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

BMJ Open. 2014 Dec 23;4(12):e005752. doi: 10.1136/bmjopen-2014-005752.

Abstract

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.

Keywords: meta-analysis; systematic review.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl Peptidase 4 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / adverse effects
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Glycated Hemoglobin / metabolism*
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Incretins / metabolism
  • Insulin / adverse effects
  • Insulin / therapeutic use
  • Insulin, Isophane / adverse effects
  • Insulin, Isophane / therapeutic use*
  • Treatment Outcome

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Incretins
  • Insulin
  • Insulin, Isophane
  • Dipeptidyl Peptidase 4