Overweight Patients Lose Nearly 30% Body Weight in Phase 3 Retatrutide Trial

In a recent update on Eli Lilly’s Phase 3 clinical studies investigating retatrutide—a GIP, GLP-1, and glucagon triple-hormone receptor agonist—the company reported that long-term use achieved substantial weight reduction, improved blood glucose markers, and reduced osteoarthritis-related pain in overweight and obese adults.

The company is using a master protocol design to conduct multiple trials running in parallel. Interim data from the TRANSCEND-T2D-1 phase 3 trial, investigating retatrutide use in diabetes, were published earlier this week.

Results from the TRIUMPH-1 Phase 3 trial have been disclosed in company press releases; however, the full trial data have not yet been published. This trial is investigating retatrutide in overweight patients, with nested sub-studies on osteoarthritis and obstructive sleep apnea.

Dual- and triple-agonists aim to overcome GLP-1 limitations

GLP-1 is a hormone released by the gut following a meal. It primarily acts on the brain to induce satiety and on the stomach to slow gastric emptying, which enhances feelings of fullness while preventing blood glucose spikes.

Based on this mechanism, GLP-1 therapies were developed; these synthetic GLP-1 receptor agonists (GLP-1RAs) mimic the effects of the natural hormone while overcoming its therapeutic limitations (such as its short half-life).

First developed to control blood glucose in diabetes, GLP-1RAs are now used in chronic weight management and have demonstrated benefits across a range of chronic conditions.

The groundbreaking uptake of GLP-1RAs is widely considered one of the fastest commercial expansions in pharmaceutical history, making it no surprise that companies are now racing to develop novel approaches to address therapeutic shortcomings. These include variability in treatment response and, in the context of weight-loss indications, treatment plateaus and rebound weight gain.

This is where glucose-dependent insulinotropic polypeptide (GIP) and glucagon come into play. Pharmaceutical companies have incorporated these hormones into dual- and triple-agonist therapies to enhance outcomes (Table 1).

Table 1: Physiological roles of GIP and glucagon, and their intended therapeutic effect.

Lilly is currently positioned among the market leaders in the GLP-1 and obesity drug market, following the launch of the dual-agonist tirzepatide. This GIP/GLP-1RA is now approved for weight loss and type 2 diabetes, marketed as Zepbound^® and Mounjaro^®, respectively.

Retatrutide shows benefits in obesity and diabetes

The pharma giant is not stopping there; having recently announced promising results for retatrutide, the most clinically advanced triple agonist.

Lilly has now released findings from the phase 3 studies TRIUMPH-1 and TRANSCEND-T2D-1, which are the first stages of two larger programs: TRIUMPH and TRANSCEND.

In TRIUMPH-1, participants on retatrutide 9 mg achieved an average of 25.9% weight loss, while those on 12 mg achieved a 28.3% reduction. Additionally, more than one-third of patients on the highest dose (12 mg) reached a body-mass index of <25, indicating normal or healthy weight after treatment.

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Nested sub-studies assessed outcomes in patients with knee osteoarthritis and obstructive sleep apnea and found clinically meaningful improvements in symptoms. These results are consistent with findings from TRIUMPH-4, another branch of the program that specifically assessed knee osteoarthritis as an indication.

Common to both TRIUMPH-1 and TRANSCEND-T2D-1 was substantial weight loss and reductions in A1C, a marker of average blood sugar levels over approximately three months.

Specifically, in the TRANSCEND-2TD-1 study, 90% of participants in the retatrutide group achieved A1C levels below 7%. This is the recommended target for most diabetic adults, and maintaining this level significantly reduces the risk of long-term complications from diabetes.

Furthermore, nearly half of patients (46%) achieved A1C levels below 5.7%, which is considered within a healthy range.

The researchers also investigated cardiovascular risk factors across the two studies, with improvements in cholesterol, blood pressure, and waist circumference. TRIUMPH-3 will specifically investigate the use of retatrutide in obese patients with established cardiovascular disease.

"By addressing weight, glycemia, and obesity-related complications together, these results highlight retatrutide's potential across the cardiometabolic spectrum and reinforce our commitment to delivering options that meet patients' needs and preferences," said Dr. Kenneth Custer, president of cardiometabolic health, Eli Lilly, in the release.

Retatrutide adverse events comparable to established GLP-1 drugs

Across both studies, adverse events were consistent with those of existing GLP-1 therapies, with reports of nausea, diarrhea, and vomiting generally increasing in groups receiving higher doses.

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Discontinuation rates were 11.3% on the highest retatrutide dose (12 mg) within the TRIUMPH-1 study, just below those reported by Gasoyan et al. (2025) for patients on semaglutide and tirzepatide (14.6%). For TRANSCEND-T2D-1 participants, discontinuation was lower at 5%.

When used for weight loss, GLP-1 therapies are associated with higher discontinuation rates than in diabetes, which is thought to result from higher doses and faster titration. As the same doses were used across the two studies, later publications may clarify whether titration played a role in adverse events and differing discontinuation rates, or whether this is primarily due to differences in tolerability.

Next-generation GLP-1 therapies: A step closer to integrated metabolic care

These results suggest a promising step forward for triple-agonists in diabetes and weight-loss management and highlight the importance of assessing cardiometabolic health holistically.

"Obesity drives more than 200 downstream diseases, yet we have historically treated those conditions one at a time and in silos," said Dr. Ania Jastreboff, lead investigator, in response to the results, highlighting the rationale behind the master protocol and spin-off studies.

For pharmaceutical companies, this approach can support a shorter timeline to a broader label. For patients, it could facilitate faster time-to-clinic and simpler treatment regimens, with a single drug able to treat many commonly coexisting morbidities.

As a new wave of GLP-1 therapies approaches, pharmaceutical companies are rightfully focusing on clinical optimization and the mutual benefits it offers.

However, this approach may only go so far. As affordability and access remain key barriers to GLP-1 therapy uptake and continuation, developers should also consider access to maximize the most influential outcome: patient impact.

Reference: Bajaj HS, Welch M, Shah P, et al. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. Lancet. 2026:S0140673626009670. doi: 10.1016/S0140-6736(26)00967-0

This article is a rework of a press release issued by Eli Lilly. Material has been edited for length and content.