Authors: Mao Watanabe, Michiko Nakanishi, Wataru Shingaki, Ryoji Gunji, Yuichi Makinose, Takashi Kanno, Shun Ishibashi
Categories: Original Research, Pemafibrate, PPARα, Prospective post-marketing surveillance, Safety, SPPARMα, Efficacy
Source: Advances in Therapy
Authors: Mao Watanabe, Michiko Nakanishi, Wataru Shingaki, Ryoji Gunji, Yuichi Makinose, Takashi Kanno, Shun Ishibashi
Pemafibrate was well tolerated and effective in clinical trials that led to its approval to treat hyperlipidemia. However, these clinical trials typically have limitations and may not sufficiently assess the performance of pemafibrate in the real-world setting. Therefore, the aim of this study was to evaluate the long-term safety and efficacy of pemafibrate in patients with hyperlipidemia in Japan.
This was a prospective, multicenter, open-label, observational post-marketing surveillance (PMS) study. Patients with hyperlipidemia were observed for 24 months from the start of pemafibrate treatment. Safety evaluations included the incidence of adverse drug reactions (ADRs), subgroup analysis of ADRs, and changes in laboratory test values. Efficacy was determined by the changes in lipid test values from baseline.
A total of 3672 cases were registered from 612 facilities in Japan. In the safety analysis, 68.1% of patients were male, mean age was 60.8 years, and 37.8% were switched to pemafibrate from other dyslipidemia agents. In total, 147 patients (4.07%) experienced ADRs; serious ADRs were reported in 8 patients (0.22%). The most common ADRs included abnormalities in laboratory tests (n = 60; 1.66%), hepatobiliary disorders (n = 24, 0.66%), musculoskeletal and connective tissue disorders (n = 14, 0.39%), and metabolic and nutritional disorders (n = 14, 0.39%). No incidents of rhabdomyolysis occurred, and 37 (1.02%) patients experienced rhabdomyolysis-related ADRs. Renal-related ADRs occurred in 13 patients (0.36%). When subdivided by patient background, the incidence of ADRs was significantly higher in patients aged ≥ 75 years than < 75 years (P = 0.028). There were no significant differences in other subgroups. The mean percent change in mixed fasting and non-fasting triglyceride levels was − 35.2% (P < 0.001). High- and low-density lipoprotein cholesterol levels both increased significantly.
This PMS study demonstrated the safety and efficacy of pemafibrate after long-term administration in patients with hyperlipidemia.
The online version contains supplementary material available at 10.1007/s12325-025-03294-5.
Pemafibrate/PARMODIA^®^ tablets were approved in Japan in 2017 as a highly selective PPARα modulator with few adverse effects.This study evaluated the safety and efficacy of long-term pemafibrate administration in real-world clinical practice.No particular safety concerns were identified with pemafibrate, and its long-term efficacy was also confirmed.Pemafibrate is useful for the long-term treatment of patients with hyperlipidemia.
Elevated levels of low-density lipoprotein cholesterol (LDL-C) increase the risk of atherosclerotic cardiovascular disease (ASCVD); statins are the mainstay prophylactic treatment of ASCVD [1]. Residual lipid abnormalities such as high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) are treated with therapeutic agents such as fibrates and ezetimibe [2].
Fibrates, peroxisome proliferator-activated receptor α (PPARα) agonists, reduce TG and TG-rich lipoprotein (TRL) cholesterol and increase HDL-C, thereby improving atherogenic dyslipidemia [3]. To improve on the potency and limited selectivity for PPARα of existing fibrates, a novel selective PPARα modulator (SPPARMα), pemafibrate, was developed [4]. Pemafibrate, which represents a unique therapeutic class distinct from fibrates by inducing PPARα‑mediated beneficial effects and minimizing unwanted hepatic and renal adverse effects, offers a new therapeutic option either as monotherapy or as an add‑on to statin therapy [5, 6]. In contrast to conventional fibrates, which are principally excreted via the kidneys, pemafibrate is primarily excreted via the liver [7].
