Journal of Human Hypertension (2006) 20, 478–481 & 2006 Nature Publishing Group All rights reserved 0950-9240/06 $30.00 www.nature.com/jhh COMMENTARY Dual ACE/NEP inhibitors – more than playing the ACE card

KAM Jandeleit-Dahm Baker Heart Research Institute, Danielle Alberti JDRF Centre for Diabetes Complications, Wynn Domain, Melbourne, Victoria, Australia

Journal of Human Hypertension (2006) 20, 478–481. doi:10.1038/sj.jhh.1002018; published online 16 March 2006

Background lin-1 (ET-1).3,4 Atrial natriuretic peptide mediates increased urine production, natriuresis and urinary Vasopeptidase inhibition is a novel therapeutic cGMP excretion. Furthermore, ANP inhibits approach in the treatment of cardiovascular diseases and aldosterone secretion.5 such as hypertension and . The concept However, long-term studies with NEP inhibitors of dual inhibition of the two enzymes, have demonstrated only limited beneficial effects in converting enzyme (ACE) and neutral endopep- heart failure and hypertension, mainly due to a loss tidase (NEP) by a single molecule has shown of efficacy. This has been explained as the long-term major benefits and potentially superiority versus antihypertensive effect of NEP inhibitors may be other agents in various experimental models of 1 offset by a counteracting activation of the renin– hypertension, heart failure and renal disease. The angiotensin system (RAS) and the sympathetic underlying presumed rationale for the combined nervous system and/or by downregulation of ANP inhibition of ACE and NEP is to block the vasocons- receptors.6 trictor angiotensin II (AII) and simultaneously increase the vasodilator, atrial natriuretic peptide (ANP) by decreasing its enzymatic degradation. Furthermore, both vasoactive hormones, AII and Angiotensin converting enzyme/neutral ANP appear to have actions beyond their haemody- endopeptidase inhibitors namic effects. AII meditates proliferation, fibrosis, inflammation and oxidative stress whereas ANP has Based on a large body of experimental evidence it antiproliferative and antifibrotic effects. Both pep- has become evident that the RAS, the kallikrein- tides have been postulated to act as endogenous kinin pathway and the natriuretic peptides are antagonists to each other.2 important modulators of cardiovascular homeosta- sis. These findings have provided the impetus to develop inhibitors that simultaneously block AII Neutral endopeptidase inhibition and increase ANP, peptides which are regulated by endothelial, membrane bound zinc-dependent en- On the basis of the positive results with ACE zymes, ACE and NEP, two enzymes with significant inhibition in a range of cardiovascular diseases, structural homology. including hypertension, diabetes and renal disease Thus, the introduction of dual metallopeptidase several investigators have started to study the inhibitors should be considered a new therapeutic potentially added beneficial effects by blocking concept in cardiovascular disease. In various ex- other endogenous enzymes involved in peptide perimental models of hypertension, heart disease activation or degradation. One of these enzymes is and renal disease combined ACE/NEP inhibition led NEP, a metallopeptidase similar in structure and to more potent and synergistic hemodynamic and distribution to ACE. renal effects than selective inhibitors of the indivi- Neutral endopeptidase catalyses the degradation dual enzymes. The antihypertensive7 and antifibro- of various endogenous vasodilator peptides includ- tic effects8–10 were associated with enhanced ing ANP, BNP, CNP, substance P and as , natriuresis and improved myocardial well as vasoconstrictor peptides including endothe- function.11 Part of the beneficial effects of ACE inhibitors in Correspondence: Dr KAM Jandeleit-Dahm, Baker Heart Research hypertension and heart failure as well as in the Institute, Danielle Alberti JDRF Centre for Diabetes Complica- acute stages after myocardial infarction12 have been tions, Wynn Domain, Commercial Road, Melbourne 3004, Victoria, Australia. attributed to the inhibition of kinin degradation E-mail: [email protected] resulting in increased endothelial NO bioavailabil- Published online 16 March 2006 ity. Neutral endopeptidase also inhibits kinin Dual ACE/NEP inhibitors – more than playing the ACE card KAM Jandeleit-Dahm 479 degradation thus increasing kinin concentrations. 