Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis

Abstract

Objective To quantify the risk of hypoglycaemia associated with the concomitant use of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas compared with placebo and sulphonylureas.Design Systematic review and meta-analysis.Data sources Medline, ISI Web of Science, SCOPUS, Cochrane Central Register of Controlled Trials, and clinicaltrial.gov were searched without any language restriction.Study selection Placebo controlled randomised trials comprising at least 50 participants with type 2 diabetes treated with DPP-4 inhibitors and sulphonylureas.Review methods Risk of bias in each trial was assessed using the Cochrane Collaboration tool. The risk ratio of hypoglycaemia with 95% confidence intervals was computed for each study and then pooled using fixed effect models (Mantel Haenszel method) or random effect models, when appropriate. Subgroup analyses were also performed (eg, dose of DPP-4 inhibitors). The number needed to harm (NNH) was estimated according to treatment duration.Results 10 studies were included, representing a total of 6546 participants (4020 received DPP-4 inhibitors plus sulphonylureas, 2526 placebo plus sulphonylureas). The risk ratio of hypoglycaemia was 1.52 (95% confidence interval 1.29 to 1.80). The NNH was 17 (95% confidence interval 11 to 30) for a treatment duration of six months or less, 15 (9 to 26) for 6.1 to 12 months, and 8 (5 to 15) for more than one year. In subgroup analysis, no difference was found between full and low doses of DPP-4 inhibitors: the risk ratio related to full dose DPP-4 inhibitors was 1.66 (1.34 to 2.06), whereas the increased risk ratio related to low dose DPP-4 inhibitors did not reach statistical significance (1.33, 0.92 to 1.94).Conclusions Addition of DPP-4 inhibitors to sulphonylurea to treat people with type 2 diabetes is associated with a 50% increased risk of hypoglycaemia and to one excess case of hypoglycaemia for every 17 patients in the first six months of treatment. This highlights the need to respect recommendations for a decrease in sulphonylureas dose when initiating DPP-4 inhibitors and to assess the effectiveness of this risk minimisation strategy.

Efficacy and safety of gemigliptin, a dipeptidyl peptidase‐4 inhibitor, in patients with type 2 diabetes mellitus inadequately controlled with combination treatment of metformin and sulphonylurea: a 24‐week, multicentre, randomized, double‐blind, placebo‐controlled study (TROICA study)

“…Although there was no case of severe hypoglycaemia in the present study, the addition of DPP-4 inhibitors to high dose of sulphonylureas led to an increased risk of hypoglycaemia. 32 There was a modest but significant increase in weight in the gemigliptin group compared with the placebo group. DPP-4 inhibitors were not shown to increase weight when used as monotherapy and in combination with metformin 34,35 or as an add-on to insulin 36 ; however, modest weight gain was reported in the clinical trials of other DPP-4 inhibitors as an add-on to metformin and sulphonylurea.…”

“…In the present trial, we added gemigliptin while maintaining a high dose of glimepiride and metformin to investigate the effect of gemigliptin as a third antidiabetic medication in combination with metformin and glimepiride. Although there was no case of severe hypoglycaemia in the present study, the addition of DPP‐4 inhibitors to high dose of sulphonylureas led to an increased risk of hypoglycaemia . The dose adjustment of sulphonylurea should be considered when adding a DPP‐4 inhibitor.…”

“…11,12 The observed improvement in Although DPP-4 inhibitors are not associated with an increased risk of hypoglycaemia when used in monotherapy, the combination of sulphonylurea and DPP-4 inhibitors can increase the risk of hypoglycaemia. 32 A recent meta-analysis showed that the addition of a DPP-4 inhibitor to sulphonylurea increased the risk of hypoglycaemia by 50%. 32 In the present study, gemigliptin was also associated with a higher incidence of hypoglycaemia (9.4% vs 2.7%).…”

“…32 A recent meta-analysis showed that the addition of a DPP-4 inhibitor to sulphonylurea increased the risk of hypoglycaemia by 50%. 32 In the present study, gemigliptin was also associated with a higher incidence of hypoglycaemia (9.4% vs 2.7%). This tendency has been consistently reported with other DPP-4 inhibitors.…”

Cardiovascular safety of therapies for type 2 diabetes

“…There may be an increase in the risk of hypoglycemia when DPP-4 inhibitors are combined with sulfonylureas [74]. Dose reduction for sulfonylureas is therefore recommended in combination therapy, although the effects on overall glycemic control must be weighed into management decisions.…”