NPC Archive Item: Meta-analysis of observational studies on cardiovascular effects of metformin plus sulphonylureas — no need to change practice

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Rao AD, Kuhadiya N, Reynolds K, et al. Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality? A meta-analysis of observational studies. Diabetes Care. Published online ahead of print May 5, 2008 DOI: 10.2337/dc08-0167

A meta-analysis of observational studies suggests the possibility that a combination of metformin and a sulphonylurea increases the risk of cardiovascular (CV) events (fatal or non-fatal) compared with diet or monotherapy with metformin or a sulphonylurea. However, no significant increased risk of CV death or all-cause mortality was found. This study should not change clinical practice as it has many limitations that question the validity of the findings. Where another oral antidiabetic drug is required in addition to metformin, there are presently no alternative drugs to sulphonylureas that have been proven to offer any better CV safety.

What was the study?
The authors identified and carried out a meta-analysis of data from nine observational studies in people with type 2 diabetes that compared the combination of metformin and a sulphonylurea with either diet alone, metformin alone, or a sulphonylurea alone. The number of patients included in the studies ranged from 910 to more than 39,000, and the mean follow-up time ranged from 2.1 years to 7.7 years.

What did it find?
For individuals with type 2 diabetes prescribed combination therapy of sulfonylureas and metformin, no significant increased risks were found for all-cause mortality (pooled relative risk [RR] 1.19, 95%CI 0.88 to 1.62) or for CV disease mortality (RR 1.29, 95%CI 0.73 to 2.27) compared with reference treatment. However, for the composite outcome of CV disease hospitalisation or mortality, there was a significantly increased risk (RR 1.43, 95%CI 1.10 to1.85), i.e. fatal or non-fatal events, compared with reference treatment.

What are the limitations of the study?
Reference groups varied and not all studies reported all-cause mortality, CV mortality or CV hospitalisations. There was also considerable heterogeneity between the studies that reported all-cause mortality, CVD mortality, and CV hospitalisations or mortality. The authors were unable to explore the reasons for the sources of this variability. The limitations of the study are recognised by the authors, who point out that it should not be used as a basis for clinical decision making; it merely generates hypotheses.

Why this should not change practice?
As well as the many limitations of the studies, there are other reasons why this study should not change practice. Metformin is the only oral hypoglyacemic agent proven to reduce the risk of macrovascular endpoints. It is the first-choice oral hypoglyacemic drug in NICE diabetes guidance (currently being reviewed). If another drug is needed in addition, there is no evidence that any of the newer oral antidiabetic drugs offer a more effective or safer alternative to sulphonylureas with regard to CV outcomes. Glitazones are associated with an increased risk of heart failure, and rosiglitazone has been associated with an increased risk of myocardial infarction and death. There are no long term safety data with the gliptins. For more information, see the blogs on glitazones and the type 2 diabetes floor of NPC.

Why health professionals need read no further?
Health professionals are bombarded by information. It is important to read only relevant and valid information – and screen for relevancy first. Even though the measures looked at in this paper were outcomes important to patients, and type 2 diabetes is a common condition, there are few feasible alternatives to metformin plus a sulphonylurea. As the paper is unlikely to require a change in practice, it fails the relevancy criteria, regardless of its validity. For more information on filtering for relevance and validity, see the evidence informed decision making section of NPC

This study was not funded. The lead author is a Professor of Medicine and Pharmacology at Tulane University School of Medicine, New Orleans, USA.

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