Novel Triple Agonist Nabs Biggest Weight Loss Yet in Obesity Trial

SAN DIEGO -- An investigational triple-hormone receptor agonist yielded major weight loss in people with obesity, a phase II trial showed.

By 24 weeks, patients on any of the four doses of once-weekly injectable retatrutide lost a significantly greater amount of weight than those on placebo -- achieving the trial's primary endpoint -- reported Ania M. Jastreboff, MD, PhD, of Yale University School of Medicine in New Haven, Connecticut, and colleagues, during the American Diabetes Association (ADA) Scientific Sessions and in the New England Journal of Medicine.

Average change in body weight among the groups at this time were:

• -7.2% for the 1-mg group
• -12.9% for the combined 4-mg group
• -17.3% for the combined 8-mg group
• -17.5% for the 12-mg group
• -1.6% for the placebo group

Patients taking retatrutide continued to lose a substantial amount of weight compared with placebo at week 48, achieving one of the trial's secondary endpoints. By this time point, patients in the highest-dose group lost nearly a quarter of their body weight, with average changes of -8.7%, -17.1%, -22.8%, -24.2% for the 1-mg, combined 4-mg, combined 8-mg, and 12-mg groups compared with -2.1% with placebo.

"We have not seen results like this before in a trial of less than 1-year duration with an anti-obesity medication," Jastreboff said during an ADA press conference. "The weight loss had not yet plateaued, meaning that participants were [still] losing weight at the time the trial product was discontinued."

"I think this raises the bar," added panel member Carel Le Roux, PhD, of University College Dublin in Ireland, who wasn't involved with the study. "This is really impressive. This is beyond my wildest dreams. To see something like this in my lifetime is pretty impressive."

Retatrutide acts as an agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon receptors.

All of the patients in the highest-dose group achieved a clinically relevant weight loss of at least 5% by week 48, while 93% achieved a ≥10% weight loss and 83% achieved a ≥15% weight loss.

A total of 13 retatrutide patients and one placebo patient had a body mass index (BMI) decrease to 22 or lower, but none decreased below 19.

Average waist circumference drops with retatrutide ranged from -6.5 cm up to -19.6 cm compared with -2.6 cm with placebo.

The triple agent tended to yield larger magnitudes of weight loss in people with more severe obesity (BMI 35+), as well as female patients. Jastreboff pointed out that these agents tend to induce greater weight loss in women and that prior trials of obesity drugs typically enroll more women. However, her group made it a point to enroll an equal number of men (51.8% of participants), which "may have dampened the efficacy results."

As expected with an agent containing a GLP-1 receptor agonist, the most common adverse events were gastrointestinal-related, but were mostly mild to moderate, including nausea, diarrhea, vomiting, and constipation. Similarly, there was a slight heart rate increase also seen with other agents in this class, which peaked at week 24 of treatment and then declined.

Among the 338 adults enrolled, all had a BMI of 30 or higher or a BMI of 27 plus a weight-related condition (average baseline BMI 37.3). Those with diabetes were excluded from this trial, although 36% had prediabetes.

Randomized in a 2:1:1:1:1:2:2 ratio, participants received either 1 mg, 4 mg (initial dose of 2 mg), 4 mg (initial dose of 4 mg), 8 mg (initial dose of 2 mg), 8 mg (initial dose of 4 mg), or 12 mg (initial dose of 2 mg), or placebo once weekly. In addition, all the participants were guided on lifestyle interventions in the form of dietary counseling, but did not adhere to a specific calorie deficit.

Jastreboff said the phase III TRIUMPH-3 trial will test retatrutide on obesity and obesity-related conditions.

Big Benefits in Type 2 Diabetes, Too

Retatrutide also yielded significant improvements in glycemic control in another phase II trial focused on people with type 2 diabetes.

Also presented at ADA and published in The Lancet, all doses tested outperformed placebo at reducing HbA1c, and most were also better than dulaglutide (Trulicity) 1.5 mg by week 24:

• Retatrutide 0.5 mg: -0.43% change in HbA1c
• 4-mg escalation group: -1.39%
• 4-mg group: -1.30%
• 8-mg slow escalation group: -1.99%
• 8-mg fast escalation group: -1.88%
• 12-mg escalation group: -2.02%
• Dulaglutide: -1.41%
• Placebo: -0.01%

These HbA1c improvements were all maintained through to the end of the trial at 36 weeks. Significantly more patients on maintenance doses of 4 mg or higher achieved an HbA1c below 5.7% -- attaining normoglycemia, including 27% of patients on the 12-mg dose.

Substantial drops in body weight were also noted, with patients seeing up to a 16.94% weight loss by week 36.

"This you have never seen in type 2 diabetes. This is a real wow," said lead investigator Julio Rosenstock, MD, of Velocity Clinical Research at Medical City Dallas. "Not a single drug has achieved 17% [weight loss in type 2 diabetes]. And you ain't seen nothing yet, because you see at 36 weeks, you continue to lose weight."

"In type 2 diabetes, for whatever reason, we get 30% less weight loss, but this [weight loss] is consistent with what you get with semaglutide [Wegovy]," he noted.

Again, the most common adverse events reported were mild-to-moderate gastrointestinal events, including nausea, diarrhea, vomiting, and constipation. While there were no severe events, three retatrutide patients experienced moderate hypoglycemia.

Discussing the mechanism behind the glucagon agonist component of the triple agonist, Stephen Bain, MD, and Thinzar Min, MD, both of Swansea University Medical School in Wales, noted in an accompanying commentary that "if glucagon agonism induces increased energy expenditure, a mechanism quite different to the satiety induced by GLP-1, then long-term cardiovascular outcome trials will almost certainly be requested by regulators, slowing the pathway to clinical use."

Also Works for NAFLD

Retatrutide was also able to reduce the amount of liver fat in a subset of patients with obesity and nonalcoholic fatty liver disease (NAFLD).

In a third study presented at ADA, the highest two doses were able to reduce liver fat by over 80% by week 24 compared with placebo:

• 1 mg: -42.9%
• 4 mg: -57.0%
• 8 mg: -81.4%
• 12 mg: -82.4%
• Placebo: 0.3%

While most liver fat reduction occurred in the first 24 weeks, the 12-mg dose reduced liver fat by 86% by week 48.

Liver fat content dropped below 5% at week 24 in the majority of patients on the highest three doses, leading to resolution of NAFLD. This occurred in 52% of the 4-mg group, 79% of the 8-mg group, and 86% of the 12-mg group.

"Biologically, the addition of glucagon receptor agonism to GIP and GLP-1 ... enhances liver fat clearance and may provide greater efficacy in the treatment of NAFLD and NASH [nonalcoholic steatohepatitis]," said co-author Lee Kaplan, MD, PhD, of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

Weight loss was similar in the NAFLD subgroup and the larger obesity trial population.