Editorial
The Clinical Implication of Pemafibrate, a Novel Selective PPARα Modulator
2025 年 32 巻 2 号 p. 120-121
詳細
2025 年 32 巻 2 号 p. 120-121
See article vol. 32: 125-140
Fibrates that activate peroxisome proliferator-activated receptor α (PPARα) have been used to reduce triglycerides (TG) and increase high-density lipoprotein-cholesterol (HDL-C) for many years. Although meta-analyses have revealed that fibrates are effective for the primary and secondary prevention of cardiovascular diseases1, 2), there are no conclusive randomized clinical trials. Fibrates have several dose-related adverse effects, including elevated serum creatinine and alanine aminotransferase levels3). Therefore, safer and more active drugs are required. In such an environment, pemafibrate, a novel selective peroxisome proliferator-activated receptor α (PPARα) modulator, has been developed as a highly active and selective PPARα agonist4, 5). Clinical trials in Japan have demonstrated that pemafibrate monotherapy or combined therapy with statins results in a robust reduction of TG with a lower risk of adverse effects than other existing PPARα agonists6, 7).
Dai et al. demonstrated the effects of pemafibrate on serum lipid, creatinine, and alanine aminotransferase levels with superior efficacy to fenofibrate8). Like Japanese patients, Chinese patients also benefited from serum lipid improvement with reduced TG, non-HDL-C, and remnant cholesterol levels and increased HDL-C and apolipoprotein (apo) A1 levels. In addition, they clarified that pemafibrate reduced alanine aminotransferase, alkaline phosphatase, and glutamyl transpeptidase, with no significant change in creatine kinase and creatinine levels. These results emphasize the importance of highly active and selective PPARα agonists.
The PROMINENT study was expected to prevent atherosclerotic cardiovascular disease (ASCVD) events by lowering TG, non-HDL-C, and remnant cholesterol and increasing HDL-C9). Changes in lipid levels at 4 months after pemafibrate administration compared to the placebo were -26.2% for TG, -25.8% for VLDL-cholesterol, -25.6% for remnant cholesterol, -27.6% for apo CIII, and 4.8% for apo B. However, no significant difference was found in the composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes between the pemafibrate and placebo groups. The speculated reasons for negative results include a strong reduction of LDL-C with moderate-to high-intensity statin use, followed by lower percentage of TG reduction than previous trials via the use of statin and a decrease in TG in the placebo group, or large numbers of obese patients (32.0 kg/m2 median body mass index) with type 2 diabetes (T2DM), among other reasons10). Remnant lipoproteins are atherogenic, and non-HDL-Cs (LDL- and TG-rich lipoproteins, including remnant lipoproteins) are strong predictors of ASCVD events11-14). It may be possible to effectively prevent ASCVD if the protocol is programmed in the appropriate populations characterized by dyslipidemia with high TG and limited statin use and without excessive BMI or advanced T2DM4, 10). Patients with high non-HDL-C levels or no history of ASCVD may also be candidates.
Recently, the pathology and treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) have attracted attention. Terms of nonalcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been used as fatty liver with the exclusion of causes of alcohol consumption. NAFLD/NASH is associated with an increased ASCVD15). Essentially, the treatment of NAFLD/NASH is diet therapy, and this is not altered in the case of MASLD/MASH, although viral hepatitis and other causes are also of concern. Pemafibrate is expected to be more effective against hepatic dysfunction than previous fibrates. Nakajima et al. reported that, in a double-blind, placebo-controlled, randomized multicenter trial, magnetic resonance elastography (MRE)-based liver stiffness significantly decreased compared to placebo at week 48, with a significant reduction in ALT and LDL-C16). Patients who use fibrates to prevent ASCVD may be subjects with MASLD/MASH. The report of Dai et al. may assist in the use of pemafibrate as a drug therapy for MASLD/MASH, followed by reduction of ASCVD.
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