Do DPP-4 Inhibitors Cause Heart Failure Events by Promoting Adrenergically Mediated Cardiotoxicity? Clues from Laboratory Models and Clinical Trials

Circulation Research

Volumn 122, Issue 7, 2018, Pages 928-932

  Packer, Milton ^a  

^a BAYLOR UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

diabetic cardiomyopathies; growth substances; heart failure; neuropeptide Y; sympathetic nervous system

Indexed keywords

ANTIDIABETIC AGENT; DIPEPTIDYL PEPTIDASE IV INHIBITOR;

ADRENERGIC NERVE CELL; ADRENERGIC SYSTEM; ANIMAL; CARDIOTOXICITY; CLINICAL TRIAL (TOPIC); CYTOLOGY; DRUG EFFECT; HEART FAILURE; HUMAN;

ADRENERGIC NEURONS; ANIMALS; CARDIOTOXICITY; CLINICAL TRIALS AS TOPIC; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; HEART FAILURE; HUMANS; HYPOGLYCEMIC AGENTS; SYMPATHETIC NERVOUS SYSTEM;

EID: 85048507164     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.118.312673     Document Type: Article

References (59)

1. Packer M. Worsening heart failure during the use of dipeptidyl peptidase-4 inhibitors in type 2 diabetes: novel pathophysiological mechanisms, spectrum of clinical risks, and potential influence of concomitant antidiabetic medications. JACC Heart Fail. In press.
2. US Food and Drug Administration. Diabetes Medications Containing Saxagliptin and Alogliptin: Drug Safety Communication-Risk of Heart Failure. April 5, 2016. https://www. fda. gov/safety/ medwatch/safetyinformation/ safetyalertsforhumanmedicalproducts/ ucm494252. htm.
3. Scirica BM, Braunwald E, Raz I, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2015;132:e198. doi: 10. 1161/CIR. 0000000000000330.
4. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Lam H, White WB; EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067-2076. doi: 10. 1016/S0140-6736(14)62225-X.
5. McMurray JJV, Ponikowski P, Bolli GB, Lukashevich V, Kozlovski P, Kothny W, Lewsey JD, Krum H; VIVIDD Trial Committees and Investigators. Effects of vildagliptin on ventricular function in patients with type 2 diabetes mellitus and heart failure: a randomized placebo-controlled trial. JACC Heart Fail. 2018;6:8-17. doi: 10. 1016/j. jchf. 2017. 08. 004.
6. Rosenstock J, Marx N, Neubacher D, Seck T, Patel S, Woerle HJ, Johansen OE. Cardiovascular safety of linagliptin in type 2 diabetes: a comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events. Cardiovasc Diabetol. 2015;14:57. doi: 10. 1186/ s12933-015-0215-2.
7. Gantz I, Chen M, Suryawanshi S, Ntabadde C, Shah S, O'Neill EA, Engel SS, Kaufman KD, Lai E. A randomized, placebo-controlled study of the cardiovascular safety of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2017;16:112. doi: 10. 1186/s12933-017-0593-8.
8. Clifton P. Do dipeptidyl peptidase IV (DPP-IV) inhibitors cause heart failure? Clin Ther. 2014;36:2072-2079. doi: 10. 1016/j. clinthera. 2014. 10. 009.
9. Li L, Li S, Deng K, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ. 2016;352:i610.
10. Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24:689-697. doi: 10. 1016/j. numecd. 2014. 01. 017.
11. Raschi E, Poluzzi E, Koci A, Antonazzo IC, Marchesini G, De Ponti F. Dipeptidyl peptidase-4 inhibitors and heart failure: analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System. Nutr Metab Cardiovasc Dis. 2016;26:380-386. doi: 10. 1016/j. numecd. 2016. 02. 006.
12. Suh S, Seo GH, Jung CH, Kim MK, Jin SM, Hwang YC, Lee BW, Kim JH. Increased risk of hospitalization for heart failure with newly prescribed dipeptidyl peptidase-4 inhibitors and pioglitazone using the Korean health insurance claims database. Diabetes Metab J. 2015;39:247-252. doi: 10. 4093/dmj. 2015. 39. 3. 247.
