Article Text

Safety and effectiveness of dipeptidyl peptidase-4 inhibitors versus intermediate-acting insulin or placebo for patients with type 2 diabetes failing two oral antihyperglycaemic agents: a systematic review and network meta-analysis
  1. Andrea C Tricco1,
  2. Jesmin Antony1,
  3. Paul A Khan1,
  4. Marco Ghassemi1,
  5. Jemila S Hamid2,
  6. Huda Ashoor1,
  7. Erik Blondal1,
  8. Charlene Soobiah1,
  9. Catherine H Yu1,
  10. Brian Hutton3,
  11. Brenda R Hemmelgarn4,
  12. David Moher3,
  13. Sumit R Majumdar5,
  14. Sharon E Straus1,6
  1. 1Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
  2. 2Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
  3. 3Clinical Epidemiology Program, Ottawa Hospital Research Institute and the Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  4. 4Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
  5. 5Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
  6. 6Department of Geriatric Medicine, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Sharon E Straus; sharon.straus{at}


Objective To evaluate the effectiveness and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors versus intermediate-acting insulin for adults with type 2 diabetes mellitus (T2DM) and poor glycaemic control despite treatment with two oral agents.

Setting Studies were multicentre and multinational.

Participants Ten studies including 2967 patients with T2DM.

Interventions Studies that examined DPP-4 inhibitors compared with each other, intermediate-acting insulin, no treatment or placebo in patients with T2DM.

Primary and secondary outcome measures Primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes were healthcare utilisation, body weight, fractures, quality of life, microvascular complications, macrovascular complications, all-cause mortality, harms, cost and cost-effectiveness.

Results 10 randomised clinical trials with 2967 patients were included after screening 5831 titles and abstracts, and 180 full-text articles. DPP-4 inhibitors significantly reduced HbA1c versus placebo in network meta-analysis (NMA; mean difference (MD) −0.62%, 95% CI −0.93% to −0.33%) and meta-analysis (MD −0.61%, 95% CI −0.81% to −0.41%), respectively. Significant differences in HbA1c were not observed for neutral protamine Hagedorn (NPH) insulin versus placebo and DPP-4 inhibitors versus NPH insulin in NMA. In meta-analysis, no significant differences were observed between DPP-4 inhibitors and placebo for severe hypoglycaemia, weight gain, cardiovascular disease, overall harms, treatment-related harms and mortality, although patients receiving DPP-4 inhibitors experienced less infections (relative risk 0.72, 95% CI 0.57 to 0.91).

Conclusions DPP-4 inhibitors were superior to placebo in reducing HbA1c levels in adults with T2DM taking at least two oral agents. Compared with placebo, no safety signals were detected with DPP-4 inhibitors and there was a reduced risk of infection. There was no significant difference in HbA1c observed between NPH and placebo or NPH and DPP-4 inhibitors.

Trial registration number PROSPERO # CRD42013003624.

  • systematic review
  • meta-analysis

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