Sacubitril/Valsartan: Boosting Natriuretic Peptides
Blood Pressure Peptides
20% reduction
The PARADIGM-HF trial showed sacubitril/valsartan reduced the composite of cardiovascular death and heart failure hospitalization by 20% compared to enalapril.
Kondo et al., JACC Heart Failure, 2025
Kondo et al., JACC Heart Failure, 2025
View as imageMost peptide drugs deliver synthetic peptides to the body. Sacubitril/valsartan does the opposite: it prevents the body from destroying the peptides it already makes. Sold under the brand name Entresto, this combination drug inhibits neprilysin, the enzyme responsible for breaking down natriuretic peptides, while simultaneously blocking the angiotensin II receptor. The result is higher circulating levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and other vasoactive peptides that dilate blood vessels, reduce fluid retention, and protect the heart from pathological remodeling.[1] A 2025 meta-analysis in JACC Advances confirmed that sacubitril/valsartan reduces N-terminal pro-BNP levels more effectively than ACE inhibitors or angiotensin receptor blockers alone.[2] This article examines the mechanism, the clinical evidence, and where the drug is headed.
Key Takeaways
- Sacubitril/valsartan combines neprilysin inhibition (raising natriuretic peptide levels) with angiotensin receptor blockade (blocking vasoconstriction) in a single pill
- The PARADIGM-HF trial showed a 20% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization versus enalapril (HR 0.80, 95% CI 0.73-0.87, P < 0.001)
- A 2025 meta-analysis across randomized trials confirmed superiority over both ACE inhibitors and ARBs for reducing NT-proBNP (Evbayekha et al., JACC Advances, 2025)
- The REVERSE-LVH trial found sacubitril/valsartan reduced diffuse interstitial fibrosis in hypertensive heart disease compared to valsartan alone (Lee et al., Nature Communications, 2025)
- Quadruple combination therapy (SGLT2i + GLP-1RA + ARNI + MRA) is emerging as the next frontier in heart failure with preserved ejection fraction (Ke et al., 2026)
- Sacubitril/valsartan benefits extend beyond heart failure to include blood pressure reduction in dialysis patients and suppression of transplant vasculopathy
How Natriuretic Peptides Protect the Heart
The natriuretic peptide system is one of the body's primary defenses against cardiovascular stress. When heart muscle cells are stretched by excess fluid or pressure, they release ANP and BNP into the bloodstream. These peptides act on receptors in blood vessels, kidneys, and the adrenal glands to produce a coordinated response: blood vessels relax (reducing blood pressure), the kidneys excrete more sodium and water (reducing fluid volume), and aldosterone secretion decreases (preventing further fluid retention).[3]
A 2021 review in Pharmacology and Therapeutics described this system as a "cardioprotective counterregulatory mechanism" that opposes the harmful effects of the renin-angiotensin-aldosterone system (RAAS).[4] In healthy people, these two systems balance each other. In heart failure, the RAAS is overactivated while natriuretic peptides are rapidly degraded by neprilysin. The net result is vasoconstriction, fluid retention, and progressive cardiac remodeling.
ANP, BNP, and C-type natriuretic peptide (CNP) each have distinct roles. ANP is released primarily from the atria and acts on the kidneys to promote sodium excretion. BNP is released from the ventricles in response to volume overload and wall stress, and serves as both a hormone and a diagnostic biomarker (clinicians measure NT-proBNP in blood tests to assess heart failure severity). CNP is produced by endothelial cells and fibroblasts, acting locally on blood vessels to prevent vascular remodeling and atherosclerosis. A 2025 study demonstrated that endothelium-derived CNP prevents the development of vascular disease, establishing it as a local autocrine/paracrine protective signal rather than a circulating hormone.[5]
All three natriuretic peptides are substrates of neprilysin. When neprilysin is inhibited by sacubitril, all three accumulate to higher levels, amplifying their combined protective effects across the heart, kidneys, and blood vessels.
