High LDL-C Bad for CAD but Good for CKD? Optimal Range Proposed

Emma A. Arigi, PhD, for Medscape

March 17, 2022

The study covered in this summary was published on SSRN.com as a preprint and has not yet been peer reviewed.

Key Takeaways

  • In a traditional observational analysis, associations of LDL-C with incident chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), and all-cause mortality were U-shaped or J-shaped.

  • Mendelian randomization (MR) analyses suggested that elevated LDL-C has a positive effect on ASCVD but an inverse effect on CKD, the latter mediated by HDL-cholesterol levels and triglycerides. No relation was observed between LDL-C levels and all-cause mortality.

  • CKD risk decreased or stayed relatively low with increasing LDL-C levels.

  • LDL-C concentrations of 3.5 to 4.5 mmol/L, although considered higher than optimal, indicated the lowest risk for CKD and all-cause mortality.

Why This Matters

  • Although some observational studies point to nonlinear associations of LDL-C with cardiorenal diseases and mortality, the causal nature of these findings is not clear.

  • This may be the first study to examine the nonlinear relation between LDL-C and CKD, ASCVD, and all-cause mortality, and to determine the range of LDL-C concentration with the lowest risk of adverse outcomes in the general population.

Study Design

  • The prospective study was based on a UK Biobank cohort that included more than 300,000 participants 37 to 73 years of age between 2006 and 2010.

  • Participants with self-reported use of lipid-lowering drugs were excluded.

  • The study’s endpoints were CKD, ASCVD, and all-cause mortality.

  • Researchers used traditional statistical methods, as well as nonlinear and linear MR approaches, to examine the shape of associations between LDL-C concentrations and rates of CKD, ASCVD, and all-cause mortality.

  • Genetic variants used for MR were selected from a sample associated with LDL-C and excluded any with known pleiotropic effects on common risk factors, such as smoking, alcohol use, body mass index, blood pressure, and some other metabolic biomarkers.

Key Results

  • Significant nonlinear (U-shaped or J-shaped) associations between LDL-C and clinical outcomes (P < .001 for each of CKD, ASCVD, and all-cause mortality) emerged in the observational analysis.

  • Participants with low LDL-C levels (≤1.8 mmol/L) showed nearly twofold increased adjusted hazard ratios (HR) for CKD (HR, 1.77; 95% CI, 1.38 - 2.27; P < .001) and all-cause mortality (HR, 1.92; 95% CI, 1.56 - 2.36; P < .001), compared with those with LDL-C levels of 3.0 to 3.4 mmol/L.

  • The corresponding HRs among those with LDL-C of 6.0 mmol/L or more were 1.27 (95% CI, 1.01 - 1.60) for CKD and 1.73 (95% CI, 1.52 - 1.97) for ASCVD.

  • Predicted LDL-C levels in the linear MR analysis had an inverse effect on CKD risk (HR, 0.84; 95% CI, 0.73 - 0.96; = .011)], a positive relation with ASCVD risk (HR, 1.41; 95% CI, 1.29 - 1.53; P < .001), and no evident association with all-cause mortality (P = .290).


  • Misclassification of outcomes was possible because of how data were collected, which was through a combination of patient self-reporting and primary care and hospital records and death registries.

  • Limited follow-up data made it likely that some individuals who eventually started on cholesterol-lowering medications were missed.

  • The inclusion of relatively healthy participants might have limited the number of endpoints.

  • The cohort was predominantly White and British, limiting the generalizability of the results.

  • The findings were not independently or prospectively validated.


  • This study was supported by the National Key Research and Development Program of China and the Fundamental Research Funds for the Central Universities, Sun Yat-sen University.

  • One of the authors received research grants from and has served as a consultant or lecturer to numerous drug companies; the others declared no competing interests.

This is a summary of a preprint research study, "Investigating Linear and Nonlinear Associations of LDL Cholesterol With Chronic Kidney Disease, Atherosclerotic Cardiovascular Disease and All-Cause Mortality: A Prospective and Mendelian Randomization Study," written by Zhenqian Wang from Sun Yat-sen University (SYSU) - School of Public Health, China, and colleagues on SSRN.com provided to you by Medscape. This study has not yet been peer reviewed. The full text of the preprint can be found on SSRN.com


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