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MyDeficiencies

Sacubitril/valsartan

Angiotensin Receptor-Neprilysin Inhibitor

Also sold as Entresto.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Sacubitril/valsartan is a fixed-dose combination of two mechanistically distinct components, and the two must be scored separately. Valsartan, its angiotensin-receptor-blocking half, carries the same well-established renin-angiotensin-aldosterone system (RAAS) mechanism as every other ARB in this series: blocking AT1 receptors suppresses aldosterone-driven renal potassium excretion, so the body retains potassium rather than losing it. That is the dossier's central, drug-specific finding, and it is graded red on the strength of two large, drug-specific interventional data sets (the PARADIGM-HF and PARAGON-HF trial programs) rather than inherited by assumption from the ARB class. Sacubitril, the neprilysin-inhibiting half, was investigated on its own terms: neprilysin degrades natriuretic peptides, bradykinin, substance P, adrenomedullin, and amyloid-beta, and inhibiting it raises levels of all of these, but none of them are a vitamin, mineral, or trace element, and no study found for this dossier attaches a nutrient-status claim to the neprilysin-inhibition mechanism specifically. There is no depletion machinery here in the classical sense: minimal CYP450 metabolism, no chelation, no gastric pH change, no enzyme induction.

ARNI (neprilysin inhibitor + ARB) · ATC C09DX04 · also sold as Entresto · reviewed 2026-09-05, expanded 2026-09-10. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Sacubitril/valsartan in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
severe: 2+ Tier A sources with this drug in the cohort, direct measurement, consistent direction, clinically meaningful, named mechanism, no substantial contradicting Tier A evidence. Governance default:
Orange — Moderate
moderate: 1+ Tier A source with this drug in the cohort, a real but bounded deficit (exposure window, subgroup, low frequency, or functional marker). Governance default:
Yellow — Low
low/theoretical: mechanistic (Tier B) or class-extrapolated (Tier C) evidence only, or a context flag (confounding, reverse-direction interaction). Governance default:
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: no color, no tier: assigned only when neither Tier B/C mechanistic or class evidence, nor a circulating consumer claim to rebut, exists. A genuine evidence gap, printed as one — never converted into a safety reassurance and never forced into yellow or white. No governance state.

What the research found

Potassium

Red — Severe

See study details

Sacubitril/valsartan, through its valsartan/AT1-blockade component, measurably raises serum potassium and carries a labeled hyperkalemia risk; this is potassium excess, and supplementation would compound the hazard, not correct a deficiency.

Full detail and limits

What the grade means here: severe: 2+ Tier A sources with this drug in the cohort, direct measurement, consistent direction, clinically meaningful, named mechanism, no substantial contradicting Tier A evidence. Governance default: Red · retention

Limits on what this shows

  • Key negative / null findings: The label's own pooled figures show sacubitril/valsartan does not produce meaningfully less overall hyperkalemia than enalapril (~16% vs ~16%) or than valsartan alone (~18% vs ~20%) — the drug is not "potassium-neutral" relative to other RAAS blockers at the whole-trial level. The favorable MRA-subgroup finding (see above) is a real, drug-specific, and directionally important counter-context, but it is a comparator-specific finding (sacubitril/valsartan vs enalapril in patients also taking an MRA), not evidence that sacubitril/valsartan is free of hyperkalemia risk in general.
  • At-risk subgroups: Severe renal impairment, diabetes, hypoaldosteronism, high dietary potassium intake, and concomitant potassium-sparing diuretics, potassium supplements, or MRAs (per label). HFrEF patients frequently fall into several of these categories simultaneously.

Regulatory status

FDA label carries an explicit Warnings and Precautions section on hyperkalemia (5.3), instructing periodic serum potassium monitoring and dose reduction/interruption as needed. Concomitant potassium supplements, potassium-sparing diuretics, and potassium-containing salt substitutes are flagged as raising serum potassium further.

Population evidence

PARADIGM-HF (McMurray et al., NEJM 2014; N=8,399, HFrEF, NYHA II-IV, LVEF ≤40%, randomized double-blind, sacubitril/valsartan 97/103 mg BID vs enalapril 10 mg BID): per FDA label pooled safety data, approximately 16% of patients in both the sacubitril/valsartan and enalapril arms had potassium >5.5 mEq/L during the double-blind period. PARAGON-HF (HFpEF population, sacubitril/valsartan vs valsartan alone, per FDA label): approximately 18% of sacubitril/valsartan-treated patients and 20% of valsartan-treated patients had potassium >5.5 mEq/L. A secondary analysis of PARADIGM-HF restricted to mineralocorticoid receptor antagonist (MRA) users (Desai et al., JAMA Cardiology 2017) found severe hyperkalemia was less frequent with sacubitril/valsartan than enalapril: 2.2 vs 3.1 per 100 patient-years in baseline MRA users (HR 1.37, 95% CI 1.06-1.76, P=.02) and 2.3 vs 3.3 per 100 patient-years in new MRA initiators (HR 1.43, 95% CI 1.13-1.81, P=.003), both favoring sacubitril/valsartan.

