Lilly's oral GLP-1, orforglipron, superior to oral semaglutide in head-to-head trial
Eli Lilly (NYSE:LLY) announced positive topline results from ACHIEVE-3, a Phase 3 head-to-head trial comparing its oral GLP-1 drug orforglipron against oral semaglutide in 1,698 adults with type 2 diabetes. The 52-week trial demonstrated orforglipron's superiority, with the highest dose (36mg) achieving a 2.2% A1C reduction versus 1.4% with oral semaglutide's highest dose (14mg).
In key secondary endpoints, orforglipron 36mg showed 73.6% greater relative weight loss, with patients losing an average of 19.7 lbs (9.2%) compared to 11.0 lbs (5.3%) with oral semaglutide 14mg. Notably, 37.1% of participants on the highest orforglipron dose achieved near-normal blood sugar (A1C <5.7%) versus 12.5% for oral semaglutide. Lilly plans to submit orforglipron for regulatory approval in 2026.
Eli Lilly (NYSE:LLY) ha comunicato risultati positivi di topline da ACHIEVE-3, un trial di fase 3 head-to-head che confronta il suo farmaco orale GLP-1 orforglipron con l’orale semaglutide in 1.698 adulti con diabete di tipo 2. Il trial di 52 settimane ha dimostrato la superiorità di orforglipron, con la dose più alta (36 mg) che ha ottenuto una riduzione A1C del 2,2% contro il 1,4% della dose più alta di semaglutide orale (14 mg).
Negli endpoint secondari chiave, orforglipron 36 mg ha mostrato una riduzione relativa del peso del 73,6% superiore, con una perdita media di 9,2% (19,7 libbre) rispetto al 5,3% (11,0 libbre) con semaglutide orale 14 mg. In particolare, il 37,1% dei partecipanti alla dose più alta di orforglipron ha raggiunto livelli di colesterolo nel sangue quasi normali (A1C < 5,7%), contro il 12,5% per semaglutide orale. Lilly intende presentare orforglipron per l’approvazione regolatoria nel 2026.
Eli Lilly (NYSE:LLY) anunció resultados positivos de topline de ACHIEVE-3, un ensayo de fase 3 head-to-head que compara su fármaco oral GLP-1 orforglipron con la semaglutida oral en 1.698 adultos con diabetes tipo 2. El ensayo de 52 semanas demostró la superioridad de orforglipron, con la dosis más alta (36 mg) logrando una reducción de A1C del 2,2% frente al 1,4% de la dosis más alta de semaglutida oral (14 mg).
En los principales endpoints secundarios, orforglipron 36 mg mostró una reducción de peso relativa un 73,6% mayor, con una pérdida media de 9,2% (19,7 lb) frente a 5,3% (11,0 lb) con semaglutida oral 14 mg. Cabe destacar que el 37,1% de los participantes con la dosis más alta de orforglipron alcanzó niveles casi normales de azúcar en sangre (A1C < 5,7%) frente al 12,5% de semaglutida oral. Lilly planea presentar orforglipron para aprobación regulatoria en 2026.
Eli Lilly (NYSE:LLY)가 ACHIEVE-3의 긍정적인 topline 결과를 발표했습니다. 이는 경구 GLP-1 약물인 orforglipron과 경구 세마글루타이드의 2형 당뇨병 환자 1,698명을 대상으로 한 3상 직대비 임상입니다. 52주 연구에서 가장 높은 용량 36mg의 orforglipron이 우위를 보였으며, A1C 감소 2.2%를 달성했고 경구 세마글루타이드의 최고 용량 14mg은 1.4%였습니다.
주요 2차 평가항목에서 orforglipron 36mg는 체중 감소가 상대적으로 73.6% 더 크다고 나타났고, 평균 9.2%의 체중 감소(19.7파운드)로 경구 세마글루타이드 14mg의 11.0파운드(5.3%)를 상회했습니다. 특히 최고 용량의 orforglipron을 복용한 참가자의 37.1%가 거의 정상 혈당(A1C < 5.7%)에 도달한 반면 세마글루타이드 경구의 경우 12.5%였습니다. Lilly는 2026년 regulatory approval을 목표로 orforglipron의 제출을 계획하고 있습니다.