For a deeper look at ANP specifically, see ANP: The Atrial Peptide That Lowers Blood Pressure. For the opposing system, see The Renin-Angiotensin System: How Peptides Control Blood Pressure.
The Dual Mechanism: Neprilysin Inhibition Plus AT1 Blockade
Sacubitril/valsartan combines two pharmacological actions:
Sacubitril is a prodrug. After oral ingestion, it is converted to sacubitrilat, which inhibits neprilysin (neutral endopeptidase 24.11). Neprilysin is the enzyme that degrades ANP, BNP, CNP, bradykinin, adrenomedullin, and substance P. By blocking neprilysin, sacubitril allows these vasoactive peptides to accumulate and exert their protective effects for longer. A 2026 pharmacology review described sacubitril as "preventing the enzymatic destruction of the very peptides the heart produces to protect itself."[1]
Valsartan blocks the angiotensin II type 1 (AT1) receptor. Angiotensin II is a potent vasoconstrictor peptide produced by the renin-angiotensin system. Blocking its receptor prevents vasoconstriction, aldosterone release, and the fibrotic remodeling that angiotensin II promotes in heart tissue.
The combination is necessary because inhibiting neprilysin alone would be insufficient. Neprilysin also degrades angiotensin II. If neprilysin is blocked without AT1 blockade, angiotensin II levels could rise and counteract the benefits of increased natriuretic peptides. The valsartan component prevents this paradoxical effect.[4]
This is why earlier attempts to combine neprilysin inhibitors with ACE inhibitors (rather than ARBs) failed. The combination of neprilysin inhibition and ACE inhibition caused dangerous angioedema because both bradykinin-degrading pathways were blocked simultaneously. Using an ARB instead of an ACE inhibitor avoids this problem because ARBs do not affect bradykinin metabolism. The valsartan component blocks angiotensin II at the receptor level without interfering with the enzyme that degrades bradykinin. This pharmacological distinction, subtle on paper, was the key insight that made sacubitril/valsartan clinically viable after the failure of the earlier combination drug omapatrilat.
The drug is taken as a single tablet twice daily, available in three dose strengths (24/26 mg, 49/51 mg, and 97/103 mg of sacubitril/valsartan respectively). Patients are typically started at the lowest dose and uptitrated over several weeks to the target dose of 97/103 mg twice daily, with blood pressure monitoring to prevent symptomatic hypotension.
For how ACE inhibitors work through peptide enzyme blockade, see ACE Inhibitors: How Blocking a Peptide Enzyme Lowers Blood Pressure.
The Landmark Trials: PARADIGM-HF and Beyond
PARADIGM-HF
The trial that established sacubitril/valsartan enrolled 8,442 patients with heart failure and reduced ejection fraction (LVEF 40% or less) across 47 countries. Patients were randomized to sacubitril/valsartan (200 mg twice daily) or enalapril (10 mg twice daily), the ACE inhibitor that had been the standard of care for over two decades. The trial was stopped early by the data safety monitoring board because sacubitril/valsartan was clearly superior.
The numbers were striking. The composite primary endpoint (cardiovascular death or heart failure hospitalization) was reduced by 20% (hazard ratio 0.80, 95% CI 0.73-0.87, P < 0.001). Cardiovascular death alone was reduced by 20% (HR 0.80, 95% CI 0.71-0.89). All-cause mortality was reduced by 16%. Heart failure hospitalizations dropped by 21%. Using actuarial projections, patients aged 55 randomized to sacubitril/valsartan were estimated to gain an average of 1.4 years of survival compared to enalapril. For patients aged 65, the estimated gain was 1.3 years.
These results changed heart failure treatment guidelines worldwide. The American College of Cardiology and American Heart Association updated their recommendations in 2016 to include sacubitril/valsartan as a replacement for ACE inhibitors in patients with chronic symptomatic HFrEF.
