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As blogged previously, innovative new weight management medications are being explored at a frenetic pace. Many of these new approaches are adding on additional hormone-based strategies to the GLP1 receptor agonist backbone that has become well established as an effective weight management strategy.

Glucagon receptor agonism is one of these avenues being explored. At first blush, this 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).

Survodutide is a dual GLP1 and glucagon receptor agonist, with results of a phase 2 study for weight management just published . This study enrolled 387 people with BMI 27, without diabetes, to various doses of subcutaneous (injected under the skin) weekly survodutide vs placebo for 46 weeks. The study was completed by 80% of participants, though only 61% of those receiving survodutide and 60% of those receiving placebo completed the full 46 weeks of treatment. A dose-dependent weight loss was observed, with the highest dose (4.8mg) group achieving -14.9% weight loss (vs -2.8% with placebo), with weight still decreasing at the end of the 46 week study. Gastrointestinal side effects were the most common, most frequently during the dose escalation phase.

It would be interesting to see if side effects would be less common with a slower dose escalation, and to see what the full capacity of survodutide may be for weight loss in longer trials. Survodutide is currently under investigation in phase 3 trials for weight management in people with or without type 2 diabetes, and in a cardiovascular outcome trial (disclosure: I am the Canadian national lead investigator of these trials).

Other GLP1/glucagon dual agonists are under investigation as well. A phase 3 obesity study of mazdutide has been completed in Chinese adults wtih overweight or obesity, with results not yet available. Other GLP1/glucagon dual agonists are being considered for further investigation, potentially with a focus on obesity and fatty liver disease (survodutide is also being investigated for fatty liver disease). The various GLP1/glucagon dual agonists that are/have been explored have quite a heterogeneous effect on weight, sugars, and fatty liver, which may reflect differences in potency, balance of GLP1 vs glucagon activity, and perhaps differential triggering of signaling pathways downstream from the receptors.

BOTTOM LINE: Dual GLP1/glucagon receptor agonists may become a player in the obesity treatment space in coming years. I’m excited to see how future data unfolds!

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.

Disclaimer: I am an investigator in clinical trials of survodutide.  I receive honoraria as a continuing medical education speaker and consultant from the makers of survodutide (Boehringer Ingelheim).

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