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Dipeptidyl Peptidase 4 Inhibition Increases Postprandial Norepinephrine via Substance P (NK1 Receptor) During RAAS Inhibition.
J Endocr Soc 2019; 3(10):1784-1798JE

Abstract

Context

Dipeptidyl peptidase 4 (DPP4) inhibitors may increase the risk of heart failure. Decreased degradation of vasoactive peptides like substance P [also degraded by angiotensin-converting enzyme (ACE)] and Y1 agonists peptide YY (PYY 1-36) and neuropeptide Y (NPY 1-36) could contribute.

Objective

This study tested the hypothesis that there is an interactive effect of DPP4 inhibition and ACE inhibition (vs antihypertensive control subjects) on vasoactive peptides after a mixed meal.

Participants and Design

Fifty-three patients with type 2 diabetes and hypertension were randomized to double-blind treatment with ramipril, valsartan, or amlodipine for 15 weeks in parallel groups. During the 5th, 10th, and 15th weeks, participants also received placebo + placebo, sitagliptin 100 mg/d + placebo, and sitagliptin + aprepitant 80 mg/d in random order. On the last day of each crossover treatment, participants underwent a mixed-meal study.

Results

Sitagliptin increased postprandial glucagon-like peptide-1 and decreased glucose in all antihypertensive groups. Sitagliptin increased NPY 1-36 and decreased Y2 agonists NPY 3-36 and PYY 3-36 in all groups. During ramipril or valsartan, but not amlodipine, sitagliptin increased postprandial norepinephrine; substance P receptor blockade with aprepitant prevented this effect. Despite increased norepinephrine, sitagliptin decreased postprandial blood pressure during ACE inhibition.

Conclusion

DPP4 inhibition increases postprandial concentrations of the Y1 agonist NPY 1-36. During treatment with an ACE inhibitor or angiotensin receptor blocker, DPP4 inhibition increased postprandial norepinephrine through a substance P receptor-dependent mechanism. Increased NPY 1-36 and norepinephrine could increase risk of heart failure but did not result in higher postprandial blood pressure.

Authors+Show Affiliations

Division of Clinical Pharmacology, Vanderbilt Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Division of Endocrinology, Diabetes, and Metabolism, Vanderbilt Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania Department of Medicine, Philadelphia, Pennsylvania.Division of Clinical Pharmacology, Vanderbilt Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.Division of Clinical Pharmacology, Vanderbilt Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.Service de Pharmacologie Clinique, Laboratoire des Catecholamines et Peptides, University Hospital of Lausanne, Lausanne, Switzerland.Service de Pharmacologie Clinique, Laboratoire des Catecholamines et Peptides, University Hospital of Lausanne, Lausanne, Switzerland.Division of Clinical Pharmacology, Vanderbilt Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.Division of Clinical Pharmacology, Vanderbilt Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31528826

Citation

Wilson, Jessica R., et al. "Dipeptidyl Peptidase 4 Inhibition Increases Postprandial Norepinephrine Via Substance P (NK1 Receptor) During RAAS Inhibition." Journal of the Endocrine Society, vol. 3, no. 10, 2019, pp. 1784-1798.
Wilson JR, Kerman SJ, Hubers SA, et al. Dipeptidyl Peptidase 4 Inhibition Increases Postprandial Norepinephrine via Substance P (NK1 Receptor) During RAAS Inhibition. J Endocr Soc. 2019;3(10):1784-1798.
Wilson, J. R., Kerman, S. J., Hubers, S. A., Yu, C., Nian, H., Grouzmann, E., ... Brown, N. J. (2019). Dipeptidyl Peptidase 4 Inhibition Increases Postprandial Norepinephrine via Substance P (NK1 Receptor) During RAAS Inhibition. Journal of the Endocrine Society, 3(10), pp. 1784-1798. doi:10.1210/js.2019-00185.
Wilson JR, et al. Dipeptidyl Peptidase 4 Inhibition Increases Postprandial Norepinephrine Via Substance P (NK1 Receptor) During RAAS Inhibition. J Endocr Soc. 2019 Oct 1;3(10):1784-1798. PubMed PMID: 31528826.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dipeptidyl Peptidase 4 Inhibition Increases Postprandial Norepinephrine via Substance P (NK1 Receptor) During RAAS Inhibition. AU - Wilson,Jessica R, AU - Kerman,Scott Jafarian, AU - Hubers,Scott A, AU - Yu,Chang, AU - Nian,Hui, AU - Grouzmann,Eric, AU - Eugster,Philippe J, AU - Mayfield,Dustin S, AU - Brown,Nancy J, Y1 - 2019/07/01/ PY - 2019/05/15/received PY - 2019/06/25/accepted PY - 2019/9/19/entrez PY - 2019/9/19/pubmed PY - 2019/9/19/medline KW - DPP4 KW - dipeptidyl peptidase-4 inhibition KW - hypertension KW - sitagliptin KW - substance P KW - type 2 diabetes mellitus SP - 1784 EP - 1798 JF - Journal of the Endocrine Society JO - J Endocr Soc VL - 3 IS - 10 N2 - Context: Dipeptidyl peptidase 4 (DPP4) inhibitors may increase the risk of heart failure. Decreased degradation of vasoactive peptides like substance P [also degraded by angiotensin-converting enzyme (ACE)] and Y1 agonists peptide YY (PYY 1-36) and neuropeptide Y (NPY 1-36) could contribute. Objective: This study tested the hypothesis that there is an interactive effect of DPP4 inhibition and ACE inhibition (vs antihypertensive control subjects) on vasoactive peptides after a mixed meal. Participants and Design: Fifty-three patients with type 2 diabetes and hypertension were randomized to double-blind treatment with ramipril, valsartan, or amlodipine for 15 weeks in parallel groups. During the 5th, 10th, and 15th weeks, participants also received placebo + placebo, sitagliptin 100 mg/d + placebo, and sitagliptin + aprepitant 80 mg/d in random order. On the last day of each crossover treatment, participants underwent a mixed-meal study. Results: Sitagliptin increased postprandial glucagon-like peptide-1 and decreased glucose in all antihypertensive groups. Sitagliptin increased NPY 1-36 and decreased Y2 agonists NPY 3-36 and PYY 3-36 in all groups. During ramipril or valsartan, but not amlodipine, sitagliptin increased postprandial norepinephrine; substance P receptor blockade with aprepitant prevented this effect. Despite increased norepinephrine, sitagliptin decreased postprandial blood pressure during ACE inhibition. Conclusion: DPP4 inhibition increases postprandial concentrations of the Y1 agonist NPY 1-36. During treatment with an ACE inhibitor or angiotensin receptor blocker, DPP4 inhibition increased postprandial norepinephrine through a substance P receptor-dependent mechanism. Increased NPY 1-36 and norepinephrine could increase risk of heart failure but did not result in higher postprandial blood pressure. SN - 2472-1972 UR - https://www.unboundmedicine.com/medline/citation/31528826/Dipeptidyl_Peptidase_4_Inhibition_Increases_Postprandial_Norepinephrine_via_Substance_P_(NK1_Receptor)_During_RAAS_Inhibition L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31528826/ DB - PRIME DP - Unbound Medicine ER -