Effect of Pemafibrate on Cerebrovascular Atherosclerosis in Patients with Stroke and Hypertriglyceridemia

Takao Hoshino; Kentaro Ishizuka; Misa Seki; Megumi Hosoya; Sono Toi; Takafumi Mizuno; Satoko Arai; Sho Wako; Shuntaro Takahashi; Rie Oshima; Kazuo Kitagawa

doi:10.5551/jat.65277

Abstract

Aims: The Pemafibrate for Prevention of Atherosclerotic Diseases in Stroke (PPAR Stroke) study aimed to assess the effects of pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, on the progression of cerebrovascular atherosclerosis in patients with stroke and hypertriglyceridemia.

Methods: Ninety-nine patients (mean age, 65.6 years; male, 74.7%) with hypertriglyceridemia and a history of stroke or transient ischemic attack of non-cardioembolic origin were included in this prospective single-arm study. Hypertriglyceridemia was defined as a fasting serum triglyceride (TG) level ≥ 150 mg/dL. All patients were treated with pemafibrate (0.2 mg or 0.1 mg/day) for 2 years. The primary outcome was change in carotid intima-media thickness (IMT) from baseline at 2 years, as assessed using carotid ultrasonography. The secondary outcomes were changes in blood biomarker levels and progression of intracranial artery stenosis on magnetic resonance angiography.

Results: The mean TG level significantly decreased from 269 mg/dL at baseline to 139 mg/dL at 2 years (P＜0.001) and high-density lipoprotein cholesterol level increased from 49 to 54 mg/dL (P＜0.001), whereas low-density lipoprotein cholesterol level remained unchanged. Significant reductions in high-sensitivity C-reactive protein and interleukin-6 levels were also observed (P=0.003 and P=0.002, respectively). With regard to mean IMT in the internal carotid arteries, the difference was significant for the left side (1.59 mm at baseline vs. 1.52 mm at 2 years; P=0.009) and borderline significant for the right side (1.32 mm at baseline vs. 1.28 mm at 2 years; P=0.053). Among the 48 stenotic lesions in the intracranial arteries, regression and progression was observed in 9 (18.8%) and 4 (8.3%) cases, respectively.

Conclusions: Pemafibrate was observed to have TG-lowering and anti-inflammatory effects and could attenuate atherosclerosis progression in the intra- and extracranial arteries of patients with stroke and hypertriglyceridemia.

See editorial vol. 32: 670-672

Introduction

Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipid management in patients with stroke¹⁾. However, a substantial risk of vascular events can persist even after intensive LDL-C control. Triglyceride (TG)-lowering therapy has emerged as a good option for managing risk reduction beyond LDL-C control²⁾. Epidemiological studies indicate that hypertriglyceridemia is an independent risk factor of future atherosclerotic cardiovascular disease (ASCVD)³⁾. Furthermore, we reported that serum TG concentration ≥ 150 mg/dL was associated with an increased risk of recurrent ASCVD independently of baseline LDL-C levels or statin use in patients with stroke^{4, 5)}. Notably, hypertriglyceridemia was strongly correlated with intracranial artery atherosclerosis, and TG-related residual risk was higher among patients with atherothrombotic stroke than with strokes of other etiologies.

Fibrates are peroxisome proliferator-activated receptor alpha (PPARα) agonists that have been the most effective agents for lowering TG levels. However, their efficacy in ASCVD prevention remains controversial, as some randomized clinical trials have reported significant cardiovascular benefits, but others have not⁶⁾. Pemafibrate, a novel selective PPARα modulator, has recently been reported to not reduce the risk of ASCVD in patients with diabetes and hypertriglyceridemia⁷⁾. Pemafibrate differs from conventional PPARα agonists such as fenofibrate in terms of molecular structure, more robust reduction in TG levels, and a favorable safety profile⁸⁾. The use of pemafibrate in Japan was approved in 2018, ahead of other countries, and clinical outcome data are still scarce, especially for secondary stroke prevention.