The safety and efficacy of pemafibrate have been evaluated through clinical trials prior to approval, and post-marketing surveillance (PMS) was conducted for a period of 3 months [8–14]. In addition, the PROMINENT trial, a large, international randomized controlled trial in patients with type 2 diabetes mellitus with high TG and low HDL-C levels, showed that a high incidence of renal-related, particularly chronic kidney disease (CKD), acute kidney injury (AKI), and diabetic nephropathy (DN), venous thromboembolism (VTE), pulmonary embolism (PE), and deep vein thrombosis (DVT) adverse events (AEs) were reported [15]. The safety and efficacy data were collected under controlled conditions or for a limited duration, and need to be evaluated on a larger scale and longer duration in routine clinical practice involving hyperlipidemia in patients with diverse backgrounds.
The aim of this study was to investigate the 24-month long-term safety and efficacy of pemafibrate in patients with hyperlipidemia in the post-marketing setting.
The methodology of this study has been previously described in detail [9]. Briefly, this was a prospective, multicenter, open-label, observational PMS study, where patients were enrolled by a central registration method, using an internet-based electronic case data collection (EDC) system via a questionnaire (data entered by the physician in charge of the investigation). Patients with hyperlipidemia who were eligible to receive pemafibrate, who had not used this drug in the past, and whose TG levels were measured within 3 months before the start of administration were included in the survey. Patients were observed for 24 months from baseline, during which laboratory information and AEs/adverse drug reactions (ADRs) were collected. Laboratory information was collected regardless of whether the patient was fasting or not. Important safety and efficacy considerations according to the Pharmaceutical Risk Management Plan (RMP) were identified risks (rhabdomyolysis), potential risks (elevated LDL-C levels), missing information (hepatic impairment, renal impairment, age 75 years or older, and safety following long-term administration), and efficacy information (long-term efficacy) regarding pemafibrate use [16].
The target sample size of 3000 was set to ensure enough power to detect unknown ADRs with a frequency of 0.1% and a confidence level of 95%.
The EDC system compiled characteristics including patient sex, date of birth (or age), date of first administration of pemafibrate, eligibility for inclusion in this study, height, weight, body mass index (BMI), and current or previous disease at the time of pemafibrate initiation.
The total daily dose, number of daily doses, duration of treatment, details and reasons for dose change, interruption, and discontinuation were recorded at baseline, months 1, 3, 6, 12, 18, and 24, and at the last observation. Concomitant drugs and drugs for dyslipidemia that were discontinued at the start of pemafibrate administration were also documented.
Blood pressure (BP) measurements (systolic BP [SBP] and diastolic BP [DBP]) were documented. Lipid test items were TG, HDL-C, total cholesterol (TC), non-HDL-C (calculated as TC minus HDL-C), and LDL-C (if no direct test was performed, the Friedewald formula was used). Blood test items were serum creatinine (sCr), estimated glomerular filtration rate (eGFR; calculated value), creatine phosphokinase (CPK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (γ-GT), total bilirubin, and glycated hemoglobin (HbA1c).
AEs (defined as any untoward or unintended sign, including laboratory abnormalities, symptom, or illness that occurred when pemafibrate was administered) and ADRs (defined as AEs for which a causal relationship with pemafibrate could not be ruled out) were recorded according to the system organ class (SOC) and preferred term (PT) of the MedDRA/J Version 25.1. Details of the date of occurrence, seriousness, treatment of the AE, outcome of the event, and causality with pemafibrate were determined in this survey. AEs were judged as serious if they were (1) fatal, (2) life-threatening, (3) requiring hospitalization for treatment or prolongation of hospitalization, (4) causing permanent or significant disability or dysfunction, (5) causing congenital anomalies or birth defects, (6) other medically important conditions.
The incidence, type and severity of AEs/ADRs, incidence of rhabdomyolysis-related events, renal-related events, elevation of LDL-C (defined in Table S1 in the electronic supplementary material), and changes in laboratory test values were used to evaluate the safety of pemafibrate. Efficacy of pemafibrate was determined by the changes in lipid test values from baseline. In addition, the safety of pemafibrate in patients with hepatic impairment, renal impairment, and in those aged 75 years or older was evaluated.
