Retatrutide Delivers Substantial Weight Loss in Type 2 Diabetes

The investigational triple agonist retatrutide substantially improved glycemic control and body weight in adults with obesity and type 2 diabetes, a phase III trial showed.

Among 1,152 participants, average percentage of body weight loss at week 80 in the treatment regimen estimand was:

• 11.9% (28.4 lb) with retatrutide 4 mg
• 16.8% (40.3 lb) with retatrutide 9 mg
• 18.8% (45.6 lb) with retatrutide 12 mg
• 5.1% (12.8 lb) with placebo

“We know that people with type 2 diabetes lose less weight than people without diabetes. We see this irrespective of the weight-loss method, whether it’s pharmacotherapy or metabolic surgery,” said Juan P. Frias, MD, of the Los Angeles Institute for Metabolic Research, who presented the findings at the European Association for the Study of Diabetes (EASD) annual meeting.

But the level of weight loss seen in the current trial — TRIUMPH-2 — through the use of anti-obesity drugs had previously only been observed in patients without diabetes, the investigators noted in The Lancet, where the findings were simultaneously published. Prior clinical trial data have shown patients with diabetes lost an average of 13.2% and 15.7% of their body weight with high-dose semaglutide (Wegovy HD) and tirzepatide (Zepbound), respectively.

“There is an unmet need for more efficacious weight reduction in individuals with obesity and type 2 diabetes,” according to the study authors, and drugmakers are looking to fill this need.

Another investigational therapy — a combination of the amylin agonist eloralintide plus tirzepatide — achieved a 23.3% weight loss in a type 2 diabetes population in data also presented at EASD.

In TRIUMPH-2’s efficacy estimand (which assumes all participants take the study medication as intended without intercurrent events), weight loss reached 20.8% with the highest retatrutide dose.

“Here [in the efficacy estimand], we’re reaching that threshold beyond 20% weight loss where over 50% of patients had greater than 15% weight loss,” Frias said. He noted, however, that this remained lower than the 28.3% weight loss observed in TRIUMPH-1, which tested the injectable in individuals without diabetes.

Retatrutide’s capacity for substantial weight loss has garnered much social media attention and even spurred a “gray market” for the unapproved drug.

“The reason we’re getting more robust weight loss compared to selective GLP-1 receptor agonists and dual agonists [like] tirzepatide is because we’re engaging yet another system here,” Frias explained. “We have GIP, GLP-1, and glucagon, and these three hormones act centrally to reduce appetite through both distinct and overlapping mechanisms. In type 2 diabetes, it looks like you need to engage as many of these pathways as possible.”

In addition to weight loss, retatrutide yielded significant reductions in HbA1c. Atop background diabetes therapy, mean changes from baseline were -1.38% with the 4-mg dose, -1.50% with the 9-mg dose, and -1.45% with the 12-mg dose, as compared with -0.45% with placebo. Up to 40% of retatrutide-treated participants achieved normoglycemia (HbA1c under 5.7%).

Several cardiometabolic secondary endpoints also improved. Patients receiving retatrutide achieved reductions from baseline of up to:

• 15.4 cm in waist circumference
• 35.6% in triglycerides
• 16.5% in non-HDL cholesterol
• 56.1% in high-sensitivity C-reactive protein

The double-blind, parallel-group trial was conducted across 92 medical and research centers in eight countries. Participants were randomized 1:1:1:1 to receive once-weekly subcutaneous injections of retatrutide or placebo.

Eligible participants had a body mass index (BMI) of at least 27 with type 2 diabetes (HbA1c 6.5-10.5%) on stable background glucose-lowering therapy (up to three oral agents) for at least 90 days prior to screening, alongside a history of diet-based weight-loss attempts.

At baseline, average BMI was 38.2, HbA1c was 7.71%, median duration of obesity was 21 years, and median duration of diabetes was 5.6 years.

Overall, 3-11% of patients in the retatrutide groups discontinued study treatment because of adverse events compared with 5% of placebo recipients. Gastrointestinal (GI) events — primarily nausea, diarrhea, and constipation — were the most frequent adverse events. However, treatment discontinuation due to GI symptoms was low (0-2% with retatrutide vs 1% with placebo).

Hypotension and dysesthesia occurred more frequently in the retatrutide arms. Seven patients died during the trial (one on retatrutide arm, three on the 9-mg retatrutide arm, and one on 12-mg retatrutide arm); all were deemed unrelated to the study interventions.

Study limitations included the absence of an active comparator arm and lack of data on body composition to evaluate the proportion of lean mass loss versus fat loss.

Developer Eli Lilly said it plans to submit data to the FDA for an approval in early 2027.