Uric Acid: Role in Cardiovascular Disease and Effects of Losartan
Studies suggest that serum uric acid is an important, independent risk factor for cardiovascular and renal disease especially in patients with hypertension, heart failure, or diabetes. Further, patients with hypertension and hyperuricemia have a 3- to 5-fold increased risk of experiencing coronary artery disease or cerebrovascular disease compared with patients with normal uric acid levels. Although the mechanisms by which uric acid may play a pathogenetic role in cardiovascular disease is unclear, hyperuricemia is associated with deleterious effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness, hemorheology, and aggregation.
Xanthine oxidase inhibitors (e.g., allopurinol) or a variety of uricosuric agents (e.g., probenecid, sulfinpyrazone, benzbromarone, and benziodarone) can lower elevated uric acid levels but it is unknown whether these agents reversibly impact cardiovascular outcomes.
However, the findings of the recent LIFE study in patients with hypertension and left ventricular hypertrophy suggest the possibility that a treatment-induced decrease in serum uric acid may indeed attenuate cardiovascular risk. LIFE showed that approximately 29% of the treatment benefit of a losartan-based versus atenolol-based therapy on the primary composite endpoint (death, myocardial infarction, or stroke) may be ascribed to differences in achieved serum uric acid levels. Overall, serum uric acid may be a powerful tool to help stratify risk for cardiovascular disease.
The losartan produces a uricosuric effect in healthy volunteers, hypertensive patients. Typically decreasing serum uric acid levels by 20% to 25%. Losartan is active agent blocking uric acid reabsorption in the proximal tubule of the kidney. The uricosuric action of losartan is not shared by other antihypertensive agents. ACE inhibitors increase uric acid excretion but the effect is modest and does not decrease serum uric acid levels. Diuretics have a propensity to increase serum uric acid levels and may even, rarely, provoke attacks of gout. Losartan can offset the elevations in serum uric acid levels occurring with hydrocholorothiazide or indapamide.
To date, the attenuating effect of losartan on serum and urinary uric acid levels has not been associated with untoward adverse effects, including flank pain or renal stone formation. Because losartan tends to increase urine pH, which increases the solubility of uric acid, the risk of supersaturation seems to be avoided.