Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study

It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary level statistics from the Genomic Investigation of Statin Therapy (GIST, n(max)=40,914) and DIAGRAM (n(max)=159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (r(genetic)=0.36, s.e.=0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95%CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95%CI: −0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin-users, as the presence of non-statin users in the DIAGRAM dataset may have substantially diluted our effect estimate.