MILAN — The phase III SYNCHRONIZE-2 trial evaluated survodutide in adults with type 2 diabetes and obesity. The findings of the study were published in the New England Journal of Medicine.

Sean Wharton reported the SYNCHRONIZE-2 trial results at the European Association for the Study of Diabetes (EASD) annual meeting in Milan. Wharton is an MD who served as a subject in the presentation of these data.

The trial included 752 participants who received at least one dose of study drug, with 3 participants excluded due to eligibility errors. Enrollment ran from November 2023 through March 2026, with the last participant visit expected in the second quarter of 2026. The study enrolled 250 participants in the 3.6-mg group, 251 in the 6-mg group, and 251 in the placebo group.

All participants had type 2 diabetes and a body mass index (BMI) of 27 or higher. The mean age of participants was 55.7 years, and the mean BMI was 36.5. Men comprised 49.3% of the cohort.

Survodutide treatment was administered via once-weekly subcutaneous injection. The study excluded patients taking insulin, and most participants had relatively well-controlled glycemic levels at baseline while managing their condition with oral glucose-lowering medications.

In the SYNCHRONIZE-2 trial, 78.7% of participants were treated with metformin at baseline, indicating a common concomitant therapy for type 2 diabetes. In the trial, 34.2% of participants were using sodium glucose co-transporter-2 (SGLT2) inhibitors at baseline. Additionally, 58.6% of participants were on lipid-lowering medications at baseline, showing the frequent presence of dyslipidemia among the study population. In the trial, 69.0% of participants had hypertension as an obesity-related complication, reflecting the high prevalence of comorbid conditions in this population.

The trial had a diverse geographic representation, with 36.2% of participants from Europe, 32.8% from North America, and 22.3% from East Asia. The weight loss achieved in the SYNCHRONIZE-2 trial was lower than the maximal 13% loss seen in the SYNCHRONIZE-1 trial. The SYNCHRONIZE-1 trial excluded participants with diabetes.

Gastrointestinal events led 18% of participants in both survodutide treatment groups to discontinue the trial regimen. Overall adverse events led to treatment discontinuation in 26% of patients in both survodutide groups. Overall adverse events led to treatment discontinuation in 9% of patients in the placebo group. In the placebo group, 38.6% of participants experienced gastrointestinal adverse events.

The SYNCHRONIZE-2 trial used a 24-week, six-step dose escalation phase for the 6-mg dose. Andreas Birkenfeld, an MD and PhD who acted as a critic in reviewing the data, commented on the protocol design. "This dosing, as far as I understand it, was requested by the FDA," Birkenfeld said.

He added that side effects are linked to the escalation schedule. "We know that side effects, such as nausea, increase with the duration of dose escalation and the number of dose steps," he said.

Birkenfeld also addressed the safety profile observed in the trial. "It's reassuring we see no additional safety signal beyond what we already know." However, he noted that tolerability issues persist. "Tolerability remains the key caveat that has to be addressed in the future."

Boehringer Ingelheim stated that upcoming trials will incorporate more flexible, patient-centered titration strategies to improve tolerability. Sean Wharton provided further context on the metabolic outcomes. "Survodutide was associated with improvements in other cardiometabolic parameters, including systolic blood pressure, waist circumference, and lipids," Wharton said.

Comparative clinical data provides context for these results. Tirzepatide (Zepbound) is associated with up to 16% weight loss and a 2.2-percentage point HbA1c reduction. Discontinuation rates due to gastrointestinal events were up to 2% with investigational retatrutide.

Why It Matters

The SYNCHRONIZE-2 trial addresses a complex patient population where type 2 diabetes and obesity frequently coexist. The high prevalence of hypertension and the widespread use of metformin and SGLT2 inhibitors at baseline illustrate the medical complexity of treating these conditions together. The geographic diversity of the trial participants suggests the findings may have broad applicability across different regions, including Europe, North America, and East Asia.

Tolerability remains a central issue for dual agonist therapies, as evidenced by the discontinuation rates linked to gastrointestinal events. The regulatory influence on dosing schedules, as noted by critics, shows the balance between efficacy and patient adherence. Future development of survodutide will depend on implementing more flexible titration strategies to mitigate these side effects while maintaining metabolic benefits.

What's New

Eli Lilly reported results from its Phase 3 "Triumph-4" trial finding that patients lost an average of 28.7% of their body weight. In a Phase 3 trial, participants receiving a 4-mg weekly injection of retatrutide lost an average of 29.8 pounds after 80 weeks. In a Phase 3 trial, participants receiving a 9-mg weekly injection of retatrutide lost an average of 45.4 pounds after 80 weeks. In a Phase 3 trial, participants receiving a 12-mg weekly injection of retatrutide lost an average of 49.6 pounds after 80 weeks.

Juan P. Frías, an MD, provided commentary on the broader landscape of diabetes and obesity treatment. "The vast majority of people with type 2 diabetes are also living with obesity, and treating the two together has always been a challenge," Frías said. He also noted the impact of competing therapies. "Retatrutide reduced both weight and blood sugar substantially, with more than half of participants no longer qualifying as having obesity and up to 40% reaching an A1C in the normal range," Frías said.