The Pemafibrate for the Prevention of Atherosclerotic Diseases in Stroke (PPAR Stroke) study aimed to evaluate the effects of pemafibrate on the progression of atherosclerotic diseases in cervicocephalic arteries among patients with stroke and hypertriglyceridemia. The present report describes outcome data after 2 years of pemafibrate therapy.

Methods

Patients and Methods

The PPAR Stroke study (UMIN registration: UMIN000040619, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000046346) was a single-center, prospective, observational study that aimed to assess the effects of pemafibrate on progression of atherosclerotic diseases in the cervicocephalic arteries among patients with hypertriglyceridemia who had experienced an ischemic stroke or transient ischemic attack (TIA). The study adhered to the ethical guidelines of the 1975 Declaration of Helsinki in line with the Ethical Guidelines for Epidemiological Research by the Japanese government and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The study protocol was approved by the ethics committee of Tokyo Women’s Medical University Hospital (approval no. 5325). Written informed consent was obtained from all patients. The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Additional details regarding the study design and data on the changes in lipid profiles after 3-month pemafibrate therapy have been published elsewhere⁹⁾. Patients aged ≥ 20 years who had experienced an ischemic stroke or TIA of non-cardioembolic origin more than 1 week prior to inclusion were considered eligible for participation in this study. All strokes and TIAs were diagnosed by board-certified stroke neurologists based on neurological and radiological findings. The inclusion criterion was having elevated TG levels (≥ 150 mg/dL) under fasting conditions. If a patient had comorbid hyper-LDL cholesterolemia, we prioritized the administration of statins and reassessed the presence or absence of hypertriglyceridemia after at least 2 weeks of statin therapy. The exclusion criteria were (1) contraindications for pemafibrate administration (e.g., severe liver dysfunction or severe kidney dysfunction); (2) a history or planning of carotid endarterectomy or stenting; and (3) stroke or TIA with high-risk cardioembolic sources according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria¹⁰⁾. Baseline data on demographic characteristics, medical history, physical examination results, laboratory and radiological findings, and treatments were obtained using a structured case report form. Blood samples were collected under fasting conditions. All patients underwent carotid ultrasonography and brain magnetic resonance imaging (MRI) and angiography (MRA) at baseline.

Treatment and Follow-Up

Patients were instructed to take a 0.1 mg pemafibrate tablet twice a day. As recommended by the manufacturer, the dose was reduced to 0.1 mg once daily for patients with a serum creatinine level of 1.5–2.5 mg/dL. Other lipid-lowering agents, including statins, could be used concurrently at the discretion of the attending physicians.

Follow-up visits were scheduled at 3 months after enrollment and every year thereafter for 2 years. At each follow-up visit, data regarding physical examinations results, blood test results, compliance, concomitant treatments, occurrence of clinical events, and modified Rankin Scale score were collected. Carotid ultrasonography and brain MRI and MRA were scheduled at the 2-year follow-up visit.

Evaluation of Cervicocephalic Artery Atherosclerosis

All patients underwent carotid ultrasonography according to standard procedures¹¹⁾ using a high-resolution B-mode ultrasound system (Nemio SSA-550A, Toshiba) with a 7.5-MHz transducer by trained ultrasonographers who were blinded to the purpose of the study. The intima-media thickness (IMT) of the far wall was measured on both sides of the common carotid artery, carotid artery bulb, and internal carotid artery. Plaques were included in the IMT measurements. The degree of stenosis was measured according to the European Carotid Surgery Trial criteria¹²⁾.

Intracranial artery atherosclerosis was examined using 3 dimensional time-of-flight MRA (Ingenia 1.5 T, Philips; Magnetom Avanto Fit 1.5 T, Siemens) of the internal carotid (C1 and C2 segments), middle cerebral (M1 and M2 segments), vertebral (V4 segment), basilar, and posterior cerebral (P1 and P2) arteries. The narrowest diameter of each stenosed vessel was measured and divided by the diameter of the normal vessel proximal to the lesion, or distal to the lesion if the proximal artery was also diseased. Based on the calculated stenosis percentage, intracranial artery stenosis (ICAS) was classified into one of five grades according to previously published criteria^{13, 14)}: normal, mild (＜50%), moderate (≥ 50%), severe (absence of the blood flow signal at the stenotic lesion but presence of the signal distal to stenosis), or occluded (absence of the blood flow signal both at the stenotic lesion and distally). A change of ≥ 1 severity grade was defined as progression or improvement.

