A meta-analysis has suggested that the addition of a DPP-4 inhibitor to existing sulphonylurea (SU) therapy is associated with a 50% increased risk of hypoglycaemia in type 2 diabetes patients and one excess case for every 17 patients treated in the first six months. These findings emphasise the importance of following the recommendation to reduce SU dose when commencing a DPP-4 inhibitor.

Placebo-controlled, randomised, double blind trials of type 2 diabetes patients treated with SUs and DPP-4 inhibitors were searched for on Medline, ISI Web of Science, SCOPUS and the Cochrane Central Register of Controlled Trials. Risk of bias in each trial was assessed using the Cochrane Collaboration tool. Two authors screened potentially eligible trials, and approached the authors for relevant data if not included in the text.

Ten studies were eligible for inclusion, covering a total of 6,546 participants. DPP-4 inhibitors and SUs were given to 4,020 of the patients and placebo plus SU to 2,526.

The data from the trials was pooled and subjected to statistical analysis. The addition of DPP-4 inhibitors was associated with a 50% increase in the risk of hypoglycaemia and one excess case for every 17 patients treated in the first six months. The risk ratio (RR) for hypoglycaemia in the DPP-4 plus SU compared with SU plus placebo patients was 1.52 (95% CI: 1.29-1.80). The number needed to harm (NNH) was 17 (95% CI: 11-30) for ≤ 6 months’ treatment, falling to NNH = 15 (95% CI: 9-26) for 6.1-12 months’ treatment and NNH = 8 (95% CI: 5-15) for treatment duration > 1 year.

No difference was found between low and high doses of DPP-4 inhibitor, although at the lower dose the increased risk of hypoglycaemia did not achieve statistical significance.

The authors suggest this is quite a powerful meta-analysis in terms of the number of patients and quality of the studies. However, they acknowledge that the studies did use different definitions of hypoglycaemia.

Several recent publications have suggested that the paradigm of diabetes treatment in type 2 diabetes may be focused on more nuanced glycaemic targets and the avoidance of hypoglycaemia, which is now known to be associated with an increasing number of adverse health outcomes.

SUs are associated with as many hypoglycaemic episodes as insulin, and there is increasing evidence that they may be associated with poor long-term outcomes. Their role as a mainstay of future hypoglycaemic treatment is increasingly questioned, but at present GPs will see patients on these drugs every day, and will frequently be adding more medications to go with them.

This paper is a timely reminder to follow the recommendation to reduce the dose of SU when adding DPP-4 inhibitor therapy to reduce the risk of hypoglycaemia.

Dr Matthew Lockyer