Share this article on:

Fibrates in hypertension: where do we stand?

Gremmels, Hendrik; Joles, Jaap, A.

doi: 10.1097/HJH.0000000000001711
Editorial Commentaries

Department of Nephrology and Hypertension, UMCU, Utrecht, The Netherlands

Correspondence to Jaap A. Joles, DVM, PhD, Department of Nephrology and Hypertension, UMCU, Utrecht, The Netherlands. E-mail: j.a.joles@umcutrecht.nl

Received 5 February, 2018

Accepted 5 February, 2018

In 1993, Roman et al. [1] showed that the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist clofibrate reduced blood pressure in Dahl salt-sensitive rats on an 8% salt diet. Importantly, cessation of clofibrate caused a rebound of arterial pressure to baseline values, stressing that this was a direct and reversible effect. Subsequently, the same group and others have shown that in various models of salt-sensitive hypertension, both clofibrate and fenofibrate can prevent the development of a positive sodium balance or even reverse the sodium balance from positive to negative at a later stage [2–4]. There is also evidence that fenofibrate can reduce salt-sensitive hypertension in humans [5]. The signalling route from PPARalpha via Cyp4a induces the production of the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (HETE), which appears to be required for this natriuresis [6]. Salt-sensitive rodent models are listed in Table 1.

TABLE 1

TABLE 1

Moreover, rodent models of hypertension depending on activation of the renin–angiotensin system at normal salt intake such as angiotensin II infusion [7], reduced renal perfusion in the two-kidney one-clip model [8] or in abdominal aorta constriction between the left and right renal arteries [9] also show a fall in arterial pressure with fibrate treatment. Antihypertensive effects have also been reported at normal salt intake in the high-fat diet model of the metabolic syndrome wherever salt retention is also reversed [10]. Similar observations have often been reported in the deoxycorticosterone acetate-salt model [11] and at normal salt intake in spontaneously hypertensive rats (SHR) [12]. An overview of rodent studies with hypertension at normal salt intake is provided in Table 2.

TABLE 2

TABLE 2

So far so good; however, there are a number of observations, mostly to be found in Table 2, that do not fit easily into this picture. Fenofibrate would be expected to be ineffective whenever hypertension is induced in transgenic mice lacking PPARalpha. Alarmingly, however, PPARalpha-deficient mice show adverse effects of fenofibrate. This was first reported in 2007 in the thoracic aorta constriction (TAC) model of chronic pressure overload cardiac hypertrophy, diastolic heart failure and cardiac fibrosis [13]. Actually, the authors were expecting beneficial effects because of pleiotropic effects of fenofibrate, but in the PPARalpha-deficient mice, fenofibrate aggravated myocardial fibrosis and lung edema and decreased survival without any effect on blood pressure. Soon after, another group reported that in double transgenic renin and angiotensinogen Tsukuba hypertensive mice (THM), fenofibrate further increased blood pressure, whereas PPARalpha-deficient THM mice (obtained by double crossing the two strains) were in fact protected against hypertension, myocardial fibrosis and atherosclerosis [14]. Fenofibrate was also found to induce cardiac hypertrophy in mice lacking muscle ring finger-1 (MuRF1), an ubiquitin ligase and inhibitor of PPARalpha [15] that is essential in the setting of HETE, therapeutic regression of cardiac hypertrophy [16]. In SHR, two more recent reports document adverse cardiac remodelling and hypertrophy, as well as fibrosis and oxidative stress even though arterial pressure was reduced [12,17]. Although there remains substantial unexplained heterogeneity in response to fibrates, it appears that setting of preexistent or stimulated left ventricular hypertrophy, fenofibrate can have unfavourable pleiotropic effects.

Studies with fibrates in humans show inconsistent results on blood pressure. A few smaller studies show a reduction in BP in dyslipidemic patients [18–20]. Larger and controlled studies failed to replicate this effect, however [21–25]. A study by Subramanian et al. [26] even showed an increase in BP after fenofibrate administration in healthy controls. Although many of the smaller, positive studies may suffer from confounding because of a lack of control group, an elegant cross-over study by Gilbert et al. [5] showed that there may only be a responsive subgroup in patients with salt-sensitive hypertension.

