Abstract
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, nmax=40,914) and DIAGRAM (nmax=159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (rgenetic=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.
Highlights
It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low low-density lipoprotein cholesterol (LDL-C) concentrations, or due to the statin-induced proportional change in LDL-C
A multivariable Mendelian randomization (MR)-analysis where we adjust for effects of all single nucleotide polymorphisms (SNPs) on fasted LDLC did not lead to different conclusions regarding the effect of statin response on T2D risk
The findings from the MR analyses suggest that statin-induced proportional change of LDLC is unlikely to influence T2D risk
Summary
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. Apparent causal effects on T2D have been shown both for overall genetic predisposition to lower LDL-C concentrations [7,8,9] as well as for HMGCR-, NPC1L1-, and PCSK9-gene specific (i.e. on target) mechanisms of lowering LDL-C [9,10,11,12,13] These findings, and recent reanalysis of statin trial data using Egger regression [14], suggest that statin-related dysglycaemia might be mediated largely through LDL-C lowering mechanisms rather than through proposed pleiotropic mechanisms of statins [15]. Genetic instruments have not been proposed before to examine whether the greater absolute cardiovascular disease (CVD) risk reduction conferred by statin therapy in individuals with T2D could result from greater proportional statin-induced LDL-C lowering. We aimed to use these data to examine the causal direction of the relationship between proportional statin response and T2D using a bidirectional two-sample MR approach
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