This synthesis combines outputs from four AI models (Claude AI, Perplexity AI, Grok AI, and ChatGPT AI) responding to an identical following query:
"When used with Eplerenone to treat primary aldosteronism, what is the best combination of a second medication that helps reduce hypertension and has no ED side effect and the least amount of other side effects, plus has the highest efficiency and further has a positive effect on the kidney. List and include ARB's, Diuretics, CCB's, ARB's and SGLT2 inhibitors. Included in the comparison ranking metoprolol, lisinopril, Amlodipine, Chlorthalidone, Empagliflozin or Dapagliflozin (SGLT2 inhibitor), Telmisartan or Valsartan (ARB) and nebivolol and any other effective medication that would qualify in the comparison."
Primary aldosteronism (PA) is a common secondary cause of hypertension, often managed with eplerenone as a first-line mineralocorticoid receptor antagonist (MRA) to minimize sexual side effects. When additional therapy is required, selection must prioritize agents with no erectile dysfunction (ED) risk, minimal overall side effects, high antihypertensive efficacy, and positive renal effects. A consensus ranking was derived by aggregating individual rankings, emphasizing shared priorities across models. SGLT2 inhibitors and ARBs emerged as top choices due to superior renal protection, ED neutrality or improvement, and tolerability. The report includes a concise ranking table, justifications, findings, references ordered by applicability, and a summarizing conclusion.
The table synthesizes rankings from all four AI outputs, assigning consensus ranks based on frequency of high placement (e.g., top 1-3 across models), weighted by criteria alignment (ED risk: none/improves > neutral > causes; renal protection: excellent > good > moderate/neutral; BP efficacy: high > moderate; side effects: minimal > moderate > significant). Ties reflect similar consensus scores.
| Consensus Rank | Medication/Class | ED Risk | Renal Protection | BP Efficacy | Overall Side Effects | Key Consensus Justification |
|---|---|---|---|---|---|---|
| 1 | SGLT2 Inhibitors (Empagliflozin or Dapagliflozin) | None (may improve) | Excellent | Moderate-High | Minimal (e.g., mild UTIs, polyuria) | Top-ranked by Claude, Grok, and tied in ChatGPT; unique hyperkalemia mitigation with eplerenone, strong renal/CV benefits; minimal ED/side effects. |
| 2 | ARBs (Telmisartan or Valsartan) | None (may improve) | Excellent | High | Minimal (e.g., rare hyperkalemia) | Top-ranked by Perplexity and ChatGPT, high in Claude/Grok; robust renal protection, no ED risk, high efficacy; monitor K+ with eplerenone. |
| 3 | Nebivolol (Beta-blocker) | None (may improve via NO release) | Moderate | Moderate | Good (less fatigue than others) | Mid-high in all (e.g., 4th in Claude/Grok/ChatGPT); best beta-blocker for ED preservation; useful if beta-blockade indicated. |
| 4 | Amlodipine (CCB) | Neutral/None | Moderate | High | Moderate (e.g., edema) | Consistent mid-rank (e.g., 5-6th); strong BP control, no ED; less renal benefit than top tiers. |
| 5 | Lisinopril (ACE-I) | Neutral/None | Very Good | Moderate-High | Moderate (e.g., cough, hyperkalemia risk) | Mid-low (e.g., 5-7th); good renal protection but higher hyperkalemia/cough vs. ARBs. |
| 6 | Chlorthalidone (Diuretic) | High (causes in some) | Limited/Neutral | High | Significant (e.g., electrolytes, metabolic) | Low-mid (e.g., 6-8th); potent BP but ED/metabolic risks; avoid unless volume-driven. |
| 7 | Metoprolol (Beta-blocker) | High (causes) | Moderate/Neutral | Moderate | Moderate (e.g., fatigue, ED) | Bottom-ranked across all; high ED risk, no unique benefits. |
Primary aldosteronism (PA) accounts for up to 20% of resistant hypertension cases, driven by excess aldosterone leading to hypertension, hypokalemia, and heightened cardiorenal risks. Eplerenone, a selective MRA, is preferred over spironolactone for its lower anti-androgenic effects, reducing gynecomastia and ED risks. However, many patients need add-on therapy for BP control. The query emphasized agents with no ED risk, minimal side effects, high efficacy, and renal benefits, including ARBs, diuretics, CCBs, SGLT2 inhibitors, and specifics like metoprolol, lisinopril, amlodipine, chlorthalidone, empagliflozin/dapagliflozin, telmisartan/valsartan, and nebivolol. This synthesis integrates four AI-generated "research papers" to provide a unified, evidence-based recommendation as of November 20, 2025.
