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Orf5.5
Orforglipron Research
Mostly mechanism / observationalLimited safety
11 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most Orforglipron studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from high-quality meta-analyses and randomised trials published 2023–2026 with a typical study size of 559 participants.
Based on 11 studies · 1 meta-analysis · 9 RCTs · 9,536 total participants
Confidence
High
By outcome
Blood sugar & glycemic control
Mostly mechanism / observational8 studies
Weight management
Mostly mechanism / observational6 studies
Safety & adverse effects
Mostly mechanism / observational6 studies
Active research area
11 studies in the last 5 years · Latest meta-analysis: 2026
20232026
1RCTn=3,127 · very large study2025
The mean change in body weight from baseline to week 72 was -7.5%... with 6 mg of orforglipron, -8.4%... with 12 mg, and -11.2%... with 36 mg, as compared with -2.1%... with placebo (P<0.001 for all comparisons).
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. · N Engl J Med (2025)
Phase-3 multinational double-blind RCT in 3,127 adults with obesity WITHOUT diabetes; once-daily oral orforglipron 6/12/36 mg vs placebo for 72 weeks
Mean weight loss -11.2% at 36 mg vs -2.1% placebo; ≥10% loss in 54.6%, ≥15% in 36.0%, ≥20% in 18.4% (36 mg)
Waist circumference, systolic blood pressure, triglycerides and non-HDL cholesterol all improved vs placebo
At week 40, the estimated mean change from baseline in the glycated hemoglobin level was -1.24 percentage points with the 3-mg dose, -1.47 with the 12-mg dose, -1.48 with the 36-mg dose, and -0.41 with placebo.
Rosenstock J, Hsia S, Nevarez Ruiz L, Eyde S, Cox D, Wu WS, Liu R, Li J, Fernández Landó L, Denning M, Ludwig L, Chen Y; ACHIEVE-1 Trial Investigators. · N Engl J Med (2025)
Phase-3 double-blind RCT in 559 adults with early type 2 diabetes managed by diet/exercise; once-daily oral orforglipron 3/12/36 mg vs placebo for 40 weeks
All doses superior to placebo on HbA1c (placebo-adjusted up to -1.07 percentage points); mean HbA1c reached ~6.5-6.7%
Change from baseline in mean HbA1c was -1.23%, -1.50%, and -1.56% with orforglipron 3 mg, 12 mg, and 36 mg, respectively, versus -0.81% with dapagliflozin 10 mg.
Welch M, Forst T, Jia W, Del Pino PO, Denning M, Wu WS, Li J, Liu R, Eifu M, Chen Y; ACHIEVE-2 Trial Investigators. · Lancet (2026)
Phase-3 non-inferiority RCT (n=962) in type 2 diabetes inadequately controlled on metformin; once-daily oral orforglipron 3/12/36 mg vs dapagliflozin 10 mg over 40 weeks
All orforglipron doses non-inferior and statistically superior to dapagliflozin on HbA1c (treatment differences -0.42% to -0.75%; all p<0.0001)
Mild-to-moderate GI events in 46-54% of orforglipron groups vs 12% with dapagliflozin
At week 40, the mean changes from baseline in HbA1c were -1.58%, -1.88%, and -1.82% with orforglipron 3 mg, 12 mg, and 36 mg once daily, respectively, vs -0.79% with placebo.
Giorgino F, D'Souza S, Ludwig L, Kiyosue A, Ibriga H, Rha H, Denning M, Wu WS, Fernández Landó L, Tobian J. · JAMA (2026)
Phase-3 double-blind RCT (n=546) of orforglipron 3/12/36 mg vs placebo added to titrated insulin glargine in type 2 diabetes over 40 weeks
Each dose superior to placebo on HbA1c (placebo-adjusted -0.78% to -1.08%; P<.001)
Mean body-weight change -2.6% to -5.4% vs +0.2% placebo
the mean percent change in bodyweight from baseline to week 72 was -5·1%... with 6 mg... -7·0%... with 12 mg... and -9·6%... with 36 mg orforglipron... versus -2·5%... with placebo (all p<0·0001 compared with placebo).
Horn DB, Ryan DH, Kis SG, Alves B, Mu Y, Kim SG, Aberle J, Bain SC, Allen S, Sarker E, Wu Q, Stefanski A, Jouravskaya I; ATTAIN-2 Trial Investigators. · Lancet (2026)
Phase-3 double-blind RCT (n=1613) of once-daily oral orforglipron 6/12/36 mg vs placebo over 72 weeks in adults with obesity/overweight AND type 2 diabetes (HbA1c 7-10%)
Mean weight loss -9.6% at 36 mg vs -2.5% placebo (ETD -7.1%); all prespecified weight, cardiometabolic and HbA1c measures improved vs placebo
Weight loss in this T2D population was lower than in ATTAIN-1's diabetes-free obesity cohort (-9.6% vs -11.2% at 36 mg) — consistent with the smaller weight effect typically seen when diabetes is present
The primary objective of non-inferiority was met and both orforglipron doses showed superiority to both semaglutide doses, including orforglipron 12 mg versus semaglutide 14 mg.
