Dipeptidyl Peptidase 4 Inhibition Stimulates Distal Tubular Natriuresis and Increases in Circulating SDF-1α1-67 in Patients With Type 2 Diabetes.

Abstract

OBJECTIVE:

Antihyperglycemic agents, such as empagliflozin, stimulate proximal tubular natriuresis and improve cardiovascular and renal outcomes in patients with type 2 diabetes. Because dipeptidyl peptidase 4 (DPP-4) inhibitors are used in combination with sodium-glucose cotransporter 2 (SGLT2) inhibitors, we examined whether and how sitagliptin modulates fractional sodium excretion and renal and systemic hemodynamic function.

RESEARCH DESIGN AND METHODS:

We studied 32 patients with type 2 diabetes in a prospective, double-blind, randomized, placebo-controlled trial. Measurements of renal tubular function and renal and systemic hemodynamics were obtained at baseline, then hourly after one dose of sitagliptin or placebo, and repeated at 1 month. Fractional excretion of sodium and lithium and renal hemodynamic function were measured during clamped euglycemia. Systemic hemodynamics were measured using noninvasive cardiac output monitoring, and plasma levels of intact versus cleaved stromal cell-derived factor (SDF)-1α were quantified using immunoaffinity and tandem mass spectrometry.

RESULTS:

Sitagliptin did not change fractional lithium excretion but significantly increased total fractional sodium excretion (1.32 ± 0.5 to 1.80 ± 0.01% vs. 2.15 ± 0.6 vs. 2.02 ± 1.0%, P = 0.012) compared with placebo after 1 month of treatment. Moreover, sitagliptin robustly increased intact plasma SDF-1α1-67 and decreased truncated plasma SDF-1α3-67. Renal hemodynamic function, systemic blood pressure, cardiac output, stroke volume, and total peripheral resistance were not adversely affected by sitagliptin.

CONCLUSIONS:

DPP-4 inhibition promotes a distal tubular natriuresis in conjunction with increased levels of intact SDF-1α1-67. Because of the distal location of the natriuretic effect, DPP-4 inhibition does not affect tubuloglomerular feedback or impair renal hemodynamic function, findings relevant to using DPP-4 inhibitors for treating type 2 diabetes.

• Authors: Julie A Lovshin, Harindra Rajasekeran, Yulyia Lytvyn, Leif E Lovblom, Shajiha Khan, Robel Alemu, Amy Locke, Vesta Lai, Huaibing He, Lucinda Hittle, Weixun Wang, Daniel J Drucker, David Z I Cherney
• Journal: Diabetes care (Diabetes Care) Vol. 40 Issue 8 Pg. 1073-1081 (08 2017) ISSN: 1935-5548 [Electronic] United States
• PMID: 28550195 (Publication Type: Journal Article, Randomized Controlled Trial)
• Copyright: © 2017 by the American Diabetes Association.

Chemical References

• CXCL12 protein, human
• Chemokine CXCL12
• Dipeptidyl-Peptidase IV Inhibitors
• Hypoglycemic Agents
• SLC5A2 protein, human
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• Sitagliptin Phosphate

Topics

• Aged
• Blood Pressure (drug effects)
• Chemokine CXCL12 (blood)
• Diabetes Mellitus, Type 2 (blood, drug therapy)
• Dipeptidyl-Peptidase IV Inhibitors (administration & dosage, adverse effects)
• Double-Blind Method
• Female
• Hemodynamics
• Humans
• Hypoglycemic Agents (administration & dosage, adverse effects)
• Kidney (drug effects, metabolism)
• Male
• Middle Aged
• Natriuresis (drug effects)
• Prospective Studies
• Sitagliptin Phosphate (administration & dosage, adverse effects)
• Sodium-Glucose Transporter 2 (blood)
• Sodium-Glucose Transporter 2 Inhibitors