Clinical trials and meta-analyses have shown that
statins can dose dependently increase the incidence of new-onset
diabetes mellitus (DM) especially in patients with underlying abnormalities of
carbohydrate homeostasis. 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. Additionally, Mendelian randomization studies have shown that genetic variants as proxies of other drugs that increase
LDL receptor expression (
ezetimibe and
proprotein convertase subtilisin/kexin type 9 [
PCSK9] inhibitors) also increase the risk of new-onset DM. This concept is supported by the fact of decreased DM prevalence in patients with
familial hypercholesterolemia who have decreased
LDL receptor expression. In contrast,
hypolipidemic drugs, such as the
cholesteryl ester transfer protein inhibitors, that decrease
LDL cholesterol without directly interfering with the
LDL receptor expression do not seem to detrimentally affect
carbohydrate homeostasis. However, the clinical trials of
ezetimibe and
PCSK9 inhibitors have not shown an increased DM risk, possibly suggesting that other potential non-well-defined "off-target effects" of
hypolipidemic drugs may affect
carbohydrate homeostasis. Thus, the long-term effect of
hypolipidemic drugs on DM risk depends not only on their final mechanism of hypolipidemic action but also on other "on-target" and "off-target" effects of these drugs.