Eli Lilly (NYSE:LLY) a annoncé des résultats positifs des topline d’ACHIEVE-3, essai de phase 3 en tête-à-tête comparant son médicament oral GLP-1, l’orforglipron, à la sémapglutide orale chez 1 698 adultes atteints de diabète de type 2. L’essai de 52 semaines a montré la supériorité de l’orforglipron, avec la dose la plus élevée (36 mg) atteignant une réduction de l’A1C de 2,2% contre 1,4% pour la dose maximale de sémapglutide orale (14 mg).
Aux endpoints secondaires clés, l’orforglipron 36 mg a montré une perte de poids relative 73,6% plus importante, avec une moyenne de perte de 9,2% (19,7 lb) contre 5,3% (11,0 lb) avec le sémapglutide oral 14 mg. Notamment, 47,1% des participants à la dose la plus élevée d’orforglipron ont atteint un taux de sucre sanguin presque normal (A1C < 5,7%) contre 12,5% pour le sémapglutide oral. Lilly prévoit de déposer une demande d’approbation réglementaire pour orforglipron en 2026.
Eli Lilly (NYSE:LLY) hat positive Topline-Ergebnisse aus ACHIEVE-3 bekannt gegeben, einer Phase-3-Head-to-Head-Studie, die sein orales GLP-1-Mittel orforglipron mit dem oralen Semaglutid bei 1.698 Erwachsenen mit Typ-2-Diabetes vergleicht. Die 52-Wochen-Studie zeigte die Überlegenheit von orforglipron, wobei die höchste Dosis (36 mg) eine A1C-Senkung von 2,2% erzielte gegenüber 1,4% bei der höchsten Dosis von oralem Semaglutid (14 mg).
Bei wichtigen sekundären Endpunkten zeigte orforglipron 36 mg eine relative Gewichtsabnahme von 73,6% mehr, mit einem durchschnittlichen Verlust von 9,2% (19,7 Pfund) gegenüber 5,3% (11,0 Pfund) bei oralem Semaglutid 14 mg. Bemerkenswert ist, dass 37,1% der Teilnehmer mit der höchsten orforglipron-Dosis nahezu normales Blutzucker-Niveau erreichten (A1C < 5,7%) gegenüber 12,5% für orales Semaglutid. Lilly plant, orforglipron im Jahr 2026 regulatorisch zulassen zu lassen.
إيلي ليلي (NYSE:LLY) أعلنت عن نتائج إيجابية رئيسة من ACHIEVE-3، تجربة عشوائية متقدمة من المرحلة الثالثة تقارن دواء GLP-1 الفموي أورفورغليبрон بسماغلوتايد فموي في 1,698 مريضاً بالغاً مصاباً بمرض السكري من النوع 2. أظهرت تجربة الـ52 أسبوعاً تفوق أورفورغليبрон، حيث حققت الجرعة الأعلى (36 ملغ) انخفاضاً في A1C بنسبة 2.2% مقابل 1.4% مع جرعة السماغلوتايد الفموية الأعلى (14 ملغ).
في end points الثانوية الرئيسية، أظهر أورفورغليبрон 36 mg انخفاض وزن نسبي بنسبة أكبر بمقدار 73.6%، بمعدل فقدان 9.2% (19.7 رطلاً) مقارنة بـ 11.0 رطلاً (5.3%) مع سماغلوتايد فموي 14 mg. من الجدير بالذكر أن 37.1% من المشاركين على أعلى جرعة من أورفورغليبрон وصلوا إلى مستويات سكر دم شبه طبيعية (A1C < 5.7%) مقابل 12.5% للسماغلوتايد الفموي. تخطط ليلي لإيجاز أوفورغليبрон للموافقة التنظيمية في 2026.
