PCSK9 and carbohydrate metabolism: A double-edged sword

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a paramount role in the degradation of low-density lipoprotein (LDL) receptors (LDLR) on the hepatic cells surface and subsequently affects LDL particles catabolism and LDL cholesterol (LDL-c) levels. The anti-PCSK9 monoclonal antibodies lead to substantial decrease of LDL-c concentration. PCSK9 (which is also expressed in pancreatic delta-cells) can decrease LDLR and subsequently decrease cholesterol accumulation in pancreatic beta-cells, which impairs glucose metabolism and reduces insulin secretion. Thus, a possible adverse effect of PCSK9 inhibitors on carbohydrate metabolism may be expected by this mechanism, which has been supported by the mendelian studies results. On the other hand, clinical data have suggested a detrimental association of PCSK9 with glucose metabolism. So, the inhibition of PCSK9 may be seen as a double-edged sword regarding carbohydrate metabolism. Completed clinical trials have not shown a detrimental effect of PCSK9 inhibitors on diabetes risk, but their short-term duration does not allow definite conclusions.

Effect of alirocumab on lipids and lipoproteins in individuals with metabolic syndrome without diabetes: Pooled data from 10 phase 3 trials

“…Individuals with metabolic syndrome have a range of clinical and metabolic characteristics that may impact the efficacy and/or safety of a PCSK9 inhibitor, including obesity, high triglycerides/low HDL‐C, high blood glucose and insulin resistance. For example, PCSK9 appears to have a role in glucose metabolism and PCSK9 levels have been shown to correlate with glycaemic parameters and insulin resistance, although evidence is conflicting among different studies . Insulin signalling, which is known to influence LDL‐receptor expression (the target of PCSK9), is often dysregulated in metabolic syndrome .…”

Anacetrapib, a New CETP Inhibitor: The New Tool for the Management of Dyslipidemias?

“…Mendelian randomization trials have shown that hypolipidemic drugs that reduce LDL receptors’ activity are associated with a detrimental effect on carbohydrate homeostasis [ 26 , 27 , 28 , 29 ], which has received much attention taking into account the wide use of these hypolipidemic drugs. The beneficial effect of CETP inhibitors on glucose homeostasis, as shown in the REVEAL trial and previous studies [ 9 , 30 ], can possibly counteract the dysglycemic effect of other hypolipidemic drugs.…”

Beyond sports: Efficacy and safety of creatine supplementation in pathological or paraphysiological conditions of brain and muscle

“…Of course, alternative courses of action are possible, for example stopping statins altogether and treating the patient with alternative drugs. It should be remembered, although, that one such alternative, PCSK9 inhibitors, is very expensive, shows low treatment adherence by the patients and may decrease glucose tolerance …”

“…It should be remembered, although, that one such alternative, PCSK9 inhibitors, is very expensive, 70 shows low treatment adherence by the patients 71 and may decrease glucose tolerance. 72 Further-Furthermore, lowering low-density lipoprotein (LDL)-cholesterol may not, by itself, be effective in preventing cardiovascular events, as shown by a recent study where Evacetrapib, an inhibitor of cholesteryl ester transfer protein was not able to prevent cardiovascular events despite a reduction in LDL-cholesterol levels. 73 Supple-Supplementation with coenzyme Q10 has been also advocated in the prevention of statin-induced myopathy.…”