Discussion
obesity, diarrhoea, gastrointestinal symptoms, nausea, Reductions in blood pressure, gastrointestinal adverse, hyperlipidaemia, vomiting, weight reduction, overweight, hepatic steatosis, hypertension, hyperuricaemia
OBESITY, OBESE, ADVERSE EVENTS, HYPERLIPIDAEMIA, INSULIN RESISTANCE, ADIPOSITY, HEPATIC STEATOSIS, CONCOMITANT DISEASE, METABOLIC DISORDERS, HYPERTENSION, HYPERURICAEMIA
In this randomised, double-blind, placebo-controlled phase 2 trial, once-weekly mazdutide dosed up to 6 mg for 24 weeks achieved significant and clinically relevant body weight reduction in Chinese overweight adults or adults with obesity, together with improvements on multiple cardio-metabolic risk factors. Mazdutide was well tolerated in all doses and showed an overall favourable safety profile, similar to other GLP-1 receptor agonists and co-agonistsSince Chinese people are likely to have higher body fat content and higher cardiovascular risks than White people at given BMI levels, BMI cut-offs for overweight and obesity in China (24 kg/mOn the other hand, 83.9% of the participants were classified as obese at baseline and 62.9% had baseline BMI of 30 kg/mWaist circumference, with high correlation with visceral adiposity, is independently associated with cardiovascular riskReductions in HbA1c, fasting plasma glucose and HOMA-IR were observed with all mazdutide doses, implying potential glycaemic benefits and improvement on insulin resistance in non-diabetic Chinese overweight adults or adults with obesity. Improvements on other cardio-metabolic risk factors, including blood pressure and lipids, were observed with all mazdutide doses, most notably with mazdutide 4.5 and 6 mg. Robust reductions in ALT and serum uric acid levels were evident with mazdutide, irrespective of doses. In this study, hyperlipidaemia (41.9%), hepatic steatosis (33.5%), hyperuricaemia (30.2%) and hypertension (16.5%) were the most common concomitant diseases at baseline. Reductions in blood pressure, lipids, ALT and serum uric acid provide comprehensive cardio-metabolic benefits to Chinese overweight adults or adults with obesity, dramatically alleviating metabolic disorders.The most common adverse events reported with mazdutide were mainly gastrointestinal symptoms, which was consistent with the safety profiles of GLP-1-based therapies. Higher incidence of nausea, diarrhoea and vomiting were generally associated with higher doses of mazdutide. Most gastrointestinal symptoms were mild and moderate in severity, transient, and manageable with concomitant medication to alleviate symptoms or dose reductions. Importantly, the low incidence of adverse events leading to study drug discontinuation is a major strength of this study. Chronic weight management often requires long-term medication. Intolerable gastrointestinal adverse events may lead to early discontinuation and is of special concern for GLP-1 receptor agonists and co-agonistsDue to the cardio-stimulant effects of glucagon, more pronounced increase in heart rate is expected with GLP-1 and glucagon receptor dual agonists than GLP-1 receptor mono-agonistsThe main limitation of this study is the relatively short treatment period. As discussed above, the majority of participants with BMI greater than 30 kg/mIn summary, 24-week treatment with mazdutide at doses of 3 mg, 4.5 mg and 6 mg all led to clinically meaningful and significant body weight reductions versus placebo. Compared with placebo, greater improvements on multiple cardio-metabolic risk factors were observed with mazdutide. Mazdutide dosed up to 6 mg showed favourable tolerability and safety profiles. Taken together, these data support future developments of mazdutide for long-term body weight management in Chinese overweight adults or adults with obesity.