Novel GIP/GLP-1 Yields Uneven Findings in Diabetes Patients With Obesity

An investigational dual GIP/GLP-1 agonist achieved modest weight loss in adults with type 2 diabetes and obesity, the phase III SYNCHRONIZE-2 trial showed, but tolerability remains a concern.

Participants taking 3.6 mg and 6 mg of survodutide lost an average of 8.2% and 9.8% of their body weight by week 76, respectively, compared with an average of 3.9% for those in the placebo group, reported Sean Wharton, MD, of Wharton Medical Clinic Weight and Diabetes Management in Hamilton, Ontario, Canada, at the European Association for the Study of Diabetes (EASD) annual meeting in Milan.

Weight reduction of at least 5% — the standard threshold for clinically significant weight loss — occurred in 57.6%, 64.5%, and 35.1% of participants, respectively (P<0.001 for all comparisons with placebo).

In addition, mean HbA1c levels (mean baseline 7.4%) decreased by 0.9 percentage points in the 3.6-mg group, 0.8 percentage points in the 6-mg group, and 0.2 percentage points in the placebo group.

“Survodutide was associated with improvements in other cardiometabolic parameters, including systolic blood pressure, waist circumference, and lipids,” Wharton noted.

The weight loss reported in the higher-dose group with the treatment-regimen estimand is “a magnitude associated with cardiovascular benefits and reductions in metabolic and mechanical complications as well as improvement in quality of life,” Wharton and colleagues wrote in the New England Journal of Medicine, where the findings were simultaneously published.

However, they acknowledged that the weight loss achieved in this trial was lower than the maximal 13% loss seen in SYNCHRONIZE-1, which excluded participants with diabetes. That earlier trial was the first to flag tolerability concerns with the dual agent.

In SYNCHRONIZE-2, 73% to 78% of participants in the survodutide groups experienced gastrointestinal adverse events — though most were mild to moderate and transient — compared with 38.6% of those in the placebo group. Gastrointestinal events spurred 18% of participants in both treatment groups to discontinue the trial regimen versus only 1.2% in the placebo group.

Overall adverse events leading to treatment discontinuation occurred in 26% of patients in both survodutide groups compared with 9% of patients in the placebo group.

“It’s reassuring we see no additional safety signal beyond what we already know,” noted Andreas Birkenfeld, MD, PhD, of University Hospital Tübingen in Germany, at the EASD meeting, though he pointed out that discontinuation rates due to gastrointestinal events were markedly higher with survodutide versus comparable agents (up to 5% with semaglutide HD [Wegovy HD] and up to 2% with investigational retatrutide).

The high discontinuation rate might be explained by the dosing strategy, Birkenfeld suggested, pointing to the 24-week, six-step dose escalation phase for the 6-mg dose. “This dosing, as far as I understand it, was requested by the FDA. We know that side effects, such as nausea, increase with the duration of dose escalation and the number of dose steps.”

Tolerability remains the “key caveat that has to be addressed in the future,” he emphasized.

Developer Boehringer Ingelheim said upcoming trials will incorporate more flexible, patient-centered titration strategies to improve tolerability.

In addition to higher discontinuation rates compared with other agents, survodutide also fell on the lower end for both weight loss and HbA1c reduction:

• Semaglutide HD: Up to 14% weight loss, with a 1.7-percentage point HbA1c reduction
• Tirzepatide (Zepbound): Up to 16% weight loss, with a 2.2-percentage point HbA1c reduction
• Retatrutide: Up to 20% weight loss, with a 1.54-percentage point HbA1c reduction

The multinational, double-blind SYNCHRONIZE-2 trial enrolled 250 participants in the 3.6-mg group, 251 in the 6-mg group, and 251 in the placebo group from November 2023 through March 2026. All participants had type 2 diabetes and a body mass index (BMI) of 27 or higher. Mean age was 55.7 years, mean BMI was 36.5, and 49.3% were men. Treatment was administered via once-weekly subcutaneous injection.

The study excluded patients taking insulin, limiting the generalizability of the findings to the broader population with type 2 diabetes. Additionally, most participants had relatively well-controlled glycemic levels at baseline while managing their condition with oral glucose-lowering medications.

Survodutide is also undergoing evaluation for other metabolic conditions, with data from a cardiovascular outcomes trial expected later this year.