Eli Lilly (NYSE:LLY) 宣布 ACHIEVE-3 的 topline 初步结果，该研究为3期头-to-头比较，比较其口服 GLP-1 药物 orforglipron 与口服 semaglutide，在 1,698 名2 型糖尿病成年人中进行。为期 52 周的试验显示 orforglipron 的优越性，最高剂量 (36 mg) 实现 A1C 降低 2.2%，相比口服 semaglutide 最高剂量 (14 mg) 的 1.4%。
在关键次要终点方面，orforglipron 36 mg 显示出相对体重下降 高出 73.6%，平均减重 9.2%（19.7 磅），而口服 semaglutide 14 mg 为 5.3%（11.0 磅）。值得注意的是，使用最高剂量的 orforglipron 的参与者中有 37.1% 实现接近正常的血糖水平（A1C < 5.7%），而口服 semaglutide 为 12.5%。Lilly 计划于 2026 年提交 orforglipron 的监管审批。
- Orforglipron demonstrated superior A1C reduction vs oral semaglutide (2.2% vs 1.4% at highest doses)
- 73.6% greater relative weight loss at highest dose vs competitor (19.7 lbs vs 11.0 lbs)
- 37.1% of participants achieved near-normal blood sugar vs 12.5% with competitor's highest dose
- Clinically meaningful improvements in cardiovascular risk factors
- No hepatic safety signals observed
- Higher treatment discontinuation rates due to adverse events (9.7% vs 4.9% at highest doses)
- Regulatory submission not planned until 2026
- Most common adverse events were gastrointestinal-related
Insights
Lilly's oral GLP-1 orforglipron strongly outperformed Novo's oral semaglutide in diabetes trial, potentially reshaping market dynamics in 2026.
Lilly's head-to-head clinical trial results for orforglipron versus oral semaglutide represent a significant competitive advantage in the lucrative GLP-1 market. The ACHIEVE-3 trial demonstrated orforglipron's superior efficacy across all measured endpoints, with the 36mg dose reducing A1C by 2.2% compared to just 1.4% with oral semaglutide's highest dose—a substantial 57% improvement. Even more impressive, 37.1% of patients on high-dose orforglipron achieved near-normal blood sugar levels (A1C <5.7%) versus only 12.5% with high-dose semaglutide.
The weight loss differential is equally compelling, with orforglipron 36mg producing 9.2% body weight reduction compared to 5.3% with semaglutide 14mg—a 73.6% relative improvement. These efficacy advantages come with slightly higher discontinuation rates due to adverse events (9.7% vs 4.9% at highest doses), though the safety profile remains consistent with previous trials.
Strategically, this positions Lilly to potentially capture significant market share from Novo Nordisk when orforglipron launches, likely in 2026-2027 following regulatory submissions. The once-daily oral dosing provides a substantial convenience advantage over injectable GLP-1s while delivering comparable or better efficacy. The data strengthens Lilly's expanding GLP-1 portfolio, which already includes injectable tirzepatide (Mounjaro/Zepbound). The "broad scalability" mentioned suggests manufacturing advantages that could help Lilly address the supply constraints that have limited GLP-1 market growth. This represents a potential multibillion-dollar commercial opportunity in the rapidly growing diabetes and obesity treatment markets.
Orforglipron shows remarkable clinical superiority over semaglutide in diabetes management with substantially better glycemic control and weight reduction.
The ACHIEVE-3 trial results represent a potential breakthrough in oral diabetes treatment. The glycemic efficacy demonstrated by orforglipron is exceptional—the 36mg dose achieved a 2.2% A1C reduction compared to 1.4% with semaglutide 14mg. This 0.8% additional A1C reduction is clinically meaningful and would significantly improve long-term outcomes for patients.
Most striking is that 37.1% of patients on high-dose orforglipron achieved an A1C below 5.7%—essentially reaching non-diabetic levels—compared to only 12.5% with high-dose semaglutide. This suggests orforglipron could fundamentally change treatment goals from simply "controlling" diabetes to potentially inducing a diabetes remission-like state in a substantial proportion of patients.
The weight loss profile is equally impressive. The 9.2% weight reduction (19.7 lbs) with orforglipron 36mg substantially exceeds semaglutide's 5.3% (11.0 lbs). Combined with improvements in cardiovascular risk markers (non-HDL cholesterol, systolic blood pressure, and triglycerides), this suggests orforglipron could offer comprehensive cardiometabolic benefits beyond glycemic control.
The higher discontinuation rates with orforglipron (9.7% vs. 4.9% at highest doses) suggest somewhat greater gastrointestinal side effects, which is the typical limiting factor for GLP-1 medications. However, this is expected and manageable with appropriate titration. The absence of hepatic safety signals is reassuring, as liver concerns have limited other oral diabetes medications historically.