Clinical results in the primary and secondary prevention of cardiovascular events using fibrates show modest and heterogeneous, but overall positive results [27]. It must be noted, however, that a substantial part of the evidence for clinical efficacy is from studies with clofibrate, which has been discontinued because of safety concerns [28]. In accordance with animal studies, primary prevention – where there is little end-organ damage – has also been explored with positive results, though numbers-needed-to-treat are large [29].

It is not inconceivable that, similar to animals, there is only a subgroup of patients that will respond favourably to fibrates. More alarmingly, the above-mentioned preclinical results suggest that fibrates may be actually harmful in certain conditions. For these reasons, it is of great importance that exact indications and the nature of pleiotropic effects of fibrates are further specified.

In the current issue of the Journal of Hypertension, Castiglioni et al. [30] administered fenofibrate to stroke-prone SHR (SHRSP) on the so-called Japanese high-salt diet (1% NaCl in drinking water). Interestingly, in young SHRSP treated from 2 to 4 months of age, they found beneficial antifibrotic cardiac and renal effects with improved systolic and diastolic function and prevention of proteinuria of concomitant fenofibrate treatment. However, no experiments were performed in older SHRSP. As previously reported by this group, survival in male SHRSP on this high-salt diet is poor [31,32]. However, female SHRSP appears to have a longer survival and thus more opportunity to develop chronic cardiac and renal injury [33]. In the context of the potential adverse effects of fibrates in the setting of preexistent target-organ damage, it would be interesting to start the high-salt diet at 6 weeks of age, but to delay initiation of fibrates to a later age in female SHRSP, for example, to 3 months of age, to probe whether the beneficial effects of fenofibrate on preexistent target-organ damage are then still present.

Back to Top | Article Outline

ACKNOWLEDGEMENTS

The authors are supported by the Netherlands Cardiovascular Research Initiative: an initiative supported by the Dutch Heart Foundation (CVON2014-11 RECONNECT).

