Metabolic, enterohepatic and gut microbial effects of atorvastatin in healthy men

Objective: Statins are low-density lipoprotein cholesterol-lowering drugs that are highly effective in the prevention of cardiovascular disease and death. Evidence that statin therapy increases the risk of type 2 diabetes is accumulating, but the mechanism behind this phenomenon remains obscure. Design: A clinical, randomised, placebo-controlled, double-blind, crossover study. Methods: Here, we investigated the effect of atorvastatin on fasting and postprandial circulating concentrations of glucose, gluco-regulatory hormones, bile acid profiles as well as gut microbiota composition. Fifteen healthy men came in for a mixed meal test following 14 days of treatment with atorvastatin (40 mg once-daily during week one and 80 mg once-daily during week two) or placebo. Results: Treatment with atorvastatin did not affect postprandial plasma glucose or insulin concentrations, but basal as well as postprandial concentrations of glucagon were increased compared with placebo. Postprandial plasma concentrations of the gut-derived incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 were increased after atorvastatin treatment compared with placebo. Also, postprandial concentrations of taurine-conjugated primary bile acids increased, whereas glycine-conjugated secondary bile acids decreased. Microbiota composition was not affected by atorvastatin treatment. Conclusions: Atorvastatin treatment did not alter glucose or insulin concentrations, nor did it alter gut microbiota composition. However, we found that atorvastatin treatment increased fasting and postprandial glucagon concentrations, which may point to hyperglucagonaemia as a possible link between statin treatment and type 2 diabetes. Clinicaltrials.gov: NCT03018444. Significance Statement: This randomised, placebo-controlled, double-blind, crossover study reveals that short-term high-dose atorvastatin treatment increases fasting and postprandial glucagon levels and alters amino acid and bile acid profiles without affecting glucose, insulin, or gut microbiota in healthy men. These findings suggest hyperglucagonaemia as a potential mechanistic contributor to the increased risk of type 2 diabetes associated with statin therapy.