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Effect of Micronized Fenofibrate and Losartan Combination on Uric Acid Metabolism in Hypertensive Patients with Hyperuricemia

Elisaf, M.; Tsimichodimos, V.; Bairaktari, E.*; Siamopoulos, K. C.

Journal of Cardiovascular Pharmacology: July 1999 - Volume 34 - Issue 1 - p 60-63

It has been reported that micronized fenofibrate and losartan can significantly decrease serum uric acid levels by augmenting uric acid excretion. We undertook this study to evaluate the effects of the combination treatment with micronized fenofibrate and losartan in nondiabetic hypertensive dyslipidemic patients with hyperuricemia (serum uric acid, >7 mg/dl). A total of 25 patients (15 men, 10 women) aged 21-66 years was studied. In all patients, serum lipid parameters, including Lp(a), fibrinogen, and uric acid levels, as well as fractional excretion of uric acid (FEUA) were obtained before treatment, 8 weeks after micronized fenofibrate treatment (200 mg daily), and 8 weeks after combination therapy with micronized fenofibrate (200 mg daily) and losartan (50 mg daily). Fenofibrate alone significantly decreased total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, Apo B, Lp(a), fibrinogen, and uric acid levels (from 7.6 ± 0.55 to 5.6 ± 0.5 mg/dl; p < 0.0001) and increased high-density lipoprotein (HDL) cholesterol, Apo A1, and FEUA (from 6.5 ± 1.8% to 12.2 ± 4%; p < 0.0001). The addition of losartan beyond the decrease in blood pressure values did not significantly alter serum metabolic parameters. However, a small additional decrease in serum uric acid levels (from 5.6 ± 0.5 to 4.9 ± 1 mg/dl; p < 0.05) was found because of a further increase in FEUA (from 12.2 ± 4% to 14 ± 5.5%; p < 0.05). It is concluded that the combination of micronized fenofibrate and losartan is useful for the management of patients with multiple metabolic abnormalities, including hyperuricemia.

Department of Internal Medicine and *Biochemistry Laboratory, Medical School, University of Ioannina, Ioannina, Greece

Received November 2, 1998; revision accepted February 18, 1999.

Address correspondence and reprint requests to Dr. M. Elisaf at Department of Internal Medicine, Medical School, University of Ioannina, 451 10 Ioannina, Greece.

Increased uric acid concentrations in the blood are commonly encountered in essential hypertension and may be an independent risk factor for hypertension-associated morbidity and mortality (1-3). Additionally, lipid abnormalities, including increased triglyceride levels, also are found more frequently in untreated hypertensives than in normotensives (4,5). Furthermore, most studies have demonstrated a positive correlation between serum uric acid and triglyceride levels (6,7). Thus the coexistence of hypertension, dyslipidemia, and hyperuricemia is not uncommon, an association that may, in turn, reflect the presence of insulin resistance-induced polymetabolic syndrome (8). Along with the management of hypertension and dyslipidemia in these patients, every attempt should be made to reduce uric acid levels without medications by dietary manipulation and reduction of alcohol consumption. If these measures fail, treatment with a uric acid-reducing drug should be considered for the patient with high serum uric acid levels, a procedure that is costly and associated with a potential drug toxicity (9). It has been reported that fenofibrate and losartan can significantly decrease serum uric acid levels by augmenting uric acid excretion (10,11). We undertook this study to evaluate the effects of the combination treatment with micronized fenofibrate and losartan in nondiabetic hypertensive dyslipidemic patients with hyperuricemia.

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The study involved 25 adult patients with stage 1 untreated hypertension [blood pressure (BP), 140-159/90-99 mm Hg], mixed dyslipidemia (characterized by the following values measured in patients on a stable dietary regimen: total cholesterol, >200 mg/dl; LDL cholesterol, >130 mg/dl; and triglycerides, >200 and ≤400 mg/dl), and hyperuricemia (serum uric acid levels, >7 mg/dl). Patients' characteristics relevant to this study are described in Table 1. All participants were followed up as outpatients in the Lipid and Hypertension Clinic at our University Hospital. Each patient had normal hepatic and renal-function tests, and none had any other significant disease or laboratory abnormality that may have compromised his or her safety by participation in this study. Additional exclusion criteria included (a) diabetes mellitus (fasting plasma glucose, >126 mg/dl); (b) history of myocardial infarction or unstable angina; (c) thyroid dysfunction [thyroid-stimulating hormone (TSH) levels, >5 μU/ml at screening]; (d) consumption of drugs that may influence BP values, lipid parameters, or uric acid levels; and (e) physical or psychosocial disorders that could interfere with protocol adherence.



