The class
Mendelian randomization finds HDL cholesterol protective against diabetic retinopathy, but genetically proxied CETP inhibition shows no effect (Atherosclerosis 2023)
Original title: Associations of genetically determined lipid traits and lipid-modifying agents with the risk of diabetic retinopathy: A Mendelian randomization study
Using UK Biobank genetic instruments for HDL cholesterol, LDL cholesterol, triglycerides, apolipoprotein A-I and apolipoprotein B, researchers performed univariable and multivariable Mendelian randomization to test causal associations between lipid traits and diabetic retinopathy, then used protein and expression quantitative trait loci to estimate the causal relevance of CETP inhibitors specifically for severe nonproliferative and proliferative diabetic retinopathy. Genetically determined HDL cholesterol was inversely associated with risk of severe nonproliferative diabetic retinopathy (odds ratio 0.70) and proliferative diabetic retinopathy (odds ratio 0.90), consistent across sensitivity analyses. However, no association was found between genetically proxied CETP inhibitors and diabetic retinopathy risk, suggesting that while HDL cholesterol itself is causally protective, current HDL-C-raising agents such as CETP inhibitors may not translate this benefit into reduced diabetic retinopathy risk.
Original abstract
Background And Aims: The evidence that dyslipidemia is associated with hyperglycemia calls for an investigation of whether dyslipidemia, as well as lipid-modifying agents, could affect the subsequent development of diabetic retinopathy (DR). Therefore, we aimed to address these unanswered questions by utilizing Mendelian randomization (MR) analysis.
Methods: Genetic variants were selected from the UK Biobank as instruments to serve as proxies for lipid traits [high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (APOA-I) and apolipoprotein B (APOB)]. Univariable and multivariable MR analyses were performed to examine the associations of these lipid traits with DR and different levels of severity of DR. Based on the evidence for the effects of lipids on outcomes, we estimated the causal relevance of cholesteryl ester transfer protein (CETP) inhibitors in severe nonproliferative and proliferative DR using protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) as instruments.
Results: Genetically determined HDL-C levels were inversely associated with the risk of severe nonproliferative DR (OR = 0.70, 95% CI = 0.52-0.94) and proliferative DR (OR = 0.90, 95% CI = 0.83-0.97) in the main analyses utilizing the inverse variance-weighted (IVW) MR method and a couple of sensitivity analyses. No association was noted between genetically proxied CETP inhibitors and DR.
Conclusions: This MR study suggests the casual protective roles of HDL-C in severe nonproliferative DR and proliferative DR, which calls for further studies to confirm these findings. Current lipid-modifying agents acting on HDL-C may not reduce the risk of DR and new treatments are required in the future.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.