Sacubitril/Valsartan
Prescription ·Exploratory record · not publication-reviewed ·Updated July 13, 2026
Sacubitril/valsartan is a first-in-class ARNI that combines neprilysin inhibition with AT1 receptor blockade. The PARADIGM-HF trial demonstrated a 20% reduction in cardiovascular death and heart failure hospitalization compared to enalapril, establishing it as a cornerstone of HFrEF therapy. It has largely replaced ACE inhibitors as the preferred RAAS inhibitor in HFrEF.
Exploratory record, not a reviewed medical publication.
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What the research says.
A quick, data-only summary. The full evidence, dosing, and sources are below.
Sacubitril/valsartan is a first-in-class ARNI that combines neprilysin inhibition with AT1 receptor blockade. NutriStack rates the supporting evidence as strong. Common adult dosing is Starting: 24/26 mg or 49/51 mg twice daily; Target: 97/103 mg twice daily (as prescribed by your physician), though a prescriber sets the actual dose. With long-term use it can deplete zinc. This profile indexes 10 sources.
- Hypotension (most common reason for dose reduction)
- Hyperkalemia
- Cough (less than ACE inhibitors)
- Concurrent ACE inhibitor use (36-hour washout period required)2
- History of angioedema with ACE inhibitors or ARBs
The bottom line
Evidence rating strong. Most-documented uses: superior to enalapril in reducing cv death and hf hospitalization (paradigm-hf), 20% reduction in cardiovascular death vs enalapril, reduces cardiac remodeling. 10 sources indexed (2020–2023), with 0 interaction records on file.
How it works, mechanistically.
Core mechanism
Combines two mechanisms: sacubitril (a prodrug) is converted to sacubitrilat, which inhibits neprilysin, an enzyme that degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, and adrenomedullin. This enhances these beneficial peptides' vasodilatory, natriuretic, and anti-fibrotic effects. Valsartan blocks the AT1 receptor, preventing the deleterious effects of angiotensin II. The combination provides both neurohormonal suppression and enhancement of protective pathways.1,2
Dosing & protocol.
Can be taken with or without food; 36-hour washout required when switching from an ACE inhibitor to prevent angioedema
What it depletes.
Nutrients this medication can lower over time, and what to replace.
Zinc
MildARB therapy can modestly increase urinary zinc losses in some users, though typically less than ACE inhibitors.
Full safety detail.
Side effects
- Hypotension (most common reason for dose reduction)
- Hyperkalemia
- Cough (less than ACE inhibitors)
- Dizziness
- Renal impairment
- Angioedema (rare)
Contraindications
- Concurrent ACE inhibitor use (36-hour washout period required)2
- History of angioedema with ACE inhibitors or ARBs
- Pregnancy
- Concurrent aliskiren in diabetic patients
- Severe hepatic impairment (Child-Pugh C)
Sources, by evidence tier.
Numbered references. Citations throughout the page link here.
