mean (SE), with MBE (SE) and MMRM analysis (efficacy estimand) shown in the side panel. (C) Proportion of participants meeting HbA 1698 participants had an adjudication-confirmed major 1c targets <7·0%, ≤6·5%, and <5·7% at 52 weeks (treatment regimen estimand) adverse cardiovascular event and incidence was similar with p values for risk difference; the proportion of participants with HbA 1c across treatment groups (table 2). <5·7% was not controlled for type 1 errors; the proportion was calculated with Mean estimated glomerular filtration rate decreased imputed data from a logistic regression model with primary multiple imputation. (D) Proportion of participants with HbA targets <7·0%, throughout the 52 weeks in all groups (–3·1 to –5·4 mL 1c ≤6·5%, and <5·7% at 52 weeks (efficacy estimand) with p values for risk per min per 1·73 m²) with no clinically relevant difference; the proportion of participants with HbA <5·7% was not controlled 1c dierences between the orforglipron and semaglutide for type 1 errors; the proportion was calculated with imputed data from logistic groups (appendix p 39). Urine albumin to creatinine regression with multiple imputation under a missing at random assumption. (E) Change from baseline in FSG over time from MMRM analysis (efficacy ratio also decreased in all groups, with greater percentage estimand); this endpoint was not controlled for type 1 error. (F) 7-point self- reductions with orforglipron (–31·4% [SE 3·0] on 12 mg monitored blood glucose profiles at baseline and week 52 from MMRM (efficacy and –32·5% [3·1] on 36 mg) versus semaglutide (–14·5% estimand). Data are MBE (SE), unless otherwise noted, at 52 weeks for all [4·2] on 7 mg and –23·8% [3·5] in 14 mg) at week 52 randomly assigned participants. The primary and key secondary objectives were tested under a multiplicity-controlled procedure at a two-sided α level of 0·05 (appendix p 39). and p values presented are unadjusted two-sided for superiority. Arrows indicate Based on evaluation of fundus photographs collected at when the randomly assigned dose of orforglipron 12 mg or 36 mg and baseline, 234 (14%) of 1696 participants assessed had semaglutide 7 mg or 14 mg were achieved (end of lead-in period). FSG=fasting diabetic retinopathy at baseline, primarily mild non- serum glucose. ETD=estimated treatment differences. MBE=model-based estimate. MMRM=mixed model repeated measures. *MBE (SE). proliferative retinopathy (178 [10%] of 1696; appendix www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 9 Articles –2 –4 –3·9 –6 –5·3 –6·1 –8 –8·2 –10 p<0·0001 –12 p<0·0001 p<0·0001 –100 10 www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 )%( enilesab morf egnahc thgiewydoB A B Overall mean baseline bodyweight 97·0 kg Orforglipron Orforglipron Semaglutide Semaglutide 0 4 812162024 32 40 52 52* 12 mg 36 mg 7 mg 14 mg Time since randomisation (weeks) p<0·0001 p<0·0001 p<0·0001 –2 –4 –3·7% –5·3% –6 –6·7% –8 –9·2% –10 –12 –100 )%( enilesab morf egnahc thgiewydoB 80 40 0 thgiewydob gniteem stnapicitraP )%( tegrat ssol C D Overall mean baseline waist circumference 112·3 cm 69 –2 49 43 –4 28 21 23 –6 13 12 5 6 –8 ≥5% weight loss ≥10% weight loss ≥15% weight loss 0 8 16 24 32 40 52 Time since randomisation (weeks) egnahc ecnerefmucric tsiaW )mc( enilesab morf –3·7 cm –5·1 cm –5·8 cm –7·4 cm 0 –10 –20 –100 )%( enilesab morf egnahc elfiorp dipiL E 6·8 6·3 5·4 3·9 2·0 0·2 –0·5 –2·1–1·9 –2·9 –1·9–2·5 –5·0 –5·5 –4·3 –4·3 –5·4 –7·7 –12·5 –13·4 –14·8 –16·0 –14·9 –16·9 Triglycerides Non-HDL HDL Total cholesterol LDL VLDL F Overall mean baseline systolic blood pressure 129·2 mm Hg –2 –2·0 mm Hg –2·7 mm Hg –4 –4·5 mm Hg –5·4 mm Hg –6 –8 egnahc erusserp doolb cilotsyS )gH mm( enilesab morf Figure 3: Bodyweight changes, proportion of participants achieving weight loss targets, lipid profiles, and systolic blood pressure changes (A) Percentage change from baseline in bodyweight at 52 weeks from ANCOVA with multiple