Effect Of LCZ696 Research Articles

1797-P: Effect of LCZ696 and Its Components Sacubitril and Valsartan on Insulin Secretion and Glucose Homeostasis in Mice

In type 2 diabetes, HbA1c decreases upon treatment of heart failure with the angiotensin receptor-neprilysin (NEP) inhibitor LCZ696 (LCZ). We sought to determine whether the components of LCZ, the NEP inhibitor sacubitril (SAC) and angiotensin receptor blocker valsartan (VAL), enhance insulin secretion and if so, their effects are additive when combined in LCZ. C57BL/6 mice fed high fat diet (HFD) received injections of vehicle (VEH) or low-dose streptozotocin (3 × 30 mg/kg; STZ), the latter to induce diabetes. Mice were continued for 8 weeks on HFD alone (CTL) or supplemented with LCZ (114 mg/kg/d), SAC (48 mg/kg/d) or VAL (54 mg/kg/d). All drugs significantly reduced body weight gain in both VEH and STZ groups, with LCZ being more effective than SAC (Table). SAC and VAL, but not LCZ, lowered fed and fasting plasma glucose and increased insulin release during an IV glucose tolerance test (IVGTT) in STZ mice only (Table). In VEH and STZ mice, insulin sensitivity was similar among the 4 treatment groups; however, SAC enhanced glucose disposal during IVGTT (Table). None of the treatments altered pancreatic ß- and α-cell mass or lipolysis (not shown). In sum, SAC and VAL exert beneficial anti-obesity, glycemic and insulinotropic effects when given alone in obese and/or diabetic mice. Additional studies are needed to understand why, when SAC and VAL are combined in LCZ, only anti-obesity effects are observed. Disclosure N. Esser: None. C.R. Schmidt: None. B. Barrow: None. L. Cronic: None. D.J. Hackney: None. S.M. Mongovin: None. R.L. Hull: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation (LCZ696BUSNC09T)

Effect of LCZ696 on Cardiac Fibrosis Induced by Beta-Adrenergic Stimulation in Rat

Effect of LCZ696 on Cardiac Fibrosis Induced by Beta-Adrenergic Stimulation in Rat

Elevation in high-sensitivity troponin T in heart failure and preserved ejection fraction and influence of treatment with the angiotensin receptor neprilysin inhibitor LCZ696.

Elevated high-sensitivity troponin is associated with increasing disease severity in patients with stable heart failure with reduced ejection fraction, but less is known about the association in heart failure with preserved ejection fraction. We examined the prevalence of elevated high-sensitivity troponin T (hs-TnT) in 298 patients with heart failure with preserved ejection fraction enrolled in the Prospective comparison of angiotensin receptor neprilysin inhibitor with angiotensin receptor blocker on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial, in which the angiotensin receptor neprilysin inhibitor LCZ696 reduced markers of heart failure severity compared with valsartan. We assessed the association between hs-TnT and cardiac structure and function, and the effect of LCZ696, compared with valsartan, on hs-TnT over 36 weeks. Elevated hs-TnT in the myocardial injury range (>0.014 μg/L) was found in 55% of patients and was associated with older age, history of diabetes mellitus, higher N-terminal pro-brain natriuretic peptide, lower estimated glomerular filtration rate, and larger left atrial size, left ventricular volume, and mass. LCZ696 treatment reduced hs-TnT to a greater extent at 12 weeks (12% reduction; P=0.05) and at 36 weeks (14% reduction; P=0.03) compared with valsartan. Troponin T was elevated in a substantial number of patients enrolled in a heart failure with preserved ejection fraction clinical trial and was associated with abnormalities of cardiac structure, function, and elevated baseline N-terminal pro-brain natriuretic peptide. Decreases in hs-TnT with LCZ696 in parallel with improvement in N-terminal pro-brain natriuretic peptide and left atrial size suggest that the angiotensin receptor neprilysin inhibitor LCZ696 may reduce this measure of myocardial injury in heart failure with preserved ejection fraction. http://www.clinicaltrials.gov. Unique identifier: NCT00887588.

