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

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.

Keywords: Intima-media thickness; Intracranial artery; Pemafibrate; Peroxisome proliferator-activated receptor alpha (PPARα); Triglycerides.

Supplementary Fig.1.

Study flow chart

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.

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.