title: Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials.
abstract: BACKGROUND
  Some glucose-lowering drugs or strategies adversely affect cardiovascular outcomes. We aimed to assess the extent to which glucose lowering by various drugs or strategies increases the risk of heart failure in patients with or at risk for type 2 diabetes, and to establish whether risk is associated with achieved differences in glycaemia or weight control.
  
  
  METHODS
  We searched Ovid Medline, the Cochrane Library, and meeting abstracts up to Feb 20, 2015, for large randomised controlled trials of glucose-lowering drugs or strategies that assessed cardiovascular outcomes. The primary endpoint was incidence of heart failure. We derived pooled risk ratios (RRs) with random-effects models.
  
  
  RESULTS
  We included data from 14 trials, with mean duration 4·3 (2·3) years, comprising 95 502 patients, of whom 3907 (4%) patients developed a heart failure event. Glucose-lowering drugs or strategies were associated with a 0·50% (SD 0·33) reduction in HbA1c and a 1·7 kg (2·8) weight gain. Overall, glucose-lowering drugs or strategies increased the risk of heart failure compared with standard care (RR 1·14, 95% CI 1·01-1·30; p=0·041). The magnitude of this effect varied dependent on the method of glucose lowering (p for interaction=0·00021). Across drug classes, risk was highest with peroxisome proliferator-activated receptor agonists (RR 1·42, 95% CI 1·15-1·76; six trials), intermediate with dipeptidyl peptidase-4 inhibitors (1·25, 1·08-1·45; two trials), and neutral with insulin glargine (0·90, 0·77-1·05; one trial). Target-based intensive glycaemic control strategies (RR 1·00, 95% CI 0·88-1·13; four trials) and intensive weight loss (0·80, 95% CI 0·62-1·04; one trial) were also not associated with development of heart failure. Meta-regression analysis showed that for every 1·0 kg of weight gain associated with glucose-lowering drugs or strategies, there was a 7·1% (95% CI 1·0-13·6) relative increase in the risk of heart failure compared with standard care (p=0·022).
  
  
  CONCLUSIONS
  Compared with standard care, glycaemic lowering by various drugs or strategies might increase the risk of heart failure, with the magnitude of risk dependent on the method of glucose lowering and, potentially, weight gain.
  
  
  BACKGROUND
  None.
authors: Women's College Research Institute and Cardiovascular Division, Department of Medicine, Women's College Hospital, Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada; Peter Munk Cardiac Centre, University Health Network, Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada. Electronic address: jay.udell@utoronto.ca.
authors: Jacob A
authors: JA
authors: Udell
authors: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Matthew A
authors: MA
authors: Cavender
authors: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Deepak L
authors: DL
authors: Bhatt
authors: Division of Cardiology, St Luke's-Roosevelt Hospital, Mount Sinai Health System, New York, NY, USA.
authors: Saurav
authors: S
authors: Chatterjee
authors: Peter Munk Cardiac Centre, University Health Network, Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada.
authors: Michael E
authors: ME
authors: Farkouh
authors: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Benjamin M
authors: BM
authors: Scirica
mesh_terms: D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000453:epidemiology*; D006333:Heart Failure / Q000139:chemically induced* / Q000150:complications / Q000453:epidemiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors
chemical_list: D007004:Hypoglycemic Agents