title: An initial reduction in serum uric acid during angiotensin receptor blocker treatment is associated with cardiovascular protection:  a post-hoc analysis of the RENAAL and IDNT trials.
abstract: OBJECTIVE
  Increased levels of serum uric acid (SUA) are thought to be an independent risk marker for cardiovascular complications. Treatment with the angiotensin receptor blocker (ARB) losartan lowers SUA in contrast to other ARBs. Whether reductions in SUA during ARB therapy are associated with cardiovascular protection is unclear. We aimed to investigate this.
  
  
  METHODS
  In a post-hoc analysis of the Reduction of Endpoints in Non insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy (IDNT) trials we determined whether the short-term effect of losartan and of irbesartan on SUA is related with long-term cardiovascular outcome by means of Cox regression.
  
  
  RESULTS
  Compared to placebo, losartan significantly changed SUA [-0.16  mg/dl; 95% confidence interval (CI) -0.01 to -0.30; P = 0.031], whereas irbesartan did not (-0.09  mg/dl; (95% CI 0.09 to -0.28; P = 0.30). Each 0.5  mg/dl decrement in SUA during losartan treatment in the first 6 months resulted in a reduction in the risk of cardiovascular outcomes by 5.3% (95% CI 0.9 to 9.9; P = 0.017). Losartan reduced the risk of cardiovascular outcomes by 9.2% (95% CI -7.9 to 23.6). Adjustment for the 6-month change in SUA attenuated the treatment effect to 4.6% (95% CI -16.2 to 22.0), suggesting that part of the cardiovascular protective effect of losartan is attributable to its short-term effect on SUA.
  
  
  CONCLUSIONS
  Losartan but not irbesartan significantly lowers SUA compared to placebo in patients with type 2 diabetes and nephropathy. The degree of reduction in SUA explains part of the cardiovascular effect of losartan. This supports the hypothesis that SUA is a modifiable risk factor for cardiovascular disease, at least in type 2 diabetics with nephropathy.
authors.affiliation: Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Smink
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.forename: Gozewijn D
authors.initials: GD
authors.lastname: Laverman
authors.forename: Tomas
authors.initials: T
authors.lastname: Berl
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.forename: Hiddo J
authors.initials: HJ
authors.lastname: Lambers Heerspink
mesh_terms: D000328:Adult; D000368:Aged; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects; D003627:Data Interpretation, Statistical; D003928:Diabetic Nephropathies / Q000188:drug therapy; D005260:Female; D006801:Humans; D000077405:Irbesartan; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D016016:Proportional Hazards Models; D012306:Risk; D012307:Risk Factors; D013777:Tetrazoles / Q000494:pharmacology*; D016896:Treatment Outcome; D014527:Uric Acid / Q000097:blood*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D010919:Placebos; D013777:Tetrazoles; D014527:Uric Acid; D000077405:Irbesartan; D019808:Losartan