Standard Angiotensin-converting Enzyme Inhibitor Research Articles

MO069: Therapeutic Effects of Semaglutide as Mono and Combination Treatment with Lisinopril in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease

Abstract BACKGROUND AND AIMS Obesity, hyperglycemia and hypertension are critical risk factors for the onset and progression of diabetic kidney disease (DKD). Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular and renal outcomes in type 2 diabetes patients. We have recently profiled the effects of SGLT2 and angiotensin-converting enzyme (ACE) inhibition in a model of advanced DKD facilitated by adeno-associated virus (AAV)-mediated renin overexpression in uninephrectomized (UNx) diabetic db/db mice (Østergaard et al., AJP Renal Physiol 321: F149–F161, 2021). In the present study, we evaluated the nephroprotective effects of the long-acting GLP1R agonist semaglutide, a long-acting GLP1R agonist currently approved for diabetes and obesity treatment and in clinical development for DKD. Semaglutide was profiled with and without combination treatment with lisinopril, a standard ACE inhibitor, in the db/db UNx-ReninAAV mouse model of DKD. METHOD Female db/db mice received a single intravenous injection of reninAAV 1 week prior to UNx. Six weeks post-nephrectomy, mice were randomized into treatment groups based on body weight and blood glucose in the fed state, and received vehicle (SC, QD), semaglutide 30 nmol/kg or semaglutide 30 nmol/kg (SC, QD) in combination with lisinopril 30 mg/kg (PO, QD) for 11 weeks. Treatment endpoints included blood pressure, plasma/urine biochemistry and histomorphometric markers of kidney injury. RESULTS Vehicle-dosed db/db UNx-ReninAAV mice developed hallmarks of hypertensive DKD characterized by severe albuminuria and advanced glomerulosclerosis. Compared with vehicle, semaglutide significantly reduced fed blood glucose and hemoglobin A1C levels, whereas no significant effect on plasma insulin was observed. Semaglutide significantly reduced both diastolic and systolic blood pressure as well as albuminuria and urine kidney injury molecule-1 (KIM-1) levels. Semaglutide improved kidney histopathology with notable reductions in glomerulosclerosis severity and percent area of KIM-1 staining. Combined lisinopril treatment led to further improvements in blood pressure, albuminuria and glomerulosclerosis. Semaglutide with and without lisinopril coadministration did not influence plasma urea, cystatin C and kidney CD11 expression. CONCLUSION Semaglutide improved disease hallmarks in the db/db UNx-ReninAAV mouse model of advanced DKD. Further benefits on renal functional and histological markers were obtained by combination with antihypertensive standard-of-care treatment.

Was the Enalapril Dose Too Low in the PARADIGM-HF Trial?

Heart failure (HF) is a common clinical syndrome associated with significant morbidity and mortality, and there remains a clear need for innovative therapies that can modify disease progression. Sacubitril/valsartan (LCZ696) is a novel complex that combines simultaneous neprilysin inhibition and angiotensin II receptor blockade, that has demonstrated significant cardiovascular death or HF hospitalization reduction in the Prospective Comparison of Angiotensin Receptor/Neprilysin Inhibitor (ARNI) With Angiotensin-Converting Enzyme (ACE) Inhibitors to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial when compared with evidence-based doses of the gold standard ACE inhibitor enalapril. In this comprehensive review, the authors discuss historical trials that have investigated clinical outcomes utilizing variable dosing levels of ACE inhibitors or angiotensin receptor blockers in patients with HF with reduced ejection fraction. A critical analysis of the highlighted studies is proposed in the context of current HF management guidelines and HF clinical practice. In conclusion, based on current evidence, it is unclear whether a maximum recommended enalapril dose would promote improved patient outcomes compared with an intermediate dose. However, no prospective study to date comparing ACE inhibitor doses has documented that higher doses result in significant mortality reduction, although the data suggest that there may be a decrease in HF hospitalizations when compared with lower doses.

