LEADER 497

Hypouricaemia increased not only clearance Ann Rheum Dis: first published as 10.1136/ard.62.6.497 on 1 June 2003. Downloaded from ...... but also the urinary of oxy- purinol, the main active metabolite of .721 This leads to the concern and that the combination of fenofibrate or losartan with allopurinol might lower T Bardin the hypouricaemic effect of allopurinol...... In the study published in this issue of the journal there was no significant differ- Should we take advantage of their properties in ence in the magnitude of the hypouri- ? caemic effect when fenofibrate or losar- clinical practice tan was added to allopurinol or

10 , suggesting that the he interesting study published in moderate, from 3 to 30%, and was not 1 11 drug interactions were negligible. this issue of the journal by Takahashi constantly observed. In some studies, In a short recent report, urate clear- Tet al sheds light on two drugs, losar- repeated dosing with losartan resulted in ance doubled after addition of fenofi- tan and fenofibrate, which have hypouri- a gradual waning of the uricosuric effect, brate to allopurinol,20 whereas it was caemic properties, in addition to their but moderate reduction of serum uric 1 only increased by 50% in the study by main therapeutic effects. 1 acid was maintained after 3–4 weeks of Takashashi et al. An explanation for this treatment.11 12 Losartan was also shown LOSARTAN milder effect may be that in the latter to reduce the increase in serum uric acid study the drug was given to patients Losartan potassium is an orally active 12–14 caused by hydrochlorothiazide, a whose uricaemia had been previously angiotensin II receptor antagonist used finding which might be of clinical effectively reduced by classic hypouricae- for the treatment of hypertension. This significance as long term use of mic drugs. Serum uric acid level is an product and its long life metabolite in hypertensive patients is a well known important factor of glomerular filtration E-3174 are potent antagonists at the AT1 cause of secondary . However, this receptor. The observation that losartan and excretion of uric acid. A effect was generally not sufficient to smaller amount of filtered urate might increases urinary uric acid excretion and totally normalise uricaemia. Losartan reduces serum uric acid level was first have decreased the ability of fenofibrate also significantly raises urine pH, an to inhibit urate tubular reabsorption. made in a pilot study conducted in interesting property, not shared by other healthy subjects and published in 1992. uricosuric drugs, which might counter- Uric acid fractional clearance was mainly EFFECT ON BLOOD PRESSURE balance the risk of uric acid stone associ- AND CARDIOVASCULAR DISEASE increased during the first four hours ated with increased uric acid excretion.12 after drug intake in a time course In the absence of gout, the usefulness of the uricosuric action of losartan and consistent with a direct effect of the FENOFIBRATE drug. The increase was found to be dose fenofibrate in the management of hyper- Fenofibrate is a lipid lowering drug, the dependent and to persist after seven days tension and dyslipidaemia, respectively, 2 uricosuric property of which was re- is still difficult to appreciate. Hyperuri- of administration. Angiotensin is 15 16 ported in 1980. Fenofibrate has been caemia is a common finding in both dis-

known to lower uric acid renal http://ard.bmj.com/ shown to approximately double uric acid clearance,3 but the uricosuric effect of eases, and the uricosuric property of clearance and to significantly reduce the losartan did not appear to be mediated these drugs may be seen as beneficial as serum uric acid level in healthy it would contribute to normalisation of by angiotensin inhibition: in one study, 15 17 volunteers, in diabetic and non-dia- the uricaemia in hypertensive and/or infusion of E-3174, the active metabolite 16 18 19 betic patients with hyperlipidaemia, hyperlipidaemic subjects. Essential of losartan, did not modify uric acid 20 excretion, although it efficiently de- and in patients with gout. Lowering of hypertension is associated with in- creased blood pressure.4 The early and serum uric acid level was constantly seen creased renal vascular resistance and transient uricosuric action of losartan across studies and was clinically signifi- tubular sodium reabsorption, which are on September 23, 2021 by guest. Protected copyright. was therefore attributed mainly to the cant, ranging from 20 to 46%. The urico- known to decrease urine uric acid mother compound. Further suggestions suric property is not shared by another excretion22 23 and explain the high fre- of an effect independent of angiotensin fibrate, bezafibrate, despite a similar quency of associated hyperuricaemia. II receptor blockade came from the activity in decreasing serum lipids, so Hypertension and hypertriglyceridaemia that it does not seem to be related to the are, together with hyperuricaemia, obes- observation that the uricosuric effect did 20 not vary with a sodium diet5 and was not lipid lowering effect of fibrates. ity, glucose intolerance, and type 2 seen with other angiotensin II receptor diabetes, frequently part of the insulin antagonists.6–8 COMBINATION WITH CLASSIC resistance syndrome. High serum levels URIC ACID LOWERING DRUGS of insulin in this syndrome increase “Losartan and E-3174 target the The study by Takahashi et al examines sodium reabsorption and decrease uric urate anion exchanger URAT1” the usefulness of the combination of acid renal excretion.24 Lowering of uri- these two uricosuric drugs with the more caemia in these patients would be Losartan and its metabolite E-3174 classic uric acid lowering drugs in the indicated if hyperuricaemia is a risk fac- were recently shown to target the urate management of gout.1 The results, al- tor for cardiovascular disease and/or anion exchanger URAT1 and inhibit though positive, are a little disappoint- hypertension. Many studies have aimed urate uptake by this transporter, thus ing, as the observed decreases in serum at determining if hyperuricaemia re- reducing urate reabsorption from the uric acid were more modest than ex- mains an independent risk factor for , which is the main site pected from published data: a mean of 54 cardiovascular disease after controlling of URAT1 in the human . The µmol/l (15% reduction) was observed for other accepted risk factors. The effect was of similar order to that of with fenofibrate and of 24 or 30 µmol/l results have been conflicting. Recent .9 (11–15% reduction) with losartan. Previ- studies, such as the Framingham In most clinical studies, losartan was ous studies of normal subjects by the study,25 found that uric acid is not an found to increase the fractional excre- same group of investigators showed that independent risk factor, whereas others, tion of uric acid. The increase was both losartan potassium and fenofibrate such as the NHAMES study,26 reached

