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Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis

BMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e1369 (Published 12 March 2012) Cite this as: BMJ 2012;344:e1369

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  1. Thomas Karagiannis, research fellow1,
  2. Paschalis Paschos, research fellow1,
  3. Konstantinos Paletas, professor1,
  4. David R Matthews, professor in diabetic medicine2,
  5. Apostolos Tsapas, assistant professor13
  1. 1Metabolic Diseases Unit, Second Medical Department, Aristotle University, Konstantinupoleos 49, 54642, Thessaloniki, Greece
  2. 2Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK
  3. 3Harris Manchester College, University of Oxford, Oxford OX1 3TD
  1. Correspondence to: A Tsapas atsapas{at}auth.gr
  • Accepted 9 January 2012

Abstract

Objective To assess the efficacy and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors compared with metformin as monotherapy, or with other commonly used hypoglycaemic drugs combined with metformin, in adults with type 2 diabetes mellitus.

Design Systematic review and meta-analysis of randomised controlled trials.

Data sources Medline, Embase, the Cochrane Library, conference proceedings, trial registers, and drug manufacturers’ websites.

Eligibility criteria Randomised controlled trials of adults with type 2 diabetes mellitus that compared a DPP-4 with metformin as monotherapy or with a sulfonylurea, pioglitazone, a glucagon-like peptide-1 (GLP-1) agonist, or basal insulin combined with metformin on the change from baseline in glycated haemoglobin (HbA1c).

Data extraction The primary outcome was the change in HbA1c. Secondary outcomes included the proportion of patients achieving the goal of HbA1c <7%, the change in body weight, discontinuation rate because of any adverse event, occurrence of any serious adverse event, all cause mortality, and incidence of hypoglycaemia, nasopharyngitis, urinary tract infection, upper respiratory infection, nausea, vomiting, and diarrhoea.

Results 27 reports of 19 studies including 7136 patients randomised to a DPP-4 inhibitor and 6745 patients randomised to another hypoglycaemic drug were eligible for the systematic review and meta-analysis. Overall risk of bias for the primary outcome was low in three reports, unclear in nine, and high in 14. Compared with metformin as monotherapy, DPP-4 inhibitors were associated with a smaller decline in HbA1c (weighted mean difference 0.20, 95% confidence interval 0.08 to 0.32) and in body weight (1.5, 0.9 to 2.11). As a second line treatment, DPP-4 inhibitors were inferior to GLP-1 agonists (0.49, 0.31 to 0.67) and similar to pioglitazone (0.09, −0.07 to 0.24) in reducing HbA1c and had no advantage over sulfonylureas in the attainment of the HbA1c goal (risk ratio in favour of sulfonylureas 1.06, 0.98 to 1.14). DPP-4 inhibitors had a favourable weight profile compared with sulfonylureas (weighted mean difference −1.92, −2.34 to −1.49) or pioglitazone (−2.96, −4.13 to −1.78), but not compared with GLP-1 agonists (1.56, 0.94 to 2.18). Only a minimal number of hypoglycaemias were observed in any treatment arm in trials comparing a DPP-4 inhibitor with metformin as monotherapy or with pioglitazone or a GLP-1 agonist as second line treatment. In most trials comparing a DPP-4 inhibitor with sulfonylureas combined with metformin, the risk for hypoglycaemia was higher in the group treated with a sulfonylurea. Incidence of any serious adverse event was lower with DPP-4 inhibitors than with pioglitazone. Incidence of nausea, diarrhoea, and vomiting was higher in patients receiving metformin or a GLP-1 agonist than in those receiving a DPP-4 inhibitor. Risk for nasopharyngitis, upper respiratory tract infection, or urinary tract infection did not differ between DPP-4 inhibitors and any of the active comparators.

Conclusion In patients with type 2 diabetes who do not achieve the glycaemic targets with metformin alone, DPP-4 inhibitors can lower HbA1c, in a similar way to sulfonylureas or pioglitazone, with neutral effects on body weight. Increased unit cost, which largely exceeds that of the older drugs, and uncertainty about their long term safety, however, should also be considered.

Footnotes

  • We thank Richard Stevens for his helpful critical comments and statistical advice on the manuscript, and Claudia Filozof and Ingrid Gause-Nilsson for providing additional data regarding change in HbA1c for our analysis.

  • Contributors: TK, PP, and AT were responsible for study concept and design. TK and PP participated in the study search and data collection and extraction. TK and AT did the statistical analysis. All authors interpreted the data. TK wrote the first draft of the report, which was critically revised by DRM, KP, and AT. TK, PP, and AT had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. AT supervised the study and is guarantor.

  • Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: DRM has been a member of an advisory board for vildagliptin (Novartis) and has received consulting fees from Novartis, Novo Nordisk, GlaxoSmithKline, Merck, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Johnson and Johnson, and Janssen Global Services; AT has been a member of an advisory board for liraglutide (Novo Nordisk), has received lecture fees and a research grant from Novartis, and has received support with an educational grant from Novo Nordisk.

  • Ethical approval: Not required.

  • Data sharing: Additional data regarding forest plots are available on request from the corresponding author.

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