title: Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials.
abstract: OBJECTIVE
  To assess the effect of targeting intensive glycaemic control versus conventional glycaemic control on all cause mortality and cardiovascular mortality, non-fatal myocardial infarction, microvascular complications, and severe hypoglycaemia in patients with type 2 diabetes.
  
  
  METHODS
  Systematic review with meta-analyses and trial sequential analyses of randomised trials.
  
  
  METHODS
  Cochrane Library, Medline, Embase, Science Citation Index Expanded, LILACS, and CINAHL to December 2010; hand search of reference lists and conference proceedings; contacts with authors, relevant pharmaceutical companies, and the US Food and Drug Administration.
  
  
  METHODS
  Randomised clinical trials comparing targeted intensive glycaemic control with conventional glycaemic control in patients with type 2 diabetes. Published and unpublished trials in all languages were included, irrespective of predefined outcomes.
  
  
  METHODS
  Two reviewers independently assessed studies for inclusion and extracted data related to study methods, interventions, outcomes, risk of bias, and adverse events. Risk ratios with 95% confidence intervals were estimated with fixed and random effects models.
  
  
  RESULTS
  Fourteen clinical trials that randomised 28,614 participants with type 2 diabetes (15,269 to intensive control and 13,345 to conventional control) were included. Intensive glycaemic control did not significantly affect the relative risks of all cause (1.02, 95% confidence interval 0.91 to 1.13; 28,359 participants, 12 trials) or cardiovascular mortality (1.11, 0.92 to 1.35; 28,359 participants, 12 trials). Trial sequential analyses rejected a relative risk reduction above 10% for all cause mortality and showed insufficient data on cardiovascular mortality. The risk of non-fatal myocardial infarction may be reduced (relative risk 0.85, 0.76 to 0.95; P=0.004; 28,111 participants, 8 trials), but this finding was not confirmed in trial sequential analysis. Intensive glycaemic control showed a reduction of the relative risks for the composite microvascular outcome (0.88, 0.79 to 0.97; P=0.01; 25,600 participants, 3 trials) and retinopathy (0.80, 0.67 to 0.94; P=0.009; 10,793 participants, 7 trials), but trial sequential analyses showed that sufficient evidence had not yet been reached. The estimate of an effect on the risk of nephropathy (relative risk 0.83, 0.64 to 1.06; 27,769 participants, 8 trials) was not statistically significant. The risk of severe hypoglycaemia was significantly increased when intensive glycaemic control was targeted (relative risk 2.39, 1.71 to 3.34; 27,844 participants, 9 trials); trial sequential analysis supported a 30% increased relative risk of severe hypoglycaemia.
  
  
  CONCLUSIONS
  Intensive glycaemic control does not seem to reduce all cause mortality in patients with type 2 diabetes. Data available from randomised clinical trials remain insufficient to prove or refute a relative risk reduction for cardiovascular mortality, non-fatal myocardial infarction, composite microvascular complications, or retinopathy at a magnitude of 10%. Intensive glycaemic control increases the relative risk of severe hypoglycaemia by 30%.
authors: Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Denmark. bh@ctu.rh.dk
authors: Bianca
authors: B
authors: Hemmingsen
authors: Søren S
authors: SS
authors: Lund
authors: Christian
authors: C
authors: Gluud
authors: Allan
authors: A
authors: Vaag
authors: Thomas
authors: T
authors: Almdal
authors: Christina
authors: C
authors: Hemmingsen
authors: Jørn
authors: J
authors: Wetterslev
mesh_terms: D001786:Blood Glucose; D002318:Cardiovascular Diseases / Q000097:blood / Q000401:mortality*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000401:mortality* / Q000517:prevention & control*; D003925:Diabetic Angiopathies / Q000097:blood / Q000401:mortality*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin