To investigate whether 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) use is associated with an increased risk of diabetes mellitus and hyperglycemia, we performed a nested case-control study using a postmarketing surveillance database in Japan.
Mendelian randomization studies support these findings since genetic variants in the gene encoding the target of statins, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, are associated with increased incidence of new-onset DM, suggesting that the so-called diabetogenic effect of statins is an "on-target effect" possibly related to their main mechanism of action, that is the increased low-density lipoprotein (LDL) receptor expression.
In this study, variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level.
HMGCR, our positive control, associated with LDL-C, CAD and a glycemic composite (derived from GWAS meta-analysis of four glycemic traits and diabetes).
In a major Mendelian randomization study of variants in the HMGCR gene, which encodes the protein through which statins exert their effect, two polymorphisms associated with lower LDL-cholesterol were also associated with higher weight, higher waist circumference, higher glucose and higher diabetes risk.
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.
These analyses suggested that genotypes of few inflammatory genes, a SNP in HMGCR gene, middle age, gender, low HDL and diabetes were very informative variables to predict the risk of AMI.
We evaluated the association of a single nucleotide polymorphism (rs17238540) in the HMGCR gene with lipid-lowering response to statins in a large population-based cohort of patients with diabetes.