All analyses were conducted in both the safety and efficacy analysis sets. The safety analysis set was defined as all patients who visited at least one site after at least one dose of pemafibrate, excluding patients with protocol violations. The efficacy analysis set was defined as patients in the safety analysis set who had at least one available TG test value after initiating pemafibrate treatment.
Continuous efficacy variables were summarized using mean ± standard deviation (SD), and categorical variables of safety and patient characteristics were summarized using the numbers of patients and percentages. Subgroup analysis of the incidences of any ADR by major patient characteristics were compared using the Fisher’s exact test, chi-square test, and Cochran–Armitage test. The one-sample* t* test or Wilcoxon signed rank test was performed for changes or percent changes from before administration up to each measurement period in clinical tests such as safety tests and lipid tests, including TG. P values were calculated with the significance level set at the two-sided 5% level. SAS Ver. 9.4 (SAS Institute Japan) was used for all statistical analyses.
This PMS study was conducted in compliance with the “Ordinance of the Ministry of Health, Labour and Welfare (No. 171 of December 20, 2004) concerning standards for post-marketing surveillance and testing of pharmaceuticals” (Ordinance on the Good Post-Marketing Study Practice) and other relevant laws and regulations in Japan. This PMS protocol was agreed to by the Japanese regulatory authority (Pharmaceuticals and Medical Devices Agency). Participating institutes were contracted by Kowa Company, Ltd. Ordinance on the Good Post-Marketing Study Practice does not specify ethical review committee deliberations or the need to obtain informed consent from patients. Therefore, deliberations by ethical review committees at participating institutes were conducted at the discretion of each site. Of all 612 participating institutes, 70 required ethical approval of the study protocol, which was granted by the relevant ethical review committee at each study site. Four of those 70 institutes also required written patient consent, which was successfully obtained.
Between June 2019 and April 2020, 3672 patients were registered from 612 Japanese facilities nationwide (Fig. S1 in the electronic supplementary material). In total, 3610 patients were included in the safety analysis set (excluding patients who violated registration [n = 16] and patients without any follow-up visits [n = 39]). The efficacy analysis set comprised 3462 patients, excluding 148 patients without efficacy data. Most patients (2921/3610; 80.9%) completed the 24-month observation period. The observation period (mean ± SD) was 94.1 ± 27.9 weeks and the main reason for treatment discontinuation was loss to follow-up (Table S2 in the electronic supplementary material).
Baseline patient characteristics of the safety analysis set are shown in Table 1; 68.1% of patients were male, mean age was 60.8 years, mean BMI was 26.6 kg/m^2^, 37.8% of patients had previously received another therapeutic agent for dyslipidemia before switching to pemafibrate (defined as the switched group), and secondary prevention was 12.9%. Comorbidities included hypertension in 67.5%, diabetes in 52.8%, hepatic dysfunction in 34.0%, and renal dysfunction in 15.4% of patients. Concomitant drugs were prescribed for dyslipidemia at baseline in 41.1% of patients, including statins in 31.7%, ezetimibe in 9.4%, and polyunsaturated fatty acids in 6.5%. At the time of treatment initiation, pemafibrate was prescribed at 0.1 mg/day in 7.9% of patients, 0.2 mg/day in 87.5%, and 0.4 mg/day in 4.5%. The TG level (mean ± SD) at baseline was 382.0 ± 317.6 mg/dL in the mixed state of fasting and non-fasting. The LDL-C level (mean ± SD) was 109.1 ± 34.3 mg/dL at baseline.Table 1Baseline patient characteristics (safety analysis set)CharacteristicSafety analysis set (N = 3610), n (%)^a^Sex Male2458 (68.1) Female1152 (31.9)Age, years, mean ± SD60.8 ± 13.1 15–652080 (57.6) 65–75959 (26.6) ≥ 75571 (15.8)Duration of illness, years < 1391 (10.8) 1 to < 5861 (23.9) 5 to < 10788 (21.8) ≥ 10855 (23.7) Unknown715 (19.8)Alcohol intake No1856 (51.4) Yes1754 (48.6)Smoking history None2501 (69.3) Yes or < 5 years after smoking cessation1109 (30.7)Primary prevention3146 (87.1)Secondary prevention464 (12.9) Coronary heart disease367 (10.2) Atherothrombotic brain infarction112 (3.1)Concomitant disease at presentation Hypertension2435 (67.5) Diabetes1906 (52.8) Steatotic liver1545 (42.8) Hepatic dysfunction1229 (34.0) Renal impairment557 (15.4) Cholelithiasis72 (2.0) Cirrhosis8 (0.2)BMI, kg/m^2^, mean ± SD26.6 ± 4.3 < 18.533 (0.9) 18.5 to < 251184 (32.8) ≥ 251912 (53.0) Unknown481 (13.3)Previous treatment for dyslipidemia (switched group)1363 (37.8) Fibrate839 (23.2) Polyunsaturated fatty acid244 (6.8) Statin244 (6.8) Ezetimibe90 (2.5) Nicotinic acid drug8 (0.2) Anion exchange resin2 (0.1) Probucol2 (0.1) PCSK9 inhibitor1 (< 0.1) Other4 (0.1)Concomitant use of treatments for dyslipidemia1482 (41.1) Statin1144 (31.7) Ezetimibe339 (9.4) Polyunsaturated fatty acid233 (6.5) Nicotinic acid drug28 (0.8) PCSK9 inhibitor7 (0.2) Anion exchange resin4 (0.1) Probucol4 (0.1) Fibrate3 (0.1) Other12 (0.3)Dosage of pemafibrate, mg/day 0.1285 (7.9) 0.23159 (87.5) 0.4164 (4.5) Other2 (0.1)Mixed TG, mg/dL, mean ± SD382.0 ± 317.6TC, mg/dL, mean ± SD209.8 ± 48.1HDL-C, mg/dL, mean ± SD47.3 ± 13.0Non-HDL-C, mg/dL, mean ± SD154.9 ± 39.6LDL-C^b^, mg/dL, mean ± SD109.1 ± 34.3eGFR, mL/min/1.73 m^2^, mean ± SD71.5 ± 20.4HbA1c, NGSP %, mean ± SD6.7 ± 1.3SBP, mmHg, mean ± SD131.5 ± 15.1DBP, mmHg, mean ± SD77.5 ± 11.5BMI body mass index, DBP diastolic blood pressure, eGFR estimated glomerular filtration rate, HbA1c glycated hemoglobin, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, NGSP National Glycohemoglobin Standardization Program, PCSK9 proprotein convertase subtilisin/kexin type 9, SBP systolic blood pressure, SD standard deviation, TC total cholesterol, TG triglyceride^a^Values are expressed as n (%), unless otherwise indicated^b^Direct method and formulas
In total, 147 patients experienced ADRs (187 events); the incidence was 4.07% (Table 2). According to the SOC, abnormalities in laboratory tests were most common (n = 60; 1.66%), followed by hepatobiliary disorders (n = 24, 0.66%), musculoskeletal and connective tissue disorders (n = 14, 0.39%), and metabolic and nutritional disorders (n = 14, 0.39%) (Table S3 in the electronic supplementary material). The most frequent PT components were blood CPK increased and glycosylated hemoglobin increased, both in 14 patients (0.39%), followed by cholelithiasis in 11 patients (0.30%). Fourteen serious ADRs were reported in 8 patients (0.22%). Serious ADRs became mild or had recovered in 7 patients; one patient who had experienced emphysema complicated by pulmonary fibrosis did not recover.Table 2Incidence of adverse drug reactions (ADRs) by subgroup analysisBaseline characteristics categoryNumberPatients with ADRsP value^a^All3610147 (4.07)Sex Male245892 (3.7)0.149 Female115255 (4.8)Age, years < 753039114 (3.8)0.028 ≥ 7557133 (5.8)Concomitant disease Hepatic dysfunction—Yes122939 (3.2)0.051 No2381108 (4.5) Cholelithiasis—Yes722 (2.8)1.000 No3538145 (4.1) Renal impairment—Yes55731 (5.6)0.061 No3053116 (3.8) Hypertension—Yes2435105 (4.3)0.323 No117542 (3.6) Diabetes—Yes190676 (4.0)0.801 No170471 (4.2)BMI, kg/m^2^ < 18.5332 (6.1)0.166 ≥ 18.5, < 25118458 (4.9) ≥ 25191274 (3.9)Mixed