Rosenstock J, Yabe D, Cox D, Li J, Denning M, Wu WS, Liu R, Zhao Y; ACHIEVE-3 Investigators. · Lancet (2026)
Phase-3 open-label active-controlled non-inferiority RCT (n=1698) of oral orforglipron (12/36 mg) vs oral semaglutide (7/14 mg) over 52 weeks in type 2 diabetes inadequately controlled on metformin — the first head-to-head against the leading oral GLP-1
HbA1c change -1.71% (12 mg) and -1.91% (36 mg) orforglipron vs -1.23% (7 mg) and -1.47% (14 mg) semaglutide; orforglipron non-inferior AND statistically superior to semaglutide at matched doses
GI events more frequent with orforglipron (58-59%) than semaglutide (37-45%); AE discontinuation 9-10% vs 4-5%
Cohort 1 participants who achieved body weight plateau maintained a model-based estimate of 74.7% of body weight reduction with orforglipron compared with 49.2% with placebo (estimated treatment difference 25.5%; P<0.001) at week 52.
Aronne LJ, Horn DB, le Roux CW, Chao AM, Ho W, Halpern B, Griffin R, Xie C, Valderas EG, Lee CJ, Ribeiro A, Hyman DM, Glass L, Xavier N. · Nat Med (2026)
Phase-3b double-blind, placebo-controlled maintenance RCT: participants previously on tirzepatide (n=205) or semaglutide (n=171) in SURMOUNT-5 switched to oral orforglipron or placebo
Orforglipron preserved substantially more of the prior weight loss than placebo in both cohorts (treatment differences 25.5% and 41.7%; P<0.001)
All key secondary endpoints met; most common AEs were mild-to-moderate GI effects
At week 36, the mean change ranged from -9.4% to -14.7% with orforglipron and was -2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo.
Wharton S, Blevins T, Connery L, Rosenstock J, Raha S, Liu R, et al. · N Engl J Med (2023)
Phase-2 randomized, double-blind dose-response trial (n=272) in adults with obesity/overweight without diabetes; once-daily oral orforglipron 12/24/36/45 mg vs placebo for 36 weeks
Mean weight change -8.6% to -12.6% at week 26 (primary) and -9.4% to -14.7% at week 36 vs ~-2% placebo
Improvement across all prespecified weight-related and cardiometabolic measures
At week 26, mean change in HbA1c with orforglipron was up to -2.10% (-1.67% placebo adjusted), versus -0.43% with placebo and -1.10% with dulaglutide.
Frias JP, Hsia S, Eyde S, Liu R, Ma X, Konig M, Kazda C, Mather KJ, Haupt A, Pratt E, Robins D. · Lancet (2023)
Phase-2 double-blind dose-response RCT (n=383) in type 2 diabetes (diet/exercise ± metformin); orforglipron 3-45 mg/day vs placebo vs injectable dulaglutide 1.5 mg/week over 26 weeks
HbA1c fell up to -2.10% (-1.67% placebo-adjusted), beating both placebo (-0.43%) and dulaglutide (-1.10%)
Bodyweight fell up to -10.1 kg (-7.9 kg placebo-adjusted) vs -2.2 kg placebo and -3.9 kg dulaglutide
All OFG doses (3, 12, 24, 36 and 45 mg) increased GI AEs compared to placebo, with a clear dose-response trend... No dose increased pancreatitis risk (p > 0.05).
Hageen AW, Gadelmawla AF, Saleh AO, Abdallfatah A, Mohamed MR, El-Nemr AF, Maihoub O, Elsekhary A, Eladawi S, Ayalew BD, Mansour A, Radi AA, Abuelazm M, Flefel MG. · Endocrinol Diabetes Metab (2026)
Frequentist network meta-analysis (PRISMA) of RCTs assessing GI, hepatic and pancreatic safety of orforglipron over 26 weeks
Dose-dependent GI adverse events: high-dose 45 mg markedly raised nausea (OR 11.48), diarrhea (OR 3.99) and GI-related discontinuation (OR 10.22)
No dose increased pancreatitis risk; higher doses lowered ALT and raised lipase/pancreatic amylase without corresponding clinical events
The emergence of orally active small-molecule GLP-1 receptor agonists like danuglipron and orforglipron, which are resistant to enzymatic degradation, marks a major advance in patient-friendly drug delivery.
Son JW, le Roux CW, Blüher M, Nauck MA, Lim S. · Endocr Rev (2026)
Narrative review of next-generation GLP-1-based therapeutics for type 2 diabetes and obesity
Positions orforglipron as an orally active small-molecule (non-peptide) GLP-1 agonist resistant to enzymatic degradation — a patient-friendly delivery advance
Frames it within the broader landscape of multireceptor and oral GLP-1-based agents reshaping obesity/diabetes treatment