Outcomes

The primary outcome of the PPAR Stroke study was the change in carotid IMT at 2 years from baseline. Pre-specified secondary outcomes included changes in key laboratory biomarker levels and ICAS progression or regression.

Statistical Analysis

Quantitative variables are expressed as mean and standard deviation (in cases of normal distributions) or median and interquartile range values. Qualitative variables are expressed as frequencies and percentages. Patients were dichotomized according to median baseline TG level (i.e., 223 mg/dL) to compare baseline characteristics between patients with high versus very high TG levels. For bivariate comparisons, the t-test or Mann–Whitney U-test were used for quantitative variables and the χ² or Fisher’s exact test for categorical variables, as appropriate. Changes in laboratory test result data and carotid IMT from baseline were analyzed using the two-tailed paired t-test. For all analyses, statistical significance was set at P＜0.05.

Results

Of the 111 patients enrolled between October 2019 and June 2021, 99 patients were included in the final analysis; 12 patients were excluded: 2 due to discontinuation of the study drug, 2 due to death from malignancy within 2 years, 1 due to consent withdrawal, and 7 who were lost to follow-up (Supplementary Fig.1). Pemafibrate was used at 0.2 mg daily in 89 cases (89.9%) and at 0.1 mg daily in 10 cases (10.1%). Table 1 presents the baseline characteristics of the study participants. Patients with TG level ≥ 223 mg/dL were more likely to have a higher diastolic blood pressure and to be current smokers than those with TG level ＜223 mg/dL. Supplementary Table 1 shows the medications used at the time of enrollment. Statins were used by 73.8% of patients.

Supplementary Fig.1.

Study flow chart

Table 1.Baseline characteristics

	All (n= 99)	Triglyceride levels at baseline		P value
	All (n= 99)	＜223 mg/dL (n= 49)	≥ 223 mg/dL (n= 50)	P value
Age, years	65.6±12.7	67.2±13.0	64.1±12.3	0.22
Male	74 (74.7)	35 (71.4)	39 (78.0)	0.45
Body mass index, kg/m²	25.0±4.2	25.2±3.8	24.9±4.7	0.75
Blood pressure, mm Hg
Systolic	138±16	136±17	139±15	0.35
Diastolic	80±11	78±11	82±11	0.038
Medical history
Hypertension	77 (77.8)	39 (79.6)	38 (76.0)	0.67
Diabetes mellitus	40 (40.4)	20 (40.8)	20 (40.0)	0.93
Chronic heart failure	8 (8.1)	3 (6.1)	5 (10.0)	0.48
Coronary artery disease	10 (10.1)	6 (12.2)	4 (8.0)	0.48
Peripheral artery disease	3 (3.0)	2 (4.1)	1 (2.0)	0.54
Current smoking	9 (9.1)	1 (2.0)	8 (16.0)	0.010
Excessive alcohol	12 (12.1)	5 (10.2)	7 (14.0)	0.56
Index event				0.74
Ischemic stroke	84 (84.8)	41 (83.7)	43 (86.0)
Transient ischemic attack	15 (15.2)	8 (16.3)	7 (14.0)
TOAST classification of index event				0.63
Atherothrombosis	28 (28.3)	13 (26.5)	15 (30.0)
Small vessel disease	32 (32.3)	16 (32.7)	16 (32.0)
Other specific causes	5 (5.1)	1 (2.0)	4 (5.1)
Undetermined	34 (34.3)	19 (38.8)	15 (30.0)
ECAS ＞50% or occlusion	12 (12.4)	6 (12.5)	6 (12.2)	0.97
ICAS ＞50% or occlusion	34 (34.7)	15 (30.6)	19 (38.8)	0.40

Patients were divided into two groups according to the median of baseline triglyceride levels (＜223 mg/dL versus ≥ 223 mg/dL). Figures are expressed as mean±standard deviation or n (%).

