In the first study, involving 112,772 participants, the researchers constructed two genetic scores consisting of PCSK9 and HMGCR variants to mimic the effects of treatment with PCSK9 inhibitors and statins, respectively. They found that low-density lipoprotein (LDL) cholesterol-lowering variants in both genes were associated with a reduction in the risk for cardiovascular events, but an elevated risk for diabetes.
After adjustment for a decrease in LDL cholesterol levels of 10 mg/dL, the team found a “nearly identical” reduction of 18.9% and 19.1% in the risk for cardiovascular events with the presence of PCSK9 and HMGCR variants, respectively.
These findings suggest that “treatment with a PCSK9 inhibitor should reduce the risk of cardiovascular events by approximately the same amount as treatment with a statin,” write study authors Brian Ference (Wayne State University School of Medicine, Detroit, Michigan, USA) and colleagues in The New England Journal of Medicine.
However, the presence of PCSK9 variants was associated with an 11.2% increase in the risk for diabetes per decrease of 10 mg/dL in LDL cholesterol, and the presence of HMGCR variants was associated with a 12.7% increase in risk.
“[L]ike statins, PCSK9 inhibitors may also increase the risk of new-onset diabetes,” say the authors. However, because the proportional reduction in cardiovascular disease risk associated with PCSK9variants was “much greater” than the increased risk for diabetes, they conclude that “as with statins, the reduction in cardiovascular risk with PCSK9 inhibitors should far exceed any potential increased risk of diabetes.”
In the second study, Amand Schmidt (University College London, UK) and colleagues analyzed data from 568,448 individuals included in randomized controlled trials, observational studies, and genetic consortia to estimate the association between PCSK9 variants and type 2 diabetes risk.
The team showed that four independent PCSK9 variants were associated with a reduction in LDL cholesterol levels, ranging from 0.02 mmol/L (0.78 mg/dL) to 0.34 mmol/L (13.15 mg/dL) per LDL cholesterol-reducing allele.
When the variants were combined into a weighted gene-centric score and scaled to a reduction in LDL cholesterol of 1 mmol/L (38.67 mg/dL), presence of the variants was associated with a 29% increased risk for type 2 diabetes.
The study authors also found that PCSK9 variants were associated with increased fasting glucose, bodyweight, and waist-to-hip ratio, but not with glycated hemoglobin, fasting insulin, or body mass index.
"[G]enetic variants in PCSK9 that associate with lower concentrations of LDL cholesterol are also associated with a modestly higher risk of type 2 diabetes and with associated differences in measures of glycaemia,” write the authors in The Lancet Diabetes and Endocrinology.
They recommend that future trials of PCSK9 inhibitors should carefully monitor changes in metabolic markers, including bodyweight and glycemia, and conclude that genetic studies “could be more widely used to interrogate the safety and efficacy of novel drug targets.”