Effects of Enalapril vs losartan on uric acid concentrations in patients with metabolic syndrome Iraqi J Pharm Sci, Vol.20(2) 2011 Losartan versus enalapril on serum uric acid levels 75 Effects of Losartan versus Enalapril on Serum Uric Acid Levels in Hypertensive Patients with Metabolic Syndrome # Zeina A. A. Al-Thanoon* ,1 and Isam H. Mahmood** * Department of Pharmacology, College of Pharmacy, University of Mosul, Mosul, Iraq. ** Department of Pharmacology, College of Medicine, University of Mosul, Mosul, Iraq. Abstract To investigate the effects of losartan and enalapril on serum uric acid in hypertensive patients with metabolic syndrome, one hundred and twenty six newly diagnosed mild hypertensive patients, having markers of metabolic syndrome included in the study. The patients were divided into two groups. Group 1 (60 patients) was given losartan (50 mg/ day) and group 2 (66 patients) enalapril (20 mg/ day) for a duration of 2 months. A control group of seventy apparently healthy individuals were included. Metabolic syndrome was diagnosed according to diagnostic criteria of metabolic syndrome related to the American National Cholesterol Education Program-Adult Treatment Panel III. Serum uric acid levels were measured before and after drug administration. The results revealed a significant higher levels of uric acid were found in the hypertensive patients as compared with control group and a significant drop of uric acid was noted after treatment with losartan but not with enalapril. In conclusions: this study demonstrates significantly higher serum uric acid concentrations in hypertensive patients having markers of metabolic syndrome. Losartan but not enalapril therapy produced a significant fall in the serum uric acid level. Losartan can be useful therapeutic agent to control blood pressure and to reduce serum uric acid level in hypertensive patients having markers of metabolic syndrome and hyperuricaemia. Key words: Hypertension, metabolic syndrome, uric acid, losartan, enalapril. الخالصة عهً يسخىي انحايِط انبىنٍ فٍ يصم انذو نذي يزظً ارحفاع ظغػ انذوِّ اإلَاالبزَمنخَحّزٌ حأثُزاِث عقارٌ انهىسارحاٌ و ونذَهى عالياث انعانٍ يٍ انُىع انخفُف بانعغػ إصابخهى حذَثا يزَعا شخصىا 1ٕٔعهً وانًخالسيت األَعُِت، أخزَج هذِ انذراست . أعطُج انًدًىعت األونً عقار انهىسارحاٌ يج يدًىعت انًزظً إنً يدًىعخاٌ حسب انعالج انًعطً نهى. قس انًخالسيت األَعُتِ يٍ سهًُا شخصا 0ٓ خخُارإحى يهغ َىيُا، .أسخغزقج فخزة انعالج يذة شهزٍَ. ٕٓيهغ َىيُا، وانًدًىعت انثاَُت عقار اإلَاالبزَم 0ٓ بزَايح انىغٍُ نخعهُى ان يعاَُزيدًىعت انعبػ. شخصج انًخالسيت األَعُت حسب انًخطىعٍُ )َبذوٌ أصحاء( غبُعٍ انعغػ نُكىَىا نكم يٍ يدًىعت انًزظً) قبم وبعذ انعالج( ويدًىعت انعبػ. أظهزث انحايط انبىنٍيسخىي قُاس انكىنسخزول األيزَكٍ. حى ٍِ فٍ يصم انذو نذي يزظً ارحفاع ظغػ انذوَّ بانًقارَت يع يدًىعت انعبػانَُخائِح ارحفاعا يعُىَا يهحىظا فٍ يسخىي انحايِط انبىن ٍِ بعذ انًعاندت بعقار انهىسارحاٌ نكٍ نََُس َيع عقار األَاالبزَم. فٍ االسخُخاخاث: أظهزث واَخ فاظا يعُىَا فٍ يسخىي انحايِط انبىن ٍِ فٍ يصم انذو نذي يزظً إرحفاع ظغػ انذوَّ وانذٍَ نذَهى هذِ انذراسِت أٌ هُاك ارحفاعا يعُىَا يهحىظا فٍ يسخىي انحايِط انبىن يهحىظ فٍ يسخىي اَخفاض يعُىٌإنً يِت األَعُِت. أدي انعالج بعقار انهىسارحاٌ نكٍ نََُس انعالَج بعقار األَاالبزَمعالياُث انًخالس َُْطَزة عهً ظغِػ انذّو ونخَخفُط يسخىي انحايِط ٌَ انهىسارحاٌ عالّخاً يفُذاً نهَس ٌْ ََُكى ٍُ أَ ٍِ فٍ يصم انذو. ًَُك انبىنٍ فٍ انحايِط انبىن ٍ يزظً إرحفاع ظغػ انذوِّ وانذٍَ نذَهى عالياُث انًخالسيِت األَعُِت وفزغ انحايط انبىنٍ فٍ انذو.