Diabetes Metab J > Volume 37(5); 2013 > Article
Seok and Cha: Refocusing Peroxisome Proliferator Activated Receptor-α: A New Insight for Therapeutic Roles in Diabetes

Abstract

Although glucose-lowering treatment shows some risk lowering effects in cardiovascular diseases, risks of macrovascular and microvascular complications have still remained, and development of new therapeutic strategies is needed. Recent data have shown that peroxisome proliferator activated receptor-α (PPAR-α) plays a pivotal role in the regulation of lipid homeostasis, fatty acid oxidation, cellular differentiation, and immune response such as inflammation or vascularization related to diabetic complication. This review will re-examine the metabolic role of PPAR-α, summarize data from clinical studies on the effect of PPAR-α agonist in diabetes, and will discuss the possible therapeutic role of PPAR-α activation.

INTRODUCTION

The global prevalence of type 2 diabetes (T2D) is rapidly increasing, and considerable population suffers from diabetes-related complication [1]. T2D is closely associated with an increased risk of macrovascular and microvascular risk [2,3]. The most important aim of treatment of T2D is lowering macrovascular and microvascular risk. There have been efforts to reduce the residual risk of macrovascular and microvascular complication, and many previous clinical trials showed meaningful risk reduction of cardiovascular risk after multifactorial risk factor modifications [4-7]. However, the residual risk still remained after achieving targets for glucose, blood pressure, and low density lipoprotein (LDL) levels [8].
Focuses on activation of peroxisome proliferator activated receptors-α (PPAR-α) have been made for risk reduction of diabetic complications; however, its therapeutic role in diabetes is still controversial. With this background, we will discuss the actions of PPAR-α agonists and clinical implications for the preventions of macrovascular and microvascular complications in T2D.

PPAR AGONIST

PPARs

PPARs are a subgroup in the family of nuclear hormone receptors and are highly expressed across numerous metabolic tissues [9]. PPARs are activated by binding ligands, including fatty acids, in the cytoplasm and are then translocated to the cell nucleus.
In the nucleus, PPARs form heterodimers with retinoic acid receptors (RXR) [10-12]. The generally conserved domain structures are found in PPARs and RXRs: DNA-binding domains, ligand-binding domains, and activation domains. DNA-binding domains make the receptor bind to PPAR and RXR response elements in target gene promoters. Ligand-binding domains determine how specific pharmacologic and endogenous nuclear receptor ligands bind to and modulate receptor activity. Activation domains determine receptor activities [9].
PPARs can be influenced by variable factors and shows variable responses by clinical agonists [13]. Because DNA-binding domains are relatively large, many PPAR-agonists can attach to the ligand-binding domain in a distinctive pathway, which results in specific conformational changes and different accessory molecule recruitment. One of the reasons of unique effect of a PPAR agonist on different tissues is partially due to the variety of accessory molecules in the specific tissues. The formation of endogenous ligands or the catabolism of synthetic agonists may also vary, which may result in a wide range of responses. PPARs also can be modified by phosphorylation, and variable factors of RXR could influence on PPAR response [9].
By binding to the promoter regions of target genes, PPARs become transcription factors which regulate the expression of multiple target genes. Activation of PPARs pathways are known to result in favorable effects on glucose homeostasis and lipid metabolism [14,15]. There are three PPAR isotypes: PPAR-α, PPAR-γ, and PPAR-δ (also referred to PPAR-β).

PPAR-α agonist

PPAR-α was the first discovered PPARs and is known to promote proliferation of peroxisomes, which is involved in oxidative processes including fatty acid metabolism and inflammatory and vascular pathways [9]. PPAR-α is highly expressed in skeletal muscles and liver, which is closely correlated with fatty acid oxidation [16,17]. The primary mechanism of action of PPAR-α is increasing lipoprotein lipase activity which hydrolyzes triglyceride-rich lipoproteins, and reducing its inhibition; PPAR-α activation represses the expression of apolipoprotein (Apo) C3, which is the endogenous lipoprotein lipase repressor [9,17]. PPAR-α activation also increases the expression of fatty acid repressors such as CD36, and increases production of various enzymes correlated to β-oxidation. Activation of PPAR-α also increases levels of Apo A-I and high density lipoprotein cholesterol (HDL-C) and up-regulates cellular transporters involved in the cholesterol efflux pathway. As a result, PPAR-α activation results in increased HDL-C level, stimulates reverse cholesterol transport, and lowers triglyceride level [18,19]. In clinical practice, PPAR-α agonists (fibrates) are used for dyslipidemia by decreasing triglyceride levels and increasing HDL levels [14].