imputation by treatment for missing weight at 52 weeks (treatment regimen estimand); orforglipron 12 mg versus semaglutide 14 mg was not controlled for type 1 errors. (B) Percentage change from baseline in bodyweight over time; data are observed mean (SE), with MBE (SE) and MMRM analysis (efficacy estimand) shown in the side panel; orforglipron 12 mg versus semaglutide 14 mg was not controlled for type 1 error. (C) Proportion of participants with weight loss ≥5%, ≥10%, and ≥15% (efficacy estimand); these endpoints were not controlled for type 1 errors; the proportion was calculated with imputed data from logistic regression with multiple imputation under a missing- at-random assumption. (D) Change from baseline in waist circumference over time from MMRM (efficacy estimand); this endpoint was not controlled for type 1 errors. (E) Percentage change from baseline in lipids at 52 weeks; data are estimated percentage means (SE) with log transformation; these endpoints were not controlled for type 1 errors. (F) Change from baseline in systolic blood pressure over time from MMRM (efficacy estimand); this endpoint was not controlled for type 1 errors. Data are MBE (SE), unless otherwise noted, at 52 weeks Orforglipron 12 mg for all randomly assigned Orforglipron 36 mg participants. Arrows indicate Semaglutide 7 mg when the randomly assigned Semaglutide 14 mg dose of orforglipron 12 mg or 36 mg and semaglutide 7 mg or 14 mg were achieved. The primary and key secondary objectives were tested under a multiplicity-controlled procedure at a two-sided α level of 0·05 and p values presented are unadjusted two-sided for superiority. MBE=model-based estimate. 0 4 8 12 16 20 24 32 40 52 MMRM=mixed model Time since randomisation (weeks) repeated measures. *MBE (SE). Articles p 40). The proportion of participants with worsening in semaglutide 7 mg; appendix p 40). Overall, 84 (4·9%) of diabetic retinopathy category on fundus photographs 1698 participants had an adverse event of diabetic was similar across orforglipron and semaglutide groups retinopathy or a potentially related complication, with a in the total population (23 [6%] of 358 on orforglipron similar frequency across the orforglipron and 12 mg, 27 [8%] of 360 on orforglipron 36 mg, 26 [7%] semaglutide groups (table 2). None of the adverse events of 381 on semaglutide 14 mg, and 29 [8%] of 371 on of diabetic retinopathy resulted in visual loss and no semaglutide 7 mg) and in the subset with diabetic ophthalmological interventions were reported related to retinopathy at baseline (nine [18%] of 51 on orforglipron these events. 12 mg, ten [18%] of 55 on orforglipron 36 mg, seven Mean reductions in ALT and AST from baseline were [13%] of 53 on semaglutide 14 mg, and 12 [24%] of 49 on observed across all groups at week 52 (appendix p 39). Orforglipron Orforglipron Semaglutide Semaglutide Overall 12 mg (n=424) 36 mg (n=423) 7 mg (n=426) 14 mg (n=425) (n=1698) Participants with ≥1 treatment-emergent adverse event 317 (75%) 318 (75%) 303 (71%) 308 (72%) 1246 (73·4%) Serious adverse events 21 (5%) 40 (9%) 19 (4%) 24 (6%) 104 (6·1%) Deaths 1 (<1%) 1 (<1%) 2 (<1%) 0 4 (0·2%) Adverse event leading to study treatment discontinuation 37 (9%) 41 (10%) 19 (4%) 21 (5%) 118 (6·9%) Gastrointestinal adverse events leading to study treatment 26 (6%) 25 (6%) 11 (3%) 13 (3%) 75 (4·4%) discontinuation Nausea 6 (1%) 5 (1%) 3 (1%) 4 (1%) 18 (1·1%) Vomiting 6 (1%) 9 (2%) 3 (1%) 4 (1%) 22 (1·3%) Diarrhoea 2 (<1%) 5 (1%) 4 (1%) 0 11 (0·6%) Abdominal pain 2 (<1%) 3 (1%) 0 0 5 (0·3%) Dyspepsia 5 (1%) 1 (<1%) 0 0 6 (0·4%) Decreased appetite 0 3 (1%) 1 (<1%) 0 4 (0·2%) Constipation 0 0 0 1 (<1%) 1 (0·1%) Treatment-emergent adverse events occurring in ≥5% of participants in any treatment group by preferred term Nausea 111 (26%) 114 (27%) 54 (13%) 90 (21%) 369 (21·7%) Diarrhoea 91 (21%) 97 (23%) 55 (13%) 76 (18%) 319 (18·8%) Vomiting 72 (17%) 70 (17%) 32 (8%) 44 (10%) 218 (12·8%) Dyspepsia 