Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?

Abstract

All fibrates are peroxisome proliferators-activated receptors (PPARs)-alpha agonists with ability to decrease triglyceride and increase high density lipoprotein- cholesterol (HDL-C). However, bezafibrate has a unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta) at comparable doses. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. Selective PPAR gamma agonists (thiazolidinediones) are used to treat type 2 diabetes mellitus (T2DM). They improve insulin sensitivity by up-regulating adipogenesis, decreasing free fatty acid levels, and reversing insulin resistance. However, selective PPAR gamma agonists also cause water retention, weight gain, peripheral edema, and congestive heart failure. The expression of PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence) suggests its potential fundamental role in cellular biology. PPAR beta/ delta effects correlated with enhancement of fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate PPAR beta/delta in fuel combustion and suggest that pan-PPAR agonists that include a component of PPAR beta/delta activation might offset some of the weight gain issues seen with selective PPAR gamma agonists, as was demonstrated by bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined PPAR gamma and alpha action can target simultaneously insulin resistance and atherogenic dyslipidemia, whereas PPAR beta/delta properties may prevent the development of overweight. Bezafibrate, as all fibrates, significantly reduced plasma triglycerides and increased HDL-C level (but considerably stronger than other major fibrates). Bezafibrate significantly decreased prevalence of small, dense low density lipoproteins particles, remnants, induced atherosclerotic plaque regression in thoracic and abdominal aorta and improved endothelial function. In addition, bezafibrate has important fibrinogen-related properties and anti-inflammatory effects. In clinical trials bezafibrate was highly effective for cardiovascular risk reduction in patients with metabolic syndrome and atherogenic dyslipidemia. The principal differences between bezafibrate and other fibrates are related to effects on glucose level and insulin resistance. Bezafibrate decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. Currently statins are the cornerstone of the treatment and prevention of cardiovascular diseases related to atherosclerosis. However, despite the increasing use of statins as monotherapy for low density lipoprotein- cholesterol (LDL-C) reduction, a significant residual cardiovascular risk is still presented in patients with atherogenic dyslipidemia and insulin resistance, which is typical for T2DM and metabolic syndrome. Recently, concerns were raised re...

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

“…It is reported that PGC-1α enhances mitochondrial activity through partner transcription factors: nuclear respiratory factors (NRFs) and peroxisome proliferator-activated receptors (PPARs) (44). We tested oltipraz and bezafibrate, known to activate PGC-1α/NRF2 and PGC-1α/PPARs, respectively, for their synergistic tumor-suppression activity with anti-PD-L1 mAb (46,47). Both oltipraz and bezafibrate strongly enhanced tumor-growth suppression and animal-survival activities by anti-PD-L1, whereas these chemicals alone did not show any effects on tumor growth (Fig.…”

Association and Interaction ofPPARα,δ,andγGene Polymorphisms with Low-Density Lipoprotein-Cholesterol in a Chinese Han Population

“…Since the year that Issemann et al (1990) first found PPARs, increasing evidence has proved that PPARs play an important role in lipid metabolism and could be functioned as regulators affecting the level of LDL-C (Azhar, 2010). Moreover, it has also been known that a few drugs, such as fibrates, could be used for LDL-lowering therapy by activating PPARs (Tenenbaum and Fisman, 2012).…”

Role of peroxisome proliferator-activated receptor α and ϒ-2 in primary and secondary prophylaxis of atherosclerosis

“…Известно, что активация PPAR γ 2 сопровожда ется увеличением синтеза белков глюкозотранс портеров 1 го и 4 го типов и, следовательно, повы шением чувствительности тканей к инсулинy, сни жением уровня свободных жирных кислот за счет активации липопротеинлипазы на генном уровне [3,9,12,48].…”

“…Кроме этого, терапия тиазолидиндионами нормализует функционирование β клеток подже лудочной железы, регулирует адипогенез [3,23,48].…”

“…Вместе с тем рядом авторов показано, что тиазоли диндионы могут приводить к развитию таких побоч ных эффектов, как задержка воды в организме, уве личение массы тела, периферические отеки, застой ная сердечная недостаточность и анемия [12,37,48].…”