PPAR-γ agonist

PPAR-γ is highly expressed in adipocytes, skeletal muscle, liver, and kidney. PPAR-γ has been known to regulate expression of genes that mediate general energy metabolism, such as adipocyte differentiation and insulin action [15]. PPAR-γ is correlated with increasing insulin sensitivity and glucose uptake, adiponectin, and fatty acid uptake [9,20]. Therefore, selective PPAR-γ agonists (thiazolidinediones) had been widely used in clinical practice to treat T2D [21]. However, the use of thiazolidinediones requires caution because some had shown several undesirable side effects, such as water retention, peripheral edema, and congestive heart failure, osteoporosis, and while still under controversy, possible increased risk of bladder cancer [22-24].

PPAR-β/δ agonist

PPAR-β/δ can be found in almost all cell types and tissues, which suggests their crucial role across the whole body [25]. Previous in vivo data have shown that selective overexpression of PPAR-β/δ in mouse adipose tissue induces significant weight loss and provides protection against obesity and dyslipidemia after high fat diet [26]. The metabolic effects of PPAR-β/δ are correlated with increased fatty acid oxidation, energy consumption, and adaptive thermogenesis. Although PPAR-β/δ agonists are not currently used in clinical practice, some clinical studies on pan-PPAR agonist, including bezafibrate, show potentially favorable metabolic benefits of pan-PPAR agonist that includes PPAR-β/δ activation, especially in offseting weight gain issues of selective PPAR-γ agonist [25,27].

THE THERAPEUTIC POTENTIAL OF PPAR-α AGONIST IN DIABETES

PPAR-α agonist in macrovascular complications

There are two major clinical studies about the effects of fenofibrates on cardiovascular complication. One is the Fenofibrate Intervention and Event Lowering in Diabetes Study (FIELD), which included 9,795 subjects with diabetes mellitus and dyslipidemia [28,29]. In this study, fenofibrate did not reduce the composite primary end point of nonfatal myocardial infarction and coronary heart disease mortality (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.75 to 1.05) compared with placebo. Fenofibrate showed significantly reduced nonfatal myocardial infarction (HR, 0.79; 95% CI, 0.62 to 0.94), with nonsignificantly increased mortality in coronary heart disease (HR, 1.19; 95% CI, 0.90 to 1.57). Fenofibrate showed significantly reduced composite end point of cardiovascular disease mortality, myocardial infarction, stroke, and coronary or carotid revascularization (HR, 0.89; 95% CI, 0.80 to 9.99). In post hoc analysis, fenofibrate reduced 5-year composite risk of myocardial infarction, stroke, and death in subjects with metabolic syndrome (adjusted HR, 0.89; 95% CI, 0.79 to 1.00) or without (adjusted HR, 0.88; 95% CI, 0.62 to 1.19). Subjects with metabolic syndrome had higher baseline risk, which may explain the greater absolute benefits in those subjects [30].
The other study is the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which included 5,518 subjects with diabetes mellitus, with hemoglobin A1c (HbA1c) greater than 7.5%, and elevated cardiovascular disease risk factors [5,31]. They were randomized to masked fenofibrate or placebo, each on a background of open-label simvastatin. After a mean follow-up period of 4.7 years, the annual primary outcome (the first occurrence of a major cardiovascular event including nonfatal myocardial infarction, stroke, or cardiovascular death) rate was 2.2% in fenofibrate group and 2.4% in placebo group (HR, 0.92; 95% CI, 0.79 to 1.08). Fenofibrate did not show a significant reduction in nonfatal myocardial infarction and cardiovascular mortality [5]. They concluded that this combination of lipid treatment does not improve cardiovascular outcomes.
The effects of gemfibrozil on cardiovascular complications were also examined by two large trials. The Helsinki Heart Study included 4,180 men aged 40 to 55 years with primary dyslipidemia (defined as non-HDL-C level >5.2 mmol/L) [32]. Within 1 year after being randomized to either gemfibrozil or placebo, HDL-C and LDL-cholesterol (LDL-C) improved in the former group by 10%, whereas minimal changes were observed in the latter group. Compared to placebo group, gemfibrozil group showed lower events of fatal or nonfatal myocardial infarction (relative risk reduction [RRR], 34%; 95% CI, 8.2 to 52.6) at 5-year follow-up.
The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial also showed similar results. In this study, 2,531 men with cardiovascular disease, HDL-C level <1.0 mmol/dL, and LDL-C level 3.6 mmol/dL were randomized to gemfibrozil or placebo [33]. After 5 years, gemfibrozil reduced primary composite end point of combined incidence of nonfatal myocardial infarction (RRR, 23%; 95% CI, 4 to 38) or cardiac death (RRR, 22%; 95% CI, 2 to 41). These trials showed that gemfibrozil may reduce the risk of myocardial infarction and cardiac death in high risk patients.

