title: Evidence for a dose effect of renin-angiotensin system inhibition on progression of microalbuminuria in Type 2 diabetes: a meta-analysis.
abstract: OBJECTIVE
  Renin-angiotensin inhibitors in Type 2 diabetes and microalbuminuria reduce renal and cardiovascular risk, but evidence supporting use of maximal tolerated dose is unclear. We aimed to determine the extent of renin-angiotensin inhibitor dose-dependent effects from randomized trials carried out in a clinical setting.
  
  
  METHODS
  In a meta-analysis of randomized clinical trials, alternate doses of angiotensin receptor blockers or angiotensin converting enzyme inhibitors in patients with Type 2 diabetes and microalbuminuria were compared. MEDLINE, EMBASE and the Cochrane Register of Controlled Trials were searched from January 2006 to August 2010. Trials prior to January 2006 were identified from a prior systematic review. Identified outcomes were albumin excretion rate, progression and regression of albuminuria and adverse events.
  
  
  RESULTS
  Four trials including 1051 patients compared doses of angiotensin receptor blockers. No trials compared doses of angiotensin converting enzyme inhibitor. The percentage decline in albumin excretion rate from baseline was greater with higher doses (18% higher, 95% CI 8-28%), the regression to normoalbuminuria was greater (OR 1.66, 95% CI 1.22-2.27), with less progression to macroalbuminuria (OR 0.62, CI 0.38-1.02). Adverse events were fewer with lower-dose angiotensin receptor blockers (OR 1.32, 95% CI 0.90-1.92).
  
  
  CONCLUSIONS
  Higher-dose compared with lower-dose angiotensin receptor blockers in Type 2 diabetes with microalbuminuria are associated with significantly reduced albumin excretion rate and increased regression to normoalbuminuria. Adverse events are more frequent, but not significantly so. There is potential for trials to determine clinical cardiovascular and renal outcomes at differing doses. Our findings support current recommendations to titrate renin-angiotensin inhibitors to maximum dose whilst considering risk of adverse side effects with higher doses.
authors.affiliation: National Institute for Health Research, School for Primary Care Research, Department of Primary Health Care, University of Oxford, Oxford, UK. Claire.Blacklock@dphpc.ox.ac.uk
authors.forename: C L
authors.initials: CL
authors.lastname: Blacklock
authors.forename: J A
authors.initials: JA
authors.lastname: Hirst
authors.forename: K S
authors.initials: KS
authors.lastname: Taylor
authors.forename: R J
authors.initials: RJ
authors.lastname: Stevens
authors.forename: N W
authors.initials: NW
authors.lastname: Roberts
authors.forename: A J
authors.initials: AJ
authors.lastname: Farmer
mesh_terms: D000419:Albuminuria / Q000188:drug therapy* / Q000209:etiology; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage* / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy; D019317:Evidence-Based Medicine; D006801:Humans; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic; D012084:Renin-Angiotensin System / Q000187:drug effects*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors