Fibroblast growth factor 21 (FGF21) is a human metabolic hormone that is being pursued in early stage clinical trials as pharmacological target to treat a range of metabolic diseases. In animal models, increased FGF21 signalling has been shown to have beneficial effects on cardiometabolic outcomes, Alzheimer’s disease risk and lifespan. However, studies investigating the effect of FGF21 signalling on these clinical outcomes in humans have been inconclusive. In this study, a genetic variant associated with higher circulating FGF21 levels was leveraged to investigate its clinical effects in humans. Higher genetically proxied circulating FGF21 levels were associated favourably with lipid levels, blood pressure traits, waist-to-hip ratio, chronic inflammation, cardiovascular outcomes, Alzheimer’s disease risk and lifespan. These findings may be used to anticipate the effects of pharmacologically increasing FGF21 signalling and inform the design of further clinical trials.

Growth-differentiation factor 15 (GDF15) is an inflammatory cytokine involved in energy homeostasis. Its circulating levels are acutely increased by the type 2 diabetes medication metformin, resulting in reduced appetite and weight loss. We identified a genetic variant at the GDF15 gene to proxy a small, lifelong increase in circulating GDF15 levels, and leveraged it in colocalization and Mendelian randomization analyses to investigate the effects of chronically elevated GDF15 levels on body mass index (BMI) and type 2 diabetes liability. The results provide human genetic evidence supporting that chronically elevated GDF15 levels increase BMI. There was no genetic evidence to support bi-directional effects, or that chronically elevated GDF15 levels directly affect liability to type 2 diabetes. Our results contrast the BMI lowering effects of an acute increase in GDF15 levels observed after metformin use. These findings have direct implications for informing pharmacological strategies aimed at targeting GDF15 levels for weight loss.