IMPORTANCE: Low-density lipoprotein cholesterol (LDL-C)-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, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near $NPC1L1$ are associated with the risk of type 2 diabetes.

OBJECTIVE: To investigate whether LDL-C-lowering alleles in or near $NPC1L1$ and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, $HMGCR$, $PCSK9$, $ABCG5/G8$, $LDLR$) 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-C-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 and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016.

EXPOSURES: Low-density lipoprotein cholesterol-lowering alleles in or near $NPC1L1$, $HMGCR$, $PCSK9$, $ABCG5/G8$, and $LDLR$.

MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) for type 2 diabetes and coronary artery disease.

RESULTS: Low-density lipoprotein cholesterol-lowering genetic variants at $NPC1L1$ were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42-0.88]; $P$ = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70-3.43]; $P$ < .001). For $PCSK9$ genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; $P$ = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk ($I2$ = 0% for heterogeneity in genetic associations; $P$ = .93). However, associations with type 2 diabetes were heterogeneous ($I2$ = 77.2%; $P$ = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles.

CONCLUSIONS AND RELEVANCE: In this meta-analysis, exposure to LDL-C-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-C-lowering therapy.