Sacubitril Valsartan (ARNI) – Entresto Mechanism of Action in HFrEF

Sacubitril Valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI in short). It is available by the brand names Entresto and Uperio. Entersto mechanism of action is unique and is especially recommended in patients with Heart Failure and reduced Ejection Fraction.

Entresto is a combination of a neprilysin antagonist (Sacubitril) and an ARB (Valsartan). This combination drug was designed to prevent the harmful effects of renin-angiotensin-aldosterone (RAAS) activation. It also raises levels of potentially beneficial endogenous vasoactive Peptides, especially natriuretic peptides that are normally degraded by the enzyme Neprilysin.

Entresto Mechanism of Action in HFrEF:

HF therapy is focused on reducing neurohormonal activation that causes damage to the RAAS, and the sympathetic nervous system. Another strategy for treating HF is to augment beneficial counter-regulatory systems such as natriuretic Peptides. The inhibition of neprilysin, a neutral endopeptidase, raises endogenous vasoactive peptide levels, which may have beneficial effects on patients with HF.

There have been two pharmacologic strategies to inhibit neprilysin as well as the RAAS system. While the first (omapatrilat), was hampered by an unacceptable adverse reaction, the second (sacubitril–valsartan), has shown improved outcomes for patients with HFrEF than the ACE inhibitor.

Omapatrilat Vs Entresto Mechanism of Action in HFrEF:

Omapatrilat is a compound that inhibited neprilysin, angiotensin-converting protein (ACE), and aminopeptidase P. This resulted in increased levels of bradykinin and unacceptable rates of angioedema. 

The combination of a neprilysin inhibitor with an angiotensin-receptor blocker (ARB), to make an angiotensin-receptor-neprilysin inhibitor (ARNI) was the strategy that proved most successful in improving outcomes in HFrEF.

The ARB blocks the angiotensin-2 levels that are elevated due to neprilysin inhibitors. PARADIGM-HF showed that angioedema caused by ARNI was not significantly higher than that of the ACE inhibitor [Ref]. The rates of angioedema in acute HF patients were similar to those seen in PIONEER-HF. They did not differ between the sacubitril/valsartan (0.2%) and enalapril (1.4%) groups. Furthermore, Sacubitril Valsartan significantly reduced NT-Pro BNP compared to enalapril [Ref].

It is unclear what mechanism is responsible for the incremental benefits of neprilysin inhibitors over ARB alone. Ecadotril (a pure neprilysin inhibitor) was not found to be beneficial in patients with HF [Ref]. This is likely because the increased levels of angiotensin I, which can have deleterious effects on HF, offset the benefits of increasing favorable neurohormones (the Natriuretic Peptides).

In the ASCEND HF trial, the clinical outcomes for acute HF were not improved by the administration of nesiritide (B-type natriuretic peptide).

Clinical studies have shown that ARNI can reverse adverse remodeling in patients suffering from HFrEF. EVALUATE-HF, a short-term, randomized trial in 464 patients with heart failure (HFrEF), found that changes in aortic characteristic and ejection fractions were similar to sacubitril/valsartan and Enalapril. However, there was a significant decrease in left atrial volume with ARNI [Ref].

Entresto Mechanism of Action and effect on Kidney function:

Preclinical and clinical evidence suggests that ARNI therapy could have positive effects on kidney function and glucose control in diabetics Mellitus.

Compared to ARB alone in a rat model for diabetic nephropathy, ARNI was more effective at reducing proteinuria, renal tubular injury, and blood pressure change.

A secondary analysis by PARADIGM-HF showed that patients who were treated with sacubitril/valsartan had a slower decline in estimated glomerular filtration rate than patients who were treated with enalapril. 

Sacubitril Valsartan effect on Blood Glucose:

Patients with diabetes saw a greater benefit when treated with Entresto, regardless of any changes in the glycated hemoglobin. Hemoglobin A1c levels dropped by 0.16 percent in patients with type 2 diabetes and HFrEF who were enrolled in PARADIGM-HF. Patients receiving sacubitril–valsartan had a 29 percent decrease in insulin use (compared to 10 percent for patients who received enalapril).

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