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Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Review Article

A Contemporary Overview of PPARα/γ Dual Agonists for the Management of Diabetic Dyslipidemia

Author(s): Pitchai Balakumar*, Nanjaian Mahadevan and Ramanathan Sambathkumar

Volume 12, Issue 3, 2019

Page: [195 - 201] Pages: 7

DOI: 10.2174/1874467212666190111165015

Abstract

Background: Diabetes mellitus and concomitant dyslipidemia, being referred to as ‘diabetic dyslipidemia’, are the foremost detrimental factors documented to play a pivotal role in cardiovascular illness. Diabetic dyslipidemia is associated with insulin resistance, high plasma triglyceride levels, low HDL-cholesterol concentration and elevated small dense LDL-cholesterol particles. Maintaining an optimal glucose and lipid levels in patients afflicted with diabetic dyslipidemia could be a major task that might require a well-planned diet-management system and regular physical activity, or otherwise an intake of combined antidiabetic and antihyperlipidemic medications. Synchronized treatment which efficiently controls insulin resistance-associated diabetes mellitus and co-existing dyslipidemia could indeed be a fascinating therapeutic option in the management of diabetic dyslipidemia. Peroxisome proliferator-activated receptors α/γ (PPARα/γ) dual agonists are such kind of drugs which possess therapeutic potentials to treat diabetic dyslipidemia. Nevertheless, PPARα/γ dual agonists like muraglitazar, naveglitazar, tesaglitazar, ragaglitazar and aleglitazar have been reported to have undesirable adverse effects, and their developments have been halted at various stages. On the other hand, a recently introduced PPARα/γ dual agonist, saroglitazar is an emerging therapeutic agent of glitazar class approved in India for the management of diabetic dyslipidemia, and its treatment has been reported to be generally safe and well tolerated.

Conclusion: Some additional and new compounds, at initial and preclinical stages, have been recently reported to possess PPARα/γ dual agonistic potentials with considerable therapeutic efficacy and reduced adverse profile. This review sheds light on the current status of various PPARα/γ dual agonists for the management of diabetic dyslipidemia.

Keywords: PPARα/γ dual agonists, insulin resistance, diabetic dyslipidemia, adverse effects, cardiovascular events, oedema.

