The online version of this article (doi:10.1186/1475-2840-11-140) contains supplementary material, which is available to authorized users.
AT received speaker fee and travel expenses support from Abbott, Tribute, Novartis and Merck.
EZF declares that he has no competing interests.
Both authors have equally contributed in the conception and drafting of the manuscript. Both authors read and approved the final manuscript.
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 regarding the development of diabetes in statin-treated patients. Combined bezafibrate/statin therapy is more effective in achieving a comprehensive lipid control and residual cardiovascular risk reduction. Based on the beneficial effects of pan-PPAR agonist bezafibrate on glucose metabolism and prevention of new-onset diabetes, one could expect a neutralization of the adverse pro-diabetic effect of statins using the strategy of a combined statin/fibrate therapy.
Poirier H, Niot I, Monnot MC, Braissant O, Meunier-Durmort C, Costet P, Pineau T, Wahli W, Willson TM, Besnard P: Differential involvement of peroxisome-proliferator-activated receptors alpha and delta in fibrate and fatty-acid-mediated inductions of the gene encoding liver fatty-acid-binding protein in the liver and the small intestine. Biochem J. 2001, 355: 481-488. 10.1042/0264-6021:3550481. PubMedCentralCrossRefPubMed
Dressel U, Allen TL, Pippal JB, Rohde PR, Lau P, Muscat GE: The peroxisome proliferator-activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol Endocrinol. 2003, 17: 2477-2493. 10.1210/me.2003-0151. CrossRefPubMed
The BIP Study Group: Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000, 102: 21-27. CrossRef
Ayaori M, Momiyama Y, Fayad ZA, Yonemura A, Ohmori R, Kihara T, Tanaka N, Nakaya K, Ogura M, Sawada S, Taniguchi H, Kusuhara M, Nagata M, Nakamura H, Ohsuzu F: Effect of bezafibrate therapy on atherosclerotic aortic plaques detected by MRI in dyslipidemic patients with hypertriglyceridemia. Atherosclerosis. 2008, 196: 425-433. 10.1016/j.atherosclerosis.2006.11.035. CrossRefPubMed
Jonkers IJ, Mohrschladt MF, Westendorp RG, van der Laarse A, Smelt AH: Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial. Am J Med. 2002, 112: 275-280. 10.1016/S0002-9343(01)01123-8. CrossRefPubMed
Madrid-Miller A, Moreno-Ruiz LA, Borrayo-Sánchez G, Almeida-Gutiérrez E, Martínez-Gómez DF, Jáuregui-Aguilar R: Impact of bezafibrate treatment in patients with hyperfibrinogenemia and ST-elevation acute myocardial infarction: a randomized clinical trial. Cir Cir. 2010, 78: 229-237. PubMed
Sano K, Nakamura T, Hirano M, Kitta Y, Kobayashi T, Fujioka D, Saito Y, Yano T, Watanabe K, Watanabe Y, Mishina H, Obata JE, Kawabata K, Kugiyama K: Comparative study of bezafibrate and pravastatin in patients with coronary artery disease and high levels of remnant lipoprotein. Circ J. 2010, 74: 1644-1650. 10.1253/circj.CJ-10-0079. CrossRefPubMed
Ericsson CG, Nilsson J, Grip L, Svane B, Hamsten A: Effect of bezafibrate treatment over five years on coronary plaques causing 20% to 50% diameter narrowing (The Bezafibrate Coronary Atherosclerosis Intervention Trial [BECAIT]). Am J Cardiol. 1997, 80: 1125-1129. 10.1016/S0002-9149(97)00626-7. CrossRefPubMed
Elkeles RS, Diamond JR, Poulter C, Dhanjil S, Nicolaides AN, Mahmood S, Richmond W, Mather H, Sharp P, Feher MD: Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study. Diabetes Care. 1998, 21: 641-648. 10.2337/diacare.21.4.641. CrossRefPubMed
Taniguchi A, Fukushima M, Sakai M, Tokuyama K, Nagata I, Fukunaga A, Kishimoto H, Doi K, Yamashita Y, Matsuura T, Kitatani N, Okumura T, Nagasaka S, Nakaishi S, Nakai Y: Effects of bezafibrate on insulin sensitivity and insulin secretion in non-obese Japanese type 2 diabetic patients. Metabolism. 2001, 50: 477-480. 10.1053/meta.2001.21028. CrossRefPubMed
Tenenbaum H, Behar S, Boyko V, Adler Y, Fisman EZ, Tanne D, Lapidot M, Schwammenthal E, Feinberg M, Matas Z, Motro M, Tenenbaum A: Long-term effect of bezafibrate on pancreatic beta-cell function and insulin resistance in patients with diabetes. Atherosclerosis. 2007, 194: 265-271. 10.1016/j.atherosclerosis.2006.08.005. CrossRefPubMed
Tenenbaum A, Motro M, Fisman EZ, Schwammenthal E, Adler Y, Goldenberg I, Leor J, Boyko V, Mandelzweig L, Behar S: Peroxisome proliferator-activated receptors ligand bezafibrate for prevention of type 2 diabetes mellitus in patients with coronary artery disease. Circulation. 2004, 109: 2197-2202. 10.1161/01.CIR.0000126824.12785.B6. CrossRefPubMed
Hansen BC, Tigno XT, Bénardeau A, Meyer M, Sebokova E, Mizrahi J: Effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ agonist on glycemic and lipid parameters in a primate model of the metabolic syndrome. Cardiovasc Diabetol. 2011, 10: 7-10.1186/1475-2840-10-7. PubMedCentralCrossRefPubMed
Hiuge A, Tenenbaum A, Maeda N, Benderly M, Kumada M, Fisman EZ, Tanne D, Matas Z, Hibuse T, Fujita K, Nishizawa H, Adler Y, Motro M, Kihara S, Shimomura I, Behar S, Funahashi T: Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level. Arterioscler Thromb Vasc Biol. 2007, 27: 635-641. 10.1161/01.ATV.0000256469.06782.d5. CrossRefPubMed
Sacks FM, Tonkin AM, Shepherd J, Braunwald E, Cobbe S, Hawkins CM, Keech A, Packard C, Simes J, Byington R, Furberg CD, for the Prospective Pravastatin Pooling Project: Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors. Circulation. 2000, 102: 1893-1900. 10.1161/01.CIR.102.16.1893. CrossRefPubMed
Daida H, Takayama T, Hiro T, Yamagishi M, Hirayama A, Saito S, Yamaguchi T, Matsuzaki M, for the COSMOS Investigators: High HbA1c levels correlate with reduced plaque regression during statin treatment in patients with stable coronary artery disease: Results of the coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS). Cardiovasc Diabetol. 2012, 11: 87-10.1186/1475-2840-11-87. PubMedCentralCrossRefPubMed
Verhagen SN, Wassink AM, van der Graaf Y, Gorter PM, Visseren FL, SMART Study Group: Insulin resistance increases the occurrence of new cardiovascular events in patients with manifest arterial disease without known diabetes. the SMART study. Cardiovasc Diabetol. 2011, 10: 100-10.1186/1475-2840-10-100. PubMedCentralCrossRefPubMed
Sukhija R, Prayaga S, Marashdeh M, Bursac Z, Kakar P, Bansal D, Sachdeva R, Kesan SH, Mehta JL: Effect of statins on fasting plasma glucose in diabetic and nondiabetic patients. J Investig Med. 2009, 57: 495-499. PubMed
Coleman CI, Reinhart K, Kluger J, White CM: The effect of statins on the development of new-onset type 2 diabetes: a meta-analysis of randomized controlled trials. Curr Med Res Opin. 2006, 24: 1359-1362. CrossRef
Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y, et al: Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet. 2010, 375: 735-742. 10.1016/S0140-6736(09)61965-6. CrossRefPubMed
Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJ, de Lemos JA, Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N, Ray KK: Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011, 305: 2556-2564. 10.1001/jama.2011.860. CrossRefPubMed
Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JG, Cornel JH, Dunselman P, Fonseca C, Goudev A, Grande P, Gullestad L, Hjalmarson A, Hradec J, Jánosi A, Kamenský G, Komajda M, Korewicki J, Kuusi T, Mach F, Mareev V, McMurray JJ, Ranjith N, Schaufelberger M, Vanhaecke J, van Veldhuisen DJ, Waagstein F, Wedel H, Wikstrand J, CORONA Group: Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007, 357: 2248-2261. 10.1056/NEJMoa0706201. CrossRefPubMed
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ, JUPITER Study Group: Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008, 359: 2195-2207. 10.1056/NEJMoa0807646. CrossRefPubMed
Zaharan NL, Williams D, Bennett K: Statins and Risk of Treated Incident Diabetes in a Primary Care Population. Br J Clin Pharmacol. 2012, 10.1111/j.1365-2125.2012.04403.x.
Rautio N, Jokelainen J, Oksa H, Saaristo T, Peltonen M, Vanhala M, Puolijoki H, Moilanen L, Tuomilehto J, Keinänen-Kiukaanniemi S, Uusitupa M: Do statins interfere with lifestyle intervention in the prevention of diabetes in primary healthcare? One-year follow-up of the FIN-D2D project. BMJ Open. 2012, 2 (5): pii: e001472. CrossRef
Waters DD, Ho JE, DeMicco DA, Breazna A, Arsenault BJ, Wun CC, Kastelein JJ, Colhoun H, Barter P: Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol. 2011, 57: 1535-1545. 10.1016/j.jacc.2010.10.047. CrossRefPubMed
Scandinavian Simvastatin Survival Study Study Group: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994, 344: 1383-1389.
Teramoto T: Pitavastatin: clinical effects from the LIVES Study. Atheroscler. 2011, 12: 285-288. 10.1016/S1567-5688(11)70888-1. CrossRef
Beggs PW, Clark DW, Williams SM, Coulter DM: A comparison of the use, effectiveness and safety of bezafibrate, gemfibrozil and simvastatin in normal clinical practice using the New Zealand Intensive Medicines Monitoring Programme (IMMP). Br J Clin Pharmacol. 1999, 47: 99-104. PubMedCentralCrossRefPubMed
Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, Ceska R, Chapman MJ, Dodson PM, Fioretto P, Ginsberg HN, Kadowaki T, Lablanche JM, Marx N, Plutzky J, Reiner Z, Rosenson RS, Staels B, Stock JK, Sy R, Wanner C, Zambon A, Zimmet P: The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008, 102: 1K-34K. 10.1016/j.amjcard.2008.10.002. CrossRefPubMed
Kehely A, MacMahon M, Barbir M, Wray R, Hunt BJ, Prescott RJ, Thompson GR: Combined bezafibrate and simvastatin treatment for mixed hyperlipidaemia. QJM. 1995, 88: 421-427. PubMed
Tenenbaum A, Medvedofsky D, Fisman EZ, Bubyr L, Matetzky S, Tanne D, Klempfner R, Shemesh J, Goldenberg I: Cardiovascular events in patients received combined fibrate/statin treatment versus statin monotherapy: Acute Coronary Syndrome Israeli Surveys data. PLoS One. 2012, 7 (4): e35298-10.1371/journal.pone.0035298. PubMedCentralCrossRefPubMed
- Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?
Enrique Z Fisman
- BioMed Central
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