Combination Therapy with Pemafibrate (K-877) and Pitavastatin Improves Vascular Endothelial Dysfunction in Dahl/Salt-sensitive Rats Fed a High-salt and High-fat Diet​

Abstract

Background: Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats.Methods: Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated.Results: After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone.Conclusions: Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.

Retinal degeneration induced in a mouse model of ischemia–reperfusion injury and its management by pemafibrate treatment

“…In fact, several previous studies demonstrated that an increase in serum levels of TG may be associated with an increased risk of the development of retinopathies 113–115 . Based on our present and previous data as well as others, oral administrations of pemafibrate showed strong reducing effects on serum TG levels 18,20,46,116,117 . In this regard, oral administrations of pemafibrate could effectively reduce the risk of the development and/or progression of retinopathies in humans.…”

“…To manage retinal degeneration caused by retinal I/R injury, pemafibrate was orally administered to adult mice daily according to the timeline of the experiments (Figure 1A). The dose of pemafibrate was determined based on previous administration protocols 20,23,45,46 . Retinal I/R injury was induced in mice 4 days after oral administration of pemafibrate.…”

Personalized management of dyslipidemias in patients with diabetes—it is time for a new approach (2022)

“…The beneficial effect of fenofibrate on the prognosis of DMT2 patients and dyslipidemia was also confirmed by Koopal et al In a study involving 17,142 patients from the FIELD (the Fenofibrate Intervention and Event Lowering in Diabetes), ACCORD (the Action to Control Cardiovascular Risk in Diabetes), and SMART (Second Manifestations of ARTerial disease) studies [61]. Unfortunately, the Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT) phase 3 study with pemafibrate was prematurely discontinued (April 2022) due to the unlikely achievement of the primary endpoint [62][63][64]. The REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) showed that the use of icosapent ethyl (IPE) in patients with high TG and diabetes type 2 led to a reduction risk of CV death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina by 25% (HR = 0.77; 95% CI: 0.68-0.87).…”

Impact of pitavastatin on new-onset diabetes mellitus compared to atorvastatin and rosuvastatin: a distributed network analysis of 10 real-world databases

“…Previous randomized clinical trial demonstrated that pitavastatin 4 mg compared with pitavastatin 1 mg therapy significantly reduced LDL-C and clinical outcomes irrespective of renal function state [ 10 ]. When used in combination, pitavastatin and pemafibrate improved lipid profile and endothelial function in hypertension and insulin resistance model rats [ 11 ]. Ihm et al also reported combination therapy with pitavastatin and fenofibrate more effectively reduced non-HDL-C compared with pitavastatin monotherapy in patients with a high risk for cardiovascular disease [ 12 ].…”