title: The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies.
abstract: BACKGROUND
  Patients with type 2 diabetes mellitus (T2DM) are at high risk of heart failure. A summary of the effects of blood glucose-lowering drugs other than glitazones on the risk of heart failure in routine clinical practice is lacking. The objective of this study was to conduct a systematic review and meta-analysis of observational studies on the risk of heart failure when using blood glucose-lowering drugs.
  
  
  METHODS
  We systematically identified and reviewed cohort and case-control studies in which the main exposure of interest was noninsulin blood glucose-lowering medications in patients with T2DM. We searched Medline, Embase, and the Cochrane Library to identify publications meeting prespecified eligibility criteria. The quality of included studies was assessed with the Newcastle-Ottawa Scale and the RTI item bank. Results were combined using fixed and random-effects models when at least 3 independent data points were available for a drug-drug comparison.
  
  
  RESULTS
  The summary relative risk of heart failure in rosiglitazone users versus pioglitazone users (95% CI) was 1.16 (1.05-1.28) (5 cohort studies). Heterogeneity was present (I2 = 66%). For new users (n = 4) the summary relative risk was 1.21 (1.14-1.30) and the heterogeneity was reduced (I2 = 31%);. The summary relative risk for rosiglitazone versus metformin was 1.36 (95% CI, 1.17-1.59) (n = 3). The summary relative risk (95% CI) of heart failure in sulfonylureas users versus metformin users was 1.17 (95% CI, 1.06-1.29) (5 cohort studies; I2 = 24%) and 1.22 (1.02-1.46) when restricted to new users (2 studies).Information on other comparisons was very scarce. Information on dose and duration of treatment effects was lacking for most comparisons. Few studies accounted for disease severity; therefore, confounding by indication might be present in the majority of the within-study comparisons of this meta-analysis.
  
  
  CONCLUSIONS
  Use of glitazones and sulfonylureas was associated with an increased risk of heart failure compared with metformin use. However, indication bias cannot be ruled out. Ongoing large multidatabase studies will help to evaluate the risk of heart failure in treated patients with diabetes, including those using newer blood glucose-lowering therapies.
authors.affiliation: RTI Health Solutions, Trav, Gracia 56 Atico 1 08006, Barcelona, Spain. cvaras@rti.org.
authors.forename: Cristina
authors.initials: C
authors.lastname: Varas-Lorenzo
authors.forename: Andrea V
authors.initials: AV
authors.lastname: Margulis
authors.forename: Manel
authors.initials: M
authors.lastname: Pladevall
authors.forename: Nuria
authors.initials: N
authors.lastname: Riera-Guardia
authors.forename: Brian
authors.initials: B
authors.lastname: Calingaert
authors.forename: Lorna
authors.initials: L
authors.lastname: Hazell
authors.forename: Silvana
authors.initials: S
authors.lastname: Romio
authors.forename: Susana
authors.initials: S
authors.lastname: Perez-Gutthann
mesh_terms: D015982:Bias; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D016009:Chi-Square Distribution; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D006333:Heart Failure / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008687:Metformin / Q000009:adverse effects; D016017:Odds Ratio; D018570:Risk Assessment; D012307:Risk Factors; D013453:Sulfonylurea Compounds / Q000009:adverse effects*; D045162:Thiazolidinediones / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D008687:Metformin