PPAR-α agonist in microvascular complications

Activation of PPAR-α results in inhibition of several mediators of vascular damage, including inflammation, endothelial dysfunction, lipotoxicity, and thrombosis [34,35]. In addition, fenofibrate showed an effect on decreasing uric acid [36,37]. Due to these effects, activation of PPAR-α has been suggested to possibly affect the prevention of diabetic nephropathy or retinopathy [34,35,38-40].
Diabetic nephropathy is one of the most important causes of chronic kidney disease. Recent studies suggest that lipotoxicity by lipid accumulation in kidney is one of risk factors for diabetic nephropathy [39,41,42]. Dyslipidemia, oxidative stress, and inflammation closely correlated with renal dysfunction. Therefore, PPAR-α could have a therapeutic role in diabetic nephropathy, which is being supported by increasing amount of evidence [43,44]. In a previously reported in vitro study, after treatment of human glomerular microvascular endothelial cells with fenofibrate, transient activation of adenosine monophosphate-activated protein kinase, induction of the phosphorylation of protein kinase B, eNOS activation, and nitric oxide production occurred [35]. Another in vivo study reported that fenofibrate treatment in diabetic rat prevented the development of diabetes-induced lipid elevation, vascular endothelial dysfunction, and oxidative stress. In this study, fenofibrate prevented the induction of diabetic nephropathy by reducing proteinuria and blood urea nitrogen [43]. Unfortunately, few clinical studies have confirmed renoprotective effect of PPAR-α activation in diabetic nephropathy. In the FIELD study, fenofibrate reduced albuminuria (albumin/creatinine ratio by 24% vs. 11%; P<0.001) and slowed estimated glomerular filtration rate loss over 5 years compared with placebo [45]. The investigators of this trial suggested that fenofibrate could have a protective role against the loss of underlying renal function in T2D. In FIELD Study, plasma creatinine was noted to be increased during fenofibrate therapy, but was quickly reversed after placebo assignment. Other study suggested that fenofibrate-induced increase in creatinine production was associated with enhanced metabolic production rate of creatinine, rather than with impairment of renal function [46].
The Diabetes Atherosclerosis Intervention Study included subjects with T2D treated with fenofibrate for an average of 38 months. This study suggested that fenofibrate reduced progression of normal albumin excretion to microalbuminuria [47]. Other PPAR-α agonist such as gemfibrozil and bezafibrate also showed reno-protective effect in diabetic nephropathy [48,49].
The effect of PPAR-α activation on diabetic retinopathy was examined in the FIELD study. The FIELD study showed fenofibrate reduced the need for laser photocoagulation for either macular edema or proliferative retinopathy compared to placebo (3.4% vs. 4.9%; P<0.001) [50]. The ACCORD Eye study showed similar results: intensive treatment of dyslipidemia (160 mg fenofibrate daily plus simvastatin or placebo plus simvastatin) resulted in reduced progression rates of diabetic retinopathy [51].