Graphical Abstract

[1]
Chehade, J.M.; Gladysz, M.; Mooradian, A.D. Dyslipidemia in type 2 diabetes: prevalence, pathophysiology, and management. Drugs, 2013, 73, 327-339.
[2]
Chigurupati, S.; Dhanaraj, S.A.; Balakumar, P. A step ahead of PPARγ full agonists to PPARγ partial agonists: therapeutic perspectives in the management of diabetic insulin resistance. Eur. J. Pharmacol., 2015, 755, 50-57.
[3]
Ferré, P. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes, 2004, 53, S43-S50.
[4]
Balakumar, P.; Jagadeesh, G. PPAR ligands and cardiovascular disorders: friend or foe. Curr. Mol. Pharmacol., 2012, 5, 219-223.
[5]
Balakumar, P.; Rose, M.; Ganti, S.S.; Krishan, P.; Singh, M. PPAR dual agonists: are they opening Pandora’s Box? Pharmacol. Res., 2007, 56, 91-98.
[6]
Balakumar, P.; Rohilla, A.; Mahadevan, N. Pleiotropic actions of fenofibrate on the heart. Pharmacol. Res., 2011, 63, 8-12.
[7]
Balakumar, P.; Kathuria, S. Submaximal PPARγ activation and endothelial dysfunction: new perspectives for the management of cardiovascular disorders. Br. J. Pharmacol., 2012, 166, 1981-1992.
[8]
Balakumar, P.; Maung-U, K.; Jagadeesh, G. Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacol. Res., 2016, 113, 600-609.
[9]
Nissen, S.E.; Wolski, K.; Topol, E.J. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA, 2005, 294, 2581-2586.
[10]
Conlon, D. Goodbye glitazars? Br. J. Diabetes Vasc. Dis., 2006, 6, 135-137.
[11]
Ratner, R.E.; Parikh, S.; Tou, C. GALLANT 9 Study Group. Efficacy, safety and tolerability of tesaglitazar when added to the therapeutic regimen of poorly controlled insulin-treated patients with type 2 diabetes. Diab. Vasc. Dis. Res., 2007, 4, 214-221.
[12]
Tseng, C.H.; Tseng, F.H. Peroxisome proliferator-activated receptor agonists and bladder cancer: lessons from animal studies. J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev, 2012, 30, 368-402.
[13]
Erdmann, E.; Califf, R.; Gerstein, H.C.; Malmberg, K.; Ruilope, L.; Schwartz, G.G.; Wedel, H.; Volz, D.; Ditmarsch, M.; Svensson, A.; Bengus, M. Effects of the dual peroxisome proliferator-activated receptor activator aleglitazar in patients with Type 2 Diabetes mellitus or prediabetes. Am. Heart J., 2015, 170, 117-122.
[14]
Joshi, S.R. Saroglitazar for the treatment of dyslipidemia in diabetic patients. Expert Opin. Pharmacother., 2015, 16, 597-606.
[15]
Cox, S.L. Muraglitazar: An agent for the treatment of type 2 diabetes and associated dyslipidemia. Drugs Today (Barc), 2005, 41, 579-587.
[16]
Buse, J.B.; Rubin, C.J.; Frederich, R.; Viraswami-Appanna, K.; Lin, K.C.; Montoro, R.; Shockey, G.; Davidson, J.A. Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes. Clin. Ther., 2005, 27, 1181-1195.
[17]
Doggrell, S.A. Muraglitazar: beneficial or detrimental in the treatment of Type 2 diabetes? Expert Opin. Pharmacother., 2006, 7, 1229-1233.
[18]
Rubin, C.J.; Viraswami-Appanna, K.; Fiedorek, F.T. Efficacy and safety of muraglitazar: a double-blind, 24-week, dose-ranging study in patients with type 2 diabetes. Diab. Vasc. Dis. Res., 2009, 6, 205-215.
[19]
Long, G.G.; Reynolds, V.L.; Lopez-Martinez, A.; Ryan, T.E.; White, S.L.; Eldridge, S.R. Urothelial carcinogenesis in the urinary bladder of rats treated with naveglitazar, a gamma-dominant PPAR alpha/gamma agonist: lack of evidence for urolithiasis as an inciting event. Toxicol. Pathol., 2008, 36, 218-231.