Patients were instructed to follow an American Heart Association step I diet and were admitted to this study if they met all of the criteria after initial dietary counseling and lifestyle recommendations for ≥8 weeks. At the same time, the patients were encouraged to follow a low-salt, high-potassium diet to control BP. Then they started micronized fenofibrate, 200 mg once daily, for 4 weeks. As at the end of this time, BP remained >140/90 mm Hg, losartan, 50 mg, once daily was added for another 4 weeks, whereas fenofibrate treatment was continued. At each visit, BP was measured, and fasting (14-h) blood samples were obtained for the determination of serum lipid parameters [total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein (Apo)A1, ApoB, Lp(a)], serum insulin, creatinine, and uric acid levels, and plasma glucose and fibrinogen levels. A fresh urine specimen also was obtained within 4 h after the losartan intake for the measurement of creatinine, sodium, and uric acid levels.

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Laboratory determinations

Serum cholesterol and triglyceride were determined by enzymatic colorimetric assay by using an RA 1000 analyzer (Technicon Instruments, New York, NY, U.S.A.), whereas HDL cholesterol was determined enzymatically in the supernatant after precipitation of other lipoproteins with dextran sulfate/magnesium. LDL cholesterol was calculated by using the Friedewald formula. Serum ApoA1 and ApoB were measured by immunonephelometry with the aid of a Beckman array analyzer (Beckman Instruments, Fullerton, CA, U.S.A.). Lp(a) levels were determined by the enzyme immunoassay Macra Lp(a) (Terumo Medical Corporation Diagnostic Division, Elkton, MD, U.S.A.). This assay used first a monoclonal antibody against Apo(a) that does not cross-react against plasminogen, and second, polyclonal antibody directed against the Apo(a) portion of Lp(a). The lower limit of detectability was 0.8 mg/dl. In cases of Lp(a) levels <0.8 mg/dl, the value of 0.8 mg/dl was used for statistical reasons. The intraassay and the interassay coefficients of variation were <6% and 10.3%, respectively. Plasma fibrinogen levels were measured by the Clauss method. Serum and urine uric acid levels were determined by a uricase/PAP method, whereas plasma glucose levels were measured by the hexokinase method. Finally, insulin levels were determined by a Microparticle Enzyme Immunoassay (Abbott Laboratories, Diagnostic Division, Tokyo, Japan). A standard formula was used for the calculation of the fractional excretion (FE) of uric acid.

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Statistical analysis

The results are expressed as mean ± SD. Because of the skewed distribution of Lp(a) and fibrinogen levels, their concentrations are given as median and range. Paired Students' t test or Wilcoxon signed-ranks test was used for statistical analysis. Correlation coefficients were obtained by linear regression analysis or by the nonparametric Spearman rank test, where appropriate. Statistical significance was accepted at p < 0.05.

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There was no significant change in mean body weight throughout the study, and every effort was made for the participants to sustain their dietary habits. As shown in Table 2, micronized fenofibrate decreased triglycerides by 33%, total cholesterol by 10.3%, LDL cholesterol by 13.4%, ApoB by 20.1%, and increased HDL cholesterol and ApoA1 levels by 11.1 and 10.6%, respectively. A small significant decrease in serum Lp(a) concentration also was found. Nevertheless, a significant decrease in median serum Lp(a) concentration was evident in patients with increased (>20 mg/dl) baseline Lp(a) concentration (n = 13; from a median value of 25.2 mg/dl to median value 21.6 mg/dl; p = 0.05). Plasma fibrinogen levels were significantly decreased after 4 weeks' treatment with fenofibrate in the 18 nonsmoker participants in the study. However, no correlation was found between the changes in serum triglycerides and plasma fibrinogen levels (r = 0.16; p = NS).



In our cohort, serum uric acid levels were not correlated with body weight, body mass index (BMI), BP, or serum lipid parameters, including triglycerides, but they were inversely correlated with the FE of uric acid (r = −0.31; p = 0.05). Micronized fenofibrate appeared to decrease serum uric acid levels by significantly increasing uric acid excretion (evidenced by a profound increase in the FE of uric acid). The addition of losartan beyond the decrease in BP values (from 153/98 to 146/91 mm Hg; p < 0.01; for both systolic and diastolic BP) did not significantly alter serum metabolic parameters. However, an additional decrease in serum uric acid levels (by ≈12.5%) was found, because of, at least in part, a further increase (by 14.8%) in uric acid excretion.