13. Lovshin JA, Rajasekeran H, Lytvyn Y, Lovblom LE, Khan S, Alemu R, Locke A, Lai V, He H, Hittle L, Wang W, Drucker DJ, Cherney DZI. Dipeptidyl peptidase 4 inhibition stimulates distal tubular natriuresis and increases in circulating SDF-1?1-67 in patients with type 2 diabetes. Diabetes Care. 2017;40:1073-1081. doi: 10. 2337/dc17-0061.
14. Packer M. Is the way to someone's heart through their stomach? The cardiorenal paradox of incretin-based hypoglycemic drugs in heart failure. Circ Heart Fail. 2017;10:e004551. doi: 10. 1161/CIRCHEART FAILURE. 117. 004551.
15. Aoyama M, Kawase H, Bando YK, Monji A, Murohara T. Dipeptidyl peptidase 4 inhibition alleviates shortage of circulating glucagon-like peptide-1 in heart failure and mitigates myocardial remodeling and apoptosis via the exchange protein directly activated by cyclic AMP 1/rasrelated protein 1 axis. Circ Heart Fail. 2016;9:e002081. doi: 10. 1161/ CIRCHEARTFAILURE. 115. 002081.
16. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991;325:1468-1475. doi: 10. 1056/ NEJM199111213252103.
17. Zaccolo M, Pozzan T. Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science. 2002;295:1711-1715. doi: 10. 1126/science. 1069982.
18. Di Benedetto G, Zoccarato A, Lissandron V, Terrin A, Li X, Houslay MD, Baillie GS, Zaccolo M. Protein kinase A type I and type II define distinct intracellular signaling compartments. Circ Res. 2008;103:836-844. doi: 10. 1161/CIRCRESAHA. 108. 174813.
19. Ye Y, Keyes KT, Zhang C, Perez-Polo JR, Lin Y, Birnbaum Y. The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA. Am J Physiol Heart Circ Physiol. 2010;298:H1454-H1465. doi: 10. 1152/ ajpheart. 00867. 2009.
20. Vila Petroff MG, Egan JM, Wang X, Sollott SJ. Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes. Circ Res. 2001;89:445-452.
21. Lorenz M, Lawson F, Owens D, Raccah D, Roy-Duval C, Lehmann A, Perfetti R, Blonde L. Differential effects of glucagon-like peptide-1 receptor agonists on heart rate. Cardiovasc Diabetol. 2017;16:6. doi: 10. 1186/ s12933-016-0490-6.
22. Ceholski DK, Turnbull IC, Pothula V, Lecce L, Jarrah AA, Kho C, Lee A, Hadri L, Costa KD, Hajjar RJ, Tarzami ST. CXCR4 and CXCR7 play distinct roles in cardiac lineage specification and pharmacologic ?-adrenergic response. Stem Cell Res. 2017;23:77-86. doi: 10. 1016/j. scr. 2017. 06. 015.
23. Zhu X, Gillespie DG, Jackson EK. NPY1-36 and PYY1-36 activate cardiac fibroblasts: an effect enhanced by genetic hypertension and inhibition of dipeptidyl peptidase 4. Am J Physiol Heart Circ Physiol. 2015;309:H1528-H1542. doi: 10. 1152/ajpheart. 00070. 2015.
24. Devin JK, Pretorius M, Nian H, Yu C, Billings FT IV, Brown NJ. Substance P increases sympathetic activity during combined angiotensinconverting enzyme and dipeptidyl peptidase-4 inhibition. Hypertension. 2014;63:951-957. doi: 10. 1161/HYPERTENSIONAHA. 113. 02767.
25. Valdemarsson S, Edvinsson L, Ekman R, Hedner P, Sjöholm A. Increased plasma level of substance P in patients with severe congestive heart failure treated with ACE inhibitors. J Intern Med. 1991;230:325-331.
26. Baerts L, Waumans Y, Brandt I, Jungraithmayr W, Van der Veken P, Vanderheyden M, De Meester I. Circulating stromal cell-derived factor 1? levels in heart failure: a matter of proper sampling. PLoS One. 2015;10:e0141408. doi: 10. 1371/journal. pone. 0141408.
27. Ullman B, Jensen-Urstad M, Hulting J, Lundberg JM. Neuropeptide Y, noradrenaline and invasive haemodynamic data in mild to moderate chronic congestive heart failure. Clin Physiol. 1993;13:409-418.
28. Paulus WJ, Dal Canto E. Distinct myocardial targets for diabetes therapy in heart failure with preserved or reduced ejection fraction. JACC Heart Fail. 2018;6:1-7. doi: 10. 1016/j. jchf. 2017. 07. 012.
