Management of Worsening Renal Function in HFpEF on Triple Neurohormonal Blockade
Primary Recommendation
Continue the SGLT2 inhibitor, ACEi, and MRA at current doses without dose reduction, as modest creatinine elevations (up to 30% above baseline) during guideline-directed medical therapy optimization are acceptable and should not prompt discontinuation, particularly when these medications provide mortality and hospitalization benefits in HFpEF. 1, 2
Understanding the Creatinine Drift
This creatinine increase (0.8–1.1 → 1.26–1.39 mg/dL) represents approximately a 15-25% rise, which falls well within the acceptable range during GDMT optimization. 2
Changes in kidney function during GDMT optimization must be interpreted in the context of decongestion—worsening kidney function with successful decongestion is associated with lower mortality than failure to decongest with stable kidney function. 2
SGLT2 inhibitors cause a mild and transient drop in eGFR that occurs soon after treatment initiation, but they offer long-term kidney protection despite this initial effect. 1
The current eGFR of 42 mL/min/1.73 m² remains above the safety threshold for continuing all three medications: SGLT2 inhibitors can be used if eGFR ≥30 mL/min/1.73 m² for empagliflozin or ≥20 mL/min/1.73 m² for dapagliflozin, ACEi can be continued, and MRAs are recommended if eGFR >30 mL/min/1.73 m². 1, 2
Prioritize HFpEF Treatment Over Osteoporosis Management
The mortality and morbidity benefits from continuing GDMT for HFpEF significantly outweigh the risks of temporarily holding bisphosphonate therapy. 1
Why This Matters:
SGLT2 inhibitors provide a 21% reduction in the composite endpoint of HF hospitalization or cardiovascular death in HFpEF patients, driven primarily by a 29% reduction in HF hospitalizations. 1
MRAs and ACEi reduce hospitalizations in selected HFpEF patients, particularly those with LVEF on the lower end of the spectrum. 1
Discontinuing RAASi (ACEi/MRA) after renal function changes is associated with a two to fourfold higher risk of subsequent adverse cardiovascular events compared to continuing therapy. 2
Osteoporosis Management Strategy:
Holding zoledronic acid (Reclast) at eGFR 42 mL/min/1.73 m² is appropriate per manufacturer recommendations (typically requires eGFR ≥35 mL/min/1.73 m²). 2
Consider alternative osteoporosis therapies that do not require specific eGFR thresholds, such as denosumab (Prolia), which is not renally cleared and can be used safely in CKD. 2
Optimize non-pharmacologic bone health: ensure adequate calcium (1200 mg daily) and vitamin D (800-1000 IU daily) supplementation, weight-bearing exercise as tolerated, and fall prevention strategies. 2
Monitoring Protocol
Implement close surveillance without medication changes: 2
Recheck creatinine, potassium, and BUN in 1-2 weeks after any clinical change or concern.
If creatinine stabilizes or improves, continue current regimen and monitor monthly for 3 months, then quarterly.
Monitor potassium levels closely with MRA therapy—modest increases in creatinine are acceptable, but potassium >5.5 mEq/L requires intervention. 1
If hyperkalemia develops, consider potassium binders (patiromer or sodium zirconium cyclosilicate) rather than discontinuing life-saving medications. 2
When to Modify Therapy
Only reduce or discontinue GDMT if: 2
Creatinine increases >30% above baseline (would be >1.43 mg/dL in this patient) AND patient shows signs of acute kidney injury (oliguria, volume depletion, acute illness).
eGFR falls below 30 mL/min/1.73 m² for empagliflozin or MRA (below 20 mL/min/1.73 m² for dapagliflozin).
Potassium rises >5.5 mEq/L despite dietary modification and diuretic adjustment—first try potassium binders before stopping MRA. 2
Patient develops symptomatic hypotension (SBP <80 mmHg with symptoms) unresponsive to addressing reversible causes. 2
If Modification Becomes Necessary:
Reduce medications in this specific order: 2
First: Reduce ACEi dose by 50% (maintains some RAAS blockade while improving renal hemodynamics).
Second: If inadequate response, reduce MRA dose by 50% or switch to alternate-day dosing.
Last resort: Discontinue ACEi entirely before stopping SGLT2i or MRA, as SGLT2i provides the most consistent benefit across the HFpEF spectrum. 1
Address Reversible Causes of Renal Dysfunction
Before modifying GDMT, systematically evaluate for: 2
Volume depletion: Assess for excessive diuresis, inadequate oral intake, or gastrointestinal losses. If present, reduce loop diuretic dose temporarily.
Acute illness: Screen for infection, dehydration, or other acute processes that may be contributing to prerenal azotemia.
Nephrotoxic medications: Review medication list for NSAIDs, contrast agents, or other nephrotoxins and discontinue if present.
Urinary obstruction: Particularly relevant given history of tongue cancer—ensure no obstructive uropathy from pelvic malignancy or treatment effects.
Special Considerations for This Patient
Atrial Fibrillation on Anticoagulation:
Continue apixaban (Eliquis) without dose adjustment unless eGFR falls below 25 mL/min/1.73 m² or creatinine rises above 2.5 mg/dL. 2
Monitor for bleeding risk, particularly if adding or adjusting other medications.
History of Tongue Cancer:
Ensure adequate nutrition and hydration, as cancer survivors may have altered oral intake affecting volume status. 2
Consider whether prior radiation therapy may have contributed to cardiac or vascular disease affecting renal perfusion.
Common Pitfalls to Avoid
Never discontinue GDMT for asymptomatic creatinine elevation <30% above baseline—this is an expected physiological response to neurohormonal blockade. 2
Do not prioritize osteoporosis treatment over HFpEF management—cardiovascular mortality risk far exceeds fracture risk in this population. 1
Avoid stopping all three medications simultaneously—if modification is truly necessary, reduce one at a time in the order specified above. 2
Do not assume creatinine elevation equals medication harm—SGLT2 inhibitors and RAAS inhibitors provide long-term renoprotection despite initial eGFR dips. 1, 2