TG, mg/dL < 5002942125 (4.2)0.280 ≥ 50066822 (3.3)eGFR, mL/min/1.73 m^2^ G1 (≥ 90)51917 (3.3)0.202 G2 (≥ 60 to < 90)183078 (4.3) G3 (≥ 30 to < 60)90543 (4.8) G4/5 (< 30)372 (5.4)Concomitant use of statins—Yes114454 (4.7)0.205 No246693 (3.8)Concomitant use of ezetimibe—Yes33916 (4.7)0.473 No3271131 (4.0)Dose of pemafibrate, mg/day 0.128516 (5.6)0.146 0.23159128 (4.1) 0.41643 (1.8)Values are expressed as n (%)BMI body mass index, eGFR estimated glomerular filtration rate, TG triglyceride^a^Fisher’s exact test performed for two categories. Chi-square test performed for more than two categories. Items for which the Fisher’s exact test or chi-square test were not performed, the Cochran-Armitage test was performed
Of the 105 patients who had discontinued administration because of AEs, 60 patients (1.66%) had experienced ADRs as deemed by study physicians, of which the major PTs were myalgia (n = 7; 0.19%), blood CPK increased (n = 7; 0.19%), pruritus (n = 6; 0.17%), cholelithiasis (n = 6; 0.17%), dyspepsia (n = 3; 0.08%), and renal impairment (n = 3; 0.08%). The cumulative incidence of ADRs in days is shown in Fig. 1. The cumulative incidence of ADRs was high for the first 3 months of treatment, and then slowed down.Fig. 1Time course of the cumulative incidence of adverse drug reactions (ADRs). CI confidence interval
Although rhabdomyolysis did not occur in this study, 37 (1.02%) patients experienced rhabdomyolysis-related ADRs, including blood CPK increased (n = 14; 0.39%), myalgia (n = 8; 0.22%), renal impairment (n = 6; 0.17%), glomerular filtration rate (GFR) decreased (n = 4; 0.11%), blood creatinine increased (n = 3; 0.08%), myositis (n = 1; 0.03%), and muscle weakness (n = 1; 0.03%) (Table S3 in the electronic supplementary material). Elevation of LDL-C was observed in 10 patients (0.28%) following laboratory testing and in 1 patient (0.03%) who had developed hypercholesterolemia. Renal-related ADRs occurred in 13 patients (0.36%); renal impairment in 6 patients (0.17%), GFR decreased in 4 patients (0.11%), and blood creatinine increased in 3 patients (0.08%). We also investigated ADRs that were observed as AEs in the PROMINENT trial [15]; CKD, AKI, DN, VTE, PE, and DVT did not occur.
Table 2 shows the incidence of ADRs subdivided by patient characteristics, concomitant disease and drugs, and the dosage of pemafibrate at baseline. The subgroup analysis of ADR by patient age showed that ADRs occurred in 5.8% (33/571) of patients ≥ 75 years old and 3.8% (114/3039) of those < 75 years old. In the subgroup analysis of pemafibrate daily dose at baseline, the percentage of patients who experienced ADRs was 5.6% (16/285) in patients on a dose of pemafibrate 0.1 mg/day, 4.1% (128/3159) in those on pemafibrate 0.2 mg/day, and 1.8% (3/164) in those on pemafibrate 0.4 mg/day. The percentage of patients with ADRs according to their concomitant disease at presentation was 3.2% (39/1229) with hepatic impairment, 4.5% (108/2381) without hepatic impairment, 5.6% (31/557) with renal impairment, and 3.8% (116/3053) without renal impairment. The number of patients with ADRs according to the presence or absence of prior drugs for hyperlipidemia was 4.7% (54/1144) with statins, 3.8% (93/2466) without statins, 4.7% (16/339) with ezetimibe, and 4.0% (131/3271) without ezetimibe. When subdivided by baseline eGFR, the number of patients with ADRs according to CKD severity classification in each subgroup was 3.3% (17/519) in G1 (eGFR ≥ 90 mL/min/1.73 m^2^), 4.3% (78/1830) in G2 (eGFR ≥ 60 to < 90 mL/min/1.73 m^2^), 4.8% (43/905) in G3 (eGFR ≥ 30 to < 60 mL/min/1.73 m^2^), and 5.4% (2/37) in G4 and 5 (eGFR < 30 mL/min/1.73 m^2^). There were no significant differences in the frequency of ADRs by patient characteristic or parameter other than age.
