High LDL-C Not Causally Linked to Risk for Retinopathy and Neuropathy

diabetic retinopathy
Investigators analyzed whether high LDL-C causally relates to risk for retinopathy, neuropathy, chronic kidney disease, and peripheral artery disease in the general population.

High low-density lipoprotein cholesterol (LDL-C) levels are genetically associated with a high risk for chronic kidney disease (CKD) and certain forms of vascular disease, according to study results published in the Journal of American College of Cardiology.

To test the hypothesis that high LDL-C levels are causally associated with high risk for retinopathy, peripheral neuropathy, CKD, and lower extremity peripheral arterial disease (PAD) in the general population, researchers used one-sample Mendelian randomization (MR) and included individuals from 2 similar studies of the Danish general population: the CCHS (Copenhagen City Heart Study) and the CGPS (Copenhagen General Population Study) (N=116,419).

Researchers tested whether LDL-C levels predicted the risk for disease observationally, whether 11 genetic variants were associated with high LDL-C levels, and whether genetic variants associated with high LDL-C were also associated with risk for disease. They used instrument variable analysis to obtain a causal risk estimate. Researchers performed a meta-analysis to estimate the effect of lowering LDL-C with statin therapy upon change in estimated glomerular filtration rate (eGFR). To validate the results, researchers conducted 2-sample MR analyses with summary-level data from the Global Lipid Genetics Consortium (GLGC) (n=94,595) and the UK Biobank (n=408,455).

Observationally, high LDL-C was not associated with a high risk for retinopathy or neuropathy. Stepwise increases in risk for CKD and PAD were observed with higher LDL-C (both Ptrend <.001), with hazard ratios (HRs) of 1.05 (95% CI, 0.97-1.13) for CKD and 1.41 (95% CI, 1.23-1.62) for PAD in participants with LDL-C levels >95th percentile vs <50th percentile.

Summary-level data for retinopathy, neuropathy, and PAD had similar results from the GLGC and UK Biobank studies. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1-mg/dL higher LDL-C was 1.06 (95% CI, 0.24-4.58) for retinopathy, 1.05 (95% CI, 0.64-1.72) for neuropathy, 3.83 (95% CI, 2-7.34) for CKD, and 2.09 (95% CI, 1.3-2.38) for PAD. For CKD, a 1-mg/dL lower LDL-C conferred a higher eGFR of 1.95 mL/min/1.73 m² (95% CI, 1.88-2.02 mL/min/1.73 m²) observationally, 5.92 mL/min/1.73 m² (95% CI, 4.97-6.86 mL/min/1.73 m²) genetically, and 2.69 mL/min/1.73 m² (95% CI, 1.48-3.94 mL/min/1.73 m²) through statin therapy.

Limitations of this study included selected genetic variants that are associated with confounders of the exposure-outcome association in addition to being associated with high LDL-C levels. The selected samples in the confirmation cohort used in the 2-sample MR may not be representative of the general population and therefore may not be completely comparable. The participation rate was low in the UK Biobank, and healthy participant bias could explain some of the differences in the prevalence of and risk estimates for CKD between CCHS and CGPS and the UK Biobank, along with the substantial differences in follow-up time. The calculation for eGFR came from a single measurement of plasma creatine, which may lead to misclassification of kidney disease.

Related Articles

High LDL-C levels were observationally and genetically associated with a high risk for PAD and CKD but were not causally associated with a high risk for retinopathy and peripheral neuropathy.

Statin trials confirmed findings from the Copenhagen studies that lower LDL-C is causally related to better kidney function. Because of the genetic association of high LDL-C with a high risk for CKD and certain forms of vascular disease, future studies should investigate the range of microvascular diseases that could be prevented by lowering LDL-C.


Emanuelsson F, Nordestgaard BG, Tybjærg-Hansen A, Benn M. Impact of LDL cholesterol on microvascular versus macrovascular disease: a Mendelian randomization study. J Am Coll Cardiol . 2019;74(11):1465-1476.