Using genetics to aid detection of adverse drug effects: a Mendelian randomisation analysis of genetically proxied GLP-1RA in 1,020,464 participants across three population-based cohorts

Background: GLP-1 receptor agonists (GLP1-RAs) are an established treatment for type 2 diabetes mellitus (T2DM) and obesity. Their widespread use is set to increase through both indication expansion and patent expiry. As well as efficacy, it is crucial to understand the safety of this drug class to enable optimal use. Here we demonstrate how a genetic approach can augment signal-detection and post-market authorization surveillance. Methods: We used single nucleotide polymorphisms (SNPs) in GLP1R to recapitulate the effect of agonism with GLP1RAs on circulating glucose, glycated hemoglobin (HbA1c), body mass index (BMI) and risk of type 2 diabetes (T2DM) using Mendelian randomisation. We then tested if the adverse effect highlighted by medicines regulators of pancreatitis and the emerging effect of sarcopenia were causally related to GLP1R agonism, using this approach. Analyses were conducted in UK biobank and replicated in FinnGen and All of Us, results being combined using meta-analysis. Analyses were further stratified by a priori risk factors of age and alcohol consumption. Results: Genetically proxied GLP-1R agonism was associated with a reduction in glucose (exp({beta}) = 0.95 95% CI [0.94, 0.97]), HbA1c (exp({beta}) = 0.94 95% CI [0.92, 0.95]), and BMI (exp({beta})=0.98 95% CI [0.97, 0.99]); and a reduced risk of T2DM (OR = 0.82 95% CI [0.79 to 0.86]). Risk of acute and chronic pancreatitis was however increased (OR = 1.10 95% CI [1.01 to 1.20] and OR = 1.05 95% CI [0.95, 1.17], respectively), which varied as a function of age with risk most pronounced in those aged 50-59 years-old (OR = 1.79 95% CI [1.43, 2.24], OR = 1.57 95% CI [1.16, 2.12]) and in drinkers (OR = 1.32 95% CI [1.12, 1.54], OR = 1.36 95% CI [1.12, 1.65]). Risk of sarcopenia also increased (OR 1.34; 95% CI 1.05,1,71). Conclusions: Genetically proxied agonism with GLP-1RAs recapitulated the pharmacological effects of GLP1-1RAs on glycaemic traits, BMI and T2DM risk. This approach supports a causal effect of GLP-1RAs on the well reported adverse effects of pancreatitis and further indicates age and alcohol consumption as risk modifying effects. The less well reported but emerging effect of sarcopenia appears to also be casually related to agonism at GLP-1R. These analyses suggest a genetic approach could be used as an adjunct to signal detection studies to enhance safety regulation as well as personalisation of the use of these drugs.