Dataset Information

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:

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.

SUBMITTER: Tricco AC

PROVIDER: S-EPMC4275675 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Publications

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.

Tricco Andrea C AC Antony Jesmin J Khan Paul A PA Ghassemi Marco M Hamid Jemila S JS Ashoor Huda H Blondal Erik E Soobiah Charlene C Yu Catherine H CH Hutton Brian B Hemmelgarn Brenda R BR Moher David D Majumdar Sumit R SR Straus Sharon E SE

BMJ open 20141223 12

<h4>Objective</h4>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.<h4>Setting</h4>Studies were multicentre and multinational.<h4>Participants</h4>Ten studies including 2967 patients with T2DM.<h4>Interventions</h4>Studies that examined DPP-4 inhibitors compared with each other, intermediate-acting insulin, no tr ...[more]

PMID: 25537781

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Project description:BackgroundType 2 diabetes mellitus (T2DM) results from insulin resistance and relative insulin deficiency. T2DM treatment is a step-wise approach beginning with lifestyle modifications (for example, diet, exercise), followed by the addition of oral hypoglycemic agents (for example, metformin). Patients who do not respond to first-line therapy are offered second-line therapy (for example, sulfonylureas). Third-line therapy may include insulin and/or dipeptidyl peptidase-4 (DPP-4) inhibitors.It is unclear whether DPP-4 inhibitors are safer and more effective than intermediate acting insulin for third-line management of T2DM. As such, our objective is to evaluate the comparative effectiveness, safety and cost-effectiveness of DPP-4 inhibitors versus intermediate acting insulin for T2DM patients who have failed both first- and second-line diabetes treatments.Design/methodsElectronic searches of MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and grey literature (for example, trial registries, public health websites) will be conducted to identify studies examining DPP-4 inhibitors compared with each other, intermediate acting insulin, no treatment, or placebo for adults with T2DM. The outcomes of interest include glycosylated hemoglobin (A1C) (primary outcome), as well as emergency department visits, physician visits, hospital admissions, weight gain, quality of life, microvascular complications, macrovascular complications, all-cause mortality, and cost (secondary outcomes). Randomized clinical trials (RCTs), quasi-RCTs, non-RCTs, controlled before-after, interrupted time series, cohort studies, and cost studies reporting data on these outcomes will be included. Eligibility will not be restricted by publication status, language of dissemination, duration of study follow-up, or time period of study conduct.Two reviewers will screen the titles and abstracts resulting from the literature search, as well as potentially relevant full-text articles, in duplicate. Data will be abstracted and quality will be appraised by two team members independently. Conflicts at all levels of screening and abstraction will be resolved through team discussion.Our results will be described narratively. Random effects meta-analysis and network meta-analysis will be conducted, if feasible and appropriate.DiscussionOur systematic review results can be used to determine the most effective, safe and cost-effective third-line strategies for managing T2DM. This information will be of great use to health policy-makers and clinicians, as well as patients living with T2DM and their families.Trial registrationPROSPERO registry number: CRD42013003624.

Project description:Pathways of bulk protein degradation controlled by insulin and isoprenaline (isoproterenol) were distinguished in Langendorff-perfused rat hearts. Proteins were biosynthetically labelled in vitro with [3H]leucine, followed by addition of 2 mM non-radioactive leucine to competitively prevent reincorporation. Rapidly degraded proteins were eliminated during a 3 h preliminary perfusion period without insulin. One third of bulk myocardial protein degradation was inhibited by isoprenaline as described previously. An insulin concentration of 5 nM maximally inhibited proteolysis, beginning within 2 min. Inhibition reached 32% within 1.25 h and 35% after 1.5 h. The minimum effective insulin concentration was approx. 10-50 pM, which caused 10-20% inhibition. Following 3 h of perfusion without insulin, the lysosomal inhibitor, chloroquine (30 microM), inhibited 38% of bulk degradation. The 35% proteolytic inhibition caused by insulin was followed by very little further inhibition on subsequent concurrent infusion of chloroquine, i.e. the inhibitory effects of insulin and chloroquine were not additive. In contrast, prior inhibition of lysosomal proteolysis by insulin or chloroquine did not prevent the subsequent additive inhibition caused by isoprenaline. Insulin and beta-agonists additively inhibited approx. two-thirds of bulk degradation. The biguanide antihyperglycaemic agent phenformin (2 microM) inhibited 35% of bulk degradation, beginning at 2 min and reaching a near maximum at approx. 1.25-1.5 h. Following inhibition of proteolysis with phenformin (20 microM), subsequent infusion of chloroquine (30 microM) produced only a slight additional inhibition. Following inhibition of 35% of degradation by 1.5 h of perfusion with insulin (5 nM), subsequent exposure to phenformin (2 microM) produced only a slight additional inhibition which did not exceed 38% of basal proteolysis. Thus insulin and phenformin both inhibit lysosomal proteolysis; however, the adrenergic-responsive pathway is distinct.

Dataset Information

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.

Objective

Setting

Participants

Interventions

Primary and secondary outcome measures

Results

Conclusions

Trial registration number

Publications

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.

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