29. Song DK, Hong YS, Lee H, Oh JY, Sung YA, Kim Y. Increased epicardial adipose tissue thickness in type 2 diabetes mellitus and obesity. Diabetes Metab J. 2015;39:405-413. doi: 10. 4093/dmj. 2015. 39. 5. 405.
30. Pastel E, McCulloch LJ, Ward R, Joshi S, Gooding KM, Shore AC, Kos K. GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction. Clin Sci (Lond). 2017;131:343-353. doi: 10. 1042/ CS20160803.
31. Kim D, Kim J, Yoon JH, et al. CXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice. Diabetologia. 2014;57:1456-1465. doi: 10. 1007/s00125-014-3237-5.
32. Peng H, Zhang H, Zhu H. Blocking CXCR7-mediated adipose tissue macrophages chemotaxis attenuates insulin resistance and inflammation in obesity. Biochem Biophys Res Commun. 2016;479:649-655. doi: 10. 1016/j. bbrc. 2016. 09. 158.
33. Patel VB, Shah S, Verma S, Oudit GY. Epicardial adipose tissue as a metabolic transducer: role in heart failure and coronary artery disease. Heart Fail Rev. 2017;22:889-902. doi: 10. 1007/s10741-017-9644-1.
34. Chu PY, Zatta A, Kiriazis H, Chin-Dusting J, Du XJ, Marshall T, Kaye DM. CXCR4 antagonism attenuates the cardiorenal consequences of mineralocorticoid excess. Circ Heart Fail. 2011;4:651-658. doi: 10. 1161/ CIRCHEARTFAILURE. 110. 960831.
35. Mulvihill EE, Varin EM, Ussher JR, Campbell JE, Bang KW, Abdullah T, Baggio LL, Drucker DJ. Inhibition of dipeptidyl peptidase-4 impairs ventricular function and promotes cardiac fibrosis in high fat-fed diabetic mice. Diabetes. 2016;65:742-754. doi: 10. 2337/db15-1224.
36. Chu PY, Walder K, Horlock D, Williams D, Nelson E, Byrne M, Jandeleit-Dahm K, Zimmet P, Kaye DM. CXCR4 antagonism attenuates the development of diabetic cardiac fibrosis. PLoS One. 2015;10:e0133616. doi: 10. 1371/journal. pone. 0133616.
37. Dehlin HM, Manteufel EJ, Monroe AL, Reimer MH Jr, Levick SP. Substance P acting via the neurokinin-1 receptor regulates adverse myocardial remodeling in a rat model of hypertension. Int J Cardiol. 2013;168:4643-4651. doi: 10. 1016/j. ijcard. 2013. 07. 190.
38. Wei SG, Zhang ZH, Yu Y, Weiss RM, Felder RB. Central actions of the chemokine stromal cell-derived factor 1 contribute to neurohumoral excitation in heart failure rats. Hypertension. 2012;59:991-998. doi: 10. 1161/ HYPERTENSIONAHA. 111. 188086.
39. Wei SG, Zhang ZH, Yu Y, Felder RB. Central SDF-1/CXCL12 expression and its cardiovascular and sympathetic effects: the role of angiotensin II, TNF-?, and MAP kinase signaling. Am J Physiol Heart Circ Physiol. 2014;307:H1643-H1654. doi: 10. 1152/ajpheart. 00432. 2014.
40. Dzurik MV, Diedrich A, Black B, Paranjape SY, Raj SR, Byrne DW, Robertson D. Endogenous substance P modulates human cardiovascular regulation at rest and during orthostatic load. J Appl Physiol (1985). 2007;102:2092-2097. doi: 10. 1152/japplphysiol. 00969. 2006.
41. Shanks J, Herring N. Peripheral cardiac sympathetic hyperactivity in cardiovascular disease: role of neuropeptides. Am J Physiol Regul Integr Comp Physiol. 2013;305:R1411-R1420. doi: 10. 1152/ajpregu. 00118. 2013.
42. Jackson EK, Mi Z. Sitagliptin augments sympathetic enhancement of the renovascular effects of angiotensin II in genetic hypertension. Hypertension. 2008;51:1637-1642. doi: 10. 1161/HYPERTENSIONAHA. 108. 112532.
43. Marney A, Kunchakarra S, Byrne L, Brown NJ. Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension. 2010;56:728-733. doi: 10. 1161/HYPERTENSIONAHA. 110. 156554.
44. Boschmann M, Engeli S, Dobberstein K, Budziarek P, Strauss A, Boehnke J, Sweep FC, Luft FC, He Y, Foley JE, Jordan J. Dipeptidyl-peptidase-IV inhibition augments postprandial lipid mobilization and oxidation in type 2 diabetic patients. J Clin Endocrinol Metab. 2009;94:846-852. doi: 10. 1210/jc. 2008-1400.