Mechanism

Named and direct: valsartan blocks AT1 receptors, suppressing angiotensin II-dependent aldosterone release; aldosterone normally drives distal nephron potassium excretion, so its suppression reduces urinary potassium loss and raises serum potassium. This is the identical mechanism already established for standalone ARBs and ACE inhibitors in this series, here confirmed directly in a drug-named cohort rather than inherited from the class.

Counter-evidence held on record

PARADIGM-HF's headline safety comparison found essentially equal rates of potassium >5.5 mEq/L between sacubitril/valsartan and enalapril (~16% both arms per FDA label), which argues against framing this drug as meaningfully safer overall for hyperkalemia than an ACE inhibitor. The Desai et al. 2017 secondary analysis is itself a comparator study (sacubitril/valsartan vs enalapril, not vs no RAAS blockade) and applies specifically to the subgroup on MRA therapy — a real and clinically useful finding, but it should not be generalized to "sacubitril/valsartan lowers hyperkalemia risk" without the MRA-cohort qualifier. Framing caution for the consumer-facing surface This is a retention/excess signal, not a deficiency. The correct consumer framing is "this drug can raise blood potassium and requires monitoring," never "this drug depletes potassium" or "consider a potassium supplement." Potassium supplements, salt substitutes, and potassium-sparing diuretics should be flagged as compounding risks, not remedies, and any change should go through the prescriber, who already monitors serum potassium per label.

Empty tier

Not graded — disclosed evidence gap

See study details

No nutrient was found with a Tier A, sacubitril/valsartan-specific source showing a real but bounded deficit distinct from the red-tier potassium-retention finding above.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Empty

Limits on what this shows

  • What would fill this tier: A sacubitril/valsartan-arm-specific measurement (from PARADIGM-HF, PARAGON-HF, PIONEER-HF, or a dedicated substudy) of a nutrient other than potassium — for example serum magnesium, zinc, or a B-vitamin panel — with a defined exposure window or subgroup boundary, would populate this tier. None was located.

Reasoning

The mechanism screen (absorption interference, hepatic enzyme induction, renal wasting, cofactor antagonism, mitochondrial/conjugation loss, dilutional/hormonal disturbance, microbiome disruption, altered intake, increased utilization) turned up only one present mechanism for this drug: RAAS-mediated potassium retention, which is already captured at red. No PARADIGM-HF, PARAGON-HF, or label-derived data set measures a bounded circulating or functional deficit of any other electrolyte, vitamin, or trace element specifically in sacubitril/valsartan-treated patients.

2026-09-10 update

The five-category expansion below (mitochondrial function, oxidative stress, copper, iron, gut microbiome risk, oxygen delivery/utilization, ATP production) did not surface an orange-tier candidate either; see those entries under Yellow tier and Ungraded below.

Confounding by indication

Yellow — Low

See study details

Heart failure patients prescribed sacubitril/valsartan are routinely co-prescribed loop diuretics and other RAAS-affecting drugs whose own, separately documented nutrient effects (loop-diuretic-associated thiamine and magnesium loss) must not be misattributed to the ARNI.

Full detail and limits

What the grade means here: low/theoretical: mechanistic (Tier B) or class-extrapolated (Tier C) evidence only, or a context flag (confounding, reverse-direction interaction). Governance default: Yellow · context flag

Limits on what this shows

  • Key negative / null findings: No PARADIGM-HF or PARAGON-HF substudy reports thiamine or magnesium status as an outcome for the sacubitril/valsartan arm specifically; this entry exists to pre-empt misattribution, not to assert a sacubitril/valsartan effect.
  • At-risk subgroups: Patients on concurrent high-dose loop diuretics, poor oral intake, or advanced HFrEF are at elevated risk for diuretic-driven thiamine/magnesium depletion independent of ARNI therapy.

Regulatory status

Not applicable to sacubitril/valsartan directly; this is a population-level confounder inherent to the labeled indication (HFrEF, NYHA class II-IV), which by definition selects for patients already on loop diuretics and frequently on MRAs.

Population evidence

Multiple independent studies (none including sacubitril/valsartan in the cohort — Tier C at best for this drug) have documented reduced thiamine status in heart failure patients on long-term loop diuretic therapy, and separately, ACE-inhibitor/ARB and diuretic combinations are common in this population. These findings belong to furosemide/loop-diuretic pharmacology, not to sacubitril or valsartan.

Mechanism

Loop diuretics increase urinary thiamine and magnesium losses through a distinct renal-tubular mechanism unrelated to RAAS blockade or neprilysin inhibition. No mechanism links sacubitril or valsartan themselves to thiamine or magnesium loss.

