Importance
Low-density lipoprotein (LDL) cholesterol-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, mimicking the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are also associated with the risk of type 2 diabetes.
Objective
To investigate whether LDL-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (i.e. HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes.
Design, Setting and Participants
The associations with type 2 diabetes and coronary artery disease of LDL-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50,775 individuals with type 2 diabetes and 270,269 controls including three studies and 60,801 individuals with coronary artery disease and 123,504 controls from a published meta-analysis. Data collection took place in Europe and the United States between 1991 and 2016.
Exposure
LDL-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, LDLR.
Main Outcomes and Measures
Odds ratio of type 2 diabetes and coronary artery disease.
Results
LDL-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (odds ratio for a genetically-predicted reduction of 1 mmol/L in LDL cholesterol, 0.61; 95% confidence interval, 0.42-0.88; p=0.008) and directly associated with type 2 diabetes (2.42, 1.70-3.43; p<0.001). The odds ratio of type 2 diabetes for PCSK9 genetic variants was 1.19 (95% confidence interval, 1.02-1.38, p=0.03). For a given reduction in LDL cholesterol, genetic variants were associated with a similar reduction in coronary artery disease risk (I-squared for heterogeneity in genetic associations=0.0%; p=0.93). However, associations with type 2 diabetes were heterogeneous (I-squared=77.2%; p=0.002), indicating gene-specific associations with metabolic risk for LDL-lowering alleles.
Conclusions and Relevance
In this meta-analysis, exposure to LDL-cholesterol lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL cholesterol-lowering therapy.