Telmisartan in High Cardiovascular Risk Patients

The worldwide morbidity and mortality burden of cardiovascular disease (CVD) is overwhelming and caused by increasing life expectancy and an epidemic of risk factors, including hypertension. Therapeutic options targeting different areas of the renin–angiotensin–aldosterone system (RAAS) to disrupt pathophysiological processes along the cardiovascular continuum are available. Angiotensin-converting enzyme (ACE) inhibitors are first-line treatments for CVD and angiotensin receptor blockers (ARBs) are suitable alternatives. Both ACE inhibitors and ARBs prevent CVD by lowering blood pressure (BP). Additionally, several studies have demonstrated that RAAS blockade can reduce cardiovascular risk beyond what might be expected from BP lowering alone. However, the ARBs are not all equally effective. Telmisartan is a long-lasting ARB that effectively controls BP over the full 24-hour period. Recently, the Ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET) study showed that telmisartan reduces cardiovascular events in high cardiovascular risk patients similarly to the gold standard ACE inhibitor ramipril beyond BP lowering alone, but with a better tolerability. Based on the results of the ONTARGET and Telmisartan randomized assessment study in ACE intolerant subjects with cardiovascular disease (TRANSCEND) studies, telmisartan is indicated for the reduction of cardiovascular morbidity. This article aims to review current guidelines for the management of CVD and consider key data from clinical trials and clinical practice evaluating the role of telmisartan in CVD.

Potential advantages of cell administration on the inflammatory response compared to standard ACE inhibitor treatment in experimental myocardial infarction

BackgroundBone Marrow (BM) progenitor cells can target the site of myocardial injury, contributing to tissue repair by neovascolarization and/or by a possible direct paracrine effect on the inflammatory cascade. Angiotensin Converting Enzyme inhibitors (ACE-I) are effective in reducing mortality and preventing left ventricular (LV) function deterioration after myocardial infarction.MethodsWe investigated the short term effects of BM mononuclear cells (BMMNCs) therapy on the pro-inflammatory cytokines (pro-CKs) and on LV remodelling and compared these effects over a standard ACE-I therapy in a rat model of myocardial cryodamage.Forty two adult inbread Fisher-F344 rats were randomized into three groups: untreated (UT; n = 12), pharmacological therapy (ACE-I; n = 14, receiving quinapril), and cellular therapy (BMMNCs; n = 16, receiving BMMNCs infusion). Rats underwent to a standard echocardiogram in the acute setting and 14 days after the damage, before the sacrifice. Pro-CKs analysis (interleukin (IL)1β, IL-6, tumor necrosis factor (TNF)α was performed (multiplex proteome arrays) on blood samples obtained by direct aorta puncture before the sacrifice; a control group of 6 rats was considered as reference.ResultsConcerning the extension of the infarcted area as well as the LV dimensions, no differences were observed among the animal groups; treated rats had lower left atrial diameters and higher indexes of LV function. Pro-Cks were increased in infarcted-UT rats if compared with controls, and significantly reduced by BMMNCs and ACE-I ; TNFα inversely correlated with LV fractional shortening.ConclusionAfter myocardial infarction, both BMMNCs and ACE-I reduce the pattern of pro-Ck response, probably contributing to prevent the deterioration of LV function observed in UT rats.

LESSONS FROM ONTARGET

The recently published results of the ONTARGET trial shed a new light on the cardiovascular protection of patients at high risk of a cardiovascular event.Despite a number of trials looking at the efficacy of Angiotensin Converting Enzyme inhibitors (ACEis) or Angiotensin Receptor Blockers (ARBs) in the prevention of cardiovascular events in patients with specific high risk profiles, the question of the equivalence of ACEis and ARBs remained unanswered.The ONTARGET trial has shown that telmisartan 80 mg administered for a median duration of 4.5 years to patients at high risk of developing a major cardiovascular event, is equally effective to ramipril 10 mg. In addition, telmisartan was slightly better tolerated. The comparator ramipril has been chosen as it is currently the gold standard ACEi since the results of the HOPE study, in terms of the composite outcome of cardiovascular death, myocardial infarction and stroke.Moreover, ONTARGET is the first trial to test the hypothesis of superiority of adding an ARB (telmisartan 80 mg) to an ACEi (ramipril 10 mg) over the ACEi ramipril monotherapy in cardiovascular protection of the same broad range of high-risk patients. Surprisingly, despite a more pronounced blood pressure lowering, the combination of the two agents did not lead to an additional decrease in the number of events, but had significantly more side-effects compared to ramipril monotherapy.ONTARGET is a landmark study, performed according to the highest statistical and clinical standards, providing compelling evidence and clear answers to two important clinical questions.

