Semaglutide and its siblings—tirzepatide, retatrutide and newer oral formulations—are transforming the treatment of obesity and metabolic disease. Their success is real. But does extraordinary efficacy risk making us ask too few questions?

The SELECT trial demonstrated a 20% reduction in major cardiovascular events in people with overweight or obesity, established cardiovascular disease and no diabetes. FLOW demonstrated substantial kidney protection in people with type 2 diabetes and chronic kidney disease. These are important clinical advances.

Yet we should be careful about what we infer from them. Do benefits appearing before substantial measured weight loss necessarily imply a direct vascular effect? Not necessarily. Appetite and energy intake change from the first dose; weight loss is continuous, and metabolic and inflammatory c ...