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PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

Amand F Schmidt1, Daniel I Swerdlow2, Michael V Holmes3

  • 1Institute of Cardiovascular Science, University College London, UK; Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, UK.

The Lancet. Diabetes & Endocrinology
|December 3, 2016
PubMed

Insights

Genetic variants lowering LDL cholesterol via PCSK9 were linked to increased type 2 diabetes risk and higher body weight. This suggests PCSK9 inhibitors may pose similar risks, requiring careful benefit-risk assessment.

Area of Science:

  • Genetics
  • Metabolic Diseases
  • Cardiovascular Medicine

Background:

  • Statins reduce LDL cholesterol and cardiovascular disease risk but are linked to modest hyperglycemia and increased type 2 diabetes risk.
  • PCSK9 variants influencing LDL cholesterol are investigated for their association with type 2 diabetes and related biomarkers.
  • Understanding PCSK9's impact on diabetes risk is crucial for evaluating PCSK9 inhibitors.

Purpose of the Study:

  • To investigate the association of LDL cholesterol-lowering PCSK9 genetic variants with type 2 diabetes.
  • To assess the relationship between PCSK9 variants and key diabetes-related biomarkers including glucose, HbA1c, insulin, and bodyweight.
  • To estimate the potential impact of PCSK9 inhibitors on diabetes risk based on genetic associations.

Main Methods:

  • Mendelian randomization study utilizing data from large-scale cohort studies, RCTs, case-control studies, and genetic consortia.
  • Analysis of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, rs11206510) scaled to a 1 mmol/L reduction in LDL cholesterol.
  • Meta-analyses and weighted gene-centric scores were employed to estimate associations with LDL cholesterol, fasting glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and type 2 diabetes risk.

Main Results:

  • PCSK9 variants associated with lower LDL cholesterol showed a significant association with increased fasting glucose (0.09 mmol/L), bodyweight (1.03 kg), and waist-to-hip ratio (0.006).
  • An increased odds ratio for type 2 diabetes (1.29) was observed in individuals with these PCSK9 variants.
  • No significant associations were found with HbA1c, fasting insulin, or BMI.

Conclusions:

  • PCSK9 variants linked to reduced LDL cholesterol are also associated with higher fasting glucose, increased bodyweight, and a greater risk of type 2 diabetes.
  • These findings suggest that PCSK9 inhibitor therapies may carry a risk of increased type 2 diabetes.
  • Clinical trials of PCSK9 inhibitors must carefully evaluate these safety outcomes, similar to the risk-benefit assessments performed for statins.
Abstract

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