www.annrheumdis.com 498 LEADER the opposite conclusion. Faced with this ...... a background of hydrochlorothiazide in Ann Rheum Dis: first published as 10.1136/ard.62.6.497 on 1 June 2003. Downloaded from difficulty, most doctors are of the opinion patients with hypertension. Hypertension Author’s affiliations 1995;26:112–17. that asymptomatic hyperuricaemia does T Bardin, Fédération de Rhumatologie, Hôpital 14 Schoenberger JA for the losartan research not deserve any treatment.27 However, lariboisière, 2 rue Ambroise Paré, 75010 Paris, group. Losartan with hydrochlorothiazide in France the treatment of hypertension. J Hypertens this view has been recently challenged 1995;13(suppl):S43–7. by the observation that experimental Correspondence to: Professor T Bardin; 15 Desager JP, Hullhoven R, Harvengt C. chronic hyperuricaemia in rats was [email protected] Uricosuric effect of fenofibrate in healthy volunteers. J Clin Pharmacol 1980;20:560–4. followed by the development of hyper- 16 Harvengt C, Heller F, Desager JP. tension, which could be prevented or REFERENCES Hypolipidemic and hypouricemic action of fenofibrate in various types of treated by lowering uricaemia with 1 Takahashi S, Moriwaki Y, Yamamoto T, hyperlipoproteinemia. Artery 1980;7:73–82. 28 Tsutsumi Z, Ka T, Fukuchi M. Effects of either allopurinol or . 17 Yamamoto T, Moriwaki Y, Takahashi S, combination treatment using Tsutsumi Z, Hada T. Effect of fenofibrate on anti-hyperuricaemic agents with fenofibrate plasma concentration and urinary excretion of “Chronic hyperuricaemia was and/or losartan on uric acid metabolism. Ann purine bases and oxypurinol. J Rheumatol followed by hypertension prevent- Rheum Dis 2003;52:572. 2001;28:2294–7. 2 Nakashima M, Uematsu T, Kosuge K, able by lowering uricaemia” 18 Bastow MD, Durrington PN, Ishola M. Kanamura M. Pilot study of the uricosuric Hypertriglyceridemia and : effect of DuP 753, a new angiotensin II effects of two fibric acid derivatives In this model, the increase in blood receptor antagonist, in healthy subjects. Eur J (bezafibrate and fenofibrate) in a double Clin Pharmacol 1992;42:333–5. blind, placebo-controlled trial. Metabolism pressure was mediated by increased jux- 3 Ferris TF, Gorden P. Effect of angiotensin and 1988;37:217–20. taglomerular renin expression. Hyperu- norepinephrine upon urate clearance in man. 19 Elsaf M, Tsichodimos V, Bairaktari E, ricaemia in rats was subsequently shown Am J Med 1968;44:359–65. Siamopoulos KC. Effect of micronized 4 Sweet CS, Bradstreet DC, Berman RS, Jallard fenofibrate and losartan combination on uric to cause glomerulosclerosis and renal N, Saenz A, Weidler DJ. Pharmacodynamic acid metabolism in hypertensive patients with arteriopathy, similar to the lesions seen activity of intravenous E-3174, an angiotensin hyperuricemia. J Cardiovasc Pharmacol in the kidneys of hypertensive patients.29 II antagonist, in patients with essential 1999;34:60–3. hypertension. Am J Hypertens 20 Hepburn AL, Kaye SA, Feher MD. These animal data are not directly trans- 1994;7:1035–40. Fenofibrate: a new treatment for posable to humans but suggest that 5 Burnier M, Rutschmann B, Nussberger J, hyperuricemia and gout? Ann Rheum Dis studies should be performed to investi- Versaggi J, Shahine S, Waeber B, et al. 2001;60:984–6. Salt-dependent renal effects of angiotensin II 21 Yamamoto T, Moriwaki Y, Takahashi S, gate the effect of uric acid lowering antagonist in healthy subjects. Hypertension Tsutsumi Z, Hada T. Effect of losartan drugs on blood pressure and cardiovas- 1993;22:339–47. potassium, an angiotensin II receptor cular disease in man. 6 Minghelli G, Seydoux C, Goy JJ, Burnier M. antagonist, on renal excretion of oxypurinol Uricosuric effect of the angiotensin II receptor and purine bases. J Rheumatol antagonist losartan in heart transplant 2000;27:2232–6. CONCLUSION recipients. Transplantation 1998;66:268–71. 22 Cappuccio FP, Strazzulo P, Farinaro E, In conclusion, the uricosuric effect of 7 Puig JG, Mateos F, Buno A, Ortega R, Trevisan M. Uric acid metabolism and tubular Rodriguez F, Dal-Ré R. Effect of esoprosartan sodium handling. Results from a losartan and fenofibrate may be viewed and losartan on uric acid metabolism in population-based study. JAMA by rheumatologists as an interesting patients with essential hypertension. J 1993;270:354–9. Hypertens 1999;17:1033–9. 23 Tykarski A. Evaluation of renal handling of property, which favours the choice of uric acid in essential hypertension: these drugs to treat hypertension and 8 Würzner G, Gerster JC, Chiolero A, Maillard M, Fallab-Stubi C-L, Brunner H R, et al. hyperuricemia related to decreased urate hyperlipidaemia when associated with Comparative effects of losartan and irbesartan secretion. Nephron 1991;59:364–8. 24 Reaven GM. The kidney: an unwilling

