Survodutide, a promising agent with novel mechanism of action for treatment of obesity and type 2 diabetes

Abstract

Activation of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) may result in synergistic effects on glycemic control and weight reduction. Survodutide is a dual agonist of GLP-1R and GCGR under development for treatment of type 2 diabetes, obesity and non-alcoholic steatohepatitis (NASH). In a phase 2 trial of 16-week duration including patients with type 2 diabetes, subcutaneous survodutide given once weekly reduced glycated hemoglobin (HbA1c) levels by 1.5% versus placebo, which was comparable to the reduction achieved by semaglutide (1.0 mg/w). In another phase 2 trial of obese subjects without diabetes, percent weight loss with the highest dose of survodutide was 12.1% versus placebo and did not reach a plateau up to the end of follow-up at 46 weeks. Use of survodutide was associated with significant reduction in systolic and diastolic blood pressure and plasma triglycerides. The most common adverse effects of survodutide were gastrointestinal (GI) disorders reported by 55% of patients (versus 22% with placebo) in the diabetes trial and by 75% (versus 42% with placebo) in the obesity trial. Drug discontinuation rates were 16-25% with survodutide, 4% with semaglutide and 4-5% with placebo. Results of a phase 2 trial including patients with NASH are pending. The major limitation of survodutide is suboptimal tolerability due to GI adverse effects attributed in part to rapid dose escalation. Overall, survodutide is a promising candidate drug with a novel mechanism of action for treatment of type 2 diabetes and obesity. Phase 3 clinical trials, with slower dose titration of survodutide should clarify its efficacy and safety in a broader population of patients with type 2 diabetes, obesity and NASH.