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Over the last 5 years, major randomized clinical trials and meta-analyses of these trials have indicated that statin therapy, which inhibits 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), is associated with a modestly higher risk of developing diabetes in a dose-dependent fashion.1,2 Statins act by reducing the synthesis of cholesterol, which then drives an increase in hepatic low-density lipoprotein (LDL) receptor expression, the key step leading to a reduction in circulating LDL cholesterol levels. Further supportive data for this relationship have emerged from genetic studies, typically less prone to confounding than observational studies, which have linked genetically determined lower LDL cholesterol to higher diabetes risk.3,4 In one such study, individuals with lower circulating LDL cholesterol due to variants in the HMGCR gene, a proxy for statin therapy, displayed higher glucose levels, higher weight, and increased diabetes risk,3 consistent with data from randomized clinical trials. However, the exact mechanism by which any such effect is mediated remains unclear.
Preiss D, Sattar N. Does the LDL Receptor Play a Role in the Risk of Developing Type 2 Diabetes?. JAMA. 2015;313(10):1016–1017. doi:10.1001/jama.2015.1275