45. Jackson EK, Dubinion JH, Mi Z. Effects of dipeptidyl peptidase iv inhibition on arterial blood pressure. Clin Exp Pharmacol Physiol. 2008;35:29-34 doi: 10. 1111/j. 1440-1681. 2007. 04737. x.
46. Sipido KR. CaM or cAMP: linking beta-adrenergic stimulation to 'leaky' RyRs. Circ Res. 2007;100:296-298. doi: 10. 1161/01. RES. 0000259326. 68260. 20.
47. Antos CL, Frey N, Marx SO, Reiken S, Gaburjakova M, Richardson JA, Marks AR, Olson EN. Dilated cardiomyopathy and sudden death resulting from constitutive activation of protein kinase a. Circ Res. 2001;89:997-1004.
48. Zhang X, Szeto C, Gao E, et al. Cardiotoxic and cardioprotective features of chronic ?-adrenergic signaling. Circ Res. 2013;112:498-509. doi: 10. 1161/CIRCRESAHA. 112. 273896.
49. Dwinell MB, Ogawa H, Barrett KE, Kagnoff MF. SDF-1/CXCL12 regulates cAMP production and ion transport in intestinal epithelial cells via CXCR4. Am J Physiol Gastrointest Liver Physiol. 2004;286:G844-G850. doi: 10. 1152/ajpgi. 00112. 2003.
50. LaRocca TJ, Schwarzkopf M, Altman P, Zhang S, Gupta A, Gomes I, Alvin Z, Champion HC, Haddad G, Hajjar RJ, Devi LA, Schecter AD, Tarzami ST. 2-Adrenergic receptor signaling in the cardiac myocyte is modulated by interactions with CXCR4. J Cardiovasc Pharmacol. 2010;56:548-559. doi: 10. 1097/FJC. 0b013e3181f713fe.
51. Miyoshi T, Nakamura K, Yoshida M, Miura D, Oe H, Akagi S, Sugiyama H, Akazawa K, Yonezawa T, Wada J, Ito H. Effect of vildagliptin, a dipeptidyl peptidase 4 inhibitor, on cardiac hypertrophy induced by chronic beta-adrenergic stimulation in rats. Cardiovasc Diabetol. 2014;13:43. doi: 10. 1186/1475-2840-13-43.
52. Lee TM, Chen WT, Chang NC. Dipeptidyl peptidase-4 inhibition attenuates arrhythmias via a protein kinase A-dependent pathway in infarcted hearts. Circ J. 2015;79:2461-2470. doi: 10. 1253/circj. CJ-15-0515.
53. Grimm M, Ling H, Willeford A, Pereira L, Gray CB, Erickson JR, Sarma S, Respress JL, Wehrens XH, Bers DM, Brown JH. CaMKII? mediates ?-adrenergic effects on RyR2 phosphorylation and SR Ca(2+) leak and the pathophysiological response to chronic ?-adrenergic stimulation. J Mol Cell Cardiol. 2015;85:282-291. doi: 10. 1016/j. yjmcc. 2015. 06. 007.
54. Mani SK, Egan EA, Addy BK, Grimm M, Kasiganesan H, Thiyagarajan T, Renaud L, Brown JH, Kern CB, Menick DR. beta-Adrenergic receptor stimulated Ncx1 upregulation is mediated via a CaMKII/AP-1 signaling pathway in adult cardiomyocytes. J Mol Cell Cardiol. 2010;48:342-351. doi: 10. 1016/j. yjmcc. 2009. 11. 007.
55. Yoo B, Lemaire A, Mangmool S, Wolf MJ, Curcio A, Mao L, Rockman HA. Beta1-adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction. Am J Physiol Heart Circ Physiol. 2009;297:H1377-H1386. doi: 10. 1152/ajpheart. 00504. 2009.
56. Mühlstedt S, Ghadge SK, Duchene J, Qadri F, Järve A, Vilianovich L, Popova E, Pohlmann A, Niendorf T, Boyé P, Özcelik C, Bader M. Cardiomyocyte-derived CXCL12 is not involved in cardiogenesis but plays a crucial role in myocardial infarction. J Mol Med (Berl). 2016;94:1005-1014. doi: 10. 1007/s00109-016-1432-1.
57. Jarrah AA, Schwarskopf M, Wang ER, LaRocca T, Dhume A, Zhang S, Hadri L, Hajjar RJ, Schecter AD, Tarzami ST. SDF-1 induces TNFmediated apoptosis in cardiac myocytes. Apoptosis. 2018;23:79-91. doi: 10. 1007/s10495-017-1438-3.
58. Luo G, Xu X, Guo W, Luo C, Wang H, Meng X, Zhu S, Wei Y. Neuropeptide Y damages the integrity of mitochondrial structure and disrupts energy metabolism in cultured neonatal rat cardiomyocytes. Peptides. 2015;71:162-169. doi: 10. 1016/j. peptides. 2015. 07. 001.
59. Robinson P, Kasembeli M, Bharadwaj U, Engineer N, Eckols KT, Tweardy DJ. Substance P receptor signaling mediates doxorubicin-induced cardiomyocyte apoptosis and triple-negative breast cancer chemoresistance. Biomed Res Int. 2016;2016:1959270. doi: 10. 1155/2016/1959270.