When approved, orforglipron would likely become a preferred first-line option after metformin for type 2 diabetes, particularly for patients with obesity or cardiovascular risk factors, given its comprehensive efficacy profile.
For the primary endpoint, orforglipron lowered A1C by
Participants taking the highest dose of orforglipron lost an average of 19.7 lbs (
The safety and tolerability of orforglipron were consistent with previous trials
"Head-to-head trials are a gold standard for comparing potential treatments," said Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health. "In this type 2 diabetes trial, orforglipron, even at the lower dose, outperformed both doses of oral semaglutide in reducing A1C. At the highest dose, orforglipron helped nearly three times as many participants reach near-normal blood sugar versus the highest dose of oral semaglutide. These results, combined with orforglipron's once-daily oral dosing and broad scalability, reinforce its potential as a foundational treatment for type 2 diabetes."
In the ACHIEVE-3 trial, orforglipron met the primary endpoint and showed superiority vs. oral semaglutide, lowering A1C by an average of
Efficacy Estimand Results | ||||
Orforglipron 12 mg | Orforglipron 36 mg | Oral 7 mg | Oral 14 mg | |
Primary Endpoint | ||||
Change in A1C | - | - | -1.1 % | -1.4 % |
Secondary Endpoints | ||||
Change in | - | - | -3.7 % | -5.3 % |
(-6.6 kg; -14.6
| (-8.9 kg; -19.7
| (-3.6 kg; -7.9 lbs)
| (-5.0 kg; -11.0
| |
Percentage of participants achieving A1C | 7.8 % | 12.5 % | ||
ip<0.001 vs. oral semaglutide 7 mg |
iip<0.001 vs. oral semaglutide 14 mg |
iiip<0.01 vs. oral semaglutide 14 mg |
ivBody weight for orforglipron 12 mg vs. oral semaglutide 14 mg was not controlled for family-wise type 1 error. |
vPercentage of participants achieving A1C < |
For the treatment-regimen estimand, each dose of orforglipron led to statistically significant improvements across the primary and all key secondary endpoints, including:1,5,6
- Change in A1C: -
1.7% (12 mg) and -1.9% (36 mg) with orforglipron vs. -1.2% (7 mg) and -1.5% (14 mg) with oral semaglutide - Percent change in weight: -
6.1% (12 mg) and -8.2% (36 mg) with orforglipron vs. -3.9% (7 mg) and -5.3% (14 mg) with oral semaglutide - Change in weight: -6.2 kg (-13.7 lbs; 12 mg) and -8.1 kg (-17.8 lbs; 36 mg) with orforglipron vs. -3.8 kg (-8.4 lbs; 7 mg) and -5.2 kg (-11.5 lbs; 14 mg) with oral semaglutide
- Percentage of participants achieving A1C <
5.7% :21.4% (12 mg) and31.4% (36 mg) with orforglipron vs.7.4% (7 mg) and11.7% (14 mg) with oral semaglutide
The overall safety and tolerability profile of orforglipron in ACHIEVE-3 was consistent with previous trials. The most commonly reported adverse events were gastrointestinal-related and generally mild-to-moderate in severity. Treatment discontinuation rates due to adverse events were
The detailed results of the ACHIEVE-3 trial will be presented at a future medical meeting and published in a peer-reviewed journal. Lilly expects to submit orforglipron for the treatment of type 2 diabetes to global regulatory agencies in 2026.
About orforglipron
Orforglipron (or-for-GLIP-ron) is an investigational, once-daily small molecule (non-peptide) oral glucagon-like peptide-1 receptor agonist that can be taken any time of the day without restrictions on food and water intake.7 Orforglipron was discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Lilly in 2018. Chugai and Lilly published the preclinical pharmacology data of this molecule together.8 Lilly is running Phase 3 studies on orforglipron for the treatment of type 2 diabetes and for weight management in adults with obesity or overweight with at least one weight-related medical problem. It is also being studied as a potential treatment for obstructive sleep apnea (OSA) and hypertension in adults with obesity.