47 (11%) 43 (10%) 18 (4%) 33 (8%) 141 (8·3%) Decreased appetite 30 (7%) 29 (7%) 21 (5%) 27 (6%) 107 (6·3%) Hyperglycaemia 25 (6%) 20 (5%) 68 (16%) 32 (8%) 145 (8·5%) Eructation 42 (10%) 31 (7%) 17 (4%) 14 (3%) 104 (6·1%) Abdominal distension 24 (6%) 34 (8%) 11 (3%) 14 (3%) 83 (4·9%) Gastro-oesophageal reflux disease 23 (5%) 24 (6%) 12 (3%) 18 (4%) 77 (4·5%) Constipation 56 (13%) 51 (12%) 32 (8%) 38 (9%) 177 (10·4%) Abdominal pain 21 (5%) 25 (6%) 13 (3%) 14 (3%) 73 (4·3%) Hypertension 10 (2%) 10 (2%) 14 (3%) 22 (5%) 56 (3·3%) Flatulence 22 (5%) 12 (3%) 14 (3%) 7 (2%) 55 (3·2%) All gastrointestinal adverse events 249 (59%) 245 (58%) 157 (37%) 193 (45%) 844 (49·7%) Other adverse events of interest Hypoglycaemia (blood glucose <54 mg/dL)* 3 (1%) 4 (1%) 2 (<1%) 1 (<1%) 10 (0·6%) Severe hypoglycaemia* 0 1 (<1%) 0 0 1 (0·1%) Severe persistent hyperglycaemia requiring rescue therapy 15 (4%) 12 (3%) 56 (13%) 25 (6%) 108 (6·4%) Adjudication-confirmed pancreatitis 2 (<1%) 0 0 2 (<1%) 4 (0·2%) Thyroid malignancies† 1 (<1%) 0 0 1 (<1%) 2 (0·1%) Gallbladder disorders 5 (1%) 6 (1%) 3 (1%) 4 (1%) 18 (1·1%) Cholelithiasis 4 (1%) 6 (1%) 3 (1%) 3 (1%) 16 (0·9%) Diabetic retinopathy, diabetic macular oedema, and related 21 (5%) 18 (4%) 26 (6%) 19 (4%) 84 (4·9%) complications‡ Adjudication-confirmed major adverse cardiovascular events 4 (1%) 4 (1%) 8 (2%) 3 (1%) 19 (1·1%) Data are n (%) for safety participants (all participants who received at least one dose of the study drug). *Excluding hypoglycaemic events occurring after initiation of any new antihyperglycaemic therapy. †No cases of medullary thyroid cancer were reported, and papillary thyroid cancer was reported in one (<1%) participant in the orforglipron 12 mg group and one (<1%) participant in the semaglutide 14 mg group. ‡Based on MedDRA Preferred Term search defined in appendix (p 40). Table 2: Adverse events in the safety population www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 11 Articles The percentage of participants with ALT or AST at least waist circumference and improving systolic blood 3 times, at least 5 times, or at least 10 times the upper pressure and lipid measures to a greater extent than limit of normal at any point after baseline was generally semaglutide, merits further investigation and these similar between orforglipron and semaglutide groups results might suggest a role for orforglipron in managing (appendix p 41). No-one met Hy’s Law criteria for cardiometabolic risk factors. A cardiovascular outcomes hepatocellular drug-induced liver injury. study of orforglipron is currently underway Improvements from baseline to week 52 were seen in (NCT07241390) and will identify whether these eects, in all Short Form–36 Health Survey domain and component combination with HbA₁ and weight reductions will c summary scores in all treatment groups (ecacy translate to improved cardiovascular outcomes. estimand; appendix p 43). The safety profile of orforglipron and semaglutide in this trial was generally consistent with the GLP-1 receptor Discussion agonist class in people with type 2 diabetes,25,26 although ACHIEVE-3 is the first study to directly compare the there were some slight dierences regarding ecacy and safety of two oral GLP-1 receptor agonists in gastrointestinal events and pulse rate. The most common a randomised controlled trial. It showed that both 12 mg adverse events were mostly mild-to-moderate gastro- and 36 mg orforglipron doses were superior to both 7 mg intestinal symptoms. Gastrointestinal events were and 14 mg semaglutide doses in reducing HbA₁ and reported more frequently in the orforglipron groups than c meeting HbA₁ targets of less than 7·0% and 6·5% or the semaglutide groups, and a higher proportion of c less at week 52, in a dose-dependent manner. The participants in the orforglipron groups discontinued dierence in glycaemic control was already significant at treatment due to these events. Increases from