A meta-analysis of observational studies has failed to resolve whether a combination of metformin plus a sulfonylurea to treat type 2 diabetes increases the risk of cardiovascular events.
Higher diabetes-related and all-cause mortality was described in the United Kingdom Prospective Diabetes Study among patients taking the combination, but the association was considered to be a chance finding. Subsequent studies had mixed results, showing increases and decreases in cardiovascular events, or no effect.
This new meta-analysis identified nine relevant observational studies comparing patients taking metformin plus a sulfonylurea with those on dietary therapy alone or monotherapy with one of the two drug classes. The combination was associated with non-significant increases in all-cause and cardiovascular mortality, but a significant 43% increase in a composite endpoint of cardiovascular hospitalisations or mortality.
“Our results provide a mix of reassurance and concern to prescribers of diabetes medications who use combination therapies to achieve good glycaemic control,” the researchers concluded. While use of metformin plus a sulfonylurea could assist with the early achievement of glycaemic control, treatment decisions had to balance the potential risks and benefits of all medications prescribed.
It was highly unlikely that there would be any large-scale clinical trials to examine the issue. Meta-analysis of observational studies was helpful, but had many limitations including varied comparator groups, quantitative heterogeneity across the studies, and the inclusion of subgroup analyses among the results.
There were several possible explanations for how metformin combined with a sulfonylurea might raise cardiovascular risk. Patients requiring the combination might have more aggressive diabetes with more rapid decline in glycaemic control, or the weight gain associated with sulfonylureas might negate some of the benefits achieved by metformin. In addition, hypoglycaemia from sulfonylureas might worsen cardiac abnormalities such as ischaemia and arrhythmias.
Reference
Rao, A. Kuhadiya, N. et al. 2008, ‘Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality?’ Diabetes Care vol. 31, pp. 1672-1678.
Abstract