DEVELOPMENT OF THE DUAL PPAR-α/γ AGONIST

Both PPAR-α and PPAR-γ agonist plays a pivotal role in treatment of T2D. PPAR-α activation improves lipid profile, including reduction of triglyceride levels and enhancement of HDL-C levels. PPAR-γ activation enhances insulin sensitivity and potential anti-inflammatory effects. For these reasons, interests in dual PPAR-α/γ agonist have been sparked among a number of researchers. However, the development of dual-PPAR agonist has not been steady due to safety concerns.
Tesaglitazar was the first dual PPAR-α/γ agonist with relatively weak potential, but nephrotoxicity was found, and consequently, the development was discontinued [52,53]. The use of ragaglitazar and naveglitazar was correlated with increased incidence of bladder cancer and hyperplasia in rodent studies [54,55]. Muraglitazar showed significant lipid changes, with decreases in triglyceride by up to 27% and increases in HDL-C by up to 16%. Despite of these effect, further studies on muraglitazar was also discontinued due to increases in the composite risk of nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality compared with placebo or pioglitazone in meta-analysis (relative risk, 2.23; 95% CI, 1.07 to 4.66) [56,57].
Aleglitazar is another dual PPAR-α/γ agonist and equally stimulates PPAR-α and PPAR-γ genes [58]. In the phase II Effect of the Dual Peroxisome Proliferator-Activated Receptor-α/γAgonist Aleglitazar on Risk of Cardiovascular Disease in Patients With Type 2 Diabetes (SYNCHRONY) study, aleglitazar showed dose-dependent metabolic benefits, including significant dose-dependent reduction in HbA1c of -0.36% (4 mmol/mol, 50 µg; P=0.048) to -1.35% (15 mmol/mol, 600 µg; P<0.0001) in 16 weeks of treatment compared to placebo. Aleglitazar also showed significant beneficial effects on lipid profile: significant decreases in triglyceride and increases in HDL-C were found (-43% and +21%, respectively, with 150 µg). At a dose of 150 µg or higher, aleglitazar also significantly decreased LDL-C (placebo-adjusted reduction rate -15.5% with 150 µg) compared to placebo. The effects of 150 µg of aleglitazar on triglycerides, HDL-C, and LDL-C were greater than 45 mg of pioglitazone. Further study has found treatment of aleglitazar to result in a shift from the atherogenic small dense LDL particles associated with T2D to larger LDL particles [59]. Reported adverse events with aleglitazar were similar to pioglitazone, with mild increases body weight and edema. However, no serious adverse events such as cardiovascular disease or hepatotoxicity have been confirmed as of yet, with the exception of a reversible small decline in glomerular filtration rate [60]. The phase III Cardiovascular Outcomes Study to Evaluate the Potential of Aleglitazar to Reduce Cardiovascular Risk in Patients With a Recent Acute Coronary Syndrome (ACS) Event and Type 2 Diabetes Mellitus (ALECARDIO) study is now ongoing: this randomized controlled clinical trial will examine whether aleglitazar (150 µg daily dose) can decrease cardiovascular morbidity and mortality in T2D patients who have suffered from a recent acute coronary syndrome event (NCT01042769).

CONCLUSIONS

Although modification of multiple risk factors of microvascular and macrovascular complication of T2D has resulted in risk reduction, the concern for remaining risk has been continuously raised, and further reducing this remaining risk has been the main therapeutic issues in T2D.
Activation of PPAR-α has been suggested as an important therapeutic target for patients with T2D through playing an important role in regulation of energy metabolism. Further research is required to determine whether PPAR-α agonist shows actual risk reduction for microvascular complication. Furthermore, the development of dual PPAR-α/γ agonist has been of great interest because of its mechanism which may potentially provide benefits on both lipid profile and glycemic control. The effect of dual PPAR-α/γ agonist on glycemic control, lipid profile, cardiovascular outcomes, and safety issues also should be verified with further studies.

NOTES

No potential conflict of interest relevant to this article was reported.