Table S4 in the electronic supplementary material shows the changes in safety parameters in the safety analysis set at baseline, after 24 months, and at the last observation carried forward (LOCF). There were no significant changes in CPK throughout the study period. There were significant decreases in AST, ALT, γ-GT, and total bilirubin. After 24 months and at the LOCF, significant increases in SBP and decreases in DBP were noted. The eGFR transition from baseline to 24 months and at the LOCF is shown in Fig. S2 of the electronic supplementary material.
Mixed TG levels, including fasting and non-fasting values (mean ± SD), decreased from 380.5 ± 302.7 mg/dL at baseline to 232.0 ± 214.2 mg/dL after 1 month, and then fluctuated slightly, reaching the numerically lowest value of 200.4 ± 184.2 mg/dL (− 36.1%, P < 0.001) after 24 months (Table S5 in the electronic supplementary material; Fig. 2). The HDL-C and LDL-C levels (mean ± SD) both increased significantly from 47.2 ± 12.9 mg/dL and 109.2 ± 34.3 mg/dL at baseline to 51.6 ± 14.1 mg/dL and 111.1 ± 31.1 mg/dL at the LOCF (% changes were 11.4%, P < 0.001 and 9.3%, P < 0.001), respectively. TC and non-HDL-C levels decreased significantly by − 4.9% (P < 0.001) and − 7.0% (P < 0.001) at the LOCF, respectively.Fig. 2Changes in serum triglyceride levels at baseline, months 1, 3, 6, 12, 18, and 24, and at the last observation carried forward (LOCF). One-sample t tests were performed for percent changes before administration and at each measurement point. P < 0.001 at each time point. SD standard deviation, TG triglyceride
The change from baseline to LOCF in mixed TG in patients who had received prior treatment for dyslipidemia (switched group) was − 20.8 ± 51.2% (Table S6 of the electronic supplementary material), and for those who received additional pemafibrate (add-on group) it was − 44.1 ± 37.1%. Mixed TG change at the LOCF was − 37.3 ± 39.9% and − 34.3 ± 46.4% in patients with and without statins at baseline, respectively; mixed TG levels were significantly reduced in both these groups. We observed that the higher the baseline TG, the greater the rate of TG decrease. According to baseline LDL-C levels, LDL-C increased significantly in the baseline LDL-C < 140 mg/dL group and decreased significantly in the baseline LDL-C ≥ 140 mg/dL groups (Table S7 of the electronic supplementary material).
In this PMS study of pemafibrate to treat patients with hyperlipidemia in the long term, no safety concerns were observed in daily clinical practice and a stable TG-lowering effect was confirmed.
Following the long-term administration of pemafibrate in the real-world setting, the incidence of ADRs was 4.07%, and there were no safety concerns compared with the short-term administration in clinical trials for approval, where ADRs were observed in 14.5% of patients [17]. On the basis of the Kaplan-Meier analysis of the cumulative incidence of ADRs in our study, there was no trend of an increase in the incidence of ADRs with long-term administration. There was no difference in the incidence of ADRs between groups according to the dose of pemafibrate, but the incidence of ADRs appeared to increase as the dose decreased. This may be due to a bias in that low doses of pemafibrate were administered to patients with a background of high concern for ADRs in daily clinical practice.
