Retatrutide for type 2 diabetes: what the phase 2 trial and TRIUMPH-2 found
A triple agonist that includes glucagon might be expected to raise blood sugar. In people with type 2 diabetes it did the opposite: the phase 2 trial in The Lancet reported HbA1c reductions of about two percentage points on the higher doses at 24 weeks, more than dulaglutide, and the phase 3 TRIUMPH-2 trial reported 20.8% weight loss at 80 weeks with a 1.5-point HbA1c reduction on 12 mg.
Key facts
- The phase 2 diabetes trial randomised 281 adults with type 2 diabetes to placebo, dulaglutide 1.5 mg or retatrutide 0.5 to 12 mg weekly for 36 weeks.
- HbA1c change at 24 weeks: about −2.0 percentage points on 8 mg and 12 mg, −1.41 on dulaglutide, −0.01 on placebo.
- Weight change at 36 weeks: −16.94% on 12 mg, −3.00% on placebo, −2.02% on dulaglutide.
- TRIUMPH-2 (1,152 adults, 80 weeks): weight −12.7%, −19.1% and −20.8% on 4, 9 and 12 mg versus −4.0% on placebo; HbA1c −1.4 to −1.6 points from 7.7%.
Photograph: editorial illustration for this article. It does not show retatrutide.
On this page
Why was diabetes the hard test for a glucagon agonist?
Glucagon raises blood glucose. It is the hormone injected to rescue someone from severe hypoglycaemia. Building a diabetes drug that activates the glucagon receptor therefore looked, on paper, like a contradiction, and the phase 2 diabetes trial was the test of whether the GIP and GLP-1 components of retatrutide could more than cancel the glucose-raising effect. The discovery paper had shown this balance in animals and in early human data[6]; the diabetes trial showed it at scale. The pharmacology is set out in our mechanism article.
What did the phase 2 diabetes trial find?
Published in The Lancet in 2023, the trial randomised 281 adults with type 2 diabetes, on diet and exercise alone or on stable metformin, to placebo, dulaglutide 1.5 mg weekly, or retatrutide at 0.5, 4, 8 or 12 mg weekly with different escalation schedules, for 36 weeks. The primary endpoint was the change in HbA1c at 24 weeks[1].
HbA1c fell by about 2.0 percentage points on the 8 mg and 12 mg groups at 24 weeks, by 1.41 on dulaglutide and by 0.01 on placebo. Body weight at 36 weeks changed by −16.94% on 12 mg, against −3.00% on placebo and −2.02% on dulaglutide[1]. In other words, the triple agonist matched or beat an established GLP-1 drug on glucose and produced roughly eight times its weight loss.
What did TRIUMPH-2 add?
TRIUMPH-2 (NCT05929079) is the phase 3 trial in 1,152 adults with type 2 diabetes and obesity or overweight. It started on 11 July 2023 and reached primary completion on 16 June 2026[3]. Lilly's topline announcement of 23 July 2026 reported mean weight change at 80 weeks of −12.7% on 4 mg, −19.1% on 9 mg and −20.8% on 12 mg, against −4.0% on placebo, and HbA1c reductions of 1.4, 1.6 and 1.5 percentage points from a baseline of 7.7%, against 0.2 on placebo. Diarrhoea (27.4% to 33.6% versus 13.2%) and nausea (13.7% to 28.0% versus 8.0%) were the most common adverse events, and discontinuation for adverse events ranged from 3.8% to 11.6% across retatrutide arms versus 4.9% on placebo[2].
| Phase 2 (Lancet 2023) | TRIUMPH-2 (topline 2026) | |
|---|---|---|
| Participants | 281 | 1,152 |
| Duration | 36 weeks | 80 weeks |
| HbA1c change, top dose | about −2.0 points at 24 weeks | −1.5 points at 80 weeks |
| Weight change, top dose | −16.94% at 36 weeks | −20.8% at 80 weeks |
| Placebo weight change | −3.00% | −4.0% |
| Discontinuation for AE | dose-related | 3.8% to 11.6% vs 4.9% |
Two things stand out. Weight loss in people with diabetes is smaller than in people without, as it is for every drug in this class (TRIUMPH-1 reported −28.3% at the same dose in adults without diabetes). And the HbA1c reduction at 80 weeks is smaller than the 24-week phase 2 figure, which is expected as glucose control approaches normal and baseline values differ between trials.
