title: Effect of a reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the reduction of endpoints in non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan Trial.
abstract: Emerging data show that increased serum uric acid (SUA) concentration is an independent risk factor for end-stage renal disease. Treatment with the antihypertensive drug losartan lowers SUA. Whether reductions in SUA during losartan therapy are associated with renoprotection is unclear. We therefore tested this hypothesis. In a post hoc analysis of 1342 patients with type 2 diabetes mellitus and nephropathy participating in the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan Trial, we determined the relationship between month 6 change in SUA and renal endpoints, defined as a doubling of serum creatinine or end-stage renal disease. Baseline SUA was 6.7 mg/dL in placebo and losartan-treated subjects. During the first 6 months, losartan lowered SUA by -0.16 mg/dL (95% CI: -0.30 to -0.01; P=0.031) as compared with placebo. The risk of renal events was decreased by 6% (95% CI: 10% to 3%) per 0.5-mg/dL decrement in SUA during the first 6 months. This effect was independent of other risk markers, including estimate glomerular filtration rate and albuminuria. Adjustment of the overall treatment effects for SUA attenuated losartan's renoprotective effect from 22% (95% CI: 6% to 35%) to 17% (95% CI: 1% to 31%), suggesting that approximately one fifth of losartan's renoprotective effect could be attributed to its effect on SUA. Losartan lowers SUA levels compared with placebo treatment in patients with type 2 diabetes mellitus and nephropathy. The degree of reduction in SUA is subsequently associated with the degree in long-term renal risk reduction and explains part of losartan's renoprotective effect. These findings support the view that SUA may be a modifiable risk factor for renal disease.
authors.affiliation: Department of Clinical Pharmacology, University Medical Centre Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Yan
authors.initials: Y
authors.lastname: Miao
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Ottenbros
authors.forename: Goos D
authors.initials: GD
authors.lastname: Laverman
authors.forename: Barry M
authors.initials: BM
authors.lastname: Brenner
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.forename: Diederick E
authors.initials: DE
authors.lastname: Grobbee
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Shahinfar
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.forename: Hiddo J
authors.initials: HJ
authors.lastname: Lambers Heerspink
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D003404:Creatinine / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014527:Uric Acid / Q000097:blood*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D014527:Uric Acid; D003404:Creatinine; D019808:Losartan