Effect of dipeptidyl peptidase-4 inhibitors on circulating tumor necrosis factor-α concentrations: A systematic review and meta-analysis of controlled trials

Highlights

• Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control.

• There is controversial evidence on the anti-inflammatory activity of DPP-4 inhibitors.

• This meta-analysis assessed the effect of DPP-4 inhibitors on plasma TNF-α.

• Meta-analysis of clinical trials suggested significant reduction of plasma TNF-α with DPP-4 inhibitors.

• The TNF-α-lowering effect was not different between sitagliptin and vildagliptin.

Abstract

Objective

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes mellitus. There are also reports of an effect of these drugs in reducing inflammation through inhibition of tumor necrosis factor-α (TNF-α) that is an important mediator for several inflammatory processes. The present systematic review and meta-analysis were performed to evaluate the effect of DPP-4 inhibitors on circulating TNF-α levels in T2DM patients.

Methods

A systematic review and a meta-analysis were undertaken on all controlled trials of DPP-4 inhibitors that included measurement of TNF-α. The search included PubMed-Medline, Scopus, ISI Web of Knowledge and Google Scholar databases. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. Meta-regression and leave-one-out sensitivity analysis were performed to assess the modifiers of treatment response.

Results

Eight eligible articles (6 with sitagliptin and 2 with vildagliptin) comprising 9 treatment arms were selected for this meta-analysis. Meta-analysis suggested a significant reduction of circulating TNF-α concentrations following treatment with DPP-4 inhibitors (SMD: − 1.84, 95% CI: − 2.88, − 0.80, p = 0.001). The effect size was robust in the sensitivity analysis and not mainly driven by a single study. A subgroup analysis did not suggest any significant difference between the TNF-α-lowering activity of sitagliptin (SMD: − 1.49, 95% CI: − 2.89, − 0.10) and vildagliptin (SMD: − 2.80, 95% CI: − 4.98, − 0.61) (p = 0.326).

Conclusion

This meta-analysis of the 8 available controlled trials showed that DPP-4 inhibition in patients with type 2 diabetes mellitus was associated with significant reductions in plasma TNF-α levels with no apparent difference between sitagliptin and vildagliptin.

Introduction

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in type 2 diabetes mellitus (T2DM) by inhibiting the enzyme DPP-4 that is present on the surface of most cells, and deactivates glucagon-like peptide-1 (GLP-1) secreted by the L-cells of the small intestine.¹ DPP-4 inhibitors increase the endogenous GLP-1 levels whose main action is to stimulate glucose-dependent insulin release from the pancreatic islets and is associated with delayed gastric emptying and decreased hepatic glucagon secretion, hence these agents are not associated with hypoglycemia (unless combined with insulin or sulphonylurea drugs) and have a weight neutral effect.2., 3.

DPP-4 inhibitors are used mainly as add-on antidiabetic drugs to metformin, though monotherapy is considered in cases of metformin intolerance.² Licensed DPP-4 inhibitors (all are not available in every country) include alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin. Large clinical trials for the regulatory authorities have been undertaken to assess their cardiovascular effects that have suggested that there are no increased risks of adverse coronary heart disease outcomes in high-risk patients over 18 to 36 months apart from a potential increase in the risk of hospitalization for heart failure with saxagliptin and alogliptin.4., 5., 6.

Tumor necrosis factor-α (TNF-α) is produced by activated macrophages and T cells, and is then secreted into the circulation and aggregates into a trimeric structure that binds to specific receptors i.e. TNF receptor R1 (TNFR1) and TNFR2.⁷ This results in extensive immune effects including release of inflammatory cytokines, up-regulation of endothelial adhesion molecules and leukocyte migration, and is the target of biological antibody compounds (e.g. infliximab and adalimumab) used for chronic disease treatment.⁸

There are reports of the reduction of circulating TNF-α levels by DPP-4 inhibitors though the mechanism of this remains unclear.⁹ This potential anti-inflammatory property of DPP-4 inhibitors could be an important pleiotropic effect given that low-grade inflammation is implicated in the atherosclerotic process¹⁰ and may play an important role in the development of T2DM complications.11., 12. The present systematic review and meta-analysis were performed to evaluate the effect of DPP-4 inhibitors on circulating TNF-α levels in T2DM patients.