ECAS indicates extracranial artery stenosis; ICAS, intracranial artery stenosis; and TOAST, Trial of Org 10172 in Acute Stroke Treatment.

Supplementary Table 1.Medication use at baseline

	All (n = 99)
Lipid lowering agent
Statin	73 (73.8)
Ezetimibe	8 (8.1)
Eicosapentaenoic acid	5 (5.1)
Antihypertensive agent
Calcium channel blocker	57 (57.6)
Angiotensin II receptor blocker	40 (40.4)
Diuretic	6 (6.1)
Antidiabetic agent
Insulin	11 (11.1)
Sulfonylurea	11 (11.1)
Biguanide	17 (17.2)
α-glucosidase inhibitor	5 (5.1)
Dipeptidyl peptidase-4 inhibitor	24 (24.2)
Sodium glucose transporter-2 inhibitor	8 (8.1)
Glucagon-like peptide-1 receptor agonist	6 (6.1)
Antiplatelet agent
Clopidogrel	53 (53.5)
Aspirin	23 (23.2)
Cilostazol	8 (8.1)
Anticoagulant agent
Warfarin	7 (7.1)
Direct oral anticoagulants	9 (9.1)

Figures are expressed as n (%).

Laboratory Data

Fig.1 depicts the temporal changes in serum lipid and HbA1c levels during the 2-year pemafibrate treatment period. The mean TG level decreased significantly from 269 mg/dL at baseline to 157 mg/dL at 3 months (P＜0.001), 146 mg/dL at 1 year (P＜0.001), and 139 mg/dL at 2 years (P＜0.001). Remnant-like particle cholesterol (RLP-C) level decreased from 10.3 mg/dL to 5.1 mg/dL at 2 years (P＜0.001), and high-density lipoprotein cholesterol (HDL-C) level increased from 48.9 mg/dL to 53.4 mg/dL at 2 years (P＜0.001). In contrast, the LDL-C, lipoprotein (a), and HbA1c levels remained unchanged. Percent changes in TG, RLP-C, and HDL-C levels from baseline to 2 years were -42.8%, -41.6%%, and +11.5%, respectively (Fig.2). Fig.3 shows the changes in other blood biomarker levels. Alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (γ-GTP) levels were significantly decreased (P＜0.001 and P=0.011, respectively), whereas creatinine and homocysteine levels were increased (P=0.005 and P＜0.001, respectively) at 2 years. With regard to inflammatory markers, significant reductions in C-reactive protein, high-sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6) levels were observed (P=0.015, P=0.003, and P=0.002, respectively). Additional blood sample laboratory test results are summarized in Supplementary Table 2.

Fig.1. Changes in lipid and glucose profiles

Changes from baseline at 3months, 1 year, and 2 years in triglycerides (A), RLP-cholesterol (B), HDL-cholesterol (C), LDL-cholesterol (D), lipoprotein (a) (E), and HbA1c (F) are shown.

Data are presented as mean and standard error.

^＊P＜0.001 compared to baseline.

HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; and RLP, remnant-like lipoprotein.

Fig.2. Percent changes from baseline in lipid profiles

Percent changes from baseline at 1 year and 2 years are shown.

Data are presented as mean and standard error.

HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; and RLP, remnant-like lipoprotein.

Fig.3. Changes in key blood biomarkers

Changes from baseline at 3 months, 1 year, and 2 years in AST (A), ALT (B), γ-GTP (C), creatine kinase (D), creatinine (E), eGFR (F), homocysteine (G), CRP (H), high-sensitivity CRP (I), and interleukin-6 (J) are shown.

Data are presented as mean and standard error.

^＊P＜0.05 compared to baseline.

^＊＊P＜0.01 compared to baseline.

^＊＊＊P＜0.001 compared to baseline.

