Jessica R Wilson1,2,3, Erica M Garner2, Mona Mashayekhi2, Scott A Hubers1,4, Claudia E Ramirez Bustamante1,5, Scott Jafarian Kerman1, Hui Nian6, Cyndya A Shibao7, Nancy J Brown1,8. 1. Division of Clinical Pharmacology (J.R.W., S.A.H., C.E.R.B., S.J.K., N.J.B.), Vanderbilt Department of Medicine. 2. Division of Endocrinology, Diabetes, and Metabolism (J.R.W., E.M.G., M.M.), Vanderbilt Department of Medicine. 3. Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Mayo Clinic Florida (J.R.W.). 4. Division of Cardiology, Department of Medicine, University of Minnesota (S.A.H.). 5. Department of Medicine, Baylor College of Medicine (C.E.R.B.). 6. Department of Biostatistics, Vanderbilt University (H.N.). 7. Division of Clinical Pharmacology (C.A.S.), Vanderbilt Department of Medicine. 8. Department of Medicine, Yale School of Medicine (N.J.B.).
Abstract
BACKGROUND: DPP4 (dipeptidyl peptidase-4) inhibitors comprise a class of oral diabetes medication that have the potential for off-target cardiovascular effects. We previously showed that DPP4 inhibition attenuates the hypotensive effect of acute ACE (angiotensin-converting enzyme) inhibition and increases norepinephrine. Here, we investigated the effects of DPP4 during sustained ACE inhibition compared with during therapy with an ARB (angiotensin receptor blocker) or calcium channel blocker (neutral comparator) in a randomized, double-blinded crossover study. METHODS: We enrolled 106 adults with type 2 diabetes and hypertension and 100 received intervention. Subjects were randomized to one of 3 blood pressure arms: ramipril, valsartan, or amlodipine for a total of 15 weeks and received 3 one-week crossover therapies in random order: placebo + placebo, sitagliptin + placebo, and sitagliptin + aprepitant separated by 4-week washout. RESULTS: We found that DPP4 inhibition increased norepinephrine during ramipril but did not increase blood pressure. Aprepitant, a NK1 (substance P) receptor blocker, lowered standing heart rate during renin-angiotensin-aldosterone system blockade with ramipril or valsartan. CONCLUSIONS: Increased catecholamines during concurrent ACE and DPP4 inhibition may contribute to cardiovascular complications in patients predisposed to heart failure.
BACKGROUND: DPP4 (dipeptidyl peptidase-4) inhibitors comprise a class of oral diabetes medication that have the potential for off-target cardiovascular effects. We previously showed that DPP4 inhibition attenuates the hypotensive effect of acute ACE (angiotensin-converting enzyme) inhibition and increases norepinephrine. Here, we investigated the effects of DPP4 during sustained ACE inhibition compared with during therapy with an ARB (angiotensin receptor blocker) or calcium channel blocker (neutral comparator) in a randomized, double-blinded crossover study. METHODS: We enrolled 106 adults with type 2 diabetes and hypertension and 100 received intervention. Subjects were randomized to one of 3 blood pressure arms: ramipril, valsartan, or amlodipine for a total of 15 weeks and received 3 one-week crossover therapies in random order: placebo + placebo, sitagliptin + placebo, and sitagliptin + aprepitant separated by 4-week washout. RESULTS: We found that DPP4 inhibition increased norepinephrine during ramipril but did not increase blood pressure. Aprepitant, a NK1 (substance P) receptor blocker, lowered standing heart rate during renin-angiotensin-aldosterone system blockade with ramipril or valsartan. CONCLUSIONS: Increased catecholamines during concurrent ACE and DPP4 inhibition may contribute to cardiovascular complications in patients predisposed to heart failure.
Authors: Faiez Zannad; Christopher P Cannon; William C Cushman; George L Bakris; Venu Menon; Alfonso T Perez; Penny R Fleck; Cyrus R Mehta; Stuart Kupfer; Craig Wilson; Hung Lam; William B White Journal: Lancet Date: 2015-03-10 Impact factor: 79.321
Authors: M Castellano; D Rizzoni; M Beschi; M Böhm; E Porteri; G Bettoni; A Cinelli; E A Rosei Journal: J Cardiovasc Pharmacol Date: 1995-09 Impact factor: 3.105