Tirzepatide (Mounjaro), perhaps with a new brand name, will likely join semaglutide (Wegovy) by year’s end as an approved weight-loss treatment for people with obesity or overweight and at least one weight-related medical problem. Tirzepatide is currently only approved for diabetes but is prescribed off-label for weight loss. More potent than semaglutide, which is also approved for type 2 diabetes, tirzepatide causes an average 22.5% reduction in body-weight for people without diabetes. Tirzepatide’s developer Eli Lilly will reportedly use a priority review voucher purchased for $110 million to shave 4 months off the approval timeline for a weight-loss indication.
Prescriptions for these incretin mimetics for weight loss — on- or off-label — have skyrocketed. While patients may be shedding pounds, it’s far from certain whether these new drugs will actually improve health outcomes, and we’re concerned that the prevailing narrative hasn’t given enough air time to the potential drawbacks.
Incretin mimetics were originally developed to treat type 2 diabetes by stimulating insulin production. When diabetics lost weight, these drugs were repurposed for weight loss. Both semaglutide and tirzepatide act as agonists for glucagon-like peptide-1 (GLP-1), a hormone that slows gastric emptying and signals the brain to decrease appetite and reduce energy intake. With the addition of an agonist for another incretin (gastric inhibitory polypeptide [GIP]), tirzepatide causes greater weight reduction (although the role of GIP is uncertain).
The bottom line is that patients lose interest in eating, so they eat less. But incretin mimetics must be taken over a lifetime — once the drugs are stopped, the weight returns. Given the adverse health consequences of weight cycling, any temporary benefit of weight loss could be offset by longer-term harms of weight regain when the drugs are stopped.
Weight Loss Doesn’t Equal Better Health
These drugs may not improve health outcomes. In part that’s because for obesity they are prescribed based only on body mass index (BMI) — a measure solely defined by height and weight and developed using data only from white men. While a higher BMI may be associated with health risks in a population, BMI is a poor predictor of cardiometabolic health in individuals. What’s more, a little extra weight may be protective. A meta-analysis found that, compared to normal weight, grade 1 obesity (BMI 30 to
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