Role of Gut Microbiota in Statin-Associated New-Onset Diabetes—a Cross-Sectional and Prospective Analysis of the FINRISK 2002 Cohort

Dyslipidemia is treated effectively with statins, but treatment has the potential to induce new-onset type-2 diabetes. Gut microbiota may contribute to this outcome variability. We assessed the associations of gut microbiota diversity and composition with statins. Bacterial associations with statin-associated new-onset type-2 diabetes (T2D) risk were also prospectively evaluated.We examined shallow-shotgun-sequenced fecal samples from 5755 individuals in the FINRISK-2002 population cohort with a 17+-year-long register-based follow-up. Alpha-diversity was quantified using Shannon index and beta-diversity with Aitchison distance. Species-specific differential abundances were analyzed using general multivariate regression. Prospective associations were assessed with Cox regression. Applicable results were validated using gradient boosting.Statin use associated with differing taxonomic composition (R2, 0.02%; q=0.02) and 13 differentially abundant species in fully adjusted models (MaAsLin; q<0.05). The strongest positive association was with Clostridium sartagoforme (β=0.37; SE=0.13; q=0.02) and the strongest negative association with Bacteroides cellulosilyticus (β=-0.31; SE=0.11; q=0.02). Twenty-five microbial features had significant associations with incident T2D in statin users, of which only Bacteroides vulgatus (HR, 1.286 [1.136-1.457]; q=0.03) was consistent regardless of model adjustment. Finally, higher statin-associated T2D risk was seen with [Ruminococcus] torques (ΔHRstatins, +0.11; q=0.03), Blautia obeum (ΔHRstatins, +0.06; q=0.01), Blautia sp. KLE 1732 (ΔHRstatins, +0.05; q=0.01), and beta-diversity principal component 1 (ΔHRstatin, +0.07; q=0.03) but only when adjusting for demographic covariates.Statin users have compositionally differing microbiotas from nonusers. The human gut microbiota is associated with incident T2D risk in statin users and possibly has additive effects on statin-associated new-onset T2D risk.