One approach being evaluated to expand weight loss medication treatment strategies is to combine GLP1 and glucagon agonist activity.  As blogged previously, use of a glucagon agonist seems counterintuitive, as glucagon is known to increase blood sugars, and people with elevated weight often have diabetes, prediabetes, or are at high risk of developing diabetes. In fact, nasal or injected glucagon are emergency treatments for severe low blood sugars in people with diabetes, as glucagon causes the liver to quickly release sugar. However, the glucagon produced by our pancreas also works to reduce appetite, increases energy burn, and favorably affects lipid metabolism in the liver. If GLP1 receptor agonism were combined with glucagon receptor agonism in just the right balance, the hypothesis is that we might expect to see weight loss, benefits to the liver, and potentially a benefit to blood sugars (as GLP1 improves blood sugars). There are currently a number of GLP1/glucagon agonists under development, one of which is called mazdutide.

The GLORY-1 study, just published in the New England Journal of Medicine, is the first completed phase 3 weight management study of a dual GLP1/glucagon agonist. The study enrolled 610 adults in China with obesity, or overweight with at least one weight-related health issue, to receive mazdutide at a dose of 4mg weekly, 6mg weekly, or placebo, to assess the effect on weight.  The body mass index (BMI) criteria for obesity (28 kg/m2) and overweight (24 kg/m2) in China are lower than in USA, Canada or Europe, so the BMI of participants at baseline (31.1 kg/m2) was lower than most contemporary weight loss medication trials.  People were also younger than in most weight management trials, with average age of 34.  Also notable is that almost half of participants had metabolic-dysfunction associated fatty liver disease (MAFLD or MASLD), whereas only about 10% had prediabetes at baseline.

At 32 weeks, weight loss was 12.6% with mazdutide 6mg weekly, 10% with 4mg weekly, vs 0.5% with placebo. At week 48 there was further weight loss, with 49.5% and 35.7% of people achieving at least 15% weight loss with mazdutide 6mg and 4mg respectively (vs 2% with placebo).  Weight loss had not yet plateaued at the end of the trial, so we need a longer study to know the full capacity of this medication to reduce weight.   Metabolic health improved with mazdutide, including 8.6mmHg reduction in systolic blood pressure (vs 2.1mmHg with placebo), improvement in cholesterol, fasting glucose, liver fat content, liver enzymes, and physical function scores.

Side effects are important to scrutinize, as both GLP1 and glucagon can cause GI side effects such as nausea and vomiting.  In this study, GI side effects were mostly mild to moderate and occurred during dose escalation, with incidence increasing with higher mazdutide dose. Over 90% of participants completed study treatment.

BOTTOM LINE: Mazdutide is a dual GLP1/glucagon receptor agonist that has demostrated impressive weight loss and improvement in metabolic and liver health, in a population of Chinese adults who were fairly young and did not have a very high average BMI at the start of the study. Longer studies in more diverse populations are needed to expand knowledge on this intriguing potential emerging treatment option for obesity.

IMPORTANT SAFETY NOTE – DO NOT take currently available glucagon prescriptions in any amount in an attempt to manage weight. These are ONLY for EMERGENCY treatment of severe low blood sugar in people with diabetes (due to excessive insulin or sulfonylurea effect). Taking these in any sort of ongoing fashion would cause dangerously high blood sugars and would not be an effective weight loss strategy.

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