يصم انذو ف Introduction Some investigators have suggested that uric acid plays a causal role in the development of cardiovascular disease (1) whereas others have concluded that uric acid merely reflects other concomitant risk factors, such as hypertension, insulin resistance, obesity, or lipid abnormality (2) . Elevated serum uric acid concentrations are also found in healthy offspring of parents with coronary heart disease, indicating a possible causal relationship (3) . Krishnan et al (4) demonstrating that hyperuricemia increases the risk of developing hypertension by approximately 80%, independent of baseline blood pressure measurements, renal function, serum lipid levels, body mass index, proteinuria, alcohol use, and age. Johnson et al (5) reported that elevated uric acid level was observed in 40% to 60% of hypertensive subjects; similarly, hypertension was observed in 50% to 65% of subjects with gout. Johnson et al (6) reported that hyperuricemia was observed in 25% of treated hypertensive subjects, 50% of those without treatment, and 75% to 100% of those with malignant hypertension or renal dysfunction. # Based on oral presentation in the eighth scientific conference of the College of Pharmacy /University of Baghdad held in 23-24 February 2011. 1 Corresponding author E- mail : zeinaalkazaz@yahoo.com Received : 7/3/2011 Accepted : 19/7/2011 Iraqi J Pharm Sci, Vol.20(2) 2011 Losartan versus enalapril on serum uric acid levels 76 Serum uric acid (SUA) levels are often increased in subjects with MS. However, none of the proposed sets of diagnostic criteria include SUA levels in the definition of MS (7,8) . In 2001, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) published the most widely used set of diagnostic criteria. These criteria include elevated plasma triglyceride (TRG) levels (≥150 mg/dl[1.69 mmol/l]), decreased levels of high-density lipoprotein cholesterol (HDL-C) (<40 mg/dl[1.04 mmol/l] in men and <50 mg/dl[1.29 mmol/l] in women), elevated blood pressure (BP)(≥130/85 mm Hg), increased fasting plasma glucose levels (≥ 110 mg/dl [6.1 mmol/l]), and abdominal obesity (waist circumference >102 cm in men and >88 cm in women) (9) . It is possible that the increased cardiovascular disease risk associated with the MS is partially attributed to elevated circulating SUA concentration (7,8) . Large epidemiologic studies demonstrated that the prevalence of MS showed a graded increase according to SUA levels (10-12) . Moreover, SUA concentration was positively correlated with blood pressure (BP), body mass index, levels of fasting plasma glucose, triglycerides, high- sensitivity C-reactive protein, and inversely correlated with high density lipoprotein cholesterol levels (HDL-C) (8) . Many drugs have hypouricaemic properties, in addition to their main therapeutic effects. The oral weight loss agent sibutramine decreases serum uric acid in obese patients by 20% to 25% (13) . Similarly, in patients with type 2 diabetes and hyperuricemia, the insulin sensitizing agent troglitazone lowers serum uric acid by 20% to 25% (14) . Ramipril was found to increase the excretion of uric acid in a number of hypertensive patients (15) . The present study was conducted to investigate the effects of losartan compared with enalapril on uric acid levels in hypertensive patient having markers of metabolic syndrome. Patients and Methods One hundred and twenty six hypertensive patients having markers of metabolic syndrome participated in this study. They were divided into two groups according to the type of the drug taken. Group 1 was given losartan (Angizar 50mg, Micro Pharmaceutical Industries, Co. Ltd., India) in doses of 50mg daily. They are 28 males and 32 females, with a mean age of 56.68±6.32 years. Group 2 received enalapril (Enalapril 20mg, Asia Pharmaceutical Industries, Co. Ltd., Aleppo- Syria) in doses of 20 mg once daily. They are 30 males and 36 females with mean ages of 52.80±7.23 years. Another 70 healthy, non obese, normotensive individuals, age and gender matching with study patients, participated in the study as a control group. They were 34 males and 36 females, with mean age of 53.51±6.66 years. This open 2-month, controlled, comparative clinical trial was conducted on hypertensive patients having markers of metabolic syndrome who were seen at Ibn-Sina teaching hospital in Mosul, Iraq. The study protocol