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01.12.2014 | Research article | Ausgabe 1/2014 Open Access

BMC Cardiovascular Disorders 1/2014

The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies

BMC Cardiovascular Disorders > Ausgabe 1/2014
Cristina Varas-Lorenzo, Andrea V Margulis, Manel Pladevall, Nuria Riera-Guardia, Brian Calingaert, Lorna Hazell, Silvana Romio, Susana Perez-Gutthann
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1471-2261-14-129) contains supplementary material, which is available to authorized users.

Competing interests

RTI Health Solutions employees work on projects funded by pharmaceutical companies including manufacturers of treatments for patients with diabetes. As employees of RTI Health Solutions, Manel Pladevall, Susana Perez-Gutthann, and Cristina Varas-Lorenzo also participate in advisory boards funded by pharmaceutical companies. Lorna Hazell is an employee of the Drug Safety Research Unit, an organization that has received unconditional research grants from companies that manufacture drugs used in the treatment of diabetes, although none of these are related to this study. The authors declare that they have no competing interests.

Authors' contributions

CVL, MP, NRG, LH and SPG participated in the development of the literature search strategy; MP, NRG, and AM abstracted and compiled the data; NRG, BC, AM, MP and CVL performed the analyses; all authors oversaw design of the study and facilitated interpretation of the findings. CVL and AM drafted the manuscript; and all of the coauthors have been revising it critically for important intellectual content, read and approved the final manuscript. All authors had full access to all of the abstracted data from published studies included in this systematic review and take responsibility for the integrity of summarizing the data and the accuracy of the meta-analysis. All authors read and approved the final manuscript.



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.


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.


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 (I 2  = 66%). For new users (n = 4) the summary relative risk was 1.21 (1.14-1.30) and the heterogeneity was reduced (I 2  = 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; I 2  = 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.


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.
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