Mazdutide promising GLP-1 and glucagon receptor dual agonist for treating type 2 diabetes: Phase 2 trial

The study stated that mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful reductions in body weight and HbA1c in Chinese patients with type 2 diabetes (T2D). The study was published online on November 09, 2023, in Diabetes Care.

"Treatment with mazdutide was associated with placebo-adjusted body weight reduction up to 5.7% and HbA1c reduction up to 1.7%," the researchers reported. "Mazdutide was associated with gastrointestinal adverse effects and hypoglycemia (10.0%)."

Glucagon-like peptide 1 (GLP-1) receptor agonists combined with oral antidiabetic drugs, achieved desirable glycated haemoglobin A1c (HbA1c) targets, conferred cardiovascular protection, and improved multiple metabolic parameters in patients with T2D. However, because of the potential counteractive effect of glucagon and GLP-1 on glucose lowering, the strength of GLP-1 and glucagon receptor dual agonists is believed to be limited largely to the resolution of nonalcoholic steatohepatitis and body weight reduction.

Mazdutide (IBI362 or LY3305677) is a synthetic peptide analogue of mammalian oxyntomodulin and a once-weekly GLP-1 and glucagon receptor dual agonist. Previous studies have shown mazdutide to be well tolerated, with gastrointestinal adverse events most frequently reported. Wenying Yang, Department of Endocrinology, China-Japan Friendship Hospital, Beijing, and colleagues conducted a double-blind, randomized, placebo-controlled phase 2 trial to evaluate the safety and efficacy of mazdutide in Chinese patients with type 2 diabetes.

The study included adults with type 2 diabetes inadequately controlled with exercise and diet alone or with stable metformin (glycated haemoglobin A1c [HbA1c] 7.0–10.5% [53–91 mmol/mol]). They were randomly assigned to receive 3 mg mazdutide (n = 51), 4.5 mg mazdutide (n = 49), 6 mg mazdutide (n = 49), 1.5 mg open-label dulaglutide (n = 50), or placebo (n = 51) subcutaneously for 20 weeks. The study's primary outcome was a change in HbA1c from baseline to week 20.

The study led to the following findings:

• Mean changes in HbA1c from baseline to week 20 ranged from −1.41% to −1.67% with mazdutide (−1.35% with dulaglutide and 0.03% with placebo).
• Mean per cent changes in body weight from baseline to week 20 were dose-dependent and up to −7.1% with mazdutide (−2.7% with dulaglutide and −1.4% with placebo).
• At week 20, participants receiving mazdutide were more likely to achieve HbA1c targets of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol) and body weight loss from baseline of ≥5% and ≥10% compared with placebo-treated participants.
• The most common adverse events with mazdutide included diarrhoea (36%), decreased appetite (29%), vomiting (14%), nausea (23%), and hypoglycemia (10% [8% with placebo]).

In the phase 2 trial in Chinese patients with T2D, 20-week treatment with mazdutide showed clinically meaningful glycemic control, improvements in multiple cardiometabolic risk factors, dose-dependent body weight reduction, together with overall favourable safety and tolerability profile "

"These findings provide important evidence supporting the strength of GLP-1 and glucagon receptor dual agonists in treating type 2 diabetes and related metabolic disorders," they concluded. 

Reference:

Bo Zhang, Zhifeng Cheng, Ji Chen, Xin Zhang, Dexue Liu, Hongwei Jiang, Guoqing Ma, Xiaoyun Wang, Shenglian Gan, Juan Sun, Ping Jin, Jianjun Yi, Bimin Shi, Jianhua Ma, Shandong Ye, Guixia Wang, Linong Ji, Xuejiang Gu, Ting Yu, Pei An, Huan Deng, Haoyu Li, Li Li, Qingyang Ma, Lei Qian, Wenying Yang; Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial. Diabetes Care 20 December 2024; 47 (1): 160–168. https://doi.org/10.2337/dc23-1287