Counter-evidence held on record

If thiamine or magnesium deficiency prevalence in ARNI-treated patients tracks diuretic dose and duration rather than ARNI exposure or duration, that is direct evidence the drug being reviewed here is not the cause — consistent with hard rule 6 (confounding by indication presumed until excluded). Framing caution for the consumer-facing surface Never present this as "sacubitril/valsartan depletes thiamine" or "depletes magnesium." The correct framing is that heart failure patients on diuretics should have these checked as part of routine HF care, regardless of whether they are also on an ARNI.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial function

Yellow — Low

See study details

No source ties sacubitril/valsartan to mitochondrial nutrient depletion or dysfunction; the only drug-specific evidence located is Tier B animal data in which sacubitril/valsartan-containing regimens reduced, rather than caused, markers of cardiac and renal tissue injury.

Full detail, limits and 2 references

What the grade means here: low/theoretical: mechanistic (Tier B) or class-extrapolated (Tier C) evidence only, or a context flag (confounding, reverse-direction interaction). Governance default: Yellow · mechanistic, protective direction

Limits on what this shows

  • Key negative / null findings: Both located animal studies report tissue-injury reduction, the opposite of a burden signal; no study located reported worsened mitochondrial or cardiac-injury markers with sacubitril/valsartan exposure.
  • At-risk subgroups: None identified; this entry documents a search result and a boundary condition (combination-therapy confound), not a risk group.

Regulatory status

The ENTRESTO label names no mitochondrial toxicity signal and no interaction with mitochondrial-support nutrients (CoQ10, carnitine, riboflavin); none of these appear anywhere in the label.

Population evidence

No Tier A human study measuring a mitochondrial-function biomarker (muscle biopsy respiratory-chain activity, circulating FGF-21/GDF-15, CoQ10 level) in a sacubitril/valsartan-treated cohort was located. Tier B animal evidence located via Europe PMC search: Murić M et al., Biomedicines 2026;14(5):1115 (PMID 42193440) — dual empagliflozin + sacubitril/valsartan therapy improved ex vivo cardiac function in a rat heart-failure model; this is a combination-therapy design, so the effect cannot be attributed to sacubitril/valsartan alone. Simko F et al., Sci Rep 2026 (PMID 42129373) — sacubitril/valsartan protected against isoproterenol-induced cardiac injury in rats, associated with upregulation of the alternative RAAS pathway (ACE2/Ang(1-7)/Mas axis), a cardioprotective signal rather than a mitochondrial-toxic one.

Mechanism

None named linking sacubitril or valsartan to electron-transport-chain interference, suppressed mitochondrial biogenesis, or increased demand for a mitochondrial-support nutrient. Neither component undergoes the CYP450-mediated hepatic metabolism that is the classical route by which other drug classes (statins and CoQ10, some antiretrovirals) impose a mitochondrial burden; the PK prescreen already establishes minimal CYP450 involvement for both components.

Counter-evidence held on record

The animal data run counter to a burden hypothesis: both studies show sacubitril/valsartan-containing regimens attenuating tissue injury rather than causing it, consistent with the drug's known hemodynamic and neurohormonal mechanism of action (reduced cardiac wall stress via natriuretic peptide potentiation and RAAS blockade). Framing caution for the consumer-facing surface Per hard rule 1, any cardioprotective signal in these animal studies belongs to the drug's intended pharmacological action, not to a nutrient-deficiency or nutrient-repletion mechanism. Do not present these findings as evidence that sacubitril/valsartan "protects mitochondria" as a nutritional benefit, and do not present the absence of a burden signal as proof that no mitochondrial effect exists — it is only the evidence located as of this review.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress

Yellow — Low

See study details

Every drug-specific study located shows sacubitril/valsartan-containing regimens reducing oxidative stress markers in animal injury models, not inducing an oxidative burden that would raise antioxidant nutrient demand.

Full detail, limits and 2 references

What the grade means here: low/theoretical: mechanistic (Tier B) or class-extrapolated (Tier C) evidence only, or a context flag (confounding, reverse-direction interaction). Governance default: Yellow · mechanistic, protective direction

Limits on what this shows

  • Key negative / null findings: No study located reported sacubitril/valsartan increasing oxidative stress markers; direction is consistently protective across the animal literature found.
  • At-risk subgroups: None identified.

Regulatory status

The label makes no statement about oxidative stress markers or antioxidant nutrient interactions.

Population evidence

No Tier A human study measuring oxidative stress biomarkers (malondialdehyde, superoxide dismutase, glutathione, F2-isoprostanes) in a sacubitril/valsartan cohort was located. Tier B animal evidence: Liu P et al., Exp Biol Med 2026;251:10946 (PMID 42131082) — sacubitril/valsartan combined with bisoprolol reduced doxorubicin-induced cardiotoxicity in rats by attenuating oxidative stress; combination with bisoprolol, a beta-blocker, confounds attribution to sacubitril/valsartan alone, and doxorubicin cardiotoxicity is an active chemotherapy-injury model, not the labeled HFrEF indication. Mohyeldin M et al., Sci Rep 2026;16(1):24919 (PMID 42581319) — sacubitril/valsartan attenuated renal injury from cecal ligation and puncture (a sepsis model) in rats via TLR4/NF-κB/NLRP3 inhibition, with reduced oxidative stress and apoptosis markers; again an acute-injury model, not HFrEF.

