Hypolipidemic Drugs and Diabetes Mellitus—Mechanisms and Data From Genetic Trials

Abstract

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.

LDL-C plays a causal role on T2DM: a Mendelian randomization analysis

“…Therefore, most of these observational studies should be adjusted for potential confounding factors. Another possible explanation for the differences in results generated in our current MR study from those of previous clinical trials and metaanalysis may be due to the relative short-term duration of the trials as opposed to lifetime exposures to natural genetic variation, and potentially undefined "off-target effects" of medical treatments on carbohydrate homeostasis [39]. In fact, in response to hypolipidemic drug-cholesteryl ester transfer protein (CETP) inhibitors, which do not detrimentally affect carbohydrate homeostasis, a lower incidence of newonset DM was reported [40].…”

Common and Rare PCSK9 Variants Associated with Low-Density Lipoprotein Cholesterol Levels and the Risk of Diabetes Mellitus: A Mendelian Randomization Study

“…However, not all MR and genetic studies have revealed inverse associations between each LDL-C-level-lowering allele and an increased risk of DM [ 11 , 21 , 47 ]. Accordingly, the heterogeneity between genetic and MR studies suggests that the diabetogenic effect of LDL-C reduction is mechanism-specific, and may depend on the underlying reduction in LDL-C levels, such as pancreatic ß -cell dysfunction caused by increased intracellular cholesterol levels due to either increased LDLR expression or transmembrane cholesterol transport [ 17 , 48 ]. Furthermore, genetic studies may shed light on the effects of pleiotropy on the association between LDL-C-level-determining alleles and DM status.…”

“…Furthermore, genetic studies may shed light on the effects of pleiotropy on the association between LDL-C-level-determining alleles and DM status. For example, some studies have revealed that LDL-C-lowering alleles of HMGCR and PCSK9 variants increase body weight and waist circumference [ 17 , 18 , 19 ]. GCKR , TM6SF2 , and PNPLA3 variants were reported to be associated with diabetogenic traits such as high liver fat, in addition to being associated with reductions in LDL-C levels [ 49 ].…”

“…However, clinical trials and meta-analyses have revealed that statins increase the incidence of new-onset diabetes mellitus (DM) in a dose-dependent manner, especially in prediabetes [ 13 , 14 , 15 , 16 ]. Furthermore, MR studies using variants in HMGCR , NPC1L1 , and PCSK9 have reported that decreased LDL-C levels were associated with an increased incidence of new-onset DM [ 9 , 10 , 17 , 18 , 19 , 20 ], but this finding was not supported by other studies [ 11 , 21 ]. Whether PCSK9 inhibitors increase the risk of diabetes is also still under debate [ 22 ].…”

PCSK9 inhibitors and diabetes mellitus

“…Zvýšená expresia LDLR v dôsledku zníženej syntézy cholesterolu v bunkách pri liečbe statínmi sa preto môže podieľať na tzv. diabetogénnom efekte statínov [18].…”