A 2025 analysis in JACC Heart Failure examined the PARADIGM-HF results stratified by baseline NT-proBNP levels. The benefits of sacubitril/valsartan were consistent across patients with both high and low natriuretic peptide levels, though the absolute risk reduction was greater in patients with higher baseline NT-proBNP.[6] This finding has practical implications: patients with the most neurohormonal activation (highest NT-proBNP) derive the greatest absolute benefit from the drug's peptide-boosting mechanism.
REVERSE-LVH
A 2025 phase 2 trial published in Nature Communications tested sacubitril/valsartan against valsartan alone in patients with hypertensive heart disease. Using cardiac MRI, the researchers found that sacubitril/valsartan reduced diffuse interstitial fibrosis more than valsartan alone. This is important because fibrosis stiffens the heart and impairs its ability to fill properly. The anti-fibrotic effect suggests sacubitril/valsartan does more than manage symptoms; it may reverse the structural damage caused by chronic hypertension.[7] This finding is mechanistically coherent: natriuretic peptides have direct anti-fibrotic effects through their cGMP signaling pathway, which inhibits fibroblast proliferation and collagen synthesis. By raising natriuretic peptide levels, sacubitril amplifies this anti-fibrotic signal in cardiac tissue. If confirmed in larger trials, this would mean the drug not only slows heart failure progression but actively repairs the damage that caused it.
Chagas Disease
A 2026 randomized trial published in JAMA tested sacubitril/valsartan against enalapril in patients with heart failure due to Chagas disease, a parasitic infection that causes progressive cardiac damage. This was the first major trial to study the drug in this population, which had been excluded from PARADIGM-HF. The results demonstrated efficacy in this distinct cardiomyopathy, expanding the evidence base beyond ischemic and idiopathic heart failure.[8] The Chagas trial is particularly important because it tested the drug in a population where heart failure has a different etiology (parasitic inflammation and fibrosis rather than coronary artery disease) and a different disease trajectory. The fact that neprilysin inhibition provided benefit regardless of the underlying cause of cardiac damage reinforces the idea that natriuretic peptide amplification is a broadly protective strategy, not one limited to a specific type of heart failure.
Meta-Analytic Evidence
A 2025 systematic review and meta-analysis in JACC Advances pooled data from randomized trials comparing sacubitril/valsartan to ACE inhibitors or ARBs. The analysis confirmed that sacubitril/valsartan consistently reduced NT-proBNP levels more than either comparator. This matters clinically because NT-proBNP is both a biomarker of heart failure severity and a treatment target. The greater reduction in NT-proBNP translated to improved clinical outcomes across the pooled analysis.[2]
A 2026 review of cardiorenal safety across heart failure phenotypes found that sacubitril/valsartan's benefits extended across the ejection fraction spectrum: heart failure with reduced ejection fraction (HFrEF), mildly reduced ejection fraction (HFmrEF), and preserved ejection fraction (HFpEF). Renal outcomes were neutral to favorable, addressing earlier concerns that neprilysin inhibition might impair kidney function.[9]
The renal safety finding deserves emphasis. Neprilysin is expressed in the kidney, and some researchers worried that blocking it would disrupt local peptide processing and worsen renal function. The meta-analytic data show the opposite: by reducing cardiac preload and afterload through natriuretic peptide amplification, sacubitril/valsartan appears to protect the kidneys from the hemodynamic insults of heart failure. This is consistent with the known renal effects of natriuretic peptides, which promote glomerular filtration while reducing tubular sodium reabsorption.
