Sacubitril-valsartan

Sacubitril, an FDA-approved neprilysin inhibitor, is used in combination with valsartan for treating chronic heart failure with reduced ejection fraction (HFrEF). It was approved in 2015 under priority review, and marked a pivotal advancement in heart failure (HF) therapy.

By inhibiting neprilysin, sacubitril enhances the levels of beneficial natriuretic peptides, promoting vasodilation, natriuresis, and diuresis. When paired with valsartan, it provides synergistic cardiovascular protection, improving cardiac function and reducing the risk of hospitalization and cardiovascular death.[1]

Pharmacological Class: Angiotensin receptor neprilysin inhibitor (ARNI)[2]

Sacubitril–valsartan therapy is indicated for:

1. Chronic HFrEF

• Approved for relieving chronic HFrEF in patients categorized as New York Heart Association (NYHA) class II, III, or IV.
• Used to reduce morbidity and mortality in chronic symptomatic HFrEF.
• Alternative to angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), used alongside standard HF therapies (e.g., beta-blockers, aldosterone antagonists)

2. Heart Failure with Preserved Ejection Fraction (HFpEF)

• Advocated for mitigating HFpEF as per 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guidelines.
• Particularly beneficial for male patients having left ventricular ejection fraction (LVEF) <55–60%.
• Recommended for female patients with HFpEF regardless of LVEF, due to better clinical response linked to smaller left ventricular chamber size.
• Often initiated after sodium–glucose cotransporter-2 (SGLT2) inhibitor therapy as per the 2023 ACC Expert Consensus.

3. Pediatric HF

• FDA-approved for use in pediatric patients with HF to improve cardiac function and outcomes.

4. Cancer Therapy–Related Cardiac Dysfunction (CTRCD) (Emerging/Investigational Use)

• Shown beneficial in chemotherapy- or anthracycline-induced cardiac failure with reduced ejection fraction.
• Promising results in refractory CTRCD cases; however, further clinical validation is required.[2]

• Sacubitril is a prodrug that converts into its active form, LBQ657, a potent inhibitor of neprilysin.
• Neprilysin is a neutral endopeptidase responsible for degrading natriuretic peptides such as atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. These peptides are released in response to atrial and ventricular stress, promoting vasodilation, natriuresis, and diuresis, which help lower blood pressure and cardiac workload.
• By blocking neprilysin, sacubitril helps in reducing the cardiac preload, afterload, and ventricular wall stress.
• The rise in angiotensin II caused by neprilysin inhibition is balanced by valsartan, an ARB that prevents vasoconstriction and aldosterone release, leading to better vascular relaxation and blood pressure control.
• Together, these effects provide cardiovascular and renal protection, improve hemodynamic stability, and slow the progression of HF.[3]

• The suggested initial dose for adults is 49 mg/51 mg administered twice daily by mouth with titration every 2 to 4 weeks to reach the target maintenance dose of 97 mg/103 mg twice daily, based on individual tolerance.
• In those not previously receiving an ACE inhibitor or ARB, or in those with severe renal or moderate hepatic impairment, therapy should begin at half the usual starting dose.[4]
• In pediatric patients weighing less than 40 kg, therapy typically begins at 1.6 mg/kg twice daily, with gradual dose escalation to 2.3 mg/kg and then 3.1 mg/kg twice daily as tolerated. For children weighing 40–50 kg, the starting dose is sacubitril 24 mg/valsartan 26 mg twice daily, titrated over two-week intervals to 49 mg/51 mg and finally 72 mg/78 mg twice daily.[2]

Sacubitril–valsartan exhibits rapid absorption and dual-path activation, designed to optimize cardiovascular efficacy and therapeutic precision.

Absorption
Upon oral administration, the combination swiftly dissociates into sacubitril and valsartan. Sacubitril is rapidly hydrolyzed to its active metabolite LBQ657, achieving ~60% bioavailability. Peak plasma levels occur at 0.5 h (sacubitril), 2 h (LBQ657), and 1.5 h (valsartan). Steady state is attained within 3 days, with negligible accumulation. Food has no significant impact, allowing administration with or without meals.

Distribution
Both agents display broad tissue distribution (103 L for sacubitril, 75 L for valsartan) and high plasma protein binding (94%–97%). LBQ657 shows minimal CNS penetration (~0.28%).

Metabolism
Sacubitril undergoes esterase-mediated hydrolysis to LBQ657, while valsartan experiences limited metabolism (~20%), yielding trace hydroxyl metabolites.

Elimination
Elimination occurs through renal and fecal routes — 52%–68% (as LBQ657) and 13% of valsartan via urine, and 37%–48% (LBQ657) and 86% of valsartan via feces. The mean half-lives are 1.4 h (sacubitril), 11.5 h (LBQ657), and 9.9 h (valsartan). [2]

Sacubitril–valsartan is contraindicated in the following clinical scenarios:

• Known hypersensitivity to sacubitril and valsartan.
• History of angioedema connected with prior ACE inhibitor or ARB use.
• Use of ACE inhibitors within 36 hours of sacubitril–valsartan administration, owing to the heightened risk of angioedema.
• Concomitant therapy with aliskiren in diabetic patients may precipitate renal damage, low blood pressure, and hyperkalemia.
• Severe hepatic dysfunction (Child-Pugh C)[2, 4]

1. Dual Inhibition of the Renin-Angiotensin-Aldosterone System (RAAS)

• Concomitant use with ACE inhibitors should be avoided owing to the heightened risk of angioedema.
• Avoid combining with ARBs, as the formulation already contains valsartan.
• Sacubitril–valsartan should not be used together with aliskiren in patients with diabetes. Moreover, its combination with aliskiren should be avoided in those with renal impairment (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m²).

