Estimating direct tissue effects versus weight loss effects of incretin-based drugs for obesity on various chronic conditions.

The extent to which newer, incretin-based drugs for obesity improve disease outcomes via weight loss versus the direct effects of these drugs is the subject of intense interest. Although reductions in major adverse cardiovascular events appear to be predominantly driven by the direct tissue effects of such drugs, the associated weight loss effects must be relevant to the benefits observed in other major outcomes, albeit to differing extents. In this Personal View, we draw on evidence to support that weight loss is at least partly responsible (albeit to differing extents) for the reported benefits of incretin-based drugs for obesity in people living with heart failure with preserved ejection fraction, hypertension, chronic kidney disease, and type 2 diabetes. Concurrently, we propose that drug-induced weight loss is largely responsible for the reported improvements in osteoarthritis, obstructive sleep apnoea, and metabolic dysfunction-associated steatohepatitis outcomes. However, more evidence is needed to solidify these observations, including, when possible, trials comparing the effects of incretin-based drugs for obesity with calorie-reduced diets on both outcomes and mechanistic pathways. Such evidence has implications for public health and the design of future trials of novel drugs for obesity.