Naturally occurring variations on or near the NPC1L1 gene, which is linked to lower LDL-cholesterol levels, were associated with a higher risk of type 2 diabetes in a meta-analysis reported online Oct. 4 in JAMA.
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Some cholesterol-lowering medications, notably ezetimibe, work by inhibiting the action of the NPC1L1 gene. The findings of this meta-analysis suggest that by doing so, these cholesterol-lowering agents may raise the risk of type 2 diabetes, said Luca A. Lotta, MD, PhD, of the Medical Research Council Epidemiology Unit, University of Cambridge (U.K.), and his associates. The investigators examined gene-association analyses in several studies and databases covering 50,775 adults with type 2 diabetes and 270,269 control subjects in Europe and the United States during 1991-2016. They found that alleles at the NPC1L1 locus that are known to be associated with lower LDL-cholesterol levels also were strongly associated with higher rates of diabetes. For every genetically predicted reduction in LDL-C of 1 mmol/L, the risk for type 2 diabetes increased (odds ratio, 2.42).
The estimated absolute risk difference was 5.3 incident cases/1,000 person-years for every genetically predicted 1-mmol/L reduction in LDL-C, Dr. Lotta and his associates said (JAMA. 2016 Oct. 4. doi: 10.1001/jama.2016.14568).
These findings are consistent with reports that link cholesterol-lowering medications with weight gain and a higher incidence of new-onset type 2 diabetes, as well as with the clinical observation that patients with familial hypercholesterolemia carry a lower risk for diabetes. “These results warrant the continued monitoring of the glycemic effects of ezetimibe in clinical trials and in clinical practice,” the researchers noted.