Editorial
Triglyceride Level and Cardiovascular Risk Reduction Using Pemafibrate Compared with Fibrates
2023 Volume 30 Issue 5 Pages 429-431
Details
2023 Volume 30 Issue 5 Pages 429-431
See article vol. 30: 443-454
A recent epidemiological study in Japan shows that the prevalence of hypercholesterolemia has remained unchanged since the 1980s, but the prevalence of obesity and impaired glucose tolerance have been increasing even after the 2000s1). These changes are related to the increase in the prevalence of hypertriglyceridemia and low high-density lipoprotein (HDL) cholesterolemia. Fasting and postprandial triglyceride (TG) levels are significantly associated with cardiovascular (CV) event risk in primary and secondary prevention; the clustering of dyslipidemias strongly enhances the risk of atherosclerotic CV diseases (ASCVD)2). Recently, the nonfasting measurement of TG level was recommended for CV risk assessment by the European Atherosclerosis Society3) and the Japan Atherosclerosis Society4). Fasting and nonfasting hypertriglyceridemia levels are affected by the accumulation of TG-rich lipoproteins and their remnant lipoproteins; the accumulation of remnant lipoproteins enhances atherogenicity in patients with hypertriglyceridemia2). Many therapeutic agents for hypertriglyceridemia have been developed to prevent CV events by ameliorating hypertriglyceridemia; a previous meta-analysis showed that there was no significant correlation between the decrease in TG level and the prevalence of CV events5). Fibrates and the selective PPARα modulator pemafibrate significantly decrease TG level (−30% to −40%) and increase HDL-C level (＋35% to ＋45%)4, 6). In a subclass analysis of the ACCORD-LIPID study, fenofibrate improved primary and secondary CV outcome in selected patients with the combination of high TG and low HDL-C levels (TG ≥ 204 mg/dL and HDL-C ＜34 mg/dL); however, there was no effect in patients with type 2 diabetes mellitus using simvastatin7). The combination of hypertriglyceridemia and low HDL-Cemia is usually observed when remnant lipoproteins are accumulated2). Therefore, to prevent CV events in patients with hypertriglyceridemia, it is important to consider effective interventions for improving atherogenic lipoprotein profile besides ameliorating lipid levels.
In the current study, Nakamura et al. examined the efficacy and safety of pemafibrate and bezafibrate using a randomized crossover method to prevent population bias8). A phase II study of pemafibrate by Ishibashi et al. examined the efficacy and safety of pemafibrate and fenofibrates using a double blind, placebo-controlled, parallel-group method6). In the study by Nakamura et al., pemafibrate (0.2 mg/day) or bezafibrate (400 mg/day) were administered for 24 weeks to 60 patients (≥ 150 mg/dL). In the phase II study, patients (n=224, TG ≥ 200 mg/dL and HDL-C ＜50 mg/dL in men or 55 mg/dL in women) were divided into six groups—placebo, pemafibrate (0.025, 0.05, 0.1, or 0.2 mg/day), or fenofibrate (100 mg/day)—with administration for 12 weeks6). The average age was high in the study by Nakamura et al. (62.7±9.2 years) than in that by Ishibashi et al. (~50 years old). The sex ratio and body mass index were similar between the two studies, but the percentage of persons with type II diabetes mellitus was higher in Nakamura et al.’s study (40% vs. 10%–15%)8). TG-lowering effect in Nakamura et al.’s study and the phase II study using pemafibrate was −46.1% and −42.7%, respectively; the effect using bezafibrate was −34.7% in Nakamura’s study, and that using fenofibrate was −29.7% in the phase II study. These two studies established that the use of pemafibrate is more effective in decreasing TG levels than fenofibrate or bezafibrate, and these studies also showed that pemafibrate significantly increased HDL-C levels and significantly decreased markers for remnant lipoproteins, apoB-48 levels, and RemL-C levels similar to fenofibrate and bezafibrate8). These results clearly suggest that pemafibrate improves atherogenic lipoprotein profile besides ameliorating TG levels. Comparing these two studies, there is a significant increase in HDL-C level using pemafibrate than using fenofibrate, but there is no difference in the decrease in apoB-48 and RemL-C levels between the two drugs. The increase in apoA-1 and the decrease in RemL-C were significantly higher using pemafibrate than bezafibrate. This suggests that the change from bezafibrate to pemafibrate may further improve the atherogenic lipoprotein profile besides ameliorating lipid profile.
As for safety, same as the former phase II study, the incidence of adverse events using pemafibrate was comparable to that using bezafibrate6, 8). In Nakamura et al.’s study, %change in liver enzyme levels was markedly decreased with pemafibrate than with bezafibrate without any crucial side effect on liver function8). Recent studies showed that pemafibrate improves liver function in patients with nonalcoholic fatty liver disease9), which is likely caused by reducing myeloid cell recruitment via interactions with liver sinusoidal endothelial cells without altering hepatic TG accumulation10). Even though both pemafibrate and bezafibrate increase creatinine levels significantly, its %change was significantly lower with pemafibrate than with bezafibrate (5.72% vs. 15.5%, p＜0.001)8). Comparing patients with chronic kidney disease (CKD, estimated glomerular filtration rate [eGFR] ＜60 ml/min/1.73m2) and those without CKD (non-CKD, eGFR ≥ 60 ml/min/1.73m2), the decrease in eGFR by bezafibrate treatment was greater in the CKD group than that in the non-CKD group, whereas no difference was observed in the decrease in eGFR by pemafibrate treatment between the CKD and non-CKD groups. In daily clinical practice, decreased renal function or the presence of CKD may increase the risk of CV events or complications when patients are treated with a combination therapy of antidyslipidemic drugs. No change in renal function by pemafibrate treatment may contribute to a safer combination therapy and the appropriate achievement of treatment target.
In recent years, the number of patients with not only high LDL-C but also high TG or high remnant lipoproteins has been increasing, leading to an increased risk status of ASCVD. The results of this study may provide an effective and safe treatment option for these patients.
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