was approved by the Ethics Committees of the College of medicine and Mosul health administration. Non-diabetic patients with mild hypertension (Stage 1: Systolic 140 - 159 mmHg and Diastolic 90 - 99 mmHg) (16) , who met the diagnostic criteria of metabolic syndrome according to the American National Cholesterol Education Program-Adult Treatment Panel III (NCEP- ATP III) (9) were included in this study. Those with hepatic or renal diseases, pregnancy and lactation, hypertensive patients on antihypertensive therapy, hypersensitive patients on losartan or enalapril, gouty patients and inflammatory diseases such as rheumatoid arthritis were excluded. Markers of metabolic syndrome including, waist circumference, blood pressure, serum glucose concentration, triglycerides, and HDL-cholesterol were determined before and at the end of study period. The presence of 3 or more of such markers indicates metabolic syndrome state. Blood pressure was measured by standard mercury sphygmomanometer. Goal BP after treatment was less than 140/ 90 mmHg. Serum glucose concentration, total cholesterol, triglycerides, and HDL-cholesterol were measured by using special kits. LDL- cholesterol was calculated from Friedewald equation (17) . Serum uric acid concentration was measured at baseline and after 2 months therapy with losartan or enalapril by enzymatic method using a kit supplied by Biolabo laboratories (France). Statistical methods Standard statistical methods were used to determine the mean and standard deviation (SD). Paired student t-test was used to compare the results between before and after drug therapy. Unpaired t-test was used to compare the results of cases before and after losartan or enalapril therapy with control and to compare the results between losartan and enalapril treated groups.. The statistical results were considered significant at p=0.05 or less. Iraqi J Pharm Sci, Vol.20(2) 2011 Losartan versus enalapril on serum uric acid levels 77 Results Baseline measurement of waist circumference, Body mass index (BMI) , blood pressure, serum glucose concentrations and lipid profile of the patient's groups showed a significant elevation as compared with the control group, while HDL-cholesterol showed lowered values as compared with the controls ( P<0.001) (Table.1). Baseline uric acid levels were 306.69±67.72 µmol/l for losartan group and 302.94±56.86 µmol/l for enalapril group which showed a significant elevation (P<0.001) as compared with the control (284.95±76.52 µmol/l) (Table.1 and Table.3) respectively. Comparison of uric acid levels before and after 2 months of therapy by each drug showed a significant reduction in losartan group (P<0.001) (Table .2) but not in enalapril group (p=0.123) (Table .4). Comparison of uric acid levels between losartan group and enalapril group showed a significant reduction in the losartan group (P<0.001) as compared with the enalapril group (Table .5). Table 1: Comparison of data between control and losartan group ( before and after therapy). Parameters Mean  SD Control (n=70) Before (n=60) After (n=60) BMI (kg/m 2 ) 22.2  1.8 33.46  2.08*** 30.95  1.8*** Waist circum. (cm) 83.95  6.2 106.79  8.53*** 104.08  8.3*** SBP (mm Hg) 127.05  6.93 143.60  7.72*** 136.82  8.4*** DBP (mm Hg) 79.24  4.91 92.18  6.21*** 83.92  6.3*** FSG (mmol/L) 4.75  0.9 6.6  0.4*** 5.12  0.7*** Total-C (mmol/L) 4.45  0.63 5.28  0.74*** 4.65  0.8*** TG (mmol/L) 1.48  0.6 1.67  0.37 1.23  0.5* HDL-C (mmol/L) 1.60  0.28 1.32  0.32*** 1.54  0.4*** LDL-C (mmol/L) 2.20  0.70 3.20  0.67*** 2.84  0.8*** Uric acid ( mol/L) 284.95  76.52 306.69  67.72*** 275.92  61.63*** * Significant difference from control at p<0.05, ** at p<0.01 and *** at p<0.001 using unpaired t-test. Table 2 : Comparison of the effects of losartan before and after therapy . Parameters Mean  SD Before (n=60) After (n=60) p-value BMI (kg/m 2 ) 33.46  2.08 30.95  1.8*** <0.001 