Beyond Heart Failure: Expanding Applications
Blood Pressure in Dialysis
A 2025 randomized controlled multicenter study conducted across 10 hospitals tested sacubitril/valsartan in patients with end-stage kidney disease on dialysis who had uncontrolled hypertension. The drug lowered blood pressure more effectively than valsartan alone. This is notable because dialysis patients are typically excluded from cardiovascular trials and have limited treatment options. The neprilysin inhibition component may be particularly valuable in this population because natriuretic peptides promote sodium and water excretion through the kidneys; even in patients with minimal remaining kidney function, the vasodilatory effects of preserved natriuretic peptides can reduce blood pressure through direct vascular relaxation.[10]
Transplant Vasculopathy
A 2026 study demonstrated that sacubitril alone (without valsartan) suppressed chronic allograft vasculopathy in heart transplant recipients. This is a distinct application: after transplant, the grafted blood vessels develop progressive thickening that limits graft survival. The finding suggests that neprilysin inhibition has vascular protective effects independent of heart failure treatment.[11]
Neuroprotection
In an unexpected application, a 2026 study found that sacubitril/valsartan upregulated the Wnt/beta-catenin signaling pathway in a Parkinson's disease model. The neuroprotective effect was greater than valsartan alone and was attributed to neprilysin inhibition increasing levels of neuropeptides that activate Wnt signaling.[12] The study did not test this in humans, but it illustrates how neprilysin inhibition affects peptide signaling far beyond the cardiovascular system. Neprilysin is expressed in the brain, lungs, kidneys, and vasculature, and its substrates include not just natriuretic peptides but also substance P, bradykinin, adrenomedullin, endothelin-1, and amyloid-beta. Blocking this single enzyme alters the levels of dozens of bioactive peptides simultaneously.
Pulmonary Vascular Protection
A 2026 study demonstrated that brain natriuretic peptide itself protects against acute pulmonary embolism-induced pulmonary vascular damage. This suggests that the elevated BNP levels produced by sacubitril treatment are not merely a side effect but an active protective mechanism that shields blood vessels from injury during acute cardiovascular events.[13] The finding reinforces the concept that natriuretic peptides are not just markers of heart failure but active participants in cardiovascular protection.
BNP as Vascular Protector
A 2026 study demonstrated that brain natriuretic peptide itself protects against acute pulmonary embolism-induced pulmonary vascular damage. This suggests that the elevated BNP levels produced by sacubitril treatment are not merely a side effect but an active protective mechanism that shields blood vessels from injury during acute cardiovascular events.[13]
The Quadruple Therapy Frontier
Heart failure treatment has evolved from single-agent therapy to combinations. The current evidence supports four drug classes working together:
- ARNI (sacubitril/valsartan) blocks neprilysin and AT1
- SGLT2 inhibitor (empagliflozin, dapagliflozin) blocks glucose reabsorption in kidneys
- MRA (spironolactone, eplerenone) blocks aldosterone
- Beta-blocker (carvedilol, bisoprolol) blocks adrenergic stimulation
A 2026 study went further, reporting outcomes for patients with HFpEF receiving quadruple combination therapy that replaced the beta-blocker with a GLP-1 receptor agonist: SGLT2i + GLP-1RA + ARNI + MRA. The combination targets metabolic, neurohormonal, and peptide pathways simultaneously.[14]
This quadruple approach produced improvements in NT-proBNP levels, exercise capacity, and quality of life in the study cohort, though the observational design and small sample size limit the strength of these conclusions.
The inclusion of both an ARNI and a GLP-1RA is notable from a peptide science perspective. The ARNI increases levels of natriuretic peptides by blocking their degradation. The GLP-1RA is itself a peptide drug that mimics the incretin hormone GLP-1. Together, they represent two different strategies for leveraging peptide biology: protecting endogenous peptides from destruction, and delivering exogenous peptide analogs. For how food-derived peptides may complement these pharmacological approaches, see Food-Derived Peptides for Blood Pressure: Dairy, Fish, and Plant Sources.
Limitations and Open Questions
Sacubitril/valsartan is among the most evidence-backed drugs in cardiology, but important questions remain.
Hypotension. The most common side effect is symptomatic low blood pressure, which occurs because the drug is amplifying vasodilatory peptide signaling while simultaneously blocking vasoconstrictor signaling. This limits the achievable dose in some patients.
