Eplerenone

證據等級: L5

預測適應症: 5 個

Eplerenone: From Hypertension / Heart Failure to Pulmonary Hypertension Owing to Lung Disease and/or Hypoxia

One-Sentence Summary

Eplerenone is a selective mineralocorticoid receptor antagonist (MRA), approved internationally for hypertension and heart failure with reduced ejection fraction (HFrEF), though it is not currently registered in Taiwan. The TxGNN model predicts it may be effective for Pulmonary Hypertension Owing to Lung Disease and/or Hypoxia (Group 3 PH), with 0 clinical trials and 20 publications retrieved — all of which are general hypoxia biology reviews and do not directly study eplerenone in this indication.

Quick Overview

Item	Content
Original Indication	Hypertension; Heart failure with reduced ejection fraction (international approvals; no Taiwan registration)
Predicted New Indication	Pulmonary Hypertension Owing to Lung Disease and/or Hypoxia (Group 3 PH)
TxGNN Prediction Score	99.50%
Evidence Level	L4
Taiwan Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Eplerenone is a selective mineralocorticoid receptor antagonist (MRA) that competitively blocks the aldosterone receptor with greater selectivity than spironolactone, reducing off-target steroid side effects. The theoretical bridge to Group 3 pulmonary hypertension runs through the aldosterone–MR–RAAS axis: chronic hypoxia activates the renin–angiotensin–aldosterone system, and excess aldosterone is known to promote pulmonary vascular fibrosis, endothelial dysfunction, and right ventricular remodeling. In theory, blocking mineralocorticoid receptors could interrupt hypoxia-induced pulmonary vascular remodeling via the HIF-1α/RAAS interaction — a mechanistically coherent but as yet unvalidated pathway.

However, this reasoning is indirect. The 20 retrieved literature items are all general reviews of hypoxia biology — covering topics such as cerebral hypoxia, tumor hypoxia, and altitude physiology — and none directly evaluate eplerenone's efficacy in pulmonary hypertension. The gap between biological plausibility and actual clinical or preclinical data for this specific drug–disease pair is substantial.

It should also be noted that eplerenone's detailed mechanism of action data (MOA) was flagged as a data gap in this evidence pack, and Taiwan regulatory data is unavailable. Safety and efficacy conclusions must therefore be drawn from international sources pending further data retrieval.

Clinical Trial Evidence

Currently no related clinical trials registered.

Literature Evidence

⚠️ Important caveat: The 20 retrieved publications are general hypoxia biology reviews and are not specific to eplerenone use in pulmonary hypertension. They provide background context on the disease mechanism but do not constitute direct clinical or preclinical evidence for this drug–indication pair. The relevance classification for all items was marked as "pending" in the evidence pack.

PMID	Year	Type	Journal	Key Findings
11172576	2000	Review	Respiratory Care Clinics of North America	Reviews four core mechanisms of hypoxemia (hypoventilation, V/Q mismatch, right-to-left shunt, low FiO₂); foundational disease-mechanism background
21328446	2011	Review	Journal of Cellular Biochemistry	Hypoxia modulates growth, metabolism, angiogenesis, and pH homeostasis; contributes to vascular disease and cancer pathogenesis
31706510	2019	Review	Trends in Cancer	Deubiquitinases (DUBs) regulate HIF abundance under hypoxia; emerging role as drug targets in cancer
31961750	2020	Review	Annual Review of Immunology	Hypoxia shapes innate immunity and inflammatory responses through HIF-mediated oxygen sensing in healthy and inflamed tissue
33862277	2021	Review	Ageing Research Reviews	Hypoxia in pulmonary disease or high altitude can cause neurodegeneration; paradoxically may also confer neuroprotection in aging
34535359	2021	Review	Clinical Oncology	Tumor hypoxia drives radiotherapy and immunotherapy resistance; reviews hypoxia-targeted therapeutic modification strategies
34618295	2022	Review	Metabolic Brain Disease	Acute and chronic hypoxia cause cognitive dysfunction through multiple molecular mechanisms; clinical and preclinical evidence reviewed
37328448	2023	Original Research	Advanced Science	HIF-1α/NAT10/SEPT9 positive feedback loop drives glycolysis addiction and hypoxia tolerance in gastric cancer; anti-angiogenic resistance mechanism
40347693	2025	Review	Redox Biology	Hypoxia is a prominent but poorly understood feature of multiple sclerosis; interacts with inflammation and vascular dysfunction
40815459	2025	Opinion/Review	Revista Medica del IMSS	Hypobaric hypoxia at altitude vs sea level; differences in acclimatization between high-altitude residents and lowland visitors

Taiwan Market Information

Eplerenone is not currently registered or marketed in Taiwan. No authorization records are available in the TFDA database. Internationally, eplerenone is approved (e.g., by the US FDA and EMA) for hypertension and heart failure following myocardial infarction, marketed under brand names such as Inspra.

Safety Considerations

Please refer to the package insert for safety information.

⚠️ Critical risk flag (Rank 4 predicted indication — Malignant Renovascular Hypertension): Renovascular hypertension, especially bilateral renal artery stenosis, is a relative contraindication for mineralocorticoid receptor antagonists. Aldosterone in this context serves as a compensatory renal perfusion mechanism; MR blockade may precipitate acute kidney injury and life-threatening hyperkalemia. If any research design considers eplerenone in patients with concurrent renovascular disease, this safety signal must be explicitly addressed.

Conclusion and Next Steps

Decision: Hold

Rationale: The TxGNN model assigns a high prediction score (99.50%) for eplerenone in Group 3 pulmonary hypertension, and there is a biologically plausible mechanistic link via RAAS/aldosterone-driven pulmonary vascular remodeling. However, no clinical trials exist for this indication, and all 20 retrieved publications are general hypoxia biology reviews with no direct eplerenone-in-PH data. The evidence is classified as L4 (mechanistic inference only), which is insufficient to advance to clinical evaluation without dedicated preclinical validation.

To proceed, the following is needed:

Dedicated preclinical studies (animal models of hypoxic PH) evaluating eplerenone's effect on pulmonary arterial remodeling, right ventricular hypertrophy, and hemodynamics
Retrieval of eplerenone-specific MOA data from DrugBank to formally confirm the aldosterone–MR–HIF-1α mechanistic link (currently flagged as a data gap)
Full safety review: download and parse the TFDA package insert (or international equivalents) to establish key warnings, contraindications, and drug interactions — currently all are marked as data gaps
Targeted PubMed search refined to eplerenone AND (pulmonary hypertension OR pulmonary vascular remodeling OR right ventricular) to retrieve any missed preclinical or clinical publications not captured by the current hypoxia-broad query
Assessment of eplerenone's known safety profile (hyperkalemia, renal impairment risk) in the target population — Group 3 PH patients often carry concurrent lung disease, cardiac comorbidities, and reduced renal reserve, all of which increase MRA-related adverse event risk
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.