Sao Paulo, Brazil—The short-term risk of type 2 diabetes does not appear to be increased by use of PCSK9 inhibitors, which can dramatically decrease LDL cholesterol levels.

The meta-analysis involving more than 68,000 patients was presented at the European Society of Cardiology Congress in Barcelona, Spain.

Background information in the study notes that proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are novel drugs that potentially reduce LDL cholesterol by 50% to 60%. The monoclonal antibodies can successfully treat patients intolerant to statins and patients with familial hypercholesterolemia.

While LDL cholesterol reduction with statins and PCSK9 inhibitors significantly reduces risk of cardiovascular disease, the therapies also can interfere with insulin production, increasing diabetes risk, the study notes.

“Genetic mutations in the PCSK9 gene are associated with incident diabetes,” explained lead author Luiz Sérgio Carvalho, MD, PhD, MSc, clinical investigator, Laboratory of Atherosclerosis and Vascular Biology (AtheroLab), University of Campinas (UNICAMP) in São Paulo, Brazil. “We therefore hypothesized that treatment with PCSK9 inhibitors could lead to the development of type 2 diabetes.”

To determine if their hypothesis was true, researchers systematically reviewed all published randomized clinical trials comparing PCSK9 inhibitors with placebo in patients with primary hypercholesterolemia. Assessed by two reviewers, the primary outcome measures were plasma glycosylated hemoglobin (HbA1c), fasting blood glucose, or a new diagnosis of type 2 diabetes mellitus.

The meta-analysis involved 20 randomized clinical trials with 68,123 participants over mean follow-up of 42 weeks and median follow-up of 48 weeks. Participants, 58% male, with an average age 60 years and had baseline fasting blood glucose of 103 mg/dL and HbA1c of 5.89%.

Results indicate that, compared with placebo, PCSK9 inhibitors were associated with significant increases in fasting blood glucose of around 2% per year and in HbA1c of approximately 0.05% per year. Overall, the relative risk of incident type 2 diabetes with PCSK9 inhibitors compared with placebo was calculated at 1.04

“The small changes in fasting blood glucose and HbA1c in the short-term were not sufficient to increase the incidence of type 2 diabetes,” Carvalho pointed out.

In analyses adjusted for age and gender, however, trends towards an increased risk of type 2 diabetes in patients who experienced more intense LDL-cholesterol reduction (lowering by 55% or more), and those who were treated with PCSK9 inhibitors for more than 1 year were detected.

“We found that treatment with PCSK9 inhibitors is associated with a small but significant increase in plasma glycemia and HbA1c, without increasing the risk of incident type 2 diabetes in the short-term,” Carvalho said. “If these drugs are found to have a small or even moderate diabetogenic effect in the long-term, it is unlikely to change prescribing guidelines given their substantial benefit in reducing cardiovascular risk.”

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