Editorial
A Significant Effect of Pemafibrate on Carotid and Cerebral Atherosclerosis in Patients with Hypertriglyceridemia and Stroke
2025 Volume 32 Issue 6 Pages 670-672
Details
2025 Volume 32 Issue 6 Pages 670-672
See article vol. 32: 676-687
In Western countries, high serum triglyceride (TG) levels have been reported to be associated with the risk of coronary artery disease (CAD)1). Recently, the Suita Study, a 15.1-year prospective cohort study performed among 6,684 Japanese individuals of 30-79 years of age without a history of cardiovascular disease (CVD) and whose fasting TG levels were ＜400 mg/dL, showed that fasting TG was an independent predictor for the incidence of ischemic CVD (e.g., CAD and ischemic stroke) in Japanese individuals, after adjusting for low-density lipoprotein cholesterol (LDL-C)2). Serum TG levels have been assessed by fasting blood sampling, but some reports suggest that non-fasting blood sampling is more predictive of CV events3). Considering such studies, the latest Japan Atherosclerosis Society (JAS) Guidelines for the Prevention of ASCVD define hypertriglyceridemia as fasting TG ≥ 150 mg/dL and non-fasting TG ≥ 175 mg/dL, in consideration of the reports of epidemiological studies in Japan and consistency with the EAS/EFLM Consensus Statement4). In recent years, there has been increasing interest in TG management to prevent the development of ASCVD.
Fibrates are peroxisome proliferator-activated receptor alpha (PPARα) agonists, and are the most effective agents for lowering serum TG levels. PPARα agonists improve atherogenic lipoproteins, reverse the cholesterol transport system, and have vascular protective effects such as anti-inflammatory effects and reduction of the oxidative state (Fig.1). Briefly, PPARα agonists reduce hepatic production of apo CIII, an apoprotein of very-low-density lipoprotein (VLDL), and increase hepatic production of apo AI and AII, apoproteins of HDL, which decrease VLDL and increase HDL5). PPARα agonists increase the activity of lipoprotein lipase (LPL), which further reduces VLDL and increases HDL. PPARα agonists induce browning and improve insulin resistance in adipose tissue, thereby decreasing fatty acid (FA) release from adipose tissue, which is also associated with reduced VLDL. Reduced VLDL induces a reduction in atherogenic lipoproteins such as small dense LDL and remnant lipoproteins. PPARα agonists beneficially affect inflammation and atherosclerotic processes by modifying transcription factors such as nuclear factor-κB (NF-kB) and activator protein 1 (AP-1).
The upward and downward arrows indicate increased and decreased substances, activity, and phenomena. AP-1, activator protein 1; FA, fatty acids; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; NF-kB, nuclear factor-κB; Rem, remnant lipoproteins; Sd-LDL, small dense low-density lipoprotein; SR, scavenger receptor; TG, triglyceride; VDLD, very low-density lipoprotein.
However, the efficacy of PPARα agonists in preventing ASCVD remains controversial. A meta-analysis showed that fibrate therapy was associated with a 10% relative risk (RR) reduction for major cardiovascular events (P = 0.048) and a 13% RR reduction for coronary events (P＜0.0001); however, it had no benefit for stroke (P = 0.69), all-cause mortality (P = 0.92), CV mortality (P = 0.59), or sudden death (P = 0.19).
Pemafibrate, a novel selective PPARα modulator, differs from conventional PPARα agonists such as fenofibrate in terms of its molecular structure, more robust reduction in serum TG, and favorable safety profile6). However, the PROMINENT study failed to show that pemafibrate reduced the risk of ASCVD in patients with diabetes and hypertriglyceridemia7). Asians accounted for only 5% of the patients in both the pemafibrate and placebo groups, and the average body mass index (BMI) was very high at 32 kg/m2, making it difficult to generalize this result to the Asian population. Approximately 70% of the patients had been administered statins at the highest approved dose for treating familial hypercholesterolemia in Japan, which complicates the application of this study’s findings to the Japanese population.
In the current issue, Hoshino et al. reported that 2-year pemafibrate therapy induced regression of the carotid intima-media thickness of the internal carotid arteries in patients with hypertriglyceridemia and a history of stroke or transient ischemic attack of non-cardioembolic origin8). In their study, 48 stenotic lesions in 34 patients were examined using 3-dimensional time-of-flight magnetic resonance angiography. Among these lesions, regression was observed in 9 (18.8%) and progression was noted in 4 (8.3%). This outcome is comparable to the regression (24.4%) and progression (6.7%) observed in a previous study in which patients received cilostazol, which has been reported to reduce the restenosis rate after coronary angioplasty and stenting9). In the present study, pemafibrate improved the inflammatory status and remnant lipoproteins, in addition to improving the serum TG and HDL levels.
Pemafibrate may have multiple antiatherogenic properties, as shown in Fig.1. To evaluate the effectiveness of pemafibrate in suppressing the development of ASCVD, randomized controlled trials using pemafibrate and which preferably include a greater number of Asian patients—especially Japanese patients—are warranted.
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