9% (Po0.05). The OCTAVE study also showed Part of the beneficial effect of omapatrilat in cardiac that omapatrilat had superior antihypertensive ischemia and reperfusion injury12 appears to be effects compared to . In that trial, however, mediated via the increased kinin concentrations was observed in 2.17% of the popula- resulting from ACE and NEP inhibition. As the tion in the omapatrilat-treated groups versus 0.68% inhibition of bradykinin breakdown by ACE and in the enalapril treated group. In Afro-American NEP is additive, excess bradykinin accumulation subjects the incidence was even higher (5.54 versus may be the cause of angioedema observed with some 1.62%, respectively). This effect has been attributed ACE/NEP inhibitors and, in particular, with omapa- to firstly the rapid increase in bradykinin and its trilat. Indeed, omapatrilat has recently been shown metabolite BK-8 by simultaneously blocking both to induce extravasation in high doses.13 As the BK degrading pathways and secondly by potentially various ACE/NEP inhibitors differ in their ability a direct effect of the agent to promote extravasa- and relative potency to inhibit ACE versus NEP this tion.13 Based on these findings and, in particular, may not only influence the magnitude of kinin the incidence of this potentially life threatening production but also the antihypertensive, cardio side effect it appears unlikely that omapatrilat vascular and antifibrotic effects. will become routine for hypertension, Omapatrilat is the ACE/NEP inhibitor that has especially in the Afro-American population. been most extensively studied. Omapatrilat is a In terms of cardioprotection in chronic heart fail- potent, long acting dual metalloproteinase inhibitor ure, the IMPRESS study25 did not show a statistically (ACE IC50 ¼ 5 nmol/l, NEP IC50 ¼ 8 nmol/l) and ex- significant difference between the omapatrilat and the erts prolonged antihypertensive effects in several -treated groups after 12 weeks of treatment. experimental models of hypertension including the However, a positive trend for a beneficial effect with DOCA salt hypertensive model and the SHR.14 omapatrilat on heart failure was noted. Further studies have also demonstrated cardio- It remains controversial as to whether dual ACE/ renal protection including in myocardial ischemia NEP inhibitors confer superior cardiovascular ef- and reperfusion injury15 and in DOCA salt hyper- fects when compared to ACE inhibition alone. The tensive rats where reduced cardiac and renal fibrosis IMPRESS study25 investigating the effect of omapa- has been observed.14 In chronic heart failure, trilat versus lisinopril on exercise tolerance and omapatrilat has been shown to improve myocardial morbidity in patients with heart failure suggested an structure and function as well as being superior to advantage of omapatrilat over lisinopril. Although ACE inhibition alone.9,10,16 both treatments similarly improved exercise tread- In progressive nephropathy, ACE/NEP inhibition mill test results there was a trend in favor of was renoprotective not only by inhibiting ACE and omapatrilat on the combined end point of death or increasing ANP but also by reducing renal ET-1 admission for worsening heart failure (P ¼ 0.052) production and NO bioavailability.17–20 Further- and a significant benefit of omapatrilat in the more, more recently the beneficial renal effects of composite of death, admission or discontinuation omapatrilat have been attributed to its ability to of study treatment for worsening heart failure. increase levels of the vasodilator Angiotensin 1–7, Omapatrilat improved NYHA class more than as assessed by urinary excretion of this peptide.21 lisinopril and furthermore had some beneficial In a recent study, it was demonstrated that ACE/ effects on circulating neurohormones and cyto- NEP inhibition has beneficial functional and struc- kines.26 However, more recently, the results of the tural vasoprotective effects reducing