Back to Top | Article Outline

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

REFERENCES

1. Roman RJ, Ma YH, Frohlich B, Markham B. Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. Hypertension 1993; 21:985–988.
2. Wilson TW, Alonso-Galicia M, Roman RJ. Effects of lipid-lowering agents in the Dahl salt-sensitive rat. Hypertension 1998; 31:225–231.
3. Zhou Y, Luo P, Chang H-H, Huang H, Yang T, Dong Z, et al. Colfibrate attenuates blood pressure and sodium retention in DOCA-salt hypertension. Kidney Int 2008; 74:1040–1048.
4. Cruz A, Rodríguez-Gómez I, Pérez-Abud R, Vargas MÁ, Wangensteen R, Quesada A, et al. Effects of clofibrate on salt loading-induced hypertension in rats. BioMed Res Int 2010; 2011:1–8.
5. Gilbert K, Nian H, Yu C, Luther JM, Brown NJ. Fenofibrate lowers blood pressure in salt-sensitive but not salt-resistant hypertension. J Hypertens 2013; 31:820–829.
6. Moreno C, Maier KG, Hoagland KM, Yu M, Roman RJ. Abnormal pressure-natriuresis in hypertension: role of cytochrome P450 metabolites of arachidonic acid. Am J Hypertens 2001; 14:90S–97S.
7. Diep QN, Benkirane K, Amiri F, Cohn JS, Endemann D, Schiffrin EL. PPAR alpha activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin II-infused rats. J Mol Cell Cardiol 2004; 36:295–304.
8. Sporková A, Čertíková Chábová V, Doleželová Š, Jíchová Š, Kopkan L, Vaňourková Z, et al. Fenofibrate attenuates hypertension in Goldblatt hypertensive rats: role of 20-hydroxyeicosatetraenoic acid in the nonclipped kidney. Am J Med Sci 2017; 353:568–579.
9. Ibarra-Lara L, Cervantes-Pérez LG, Pérez-Severiano F, del Valle L, Rubio-Ruíz E, Soria-Castro E, et al. PPARα stimulation exerts a blood pressure lowering effect through different mechanisms in a time-dependent manner. Eur J Pharmacol 2010; 627:185–193.
10. Zhou Y, Huang H, Chang H-H, Du J, Wu JF, Wang C-Y, et al. Induction of renal 20-hydroxyeicosatetraenoic acid by clofibrate attenuates high-fat diet-induced hypertension in rats. J Pharmacol Exp Ther 2006; 317:11–18.
11. Newaz M, Blanton A, Fidelis P, Oyekan A. NAD(P)H oxidase/nitric oxide interactions in peroxisome proliferator activated receptor (PPAR)(-mediated cardiovascular effects. Mutat Res 2005; 579:163–171.
12. Purushothaman S, Sathik MM, Nair RR. Reactivation of peroxisome proliferator-activated receptor alpha in spontaneously hypertensive rat: age-associated paradoxical effect on the heart. J Cardiovasc Pharmacol 2011; 58:254–262.
13. Duhaney T-AS, Cui L, Rude MK, Lebrasseur NK, Ngoy S, De Silva DS, et al. Peroxisome proliferator-activated receptor (-independent actions of fenofibrate exacerbates left ventricular dilation and fibrosis in chronic pressure overload. Hypertension 2007; 49:1084–1094.
14. Tordjman KM, Semenkovich CF, Coleman T, Yudovich R, Bak S, Osher E, et al. Absence of peroxisome proliferator-activated receptor-α abolishes hypertension and attenuates atherosclerosis in the Tsukuba hypertensive mouse. Hypertension 2007; 50:945–951.
15. Parry TL, Desai G, Schisler JC, Li L, Quintana MT, Stanley N, et al. Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1. Cardiovasc Pathol 2016; 25:127–140.
16. Willis MS, Rojas M, Li L, Selzman CH, Tang R-H, Stansfield WE, et al. Muscle ring finger 1 mediates cardiac atrophy in vivo. Am J Physiol Heart Circ Physiol 2009; 296:H997–H1006.
17. Ismael S, Purushothaman S, Harikrishnan VS, Nair RR. Ligand specific variation in cardiac response to stimulation of peroxisome proliferator-activated receptor-alpha in spontaneously hypertensive rat. Mol Cell Biochem 2015; 406:173–182.
18. Jonkers IJ, de Man FH, van der Laarse A, Frölich M, Gevers Leuven JA, Kamper AM, et al. Bezafibrate reduces heart rate and blood pressure in patients with hypertriglyceridemia. J Hypertens 2001; 19:749–755.
19. Kim Il J, Tsujino T, Fujioka Y, Saito K, Yokoyama M. Bezafibrate improves hypertension and insulin sensitivity in humans. Hypertens Res 2003; 26:307–313.
20. Idzior Walus B, Sieradzki J, Rostworowski W, Zdzienicka A, Kawalec E, Wójcik J, et al. Effects of comicronised fenofibrate on lipid and insulin sensitivity in patients with polymetabolic syndrome X. Eur J Clin Invest 2000; 30:871–878.