Mechanism

Reduction of oxidative stress markers in these models is attributed to the drug's anti-inflammatory and hemodynamic effects (reduced NLRP3 inflammasome activation, reduced wall stress), not to any antioxidant-nutrient-sparing or nutrient-cofactor mechanism.

Counter-evidence held on record

Both cited studies are active-comparator or combination-therapy designs in acute-injury models (doxorubicin cardiotoxicity, surgical sepsis), not the labeled chronic HFrEF indication, and neither isolates sacubitril/valsartan as a single agent — a real limitation on how far this Tier B signal can be extended. Framing caution for the consumer-facing surface Per hard rule 1, do not relabel this protective, injury-model finding as a nutrient-status claim in either direction. It does not establish that sacubitril/valsartan lowers a person's dietary antioxidant requirement, only that it did not worsen oxidative markers in these specific animal models.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Iron

Yellow — Low

See study details

Iron deficiency is common in the heart failure population sacubitril/valsartan treats, but the evidence located ties this to the disease process itself, chiefly inflammation-driven hepcidin elevation, not to sacubitril/valsartan's pharmacology; graded and written separately from copper, per the brief for this expansion.

Full detail, limits and 4 references

What the grade means here: low/theoretical: mechanistic (Tier B) or class-extrapolated (Tier C) evidence only, or a context flag (confounding, reverse-direction interaction). Governance default: Yellow · context flag, class/indication level

Limits on what this shows

  • Key negative / null findings: No study located measured iron parameters before versus after sacubitril/valsartan initiation, or compared a sacubitril/valsartan-exposed arm against an unexposed arm; the literature located is exclusively at the population/indication level, not the drug level.
  • At-risk subgroups: HFrEF patients generally, given how common iron deficiency is reported to be in this population across the sources found; older adults specifically flagged in Maidana et al.

Regulatory status

The ENTRESTO label contains no statement regarding iron, ferritin, transferrin saturation, or hepcidin.

Population evidence

Tier C, class/indication level; cohort test fails for this drug specifically in every source below. Packer M, Circulation 2024 (PMID 38733252), "Redefining Iron Deficiency in Patients With Chronic Heart Failure" — a review of iron deficiency as a common HFrEF comorbidity. Maidana D et al., Biomedicines 2025;13(2):462 (PMID 40002874), "Targeting Inflammation and Iron Deficiency in Heart Failure: A Focus on Older Adults." Karakas M et al., Eur J Heart Fail 2025 (PMID 40740027), the FAIR-HF2/DZHK05 trial of intravenous ferric carboxymaltose in heart failure with iron deficiency, sex-specific outcomes. Akintunde AA et al., BMC Cardiovasc Disord 2025 (PMID 41286649), iron deficiency and quality of life/functional status in chronic heart failure patients in Nigeria. None of these titles names sacubitril/valsartan as the studied intervention or stratifies by ARNI exposure; they study iron deficiency as a feature of the HFrEF population, a population in which sacubitril/valsartan is now guideline-directed background therapy — materially different from evidence that the drug causes the deficiency.

Mechanism

The mechanism described in this literature for HFrEF-associated iron deficiency is inflammation-driven hepcidin elevation (blocking intestinal iron absorption and macrophage iron release), reduced dietary intake, and in some patients occult gastrointestinal losses — none of which involve sacubitril or valsartan pharmacology. No absorption-interference, chelation, or renal-iron-wasting mechanism was found for either component in the PK prescreen.

Counter-evidence held on record

This is the same confounding-by-indication logic already applied above to thiamine and magnesium (hard rule 6), extended explicitly to iron so a reader does not misattribute a well-documented HFrEF comorbidity to the ARNI itself. If iron deficiency prevalence in ARNI-treated patients tracks inflammatory burden and HFrEF severity rather than ARNI exposure or duration, that argues against the drug as the cause. Framing caution for the consumer-facing surface Never present this as "sacubitril/valsartan depletes iron" or "consider iron supplementation because of this drug." Iron status in HFrEF patients is standard-of-care to check as part of routine heart failure management, independent of ARNI use, and any repletion decision belongs to the prescriber, informed by ferritin and transferrin saturation, not by ARNI exposure.

Copper

Not graded — disclosed evidence gap

See study details

No source, at any evidence tier, and no circulating consumer claim, was located tying sacubitril/valsartan to copper status; this is a genuine evidence gap, not a safety reassurance, and it is assessed separately from iron per the brief for this expansion.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Key negative / null findings: Not applicable; there is no study to report a null result from.
  • At-risk subgroups: None identified.
  • Why no grade: Both conditions for UNGRADED are met: no Tier B/C mechanistic or class evidence exists to support even a yellow grade, and no circulating consumer claim was found to rebut as white. A dedicated search for sacubitril/valsartan and copper was attempted (Europe PMC) but returned no results before WebFetch tooling became unavailable for the remainder of this session (see Sources access note); this entry is printed as a gap in the located evidence, not as a claim that the question is settled.