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In our study, micronized fenofibrate was highly effective in normalizing the atherogenic lipoprotein phenotype in these high-risk patients as a result of its pleiotropic actions on lipid and lipoprotein metabolism (12). It is noteworthy that fenofibrate evoked not only a decrease in serum triglyceride and an increase in serum HDL cholesterol and ApoA1 levels but also a smaller decrease in serum total and LDL cholesterol, as well as in ApoB levels. Interestingly, a small decrease in serum Lp(a) levels was observed in patients with increased baseline levels, a result in keeping with that previously reported with fenofibrate as well as with other fibrates (13,14). A substantial decrease in plasma fibrinogen levels, identified as an independent risk indicator for ischemic heart disease and the severity of atherosclerosis (15), also was observed after micronized fenofibrate administration, which was independent of the change in serum triglycerides, suggesting that the drug effect was not mediated through triglycerides (16).

In our cohort, hyperuricemia was associated with a decreased FE of uric acid (normal values in our population, 11.2-17.5%), implying that the increased serum uric acid levels were, at least in part, caused by decreased urine uric acid excretion. In fact, an increased urate proximal tubular reabsorption and a depressed renal tubular secretion in concert with sodium have been described in hypertensive patients (17,18). Additionally, because hypertriglyceridemia frequently coexists with hyperuricemia, even though no correlation between serum triglyceride and uric acid levels was found in our study, it is tempting to suggest that an increased urate production being stimulated by an increased triglyceride synthesis could have also contributed to the hyperuricemia observed (19). Furthermore, in our patients with a constellation of metabolic abnormalities insulin resistance is highly possible, and decreased insulin-induced uric acid excretion may account for the observed uric acid derangements (8,20,21).

Fenofibrate reduced serum uric acid levels by 26.3% by augmenting urine uric acid excretion, showing that its hypouricemic action is of sufficient magnitude to be clinically worthwhile. The significant decrease in serum uric acid levels is comparable to that observed in previous studies after treatment with conventional fenofibrate (300 mg/day) (10,22). Because the fenofibrate-induced decrease in serum uric acid levels was independent of serum triglycerides change, it is unlikely to be related to its lipid-lowering effect. Rather, our findings indicate that a substantial part, if not all, of the hypouricemic action of fenofibrate is renally mediated, because a pronounced increase in the FE of uric acid was noticed. Additionally, the fibrates tend to produce an improvement in glucose tolerance because of a decrease in insulin resistance mediated by a decrease in circulation levels of NEFA (23). The resulting decrease in insulin levels could have contributed to the uricosuria observed. However, this decrease in insulin resistance has been extensively documented for bezafibrate, which has not been found to influence renal uric acid clearance and uric acid levels (10). Additionally, even though we did not test insulin sensitivity, fasting blood glucose, and insulin levels did not change significantly throughout the study (Table 2).

The addition of losartan besides the decrease in BP values did not significantly alter serum metabolic parameters. However, a small additional decrease in serum uric acid levels due to a further increase in the FE of uric acid was found. Inconsistent results have been described concerning the effect of losartan on uric acid excretion, whereas some studies demonstrated a significant uricosuria with losartan (11,24,25), others failed to do so (26). However, experimental data clearly showed that the uricosuric activity of losartan is, at least in part, due to inhibition of urate reabsorption in the proximal tubule, is unrelated to angiotensin II-receptor activity, and it is caused by the patent compound rather than the metabolite (27). Furthermore, losartan has a greater affinity for the urate/anion exchanger than the other angiotensin II antagonist tested (27). It should be mentioned that the uricosuric effect is transient within the day and observed mainly during the 4-6 h after drug intake; that is why urine specimens were collected within 4 h from the drug intake (11,25).

Our data confirmed the mild uricosuric and hypouricemic effect of losartan, whereas for the first time, it is shown that combination therapy with fenofibrate and losartan demonstrates an additive hypouricemic action. It should be mentioned, however, that the exaggerated uricosuria could result in an increased risk of nephrolithiasis, a risk that can be minimized by maintaining a high fluid intake and by alkalizing the urine.

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Losartan; Micronized fenofibrate; Combination therapy; Hyperuricemia; Uricosuria

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