Abstract 225: Treatment with LCZ696, an Orally Active Angiotensin Receptor Neprilysin Inhibitor Prevents Ischemic Brain Damage

Objective: Recent accumulating evidence suggests that an orally active angiotensin II receptor-neprilysin inhibitor, LCZ696, was supposed to be superior compared to angiotensin II receptor blocker (ARB), valsartan alone in treating cardiovascular disease. We previously reported that ARBs prevent ischemic brain damage using middle cerebral artery occlusion (MCAO) mouse model. Moreover, natriuretic peptides such as atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) increased by neprilysin inhibitor are also reported to protect brain damage. Therefore, we investigate the possible protective effects of valsartan (VAL) compared with LCZ696 (LCZ) (VAL+ neprilysin inhibitor; 1:1) on the prevention of ischemic damage after stroke. Methods: Focal brain ischemia was induced by MCAO with the intraluminal filament technique in 10-week male C57BL/6J mice. Mice were treated with VAL (3 mg/kg) or LCZ (6 mg/kg) orally as powder in gelatin mini-capsules daily for 2 weeks before MCAO. Ischemic area was evaluated by triphenyl tetrazolium chloride staining, cerebral blood flow (CBF) by laser-Doppler flowmetry, oxidative stress by dihydroethidium staining. Results: Telemetry method showed that systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) did not change before and after treatments. Protective effect of LCZ treatment on ischemic brain damage in each brain section seemed to be more marked than that of VAL treatment. The average ischemic area ratio showed a significant reduction in VAL and LCZ groups compared with CON group. CBF in the peripheral region around ischemic core was significantly improved after treatments. Moreover, VAL and LCZ treatments significantly decreased the increase of superoxide anion production in the cortex of ischemic side. However, significant differences of CBF and superoxide anion production were not observed in VAL and LCZ. Conclusions: Both valsartan and LCZ696 treatments exerted preventive effects on ischemic stroke. The preventive effect of LCZ696 seemed more prominent than VAL. LCZ696 could be a novel powerful approach to protect brain after stroke. Further investigation has been performed to clarify the protective effect of LCZ696 on ischemic brain damage.

Independence of the blood pressure lowering effect and efficacy of the angiotensin receptor neprilysin inhibitor, LCZ696, in patients with heart failure with preserved ejection fraction: an analysis of the PARAMOUNT trial

The first in class angiotensin receptor neprilysin inhibitor, LCZ696 has been shown to reduce levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), reduce left atrial size and improve New York Heart Association (NYHA) class in patients with heart failure with preserved ejection fraction (HFpEF). We examined whether the effects of LCZ696 were independent of systolic blood pressure (SBP) lowering. In the Prospective comparison of ARNi (angiotensin receptor neprilysin inhibitor) with ARB (angiotensin receptor blocker) on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial 301 patients were randomly assigned to LCZ696 or valsartan. We examined the relationship between SBP lowering and LCZ696 on NT-proBNP level, left atrial size, NYHA class and estimated glomerular filtration rate (eGFR). By 12 weeks blood pressure was reduced by 9 mmHg (SD 15)/5 mmHg (SD 11) in patients receiving LCZ696 in comparison with 3 mmHg (SD 17)/2 mmHg (SD 12) in those receiving valsartan. The change in NT-proBNP was poorly correlated with change in SBP (LCZ696, r = 0.17, P = 0.06; valsartan, r = 0.05, P = 0.58) After adjustment for change in SBP, the ratio of change in NT-proBNP at 12 weeks for LCZ696 vs. valsartan was 0.76 (95% CI 0.63-0.93, P = 0.008), and similar to the ratio not adjusting for SBP (0.76, 95% CI 0.63-0.92, P = 0.006); P for interaction was 0.38). Similarly, reduction in left atrial volume index at 36 weeks, improvement in NYHA class and eGFR were all independent of the change in SBP. In patients with HFpEF, the effect of the angiotensin receptor neprilysin inhibitor LCZ696 on NT-proBNP, left atrial volume, functional class, and eGFR was independent of reduction in SBP.