In a study appearing in the October 4 issue of JAMA, Luca A. Lotta, M.D., Ph.D., of the University of Cambridge, U.K., and colleagues examined the associations with type 2 diabetes and coronary artery disease of low-density lipoprotein cholesterol (LDL-C)-lowering genetic variants. Treatment with statins, the pharmacological agents of choice for LDL-C-lowering therapy in cardiovascular prevention, is associated with weight gain and a higher incidence of new-onset type 2 diabetes.
The researchers conducted a meta-analyses of genetic association studies, and 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.
The authors found that LDL-C-lowering genetic variants at the gene NPC1L1 were inversely associated with coronary artery disease and directly associated with type 2 diabetes. For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk. However, associations with type 2 diabetes were heterogeneous (dissimilar), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles.
"In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near the NPC1L1 gene was associated with a higher risk of type 2 diabetes," the authors write.
"The results of this study show that multiple LDL-C lowering mechanisms, including those mediated by the molecular targets of available LDL-C-lowering drugs (i.e., statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors), are associated with adverse metabolic consequences and increased type 2 diabetes risk."
"In general, unlike the association of LDL-C-lowering alleles [an alternative form of a gene] with cardiovascular risk, the association of these alleles with metabolic risk appears to be specific to particular genes, which in turn might suggest that the adverse consequences of lipid-lowering agents on diabetes risk could be specific to a particular drug target. This may have clinical implications for the future of lipid-lowering therapy in the context of the increasing number of approved drugs acting on different molecular targets. The overall safety profile of these drugs, including the magnitude of risk of new-onset type 2 diabetes, may be relevant to the choice of specific agent for subsets of the patient population (e.g., those at high risk for type 2 diabetes who are candidates for lipid-lowering therapy)," the researchers write.