Regulatory status

The label makes no statement about copper.

Population evidence

None located at Tier A, B, or C for sacubitril/valsartan or for the ARNI/ARB/neprilysin-inhibitor class. Unlike the zinc claim already addressed below in "Claims that fail verification" (which at least traces to a single losartan study), no copper-specific study of any RAAS-acting drug was located in this review.

Mechanism

None of the mechanism-screen categories (absorption interference, hepatic enzyme induction, renal wasting, cofactor antagonism, mitochondrial/conjugation loss, dilutional/hormonal disturbance, microbiome disruption, altered intake, increased utilization) point to a copper-specific pathway for either sacubitril or valsartan. Ceruloplasmin, the copper transporters (ATP7A/B, CTR1), and copper-dependent enzymes are not mentioned anywhere in the label or in the literature searched.

Counter-evidence held on record

None exists to counter; there is nothing to rebut. Framing caution for the consumer-facing surface Never state or imply that "no evidence of harm" equals "evidence of no harm." This entry should be revisited if a copper-specific study of sacubitril/valsartan, or of the ARB/neprilysin-inhibitor class, is published.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk

Not graded — disclosed evidence gap

See study details

No sacubitril/valsartan-specific microbiome study, and no class-level RAAS-blocker microbiome study, was located; heart failure itself is independently described as associated with gut changes in the general cardiology literature, which would need to be ruled out before any future drug-specific finding could be attributed to the ARNI.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Key negative / null findings: None available; the search could not be completed.
  • At-risk subgroups: None identified.
  • Why no grade: Neither Tier B/C evidence nor a circulating consumer claim was confirmed this session (the consumer-claim search also could not be completed); printed as a gap. Confounding by indication is flagged prospectively per hard rule 2: gut dysbiosis in heart failure patients is described elsewhere in the cardiology literature as linked to gut-wall venous congestion and low cardiac output altering permeability and flora, so any future microbiome difference found in ARNI-treated HFrEF patients would need to be checked against untreated HFrEF and healthy controls before being attributed to the drug.

Regulatory status

The label makes no statement about gut flora.

Population evidence

A literature search for sacubitril/valsartan and gut microbiome/microbiota returned no drug-specific results before WebFetch access became unavailable for the remainder of this session; a broader search for heart-failure-associated gut microbiome changes could not be completed for the same reason (see Sources access note). This entry documents an incomplete search, not a confirmed absence of literature.

Mechanism

No absorption interference, bile-acid sequestration, or antimicrobial activity is described for either component; sacubitril and valsartan are not antibiotics and have no established antimicrobial spectrum.

Counter-evidence held on record

None available; the search was not completed. Framing caution for the consumer-facing surface Do not convert this gap into "sacubitril/valsartan is gut-safe." The honest state is that this specific question has essentially no confirmed published literature located yet, for this drug or its class.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

ATP production

Yellow — Low

See study details

The one drug-adjacent mechanistic signal located concerns cellular energy-sensing (AMPK activation) improving, not impairing, cardiorenal function in a combination-therapy animal model; no evidence of an ATP-production deficit attributable to sacubitril/valsartan was found, and this is graded and written separately from oxygen delivery/utilization.

Full detail, limits and 2 references

What the grade means here: low/theoretical: mechanistic (Tier B) or class-extrapolated (Tier C) evidence only, or a context flag (confounding, reverse-direction interaction). Governance default: Yellow · mechanistic, combination-therapy bound

Limits on what this shows

  • Key negative / null findings: None to report: no study located tested the negative hypothesis (an ARNI-induced ATP deficit) directly. The absence of such a study is itself the finding, not a null result to cite.
  • At-risk subgroups: None identified.

Regulatory status

The label does not address cellular energy metabolism or ATP.

Population evidence

No Tier A human study located. Tier B: Li et al., FASEB J 2026;40(6):e71594 (PMID 41854484), "Combined Empagliflozin and Sacubitril/Valsartan Therapy Additively Improves Cardiorenal Function Through AMPK Activation." AMPK is the principal cellular sensor of the ATP/AMP ratio and a driver of mitochondrial biogenesis and fatty-acid oxidation; the study reports the combination increasing AMPK activation, a signal of improved cellular energy handling. This is a combination-therapy design (empagliflozin, an SGLT2 inhibitor, plus sacubitril/valsartan), so the AMPK effect cannot be attributed to sacubitril/valsartan in isolation — a real limitation, not a footnote, and the reason this entry is bounded to yellow rather than orange.

Mechanism

None named linking sacubitril or valsartan alone to impaired ATP synthesis, electron-transport-chain inhibition, or increased demand for an ATP-cycle cofactor nutrient (CoQ10, riboflavin, carnitine, or thiamine as a TCA-cycle cofactor).

