Does the treatment with PCSK9 inhibitors increase the risk of type 2 diabetes?

摘要

Cardiovascular diseases are major comorbidities in patients with type 2 diabetes mellitus. Diabetic patients often receive treatment with lipid-lowering drugs. Statins are first-line therapy for high levels of low-density lipoprotein-cholesterol (LDL-C), aiming to decrease the risk of atherosclerotic cardiovascular disease, as a main cause of death in diabetic patients 1 . Their widespread use led to a significant decrease in cardiovascular morbidity and mortality. There is increasing evidence that lipid-lowering medication (especially statins) increases the risk of type 2 diabetes in nondiabetic patients. However, their modest diabetogenic effect does not outweigh their benefits in patients with established cardiovascular disease or those at high risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a new class of drugs, with hypocholesterolemiant properties, recently approved by the Food and Drug Administration 1 . They are monoclonal antibodies that inactivate the proprotein convertase subtilisin/kexin type 9, enabling low-density lipoprotein receptor degradation. The PCSK9 inhibitors alirocumab and evolocumab may be used in patients with diabetes, when statin therapy alone, in high doses, does not succeed to lower the LDL-C levels 2 . Despite their benefits in lowering the cardiovascular risk, treatment with PCSK9 inhibitors may lead to an increase in the risk of incident diabetes. However, current data suggest that the benefits of treatment with PCSK9 inhibitors outweigh this risk. A systematic review and meta-analysis with over 96,000 patient-years, done by de Carvalho et al, evaluated the effects of PCSK9 inhibitors versus placebo in patients with primary hypercholesterolemia 3 . This meta-analysis concluded that treatment with PCSK9 inhibitors increased fasting serum glucose levels and HbA1c, compared to placebo, but this effect did not lead to an increased incidence of diabetes 3 . An association has been found between the potency and duration of treatment with PCSK9 inhibitors and the increased risk of diabetes 3 . In an analysis of FOURIER trial, Sabatine et al investigated the efficacy and safety of a PCSK9 inhibitor, evolocumab, depending on diabetes status, and its risk of developing diabetes 4 . FOURIER trial included 27,564 patients with atherosclerotic cardiovascular disease, treated with statins, who were followed for 2.2 years. At the beginning of the study, 40% of patients had diabetes and 60% did not have diabetes. Treatment with evolocumab did not increase the risk of new-onset diabetes 4 . Also, the levels of HbA1c and fasting serum glucose were similar between the groups treated with evolocumab and placebo, in patients with diabetes or those non-diabetic 4 . The authors concluded that treatment with evolocumab is not associated with a higher risk of new-onset diabetes 4 . However, the follow-up period of these patients was only 2.2 years. Their data remain to be confirmed by studies with a longer follow-up period. Da Dalt et al investigated the molecular mechanisms behind the association between the PCSK9 loss of function genetic variants and the higher serum glucose levels and increased risk of new-onset type 2 diabetes in mice 5 . They have found that PCSK9 deficiency is associated with impaired glucose tolerance, but not with insulin resistance 5 . PCSK9 effect on glucose metabolism depends on the presence of the low-density lipoprotein receptor 5 . Genetic deletion of PCSK9 in mice is associated with glucose intolerance 5 . Large, long-term studies with PCSK9 inhibitors will surely offer responses to questions regarding the correlation of these drugs with the risk of new-onset diabetes.