Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia

Abstract

Diabetic dyslipidaemia, characterized by quantitative, qualitative and kinetic changes in all major circulating lipids, contributes to the increased cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). A promising therapeutic avenue is the inhibition of the proprotein convertase subtilisin kexin 9 (PCSK9) with human monoclonal antibodies (mAbs) that potently reduce plasma low‐density lipoprotein cholesterol (LDL‐C) levels on top of statin treatment. The aim of this review is to evaluate the efficacy of PCSK9 inhibitors to lower the residual cardiovascular risk of T2DM patients and to discuss the safety of PCSK9 inhibition in these patients. PCSK9 inhibitors potently lower plasma LDL‐C levels in T2DM patients and reduce risk for the development of cardiovascular disease. Anti‐PCSK9 mAbs are generally not more or less effective in T2DM patients compared to a general high‐risk population. Nevertheless, due to their higher cardiovascular risk, the absolute risk reduction of major cardiovascular events is more significant in T2DM patients. This suggests that treatment of T2DM patients with anti‐PCSK9 mAbs could be attractive from a cost‐effectiveness perspective. Treatment with anti‐PCSK9 mAbs did not result in significant treatment‐emergent adverse effects. While genetic studies suggest a potential link between PCSK9 inhibition and glucose homeostasis, anti‐PCSK9 mAbs did not worsen glycaemic control in T2DM patients, but their safety should be verified after a longer‐term follow‐up.

Circulating PCSK9 levels are not associated with the conversion to type 2 diabetes

“…Our results are also consistent with some pre-clinical findings regarding the molecular link between PCSK9 and diabetes [27]. Using transgenic mouse models, Da Dalt et al recently demonstrated that intra-cellular PCSK9 rather that circulating PCSK9 is involved in the regulation of glucose homeostasis.…”

PCSK9 inhibitors for secondary prevention in patients with cardiovascular diseases: a bayesian network meta-analysis

“…This finding suggest that these patients might be more likely to benefit from treatment with monoclonal antibodies targeting PCSK9. On the other hand, recent studies demonstrated that loss-of-function variants in PCSK9 were associated with lower LDL-C levels but associated with increased levels of fasting glucose concentration and an increased risk for new-onset diabetes, which resulted in serious concerns about the safety of the anti-PCSK9 treatments [ 11 – 13 ]. According to our analysis, there is no significant impact of LDL-C change induced by PCSK9 inhibitors on new-onset diabetes.…”

“…This therapy may be more effective in reducing LDL-C and other atherogenic lipids in high-risk patients treated with the maximum tolerated dose of statins, as well as those who are intolerant to statins. Although there are safety concerns such as the potential risk of new-onset diabetes [ 11 – 13 ], several meta-analyses have demonstrated that PCSK9 inhibitors showed better effects in reducing LDL-C levels and improving clinical benefits than other lipid-lowering agents for the secondary prevention of cardiovascular disease [ 14 , 15 ]. However, due to the lack of direct comparisons between different medications, the optimal agent targeting PCSK9 to reduce the risk of death after cardiovascular events remains undetermined.…”

Chronic Inflammatory Demyelinating Polyradiculoneuropathy Association With Low Cholesterol Levels: A Case Report in a Patient Taking PCSK9 Inhibitor

“…The addition of cholesterol to the axons or cell bodies of neurons treated with this inhibitor restores normal axonal elongation [6]. PCSK9 inhibitors in dyslipidemia primarily focus on reduction of plasma LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB) PP levels [7].…”