REFERENCES

1. Rosenson RS, Fioretto P, Dodson PM. Does microvascular disease predict macrovascular events in type 2 diabetes? Atherosclerosis 2011;218:13-18.
2. Bloomgarden ZT. Cardiovascular disease in diabetes. Diabetes Care 2010;33:e49-e54.
3. Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men: influence of age at onset, diabetes duration, and established and novel risk factors. Arch Intern Med 2011;171:404-410.
4. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-713.
5. ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-1574.
6. Cholesterol Treatment Trialists' (CTT) Collaborators. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008;371:117-125.
7. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580-591.
8. Fruchart JC, Sacks FM, 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. Residual Risk Reduction Initiative (R3I). The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-335.
9. Brown JD, Plutzky J. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation 2007;115:518-533.
10. Rakhshandehroo M, Knoch B, Muller M, Kersten S. Peroxisome proliferator-activated receptor alpha target genes. PPAR Res 2010;2010:612089
11. DiRenzo J, Soderstrom M, Kurokawa R, Ogliastro MH, Ricote M, Ingrey S, Horlein A, Rosenfeld MG, Glass CK. Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors. Mol Cell Biol 1997;17:2166-2176.
12. Latruffe N, Cherkaoui Malki M, Nicolas-Frances V, Jannin B, Clemencet MC, Hansmannel F, Passilly-Degrace P, Berlot JP. Peroxisome-proliferator-activated receptors as physiological sensors of fatty acid metabolism: molecular regulation in peroxisomes. Biochem Soc Trans 2001;29(Pt 2):305-309.
13. Rosenson RS, Wright RS, Farkouh M, Plutzky J. Modulating peroxisome proliferator-activated receptors for therapeutic benefit? Biology, clinical experience, and future prospects. Am Heart J 2012;164:672-680.
14. Staels B, Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 2005;54:2460-2470.
15. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004;351:1106-1118.
16. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 1996;137:354-366.
17. Frederiksen KS, Wulff EM, Sauerberg P, Mogensen JP, Jeppesen L, Fleckner J. Prediction of PPAR-alpha ligand-mediated physiological changes using gene expression profiles. J Lipid Res 2004;45:592-601.
18. Arakawa R, Tamehiro N, Nishimaki-Mogami T, Ueda K, Yokoyama S. Fenofibric acid, an active form of fenofibrate, increases apolipoprotein A-I-mediated high-density lipoprotein biogenesis by enhancing transcription of ATP-binding cassette transporter A1 gene in a liver X receptor-dependent manner. Arterioscler Thromb Vasc Biol 2005;25:1193-1197.
19. Nakaya K, Tohyama J, Naik SU, Tanigawa H, MacPhee C, Billheimer JT, Rader DJ. Peroxisome proliferator-activated receptor-α activation promotes macrophage reverse cholesterol transport through a liver X receptor-dependent pathway. Arterioscler Thromb Vasc Biol 2011;31:1276-1282.
20. Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors. Lancet 1999;354:141-148.
21. Berger JP, Akiyama TE, Meinke PT. PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci 2005;26:244-251.
22. Friedland SN, Leong A, Filion KB, Genest J, Lega IC, Mottillo S, Poirier P, Reoch J, Eisenberg MJ. The cardiovascular effects of peroxisome proliferator-activated receptor agonists. Am J Med 2012;125:126-133.
23. Ferwana M, Firwana B, Hasan R, Al-Mallah MH, Kim S, Montori VM, Murad MH. Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabet Med 2013;30:1026-1032.
24. Song SO, Kim KJ, Lee BW, Kang ES, Cha BS, Lee HC. The risk of bladder cancer in korean diabetic subjects treated with pioglitazone. Diabetes Metab J 2012;36:371-378.
25. Tenenbaum A, Fisman EZ. Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention? Cardiovasc Diabetol 2012;11:140
26. Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 2003;113:159-170.
27. 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.
28. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesäniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M. FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-1861.
29. Scott R, Best J, Forder P, Taskinen MR, Simes J, Barter P, Keech A. FIELD Study Investigators. Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: baseline characteristics and short-term effects of fenofibrate [ISRCTN6478 3481]. Cardiovasc Diabetol 2005;4:13
30. Scott R, O'Brien R, Fulcher G, Pardy C, D'Emden M, Tse D, Taskinen MR, Ehnholm C, Keech A. Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study Investigators. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 2009;32:493-498.
31. ACCORD Study Group. Buse JB, Bigger JT, Byington RP, Cooper LS, Cushman WC, Friedewald WT, Genuth S, Gerstein HC, Ginsberg HN, Goff DC Jr, Grimm RH Jr, Margolis KL, Probstfield JL, Simons-Morton DG, Sullivan MD. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007;99(12A):21i-33i.
32. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Maenpaa H, Malkonen M, Manttari M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjoblom T, Nikkila EA. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-1245.
33. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-418.
34. Hiukka A, Maranghi M, Matikainen N, Taskinen MR. PPA-Ralpha: an emerging therapeutic target in diabetic microvascular damage. Nat Rev Endocrinol 2010;6:454-463.
35. Tomizawa A, Hattori Y, Inoue T, Hattori S, Kasai K. Fenofibrate suppresses microvascular inflammation and apoptosis through adenosine monophosphate-activated protein kinase activation. Metabolism 2011;60:513-522.
36. Takahashi S, Moriwaki Y, Yamamoto T, Tsutsumi Z, Ka T, Fukuchi M. Effects of combination treatment using anti-hyperuricaemic agents with fenofibrate and/or losartan on uric acid metabolism. Ann Rheum Dis 2003;62:572-575.
37. Milionis HJ, Elisaf MS. Management of hypertension and dyslipidaemia in patients presenting with hyperuricaemia: case histories. Curr Med Res Opin 2000;16:164-170.
38. Balakumar P, Arora MK, Singh M. Emerging role of PPAR ligands in the management of diabetic nephropathy. Pharmacol Res 2009;60:170-173.
39. Rutledge JC, Ng KF, Aung HH, Wilson DW. Role of triglyceride-rich lipoproteins in diabetic nephropathy. Nat Rev Nephrol 2010;6:361-370.
40. Kouroumichakis I, Papanas N, Zarogoulidis P, Liakopoulos V, Maltezos E, Mikhailidis DP. Fibrates: therapeutic potential for diabetic nephropathy? Eur J Intern Med 2012;23:309-316.
41. Balakumar P, Kadian S, Mahadevan N. Are PPAR alpha agonists a rational therapeutic strategy for preventing abnormalities of the diabetic kidney? Pharmacol Res 2012;65:430-436.
42. Kanwar YS, Wada J, Sun L, Xie P, Wallner EI, Chen S, Chugh S, Danesh FR. Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med (Maywood) 2008;233:4-11.
43. Balakumar P, Chakkarwar VA, Singh M. Ameliorative effect of combination of benfotiamine and fenofibrate in diabetes-induced vascular endothelial dysfunction and nephropathy in the rat. Mol Cell Biochem 2009;320:149-162.
44. Park CW, Zhang Y, Zhang X, Wu J, Chen L, Cha DR, Su D, Hwang MT, Fan X, Davis L, Striker G, Zheng F, Breyer M, Guan Y. PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int 2006;69:1511-1517.
45. Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR, Jenkins AJ, O'Connell RL, Whiting MJ, Glasziou PP, Simes RJ, Kesäniemi YA, Gebski VJ, Scott RS, Keech AC. Fenofibrate Intervention and Event Lowering in Diabetes Study investigators. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 2011;54:280-290.
46. Hottelart C, El Esper N, Rose F, Achard JM, Fournier A. Fenofibrate increases creatininemia by increasing metabolic production of creatinine. Nephron 2002;92:536-541.
47. Ansquer JC, Foucher C, Rattier S, Taskinen MR, Steiner G. DAIS Investigators. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis 2005;45:485-493.
48. Nagai T, Tomizawa T, Nakajima K, Mori M. Effect of bezafibrate or pravastatin on serum lipid levels and albuminuria in NIDDM patients. J Atheroscler Thromb 2000;7:91-96.
49. Smulders YM, van Eeden AE, Stehouwer CD, Weijers RN, Slaats EH, Silberbusch J. Can reduction in hypertriglyceridaemia slow progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus? Eur J Clin Invest 1997;27:997-1002.
50. Keech AC, Mitchell P, Summanen PA, O'Day J, Davis TM, Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E, Merrifield A, Laatikainen LT, d'Emden MC, Crimet DC, O'Connell RL, Colman PG. FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-1697.
51. ACCORD Study Group. ACCORD Eye Study Group. Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, Hubbard L, Esser BA, Lovato JF, Perdue LH, Goff DC Jr, Cushman WC, Ginsberg HN, Elam MB, Genuth S, Gerstein HC, Schubart U, Fine LJ. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-244.
52. Hamren B, Ohman KP, Svensson MK, Karlsson MO. 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.
53. Ratner RE, 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.
54. Oleksiewicz MB, Thorup I, Nielsen HS, Andersen HV, Hegelund AC, Iversen L, Guldberg TS, Brinck PR, Sjogren I, Thinggaard UK, Jørgensen L, Jensen MB. Generalized cellular hypertrophy is induced by a dual-acting PPAR agonist in rat urinary bladder urothelium in vivo. Toxicol Pathol 2005;33:552-560.
55. Long GG, Reynolds VL, Lopez-Martinez A, Ryan TE, White SL, Eldridge SR. 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.
56. Kendall DM, Rubin CJ, Mohideen P, Ledeine JM, Belder R, Gross J, Norwood P, O'Mahony M, Sall K, Sloan G, Roberts A, Fiedorek FT, DeFronzo RA. Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a double-blind, randomized, pioglitazone-comparative study. Diabetes Care 2006;29:1016-1023.
57. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294:2581-2586.
58. Cavender MA, Lincoff AM. Therapeutic potential of aleglitazar, a new dual PPAR-α/γ agonist: implications for cardiovascular disease in patients with diabetes mellitus. Am J Cardiovasc Drugs 2010;10:209-216.
59. Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 2009;374:126-135.
60. Wilding JP. PPAR agonists for the treatment of cardiovascular disease in patients with diabetes. Diabetes Obes Metab 2012;14:973-982.


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