Tolerability Concerns for GLP-1/Glucagon Agonist in Obesity, MASLD

NEW ORLEANS — Treatment with survodutide led to significant weight loss and reductions in liver fat in phase III trials of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), but about a fifth of patients quit the investigational glucagon and GLP-1 receptor dual agonist due to adverse events.

Obesity Trial

In the SYNCHRONIZE-1 trial of people with obesity but without diabetes, mean body weight loss by week 76 with treatment plus lifestyle modification counseling reached 12.2% in the 3.6-mg once-weekly survodutide group and 13% in the 6.0-mg once-weekly group as compared with 5.4% with placebo, reported Carel le Roux, MBChB, PhD, of the University College Dublin School of Medicine.

“Body weight reduction with survodutide was driven predominately by loss of fat tissue,” le Roux said at the American Diabetes Association (ADA) Scientific Sessions. The findings were simultaneously published in the New England Journal of Medicine.

However, gastrointestinal adverse events — primarily nausea, vomiting, diarrhea, and constipation — occurred in 80.9-89.7% of the survodutide groups and in 47.9% of the placebo group. These events led to 17.8-20.2% of the survodutide groups discontinuing the study treatment compared with 2.9% of the placebo group. No deaths were reported.

Obesity medication development is entering a new era of combining GLP-1 agonists with other agonists of glucagon, gastric inhibitory polypeptide (GIP), or both.

“The development of glucagon receptor-GLP-1 receptor dual agonists to enhance the relative potency of the agonists at these receptors has been challenging, particularly with respect to net effects on glucose homeostasis,” the authors wrote. “In this trial, treatment with survodutide did not increase glycated hemoglobin levels in participants without diabetes mellitus; a previous phase 2 trial involving persons with obesity and type 2 diabetes showed that survodutide significantly reduced glycated hemoglobin levels.”

The double-blind trial was conducted at 116 clinical sites across 14 countries. All 725 participants had either a BMI of at least 30 or at least 27 with an obesity-related complication other than diabetes. The cohort averaged 47.1 years of age, baseline BMI of 37.9, and body weight of 239.9 lb (108.8 kg). Slightly more than 40% of participants were men.

Participants were randomized 1:1:1 to once-weekly survodutide doses adjusted up to 3.6 mg or 6 mg or placebo. Patients were also encouraged to follow a reduced-calorie diet and to exercise.

Dose flexibility was initially limited to weeks 16 to 32 after randomization, and participants were told to discontinue the study treatment if three or more doses were missed due to gastrointestinal reasons or other causes.

“This study was set up specifically to be very rigid,” le Roux said, explaining the high drop-out rate. “We wanted a rigorous result, we wanted an end result that you look at and say, ‘I trust these numbers.’ But sometimes, you can overshoot. Sometimes in your pursuit of rigorous results, we made it so difficult for patients to stay in this study that actually they had to step out because they couldn’t increase the dose because of the forced titration.”

“That also allows you and me to go back to clinic next week and think about what are the benefits and risk-benefit ratio between being very rigid and having more flexibility. Thinking about how we can keep people in our clinical trials but also our clinical practice … and be more gentle with our patients,” he noted.

MASLD Study

Survodutide also showed benefit for MASLD patients with obesity, according to the phase III SYNCHRONIZE-MASLD study, also presented at ADA.

Among 216 adults, 68.5% of survodutide-treated patients and 28.6% of placebo-treated patients had at least 30% reduction in MRI-proton density fat fraction-assessed liver fat content in the treatment regimen estimand by week 48 (P<0.0001) -- a degree of reduction previously linked to a higher likelihood of histologic improvement and resolution of metabolic dysfunction-associated steatohepatitis (MASH).

These data “suggest the potential for survodutide treatment to support meaningful improvement in several of the proposed drivers of MASH and hepatic fibrosis, addressing an area of high unmet need,” a team led by Lee Kaplan, MD, PhD, of the Obesity and Metabolism Institute in Boston, wrote in a simultaneously published paper in Nature Medicine.

The average body weight reduction over 48 weeks was 8.7% with survodutide and 1.4% with placebo (P<0.0001) in the same treatment regimen estimand used in the SYNCHRONIZE-1 trial, a conservative assessment with missing data in the survodutide arm assumed to be similar to that in the placebo arm.

Gastrointestinal events in this study were also commonly reported during the dose-escalation phase but were generally of mild-to-moderate severity. Still, 19.9% of participants in the survodutide group discontinued treatment versus 4.3% of those in the placebo group.

Participants, who were recruited from the U.S. and Spain, all had MASLD with evidence of liver inflammation or fibrosis by noninvasive tests or biopsy-confirmed MASH. Participants were randomized 2:1 to treatment with survodutide 6 mg once weekly or placebo.

Survodutide is also being studied in two global phase III clinical trials — LIVERAGE and LIVERAGE-Cirrhosis — investigating the efficacy and safety of survodutide in adults with MASH and stage 2 or 3 fibrosis and in those with compensated MASH cirrhosis (stage 4 fibrosis).