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Review
. 2016 May 3:353:i2231.
doi: 10.1136/bmj.i2231.

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

Francesco Salvo  1 , Nicholas Moore  2 , Mickael Arnaud  3 , Philip Robinson  4 , Emanuel Raschi  5 , Fabrizio De Ponti  5 , Bernard Bégaud  6 , Antoine Pariente  6
Affiliations
Review

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

Francesco Salvo et al. BMJ. .

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.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work. FS, MA, ER, FdP, and BB, and have no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. NM and PR have had specified relationships on other matters with Novartis and Takeda, which might have an interest in the submitted work. AP has had specified relationships on other matters with Novartis, which might have an interest in the submitted work. BB, NM, and AP have had specified relationships on other matters with public regulatory agencies and with health care insurance systems that might have an interest in the submitted work. All authors declare no other relationships or activities that could appear to have influenced the submitted work.

Figures

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Fig 1 Flow diagram of study identification, selection, and inclusion
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Fig 2 Risk of bias assessment across included studies
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Fig 3 Forest plot showing risk of hypoglycaemia in patients treated with dipeptidyl peptidase-4 (DPP-4) inhibitors plus sulphonylureas compared with placebo plus sulphonylureas
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Fig 4 Forest plot showing risk of hypoglycaemia in patients treated with full or low dose dipeptidyl peptidase-4 (DPP-4) inhibitors plus sulphonylureas compared with placebo plus sulphonylureas
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Fig 5 Funnel plot for publication bias. Scatter plot reporting risk ratio of the studies testing dipeptidyl peptidase-4 (DPP-4) inhibitors plus sulphonylureas compared with placebo plus sulphonylureas (horizontal axis) against their standard error (vertical axis)
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