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

Abstract

ObjectiveTo 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.SettingStudies were multicentre and multinational.ParticipantsTen studies including 2967 patients with T2DM.InterventionsStudies that examined DPP-4 inhibitors compared with each other, intermediate-acting insulin, no treatment or placebo in patients with T2DM.Primary and secondary outcome measuresPrimary 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.Results10 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).ConclusionsDPP-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 numberPROSPERO # CRD42013003624.

Comparative Effectiveness of Adding Alogliptin to Metformin Plus Sulfonylurea with Other DPP-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Network Meta-Analysis

“…The comparable efficacy of the DPP-4 inhibitors, along with other anti-diabetes treatments (SGLT-2 inhibitors, GLP-1 agonists, and the TZDs) in triple therapy have previously been reported, and the NMA performed here has further confirmed the expectation of no significant differences in key outcomes such as change in HbA1c in a clinical trial setting when comparing alogliptin with other DPP-4 inhibitors [12–14, 36–40]. For example, the mean change (%) in HbA1c for the grouped DPP-4 inhibitors compared to placebo was −0.64 and −0.65 for fixed effects and random effects models, respectively.…”

“…There currently exists no comparative trial evidence assessing the relative efficacy and safety of alogliptin as a third-line treatment option added to dual therapy with metformin and SU. Several network meta-analyses (NMA) have been performed of different classes of drug treatment for T2DM in triple therapy (following failure with metformin + SU) including DPP-4 inhibitors, although none have compared the relative efficacy of each DPP-4 treatment or included alogliptin within the DPP-4 inhibitor class [12–15]. This is because of a previous lack of available published triple therapy data for alogliptin.…”

Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis

“…1 The American Diabetes Association and the European Association for the Study of Diabetes (EASD) have recommended these drug classes as second line agents for treatment of type 2 diabetes. 2 Their effects on glucose control are well established, [3][4][5] with additional benefits of weight loss, antihypertensive effects, and minimal risk of hypoglycemia. [4][5][6][7][8][9][10][11] A recent large randomised trial (SAVOR-TIMI 53 study 12 ) including patients with type 2 diabetes with established, or at risk for, cardiovascular disease, however, suggested possible increased mortality with saxagliptin versus placebo (5.1% v 4.6%).…”

Improvement of β-cell function ameliorated glycemic variability in patients with newly diagnosed type 2 diabetes after short-term continuous subcutaneous insulin infusion or in combination with sitagliptin treatment: a randomized control trial

“…A new direction for the treatment of T2DM is to increase the actions of incretin hormones such as glucagonlike peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP). Therefore, drugs focused on the incretin system have been introduced more recently [20,21]. A recent strategy to enhance incretin hormone activ-blood pressure (BP), were assessed before and after treatment.…”

“…ity has been the development of dipeptidyl peptidase-4 (DPP-4) inhibitors [21], which can block the inactivation of GLP-1 and GIP, thus raising plasma concentrations of the intact, active form of these peptides and thereby improving islet function by increasing α-cell and β-cell sensitivity to glucose [22]. In this regard, CSII treatment including DPP-4 inhibition might have the potential of more improvement in GV.…”