title: Cardiovascular and Renal Outcomes of Renin-Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses.
abstract: BACKGROUND
  Medications aimed at inhibiting the renin-angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes.
  
  
  RESULTS
  Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke-singly and as a composite endpoint, major cardiovascular outcome-and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality-singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90-1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79-1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96-1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73-1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90-1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72-1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65-1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78-1.84). No significant differences were showed between ACE inhibitors and ARBs with respect to all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, angina pectoris, hospitalization for heart failure, ESRD, or doubling serum creatinine. Findings were limited by the clinical and methodological heterogeneity of the included studies. Potential inconsistency was identified in network meta-analyses of stroke and angina pectoris, limiting the conclusiveness of findings for these single endpoints.
  
  
  CONCLUSIONS
  In adults with diabetes, comparisons of different RAS blockers showed similar effects of ACE inhibitors and ARBs on major cardiovascular and renal outcomes. Compared with monotherapies, the combination of an ACE inhibitor and an ARB failed to provide significant benefits on major outcomes. Clinicians should discuss the balance between benefits, costs, and potential harms with individual diabetes patients before starting treatment.
  
  
  BACKGROUND
  PROSPERO CRD42014014404.
authors.affiliation: Department of Medicine, University of Valencia/INCLIVA Health Research Institute, Valencia, Spain.|Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency of Medicines and Medical Devices (AEMPS), Madrid, Spain.|Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Ferrán
authors.initials: F
authors.lastname: Catalá-López
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency of Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Macías Saint-Gerons
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency of Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: González-Bermejo
authors.affiliation: Centre for Clinical and Basic Research, Department of Medical Sciences, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy.
authors.forename: Giuseppe M
authors.initials: GM
authors.lastname: Rosano
authors.affiliation: The University of Texas School of Public Health, Houston, Texas, United States of America.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davis
authors.affiliation: Instituto Aragonés de Ciencias de la Salud, Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Zaragoza, Spain.|Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO-Salud Pública), Valencia, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ridao
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency of Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Zaragoza
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency of Medicines and Medical Devices (AEMPS), Madrid, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Montero-Corominas
authors.affiliation: Spanish Council for Scientific Research (CSIC), Barcelona, Spain.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Tobías
authors.affiliation: Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency of Medicines and Medical Devices (AEMPS), Madrid, Spain.|Area of Budgetary Stability, Ministry of Finance and Public Administrations, Madrid, Spain.
authors.forename: César
authors.initials: C
authors.lastname: de la Fuente-Honrubia
authors.affiliation: Department of Medicine, University of Valencia/INCLIVA Health Research Institute, Valencia, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Tabarés-Seisdedos
authors.affiliation: Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.|School of Epidemiology, Public Health and Preventive Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Hutton
mesh_terms: D000328:Adult; D000787:Angina Pectoris / Q000517:prevention & control; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000401:mortality / Q000517:prevention & control*; D048909:Diabetes Complications / Q000517:prevention & control*; D003920:Diabetes Mellitus / Q000188:drug therapy*; D006333:Heart Failure / Q000517:prevention & control; D006760:Hospitalization; D006801:Humans; D007676:Kidney Failure, Chronic / Q000517:prevention & control*; D009203:Myocardial Infarction / Q000517:prevention & control; D051436:Renal Insufficiency, Chronic / Q000517:prevention & control; D012084:Renin-Angiotensin System; D055502:Secondary Prevention; D020521:Stroke / Q000517:prevention & control; D000092502:Renin Inhibitors
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000092502:Renin Inhibitors