Efficacy and Safety of PCSK9 Monoclonal Antibodies in Patients With Diabetes.

PURPOSE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have proven efficacy in improving cardiovascular outcomes. Roles for the PCSK9 molecule in metabolic pathways beyond LDL receptor processing and cholesterol homeostasis are well established. PCSK9 genetic variants associated with lower LDL-C levels correlate with a higher incidence of type 2 diabetes (T2DM), calling into question the appropriateness of these drugs in patients with T2DM and those at high risk of developing diabetes, and whether cardiovascular benefit seen with PCSK9 inhibitors might be offset by resultant dysglycemia. The purpose of this review was to examine the role of PCSK9 protein in glucose homeostasis, the impact of PCSK9 inhibition in relation to glucose homeostasis, and whether some of the cardiovascular benefit seen with PCSK9 inhibitors and statins might be offset by resultant dysglycemia. METHODS: Comprehensive literature searches of electronic databases of PubMed, EMBASE, and OVID were conducted by using the search terms hyperlipidaemia, PCSK9, diabetes, and glucose as well as other relevant papers of interest collected by the authors. The retrieved papers were reviewed and shortlisted most relevant ones. FINDINGS: Genetically determined lower circulating LDL-C and PCSK9 concentrations may have an incremental effect in increasing T2DM incidence, but any perceived harm is outweighed by the reduced risk of atherosclerotic cardiovascular disease achieved through lower lifetime exposure to LDL-C. PCSK9 monoclonal antibodies are effective and safe in patients with T2DM and those at high risk of developing it. The number-needed-to-treat to prevent one atherosclerotic cardiovascular disease event in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study in the subgroup with diabetes is significantly lower than for those without. Therefore, T2DM or being at high risk to develop it should not be a reason to avoid these agents. The safety of PCSK9 inhibition in relation to glucose homeostasis may depend on the method of inhibition and whether it occurs in circulation or the cells. Data from experimental studies and randomized controlled trials suggest no detrimental effect of PCSK9 monoclonal antibodies on glucose homeostasis. More data and large randomized controlled studies are needed to assess the impact of other methods of PCSK9 inhibition on glucose homeostasis. IMPLICATIONS: PCSK9monoclonal antibodies markedly reduce LDL-C and consistently reduce cardiovascular mortality in patients with and without diabetes. Current evidence does not suggest an adverse effect of PCSK9 monoclonal antibodies on glycemic parameters.

Efficacy and safety of PCSK9 monoclonal antibodies.

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have been developed since the discovery of the PCSK9 protein in 2003. In addition to background statin treatment, they reduce low-density lipoprotein cholesterol (LDL-C) to unprecedented levels and have shown encouraging results in improving cardiovascular events. Concerns regarding the safety of PCSK9 inhibitors and very low LDL-C have somewhat been allayed after several longer-term prospective studies.Areas covered: A comprehensive literature search was carried out including article searches in electronic databases (EMBASE, PUBMED, OVID) and reference lists of relevant articles. This review examines novel research concerning PCSK9 monoclonal antibodies and cardiovascular outcomes with a special focus on their safety and tolerability. The safety of very low LDL-C concentrations and the link between LDL-C lowering and diabetes is also discussed.Expert opinion: PCSK9 monoclonal antibodies when added to background statin therapy, lowers LDL-C to previously unattainable levels. This is safe with little undesirable effects and impacts positively on cardiovascular disease. Current guidance limits their use to primary prevention. Cost effectiveness should be taken into consideration before allowing a wider use of this new class of cholesterol lowering therapy and more data on their long-term safety is welcome.