atherosclero- omapatrilat versus enalapril randomized Trial of sis,20,22 arterial stiffness and pulse pressure.23 Not utility in reducing Events (OVERTURE) trial did not only has omapatrilat been shown to reduce early show a difference in the magnitude of improvement fatty streak development22 but also the advanced in ventricular size or function after 1 year when and more complex atherosclerotic lesions observed comparing omapatrilat to enalapril treatment in in diabetes.20 This interesting finding extends the 321 patients with heart failure (NHHA classification potential utility of such agents. II or more).27,28 The Omapatrilat in Persons with Enhanced Risk of Atherosclerotic Events (OPERA) was planned to specifically investigate patients with Clinical evidence for a superior cardio- high cardiovascular risk aged above 65 years and vascular effect of ACE/NEP inhibition with hypertension,29 however, was abandoned due versus ACE inhibition to insufficient recruiting. The results of these clinical studies show that The OCTAVE study investigated the effect of there is a need to develop novel dual ACE/NEP omapatrilat versus enalapril on cardiovascular out- inhibitors with better safety profiles. comes in 5770 patients with CHF (NYHA II–IV).24 In the study presented by Johnson et al. in this Although there was no difference in terms of the issue of the Journal of Human Hypertension the primary end point between both treatment groups, clinical findings of a randomized, double controlled a post hoc analysis has shown a reduction of parallel study on 123 patients with mild to moderate cardiovascular death with omapatrilat treatment by hypertension treated with the novel ACE/NEP

Journal of Human Hypertension Dual ACE/NEP inhibitors – more than playing the ACE card KAM Jandeleit-Dahm 480 inhibitor GW660511X are presented. After a dose Triple inhibitors titration from 50 to 100 mg and then to 200 mg the antihypertensive efficacy and safety of GW 660511X The concept of triple vasopeptidase inhibition has was compared to placebo. A significant effect on recently gained interest. In this case, ACE/NEP mean systolic (À8 mm Hg) and diastolic blood inhibition is supplemented by additional inhibition pressure (À5.4 mm Hg) was noted with the dose of of endothelin converting enzyme (ECE) blocking the 200 mg daily. Furthermore, there was a significant conversion of big ET-1 to ET-1, a vasoconstrictor and reduction in the daytime 24 h mean blood pressure profibrotic agent acting in synergy with AII. Pre- with active treatment. However, surprisingly, there liminary studies in experimental settings such as the was no significant effect on nighttime 24 h mean SHR have shown that triple therapy dose depen- blood pressure. These effects were observed in dently reduced blood pressure, decreased AII and ET-1 concentrations as well as proANP, but in- association with significant inhibition of serum 30 ACE activity, increases in serum ANP concentra- creased big ET-1, ANP and bradykinin. Careful tions and urinary cGMP excretion, the well- evaluation of the safety profile of this promising described second messenger for ANP. There was therapeutic strategy in large-scale clinical trials is no effect on natriuresis. needed and mandatory before triple vasopeptidase In the mixed model analysis of variance, it was inhibitors may be considered an appropriate and shown that plasma ANP changes resulting from NEP safe option in the treatment of cardiovascular inhibition were the more powerful predictors of disease. changes in SBP and DBP when compared to serum In summary, based on the clinical evidence, the ACE activity in this study including in mild-to results are not encouraging enough for vasopepti- moderate hypertensive patients. The authors con- dase inhibitors, particularly because of the adverse clude from these findings that NEP and not ACE effect profile of these agents, to be considered for inhibition may be the predominant contributor to routine management of a range of cardiovascular the antihypertensive efficacy of GW660511X. There and renal disorders. Furthermore, it remains con- are two confounding factors in this conclusion. troversial as to whether