Varas-Lorenzo C, Riera-Guardia N, Calingaert B, Margulis A, Pladevall M, Miguel G, Romio S, Sturkenboom M, Perez-Gutthann S. Cardiovascular risk with glitazones and metformin: results from a systematic review of observational studies. Poster presented at the 29th International Conference on Pharmacoepidemiology and Therapeutic Risk Management; August 2013. [abstract] Pharmacoepidemiol Drug Saf. 2013 Oct 7; 22(S1):68.

BACKGROUND: The goal of the Safety Evaluation of Adverse Reactions in Diabetes (SAFEGUARD) project, sponsored by the European Commission, is to evaluate the cardiovascular (CV) and pancreatic safety of oral glucose-lowering drugs in type 2 diabetes mellitus (T2DM). We systematically reviewed published observational studies on the risk of acute myocardial infarction (AMI), stroke, heart failure (HF) or CV mortality in T2DM users of rosiglitazone or pioglitazone vs. metformin users.

METHODS: We searched Medline, Embase and the Cochrane Library to identify cohort or case-control studies published through November 2011 reporting the risk of CV endpoints in T2DM patients using any oral glucose-lowering medication. Of 1929 publications, 44 studies were selected; 7 reported the risk of AMI or HF in users of rosiglitazone or pioglitazone compared with risk in metformin users. No studies reported on stroke or CV mortality. Summary relative risks (sRR) were estimated using random-effects models. Heterogeneity was assessed using the chi-squared test.

RESULTS: All studies used a cohort design with one performing a nested case-control analysis. For AMI, for monotherapy regimens, the sRR (95% CI) for rosiglitazone was 1.43 (0.98–2.08; p < 0.0001 for heterogeneity; n = 6); for pioglitazone 1.21 (0.87–1.70; n = 2), compared with metformin. If rosiglitazone or pioglitazone was added to a based metformin regimen or combined with other T2DM drugs, sRR was closer to the null as compared to metformin. For HF, the sRR (95% CI) for rosiglitazone, monotherapy or in combination with other blood glucose-lowering agents, vs. metformin was 1.34 (1.10–1.62; n = 3). Based on only 2 studies, the sRR (95% CI) for pioglitazone vs. metformin was 1.14 (0.86–1.50). No studies reported on dose or duration effects.

CONCLUSIONS: Observational studies reporting on the risk of CV events associated with individual glitazones compared with metformin are scarce and heterogeneous. Results of the large ongoing SAFEGUARD project will help elucidate the CV safety of these medications.

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