Sacubitril
| Evidence Level: L3 | Predicted Indications: 10 |
Table of Contents
Sacubitril: From Heart Failure Therapy to Diabetic Nephropathy
One-Sentence Summary
Sacubitril is a neprilysin inhibitor, marketed in Singapore as a single-ingredient film-coated tablet. The approved indication text is not available in the data compiled for this report. The TxGNN model predicts it may be effective for diabetic nephropathy (the top-ranked prediction with meaningful supporting evidence), with 1 clinical trial (Phase 4, status unknown) and 15 publications currently supporting this direction. Most of the publications are preclinical studies or reviews.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available (approved indication text is empty in the Singapore licence records) |
| Predicted New Indication | Diabetic nephropathy (the top-ranked prediction, brain small vessel disease, has almost no support; see the note below) |
| TxGNN Prediction Score | 99.50% (diabetic nephropathy); the rank 1 prediction scored 99.58% |
| Evidence Level | L3 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 3 |
| Recommended Decision | Proceed with Guardrails (research-question stage) |
Note on prediction selection: The rank 1 prediction (brain small vessel disease 1 with or without ocular anomalies) and the other top-10 predictions, except diabetic nephropathy, have no clinical trials and either no literature or only unrelated literature (evidence level L5, Hold). This report therefore focuses on diabetic nephropathy, the only prediction with substantive supporting evidence.
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known pharmacology, sacubitril is a prodrug whose active metabolite inhibits neprilysin, an enzyme that breaks down natriuretic peptides. It is used together with valsartan, an angiotensin II receptor blocker (AT1 blocker).
Blocking the renin-angiotensin system is already a cornerstone of diabetic kidney disease management. Adding neprilysin inhibition raises natriuretic peptide levels, which may further reduce glomerular hypertension, oxidative stress, NF-κB-mediated inflammation and fibrosis. Several rodent studies (diabetic rat, db/db mouse and Zucker obese rat models) report renoprotective effects, and a secondary analysis of the PARADIGM-HF trial examined renal function in patients with type 2 diabetes and heart failure.
The mechanistic link is therefore biologically plausible, but renal outcomes in diabetic kidney disease in humans remain unconfirmed.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT06501651 | Phase 4 | Unknown | 297 | Randomized, controlled, multicenter study (Hyper-Save) comparing sacubitril/valsartan with valsartan over 12 weeks in patients with essential hypertension and type 2 diabetic nephropathy (2:1 randomization). No results reported. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37549515 | 2023 | Clinical study (randomized, n=112) | Int Immunopharmacol | Nifedipine controlled-release plus sacubitril/valsartan compared with nifedipine plus valsartan in diabetic nephropathy patients with hypertension |
| 29661699 | 2018 | Secondary analysis of RCT | Lancet Diabetes Endocrinol | PARADIGM-HF secondary analysis of neprilysin inhibition and renal function in type 2 diabetes with chronic heart failure |
| 40416927 | 2025 | Clinical study | Diabetes Metab Syndr Obes | BOLD-MRI evaluation of sacubitril/valsartan renal protection in diabetic nephropathy patients |
| 34734359 | 2023 | Cohort/Observational | Heart Fail Rev | Disease-modifying drugs in diabetic patients with heart failure with reduced ejection fraction |
| 37625003 | 2023 | Review | Diabetes Care | Update on the pillars of therapy slowing diabetic nephropathy progression |
| 35165832 | 2022 | Review | Curr Hypertens Rep | Newer drugs lowering blood pressure and mitigating hypertensive target organ damage |
| 35992034 | 2022 | Preclinical (rat) | Diabetes Metab Syndr Obes | Sacubitril/valsartan slowed early diabetic nephropathy progression via NLRP3 inflammasome inhibition |
| 30909895 | 2019 | Preclinical (rat) | Cardiovasc Diabetol | Sacubitril plus valsartan attenuated glomerular and tubular injury in the Zucker obese rat |
| 32596035 | 2020 | Preclinical (rat) | PeerJ | LCZ696 reduced oxidative stress, NF-κB inflammation and glomerulosclerosis in diabetic rats |
| 33870733 | 2021 | Preclinical (mouse) | Am J Physiol Renal Physiol | Effects differed between db/db and KKAy mice compared with valsartan |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16872P | MERAVO Film-Coated Tablets 50MG | Film-coated tablet | Not available |
| SIN16873P | MERAVO Film-Coated Tablets 100MG | Film-coated tablet | Not available |
| SIN16874P | MERAVO Film-Coated Tablets 200MG | Film-coated tablet | Not available |
All three licences are valid single-ingredient products (manufacturer: Biocon Pharma Limited), and none has been cancelled.
Safety Considerations
- Drug Interactions: Six moderate-level interactions were identified: nitisinone, rosuvastatin, simvastatin, cobicistat, revefenacin and alpelisib.
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Diabetic nephropathy is the only predicted indication with a plausible mechanism, a registered randomized trial, and consistent preclinical and early clinical signals. However, the only trial has unknown status and no results, and no completed Phase 2/3 RCT is available, so the evidence level is capped at L3 and the finding should be treated as a research question. All other top-10 predictions (including rank 1) lack supporting data and should stay on Hold.
To proceed, the following is needed:
- Results or status confirmation for NCT06501651, and ideally completed Phase 2/3 RCTs with renal outcomes (e.g., albuminuria, eGFR decline)
- Package insert warnings and contraindications (a blocking gap for safety screening)
- Detailed mechanism of action data
- Approved indication text for the Singapore licences
- A safety monitoring plan (e.g., blood pressure, renal function, potassium) for diabetic patients with renal impairment, and a review of the listed drug interactions (notably statins)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.