baseline in week 4 and was sustained until the end of the trial pulse and heart rate is a well established class eect of (week 52) for orforglipron. In a prespecified analysis for GLP-1 receptor agonists but were greater with orforglipron participants with higher baseline HbA₁ (>8·0%), (mean increase of 4–5 bpm) than semaglutide (mean c orforglipron further showed particularly robust ecacy increase of 1–2 bpm) in this study. Selection between oral with reductions of up to 2·6%, compared with 2·0% for options for GLP-1 receptor agonists could ultimately be those receiving semaglutide. guided by prioritisation of glycaemic control, weight In terms of therapeutic targets, 72–76% of participants reduction, and proven cardiovascular disease risk on orforglipron and 54–64% of participants on reduction, balanced against individual dierences in semaglutide met the recommended HbA₁ level of less tolerability (including sensitivity to gastrointestinal c than 7·0%.22 In ACHIEVE-3, only 7–12% of participants symptoms), administration con venience, and other receiving semaglutide developed near normoglycaemia patient-specific factors. (HbA₁ <5·7%) compared with 21–31% with orforglipron, Serious adverse events were balanced between c of these, 98–100% did not have level 2 or 3 hypoglycaemia. orforglipron 12 mg (5%) and semaglutide 7 mg (4%) and These data show that stricter glycaemic targets, 14 mg (6%) groups; however, they were slightly higher in beyond 6·5%, could now be feasibly and safely achieved the orforglipron 36 mg group (9%), although most with oral therapy. serious adverse events in this group occurred before Weight reduction can lead to clinical and metabolic receiving maintenance dose. Treatment discontinuation improvements and diabetes reversion to normoglycaemia, rates due to gastrointestinal adverse events in the in addition to reducing the risk of weight-related orforglipron groups were higher than the semaglutide complications.22 Participants receiving orforglipron had groups, and consistent with previously completed significantly greater reductions in bodyweight than those phase 3 orforglipron trials in people with obesity or receiving semaglutide, which also translated into the overweight without type 2 diabetes.27 Discontinuation proportion of participants meeting clinically meaningful rates due to gastrointestinal adverse events in the weight reduction thresholds. Weight reduction in the semaglutide groups were lower than equivalent doses in range of 5–15% has been recommended as the primary previous semaglutide phase 3 trials.26,28 Adverse events target of management for many people living with type 2 related in general to supraventricular tachyarrhythmias diabetes, with 5–10% weight reduction conferring or specifically tachycardia were infrequent and balanced metabolic improvements and more than 10% weight across treatment groups. reduction having disease-modifying eects, including Other safety outcomes of relevance to the GLP-1 receptor potential remission of diabetes and reduction in agonist class were balanced across treatment groups, cardiovascular risk.23,24 There was a weight reduction of 5% including the occurrence of adjudication-confirmed or more in 59–69% of participants on orforglipron and pancreatitis and major adverse cardiovascular events, 37–49% of participants on semaglutide, and 28–43% of thyroid malignancies, gallbladder disorders, and changes participants on orforglipron and 13–21% of participants in diabetic retinopathy. Hepatic safety was closely on semaglutide had a weight reduction of 10% or more. monitored and was similar across the two drugs. Oral semaglutide has shown cardiovascular risk Strengths of this trial include a large and diverse reduction in the SOUL trial.16 Orforglipron, by reducing population across multiple countries and consistency of 12 www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 Articles results. The reductions in HbA₁ concentration and Pharmaceutical, Novo Nordisk, and Arkray; consulting fees from Kansai c bodyweight observed with orforglipron were consistent Medical Net, Eli Lilly, Novo Nordisk, Sanofi, and Boehringer Ingelheim; payments or honoraria from Mitsubishi Tanabe, Ono Pharmaceutical, with the results already reported in ACHIEVE-119 and Boehringer Ingelheim, Kowa, Sumitomo Pharmaceutical, Eli Lilly, Novo ATTAIN-2,25 while the glycaemic ecacy of semaglutide Nordisk, Sanofi, and Taisho Pharmaceutical; roles in International was consistent with the PIONEER phase 3 trials, indicating Diabetes Federation Western Pacific Region (Executive Board), that trial conditions and execution were appropriate to The European Association for the Study of Diabetes (Global Council), The Japan Association for Diabetes Care and Education (Executive detect treatment dierences in this comparison. Board), The Japan Society of Clinical Nutrition and Metabolism Limitations include the open-label design, despite (Executive Board), The Japan Society of Diabetes Complication being masked to orforglipron doses, which could have (Executive Board), The Asian Association for the Study of Diabetes introduced bias in subjective assessments, such as (Executive Board), The Japan Diabetes Society (Auditor), The Japan Endocrine Society (Executive Board), The Japan Society of Constitutional patient-reported outcomes. Although primary and key Medicine (Executive Board), and The Japan Society of Informatics for secondary ecacy endpoints (HbA₁ c and weight) are Diabetes Mellitus (Vice President). objective measures less susceptible to bias, the awareness Data sharing of treatment assignment could still influence patient Eli Lilly provides access to all individual participant data collected behaviour and adverse event reporting. Other limitations during the trial, after anonymisation, with the exception of include that self-reported gastrointestinal adverse events pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and EU or represent a potential source of bias, although this after primary publication acceptance, whichever is later. No expiration reporting method is standard in most clinical trials, and date of data requests is currently set once data are made available. that a treatment duration beyond 52 weeks could be Access is provided after a proposal has been approved by an designed to collect longer-term safety data. independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, In conclusion, oral orforglipron was non-inferior and including the study protocol, statistical analysis plan, clinical study superior to semaglutide in terms of ecacy, with report, and blank or annotated case report forms, will be provided in a meaningful improvements in glycaemic control and secure data sharing environment. For details on submitting a request, weight reduction compared with oral semaglutide in see the instructions provided at www.vivli.org. patients with type 2 diabetes, and with larger Acknowledgments improvements in cardiometabolic risk factors and This study was funded by Eli Lilly. We thank all the clinical trial participants and their caregivers, investigators, and research team simplified administration. The overall safety profile of members. We also thank Eli Lilly employees Kendra Terrell and both orforglipron and semaglutide were consistent with Kristina Boye for providing the Short Form–36 Health Survey Version 2 the GLP-1 receptor agonist class, although patients data, Emer Farrell, Adele Crouch, Richa Kapoor, and Seán Curley for receiving orforglipron had a higher incidence of medical writing and editorial support, and Filmon Emnetu for clinical trial management support. gastrointestinal events and larger mean increases in pulse References rate than those receiving oral semaglutide. Orforglipron 1 Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists represents a potential new therapeutic option for in the treatment of type 2 diabetes—state-of-the-art. Mol Metab individuals with type 2 diabetes considering initiation of 2021; 46: 101102. GLP-1 receptor agonist therapy who might prefer an 2 Drucker DJ. GLP-1-based therapies for diabetes, obesity and beyond. Nat Rev Drug Discov 2025; 24: 631–50. alternative to the subcutaneous route of administration. 