Comparative Effectiveness of Dipeptidylpeptidase-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison

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Abstract

Objective

To compare the safety and efficacy of the dipeptidylpeptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes and inadequate glycemic control.

Design

Systematic review of randomized controlled trials (RCTs), health economic evaluation studies, systematic reviews, and meta-analyses, followed by primary Bayesian mixed treatment comparison meta-analyses (MTCs), and secondary frequentist direct-comparison meta-analyses using a random-effects model. Outcomes were reported as weighted mean change from baseline, or odds ratio (OR) with 95% credible interval.

Data sources

MEDLINE, MEDLINE In-Process, EMBASE, and BIOSIS via Dialog ProQuest; Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews via EBSCO; four diabetes and two technical congress abstracts; and health technology assessment organization websites.

Eligibility criteria

Patients with type 2 diabetes and inadequate glycemic control receiving any pharmacological anti-diabetic treatment.

Data extraction and analysis

Title/abstracts were reviewed for eligibility, followed by full-text review of publications remaining after first pass. A three-person team filtered articles and an independent reviewer checked a random selection (10%) of filtered articles. Data extraction and quality assessment of studies were also independently reviewed. Five DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin) were compared via meta-analysis (where data were available) as monotherapy, dual therapy (plus metformin, sulfonylurea, pioglitazone, or insulin), and triple therapy (plus metformin/sulfonylurea).

Results

The review identified 6,601 articles; 163 met inclusion criteria and 85 publications from 83 RCTs contained sufficient or appropriate data for analysis. MTCs demonstrated no differences between DPP-4 inhibitors in mean change from baseline in glycosylated hemoglobin (HbA _1c) or body weight, or the proportions of patients achieving HbA _1c <7% or experiencing a hypoglycemic event, apart from in patients on alogliptin plus metformin, who achieved HbA _1c <7% more frequently than those treated with saxagliptin plus metformin [OR 6.41 (95% CI 3.15–11.98) versus 2.17 (95% CI 1.56–2.95)].

Conclusions

This systematic review and MTC showed similar efficacy and safety for DPP-4 inhibitors as treatment for type 2 diabetes, either as monotherapy or combination therapy.

Electronic supplementary material

The online version of this article (doi:10.1007/s13300-014-0061-3) contains supplementary material, which is available to authorized users.

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Most cited references 115

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Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial.

Richard M. Bergenstal, Carol Wysham, Leigh MacConell … (2010)

Most patients with type 2 diabetes begin pharmacotherapy with metformin, but eventually need additional treatment. We assessed the safety and efficacy of once weekly exenatide, a glucagon-like peptide 1 receptor agonist, versus maximum approved doses of the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the thiazolidinedione, pioglitazone, in patients treated with metformin. In this 26-week randomised, double-blind, double-dummy, superiority trial, patients with type 2 diabetes who had been treated with metformin, and at baseline had mean glycosylated haemoglobin (HbA(1c)) of 8.5% (SD 1.1), fasting plasma glucose of 9.1 mmol/L (2.6), and weight of 88.0 kg (20.1), were enrolled and treated at 72 sites in the USA, India, and Mexico. Patients were randomly assigned to receive: 2 mg injected exenatide once weekly plus oral placebo once daily; 100 mg oral sitagliptin once daily plus injected placebo once weekly; or 45 mg oral pioglitazone once daily plus injected placebo once weekly. Primary endpoint was change in HbA(1c) between baseline and week 26. Analysis was by intention to treat, for all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00637273. 170 patients were assigned to receive once weekly exenatide, 172 to receive sitagliptin, and 172 to receive pioglitazone. 491 patients received at least one dose of study drug and were included in the intention-to-treat analysis (160 on exenatide, 166 on sitagliptin, and 165 on pioglitazone). Treatment with exenatide reduced HbA(1c) (least square mean -1.5%, 95% CI -1.7 to -1.4) significantly more than did sitagliptin (-0.9%, -1.1 to -0.7) or pioglitazone (-1.2%, -1.4 to -1.0). Treatment differences were -0.6% (95% CI -0.9 to -0.4, p<0.0001) for exenatide versus sitagliptin, and -0.3% (-0.6 to -0.1, p=0.0165) for exenatide versus pioglitazone. Weight loss with exenatide (-2.3 kg, 95% CI-2.9 to -1.7) was significantly greater than with sitagliptin (difference -1.5 kg, 95% CI -2.4 to -0.7, p=0.0002) or pioglitazone (difference -5.1 kg, -5.9 to -4.3, p<0.0001). No episodes of major hypoglycaemia occurred. The most frequent adverse events with exenatide and sitagliptin were nausea (n=38, 24%, and n=16, 10%, respectively) and diarrhoea (n=29, 18%, and n=16, 10%, respectively); upper-respiratory-tract infection (n=17, 10%) and peripheral oedema (n=13, 8%) were the most frequent events with pioglitazone. The goal of many clinicians who manage diabetes is to achieve optimum glucose control alongside weight loss and a minimum number of hypoglycaemic episodes. Addition of exenatide once weekly to metformin achieved this goal more often than did addition of maximum daily doses of either sitagliptin or pioglitazone. Amylin Pharmaceuticals and Eli Lilly. Copyright 2010 Elsevier Ltd. All rights reserved.

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Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes.

Pablo Aschner, Mark S. Kipnes, Jared K Lunceford … (2006)

To examine the efficacy and safety of once-daily oral sitagliptin as monotherapy in patients with type 2 diabetes. In a randomized, double-blind, placebo-controlled study, 741 patients (baseline HbA(1c) [A1C] 8.0%) were randomized to sitagliptin 100 or 200 mg or placebo for 24 weeks. Sitagliptin 100 and 200 mg produced significant (P or=9% had greater reductions in placebo-subtracted A1C with sitagliptin 100 and 200 mg (-1.52 and -1.50%, respectively) than those with baseline A1C or=8 to <9.0% (-0.80 and -1.13%, respectively). In a meal tolerance test, sitagliptin 100 and 200 mg significantly decreased 2-h postprandial glucose (PPG) (placebo-subtracted PPG -2.6 mmol/l [-46.7 mg/dl] and -3.0 mmol/l [-54.1 mg/dl], respectively). Results for the above key efficacy parameters were not significantly different between sitagliptin doses. Homeostasis model assessment of beta-cell function and proinsulin-to-insulin ratio improved with sitagliptin. The incidence of hypoglycemia was similar, and overall gastrointestinal adverse experiences were slightly higher with sitagliptin. No meaningful body weight changes from baseline were observed with sitagliptin 100 (-0.2 kg) or 200 mg (-0.1 kg). The body weight change with placebo (-1.1 kg) was significantly (P < 0.01) different from that observed with sitagliptin. In this 24-week study, once-daily sitagliptin monotherapy improved glycemic control in the fasting and postprandial states, improved measures of beta-cell function, and was well tolerated in patients with type 2 diabetes.

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Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.

Mei-Hsiang Wu, , Avraham Karasik … (2006)

The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, added to ongoing metformin therapy, were assessed in patients with type 2 diabetes who had inadequate glycemic control (HbA(1c) [A1C] >or=7 and or=1,500 mg/day) were randomly assigned to receive the addition of placebo or sitagliptin 100 mg once-daily in a 1:2 ratio for 24 weeks. Patients exceeding specific glycemic limits were provided rescue therapy (pioglitazone) until the end of the study. The efficacy analyses were based on an all-patients-treated population using an ANCOVA and excluded data obtained after glycemic rescue. At week 24, sitagliptin treatment led to significant reductions compared with placebo in A1C (-0.65%), fasting plasma glucose, and 2-h postmeal glucose. Fasting insulin, fasting C-peptide, fasting proinsulin-to-insulin ratio, postmeal insulin and C-peptide areas under the curve (AUCs), postmeal insulin AUC-to-glucose AUC ratio, homeostasis model assessment of beta-cell function, and quantitative insulin sensitivity check index were significantly improved with sitagliptin relative to placebo. A significantly greater proportion of patients achieved an A1C <7% with sitagliptin (47.0%) than with placebo (18.3%). There was no increased risk of hypoglycemia or gastrointestinal adverse experiences with sitagliptin compared with placebo. Body weight decreased similarly with sitagliptin and placebo. Sitagliptin 100 mg once-daily added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone.

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Author and article information

Contributors

K. Ian Johnson: ian.johnson@complete-grp.com

Journal

Journal ID (nlm-ta): Diabetes Ther

Journal ID (iso-abbrev): Diabetes Ther

Title: Diabetes Therapy

Publisher: Springer Healthcare (Heidelberg )

ISSN (Print): 1869-6953

ISSN (Electronic): 1869-6961

Publication date (Electronic): 25 March 2014

Publication date PMC-release: 25 March 2014

Publication date (Print): June 2014

Volume: 5

Issue: 1

Pages: 1-41

Affiliations

[ ]Takeda Pharmaceuticals International GmbH, Zurich, Switzerland

[ ]McCann Complete Medical, Macclesfield, UK

Article

Publisher ID: 61

DOI: 10.1007/s13300-014-0061-3

PMC ID: 4065303

PubMed ID: 24664619

SO-VID: 6482a974-ddf8-4505-9d38-4d460f4cf19c

History

Date received : 20 December 2013

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: alogliptin,dpp-4 inhibitor,glycosylated hemoglobin,linagliptin,mixed treatment comparison,saxagliptin,sitagliptin,type 2 diabetes mellitus,vildagliptin

Data availability:

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: alogliptin, dpp-4 inhibitor, glycosylated hemoglobin, linagliptin, mixed treatment comparison, saxagliptin, sitagliptin, type 2 diabetes mellitus, vildagliptin

Comparative Effectiveness of Dipeptidylpeptidase-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison

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Abstract

Objective

Design

Data sources

Eligibility criteria

Data extraction and analysis

Results

Conclusions

Electronic supplementary material

Related collections

Karger: Endocrinology

Most cited references 115

Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial.

Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.

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