Highlight
– Orforglipron, an oral small-molecule GLP‑1 receptor agonist, produced dose‑dependent mean weight reductions of −5.1% (6 mg), −7.0% (12 mg) and −9.6% (36 mg) at 72 weeks versus −2.5% with placebo in adults with type 2 diabetes (ATTAIN‑2).
– Glycated haemoglobin (HbA1c) and other cardiometabolic markers improved significantly across doses. The safety profile was dominated by transient, mostly mild-to-moderate gastrointestinal adverse events and higher discontinuation rates versus placebo.
Background and clinical need
Obesity is a chronic, relapsing disease that is a principal driver of insulin resistance and type 2 diabetes (T2D). Weight reduction improves glycaemic control and reduces risk factors for cardiovascular and microvascular complications. Injectable GLP‑1 receptor agonists (GLP‑1 RAs) and dual incretin agonists (e.g., tirzepatide) have established substantial weight‑loss efficacy, but the requirement for subcutaneous administration may limit uptake. An oral, small‑molecule GLP‑1 RA could combine potent metabolic effects with the convenience of oral dosing, potentially increasing access and adherence.
Study design (ATTAIN‑2)
ATTAIN‑2 was a 72‑week, phase 3, double‑blind, randomised, multicentre, placebo‑controlled trial conducted at 136 sites in ten countries (ClinicalTrials.gov NCT05872620). Adults with BMI ≥27 kg/m2 and HbA1c 7.0–10.0% were randomised 1:1:1:2, after dose escalation, to once‑daily orforglipron 6 mg, 12 mg, 36 mg, or placebo as an adjunct to lifestyle modification. The primary endpoint was mean percent change in bodyweight from baseline to week 72. The pre‑specified primary estimand was a treatment‑regimen (treatment policy) estimand that included data from all randomised participants regardless of intercurrent events; an efficacy (on‑treatment) estimand was supportive. Safety was assessed in anyone who received at least one dose of study drug.
Key findings
Population
Between June 5, 2023 and Feb 15, 2024, 1613 participants were randomised (329 to 6 mg, 332 to 12 mg, 322 to 36 mg, 630 to placebo). Mean baseline bodyweight was 101.4 kg (SD 22.5), BMI 35.6 kg/m2 (SD 6.6), and HbA1c 8.05% (SD 0.75). Approximately 89.5% (1444) completed the 72‑week study.
Primary outcome: weight
For the treatment‑regimen estimand, mean percent weight change at 72 weeks was:
- 6 mg: −5.1% (95% CI −6.0 to −4.2); estimated treatment difference (ETD) versus placebo −2.7% (95% CI −3.7 to −1.6); p<0.0001
- 12 mg: −7.0% (95% CI −7.8 to −6.2); ETD −4.5% (95% CI −5.5 to −3.6); p<0.0001
- 36 mg: −9.6% (95% CI −10.5 to −8.7); ETD −7.1% (95% CI −8.2 to −6.1); p<0.0001
- Placebo: −2.5% (95% CI −3.0 to −1.9)
These results show a clear, dose‑dependent effect with clinically meaningful weight loss at higher doses. The 36 mg dose achieved nearly 10% mean weight reduction at 72 weeks—levels that are within the range of clinically meaningful outcomes for obesity pharmacotherapy in patients with T2D.
Glycaemic control and cardiometabolic outcomes
All prespecified cardiometabolic endpoints, including HbA1c, improved statistically significantly with orforglipron versus placebo across doses. The trial report provides aggregate improvements in HbA1c and other risk markers; the magnitude of HbA1c reduction was dose‑dependent and clinically relevant for T2D management. Detailed per‑dose values and secondary endpoint confidence intervals are reported in the primary publication (Horn et al., Lancet 2025).
Safety and tolerability
Overall safety mirrored the established GLP‑1 RA class profile. The most common adverse events were gastrointestinal (nausea, vomiting, diarrhoea, constipation), generally mild to moderate and concentrated during dose escalation. Discontinuations due to adverse events were higher with orforglipron (6.1–9.9% across doses) than placebo (4.1%). Ten deaths occurred during the study: six in orforglipron groups and four in placebo; investigators judged most unrelated to treatment. One death in the 12 mg group and one in the placebo group were noted as exceptions, but for the orforglipron case investigators did not identify a treatment‑related association. No new safety signals beyond expected GLP‑1–class effects were reported, but longer follow‑up and larger populations are required to fully characterise rare risks.
