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NEW ORLEANS — The investigational triple GLP-1/GIP/glucagon receptor agonist retatrutide produced significant weight loss and A1c reduction in people with type 2 diabetes (T2D), according to full data from the TRANSCEND-T2D-1 trial. 

And in people with obesity without T2D, the drug led to significant weight loss and improvements in osteoarthritis knee pain and obstructive sleep apnea, further results from the TRIUMPH-1 trial showed. 

Improvements in cardiovascular risk factors were seen in both trials. 

“Obesity drives more than 200 downstream diseases, yet we have historically treated those conditions one at a time and in silos,” said TRIUMPH-1 lead investigator Ania Jastreboff, MD, PhD, professor of medicine and pediatrics at Yale School of Medicine, and director of the Yale Obesity Research Center, New Haven, Connecticut. 

“These findings demonstrate what may be possible when we treat obesity and impact overall health, and what this could mean for people living with obesity and its related complications,” she said in a press release. 

Both studies were presented here at the American Diabetes Association (ADA) 2026 Scientific Sessions, and results from TRANSCEND-T2D-1 were simultaneously published in The Lancet. Data from TRIUMPH-1 were gathered just prior to the ADA meeting and are not yet published. 

TRANSCEND-T2D-1: “Staggering” Weight Loss in T2D 

In the 40-week, phase 3, randomized, double-blind TRANSCEND-T2D-1 trial, 537 people with inadequately controlled T2D (A1c 7.0%-9.5%) with diet and exercise alone and a BMI of at least 23 kg/m² were randomized 1:1:1:1 to receive retatrutide (4 mg, 9 mg, or 12 mg) or placebo.

Top-line data from the trial were previously announced in March 2026 by the manufacturer Eli Lilly. 

Mean change in A1c from baseline was -1.69% with retatrutide 4 mg (n = 134), -1.86% with 9 mg (n = 133), and -1.94% with 12 mg (n = 136) vs -0.81% with placebo (n = 134). In addition, a higher proportion of patients treated with retatrutide met A1c targets of < 7.0%, ≤ 6.5%, and < 5.7% compared to placebo. The results for the efficacy estimand were similar. 

Body weight, a secondary endpoint, was reduced from a baseline of 96.9 kg by 11.5% with 4 mg retatrutide, 13.9% with 9 mg, and 15.3% with 12 mg compared to 2.6% with placebo. The weight loss with the highest retatrutide dose corresponded to an average of 36.6 lb, with weight loss continuing through the end of the treatment period.

“That is quite staggering,” TRANSCEND-T2D-1 lead investigator Harpreet Singh Bajaj, MD, chair of endocrine and metabolic research at Centricity, Brampton, Canada, said during a press briefing at the meeting.

“This magnitude of weight reduction in people with T2D has not been seen with any medications in a phase 3 study before. We know that people with diabetes lose on average less weight compared to people without diabetes,” he noted. 

Session moderator Naveed Sattar, MD, professor of cardiometabolic medicine and honorary consultant at the University of Glasgow, UK, told Medscape Medical News: “I think [this] study is exciting. The penny is dropping that we need to tackle obesity much more aggressively in T2D. This is now another tool to allow us to do that beyond semaglutide and tirzepatide.”

TRIUMPH-1: Weight Loss of Up to 30% 

In the phase 3 TRIUMPH-1 study, 2339 adults were randomized 1:1:1:1 to retatrutide (4 mg, 9 mg, or 12 mg) or placebo. In addition to weight loss, the study included results from two nested basket trials within TRIUMPH-1, one in 574 participants with knee osteoarthritis and another in 243 with moderate to severe obstructive sleep apnea.

Initial weight loss results at 80 weeks, released earlier this year, showed that those taking the 12-mg dose lost an average of 28.3% of body weight, or about 70 lb, compared with 2.2% in the placebo group, while 45.3% of participants achieved ≥ 30% weight loss. Two thirds (65.3%) taking the highest dose achieved a BMI < 30 kg/m², falling out of the obesity range, including more than a third of those who began the trial with severe obesity (BMI ≥ 40 kg/m²). Participants taking retatrutide 9 mg lost an average of about 64 lb, or nearly 26% of body weight.

In the 104-week extension, weight loss ranged from 19.2% with the 4-mg dose up to 30.3% with 12 mg, or about 85 lb. Nearly all participants lost at least 5% of body weight, more than 85% lost at least 15%, and over a quarter lost at least 35%, Jastreboff reported. 

The osteoarthritis and sleep apnea analyses showed that retatrutide reduced Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale scores by up to 4.3 points (73.1%) from a baseline of 6.0 points in participants with knee osteoarthritis and reduced the apnea-hypopnea index (AHI) by up to 36.1 events/h (60.6%) from a baseline of 58.6 events/h in those with moderate to severe obstructive sleep apnea.