Urocortin 2 combined with angiotensin-converting enzyme inhibition in experimental heart failure

Ucn2 (urocortin 2) is a recently discovered peptide with therapeutic potential in heart failure. As any new treatment is likely to be used in conjunction with standard ACEI (angiotensin-converting enzyme inhibitor) therapy, it is important that the combined effects of these agents are assessed. In the present study, we investigated the effects of Ucn2 and an ACEI (captopril) administered for 3 h, both separately and together, in eight sheep with pacing-induced heart failure. Ucn2 and captopril alone both increased CO (cardiac output; Ucn2>captopril) and decreased arterial pressure (captopril>Ucn2), left atrial pressure (Ucn2>captopril) and peripheral resistance (Ucn2=captopril) relative to controls. Compared with either treatment alone, combined treatment further improved CO and reduced peripheral resistance and cardiac preload, without inducing further falls in blood pressure. In contrast with the marked increase in plasma renin activity observed with captopril alone, Ucn2 administration reduced renin activity, whereas the combined agents resulted in intermediate renin levels. All active treatments decreased circulating levels of aldosterone (Ucn2+captopril>Ucn2=captopril), endothelin-1 and the natriuretic peptides (Ucn2+captopril=Ucn2>captopril), whereas adrenaline (epinephrine) fell only with Ucn2 (Ucn2+captopril=Ucn2), and vasopressin increased during captopril alone. Ucn2, both separately and in conjunction with captopril, increased urine output, sodium and creatinine excretion and creatinine clearance. Conversely, captopril administered alone adversely affected these renal indices. In conclusion, co-treatment with Ucn2 and an ACEI in heart failure produced significantly greater improvements in haemodynamics, hormonal profile and renal function than achieved by captopril alone. These results indicate that dual treatment with these two agents is beneficial.

Neurohormonal Intervention to Reduce Sudden Cardiac Death in Heart Failure: What is the Optimal Pharmacologic Strategy?

Sudden cardiac death (SCD) accounts for up to 50% of deaths in patients with heart failure (HF), depending on severity of symptomatic impairment and left ventricular dysfunction. Neurohormonal therapy directed at the renin-angiotensin-aldosterone system may reduce the propensity to SCD through improved hemodynamic responsiveness, reduced sympathetic tone in the myocardium and inhibition of cardiac remodelling. Angiotensin converting enzyme (ACE) inhibitors reduce overall mortality in chronic HF, the greatest benefit appearing to arises from reduction of HF progression rather than SCD. In HF patients who experience myocardial infarction (MI) reduced incidence in SCD may make a more marked contribution to the mortality benefits of ACE inhibition. Addition of beta-blocker therapy to ACE inhibition has consistently resulted in a reduction in SCD in patients with either mild-to-moderate or severe HF, and in the presence or absence of MI; the reduction in SCD is of the order of one-third versus placebo. Aldosterone blockade reduces the risk of SCD in advanced chronic heart failure (when added to ACE inhibitor) and in HF associated with acute MI (when given in addition to both ACE inhibitor and beta blocker). The evidence base suggests that for maximal SCD risk reduction in HF, beta-blocker therapy is advisable in combination with standard ACE inhibitor therapy, with addition of aldosterone blockade to this regimen for particular groups of heart failure patients.

