Selective Peroxisome Proliferator–Activated Receptor Alpha Modulators (SPPARMα): New Opportunities to Reduce Residual Cardiovascular Risk in Chronic Kidney Disease?

Abstract

Purpose of Review Chronic kidney disease (CKD) poses a major global challenge, which is exacerbated by aging populations and the pandemic of type 2 diabetes mellitus. Much of the escalating burden of CKD is due to cardiovascular complications. Current treatment guidelines for dyslipidemia in CKD prioritize low-density lipoprotein cholesterol management, but still leave a high residual cardiovascular risk. Targeting elevated triglycerides and low plasma high-density lipoprotein cholesterol, a common feature of CKD, could offer additional benefit. There are, however, safety issues with current fibrates (peroxisome proliferator–activated receptor alpha [PPARα] agonists), notably the propensity for elevation in serum creatinine, indicating the need for new approaches. Recent Findings Interactions between the ligand and PPARα receptor influence the specificity and potency of receptor binding, and downstream gene and physiological effects. The peroxisome proliferator–activated receptor alpha modulator (SPPARMα) concept aims to modulate the ligand structure so as to enhance binding at the PPARα receptor, thereby improving the ligand’s selectivity, potency, and safety profile. This concept has led to the development of pemafibrate, a novel SPPARMα agent. This review discusses evidence that differentiates pemafibrate from current fibrates, especially the lack of evidence for elevation in serum creatinine or worsening of renal function in high-risk patients, including those with CKD. Summary Differentiation of pemafibrate from current fibrates aims to address unmet clinical needs in CKD. The ongoing PROMINENT study will provide critical information regarding the long-term efficacy and safety of pemafibrate in patients with type 2 diabetes mellitus, including those with CKD, and whether the favorable lipid-modifying profile translates to reduction in residual cardiovascular risk.

Medications Activating Tubular Fatty Acid Oxidation Enhance the Protective Effects of Roux-en-Y Gastric Bypass Surgery in a Rat Model of Early Diabetic Kidney Disease

“…Similar findings were reported in the FIELD study ( 102 ). Pemafibrate, a selective PPARα modulator ( 103 ), activated PPARα and ameliorated DKD in the db/db mouse ( 104 ). A preclinical systematic review and meta-analysis assessing the impact of pharmacological targeting of PPARs in experimental renal injury is underway ( 105 ), and may help to inform the design of future studies evaluating PPARα-mediated restoration of FAO in DKD.…”

Exploring the Complex Relationship between Diabetes and Cardiovascular Complications: Understanding Diabetic Cardiomyopathy and Promising Therapies

“…In insulin-resistant states, increased FFA oxidation causes a rise in levels of ROS and promotes myocardial mitochondria dysfunction, which then accentuates mitochondrial uncoupling and elevated oxygen consumption, leading to decreased myocardial efficiency and relative cardiac ischemia. High levels of FFA also activate multiple genes transcription through PPAR-α myocyte expression and increase mitochondrial FFA transport and oxidation [ 46 , 47 ].…”