Editorial
Once-daily Extended-Release Pemafibrate Enhances Adherence and Triglyceride Control Over Twice-Daily Dosing
2024 Volume 31 Issue 11 Pages 1512-1514
Details
2024 Volume 31 Issue 11 Pages 1512-1514
See article vol. 31: 1517-1538
Cardiovascular disease (CVD) is a leading cause of death and disability. Dyslipidemia, hypertension, diabetes, and smoking are major risk factors for CVD. Managing low-density lipoprotein cholesterol (LDL-C) using HMG-CoA reductase inhibitors (statins), a cholesterol absorption inhibitor (ezetimibe), and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) is the main therapy for CVD. Although these drugs can reduce CVD by maintaining low levels of LDL-C, their risk-reducing effect is 20–30%. Thus, the residual risk of 70% must be improved. Even with controlled LDL-C levels, hypertriglyceridemia is a major residual risk factor for CVD1, 2).
Pemafibrate is a selective peroxisome proliferator-activated receptor α (PPARα) modulator (SPPARMα), which lower serums triglyceride (TG) levels and increase high-density lipoprotein cholesterol (HDL-C) levels3). In contrast to existing fibrates, SPPARMα specifically activates PPAR-α. It is also hepatically metabolized, which reduces the side effects in patients with renal dysfunction.
Although the immediate-release (IR) formulation of pemafibrate, which has been used since the beginning, has been demonstrated to be useful in lowering triglycerides and causes few side effects, its twice-daily administration has caused adherence problems. However, the newly developed pemafibrate extended-release (XR) formulation is administered once daily and is expected to improve adherence.
Most drugs for lifestyle-related diseases such as dyslipidemia, hypertension, and type 2 diabetes are in once-daily formulations, and the lower the dosing frequency, the better the adherence to the medication. Therefore, in the present study, we aimed to confirm the non-inferiority of XR (0.2 or 0.4 mg/day; once daily) to IR (0.2 mg/day; twice daily) in lowering triglyceride levels in patients with hypertriglyceridemia.
This clinical trial, conducted across multiple centers and employing a randomized, double-blind approach, enrolled individuals with fasting triglyceride levels of ≥ 200 mg/dL4). Participants received either IR pemafibrate at a dosage of 0.2 mg/day or XR pemafibrate at dosages of 0.2 mg/day or 0.4 mg/day. The primary measure of effectiveness was the percentage alteration in fasting triglyceride concentrations observed at 4, 8, and 12 weeks relative to baseline levels. Patients meeting the criteria were randomly allocated to receive IR 0.2, XR 0.2, or XR 0.4 mg/day in a 1:1:1 ratio. IR 0.2 is the positive control based on its status as the standard approved dosage, with a capacity to produce a slight disparity in triglyceride reduction in comparison to IR 0.4.
Fasting triglyceride reductions of 48.0%, 43.8%, and 48.0% were observed among 356 participants randomly assigned to receive IR 0.2, XR 0.2, and XR 0.4 mg/day, respectively. These findings confirm the comparability of XR dosing schedules and IR. The percentages of individuals who achieved fasting triglyceride levels of ＜150 mg/dL in the IR 0.2 mg/day, XR 0.2 mg/day, and XR 0.4 mg/day groups were 45.7%, 37.4%, and 51.7%, respectively. Within the subgroup initially presenting with triglyceride levels of ≥ 500 mg/dL, the percentage reductions were with IR 0.2 mg/day, XR 0.2 mg/day, and XR 0.4 mg/day were -59.3%, -52.2%, and -66.3%, respectively. XR formulations (both 0.2 and 0.4 mg/day) were found to be as effective as IR (0.2 mg/day). Notably, XR (0.4 mg/day) exhibited a more pronounced triglyceride-lowering effect than XR (0.2 mg/day), suggesting its potential suitability for individuals with elevated triglyceride levels.
Pemafibrate is an SPPARMα that regulates PPARα-targeted genes involved in lipid metabolism in the liver and improves dyslipidemia by reducing serum triglyceride (TG) levels. In an in vitro assay, pemafibrate’s ability to reduce TG and increase HDL-C was 3 orders of magnitude stronger than that of fenofibrate3). Pemafibrate treatment for 12 weeks reduced TG levels in a dose-dependent manner, and the effect was superior to that of fenofibrate5). It is approved for treating hypertriglyceridemia in the form of 0.1 mg IR tablets taken twice daily. As less frequent dosing often leads to better drug adherence, once-daily XR pemafibrate tablets have been developed to enhance adherence. Previous meta-analyses have suggested that reducing dosing frequency from multiple doses to once daily improves adherence to treatment in both acutely and chronically ill patients, suggesting that it may be beneficial to reduce dosing frequency to once daily6).
Elevated non-fasting triglyceride (TG) levels are recognized as risk factors for cardiovascular disease, independent of total cholesterol, non-HDL-C, and LDL-C levels7). In previous clinical trials using immediate-release (IR) formulations, cookie-type meal stress tests showed that postprandial TG levels returned to baseline within 6-8 hours. However, in this high-fat meal study, the TG levels remained elevated even after 6 h. Both extended-release (XR) and IR pemafibrate formulations effectively reduced postprandial TG levels, with no significant differences observed between the groups. This study provides the first evidence of the significant TG-lowering effect of pemafibrate after a hyperlipidemic meal.
In 1990, the adverse effects of combining gemfibrozil and lovastatin were documented8). Subsequently, the use of this combination was restricted due to concerns over the potential risks of myopathy and rhabdomyolysis associated with statin and fibrate therapies. Combination therapy with fibrates and statins has shown significant efficacy in beneficially modifying atherogenic lipid fractions. However, the potential side effects of this combination have limited its clinical application. Recent evidence has indicated that pemafibrate, a novel fibrate, does not interact with statins, thereby addressing these safety concerns9). Clinical studies involving over 10,000 patients have substantiated the safety profile of the statin-pemafibrate combination, revealing no increase in adverse effects in comparison to statin monotherapy10).
The results of this study indicate that the triglyceride-lowering effect of XR pemafibrate tablets is non-inferior to that of the two-dose IR tablets. This effect was also demonstrated with a high-fat diet load, which is important because hypertriglyceridemia is an important residual risk factor after obtaining LDL-C control, suggesting that pemafibrate, which has no interaction with statins, is important for lipid management in patients with high LDL-C levels and hypertriglyceridemia. XR tablets are expected to improve adherence and act as a therapeutic agent for the improvement of high TG levels.
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