About ACHIEVE-3 and ACHIEVE clinical trial program
ACHIEVE-3 (NCT06045221) is a Phase 3, 52-week, randomized, open-label trial evaluating the efficacy and safety of orforglipron compared with oral semaglutide in adults with type 2 diabetes inadequately controlled with metformin. The trial randomized 1,698 participants across the U.S., Argentina, China, Japan, Mexico and Puerto Rico to receive either 12 mg or 36 mg orforglipron or 7 mg or 14 mg oral semaglutide in a 1:1:1:1 ratio. The primary objective of the study was to demonstrate that orforglipron is non-inferior in A1C reduction from baseline after 52 weeks compared to oral semaglutide when comparing the lower and higher doses. All participants in the orforglipron treatment arms started the study at a dose of orforglipron 1 mg once-daily and then increased the dose in a step-wise approach at four-week intervals until reaching their randomized maintenance dose of 12 mg (via steps at 1 mg, 3 mg and 6 mg) or 36 mg (via steps at 1 mg, 3 mg, 6 mg, 12 mg and 24 mg). All participants in the oral semaglutide treatment arms started the study at a dose of oral semaglutide 3 mg once-daily and then increased the dose in a step-wise approach at four-week intervals until reaching their final randomized maintenance dose of 7 mg (via a step at 3 mg) or 14 mg (via steps at 3 mg and 7 mg). If participants were unable to tolerate a dose of orforglipron or oral semaglutide, they were allowed, once during the study, to reduce to the previous dose, with a minimum dose of orforglipron 3 mg or oral semaglutide 7 mg.
The ACHIEVE Phase 3 global clinical development program for orforglipron has enrolled more than 6,000 people with type 2 diabetes across five global registration trials. The program began in 2023 with results anticipated later this year and into 2026.
Endnotes and References
- Body weight for orforglipron 12 mg vs. oral semaglutide 14 mg was a prespecified secondary endpoint and showed nominal statistical significance using the efficacy estimand; however, it was not controlled for family-wise type 1 error for the efficacy estimand or treatment-regimen estimand.
- The efficacy estimand represents efficacy had all randomized participants remained on study intervention (with possible dose interruptions and/or dose modifications) for 52 weeks without initiating additional antihyperglycemic medications (>14 days of use).
- American Diabetes Association. Standards of Care in Diabetes—2020 Abridged for Primary Care Providers. Clinical Diabetes 2020; 38(1):10–38.
https://doi.org/10.2337/cd20-as01 - Not controlled for family-wise type 1 error.
- The treatment-regimen estimand represents the estimated average treatment effect regardless of adherence to study intervention or initiation of additional antihyperglycemic medications.
- Percentage of participants achieving A1C <
5.7% was not controlled for family-wise type 1 error. - Ma X, Liu R, Pratt EJ, Benson CT, Bhattachar SN, Sloop KW. Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist. Diabetes Ther. 2024 Apr;15(4):819-832. https://doi.org/10.1007/s13300-024-01554-1. Epub 2024 Feb 24. PMID: 38402332; PMCID: PMC10951152.
- Kawai T, Sun B, Yoshino H, Feng D, Suzuki Y, Fukazawa M, Nagao S, Wainscott DB, Showalter AD, Droz BA, Kobilka TS, Coghlan MP, Willard FS, Kawabe Y, Kobilka BK, & Sloop KW, Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist, Proc. Natl. Acad. Sci.
U.S.A. 117 (47) 29959-29967, https://doi.org/10.1073/pnas.2014879117 (2020).
About Lilly
Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram and LinkedIn. P-LLY
Cautionary Statement Regarding Forward-Looking Statements
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about orforglipron as a potential treatment for adults with type 2 diabetes, Lilly's ability to supply orforglipron, if approved, and the timeline for regulatory submissions, future readouts, presentations, and other milestones relating to orforglipron and its clinical trials and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study results to date, that orforglipron will prove to be a safe and effective treatment for type 2 diabetes, that orforglipron will receive regulatory approval, or that Lilly will execute its strategy as expected. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.
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Refer to: | Brooke Frost; brooke.frost@lilly.com; 317-432-9145 (Media) |
Michael Czapar; czapar_michael_c@lilly.com; 317-617-0983 (Investors) |
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