Waist circum. (cm) 106.79  8.53 104.08  8.3*** <0.001 SBP (mm Hg) 143.60  7.72 136.82  8.4*** <0.001 DBP (mm Hg) 92.18  6.21 83.92  6.3*** <0.001 FSG (mmol/L) 6.6  0.4 5.12  0.7*** <0.001 Total-C (mmol/L) 5.28  0.74 4.65  0.8 0.135(NS) TG (mmol/L) 1.67  0.37 1.23  0.5 0.240(NS) HDL-C (mmol/L) 1.32  0.32 1.54  0.4*** <0.001 LDL-C (mmol/L) 3.20  0.67 2.84  0.8 0.098(NS) Uric acid ( mol/L) 306.69  67.72 275.92  61.63*** <0.001 ***Significant difference at p<0.001 using paired t-test. NS= Not significant. Iraqi J Pharm Sci, Vol.20(2) 2011 Losartan versus enalapril on serum uric acid levels 78 Table 3:Comparison of data between control and enalapril group ( before and after therapy). Parameters Mean  SD Control (n=70) Before (n=66) After (n=66) BMI (kg/m 2 ) 22.2  1.8 32.79  1.9*** 30.6  2.18*** Waist circum. (cm) 83.95  6.2 103.44  8.87*** 100.8  8.53*** SBP (mm Hg) 127.05  6.93 145.78  5.39*** 136.95  7.58*** DBP (mm Hg) 79.24  4.91 91.44  6.15*** 86.07  5.0*** FSG (mmol/L) 4.75  0.9 6.55  0.38*** 5.35  0.66*** Total-C (mmol/L) 4.45  0.63 5. 40  0.93*** 5.42  0.76*** TG (mmol/L) 1.48  0.6 1.36  0.60 1.2  0.51* HDL-C (mmol/L) 1.60  0.28 1.40  0.3*** 1.57  0.32*** LDL-C (mmol/L) 2.20  0.70 3.26  0.72*** 3.27  0.99*** Uric acid ( mol/L) 284.95  76.52 302.94  56.86*** 289.99  50.28*** * Significant difference from control at p<0.05, ** at p<0.01 and *** at p<0.001 using unpaired t-test Table 4 : Comparison of the effects of enalapril before and after therapy . Parameters Mean  SD Before (n=60) After (n=60) p-value BMI (kg/m 2 ) 32.79  1.9 30.6  2.18*** <0.001 Waist circum. (cm) 103.44  8.87 100.8  8.53*** <0.001 SBP (mm Hg) 145.78  5.39 136.95  7.58*** <0.001 DBP (mm Hg) 91.44  6.15 86.07  5.0*** <0.001 FSG (mmol/L) 6.55  0.38 5.35  0.66*** <0.001 Total-C (mmol/L) 5. 40  0.93 5.42  0.76 0.205(NS) TG (mmol/L) 1.36  0.60 1.2  0.51 0.193(NS) HDL-C (mmol/L) 1.40  0.3 1.57  0.32 0.178(NS) LDL-C (mmol/L) 3.26  0.72 3.27  0.99 0.716(NS) Uric acid ( mol/L) 302.94  56.86 289.99  50.28 0.132(NS) ***Significant difference at p<0.001 using paired t-test. NS= Not significant. Table 5: Comparison of data after losartan and enalapril therapy. Parameters Mean  SD Losartan (n=60) Enalapril (n=66) p-value BMI (kg/m 2 ) 30.95  1.8 30.6  2.18 0.026 (NS) Waist circum. (cm) 104.08  8.3 100.8  8.53 0.605(NS) SBP (mm Hg) 136.82  8.4 136.95  7.58 0.134 (NS) DBP (mm Hg) 83.92  6.3 86.07  5.0* 0.05 FSG (mmol/L) 5.12  0.7 5.35  0.66* 0.05 Total-C (mmol/L) 4.65  0.8 5.42  0.76 0.120(NS) TG (mmol/L) 1.23  0.5 1.2  0.51 0.321(NS) HDL-C (mmol/L) 1.54  0.4 1.57  0.32 0.062(NS) LDL-C (mmol/L) 2.84  0.8 3.27  0.99 0.126(NS) Uric acid ( mol/L) 275.92  61.63 289.99  50.28*** <0.001 * Significant difference at p<0.05 and *** at p<0.001. NS= Not significant. Iraqi J Pharm Sci, Vol.20(2) 2011 Losartan versus enalapril on serum uric acid levels 79 Discussion The present study demonstrates significantly higher uric acid levels in subjects with metabolic syndrome as compared with the control group. These results are in consistent with the results obtained from many articles which also demonstrate increased levels of uric acid in patients with metabolic syndrome (8, 12, 18) . Several mechanisms were attributed to the increase of UA levels in MS. One of these mechanisms is related to insulin resistance, which is accompanied by MS. Proximal tubular reabsorption of UA occurs by an active transport mechanism closely linked to or identical with the tubular reabsorption of sodium. Insulin can enhance renal tubular sodium reabsorption in humans. Furthermore, renal excretion of UA is reduced in situations with increased renal tubular reabsorption of sodium . This relationship suggests an altered tubular sodium handling and uric acid metabolism which is constituent with hyperinsulinemia. Insulin resistance being the possible pathophysiological link (19) . Another mechanism for the increased SUA levels in