How does this compare with tirzepatide?
Tirzepatide, the approved dual agonist, reduced HbA1c by 2.01 to 2.30 percentage points over 40 weeks in SURPASS-2, against 1.86 on semaglutide 1 mg[4], and produced 12.8% to 14.7% weight loss at 72 weeks in people with diabetes and obesity in SURMOUNT-2[5]. Retatrutide's glucose effect is in the same range; its weight effect in diabetes, −20.8% at 80 weeks, is larger, with the usual warning that these are different trials. The full comparison is in retatrutide vs Mounjaro.
What about safety in people with diabetes?
The phase 2 trial reported no severe hypoglycaemia on retatrutide and a side-effect profile dominated by dose-related gastrointestinal events[1]. Participants were not on insulin or sulfonylureas, so the combination risk, which exists for all incretin-based drugs, is untested. Heart rate increased in a dose-dependent way, as in the obesity trial. Kidney and cardiovascular outcomes in people with diabetes are part of TRIUMPH-Outcomes, which runs to around 2029. Side effects across all trials are collected in GLP-3 side effects.
What is not known?
- Whether the first FDA application will include a diabetes indication; Lilly has only said it plans to file in the first quarter of 2027[2].
- How retatrutide performs on top of insulin or in people with kidney impairment, which are the subjects of separate ongoing studies.
- Whether the glucose benefit persists after stopping, since no off-drug follow-up has been published.
Frequently asked questions
Does retatrutide lower blood sugar?
Yes. In the phase 2 diabetes trial, HbA1c fell by about two percentage points at 24 weeks on the 8 mg and 12 mg doses, compared with 1.41 on dulaglutide and no change on placebo. TRIUMPH-2 reported reductions of 1.4 to 1.6 points at 80 weeks.
Why doesn't the glucagon component raise glucose?
Because the same molecule activates the GIP and GLP-1 receptors, which increase insulin when glucose is high and suppress endogenous glucagon. In the trials the net effect was a large fall in HbA1c, not a rise.
Did retatrutide cause hypoglycaemia?
The phase 2 trial reported no severe hypoglycaemia on retatrutide. Combination with insulin or sulfonylureas was not studied and is a known class risk.
Is retatrutide approved for diabetes?
No. It is not approved for any indication. Lilly plans to file with the FDA in the first quarter of 2027; whether the initial application covers diabetes, obesity or both has not been stated.
Sources
- Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. The Lancet. 2023;402(10401):529-544. DOI 10.1016/S0140-6736(23)01053-X
- Eli Lilly and Company, press release, 23 July 2026. Lilly's triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C (TRIUMPH-2 and TRIUMPH-3 topline results). https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-successful-two-additional
- ClinicalTrials.gov. A Master Protocol to Investigate the Efficacy and Safety of LY3437943 Once Weekly in Participants With Type 2 Diabetes Mellitus Who Have Obesity or Overweight (TRIUMPH-2). Phase 3, 1,152 participants, started 11 July 2023, primary completion 16 June 2026, status Completed. NCT05929079
- Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2). New England Journal of Medicine. 2021;385(6):503-515. DOI 10.1056/NEJMoa2107519
- Garvey WT, Frias JP, Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. The Lancet. 2023;402(10402):613-626. DOI 10.1016/S0140-6736(23)01200-X
- Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metabolism. 2022;34(9):1234-1247. DOI 10.1016/j.cmet.2022.07.013
DOIs were checked against the CrossRef API and trial identifiers against the ClinicalTrials.gov API v2 on 2026-09-21. Press releases are cited by URL because topline results are not yet in a peer-reviewed journal.