title: Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: A meta-analysis of placebo-controlled randomized trials.
abstract: BACKGROUND
  The impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular outcomes in patients with type II diabetes mellitus (DM) is not well established.
  
  
  METHODS
  We searched electronic databases from inception through July 2016 for randomized, placebo-controlled trials, involving SGLT-2 inhibitors. Fixed-effects summary odds ratios (OR) were constructed using Peto model.
  
  
  RESULTS
  Eighty-one trials with a total of 37,195 patients were included. The mean follow-up was 89weeks. Compared with placebo, SGLT-2 inhibitors were associated with a lower risk of all-cause mortality (OR 0.72; 95% CI 0.59-0.86; P<0.001), cardiovascular mortality (OR 0.67; 95% CI 0.53-0.84; P=0.001), and heart failure (OR 0.67; 95% CI 0.51-0.87; P=0.003), but a similar risk of myocardial infarction (OR 0.89; 95% CI 0.74-1.09; P=0.29) and stroke/transient ischemic attack (OR 1.09; 95% CI 0.87-1.37; P=0.47). The reduction in all-cause mortality was noticed with empagliflozin (OR 0.66; 95% CI 0.54-0.81; P<0.001), but not with other SGLT-2 inhibitors (ORdapagliflozin1.37; 95% CI 0.71-2.62; P=0.35; ORcanagliflozin0.82; 95% CI 0.41-1.68; P=0.59; ORluseogliflozin4.6; 95% CI 0.07-284.25; P=0.47; and ORipragliflozin4.73; 95% CI 0.08-283.14; P=0.46) (Pinteraction=0.19). Potential harm was observed with dapagliflozin on cardiovascular mortality (OR 2.15, 95% CI 0.92-5.04, P=0.08).
  
  
  CONCLUSIONS
  In patients with type II DM, SGLT-2 inhibitors appeared to reduce both all-cause and cardiovascular mortality, primarily due to reduction in the risk of heart failure. The benefit was only seen with empagliflozin. There was suggestion of potential harm with dapagliflozin, thus future trials are needed to ascertain the cardiovascular safety of other agents in this class.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States. Electronic address: mssaad@uams.edu.
authors.forename: Marwan
authors.initials: M
authors.lastname: Saad
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL, United States.
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Mahmoud
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL, United States.
authors.forename: Islam Y
authors.initials: IY
authors.lastname: Elgendy
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Jefferson University Hospital/Christiana Care Health System, Newark, DE, United States.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abuzaid
authors.affiliation: Department of Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States.
authors.forename: Amr F
authors.initials: AF
authors.lastname: Barakat
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL, United States.
authors.forename: Akram Y
authors.initials: AY
authors.lastname: Elgendy
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Al-Ani
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States.
authors.forename: Amgad
authors.initials: A
authors.lastname: Mentias
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
authors.forename: Ramez
authors.initials: R
authors.lastname: Nairooz
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL, United States.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Bavry
authors.affiliation: Division of Cardiology, Texas Tech University Health Sciences Center, El Paso, TX, United States.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukherjee
mesh_terms: D000367:Age Factors; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000453:epidemiology* / Q000517:prevention & control; D015897:Comorbidity; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012737:Sex Factors; D051297:Sodium-Glucose Transporter 2 / Q000627:therapeutic use; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
keywords: Cardiovascular outcomes; Diabetes mellitus; Meta-analysis; Mortality; Sodium–glucose cotransporter-2 inhibitors