MS is that MS is associated with increased oxidative stress (20) . Because uric acid is considered to be an effective antioxidant. The elevated SUA levels encountered in individuals with MS may reflect a compensatory mechanism counteracting the increased oxidative stress associated with the MS (21) .In the present study, only losartan causes a significant reduction of serum uric acid concentrations in patients with metabolic syndrome after 2 months of therapy. These results indicate that losartan have uricosuric effects. Many studies have demonstrated that the uricosuric effect of losartan was due to the parent compound and not to the active metabolite EXP 3174 and that this effect is independent of angiotensin II receptor blockade and is due to unique biochemical properties of losartan (22-24) . The hypouricemic effect of losartan may be due to that losartan target the urate anion exchange and diminish urate reabsorption in the proximal convoluted tubule; as a result, the urate excretion fraction is increased by 13%-30% and increases renal uric acid excretion (25) . This aspect of losartan therapy might have therapeutic advantages by reducing the risk of elevated uric acid in patient with MS, since elevated serum uric acid levels in patient with MS is regarded as a risk factor for the development of CV diseases (26) and may ameliorate hyperuricemia induced by other drugs. It was reported that the risk of death due to ischemic heart disease increased by 77% (men), and by 30% (women) when serum uric acid levels where in the highest quartile (>416 µmol/l) compared with the lowest quartile (<321 µmol/l) (27) . Data obtained from the present study showed that enalapril produce non significant effects on uric acid concentration in patients with metabolic syndrome. Data from the literature demonstrates different results. No effect was reported by Tikkanen et al., (28) , rise in SUA levels reported by De Rosa et al (29) , and and others demonstrates SUA lowering effect (8, 30) . In conclusion: This study demonstrates significantly higher serum uric acid levels in hypertensive patients having markers of metabolic syndrome. losartan therapy but not enalapril therapy produced a significant fall in serum uric acid levels. Losartan can be a useful therapeutic agent to reduce serum uric acid level in hypertensive patients having markers of metabolic syndrome and hyperuricaemia. References 1. Torun M, Yardim S, Simsek B, Burgaz S. Serum uric acid levels in cardiovascular diseases. J Clin Pharm Ther 1998; 23: 25- 29. 2. Tatli E, Aktoz M, Buyuklu M, Altun A. The relationship between coronary artery disease and uric acid levels in young patients with acute myocardial infarction. Cardiol J 2008; 15: 21-25. 3. Ronora F, Targher C, Zenere MB, Saggiani F, Cacciatori V, Tosi F, Travia D, Zenti MC, Branzi P, Santi I, Muggeo M. Relationship of uric acid concentration to cardiovascular risk factors in young men. Role of obesity and central fat distribution. Int J Obest Relat Met Disord 1996; 20: 975-980. 4. Krishnan E, Kwoh CK, Schumacher HR, Kuller L. Hyperuricemia and incidence of hypertension among men without metabolic syndrome. Hypertension 2007; 49: 298-303. 5. Johnson RJ, Feig DI, Herrera Acosta J, Kanog DH. Resurrection of uric acid as a causal risk factor in essential hypertension.Hypertension2005;45:18-20. 6. Johnson RJ, Segal MS, Srinivas T. Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link? J Am Soc Nephrol 2005; 16:1909- 1919. 7. Hoieggen A, Alderman MH, Kjeldsen SE, Julius S, Devereux RB, DeFaire U, et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004; 65: 1041-1049. 8. Tsouli SG, Liberropoulos EN, Mikhailidis DP, Athyros VG, Elisaf MS. Elevated serum uric acid levels in metabolic Iraqi J Pharm Sci, Vol.20(2) 2011 Losartan versus enalapril on serum uric acid levels 80 syndrome: an active componenet or an innocent bystander. Metab Clin and Exper 2006; 55: 1293-1301. 9. National Cholesterol Education Program- Adult Treatment Panel III. Executive summary of the Third Report (NCEP-ATP III) (2001). 10. Conen D, Wietlisbach V, Bovet P, Shamlaye C, Riesen W, Paccaud E, et al. Prevalence of hyperuricemia and relation of serum uric acid with cardiovascular risk factors in a developing country. BMC Public Health 2004; 4: 9-12. 11. Yoo TW, Sung KC, Shin HS, Kim BJ, Kim BS, Kang JH, et al. Relationship between serum uric acid concentration and insulin resistance and metabolic syndrome. Circulation 2005; 69: 928-933. 12. Lee JE, Kim YG, Choi YH, Huh W, Kim DJ, Oh HY. Serum uric acid is associated with microalbuminuria in prehypertension. Hypertension 2006; 47: 962-967. 13. McMahon FG, Fujioka K, Singh BN, Mendel CM, Rowe E, Rolston K, et al. Efficacy and safety of sibutramine in obese white and African American patients with hypertension: a 1-year, double-blind, placebo-controlled, multicenter trial. Arch Intern Med 2000; 160: 2185-2191. 14. Iwatani M, Wasada T, Katsumori K, Watanabe-Takahashi C, Kamatani N, Iwamoto Y. Troglitazone decreases serum uric acid concentrations in type II diabetic patients and non diabetics. Diabetologia 2000; 43: 814-815. 15. Labeeuw M, Pozet N, Zech PY, Hadj- Aissa A, Finaxz de Villaine J, Luville M. Influence of acute administration of ramipril on the excretion of uric acid. Arch mal Coeur Vaiss 1987; 80: 870-874. 16. The seventh report of the joint national committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (express). National Heart, Lung, and Blood Institute (JNC-7). NIH Publication 2003, No.03-5233: 25-32. 17. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of LDL-C in plasma without use of preparative ultracentrifuge. Clin Chem 1972; 18: 499- 502. 18. Schmidt MI, Duncan BB, Watson RL, Sharrett AR, Brancati FL, Heiss G. A metabolic syndrome in whites and African-Americans. The Atherosclerosis Risk in Communities baseline study. Diabetes Care1996; 19:414-418. 19. Cappuccio FP, Strazzullo P, Farinaro E, Trevisan M. Uric acid metabolism and tubular sodium handling. Results from a population-based study. JAMA 1993; 270; 354-359. 20. Evans JI, Maddux BA, Goldfine ID. The moleculer basis for oxidative stress induced insulin resistances . Antioxid Redox Signal2005; 7:1040-1052. 21. Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis?Atherosclerosis 2000; 148:131-139. 22. Liberopoulos EN, Christides D, Elisaf M. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricemia and gout. J Hypertens 2002; 20:347-351. 23. Alderman M, Aiyer KJ. Uric acid: role in cardiovascular disease and effects of losartan. Curr Med Res Opin 2004; 20:369-379. 24. Rayner BL, Trinder YA, Baines D, Isaacs S, Opie LH. Effect of losartan versus candesartan on uric acid, renal function, and fibrinogen in patients with hypertension and hyperuricemia associated with diuretics. Am J Hypertens2006; 19:208-213. 25. John DB, Mike AC. Serum Uric acid- lowering therapies: where are we heading in management of hyperuricaemia and the potential role of uricase. Curr Rheum rep 2004; 6:240-247. 26. Puddu PE, Lanti M, Menotti A, Mancini M, Zanchetti A, Cirillo M, et al. Serum uric acid for short-term prediction of cardiovascular disease incidence in the Gubbio population Study. Gubbio Study Research Group. Acta Cardiol 2001; 56:243-251. 27. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality. JAMA 2000; 283: 2404-2410. 28. Tikkanen I, Omvik P, Jensen HA. Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension. J Hypertens1995; 13:1343-1351. 29. De Rosa M, Cardace P, Rossi M, Baiano A, de Cristofaro A. Comparative effects of chronic ACE inhibition and AT1 receptor blocker losartan on cardiac hypertrophy and renal function in hypertensive patients. J Hum Hypertens 2002; 16:133- 140. 30. Reyes AJ. Cardiovascular drugs and serum uric acid. 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