[20]
Fagerberg, B.; Edwards, S.; Halmos, T.; Lopatynski, J.; Schuster, H.; Stender, S.; Stoa-Birketvedt, G.; Tonstad, S.; Halldórsdóttir, S.; Gause-Nilsson, I. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia, 2005, 48, 1716-1725.
[21]
Ratner, R.E.; Parikh, S.; Tou, C. GALLANT 9 Study Group. Efficacy, safety and tolerability of tesaglitazar when added to the therapeutic regimen of poorly controlled insulin-treated patients with type 2 diabetes. Diab. Vasc. Dis. Res., 2007, 4, 214-221.
[22]
Bays, H.; McElhattan, J.; Bryzinski, B.S. GALLANT 6 Study Group. A double-blind, randomised trial of tesaglitazar versus pioglitazone in patients with type 2 diabetes mellitus. Diab. Vasc. Dis. Res., 2007, 4, 181-193.
[23]
Hamrén, B.; Ohman, K.P.; Svensson, M.K.; Karlsson, M.O. Pharmacokinetic-pharmacodynamic assessment of the interrelationships between tesaglitazar exposure and renal function in patients with type 2 diabetes mellitus. J. Clin. Pharmacol., 2012, 52, 1317-1327.
[24]
Oleksiewicz, M.B.; Thorup, I.; Nielsen, H.S.; Andersen, H.V.; Hegelund, A.C.; Iversen, L.; Guldberg, T.S.; Brinck, P.R.; Sjogren, I.; Thinggaard, U.K.; Jørgensen, L.; Jensen, M.B. Generalized cellular hypertrophy is induced by a dual-acting PPAR agonist in rat urinary bladder urothelium in vivo. Toxicol. Pathol., 2005, 33, 552-560.
[25]
Bénardeau, A.; Benz, J.; Binggeli, A.; Blum, D.; Boehringer, M.; Grether, U.; Hilpert, H.; Kuhn, B.; Märki, H.P.; Meyer, M.; Püntener, K.; Raab, S.; Ruf, A.; Schlatter, D.; Mohr, P. Aleglitazar, a new, potent, and balanced dual PPARalpha/gamma agonist for the treatment of type II diabetes. Bioorg. Med. Chem. Lett., 2009, 19, 2468-2473.
[26]
Sanwald-Ducray, P.; Liogier D’ardhuy, X.; Jamois, C.; Banken, L. Pharmacokinetics, pharmacodynamics, and tolerability of aleglitazar in patients with type 2 diabetes: results from a randomized, placebo-controlled clinical study. Clin. Pharmacol. Ther., 2010, 88, 197-203.
[27]
Lincoff, A.M.; Tardif, J.C.; Schwartz, G.G.; Nicholls, S.J.; Rydén, L.; Neal, B.; Malmberg, K.; Wedel, H.; Buse, J.B.; Henry, R.R.; Weichert, A.; Cannata, R.; Svensson, A.; Volz, D.; Grobbee, D.E. AleCardio Investigators. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA, 2014, 311, 1515-1525.
[28]
Jani, R.H.; Kansagra, K.; Jain, M.R.; Patel, H. Pharmacokinetics, safety, and tolerability of saroglitazar (ZYH1), a predominantly PPARα agonist with moderate PPARγ agonist activity in healthy human subjects. Clin. Drug Investig., 2013, 33, 809-816.
[29]
Agrawal, R. The first approved agent in the Glitazar’s Class: Saroglitazar. Curr. Drug Targets, 2014, 15, 151-155.
[30]
Pai, V.; Paneerselvam, A.; Mukhopadhyay, S.; Bhansali, A.; Kamath, D.; Shankar, V.; Gambhire, D.; Jani, R.H.; Joshi, S.; Patel, P.A. Multicenter, Prospective, Randomized, Double-blind Study to Evaluate the Safety and Efficacy of Saroglitazar 2 and 4 mg Compared to Pioglitazone 45 mg in Diabetic Dyslipidemia (PRESS V). J. Diabetes Sci. Technol., 2014, 8, 132-141.
[31]
Jani, R.H.; Pai, V.; Jha, P.; Jariwala, G.; Mukhopadhyay, S.; Bhansali, A.; Joshi, S. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI). Diabetes Technol. Ther., 2014, 16, 63-71.
[32]
Shetty, S.R.; Kumar, S.; Mathur, R.P.; Sharma, K.H.; Jaiswal, A.D. Observational study to evaluate the safety and efficacy of saroglitazar in Indian diabetic dyslipidemia patients. Indian Heart J., 2015, 67, 23-26.