Outputs from Claude AI, Perplexity AI, Grok AI, and ChatGPT AI were analyzed for rankings, justifications, and references. Consensus was achieved by:
No new searches were conducted; synthesis relies on provided AI content.
The consensus prioritizes SGLT2 inhibitors and ARBs, reflecting shared AI emphasis on renal protection in PA's aldosterone-driven pathology. All AIs noted eplerenone's hyperkalemia risk, mitigated best by SGLT2i. ED avoidance was universal, penalizing beta-blockers like metoprolol. Findings are grouped by class, with cross-AI synthesis.
All AIs ranked these highly (Claude: 1st; Grok: 1st; Perplexity: 3-4th; ChatGPT: tied 1st in combo). They improve ED via endothelial function, provide superior renal protection (e.g., 30-40% reduction in CKD progression per EMPA-KIDNEY/DAPA-CKD), offer moderate BP reduction (3-8 mmHg), and minimize side effects (mild UTIs/polyuria). Unique benefit: Reduce hyperkalemia with eplerenone, enabling higher MRA doses. Justification: Best alignment with all criteria; extrapolates well to PA from CKD trials.
Consensus second (Perplexity: 1-2nd; ChatGPT: 1-2nd; Claude: 2-3rd; Grok: 2nd). Neutral/improves ED, excellent renal effects (proteinuria reduction, eGFR preservation), high BP efficacy (10-15 mmHg), minimal side effects. Telmisartan edges valsartan for PPAR-? activity. Hyperkalemia risk with eplerenone requires monitoring. Justification: Strong in resistant hypertension; preferred over ACE-I for tolerability.
Nebivolol ranked mid-high (Claude: 4th; Grok: 3rd; ChatGPT: 5th; Perplexity: 9th but "preferable" to metoprolol). Improves ED via NO release, moderate renal/BP effects, better tolerability. Metoprolol bottom-ranked (all AIs: 7-8th) for high ED risk (80-86% incidence), fatigue. Justification: Nebivolol only if beta-blockade needed (e.g., tachycardia); avoid metoprolol.
Mid-rank (Claude: 6th; Grok: 4th; Perplexity: 5th; ChatGPT: 3rd in combo). Neutral ED, high BP efficacy (12-18 mmHg), moderate renal protection, but edema (10-30%). Justification: Reliable add-on; no metabolic issues, but less renal benefit than top tiers.
Mid-low (Claude: 5th; Grok: 6th; Perplexity: 7th; ChatGPT: 4th). Neutral ED, very good renal protection, moderate-high BP, but cough (10-20%) and higher hyperkalemia vs. ARBs. Justification: Solid but inferior to ARBs; monitor K+.
Low-mid (Claude: 8th; Grok: 5th; Perplexity: 6th; ChatGPT: 6th). High BP efficacy (15-20 mmHg), but causes ED (22% incidence), metabolic/electrolyte issues. Limited renal benefit. Justification: Potent but avoid due to ED/side effects unless volume-expanded.
References are compiled from all AI outputs, deduplicated, and ordered by relevance: PA-specific guidelines first, then renal outcome trials, ED/side effect studies, general hypertension data.
Synthesizing outputs from four AI models reveals strong consensus on SGLT2 inhibitors (empagliflozin/dapagliflozin) as the optimal add-on to eplerenone for PA, offering ED improvement, superior renal protection, moderate-high BP efficacy, and hyperkalemia mitigation with minimal side effects. ARBs (telmisartan/valsartan) follow closely for robust renal/BP benefits and tolerability. Nebivolol stands out among beta-blockers for ED preservation, while amlodipine provides reliable BP control but less renal advantage. Lisinopril, chlorthalidone, and metoprolol rank lower due to cough/hyperkalemia, metabolic/ED risks, and high ED incidence, respectively. This hierarchy supports individualized therapy, emphasizing monitoring for hyperkalemia and renal function to optimize outcomes in PA's high-risk profile.