Meta-analyses & systematic reviews
5- 1Renal Safety of Sacubitril/Valsartan: A Meta-Analysis of Randomized Controlled TrialsPMIDZheng S, Zhang Y, Gu L et al. · Journal of cardiovascular pharmacology · 2023
Zheng S, Zhang Y, Gu L et al.. Renal Safety of Sacubitril/Valsartan: A Meta-Analysis of Randomized Controlled Trials. Journal of cardiovascular pharmacology. 2023
- 2The angiotensin receptor and neprilysin inhibitor, LCZ696, in heart failure: A meta-analysis of randomized controlled trialsPMIDChen Y, He Q, Mo DC et al. · Medicine · 2022
Chen Y, He Q, Mo DC et al.. The angiotensin receptor and neprilysin inhibitor, LCZ696, in heart failure: A meta-analysis of randomized controlled trials. Medicine. 2022
- 3Adverse Events of Sacubitril/Valsartan: A Meta-analysis of Randomized Controlled TrialsPMIDHuang Y, Zhang Y, Ma L et al. · Journal of cardiovascular pharmacology · 2021
Huang Y, Zhang Y, Ma L et al.. Adverse Events of Sacubitril/Valsartan: A Meta-analysis of Randomized Controlled Trials. Journal of cardiovascular pharmacology. 2021
- 4Safety and tolerability of sacubitril-valsartan: a systematic review and meta-analysisPMIDMartins E Pereira G, S Duarte G, Katerenchuk V et al. · Expert opinion on drug safety · 2021
Martins E Pereira G, S Duarte G, Katerenchuk V et al.. Safety and tolerability of sacubitril-valsartan: a systematic review and meta-analysis. Expert opinion on drug safety. 2021
- 5LCZ696 and preservation of renal function in heart failure: A meta-analysis of 6 randomized trialsPMIDChen X, Jin C, Xie L et al. · Reviews in cardiovascular medicine · 2020
Chen X, Jin C, Xie L et al.. LCZ696 and preservation of renal function in heart failure: A meta-analysis of 6 randomized trials. Reviews in cardiovascular medicine. 2020
Reference material
5- 6McMurray JJV et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF). N Engl J Med. 2014.Source linkedPMID
- 7Solomon SD et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction (PARAGON-HF). N Engl J Med. 2019.Source linkedPMID
- 8Chen X et al. Optimization of Clinical Trial Design and Decision-Making for Heart Failure with Preserved Ejection Fraction (HFpEF): A Meta-Analysis Based on a Placebo Response Model. Cardiovasc Ther. 2025.Source linkedPMID
- 9Zhou W, Yang X, Jin J et al.. The efficacy and safety of sacubitril/valsartan in chronic kidney disease: a systematic review and meta-analysis. International urology and nephrology. 2024Source linkedPMID
- 10Yamamoto K, Yarimizu D, Shimanishi A et al.. Efficacy and Safety of Sacubitril/Valsartan Versus Amlodipine in Japanese Patients With Essential Hypertension: A Randomized, Multicenter, Open-Label, Noninferiority Study (PARASOL Study). Journal of clinical hypertension (Greenwich, Conn.). 2025Source linkedPMID
Common questions.
Quick answers about Sacubitril/Valsartan, drawn from the data on this page.
What is Sacubitril/Valsartan?
Sacubitril/valsartan is a first-in-class ARNI that combines neprilysin inhibition with AT1 receptor blockade. The PARADIGM-HF trial demonstrated a 20% reduction in cardiovascular death and heart failure hospitalization compared to enalapril, establishing it as a cornerstone of HFrEF therapy. It has largely replaced ACE inhibitors as the preferred RAAS inhibitor in HFrEF.
What is Sacubitril/Valsartan used for?
Commonly cited benefits of Sacubitril/Valsartan include: Superior to enalapril in reducing CV death and HF hospitalization (PARADIGM-HF); 20% reduction in cardiovascular death vs enalapril; Reduces cardiac remodeling; Improves symptoms and quality of life in heart failure. NutriStack rates the overall evidence as strong.
What is a typical dose of Sacubitril/Valsartan?
A typical adult dose of Sacubitril/Valsartan is Starting: 24/26 mg or 49/51 mg twice daily; Target: 97/103 mg twice daily (as prescribed by your physician). The commonly recommended form is Oral tablet. These are general ranges, not personalized advice; confirm the right dose with a clinician.
What are the side effects of Sacubitril/Valsartan?
Reported side effects include hypotension (most common reason for dose reduction), hyperkalemia, cough (less than ace inhibitors), dizziness, renal impairment, angioedema (rare). This is educational information; check with a healthcare professional before use.
How strong is the evidence for Sacubitril/Valsartan?
NutriStack rates this as Strong, meaning multiple high-quality meta-analyses or systematic reviews converge on the same finding. Full tier criteria are at https://nutristackapp.com/methodology/evidence-tiers.
Use this with your stack
Sacubitril/Valsartan in NutriStack.
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