How ATTAIN‑2 fits into the therapeutic landscape
Injectable peptide GLP‑1 RAs and the dual GIP/GLP‑1 agonist tirzepatide have demonstrated large weight losses in obesity trials. For context, semaglutide 2.4 mg produced mean weight losses in the low‑ to mid‑teens percent range in people without diabetes (STEP trials) and more modest but substantial reductions in those with T2D (STEP 2). Tirzepatide produced even greater weight loss in some trials. ATTAIN‑2 suggests that an oral non‑peptide GLP‑1 RA can achieve clinically meaningful, dose‑dependent weight and glycaemic benefits in people with T2D, albeit with somewhat smaller mean weight reductions compared with the largest effects reported with injectable tirzepatide in non‑diabetic cohorts. Direct head‑to‑head trials are needed to determine comparative effectiveness, discontinuation tolerability, and patient preference impacts.
Mechanistic and practical considerations
Orforglipron is distinct as a small‑molecule, non‑peptide GLP‑1 receptor agonist engineered for oral bioavailability. Its pharmacology may differ from peptide GLP‑1 RAs in absorption, receptor binding kinetics, central nervous system exposure, and downstream signalling bias. Practical advantages include oral dosing, potentially simplifying initiation and adherence in patients reluctant to use injectables. However, differences in efficacy, durability, and safety (including GI tolerability and possible off‑target effects) must be carefully characterised.
Strengths and limitations
Strengths of ATTAIN‑2 include its randomised, double‑blind design, large sample size (>1600 participants), prespecified treatment‑regimen estimand, long follow‑up (72 weeks), and inclusion of patients with both overweight/obesity and T2D—an important, high‑need population.
Limitations include: the trial was not designed or powered to assess long‑term cardiovascular outcomes or rare adverse events; background glucose‑lowering medication changes (while mentioned in the study protocol) may affect HbA1c interpretation and were not detailed in the summary; generalisability to populations outside the trial’s inclusion criteria (e.g., BMI <27 kg/m2, very high HbA1c, advanced comorbidities) is uncertain. The sponsor‑funded design (Eli Lilly) is common in pharmaceutical development but requires transparent independent post‑marketing surveillance.
Clinical implications and next steps
ATTAIN‑2 provides evidence that orforglipron is an effective oral option for weight reduction and glycaemic improvement in adults with T2D and overweight or obesity. Clinicians should view orforglipron as a potentially attractive alternative to injectable therapies for patients who prefer oral medication; however, patient selection should consider tolerability, comorbidities, and need for long‑term cardiovascular risk reduction.
Key next steps needed before broad clinical adoption include:
- Longer‑term safety and durability data, including post‑marketing surveillance for rare events.
- Cardiovascular outcomes trials to determine whether the cardiorenal benefits observed with some peptide GLP‑1 RAs extend to orforglipron.
- Head‑to‑head comparative trials versus established therapies (e.g., semaglutide 2.4 mg, tirzepatide) to clarify relative efficacy, tolerability, and patient‑reported outcomes.
- Real‑world studies addressing adherence, drug–drug interactions, and effectiveness across diverse populations.
Conclusion
ATTAIN‑2 demonstrates that orforglipron, an orally administered small‑molecule GLP‑1 receptor agonist, produces dose‑dependent, clinically meaningful weight loss and improved glycaemic control over 72 weeks in adults with overweight/obesity and type 2 diabetes. The safety profile aligns with GLP‑1 receptor agonism, predominantly causing transient gastrointestinal adverse events and modestly higher discontinuation rates versus placebo. Orforglipron may broaden options for obesity pharmacotherapy in people with T2D, but long‑term safety, cardiovascular outcomes, and comparative effectiveness versus established injectable agents remain necessary to define its role in clinical practice.
Funding and trial registration
Funding: Eli Lilly and Company. ClinicalTrials.gov identifier: NCT05872620.
References
1. Horn DB, Ryan DH, Kis SG, et al.; ATTAIN‑2 Trial Investigators. Orforglipron, an oral small‑molecule GLP‑1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN‑2): a phase 3, double‑blind, randomised, multicentre, placebo‑controlled trial. Lancet. 2025 Nov 20:S0140-6736(25)02165-8. doi: 10.1016/S0140-6736(25)02165-8. Epub ahead of print. PMID: 41275875.
2. Wilding JPH, et al.; STEP 1 and STEP 2 Investigators. Once‑weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384:989–1002. (STEP program papers provide reference context for peptide GLP‑1 efficacy.)
3. Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387:205–216. (SURMOUNT‑1 trial describing tirzepatide efficacy.)
4. American Diabetes Association. Standards of Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1):S1–S220. (Guideline context on pharmacotherapy for obesity in diabetes.)
5. Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycaemia in type 2 diabetes: 2022 update—consensus recommendations. Lancet. 2022;400:101–118. (Background on incretin‑based therapies.)
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“A professional outpatient clinic scene: a middle‑aged adult patient (diverse appearance) talking with a clinician across a desk, an open medical chart and a blister pack labelled ‘oral GLP‑1’ visible, a glucose meter and a model figure indicating body weight on the table; natural lighting, clinical but empathetic mood, high realism, 3:2 aspect ratio.”
