The investigational triple hormonal agonist retatrutide produced significant weight loss along with glycemic and cardiovascular improvements in adults with type 2 diabetes (T2D) and obesity, according to new results from Eli Lilly's phase 3 TRIUMPH-2 study.
"We've seen in multiple studies, including those with bariatric surgery, that it's harder for people with type 2 diabetes to lose weight, even with the highest doses of GLP-1 or the dual GIP/GLP-1 agonist tirzepatide," said study co-author Juan Pablo Frias, MD, an endocrinologist and medical director and principal investigator at the Los Angeles Institute for Metabolic Research in California.
Now, with retatrutide, "we're seeing an efficacy estimand of over 20% weight reduction," meaning we've finally reached that threshold in people with T2D, Frias told Medscape Medical News. "It's going to give us new options," he added.
Full data from the study of the GIP/GLP-1/glucagon hormone receptor agonist were presented at the European Association for the Study of Diabetes (EASD) 2026 Annual Meeting and simultaneously published in The Lancet.
Key Points
- Retatrutide in T2D + obesity: >20% weight loss at 80 weeks.
- A1c decreased approximately 1.4–1.6 percentage points; 68%–72% reached A1c ?6.5%.
- Waist circumference, systolic blood pressure, lipids, and hs-CRP all improved vs placebo.
- Gastrointestinal adverse events were common; discontinuation rates were 8%–12% at higher doses.
- No severe hypoglycemia; dysesthesia and hypotension occurred more often with retatrutide.
The new findings follow top-line results released earlier this year, along with previous positive phase 3 trials of retatrutide in people with obesity without T2D.
Weight Loss of Up to 20%
TRIUMPH-2 enrolled 1,152 adults with T2D and a BMI of at least 27 who were using diet and exercise or up to three oral glucose-lowering medications, with a prior history of at least one unsuccessful dietary attempt to lose weight. Patients were randomly assigned to self-administer once-weekly subcutaneous injections of placebo or retatrutide in doses of either 4 mg, 9 mg, or 12 mg. A total of 965 participants completed the study, with adverse events in the retatrutide groups being the most common reason for withdrawal.
The primary endpoint was percentage bodyweight change from baseline to week 80 for the retatrutide 9-mg and 12-mg doses vs placebo. For the treatment regimen estimand (average estimated treatment effect regardless of treatment discontinuation or use of prohibited obesity management medications), weight losses of 16.9% and 18.8% were achieved with retatrutide 9 mg and 12 mg, respectively, vs 5.1% with placebo. For the efficacy estimand (assuming all participants take the study medication with no intercurrent events), weight losses were 19.1% for 9 mg and 20.8% for 12 mg, vs 4.0% with placebo (all doses P < .0001 vs placebo).
For both estimands, more patients who took retatrutide achieved weight reductions of at least 5%, 10%, 15%, 20%, and 25% than did patients who took placebo (all P < .010). The proportion of patients with weight reduction of at least 10% were 69% and 75%, respectively, for retatrutide 9-mg and 12-mg doses, vs 21% with placebo.
Mean changes from baseline to week 80 in A1c using the treatment estimand were 1.38, 1.50, and 1.45 percentage points, respectively, for retatrutide 4-mg, 9-mg, and 12-mg doses, vs 0.45 with placebo. Using the efficacy estimand, those percentage-point drops were 1.41, 1.63, and 1.54, respectively, vs 0.19 with placebo. All retatrutide doses were significantly different from placebo (P < .0001).
In addition, all retatrutide doses produced significantly greater numbers of patients achieving an A1c of 6.5% or less at week 80: 68%, 71%, and 72%, respectively, vs 29% with placebo (all P < .0001).
Other significant changes from baseline seen in the retatrutide groups compared to placebo included improvements in waist circumference, systolic blood pressure, fasting lipid profiles, and high-sensitivity C-reactive protein.
Safety Outcomes
Safety analyses included all study participants who received at least one dose of the study drug. The most frequently reported adverse events were gastrointestinal and were more common with retatrutide:
- Diarrhea: 27%, 34%, and 34% for the 4-mg, 9-mg, and 12-mg doses, respectively, vs 13% with placebo.
- Nausea: 14%, 21%, and 28%, respectively, vs 8% with placebo.
- Vomiting: 6%, 10%, and 16%, respectively, vs 4% with placebo.
Permanent treatment discontinuation occurred more frequently in the 9-mg and 12-mg retatrutide groups — 12% and 8%, respectively — compared with the 4-mg dose (4%) or placebo (5%). Gastrointestinal events were the reason for discontinuation in 2% each with retatrutide 9 mg and 12 mg, 1% with placebo, and none with retatrutide 4 mg. There were no episodes of severe hypoglycemia.
Dysesthesia (a skin burning sensation) and related adverse events occurred in 4%, 6%, and 7% with retatrutide 4 mg, 9 mg, and 12 mg, respectively, vs 1% with placebo. Hypotension was also more common with retatrutide (1%–6% vs <1% with placebo).
Deaths occurred in two patients in the 4-mg group, three patients in the 9-mg group, and one patient each in the 12-mg group and the placebo group. All deaths were deemed by the investigators to be unrelated to the study intervention.
Encouraging Results, but More Data Needed
Independent commentator Elisabeth F.C. van Rossum, MD, PhD, professor of obesity and stress hormones at Erasmus Medical Center, Rotterdam, Netherlands, told Medscape Medical News, "Although we need more long-term safety and efficacy data, it's a major step forward from purely glucose-oriented treatment to obesity-oriented treatment for type 2 diabetes."
While she praised the "nice data" from the trial, van Rossum also pointed out some study limitations and areas where more data are needed.
One limitation she noted is that the protocol allowed dose reductions for tolerability, which improves adherence but could also confound the results. A person randomly assigned to the 12-mg group, for example, could have had their dose reduced to 9 mg but would still be counted in the 12-mg group.
"So, these are very much mixed up; I think for the future we need real-world data," said van Rossum. "We know, in general, for all GLP-1-based therapies that it's more important to start low and go slow in the titration phase, maybe even slower than the schedule here."
In addition, she pointed out that body composition data were not reported in the current study, although the TRIUMPH-3 trial will include DEXA scan results. This is important because the glucagon component of retatrutide could affect muscle mass either positively or negatively. "We don't know. We need more data."
The dysesthesia side effect is also worth noting, said van Rossum. This has been seen with other GLP-1-based drugs and might relate to sensory neural signaling rather than weight loss or nutritional deficiency. "It's not unique for this study," she noted, adding that "it's not often a reason to stop treatment but something to be aware of and monitor as clinicians."
Significant Weight Loss
The weight-loss levels seen in the trial are significant. "If you have more than 15% weight loss, that can modify the disease and maybe also induce type 2 diabetes remission," said van Rossum.
Why people with T2D typically lose less weight with GLP-1 drugs is not completely understood, but she pointed to a new preprint suggesting it could relate to changes in urinary glucose excretion and energy expenditure. Because retatrutide includes a glucagon receptor agonist that increases energy expenditure, it could be partly reversing that effect.
"So maybe glucagon can be targeted even more," said van Rossum. "We need more research on this."
Finally, she noted, for those who achieve T2D remission with retatrutide, "maybe in selected individuals we can do dose de-escalation or switch to another medication, [such as] orforglipron. Future studies will have to investigate this."