Fenofibrate Delays the Need for Dialysis and Reduces Cardiovascular Risk Among Patients With Advanced CKD

Chieh-Li Yen; Pei-Chun Fan; Ming-Shyan Lin; Cheng-Chia Lee; Kun-Hua Tu; Chao-Yu Chen; Ching-Chung Hsiao; Hsiang-Hao Hsu; Ya-Chung Tian; Chih-Hsiang Chang

Disclosures

J Clin Endocrinol Metab. 2021;106(6):1594-1605. 

In This Article

Abstract and Introduction

Abstract

Context: Fenofibrate provides limited cardiovascular (CV) benefits in the general population; however, little is known about its benefit among advanced chronic kidney disease (CKD) patients.

Objective: This study compared outcomes among advanced CKD patients treated with fenofibrate, statins, a combination of both, and none of these.

Methods: This national cohort study was based on Taiwan's National Health Insurance Research Database. Patients younger than 20 years with advanced CKD were identified and further divided into 4 groups according to treatment. The inverse probability of treatment weighting was used to balance baseline characteristics. Patients received fenofibrate, statins, a combination of fenofibrate and statins, or none of these in the 3 months preceding the advanced CKD date. Main outcome measures included all-cause mortality, CV death, and incidence of permanent dialysis.

Results: The fenofibrate and statin groups exhibited a lower risk of CV death (fenofibrate vs nonuser: hazard ratio [HR]: 0.84; 95% CI, 0.75–0.94; statins vs nonuser: HR: 0.94; 95% CI, 0.90–0.97) compared with the nonuser group. The fenofibrate group further exhibited the lowest incidence of permanent dialysis (fenofibrate vs nonuser: subdistribution HR [SHR]: 0.78; 95% CI, 0.77–0.80; statins vs fenofibrate: SHR: 1.27; 95% CI, 1.26–1.29; combination vs fenofibrate: SHR: 1.15; 95% CI, 1.13–1.17). Furthermore, the combined administration of fenofibrate and high-intensity statins exhibited a lower risk of major adverse cardiac and cerebrovascular events.

Conclusion: For patients with advanced CKD, continuing fenofibrate may provide a protective effect on CV outcomes equal to that of statins, and it may further delay the need for permanent dialysis. The combination of fenofibrate and high-intensity statins may have additional benefits.

Introduction

Hyperlipidemia-related atherosclerosis is a leading cause of cardiovascular disease (CVD).[1,2] Numerous large-scale studies have shown that a high low-density lipoprotein (LDL) level is the most relevant marker for CVD in the general population.[3,4] Statins, which inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), are the most effective medication for reducing LDL level and have become the most widely used lipid-lowering agents in recent decades. Current hyperlipidemia management guidelines emphasize statin treatment; during use, the LDL target is persistently adjusted to a lower level.[5] However, for the chronic kidney disease (CKD) population, although the risk of CVD significantly increases along with a decline in renal function,[6] the LDL level is less associated with cardiovascular outcomes,[7] and the reduction in the LDL level by statin treatment exerts a weaker protective effect compared with that within the general population.[8] The discrepancy in the beneficial effect of reducing the LDL level by statin treatment between the general population and the renal impairment population is multifactorial; however, changes in cholesterol metabolism during CKD progression play an important role.[9] With a decline in renal function, major physiological changes occurring in the lipid profile are an increase in the triglyceride (TG) level and a decrease in the high-density lipoprotein (HDL) level;[9] however, the LDL level is mostly unchanged or is slightly decreased. With respect to these changes in the lipid profile, it is important to analyze the beneficial effect of using TG-lowering agents in the CKD population.

Fenofibrate is a peroxisome proliferator-activated receptor α agonist that effectively reduces the TG level and increases the HDL level and LDL particle sizes; however, it exerts a weak effect on the LDL level.[10] The FIELD study demonstrated that fenofibrate is of limited benefit in CV outcomes; therefore, its use in the general population has been overlooked. However, a previous post hoc analysis of the FIELD study indicated that the beneficial effect of fenofibrate appears to be higher among patients with renal impairment.[11] Several previous studies have also demonstrated that fenofibrate has a partially protective effect on renal outcomes, including reducing proteinuria and slightly retarding the decline in estimated glomerular filtration rate (eGFR).[12,13] However, to date, no study has evaluated the effect of fenofibrate on patients with a GFR of less than 30 mL/min/1.73 m2. We believe this lack of evidence is due mainly to 2 reasons: First, because of the unfavorable FIELD study results in which patients with a GFR of greater than 30 mL/min/1.73 m2 were enrolled, no further time- and cost-consuming randomized clinical trials (RCTs) have been designed to evaluate the effect of fenofibrate on a population with poor renal function; second, the transient elevation of creatinine after initiating fenofibrate[14] and the potential risk of rhabdomyolysis and liver function abnormalities have discouraged researchers from conducting relevant studies among patients with moderate-to-advanced CKD. Because no relevant RCTs have been conducted thus far, we considered that conducting a well-designed, large-scale, observational study may be suitable for initially evaluating this issue. We therefore used Taiwan's National Health Research Database (NHIRD), which comprises one of the largest health care cohorts in the world, to compare the effects on CV and renal outcomes among patients with advanced CKD receiving fenofibrate and statins, respectively, and concurrently.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....