Is Dipeptidylpeptidase IV the Missing Link in Angiotensin-Converting Enzyme Inhibitor–Induced Angioedema?

Abstract

A pproximately 40 million people worldwide are currently treated with angiotensin-converting enzyme (ACE) inhibitors (ACEIs) for hypertension, congestive heart failure, coronary diseases, and diabetic nephropathy. The primary mechanism of action of ACEIs is blocking of the renin angiotensin system by inhibiting the conversion of angiotensin I to the vasoconstrictor angiotensin II. Few serious adverse events specific to ACE inhibition were initially reported, because they are actually rare. However, Յ0.68 of every 100 patients seem to experience angioedema with ACEI, sometimes months and even years after the start of medication. 1 The pathophysiology of ACEI-induced angioedema is presently thought to result from the role of ACE in the degradation of other peptides including bradykinin (BK) and substance P (SP The metabolism of BK and SP by proteases is redundant, with several enzymes available to terminate their biological action. Both ACE and neutral endopeptidase (NEP) play major roles in inactivating BK and SP. 2 BK is also processed by aminopeptidase P, but a contribution of this peptidase in angioedema during ACEI is unlikely, despite a downregulation of its activity reported in some cases. 4 BK is also a substrate of kininase I, capable of cleaving the last residue off its C-terminal end to generate des-Arg 9 -BK, a fragment without affinity for the B2 receptor but an agonist on the inducible B1 receptor expressed during inflammation. 4 On the other hand, SP is sequentially truncated by dipeptidylpeptidase IV (DP-PIV) into SP3-11 and then SP5-11, which is 1000-fold less potent than the native peptide. 5 However, the physiological importance of DPPIV in the inactivation of SP and the role of a reduction of DPPIV activity in ACEI-induced angioedema had not been evaluated before the article by Byrd et al,6 published in this issue of Hypertension. ACE Inhibition and AngioedemaThe incidence of ACEI-induced angioedema ranges from 0.1% in patients treated with short-acting drugs such as captopril to 0.68% in patients treated with more potent inhibitors such as enalapril, as reported in the Omapatrilat Cardiovascular Treatment Versus Enalapril Study. 7 Recently, dual vasopeptidase inhibition seemed very promising by blocking NEP, thereby increasing circulating concentrations of natriuretic peptides, and ACE, thus hampering angiotensin II generation. Omapatrilat was the first dual inhibitor in this new class of drugs that was highly active in hypertension. 7 Unfortunately, vasopeptidase inhibitors caused up to a 2.1% rate of angioedema after a short period of treatment. Interestingly, smoking was associated with an even higher 3.9% occurrence of angioedema in omapatrilat-treated patients. 7 In contrast, diabetic patients seem less prone to develop angioedema during ACE or ACE/NEP blockade. 5 In this context, the new drug application for omapatrilat has been withdrawn pending safety reassessment. The increased rate of angioedema induced by dual ACE/NEP inhibitors strengthens the hypothesis that BK and/or SP are invol...

Cut to the chase: a review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system

“…A once‐daily application is convenient from a patient viewpoint. However, long‐acting inhibitors of DPP4 might compete with other natural substrates of DPP4 and their associated physiological functions, such as surfactant protein (SP) in rhinosinusitis and angioedema, SDF‐α in arthritis and NPY/PYY, as well as substance P in blood pressure . Recently, the FDA revised its prescribing information to include case reports on acute pancreatitis as well as polyarthritis in patients using sitagliptin .…”