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; eGFR, estimated glomerular filtration rate; γ-GTP, gamma-glutamyl transpeptidase; and hsCRP, high-sensitivity C-reactive protein.

Supplementary Table 2.Changes in laboratory data in blood samples

	Baseline	3 months	1 year	2 years
Triglycerides, mg/dL	269	157^＊＊＊	146^＊＊＊	139^＊＊＊
RLP-cholesterol, mg/dL	10.3	6.1^＊＊＊	5.1^＊＊＊	5.1^＊＊＊
HDL-cholesterol, mg/dL	48.9	53.7^＊＊＊	55.2^＊＊＊	54.3^＊＊＊
LDL-cholesterol, mg/dL	100	100	99	101
Lipoprotein (a), mg/dL	18.5	19.4	20.4	19.2
HbA1c, %	6.70	6.72	6.67	6.65
AST, IU/L	24.6	24.1	24.8	22.7^＊
ALT, IU/L	25.3	20.3^＊＊＊	20.9^＊＊	17.7^＊＊＊
γ-GTP, IU/L	50.7	31.7^＊＊＊	33.4^＊＊＊	34.7^＊＊
Creatine kinase, IU/L	112	125^＊	117	111
Creatinine, mg/dL	0.94	0.98^＊＊	0.99^＊＊	1.01^＊＊
eGFR, mL/min/1.73m²	62.0	60.1^＊＊	59.9^＊＊	59.0^＊＊
Homocysteine, μmol/L	12.5	14.6^＊＊＊	16.0^＊＊＊	15.8^＊＊＊
CRP, mg/dL	0.22	0.20	0.18	0.17^＊
High-sensitivity CRP, mg/L	1.70	1.41	1.33^＊	1.24^＊＊
Interleukin-6, pg/mL	3.04	2.35^＊＊	2.42^＊	2.38^＊＊

Mean levels are presented.

^＊P＜0.05 compared to baseline.

^＊＊P＜0.01 compared to baseline.

^＊＊＊P＜0.001 compared to baseline.

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; eGFR, estimated glomerular filtration rate; γ-GTP, gamma-glutamyl transpeptidase; HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; and RLP, remnant-like lipoprotein.

Cervicocerebral Artery Atherosclerosis

Temporal changes in carotid IMT as assessed using carotid ultrasonography are depicted in Fig.4. There were no differences in mean IMT in the common carotid arteries and carotid bulbs over 2 years. On the other hand, 2 years of pemafibrate therapy resulted in the regression of internal carotid artery IMT (significant regression on the left side: mean IMT, 1.59 mm at baseline vs. 1.52 mm at 2 years; P=0.009 and borderline significant regression on the right side: mean IMT, 1.32 mm at baseline vs. 1.28 mm at 2 years; P=0.053).

Fig.4. Changes in carotid intima-media thickness

Changes from baseline at 2 years in intima-media thickness of right CCA (A), right carotid bulb (B), right ICA (C), left CCA (D), left carotid bulb (E), and left ICA (F) are shown.

Data are presented as mean and standard error.

^＊P＜0.01 compared to baseline.

CCA indicates common carotid artery; and ICA, internal carotid artery.

Table 2 summarizes the MRA-based ICAS assessment data. Among the 48 stenotic lesions in 34 patients, regression and progression occurred in 9 (18.8%) and 4 (8.3%) lesions, respectively, at the 2-year follow-up. When patients were divided into 2 groups according to baseline TG levels (150-–200 mg/dL vs. ＞200 mg/dL) or achieved TG levels at 2 years (＜150 mg/dL vs. ＞200 mg/dL), no differences were observed in the rate of progression or regression of ICAS between the groups.