Counter-evidence held on record

The active-comparator/combination-therapy limitation is explicit above: a single Tier B study in a combination-drug design is bounded, weak evidence, which is exactly why this entry is graded yellow and not orange. Framing caution for the consumer-facing surface Do not present AMPK activation as a marketed "boosts your metabolism" or "raises your energy" benefit. It is a mechanistic animal finding in a combination-drug model, not a demonstrated human ATP-production or energy-level effect of sacubitril/valsartan alone.

Oxygen delivery / utilization

Not graded — disclosed evidence gap

See study details

No study was located measuring a nutrient-mediated oxygen-delivery or oxygen-utilization deficit (hemoglobin, or an iron-independent oxygen-carriage impairment) attributable to sacubitril/valsartan; the drug's well-established effect on cardiac output and perfusion is its labeled therapeutic mechanism, not a nutrient finding, and must not be relabeled as one. Assessed separately from ATP production, per the brief for this expansion.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Key negative / null findings: None available.
  • At-risk subgroups: None identified.
  • Why no grade: No citable Tier B/C source and no circulating consumer claim were confirmed this session for the nutrient-relevant question (oxygen carriage/utilization, independent of the iron entry already graded above); printed as a gap rather than forced into yellow on an unverified mechanism, consistent with the citation-integrity rule against citing a source not actually opened.

Regulatory status

The label describes improved hemodynamics (afterload/preload reduction via natriuretic peptide potentiation and RAAS blockade) as the therapeutic mechanism of action; it makes no statement linking the drug to hemoglobin, erythropoietin, or a nutrient-dependent oxygen-carriage pathway.

Population evidence

PARADIGM-HF and PARAGON-HF (already cited in the red-tier entry above) establish sacubitril/valsartan's clinical benefit on heart failure outcomes, which reflects improved cardiac pump function and tissue perfusion. Per hard rule 2, that is a hemodynamic and clinical-outcome finding, not a measurement of a nutrient-related oxygen-carriage marker, and it is not counted as nutrient evidence here. No study measuring hemoglobin, erythropoietin, or a B-vitamin/iron-independent oxygen-utilization marker specifically in a sacubitril/valsartan cohort was located before WebFetch tooling became unavailable this session.

Mechanism

RAAS blockade broadly (via reduced angiotensin II) is described in general nephrology and cardiology reference material as capable of modestly lowering erythropoietin-driven red-cell production, a mechanism used therapeutically for ACE-inhibitor treatment of post-transplant erythrocytosis. Whether this applies to sacubitril/valsartan specifically, and at what magnitude, could not be verified against a source actually opened in this session, so it is flagged here as an open question for a future review, not asserted as established evidence.

Counter-evidence held on record

None available for the nutrient-relevant question; PARADIGM-HF/PARAGON-HF counter-evidence on hemodynamic benefit is already on record under the red-tier potassium entry and is not re-litigated here. Framing caution for the consumer-facing surface The clinical improvement in exercise capacity and outcomes documented in PARADIGM-HF/PARAGON-HF is the drug doing its labeled job, not a sign of nutrient repletion, and must never be described as a nutrient-status finding on the consumer surface.

Claims checked and not supported

These circulate online for this medication. They are listed here only so they can be answered, never as findings, and they are not graded.

A claim with no supporting evidence is not necessarily disproven. Where evidence actually argues against a claim, that is stated below.

  • Zinc

    Where it comes from: Consumer health articles describing ARBs generally as increasing urinary zinc loss, tracing to a single interventional study of losartan (with and without hydrochlorothiazide) in hypertensive patients (Dishy et al., Clin Pharmacol Ther 2004).

    Why it fails: Fails the mandatory cohort test twice over: the source study used losartan, not valsartan or sacubitril/valsartan, and losartan's uricosuric/renal-transporter pharmacology (URAT1 inhibition) is a molecule-specific property not established for valsartan. No sacubitril/valsartan or valsartan-specific zinc study was located. No mention of zinc appears in the ENTRESTO label.

  • Coenzyme Q10

    Where it comes from: Automated phase-IV adverse-event co-occurrence pages (e.g., algorithmic "drug interaction" mining sites) list CoQ10 alongside Entresto without a stated mechanism.

    Why it fails: No mechanistic link exists between RAAS/neprilysin pharmacology and CoQ10 synthesis; the established CoQ10-depletion mechanism in cardiovascular medicine belongs to statins (HMG-CoA reductase inhibition), a different drug class entirely. This source could not be opened in full and is named here only to document that the claim circulates in low-quality automated form (Tier D); no statistic from it is cited.

What the research says is worth watching

General information from the medication label and the studies above. It is not personal medical advice, and any change belongs with your prescriber.

  • Lab · routine

    Serum potassium

    Per label: monitor periodically, especially at initiation and after dose increases, and whenever an MRA, potassium supplement, or potassium-sparing diuretic is added. This is standard RAAS-blocker monitoring, not unique to the ARNI.

  • Lab · routine

    Serum creatinine / renal function

    Label-directed: monitor creatinine and BUN, particularly in patients whose renal perfusion depends on RAAS activity (severe HFrEF); down-titrate or interrupt for a clinically significant decline in renal function.

