Have dipeptidyl peptidase-4 inhibitors ameliorated the vascular complications of type 2 diabetes in large-scale trials? The potential confounding effect of stem-cell chemokines.

Abstract

Drugs that inhibit dipeptidyl peptidase-4 (DPP-4) are conventionally regarded as incretin-based agents that signal through the glucagon-like peptide-1 (GLP-1) receptor. However, inhibition of DPP-4 also potentiates the stem cell chemokine, stromal cell-derived factor-1 (SDF-1), which can promote inflammation, proliferative responses and neovascularization. In large-scale cardiovascular outcome trials, enhanced GLP-1 signaling has reduced the risk of atherosclerotic ischemic events, potentially because GLP-1 retards the growth and increases the stability of atherosclerotic plaques. However, DPP-4 inhibitors have not reduced the risk of major adverse cardiovascular events, possibly because potentiation of SDF-1 enhances plaque growth and instability, activates deleterious neurohormonal mechanisms, and promotes cardiac inflammation and fibrosis. Similarly, trials with GLP-1 agonists and sodium-glucose cotransporter 2 inhibitors have reported favorable effects on renal function, even after only 3-4 years of treatment. In contrast, no benefits on the rate of decline in glomerular filtration rate have been seen in trials of DPP-4 inhibitors, perhaps because the renal actions of DPP-4 inhibitors are primarily mediated by potentiation of SDF-1, not GLP-1. Experimentally, SDF-1 can promote podocyte injury and glomerulosclerosis. Furthermore, the natriuretic action of SDF-1 occurs primarily in the distal tubules, where it cannot utilize tubuloglomerular feedback to modulate the deleterious effects of glomerular hyperfiltration. Potentiation of SDF-1 in experimental models may also exacerbate both retinopathy and neuropathy. Therefore, although DPP-4 inhibitors have attractive clinical features, the benefits that might be expected from GLP-1 signaling may be undermined by their actions to enhance SDF-1.

• Authors: Milton Packer
• Journal: Cardiovascular diabetology (Cardiovasc Diabetol) Vol. 17 Issue 1 Pg. 9 (01 08 2018) ISSN: 1475-2840 [Electronic] England
• PMID: 29310647 (Publication Type: Journal Article, Review)

Chemical References

• CXCL12 protein, human
• Chemokine CXCL12
• Dipeptidyl-Peptidase IV Inhibitors
• DPP4 protein, human
• Dipeptidyl Peptidase 4

Topics

• Animals
• Chemokine CXCL12 (metabolism)
• Clinical Trials as Topic
• Diabetes Mellitus, Type 2 (blood, complications, diagnosis, drug therapy)
• Diabetic Angiopathies (blood, diagnosis, etiology, prevention & control)
• Dipeptidyl Peptidase 4 (metabolism)
• Dipeptidyl-Peptidase IV Inhibitors (adverse effects, therapeutic use)
• Humans
• Risk Factors
• Signal Transduction (drug effects)
• Stem Cells (drug effects, metabolism)
• Treatment Outcome