Cellular Basis for Therapeutic Choices in Heart Failure

Stop it at the start; it’s late for medicine to be prepared when disease has grown strong through long delays. — —Ovid, Remedia Amoris A crucial experimental study in 1985 showed that the angiotensin-converting enzyme inhibitor (ACEi) captopril did more than reduce the after- and preload on the heart in failure; captopril also improved remodeling by lessening the degree of left ventricular (LV) dilation.1 A series of powerful clinical studies starting in 1987 established the crucial role of ACE inhibition in severe heart failure such that it almost became unethical to test other modalities of heart failure therapies except as add-on therapies. Thus, it was difficult to know whether the advent of the angiotensin II subtype I receptor blockers (ARBs) brought improvement beyond those of standard ACEi therapy. The most practical approach was to add an ARB such as valsartan to the therapeutic regimen of patients, 86% of whom were already receiving an ACEi.2 In the small non-ACEi group, valsartan appeared to be even more effective, but the limited size of the group made it difficult to be sure. Furthermore, the addition of valsartan to the small number of patients already being treated with ACEi and β-blockade appeared to be harmful. These defects have been remedied by another ARB, candesartan, which was evaluated in the Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) series of studies. The study by Young et al3 represents the effects of candersartan versus placebo given to a prespecified subgroup of patients with heart failure and a low ejection fraction (≤40%). They combined data from the CHARM-Alternative (participants who could not tolerate ACEi)4 and CHARM-Added (all participants already treated with an ACEi; 55% were also being treated with β-blockers and 17% with spironolactone).5 Whereas in the original …

Omapatrilat limits infarct size and lowers the threshold for induction of myocardial preconditioning through a bradykinin receptor-mediated mechanism.

Bradykinin is an important endogenous trigger of myocardial ischemic preconditioning (IPC). Through simultaneous inhibition of neutral endopeptidase and angiotensin converting enzyme, omapatrilat prevents enzymatic degradation of bradykinin. The aim of this study was to investigate if omapatrilat, through its ability to augment bradykinin levels, can augment a subthreshold IPC stimulus (Sub-IPC) and to compare the action of omapatrilat with the angiotensin-converting enzyme inhibitor, captopril. Langendorff perfused rat hearts were subjected to 35 min left coronary artery occlusion and 120 min reperfusion. Full IPC was induced with 5 min global ischemia/10 min reperfusion and substantially limited infarct size (21.5 +/- 3.5% of risk zone vs 53.4 +/- 2.0% in controls, P < 0.01). Sub-IPC (2 min global ischemia/10 min reperfusion) did not limit infarct size (48.4 +/- 3.8%). Omapatrilat (10 micromol/L) or captopril (200 micromol/L) were administered alone or in conjunction with Sub-IPC. Reduced infarct size comparable to that observed with the full IPC protocol was seen when sub-IPC was combined with either omapatrilat (19.7 +/- 2.5%) or captopril (20.3 +/- 4.9%). Omapatrilat alone caused modest reduction of infarct size (34.6 +/- 1.5%, P < 0.01 v control), an effect not observed with captopril. Hoe140, a selective kinin B(2) receptor antagonist, eliminated the cardioprotective effect of omaptrilat alone or in combination with sub-IPC. We conclude that omapatrilat elicits cardioprotection via inhibition of bradykinin degradation and that dual inhibition of angiotensin-converting enzyme and neutral endopeptidase may have beneficial effects beyond standard angiotensin-converting enzyme inhibitor therapy in patients with acute coronary syndromes who are at risk of myocardial infarction.

Angiotension II receptor blockade and hypertensive nephropathy

Angiotension II receptor blockade and hypertensive nephropathy

South Australian hypertension survey: General practitioner experiences with drug treatment

To investigate prescribing habits, educational approaches and perceived needs of general practitioners in the drug treatment of hypertension. Of 156 randomly selected South Australian general practitioners 132 responded to a questionnaire survey. Diuretics are the most commonly chosen drug for the initial management of uncomplicated moderate hypertension. Equivalent patients aged 45, 60 and 75 years would be prescribed a diuretic as drug of first choice in 41%, 55% and 68% of cases respectively. Despite this, there are wide differences in the choice of initial therapy between individual practitioners. These differences can have a substantial cost impact, given that in Australia the cost of diuretic therapy for one month can be as low as $1.97 compared with $34.08 for standard angiotensin converting enzyme inhibitor therapy for one month. There was also a perceived need, and demand, for patient education materials to assist practitioners in the drug treatment of hypertension.