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:Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists is a breakthrough in the field of neural regeneration research increasing glucagon like peptide-1 bioavailability, hence its neuroprotective activities. In this article, the authors suggest not only crossing blood-brain barrier and neurodegenerative disease as off target for dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists, but also for ophthalmic preparations for diabetic retinopathy, which may be the latest breakthrough in the field if prepared and used in an appropriate nano-formulation to target the retinal nerves. The relation of neurodegenerative diseases' different mechanisms to the dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists should be further examined in preclinical and clinical settings. The repositioning of already marketed antidiabetic drugs for neurodegenerative diseases should save the high cost of the time-consuming normal drug development process. Drug repositioning is a hot topic as an alternative to molecular target based drug discovery or therapeutic switching. It is a relatively inexpensive pathway due to availability of previous pharmacological and safety data. The glucagon like peptide-1 produced in brain has been linked to enhanced learning and memory functions as a physiologic regulator in central nervous system by restoring insulin signaling. Intranasal administration of all marketed gliptins (or glucagon like peptide-1 receptor agonists) may show enhanced blood-brain barrier crossing and increased glucagon like peptide-1 levels in the brain after direct crossing of the drug for the olfactory region, targeting the cerebrospinal fluid. Further blood-brain barrier crossing tests may extend dipeptidyl peptidase-4 inhibitors' effects beyond the anti-hyperglycemic control to intranasal spray, intranasal powder, or drops targeting the blood-brain barrier and neurodegenerative diseases with the most suitable formula. Moreover, novel nano-formulation is encouraged either to obtain favorable pharmacokinetic parameters or to achieve promising blood-brain barrier penetration directly through the olfactory region. Many surfactants should be investigated either as a solubilizing agent for hydrophobic drugs or as penetration enhancers. Different formulae based on in vitro and in vivo characterizations, working on sister gliptins (or glucagon like peptide-1 receptor agonists), different routes of administration, pharmacokinetic studies, dose response relationship studies, monitoring of plasma/brain concentration ratio after single and multiple dose, and neurodegenerative disease animal models are required to prove the new method of use (utility) for dipeptidyl peptidase-4 inhibitors as potential neuroprotective agents. Furthermore, investigations of glucagon like peptide-1 receptor agonists' neuroprotective effects on animal models will be considered carefully because they crossed the blood-brain barrier in previous studies, enabling their direct action on the central nervous system. Combination therapy of dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists with already marketed drugs for neurodegenerative disease should be considered, especially regarding the novel intranasal route of administration.

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.

Similar Datasets

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