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Drug targets for lipid modification and risk of type 2 diabetes: a cis-Mendelian randomization study

Zekai Chen1,2, Rima D Triatin1,3, Li Luo1

  • 1Department of Epidemiology, Unit of Genetic Epidemiology and Bioinformatics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Cardiovascular Diabetology
|May 15, 2026
PubMed
Abstract

Insights

Lipid-modifying drugs targeting certain genes may reduce coronary artery disease (CAD) risk without increasing type 2 diabetes (T2D) risk. Some lipid drugs show potential for reducing both CAD and T2D risk, offering insights for personalized treatment.

Area of Science:

  • Cardiovascular Genetics
  • Metabolic Disease Research
  • Pharmacogenomics

Background:

  • Lowering low-density lipoprotein cholesterol (LDL-C) is crucial for preventing coronary artery disease (CAD).
  • However, lipid-modifying drugs may elevate the risk of type 2 diabetes (T2D).
  • A comprehensive genetic analysis of T2D side effects across all lipid-modifying drugs is lacking.

Purpose of the Study:

  • To conduct a comprehensive genetic examination of type 2 diabetes (T2D) related side-effects for lipid-modifying drugs.
  • To evaluate the differential impact of various lipid-modifying drug targets on T2D and CAD risk.

Main Methods:

  • Utilized cis-Mendelian randomization with individual-level data from UK Biobank and Lifelines.
  • Identified genetic loci targeted by lipid-modifying drugs or their gene products.
  • Assessed prevalent and incident T2D as primary outcomes, with CAD as a contrast outcome.

Main Results:

  • HMGCR targeting is predicted to decrease CAD risk but increase T2D risk.
  • Targeting APOC3, LDLR, LPA, MTTP, NPC1L1, and PCSK9 may reduce CAD risk without altering T2D risk.
  • ANGPTL4 and CETP targeting show potential for reducing both CAD and T2D risk; ACLY, ANGPTL3, APOB, and LIPG showed no significant association with either outcome.

Conclusions:

  • Genetic evidence indicates varying T2D-related side effects among different lipid-modifying drugs.
  • Findings have implications for future clinical trials and personalized treatment strategies in cardiovascular and metabolic disease management.
Keywords:
cis-Mendelian randomizationLipid modificationType 2 diabetes

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