Table 2. Changes in intracranial atherosclerotic stenosis

	Total (n= 48)	Triglyceride levels at baseline		P value	Triglyceride levels at 2 years		P value
	Total (n= 48)	150–200 mg/dL (n= 18)	≥ 200 mg/dL (n= 30)	P value	＜150 mg/dL (n= 35)	≥ 150 mg/dL (n= 13)	P value
Regression	9 (18.8)	4 (22.2)	5 (16.7)	0.79	7 (20.0)	2 (15.4)	0.93
Stationary	35 (72.9)	13 (72.2)	22 (73.3)		25 (71.4)	10 (77.0)
Progression	4 (8.3)	1 (5.6)	3 (10.0)		3 (8.6)	1 (7.7)

A total of 48 stenotic lesions in 34 patients were analyzed.

Patients were divided into two groups according to triglyceride levels at baseline (150-200 mg/dL versus ≥ 200 mg/dL) or at 2 years (＜150 mg/dL versus ≥ 150 mg/dL).

Figures are expressed as n (%).

Discussion

In this single-arm observational study that included Japanese patients with hypertriglyceridemia and a history of stroke or TIA, pemafibrate strongly reduced TG and RLP-C levels by 40% and increased HDL-C levels by 10%, with no changes in LDL-C and lipoprotein (a) levels. In addition, the levels of hepatobiliary enzymes (i.e., ALT, γ-GTP) and inflammatory markers (i.e., hsCRP, IL-6) were also significantly reduced. Slight but significant increases in serum creatinine and homocysteine levels conform with previous observations^{7, 15)}. Pemafibrate therapy appeared to be well-tolerated in combination with statins. After 2 years of pemafibrate therapy, regression of the carotid IMT in the internal carotid arteries was observed on carotid ultrasonography. Pemafibrate may also have a protective effect against ICAS, as the rate of ICAS progression in the present study was substantially lower than that reported previously^{13, 14)}. Our data suggest the potential benefit of pemafibrate therapy in improving hypertriglyceridemia and cerebrovascular atherosclerosis in patients with stroke, although further placebo-controlled studies are warranted.

TG-rich lipoprotein remnants can infiltrate into the intima and cause low-grade inflammation, leading to the development of atherosclerotic plaques¹⁶⁾. Compared with LDL-C, TG-rich lipoprotein remnants carry approximately 40 times more cholesterol per particle and may have a stronger atherogenic effect¹⁷⁾. In a multi-directional Mendelian randomization study, remnant cholesterol was causally associated with low-grade inflammation and ischemic heart disease, whereas elevated LDL-C was causally associated with ischemic heart disease without inflammation¹⁸⁾. Furthermore, the results of the Progression of Early Subclinical Atherosclerosis (PESA) study indicate that hypertriglyceridemia is significantly associated with the presence of subclinical atherosclerosis and arterial inflammation, even in subjects with normal LDL-C levels¹⁹⁾. Pemafibrate was developed as a modulator of PPARα, which regulates the transcriptions of several genes involved in lipid and lipoprotein metabolism. Due to its high selectivity for PPARα, pemafibrate can reduce serum TG and increase HDL-C levels more effectively than conventional fibrates and has fewer side effects such as liver and kidney toxicity⁸⁾. Furthermore, in patients with atherogenic dyslipidemia, treatment with pemafibrate not only increased HDL-C, apo A-I, and apo A-II levels, but also improved indices related to HDL function, as shown by increases in prebeta-HDL, smaller HDL particles (HDL₃ and HDL₂), and macrophage cholesterol efflux capacity, a marker of the ability of HDL to mediate reverse cholesterol transport²⁰⁾. PPARα is also known to bind to cytokine-activated transcription factors such as nuclear factor-kappa B and activator protein-1 and inhibit inflammatory responses²¹⁾, and experimental data show that pemafibrate can have potent anti-inflammatory effects^22-24). In a mouse model, it increased cholesterol efflux to HDL-C, reduced markers of inflammation and macrophages in the aorta, and attenuated the development of atherosclerosis²²⁾. Hence, both anti-dyslipidemic and anti-inflammatory effects may explain our finding of treatment with pemafibrate preventing the progression of atherosclerosis in cervicocephalic arteries.