21. Ohta Y, Kawano Y, Iwashima Y, Hayashi S, Yoshihara F, Nakamura S. Effect of bezafibrate on office, home and ambulatory blood pressure in hypertensive patients with dyslipidemia. J Hum Hypertens 2013; 27:417–420.
22. Evans M, Anderson RA, Graham J, Ellis GR, Morris K, Davies S, et al. Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus. Circulation 2000; 101:1773–1779.
23. Hiukka A, Westerbacka J, Leinonen ES, Watanabe H, Wiklund O, Hulten LM, et al. Long-term effects of fenofibrate on carotid intima-media thickness and augmentation index in subjects with type 2 diabetes mellitus. J Am Coll Cardiol 2008; 52:2190–2197.
24. Hamilton SJ, Chew GT, Davis TME, Watts GF. Fenofibrate improves endothelial function in the brachial artery and forearm resistance arterioles of statin-treated Type 2 diabetic patients. Clin Sci 2010; 118:607–615.
25. Ye P, Li J-J, Su G, Zhang C. Effects of fenofibrate on inflammatory cytokines and blood pressure in patients with hypertriglyceridemia. Clinica Chimica Acta 2005; 356:229–232.
26. Subramanian S, DeRosa MA, Bernal-Mizrachi C, Laffely N, Cade WT, Yarasheski KE, et al. PPARα activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans. Am J Physiol-Endoc M 2006; 291:E1365–E1371.
27. Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010; 375:1875–1884.
28. Wang D, Liu B, Tao W, Hao Z, Liu M. Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane Database Syst Rev 2015. CD009580.
29. Jakob T, Nordmann AJ, Schandelmaier S, Ferreira González I, Briel M. Fibrates for primary prevention of cardiovascular disease events. New Jersey: John Wiley & Sons, Ltd; 2016.
30. Castiglioni L, Pignieri A, Fiaschè M, Giudici M, Crestani M, Mitro N, et al. Fenofibrate attenuates cardiac and renal alterations in young salt-loaded spontaneously hypertensive stroke-prone rats through mitochondrial protection. J Hypertens 2018; 36:1129–1146.
31. Gelosa P, Banfi C, Gianella A, Brioschi M, Pignieri A, Nobili E, et al. Peroxisome proliferator-activated receptor α agonism prevents renal damage and the oxidative stress and inflammatory processes affecting the brains of stroke-prone rats. J Pharmacol Exp Ther 2010; 335:324–331.
32. Rubattu S, Stanzione R, Bianchi F, Cotugno M, Forte M, Ragione Della F, et al. Reduced brain UCP2 expression mediated by microRNA-503 contributes to increased stroke susceptibility in the high-salt fed stroke-prone spontaneously hypertensive rat. Cell Death Dis 2017; 8:e2891.
33. Ballerio R, Gianazza E, Mussoni L, Miller I, Gelosa P, Guerrini U, et al. Gender differences in endothelial function and inflammatory markers along the occurrence of pathological events in stroke-prone rats. Exp Mol Pathol 2007; 82:33–41.
34. Iglarz M, Touyz RM, Viel EC, Paradis P, Amiri F, Diep QN, et al. Peroxisome proliferator-activated receptor-alpha and receptor-gamma activators prevent cardiac fibrosis in mineralocorticoid-dependent hypertension. Hypertension 2003; 42:737–743.
35. Iglarz M. Effect of peroxisome proliferator-activated receptor-alpha and -gamma activators on vascular remodeling in endothelin-dependent hypertension. Arterioscler Thromb Vasc Biol 2002; 23:45–51.
36. Lebrasseur NK, Duhaney T-AS, De Silva DS, Cui L, Ip PC, Joseph L, et al. Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension. Hypertension 2007; 50:489–496.
37. Lee DL, Wilson JL, Duan R, Hudson T, El-Marakby A. Peroxisome proliferator-activated receptor-α activation decreases mean arterial pressure, plasma interleukin-6, and COX-2 while increasing renal CYP4A expression in an acute model of DOCA-salt hypertension. PPAR Res 2011; 2011:502631.
    38. Ogata T, Miyauchi T, Sakai S, Takanashi M, Irukayama-Tomobe Y, Yamaguchi I. Myocardial fibrosis and diastolic dysfunction in deoxycorticosterone acetate-salt hypertensive rats is ameliorated by the peroxisome proliferator-activated receptor-alpha activator fenofibrate, partly by suppressing inflammatory responses associated with the nuclear factor-kappa-b pathway. J Am Coll Cardiol 2004; 43:1481–1488.
    39. Weng H, Ji X, Endo K, Iwai N. Pex11a deficiency is associated with a reduced abundance of functional peroxisomes and aggravated renal interstitial lesions: novelty and significance. Hypertension 2014; 64:1054–1060.