there is an incremental Firstly, tissue ACE inhibition is independent of beneficial effect of ACE/NEP inhibition on top of changes in plasma ACE activity and was not ACE inhibition in hypertension or heart failure, measured in this study. However, tissue ACE based on the outcomes of the recent clinical trials. inhibition is important for the antihypertensive Nevertheless, a major impediment for recommenda- effects of ACE inhibition. Secondly, the experimen- tion of routine use of these new agents remains the tal evidence supports the view that ACE inhibition potentially life threatening side effect of angio- is more important for the antihypertensive and edema. Indeed, it remains unknown, if this effect antifibrotic as well as anti-atherosclerotic effects of is specific for omapatrilat, and if other more novel dual ACE/NEP inhibitors.20 ACE/NEP inhibitors have better safety profiles. The lack of an antihypertensive effect on night- There is preliminary evidence as outlined in the time blood pressure which may be due to the half present study, that novel ACE/NEP inhibitors in- life of 12 h of the drug is likely to have significant crease bradykinin accumulation to a much lesser implications for patients with hypertension and in extent compared to omapatrilat. Thus, the therapeu- particular those with diabetes who are non-dippers. tic role for ACE/NEP inhibitors may be in the It has become increasingly evident in various patients with high cardiovascular risk and athero- clinical studies, that non-dippers are exposed to a sclerosis, potentially in the diabetic patient. Indeed, higher cardiovascular risk. The failure of a treatment the benefits and potential risks of these agents need to reduce night-time mean blood pressure may have to be carefully evaluated in any future studies. important clinical implications for long-term cardio- vascular protection, in particular in patients with a high cardiovascular risk, such as in diabetes. References However, diabetic patients were not included in the 1 McClean DR, Ikram H, Garlick AH, Richards AM, present study and the problem may be overcome by Nicholls MG, Crozier IG. The clinical, cardiac, renal, administering a second night-time dose. arterial and neurohormonal effects of omapatrilat, a In the present study, no angioedema was noted. vasopeptidase inhibitor, in patients with chronic heart This may be due to the fact that the ACE/NEP failure. J Am Coll Cardiol 2000; 36: 479–486. inhibitor GW660511X causes 2–3 times less BK1–8 2 Johnston CI, Hodsman PG, Kohzuki M, Casley DJ, production compared to omapatrilat. However, it Fabris B, Phillips PA. Interaction between atrial needs to be considered that this was only a small natriuretic peptide and the renin angiotensin aldoster- study (123 patients), in predominantly Caucasian one system. Endogenous antagonists. Am J Med 1989; 87: 24S–28S. patients and for only a short duration (20 weeks). 3 Erdos EG, Skidgel RA. Neutral endopeptidase 24.11 Longer-term studies are needed in larger populations (enkephalinase) and related regulators of peptide including patients of different ethnic backgrounds to hormones. FASEB J 1989; 3: 145–151. confirm these results and to fully characterize the 4 Dussaule JC, Stefanski A, Bea ML, Ronco P, Ardaillou safety profile of this novel ACE/NEP inhibitor. R. Characterization of neutral endopeptidase in vas-

Journal of Human Hypertension Dual ACE/NEP inhibitors – more than playing the ACE card KAM Jandeleit-Dahm 481 cular smooth muscle cells of rabbit renal cortex. Am J 19 Taal MW, Nenov VD, Wong W, Satyal SR, Sakharova O, Physiol 1993; 264: F45–52. Choi JH et al. Vasopeptidase inhibition affords greater 5 Janssen WM, de Zeeuw D, van der Hem GK, de Jong renoprotection than angiotensin-converting enzyme PE. Antihypertensive effect of a 5-day infusion of atrial inhibition alone. J Am Soc Nephrol 2001; 12: natriuretic factor in humans. Hypertension 1989; 13: 2051–2059. 640–646. 20 Jandeleit-Dahm K, Lassila M, Davis BJ, Candido R, 6 Richards AM, Wittert GA, Crozier IG, Espiner EA, Johnston CI, Allen TJ et al. Anti-atherosclerotic and Yandle TG, Ikram H et al. 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