Cardiovascular improvements from baseline were seen in both trials. In TRIUMPH-1, retatrutide was associated with reductions of up to 41.0% in triglycerides, 24.2% in non-high-density lipoprotein (non-HDL) cholesterol, 12.3 mm Hg in systolic blood pressure, and 24.1 cm in waist circumference at 80 weeks. 

In TRANSCEND-T2D-1, those taking retatrutide showed reductions of up to 39.6% in triglycerides, 19.8% in non-HDL cholesterol, 6.4 mm Hg in systolic blood pressure, and 12.4 cm in waist circumference at 40 weeks.

Adverse Events in Both Trials: A New UTI Signal

In both trials, adverse events were consistent with those seen with other incretin-based therapies, including nausea in up to 42.4% of patients with the 12-mg dose in TRIUMPH-1 and up to 26.5% with 12 mg in TRANSCEND-T2D-1. Other adverse events in both trials included diarrhea, constipation, and urinary tract infections. Most were mild to moderate and resolved during treatment. 

Urinary tract infections haven’t been seen before, Jastreboff noted. These occurred mostly in women, in 7.5%-8.8% with retatrutide vs 5.3% with placebo in TRIUMPH-1 and in 0.7%-2.9% vs 0.0% in TRANSCEND-T2D-1. 

“We don’t know, but it may be related to hydration status,” Jastreboff said during the briefing. 

“Women are more prone to UTIs anyway. Is it related to more intercourse [with weight loss]? Given that this was new, it will now be looked at as we gather more data,” she added. 

Discontinuation rates due to adverse events in TRIUMPH-1 were 4.1%, 6.9%, and 11.3% with retatrutide 4 mg, 9 mg, and 12 mg, respectively, compared with 4.9% with placebo. In TRANSCEND-T2D-1, those rates were 2.2%, 4.5%, and 5.1% with retatrutide 4 mg, 9 mg, and 12 mg, respectively, compared with 0.0% with placebo. 

In Context: Is Bigger Always Better?

Sattar noted that caution will be needed going forward. 

“I think we have to learn to go slow, as cutting the weight down fast could lead to other potential issues. Are we causing a little bit of harm in a small number of people by going too fast?” he asked. “The new UTI finding may well be linked” to this, as maybe it’s causing substantial diuresis, he added.

“We need more data just to fully ensure safety,” he said. 

Independent commentator Alice YY Cheng, MD, an endocrinologist at Trillium Health Partners and Unity Health Toronto and associate professor at the University of Toronto, Canada, said that the 30% weight loss seen in the TRIUMPH-1 extension was “a highly impressive number and not one we have seen before from a pharmacotherapy.” 

“The question I have for you, though, [is]: Is bigger always better? Is bigger always needed? And is bigger always right? And the answers are no, no, and no. Not every person requires, wants, needs, or should have weight loss at these high numbers that we are seeing in these studies...I think what we really need to be asking ourselves [is]: Is it about weight loss or is it about health gain?” she said.

Moreover, she added, “We can make fabulous tools, but we need to get it to the people who need it.” 

Patients “need to be able to get it, they need to be able to take it, they need to be able to tolerate it, and they need to be able to stay on it. And I would argue that it's actually the responsibility of all of us to play a role in that,” she concluded.

Jastreboff has disclosed conducting multicenter trials for Amgen, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Rhythm Pharmaceuticals, and serving on scientific advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly, Metsera, Novo Nordisk, Pfizer, Regeneron, Roche/Genentech, Scholar Rock, Structure Therapeutics, Syntis Bio, WW International, and Zealand. She is an academic cofounder of State 4 Therapeutics. Bajaj has reported receiving research support from Abbott Diagnostics, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Ionis Pharmaceuticals, Novartis, Novo Nordisk, Pfizer, Roche, Vertex, and Arrowhead. Sattar has reported being a consultant, advisory panel member, and/or a speaker for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gan & Lee Pharmaceuticals, GlaxoSmithKline, Kailera, Mass Medicines, Menarini Group, Metsera, Novo Nordisk, Pfizer, Roche, and Verdiva Bio. Cheng has reported being an advisory, consultant, and/or speaker for Abbott Diabetes, Amgen Canada, Aspen Pharmacare, Astellas Pharma, AstraZeneca, Bausch Health, Canada, Bayer, Boehringer Ingelheim, Biomea Fusion, Dexcom, Eisai, Eli Lilly, Gan & Lee Pharmaceuticals, Insulet, HLS Therapeutics, Merck, Novo Nordisk, Sanofi, Sandoz, and Vertex. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker and BlueSky @miriametucker.bsky.social