Supplementary Material for: Comparative Effectiveness of Lipid-Lowering Therapies in Increasing HDL Cholesterol Levels in Patients with Chronic Kidney Disease

Background: In patients with chronic kidney disease (CKD), lower and sub-functional high-density lipoprotein cholesterol (HDL-C) is associated with poor cardiovascular outcomes. Notwithstanding such poor outcomes, the primary therapeutic target in patients with CKD is low-density lipoprotein cholesterol (LDL-C), and the comparative effectiveness of commonly used lipid-lowering therapies (LLTs) in changing HDL-C levels in patients with non-dialysis-dependent CKD (NDD-CKD) remains unclear.

Methods: In this retrospective cohort study, using a target trial emulation framework, we examined a nationwide cohort of 3,562,882 US Veterans with normal kidney function enrolled between October 2004 and September 2006 and identified 247,270 incident CKD patients eligible for de novo LLT exposure, occurring during longitudinal follow-up until October 2019. We defined de novo LLT initiation using pharmacy dispensation data and followed patients for up to 1 year. We compared the intraindividual slopes of HDL-C levels in de novo fibrates and niacin users with those in statin users, using mixed-effects models adjusted for baseline and time-varying covariates. We also compared the odds of having a clinically meaningful (>10% from baseline) increase in HDL-C following LLT initiation.

Results: A total of 38,223 patients with incident CKD initiated de novo LLT (statin [n=35,284], fibrate [n=1,805], and niacin [n=1,134]). The mean (SD) age was 67.3 (10.5) years; 95.0% were men, and 20.6% were Black. Compared to statin users, the multivariable-adjusted annualized intraindividual increase of HDL-C was significantly higher following fibrate (1.15 mg/dL/year [95% CI: 0.43, 1.87]; p=0.002) and niacin monotherapy (2.51 mg/dL/year [95% CI: 1.62, 3.41]; p<0.001). Furthermore, niacin (OR: 1.37 [95% CI: 1.07, 1.75]; p=0.012) was more likely than statins to provide a clinically meaningful elevation in HDL-C. Our findings were consistent in several sensitivity analyses.

Conclusion: Among patients with NDD-CKD, de novo prescription of fibrates and niacin is associated with a greater increase in HDL-C levels compared to statins. Further studies are warranted to investigate whether such differences have meaningful effects on clinical outcomes.