title: Efficacy and safety of insulin in type 2 diabetes: meta-analysis of randomised controlled trials.
abstract: BACKGROUND
  It is essential to anticipate and limit the social, economic and sanitary cost of type 2 diabetes (T2D), which is in constant progression worldwide. When blood glucose targets are not achieved with diet and lifestyle intervention, insulin is recommended whether or not the patient is already taking hypoglycaemic drugs. However, the benefit/risk balance of insulin remains controversial. Our aim was to determine the efficacy and safety of insulin vs. hypoglycaemic drugs or diet/placebo on clinically relevant endpoints.
  
  
  METHODS
  A systematic literature review (Pubmed, Embase, Cochrane Library) including all randomised clinical trials (RCT) analysing insulin vs. hypoglycaemic drugs or diet/placebo, published between 1950 and 2013, was performed. We included all RCTs reporting effects on all-cause mortality, cardiovascular mortality, death by cancer, cardiovascular morbidity, microvascular complications and hypoglycaemia in adults ≥ 18 years with T2D. Two authors independently assessed trial eligibility and extracted the data. Internal validity of studies was analyzed according to the Cochrane Risk of Bias tool. Risk ratios (RR) with 95 % confidence intervals (95 % CI) were calculated, using the fixed effect model in first approach. The I(2) statistic assessed heterogeneity. In case of statistical heterogeneity, subgroup and sensitivity analyses then a random effect model were performed. The alpha threshold was 0.05. Primary outcomes were all-cause mortality and cardiovascular mortality. Secondary outcomes were non-fatal cardiovascular events, hypoglycaemic events, death from cancer, and macro- or microvascular complications.
  
  
  RESULTS
  Twenty RCTs were included out of the 1632 initially identified studies. 18 599 patients were analysed: Insulin had no effect vs. hypoglycaemic drugs on all-cause mortality RR = 0.99 (95 % CI =0.92-1.06) and cardiovascular mortality RR = 0.99 (95 % CI =0.90-1.09), nor vs. diet/placebo RR = 0.92 (95 % CI = 0.80-1.07) and RR = 0.95 (95 % CI 0.77-1.18) respectively. No effect was found on secondary outcomes either. However, severe hypoglycaemia was more frequent with insulin compared to hypoglycaemic drugs RR = 1.70 (95 % CI = 1.51-1.91).
  
  
  CONCLUSIONS
  There is no significant evidence of long term efficacy of insulin on any clinical outcome in T2D. However, there is a trend to clinically harmful adverse effects such as hypoglycaemia and weight gain. The only benefit could be limited to reducing short term hyperglycemia. This needs to be confirmed with further studies.
authors.affiliation: University college of General Medicine, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Erpeldinger
authors.affiliation: Department of Cardiology, CHU de Poitiers, 86000, Poitiers, France. michaela.rehman@gmail.com.
authors.forename: Michaela B
authors.initials: MB
authors.lastname: Rehman
authors.affiliation: Department of General Medicine, University Lille-Nord de France, Lille 2, Lille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Berkhout
authors.affiliation: University college of General Medicine, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pigache
authors.affiliation: University college of General Medicine, University Claude Bernard Lyon 1, Lyon, France.|SCF SHS/S2HEP (EA 4148), University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Zerbib
authors.affiliation: University college of General Medicine, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Regnault
authors.affiliation: University college of General Medicine, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Guérin
authors.affiliation: University college of General Medicine, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Irène
authors.initials: I
authors.lastname: Supper
authors.affiliation: UMR 5558, CNRS, Université Claude Bernard Lyon 1, Lyon, France.|Clinical Investigation Centre, INSERM CIC1407, Lyon, France.|Clinical Pharmacology and Clinical Trials Department, Hospices Civils de Lyon, Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cornu
authors.affiliation: UMR 5558, CNRS, Université Claude Bernard Lyon 1, Lyon, France.|Clinical Investigation Centre, INSERM CIC1407, Lyon, France.|Clinical Pharmacology and Clinical Trials Department, Hospices Civils de Lyon, Lyon, France.
authors.forename: Behrouz
authors.initials: B
authors.lastname: Kassaï
authors.affiliation: UMR 5558, CNRS, Université Claude Bernard Lyon 1, Lyon, France.|Clinical Pharmacology and Clinical Trials Department, Hospices Civils de Lyon, Lyon, France.
authors.forename: François
authors.initials: F
authors.lastname: Gueyffier
authors.affiliation: Department of General Medicine, Université de Poitiers, Poitiers, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Boussageon
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007328:Insulin / Q000009:adverse effects* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin
keywords: Hypoglycaemic drugs; Insulin; Meta-analysis; Morbidity; Mortality; Randomised Controlled Trials; Type 2 Diabetes Mellitus