Numerous studies have demonstrated that hypertriglyceridemia is an independent risk factor of ASCVD²⁾, although its treatment effect on the vascular event risk remains controversial. A post-hoc analysis of randomized controlled studies on fibrates found a significant reduction in the risk of ASCVD⁶⁾, whereas the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study, in which approximately 10,000 diabetic patients with hypertriglyceridemia were enrolled, did not show cardiovascular benefits of TG-lowering therapy with pemafibrate⁷⁾. However, because these previous studies were mainly conducted on a primary prevention cohort or on patients with coronary artery disease, the effect on cerebrovascular disease remains to be further investigated. In the present study, we focused on the changes in cervicocephalic artery atherosclerosis as early markers of future ASCVD risk. The rate of ICAS progression in our study was 8%, which is less than that in patients taking placebo (29%) or clopidogrel (16%) and comparable with that in patients taking cilostazol (9%) in previous clinical trials^{13, 14)}, although direct comparisons are not possible. Furthermore, regression of carotid IMT was also observed. Given that attenuating the progression of intra- and extracranial atherosclerosis would prevent the transition to manifest stroke, our results suggest hypertriglyceridemia as a potential target for secondary stroke prevention and could guide future clinical trials.

The significant reductions in ALT and γ-GTP levels in this study were also in line with previous findings²⁵⁾. Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, has emerged as a major health concern worldwide due to its increasing prevalence. Hepatic TG accumulation plays an important role in the development of NAFLD, and epidemiological data indicate a linear relationship between TG levels and NAFLD prevalence²⁶⁾. In addition to the risk of advanced liver disease, NAFLD is associated with an increased risk of ASCVD even after adjusting for traditional ASCVD risk factors²⁷⁾. Therefore, our data suggest the usefulness of pemafibrate in treating NAFLD, which could consequently prevent cardiovascular complications.

Limitations

This study had some limitations. First, it was a single-center, exploratory study without a control group. Owing to the small sample size, surrogate markers were used for assessing relevant endpoints. Additionally, as the study participants were Japanese, our results may not be applicable to other racial/ethnic populations. Therefore, larger, multi-center placebo-controlled studies are necessary for more comprehensive evaluations of the cardiovascular benefits of pemafibrate. Second, ICAS was assessed using time-of-flight MRA, which is more prone to false positive diagnoses than computed tomography angiography or digital subtraction angiography. Moreover, MRA is not sufficient to exclude stenosis of non-atherosclerotic origin, such as dissection, vasculitis, or other vasculopathies. Conventional catheter angiography is considered the gold standard for ICAS diagnosis, but its use was not considered feasible to maintain the inclusion of patients. Third, we did not assess the vulnerability of atherosclerotic plaque. The use of advanced imaging techniques, such as positron emission tomography, contrast-enhanced ultrasonography, or high-resolution MRI, to identify high-risk plaques would expand the understanding of the association between TG and atherosclerosis. Finally, the concomitant use of statins and other lipid-lowering, antihypertensive, antidiabetic, or antithrombotic agents could have introduced biases. Despite these limitations, the findings of our study offer novel and potentially useful information, given that clinical data on pemafibrate are scarce, especially for patients with established cerebrovascular disease.

Conclusions

In this study on patients with hypertriglyceridemia and prior stroke or TIA, 2-year treatment with pemafibrate resulted in improved lipid profiles and reductions in the levels of inflammatory markers and hepatobiliary enzymes. Furthermore, pemafibrate may have a protective effect against the progression of atherosclerotic lesions in the intra- and extracranial arteries. Larger multi-center studies with appropriate control groups are required to evaluate the impacts of pemafibrate on the risk of ASCVD.

Acknowledgements

None.

Conflict of Interest

Dr. Kitagawa reports personal fees from Kyowa Kirin, grants and personal fees from Daiichi Sankyo, and grants from Bayer and Dainihon Sumitomo outside the submitted work. Other authors have nothing to disclose.

Sources of Funding

This study was partially supported by a Grant-in-Aid for Scientific Research (C) (22K07544) from the Japan Society for the Promotion of Science.

References

責任著者(Corresponding author)

J-STAGEへの登録はこちら（無料）