on serum uric acid in hypertensive patients http://ard.bmj.com/ gout. The uricosuric effect of these drugs accomplice in syndrome X. Am J Kidney Dis with hyperuricaemia and gout. J Hypertens should be kept in mind so that steps can 1997;30:928–31. 2001;19:1855–60. 25 Culleton BF, Larson MG, Kannel WB, Levy D. be taken to prevent potential uric acid 9 Enomoto A, Kimura H, Chairoungdua A, Serum uric acid and risk of cardiovascular lithiasis, although this side effect does Shigeta Y, Jutabha P, Cha SH, et al. disease and mortality: the Framingham heart not seem to have been observed thus far. Molecular identification of a renal urate-anion study. Ann Intern Med 1999;131:7–13. exchanger that regulates blood urate levels. Moreover, it should be emphasised that 26 Fang J, Alderman MH. Serum uric acid and Nature 2002;417:447–52. cardiovascular mortality. The NHAMES I these drugs are, at present, to be consid- 10 Burnier M, Roch-Ramel F, Brunner HR. Renal epidemiologic follow-up study 1971–1992. ered as mere adjuvant treatments of effects of angiotensin II receptor blockade in JAMA 2000;283:2404–10.

normotensive subjects. Kidney Int on September 23, 2021 by guest. Protected copyright. hyperuricaemia, as they, especially losar- 27 Liang MH, Fries JF. Asymtomatic 1996;49:1787–90. hyperuricemia: the case for conservative tan, have only a mild hypouricaemic 11 Grossman E, Peleg E, Caroll J, Shamiss A, management. Ann Intern Med effect and have not been registered for Rosenthal T. Hemodynamic and humoral effect 1978;88:666–70. the treatment of gout. Whether their use of the angiotensin II receptor antagonist 28 Mazzali M, Hughes J, Kim YG, Jefferson JA, losartan in essential hypertension. Am J Kang DH, Gordon KL, et al. Elevated uric acid might be interesting in the management Hypertens 1994;7:1041–4. increases blood pressure in the rat by a novel of asymptomatic hyperuricaemia associ- 12 Shaninfar S, Simpson RL, Carides AD, crystal-independent mechanism. Hypertension ated with dyslipidaemia and/or hyper- Thiyagarajan B, Nakagawa Y, Umans JG, et 2001;38:1101–6. al. Safety of losartan in hypertensive patients 29 Mazzali M, Kanellis J, Han L, Feng L, Chen tension remains to be clarified by specific with thiazide induced hyperuricemia. Kidney Q, Kang DH, et al. Hyperuricemia induces a studies. Int 1999;56:1879–95. primary renal arteriolopathy in rats by a blood 13 Soffer BA, Wright JT, Pratt H, Wiens B, pressure-independent mechanism. Am J Ann Rheum Dis 2003;62:497–498 Goldberg AI, Sweet CS. Effects of losartan on Physiol Renal Physiol 2002;282:F991–7.

www.annrheumdis.com