3 Rivera FB, Cruz LLA, Magalong JV, et al. Cardiovascular and renal outcomes of glucagon-like peptide 1 receptor agonists among Contributors patients with and without type 2 diabetes mellitus: a meta-analysis The funder (Eli Lilly) conceived, designed, and supervised the trial, of randomized placebo-controlled trials. Am J Prev Cardiol 2024; which included site monitoring, data collection, and analysis. YZ, DC, 18: 100679. W-SW, and MD contributed to the study design. YZ and MD provided 4 Moiz A, Zolotarova T, Filion KB, Eisenberg MJ. GLP-1 receptor medical oversight during the trial. JL and RL were responsible for the agonists and blood pressure: a state-of-the-art review of data curation, formal analysis, validation, visualisation, and editing of mechanisms, evidence, and clinical implications. Am J Hypertens statistical analyses. JR and YZ wrote the first draft of the manuscript. 2025; published online Oct 23. https://doi.org/10.1093/ajh/hpaf205. JR, DY, YZ, DC, W-SW, RL, and MD drafted the manuscript. All authors 5 Liao C, Liang X, Zhang X, Li Y. The eects of GLP-1 receptor participated in the interpretation of the data and critical review of the agonists on visceral fat and liver ectopic fat in an adult population manuscript, approved the final and previous versions of the manuscript, with or without diabetes and nonalcoholic fatty liver disease: had full access to all the data in the study, and had final responsibility for a systematic review and meta-analysis. PLoS One 2023; 18: e0289616. the decision to submit for publication. 6 Yao H, Zhang A, Li D, et al. Comparative eectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid Declaration of interests profile for type 2 diabetes: systematic review and network meta- JL, MD, W-SW, RL, DC, and YZ are current employees and shareholders analysis. BMJ 2024; 384: e076410. of Eli Lilly. JR has served on scientific advisory boards and received 7 Suter B, Rhodes A, Bigeh A, Frommeyer T, Mehta LS. The role of honoraria or consulting fees from Amgen, Applied Therapeutics, GLP-1RA medications in medical weight loss and the positive Biomea Fusion, Boehringer Ingelheim, Corcept, Eccogene, Eli Lilly, impacts on lipid management. Curr Cardiovasc Risk Rep 2025; 19: 11. Novo Nordisk, Oramed Pharmaceuticals, Regeneron, Regor, Sanofi, 8 Kawai T, Sun B, Yoshino H, et al. Structural basis for GLP-1 Scholar Rock, Structure Therapeutics, and Terns Pharmaceuticals and receptor activation by LY3502970, an orally active nonpeptide has received grants and research support from Amgen, Applied agonist. Proc Natl Acad Sci USA 2020; 117: 29959–67. Therapeutics, Biomea Fusion, Boehringer Ingelheim, Corcept, Eli Lilly, 9 Boye KS, Mody R, Lage MJ, Malik RE. The relationship between Hanmi Pharmaceutical, Merck, Novo Nordisk, Oramed Pharmaceuticals, timing of initiation on a glucagon-like peptide-1 receptor agonist Pfizer, Regeneron, Regor, Sanofi, Structure Therapeutics, and Terns and glycosylated hemoglobin values among patients with type 2 Pharmaceuticals. DY reports support from Eli Lilly for the present diabetes. 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Diabetes Care 2019; small-molecule GLP-1 receptor agonist, in early type 2 diabetes. 42: 2272–81. N Engl J Med 2025; 393: 1065–76. 14 www.thelancet.com Published online February 26, 2026 https://doi.org/10.1016/S0140-6736(26)00202-3 --- [PDF原文](https://sci-net.xyz/storage/7286337/88f9488de085046aef4ea8d3e4a4efab575b749a28a489a04f1effbc43dc1c80/Efficacy-and-safety-of-once-daily-oral-orforglipron-compared-with-oral-semaglutide-in-adults.pdf) DOI: 10.1016/S0140-6736(26)00202-3