Editorial
Does Pemafibrate Lower Low-Density Lipoprotein-Cholesterol?
2025 Volume 32 Issue 11 Pages 1372-1374
Details
2025 Volume 32 Issue 11 Pages 1372-1374
See article vol. 32: 1400-1415
Hypertriglyceridemia is usually induced by metabolic abnormalities such as diabetes, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), hypothyroidism, genetic dyslipidemia, and an inadequate lifestyle, such as little exercise and a high caloric diet. It is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Fibrates that activate peroxisome proliferator-activated receptor α have been used to reduce triglyceride (TG) levels and increase high-density lipoprotein cholesterol (HDL-C) levels for many years. Although meta-analyses have revealed that fibrates are effective for the primary and secondary prevention of cardiovascular diseases1, 2), no conclusive randomized clinical trials have been conducted. The PROMINENT study with pemafibrate was expected to prevent ASCVD events by lowering TG, non-HDL-C, and remnant cholesterol levels and increasing HDL-C levels3). However, no difference was found in the composite of non-fatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes between the pemafibrate and placebo groups.
Yamashita et al. demonstrated that pemafibrate lowered low-density lipoprotein-cholesterol (LDL-C) by inhibiting cholesterol synthesis in the liver and cholesterol absorption from the intestinal tract in a post-hox analysis in a phase 2 study of pemafibrate in hypertriglyceridemia4). They measured lathosterol as a cholesterol synthetic marker and beta-sitosterol and campesterol as cholesterol absorption markers in the blood by gas chromatography. Pemafibrate significantly reduced LDL-C, apolipoprotein B, and non-HDL-C levels in a dose-dependent manner. Similarly, pemafibrate lowered the levels of lasosterol, beta-sitosterol, and campesterol. Of note, higher baseline LDL-C levels showed a more pronounced lowering of LDL-C and tended to experience a greater reduction of these markers than lower baseline levels.
Sometimes we observe that fibrates increase LDL-C levels in patients with hypertriglyceridemia. Naturally, pemafibrate promotes the metabolism of triglyceride-rich lipoproteins to LDL by TG degradation, resulting in the reduction of atherogenic remnants5-8) and transient elevation of serum LDL-C levels. However, if elevated LDL-C persists, several reasons may be imagined, such as increasing the intake of cholesterol and fat, increasing hepatic synthesis and VLDL secretion into the blood, or increasing gut absorption. Yamashita et al. clearly demonstrated that pemafibrate reduces hepatic synthesis and gut absorption4). As for the mechanisms, they discussed that pemafibrate increases both biliary and transintestinal cholesterol excretion (TICE)9), increases LDL receptor expression, decreases the number of small dense LDL, and reduces remnant lipoproteins4).
Many readers are still wondering why the PROMINENT study could not reveal a significant effect on ASCVD prevention. Yamashita et al. speculated on the reasons for the negative results10), but no clear answer has been obtained. In both pemafibrate and placebo groups, moderate-to-high-intensity statins were administered to reduce LDL-C levels, suggesting that LDL receptors are already upregulated. Supplemental data from the original paper showed that, although pemafibrate significantly decreased TG, non-HDL-C, and remnant cholesterol gradually after administration, LDL-C levels in both groups were elevated and higher in the pemafibrate group (162 mg/dL and 91 mg/dL, respectively) than in the placebo group (158, 80 mg/dL) at 4 months3). Subsequently, LDL-C levels decreased gradually to approximately 80 mg/dL at 48 months in both groups, but LDL-C was still higher in the pemafibrate group3). This difference cannot be ignored and may counteract the favorable effects of lowering TG and remnant cholesterol levels. As will be discussed later, this increase in LDL was not found in recent studies on nonalcoholic fatty liver disease (NAFLD)11-14). In addition, Yamashita et al. pointed out the results of a large number of obese patients (32.0 kg/m2 median body mass index) with type 2 diabetes mellitus (T2DM) as participants10). The initial increase in LDL-C level may be critical, suggesting that lowering the intake of fat and cholesterol is prerequising on pemafiibrate sdministration.
In contrast, the PROMINENT study revealed lower numbers of total hepatic adverse events and NAFLD with pemafibrate than with placebo3). NAFLD, which is associated with increased ASCVD11), was recently called metabolic dysfunction-associated steatotic liver disease (MASLD). Nakajima et al. reported that liver stiffness evaluated by magnetic resonance elastography decreased compared to placebo at week 48 in PEMA-FL study (PEMAfibrate randomised placebo-controlled study in patients with non-alcoholic Fatty Liver disease), with a significant reduction in ALT and LDL-C12). Sumida et al. reported that pemafibrate significantly improved the levels of alanine aminotransferase and other liver hepatic enzymes, lipid profile including total cholesterol, non-HDL-cholesterol, and hepatic fibrosis markers compared to omega-3-acid ethyl ester (LDL-C concentrations were lower in the pemafibrate group without statistical significance) in MASLD patients13). Tanigawa et al. also clearly demonstrated that, in a sub-analysis of the PEMA-FL study, pemafibrate reduced LDL-C in patients with MASLD, and the effect was greater in those with higher baseline LDL-C levels14). Importantly, these studies demonstrated that initial LDL-C elevation was not induced four weeks after pemafibrate administration. Even though these studies were all conducted in Japan, this evidence suggests that some patients, such as those with MASLD, should be a potential therapeutic target of pemafibrate in the prevention of ASCVD. Therefore, further investigations are required.
Yoshio Fujioka received a speaker’s fee from Kowa Company, Ltd.