2. Potassium-Sparing Agents

• Concomitant usage with potassium-sparing diuretics, potassium supplements, or salt substitutes may cause hyperkalemia (high potassium levels).
• Regular surveillance of serum potassium is suggested.

3. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors

• Concomitant use may worsen renal function, particularly in elderly, volume-depleted, or renally impaired people.
• Monitor renal function periodically; effects are usually reversible.

4. Lithium

• Concurrent use of lithium and angiotensin II receptor blockers is linked with elevated serum lithium levels and potential lithium toxicity.
• Monitor lithium concentrations closely during combined use. [4]

The most common side effects are:

• Hypotension
• Hyperkalemia
• Renal failure
• Cough
• Dizziness
• Angioedema[2,4]

• Monitor closely for early signs of angioedema and hypotension during treatment.
• Assess renal function and serum potassium levels regularly, especially in high-risk patients.[4]

1. Sacubitril–valsartan has demonstrated remarkable efficacy in improving outcomes for patients with chronic HF. In a pooled analysis of the PARADIGM-HF and PARAGON-HF trials involving 13,194 participants, the drug significantly reduced all-cause hospitalizations compared to standard renin-angiotensin system inhibitors. Over a 2.5-year median follow-up, sacubitril–valsartan achieved an 8% reduction in hospitalization risk (hazard ratio [HR] 0.92; 95% confidence interval [CI] 0.88–0.97; P = .002) and an absolute risk reduction of 2.1 per 100 patient-years. The most pronounced benefits were witnessed in those with LVEF < 60%, reflecting fewer cardiac and pulmonary admissions. Thus, sacubitril–valsartan proved to be a clinically superior therapy that boosts patient outcomes, lowers hospitalization rates, and improves overall HF management.[5]

2. Early initiation of sacubitril/valsartan post–acute myocardial infarction (AMI) delivers remarkable cardioprotective and remodeling benefits compared to conventional therapy. In a study involving 295 AMI patients, treatment with sacubitril/valsartan + standard care produced superior cardiac recovery versus benazepril-based regimens. At 6 months, patients receiving sacubitril/valsartan demonstrated:

• Marked reductions in N-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular end-diastolic volume, and left ventricular end-systolic volume
• Significant improvement in LVEF and heart rate variability indices
• Lower major adverse cardiac event (MACE) rate (7.6% vs. 27.6%)
• Comparable safety profile, with no rise in adverse reactions

These outcomes affirm sacubitril/valsartan’s dual advantage—protecting cardiac function while enhancing ventricular recovery. Early use post-AMI can curb ventricular remodeling, boost myocardial performance, and improve long-term prognosis, making it a cornerstone in modern cardiac therapeutics.[6]

3. A pooled meta-analysis of 14 randomized controlled trials (n = 25,167) reinforced sacubitril/valsartan as a cornerstone therapy in chronic HF, offering superior clinical outcomes compared to traditional ACE inhibitors and ARBs. The key findings were:

• Significant reduction in all-cause mortality in patients with LVEF ≤40% (relative risk [RR] 0.88; 95% CI 0.81–0.94; P = 0.0006)
• Marked decrease in HF-related rehospitalizations across all ejection fraction ranges (RR 0.85; 95% CI 0.79–0.91; P = 0.00001)
• Comparable cardiovascular mortality to ACE inhibitor/ARB regimens (RR 0.9; 95% CI 0.79–1.03; P = 0.13)

Collectively, these findings established sacubitril/valsartan as a clinically validated and mechanistically advanced therapy that improves outcomes in HF.[7]

1. Sacubitril. Drug Bank [DB09292]. Available from: https://go.drugbank.com/drugs/DB09292
2. Nicolas D, Patel P, Reed M. Sacubitril-Valsartan. [Updated 2024 Feb 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507904/. Bookshelf ID: NBK507904, PMID: 29939681.
3. Sacubitril. PubChem [9811834]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Sacubitril
4. Sacubitril. FDA Label. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/207620s025,218591s000lbl.pdf
5. Lu H, Claggett BL, Packer M, Lam CSP, Swedberg K, Rouleau J et al. Effects of Sacubitril/Valsartan on All-Cause Hospitalizations in Heart Failure: Post Hoc Analysis of the PARADIGM-HF and PARAGON-HF Randomized Clinical Trials. JAMA Cardiology. 2024 Nov 1;9(11):1047-1052.
6. Liu Z, Cui K, Wang G, Jin W, Yao Q, Zhang Y. A clinical randomized trial: Effects of early application of sacubitril/valsartan on ventricular remodeling and prognosis in acute myocardial infarction patients. Contemporary Clinical Trials Communications. 2024 Jul 25;42:101303.
7. Evbayekha E, Idowu AB, LaRue S. Sacubitril/Valsartan vs ACE Inhibitors or ARBs: A Systematic Review and Meta-Analysis of Randomized Trials. JACC: Advances. 2025 Mar;4(3):101598.