  • At-risk group

    Concurrent MRA users

    Trial-derived nuance worth surfacing to prescribers: severe hyperkalemia was less frequent with sacubitril/valsartan than enalapril specifically in MRA-treated patients (Desai et al. 2017) — a reason for closer, not looser, potassium follow-up when MRA and ARNI are combined, given both drugs affect potassium.

  • At-risk group

    Concurrent loop-diuretic users

    Thiamine and magnesium status are worth checking in HFrEF patients on long-term loop diuretics as part of routine heart-failure care — attributable to the diuretic, not to sacubitril/valsartan (see confounding-by-indication entry above).

  • Drug interaction, not a nutrient claim

    ACE inhibitors and other ARBs

    Labeled contraindication: concomitant use with an ACE inhibitor is contraindicated (angioedema risk), with a required 36-hour washout when switching between them; concomitant use with another ARB should be avoided. This is a drug-drug safety interaction and must never be filed as a nutrient-depletion entry.

  • Supplement separation

    Potassium supplements and salt substitutes

    Label-flagged as raising serum potassium further in combination with sacubitril/valsartan. No separation interval mitigates this; the interaction is additive and pharmacodynamic, not absorption-based, so avoidance rather than timing is the relevant guidance a prescriber would give.

All references used above
  1. ENTRESTO (sacubitril and valsartan) full prescribing information — FDA label, NDA 207620s018, revised 2021. Mechanism of action, pharmacokinetics (12.1, 12.3), Warnings and Precautions 5.3 (Hyperkalemia), 5.1 (Angioedema), Drug Interactions 7, Dosage and Administration 2.4 (renal impairment).
  2. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF). — N Engl J Med. 2014;371(11):993-1004. Randomized, double-blind, N=8,399, HFrEF NYHA II-IV, LVEF ≤40%. PMID 25176015. Primary trial establishing sacubitril/valsartan vs enalapril; cohort test passed (sacubitril/valsartan named study arm).
  3. Desai AS, Vardeny O, Claggett B, McMurray JJV, Packer M, Swedberg K, Rouleau JL, Zile MR, Lefkowitz M, Shi V, Solomon SD. Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With Enalapril: A Secondary Analysis of the PARADIGM-HF Trial. — JAMA Cardiol. 2017;2(1):79-85. DOI 10.1001/jamacardio.2016.4733. PMID 27842179. Secondary analysis of PARADIGM-HF restricted to MRA users; severe hyperkalemia HR 1.37 (95% CI 1.06-1.76, P=.02) baseline MRA users, HR 1.43 (95% CI 1.13-1.81, P=.003) new MRA users, favoring sacubitril/valsartan. Cohort test passed.
  4. Nougué H, Pezel T, Picard F, et al. Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study. — Eur J Heart Fail. 2019;21(5):598-605. PMID 30520545.Full text and abstract could not be retrieved (access blocked); title and journal indexing confirmed via search only. No statistic from this source is cited — it is named solely to document that a mechanistic, drug-specific study of neprilysin substrate metabolism exists, consistent with the peptide-only substrate profile described from the FDA label.
  5. Dishy V, Sofowora GG, Xie HG, et al. The effects of losartan and losartan/hydrochlorothiazide fixed combination on zinc and magnesium metabolism in patients with hypertension. — Am J Hypertens. 2004 (title and journal confirmed via search index). PMID cited by secondary consumer source as 17205995 (unconfirmed — see access note).Cohort excluded this drug: study population received losartan (±HCTZ), not valsartan or sacubitril/valsartan. Full text could not be opened (access blocked); no effect size is cited from this source. Named only to trace the origin of the circulating zinc claim addressed in "Claims that fail verification."
  6. Losartan and Zinc Loss: What You Should Know. — Suzy Cohen, RPh (consumer health blog). Consumer-tier source (Tier D) documenting that the zinc claim circulates and citing the Dishy losartan study above; does not mention sacubitril/valsartan or Entresto.
  7. Entresto and Coq10 drug interactions — a phase IV clinical study. — eHealthMe (algorithmic adverse-event co-occurrence mining tool, not a peer-reviewed study). Tier D.Page could not be opened in full (robots-disallowed/timeout); named only to document that an automated co-occurrence listing exists. No statistic is cited from this source.
  8. wellrx.com — Sacubitril-Valsartan or Entresto: Food, Alcohol, Supplements and Drug Interactions. — Consumer drug-information aggregator. Consulted for the circulating-claim audit; states "there is no lifestyle interaction information available for this medication," confirming the sparse consumer-claim landscape for this specific drug.
  9. Sacubitril/valsartan — Wikipedia (ATC code and mechanism cross-check). — Used only to confirm WHO ATC code C09DX04 and to cross-check mechanism-of-action language against the FDA label; not used as a source of clinical statistics.
