title: Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials.
abstract: OBJECTIVE
  EMPAREG OUTCOME study showed a reduction in cardiovascular events in patients treated with the sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin, as compared to placebo. Other drugs of the same class are currently been investigated for cardiovascular outcomes. In the meanwhile, a re-analysis of data collected in available studies can add relevant insight.
  
  
  METHODS
  A MEDLINE search for SGLT-2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, luseogliflozin) was performed, collecting all randomized trials up to November 16, 2015. All trials with a duration of treatment ≥12 weeks, enrolling patients with type 2 diabetes, comparing a SGLT2i with placebo or other comparators were included. The principal outcome was the effect of SGLT2i on all-cause and cardiovascular mortality. Secondary endpoints were myocardial infarction and stroke. Mantel-Haenszel odds ratio with 95 % confidence interval (MH-OR) was calculated.
  
  
  RESULTS
  A total of 71 trials were included (31,199 and 16,088 patients in SGLT2i and comparator groups). Treatment with SGLT2i was associated with a significant reduction in all-cause mortality (MH-OR 0.70 [0.59-0.83], p < 0.001), cardiovascular mortality (MH-OR 0.43 [0.36-0.53], p < 0.001), and myocardial infarction (MH-OR 0.77 [0.63-0.94], p < 0.01), but not stroke (MH-OR 1.09 [0.86-1.38], p = 0.50), with no apparent difference across molecules (after excluding cardiovascular outcome trials).
  
  
  CONCLUSIONS
  Available data suggest that the beneficial action observed with empagliflozin on all-cause and cardiovascular mortality in EMPAREG OUTCOME study is a class effect. The present meta-analysis showed a significantly reduction in myocardial infarction, with no increased risk of stroke.
authors.affiliation: Diabetology, Azienda Ospedaliero-Universitaria Careggi, Careggi Teaching Hospital, University of Florence, Via delle Oblate 4, 50141, Florence, Italy. matteo.monami@unifi.it.
authors.forename: Matteo
authors.identifier: http://orcid.org/0000-0001-9349-828X
authors.initials: M
authors.lastname: Monami
authors.affiliation: Diabetology, Azienda Ospedaliero-Universitaria Careggi, Careggi Teaching Hospital, University of Florence, Via delle Oblate 4, 50141, Florence, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dicembrini
authors.affiliation: Diabetology, Azienda Ospedaliero-Universitaria Careggi, Careggi Teaching Hospital, University of Florence, Via delle Oblate 4, 50141, Florence, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Mannucci
mesh_terms: D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000401:mortality*; D005960:Glucosides / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; C572941:ipragliflozin; C570240:empagliflozin
keywords: Cardiovascular events; Meta-analysis; Mortality; SGLT-2 inhibitors