Sulphonylurea use and cardiovascular outcomes

The withdrawal of Rosiglitazone from European markets in 2010 followed on from a meta-analysis, which suggested it increased the risk of myocardial infarction in people with type 2 diabetes. A direct consequence of this event was the FDA requirement for placebo-controlled cardiovascular outcome studies for new diabetes therapies. For the incretin drugs alone, there are currently over 66,000 patients enrolled into these studies with the first due to report later this year.

An assumption is that the traditional anti-diabetes therapies are safe but this has not always been presumed. See, for example, this statement from the introduction to the UKPDS 33 publication in the Lancet in 1998: ‘There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation’. The ORIGIN study, which assessed the cardiovascular impact of insulin glargine in over 12,000 patients seems to have given insulin a clean bill of health in this respect but what of the sulphonylureas?

2013 has seen the publication of two meta-analyses which examine the link between sulphonylurea use and cardiovascular outcomes. One made a comparison with other oral anti-diabetes agents and included over 1.3 million patients from thirty-three studies. The authors reported a significantly increased risk of cardiovascular death in patients treated with a sulphonylurea. The other meta-analysis examined data from fewer patients (~550,000) but included insulin treatments. They reported an increase in both cardiovascular and all-cause mortality with sulphonylurea therapy.

So what are clinicians meant to make of these data? Unfortunately guidance from randomized clinical trials will be lacking for some time. The only cardiovascular study which is comparing one of the new incretin drugs (linagliptin) with a sulphonylurea (the CAROLINA study) is not due to report until 2018. Perhaps it is telling, however, that the FDA has now also requested a placebo-controlled comparison (the CARMELINA study) implying that a positive result from CAROLINA might be saying more about the SU comparator than the incretin. SUs may not be as safe as originally thought but one thing does seem certain – the regulatory authorities will be less keen to target withdrawal of sulphonylureas from guidelines given their high cost-effectiveness (aka cheap acquisition costs)

Professor Steve Bain