  10. Murić M, et al. Dual Empagliflozin and Sacubitril/Valsartan Therapy Improves Ex Vivo Cardiac Function in a Rat Model of Heart Failure. — Biomedicines. 2026;14(5):1115. PMID 42193440. DOI 10.3390/biomedicines14051115. Tier B, combination-therapy rat model. Cited in the mitochondrial-function entry above.Bibliographic record (title, authors, journal, PMID, DOI) confirmed via the Europe PMC search API on 2026-09-10; full text was not opened this session because WebFetch became rate-limited/unavailable immediately after this record was retrieved. No effect size or statistic beyond the title's own description is cited from this source.
  11. Liu P, et al. Sacubitril valsartan combined with bisoprolol reduces doxorubicin-induced cardiotoxicity in rats by attenuating oxidative stress. — Exp Biol Med (Maywood). 2026;251:10946. PMID 42131082. DOI 10.3389/ebm.2026.10946. Tier B, combination-therapy rat model. Cited in the oxidative-stress entry above.Bibliographic record confirmed via the Europe PMC search API on 2026-09-10; full text not opened this session (WebFetch rate-limited). No effect size or statistic beyond the title's own description is cited from this source.
  12. Simko F, et al. Protection against isoproterenol-induced cardiac injury by sacubitril/valsartan is associated with upregulation of the alternative renin-angiotensin-aldosterone system pathway. — Sci Rep. 2026. PMID 42129373. DOI 10.1038/s41598-026-52621-5. Tier B rat model. Cited in the mitochondrial-function entry above.Bibliographic record confirmed via the Europe PMC search API on 2026-09-10; full text not opened this session (WebFetch rate-limited). No effect size or statistic beyond the title's own description is cited from this source.
  13. Mohyeldin M, et al. Sacubitril/valsartan attenuates renal injury caused by cecal ligation and puncture via TLR4/NFκB/NLRP3 inhibition and reduced oxidative stress and apoptosis in rats. — Sci Rep. 2026;16(1):24919. PMID 42581319. DOI 10.1038/s41598-026-65493-6. Tier B rat sepsis model. Cited in the oxidative-stress entry above.Bibliographic record confirmed via the Europe PMC search API on 2026-09-10; full text not opened this session (WebFetch rate-limited). No effect size or statistic beyond the title's own description is cited from this source.
  14. Li, et al. Combined Empagliflozin and Sacubitril/Valsartan Therapy Additively Improves Cardiorenal Function Through AMPK Activation. — FASEB J. 2026;40(6):e71594. PMID 41854484. DOI 10.1096/fj.202503723r. Tier B, combination-therapy model. Cited in the ATP-production entry above.Bibliographic record confirmed via the Europe PMC search API on 2026-09-10; full text not opened this session (WebFetch rate-limited). No effect size or statistic beyond the title's own description is cited from this source.
  15. Packer M. Redefining Iron Deficiency in Patients With Chronic Heart Failure. — Circulation. 2024. PMID 38733252. DOI 10.1161/circulationaha.124.068883. Tier C for sacubitril/valsartan (HFrEF-population review, drug not stratified). Cited in the iron entry above.Bibliographic record confirmed via the Europe PMC search API on 2026-09-10; full text not opened this session (WebFetch rate-limited). No effect size or statistic beyond the title's own description is cited from this source.
  16. Maidana D, et al. Targeting Inflammation and Iron Deficiency in Heart Failure: A Focus on Older Adults. — Biomedicines. 2025;13(2):462. PMID 40002874. DOI 10.3390/biomedicines13020462. Tier C for sacubitril/valsartan. Cited in the iron entry above.Bibliographic record confirmed via the Europe PMC search API on 2026-09-10; full text not opened this session (WebFetch rate-limited). No effect size or statistic beyond the title's own description is cited from this source.
  17. Karakas M, et al. Intravenous ferric carboxymaltose in heart failure with iron deficiency (FAIR-HF2 DZHK05 trial): Sex-specific outcomes. — Eur J Heart Fail. 2025. PMID 40740027. DOI 10.1002/ejhf.3742. Tier C for sacubitril/valsartan (trial of IV iron in HFrEF, not a sacubitril/valsartan-arm study). Cited in the iron entry above.Bibliographic record confirmed via the Europe PMC search API on 2026-09-10; full text not opened this session (WebFetch rate-limited). No effect size or statistic beyond the title's own description is cited from this source.
  18. Akintunde AA, et al. Impact of iron deficiency on health-related quality of life and functional status in adults with chronic heart failure in Nigeria. — BMC Cardiovasc Disord. 2025. PMID 41286649. DOI 10.1186/s12872-025-05192-8. Tier C for sacubitril/valsartan. Cited in the iron entry above.Bibliographic record confirmed via the Europe PMC search API on 2026-09-10; full text not opened this session (WebFetch rate-limited). No effect size or statistic beyond the title's own description is cited from this source.
  19. DailyMed — SACUBITRIL AND VALSARTAN search results (label-source cross-check). — National Library of Medicine DailyMed. Consulted to reconfirm the label is current and multiply-manufactured (generic entries present alongside ENTRESTO); no new clinical statistic drawn from this page.