Rhabdomyolysis, an identified risk according to the RMP [16], may be accompanied by rapid deterioration of renal function in patients on fibrates [18]. Rhabdomyolysis did not occur in this study; and, we did note that the cumulative incidence of events that are typically related to rhabdomyolysis (blood CPK increase, myalgia, renal impairment, GFR decrease, blood creatinine increase, myositis, and muscle weakness) occurred in 1.02% of patients. There were no clinically relevant changes in the main laboratory muscle-related or kidney function parameters. Taken together with a previous report of 0.02 incidents per 100 person-years [15], the development of rhabdomyolysis in daily clinical practice with pemafibrate administration is likely to be low. However, it is important to note that the risk of rhabdomyolysis is reported to be higher in patients with concomitant use of fibrates and statins, or in those with renal impairment [18, 19]; thus, these patients should continue to be monitored closely.
Increases in LDL-C were identified as a potential risk. Although LDL-C levels increased in this study, the subgroup of baseline LDL-C showed that it is likely that some populations may have an increase in LDL-C after pemafibrate administration, and others may have a decrease. This finding is consistent with previous reports, where it was evident that LDL-C changes correlated with baseline TG and LDL-C levels [8, 20]. It was assumed that the increase in LDL-C levels in this study was associated with TRL metabolism, and that there would have been a decrease in atherogenic small dense LDL as reported in previous studies [8, 20]. As such, we speculated that the increase in LDL-C levels due to pemafibrate in this study was not contributory to atherosclerosis. However, the impact on cardiovascular disease remains to be determined.
The subgroup analysis of ADRs regarding the influence of renal impairment, hepatic dysfunction, and age showed a significant effect only for age, where the incidence of ADRs was higher in patients aged ≥ 75 years than in those aged < 75 years. However, this does not present any additional safety concerns because a higher incidence of ADRs is expected in the elderly population and may also be due to general physiological decline with aging. Precautions that are generally applied to older patients should also be taken when prescribing pemafibrate to older patients.
The rates of occurrence of CKD, AKI, and DN were significantly higher in the pemafibrate group compared with the placebo group in the PROMINENT trial [15]. In comparison, there were 13 cases of renal-related ADRs (0.36%) reported in our study and no occurrences of CKD, AKI, or DN. Further investigation is needed into patients at high risk of renal-related ADRs from pemafibrate administration. In contrast to the PROMINENT trial [15], there were no occurrences of VTE, PE, or DVT events in this study. Nevertheless, since ADRs were reported on the basis of the physician’s assessment, it is possible that chest pain and peripheral edema could have been PE and DVT, respectively. The thrombogenic effects of fibrates have been a concern as reported in the FIELD trial [21]. However, the mechanism of fibrate-induced thrombogenesis is unclear, and their influence on increased thrombus formation remains controversial [22, 23].
A TG-lowering effect was maintained even after long-term administration of pemafibrate in this study. In the subgroup analysis of the TG-lowering effect, TG levels were also significantly reduced in the switched group (i.e., patients who were on existing treatment for dyslipidemia prior to switching to pemafibrate) and in the add-on group (i.e., patients in whom pemafibrate was added to existing treatment for dyslipidemia). The add-on group showed similar TG-lowering effects (− 44.1%) to those observed in the clinical trials for approval (− 39.8% to − 61.4%) [8, 10–14, 20, 24, 25]. In this study, TC and non-HDL-C decreased significantly, and HDL-C increased significantly, which were similar to the changes observed in a pooled analysis of phase 2 and 3 clinical trials with pemafibrate in Japan [26]. Overall, this PMS study confirmed the long-term lipid-improving effects of pemafibrate to treat hyperlipidemia in the real-world setting.
Limitations of this study included its observational nature and design with the absence of a control group. Also, because this was a specified use-results survey, some data on fasting and non-fasting blood sampling were mixed. We assessed lipid parameters as an efficacy endpoint, but cardiovascular events were not evaluated.
Pemafibrate was determined to be safe and efficacious following long-term administration (24 months) in the real-world setting. As with the clinical trial results, no serious safety concerns were identified. In terms of efficacy, the TG-lowering effect remained stable over a long period of time. Pemafibrate could be a useful option for treating hyperlipidemia in daily clinical practice.
Below is the link to the electronic supplementary material.Supplementary file1 (PDF 459 KB)