[33]
Ghosh, A.; Sahana, P.K.; Das, C.; Mandal, A.; Sengupta, N. Comparison of effectiveness and safety of add-on therapy of saroglitazar and fenofibrate with metformin in Indian patients with diabetic dyslipidaemia. J. Clin. Diagn. Res., 2016, 10, FC01-FC04.
[34]
Gilardi, F.; Giudici, M.; Mitro, N.; Maschi, O.; Guerrini, U.; Rando, G.; Maggi, A.; Cermenati, G.; Laghezza, A.; Loiodice, F.; Pochetti, G.; Lavecchia, A.; Caruso, D.; De Fabiani, E.; Bamberg, K.; Crestani, M. LT175 is a novel PPARα/γ ligand with potent insulin-sensitizing effects and reduced adipogenic properties. J. Biol. Chem., 2014, 289, 6908-6920.
[35]
Jeong, H.W.; Lee, J.W.; Kim, W.S.; Choe, S.S.; Kim, K.H.; Park, H.S.; Shin, H.J.; Lee, G.Y.; Shin, D.; Lee, H.; Lee, J.H.; Choi, E.B.; Lee, H.K.; Chung, H.; Park, S.B.; Park, K.S.; Kim, H.S.; Ro, S.; Kim, J.B. A newly identified CG301269 improves lipid and glucose metabolism without body weight gain through activation of peroxisome proliferator-activated receptor alpha and gamma. Diabetes, 2011, 60, 496-506.
[36]
Jung, H.Y.; Kim, B.; Ryu, H.G.; Ji, Y.; Park, S.; Choi, S.H.; Lee, D.; Lee, I.K.; Kim, M.; Lee, Y.J.; Song, W.; Lee, Y.H.; Choi, H.J.; Hyun, C.K.; Holzapfel, W.H.; Kim, K.T. Amodiaquine improves insulin resistance and lipid metabolism in diabetic model mice. Diabetes Obes. Metab., 2018, 20, 1688-1701.
[37]
Ren, T.; Yang, W.S.; Lin, Y.; Liu, J.F.; Li, Y.; Yang, L.C.; Zeng, K.Y.; Peng, L.; Liu, Y.J.; Ye, Z.H.; Luo, X.M. Ke. Y.J.; Diao, Y.; Jin, X. A novel PPARα/γ agonist, propane-2-sulfonic acid octadec-9-enyl-amide, ameliorates insulin resistance and gluconeogenesis in vivo and vitro. Eur. J. Pharmacol., 2018, 826, 1-8.
[38]
Jung, Y.; Cao, Y.; Paudel, S.; Yoon, G.; Cheon, S.H.; Bae, G.U.; Jin, L.T.; Kim, Y.K.; Kim, S.N. Antidiabetic effect of SN158 through PPARα/γ dual activation in ob/ob mice. Chem. Biol. Interact., 2017, 268, 24-30.
[39]
Ge, J.; Miao, J.J.; Sun, X.Y.; Yu, J.Y. Huangkui capsule, an extract from Abelmoschus manihot (L.) medic, improves diabetic nephropathy via activating peroxisome proliferator-activated receptor (PPAR)-α/γ and attenuating endoplasmic reticulum stress in rats. J. Ethnopharmacol., 2016, 189, 238-249.
[40]
Park, M.H.; Kim, D.H.; Kim, M.J.; Lee, E.K.; An, H.J.; Jeong, J.W.; Kim, H.R.; Kim, S.J.; Yu, B.P.; Moon, H.R.; Chung, H.Y. Effects of MHY908, a new synthetic PPARα/γ dual agonist, on inflammatory responses and insulin resistance in aged rats. J. Gerontol. A Biol. Sci. Med. Sci., 2016, 71, 300-309.
[41]
Lee, W.; Ham, J.; Kwon, H.C.; Kim, Y.K.; Kim, S.N. Anti-diabetic effect of amorphastilbol through PPARα/γ dual activation in db/db mice. Biochem. Biophys. Res. Commun., 2013, 432, 73-79.
[42]
Silva, J.C.; de Oliveira, E.M.; Turato, W.M.; Trossini, G.H.G.; Maltarollo, V.G.; Pitta, M.G.R.; Pitta, I.R.; de Las Heras, B.; Boscá, L.; Rudnicki, M.; Abdalla, D.S.P. GQ-11: A new PPAR agonist improves obesity-induced metabolic alterations in LDLr-/- mice. Int. J. Obes. (Lond)., 2018, 42, 1062-1072.
[43]
Sæther, T.; Paulsen, S.M.; Tungen, J.E.; Vik, A.; Aursnes, M.; Holen, T.; Hansen, T.V.; Nebb, H.I. Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects. Eur. J. Med. Chem., 2018, 155, 736-753.

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