    40. Sankaralingam S, Desai KM, Glaeser H, Kim RB, Wilson TW. Inability to upregulate cytochrome P450 4A and 2C causes salt sensitivity in young Sprague-Dawley rats. Am J Hypertens 2006; 19:1174–1180.
    41. Ichihara S, Obata K, Yamada Y, Nagata K, Noda A, Ichihara G, et al. Attenuation of cardiac dysfunction by a PPAR-α agonist is associated with down-regulation of redox-regulated transcription factors. J Mol Cell Cardiol 2006; 41:318–329.
    42. Hou X, Shen YH, Li C, Wang F, Zhang C, Bu P, et al. PPARα agonist fenofibrate protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress and MAPK activity. Biochem Biophys Res Commun 2010; 394:653–659.
    43. Li J, Stier CT, Chander PN, Manthati VL, Falck JR, Carroll MA. Pharmacological manipulation of arachidonic acid-epoxygenase results in divergent effects on renal damage. Front Pharmacol 2014; 5:187.
      44. Banks T, Oyekan A. Peroxisome proliferator-activated receptor α activation attenuated angiotensin type 1-mediated but enhanced angiotensin type 2-mediated hemodynamic effects to angiotensin II in the rat. J Hypertens 2008; 26:468–477.
      45. Ciuceis C, Amiri F, Iglarz M, Cohn JS, Touyz RM, Schiffrin EL. Synergistic vascular protective effects of combined low doses of PPARα and PPARγ activators in angiotensin II-induced hypertension in rats. Br J Pharmacol 2007; 151:45–53.
      46. Vera T, Taylor M, Bohman Q, Flasch A, Roman RJ, Stec DE. Fenofibrate prevents the development of angiotensin ii–dependent hypertension in mice. Hypertension 2005; 45:730–735.
      47. Jíchová Š, Doleželová Š, Kopkan L, Kompanowska-Jezierska E, Sadowski J, Červenka L. Fenofibrate attenuates malignant hypertension by suppression of the renin-angiotensin system: a study in Cyp1a1-Ren-2 transgenic rats. Am J Med Sci 2016; 352:618–630.
      48. Muller DN, Theuer J, Shagdarsuren E, Kaergel E, Honeck H, Park J-K, et al. A peroxisome proliferator-activated receptor-α activator induces renal CYP2C23 activity and protects from angiotensin ii-induced renal injury. Am J Pathol 2004; 164:521–532.
      49. Cervantes-Pérez LG, Ibarra-Lara ML, Rubio ME, Escalante B, Pérez-Severiano F, Soria-Castro E, et al. Effect of clofibrate on vascular reactivity in a model of high blood pressure secondary to aortic coarctation. Pharmacol Rep 2010; 62:874–882.
        50. Ibarra-Lara L, Del Valle-Mondragón L, Soria-Castro E, Torres-Narváez JC, Pérez-Severiano F, Sánchez-Aguilar M, et al. Peroxisome proliferator-activated receptor-α stimulation by clofibrate favors an antioxidant and vasodilator environment in a stressed left ventricle. Pharmacol Rep 2016; 68:692–702.
          51. Huang H, Morisseau C, Wang J, Yang T, Falck JR, Hammock BD, et al. Increasing or stabilizing renal epoxyeicosatrienoic acid production attenuates abnormal renal function and hypertension in obese rats. Am J Physiol Renal Physiol 2007; 293:F342–F349.
          52. Chung HW, Lim JH, Kim MY, Shin SJ, Chung S, Choi BS, et al. High-fat diet-induced renal cell apoptosis and oxidative stress in spontaneously hypertensive rat are ameliorated by fenofibrate through the PPARα–FoxO3a–PGC-1α pathway. Nephrol Dial Transplant 2012; 27:2213–2225.
          53. Mahmoud AAA, Elshazly SM. Ursodeoxycholic acid ameliorates fructose-induced metabolic syndrome in rats. PLoS One 2014; 9:e106993.
          54. Nagai Y, Nishio Y, Nakamura T, Maegawa H, Kikkawa R, Kashiwagi A. Amelioration of high fructose-induced metabolic derangements by activation of PPAR(. Am J Physiol Endocrinol Metab 2002; 282:E1180–E1190.
          55. Li CB, Li XX, Chen YG, Zhang C, Zhang MX, Zhao XQ, et al. Effects and mechanisms of PPARα activator fenofibrate on myocardial remodelling in hypertension. J Cell Mol Med 2009; 13:4444–4452.
          56. Yousefipour Z, Newaz M. PPARα ligand clofibrate ameliorates blood pressure and vascular reactivity in spontaneously hypertensive rats. Acta Pharmacol Sin 2014; 35:476–482.
          57. Yi W, Fu P, Fan Z, Aso H, Tian C, Meng Y, et al. Mitochondrial HMG-CoA synthase partially contributes to antioxidant protection in the kidney of stroke-prone spontaneously hypertensive rats. Nutrition 2010; 26:1176–1180.
          Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.