NT-proBNP interpretation. NT-proBNP is the standard biomarker for monitoring heart failure severity. Sacubitril inhibits neprilysin, which degrades BNP but not NT-proBNP. This means BNP levels become unreliable as a disease marker in patients taking sacubitril/valsartan, while NT-proBNP remains interpretable. Clinicians must switch their monitoring assay when patients start this drug.[6]
HFpEF uncertainty. While the evidence is strongest for HFrEF, benefits in HFpEF are less clearly established. The PARAGON-HF trial showed borderline results in HFpEF, with the primary endpoint narrowly missing statistical distinction (HR 0.87, 95% CI 0.75-1.01, P = 0.06). Subgroup analyses suggested benefit in women and patients with lower ejection fractions (closer to the HFrEF range). Whether neprilysin inhibition is equally effective across the full HFpEF spectrum remains an active research question, and the 2026 quadruple therapy data with GLP-1RA may point toward combination approaches rather than single-agent strategies for this challenging population.[14]
Long-term neprilysin inhibition. Neprilysin degrades amyloid-beta peptide in the brain. There has been theoretical concern that chronic neprilysin inhibition could increase amyloid-beta accumulation and Alzheimer's risk. The PARADIGM-HF and PARAGON-HF trials did not show increased cognitive decline in sacubitril/valsartan-treated patients over the trial duration (median follow-up 27 months in PARADIGM-HF), but this may be too short to detect a slowly accumulating risk. Long-term cognitive outcomes in sacubitril/valsartan patients continue to be monitored through post-marketing surveillance and dedicated registry studies. The 2026 Parkinson's disease finding of neuroprotection through Wnt/beta-catenin signaling complicates the picture, suggesting that neprilysin inhibition may have both protective and potentially harmful effects on brain peptide metabolism, depending on the specific peptide substrate.
Cost and access. As a branded combination drug, sacubitril/valsartan is substantially more expensive than generic ACE inhibitors. A month's supply of Entresto costs roughly 10 to 15 times what generic enalapril costs. This limits adoption in healthcare systems where cost is a primary driver of treatment decisions, particularly in low- and middle-income countries where heart failure prevalence is high.
The Peptide Science Lesson
Sacubitril/valsartan teaches a fundamental lesson about peptide pharmacology: sometimes the best peptide strategy is not to deliver a peptide, but to protect the ones the body already produces.
Most peptide drug development focuses on creating synthetic analogs (like GLP-1 receptor agonists for diabetes) or delivering exogenous peptides (like insulin). Sacubitril takes the opposite approach. The body produces ANP, BNP, and CNP in response to cardiovascular stress, but these peptides are rapidly degraded by neprilysin. By blocking that degradation, sacubitril amplifies an endogenous protective system rather than introducing a foreign substance.
This approach has several advantages. The peptides are already present at the right tissue locations. They are released in proportion to the physiological stress (more heart wall stretch produces more natriuretic peptide release). Their levels self-regulate based on the disease severity. And because the body is producing its own peptides, there is no immune response to a foreign molecule.
The limitation is that the approach only works when the endogenous peptide system is functional. In advanced heart failure where the cardiac myocytes are too damaged to produce adequate natriuretic peptides, boosting their levels by blocking degradation has diminishing returns. This may partly explain why the drug's benefits are most pronounced in earlier stages of heart failure.
The success of sacubitril/valsartan has inspired research into other peptidase inhibitors that could amplify endogenous peptide signaling in other disease contexts. If the principle of "protect the peptides" works for heart failure, it may work for conditions where other beneficial endogenous peptides are prematurely degraded.
The Bottom Line
Sacubitril/valsartan represents a paradigm shift in cardiovascular pharmacology: rather than delivering an exogenous drug, it amplifies the body's own protective peptide signaling by blocking the enzyme that destroys natriuretic peptides. The PARADIGM-HF trial established a 20% reduction in cardiovascular death and heart failure hospitalization. Newer studies show anti-fibrotic effects, efficacy in Chagas cardiomyopathy, blood pressure reduction in dialysis, and even neuroprotective potential. As quadruple combination therapy emerges, sacubitril/valsartan is increasingly paired with other peptide-based strategies (GLP-1RAs, SGLT2 inhibitors) to target heart failure through multiple mechanisms simultaneously.