Orforglipron's diabetes trial lands below its obesity-only result

The phase 3 programme for orforglipron — an oral, non-peptide GLP-1 receptor agonist that does not require injection or refrigeration — now has a second large trial on the record. ATTAIN-2, published in The Lancet on 20 November, tested the drug in adults who have both obesity or overweight and type 2 diabetes [s1]. The result is smaller than the one reported in September from ATTAIN-1, which enrolled adults with obesity and no diabetes [s2].

That gap is the story. It is also not a surprise.

What ATTAIN-2 did

ATTAIN-2 was a 72-week, double-blind, placebo-controlled trial run across 136 sites in ten countries [s1]. Participants had a BMI of 27 kg/m² or higher and glycated haemoglobin (HbA1c) between 7% and 10% (53–86 mmol/mol) [s1]. From 2859 people screened between 5 June 2023 and 15 February 2024, 1613 were randomly assigned, following a dose-escalation phase, in a 1:1:1:2 ratio to once-daily orforglipron 6 mg (n=329), 12 mg (n=332), 36 mg (n=322), or placebo (n=630), all as an adjunct to lifestyle modification [s1]. Of those, 757 (46.9%) were female, and 1444 (89.5%) completed the study [s1].

At baseline, mean bodyweight was 101.4 kg (SD 22.5), mean BMI 35.6 kg/m² (SD 6.6), and mean HbA1c 8.05% (SD 0.75; 64.4 mmol/mol, SD 8.2) [s1]. The trial was funded by Eli Lilly and Company [s1].

The primary endpoint was mean percent change in bodyweight at week 72, analysed first under the treatment regimen estimand — which uses data from every randomised participant regardless of whether they stopped the drug or started another one [s1]. That is the more conservative of the two standard analyses, and reporting it as primary is worth noting, because it is closer to what happens outside a trial.

The numbers

Under that estimand, mean weight change at 72 weeks was −5.1% (95% CI −6.0 to −4.2) on 6 mg, −7.0% (−7.8 to −6.2) on 12 mg, and −9.6% (−10.5 to −8.7) on 36 mg, against −2.5% (−3.0 to −1.9) on placebo [s1]. The estimated treatment differences versus placebo were −2.7 percentage points (95% CI −3.7 to −1.6) at 6 mg, −4.5 (−5.5 to −3.6) at 12 mg, and −7.1 (−8.2 to −6.1) at 36 mg, all with p<0.0001 [s1]. Every prespecified weight and cardiometabolic measure, HbA1c included, improved statistically significantly on the drug [s1].

Compare that with ATTAIN-1, the companion trial in adults who had obesity but not diabetes. There, across 3127 randomised patients on the same three doses, mean weight change at week 72 was −7.5% (95% CI −8.2 to −6.8) on 6 mg, −8.4% (−9.1 to −7.7) on 12 mg, and −11.2% (−12.0 to −10.4) on 36 mg, against −2.1% (−2.8 to −1.4) on placebo [s2].

So at the top dose: 9.6% with diabetes, 11.2% without.

Why the gap is expected, and what it does not tell you

These are two separate trials, not a randomised head-to-head, and the populations differ in more than diabetes status — baseline weight, background glucose-lowering therapy, and trial design details all differ. Any comparison between them is indirect and should be read as such.

That said, a blunted weight-loss response in people with type 2 diabetes has been a consistent feature of the incretin drug class across programmes, and ATTAIN-2's placebo arm also lost more weight than ATTAIN-1's (−2.5% versus −2.1%), which narrows the placebo-adjusted difference further [s1][s2]. The practical implication is not that the drug fails in diabetes — the placebo-adjusted difference at 36 mg was still 7.1 percentage points [s1] — but that expectations calibrated on obesity-only trial numbers will overshoot for a large share of the people most likely to be prescribed it.

Tolerability and safety

Treatment discontinuation due to adverse events ran at 6.1–9.9% across the orforglipron groups versus 4.1% on placebo in ATTAIN-2 [s1]. In ATTAIN-1 the equivalent figures were 5.3–10.3% versus 2.7% [s2]. The most common adverse events in both trials were mild-to-moderate gastrointestinal effects, predominantly during dose escalation in ATTAIN-2 [s1][s2].

Ten deaths were reported during ATTAIN-2: six in the orforglipron groups and four on placebo [s1]. Investigators deemed all of them unrelated to study treatment except one case in the placebo group and one in the 12 mg orforglipron group; for the orforglipron case, no treatment-related association was reported [s1].

What to watch

Neither trial was designed or powered to measure cardiovascular events, and neither reports them as an endpoint [s1][s2]. Both were funded by the manufacturer [s1]. ATTAIN-2 is registered as NCT05872620 and is completed [s1]; ATTAIN-1 as NCT05869903 [s2].

The open questions are the ones these trials cannot answer: how the effect holds beyond 72 weeks, how a daily oral compares against weekly injections in the same patients, and whether the tolerability profile in routine care resembles the trial's. None of that is settled by two placebo-controlled trials, however large.

This article is informational and does not constitute medical advice.

Sources

• [s1] 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. The Lancet, 20 November 2025. https://doi.org/10.1016/S0140-6736(25)02165-8
• [s2] Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment. New England Journal of Medicine, 16 September 2025. https://doi.org/10.1056/NEJMoa2511774