Acceptable Creatinine Increase with Entresto and Jardiance
Up to 30% increase in serum creatinine from baseline is acceptable when initiating Entresto (sacubitril/valsartan) and Jardiance (empagliflozin), provided there is no volume depletion, symptomatic hypotension, or uncontrolled hyperkalemia. 1
Evidence-Based Threshold
The 30% threshold is well-established for renin-angiotensin system (RAS) blockers, which includes the valsartan component of Entresto, and this same principle applies when adding these medications 1
Small elevations in serum creatinine (up to 30% from baseline) must not be confused with acute kidney injury (AKI) when using RAS blockers like Entresto 1
Analysis from the ACCORD BP trial demonstrates that patients with up to 30% creatinine increase did not have increased mortality or progressive kidney disease, and markers for AKI showed no significant elevation 1
RAS inhibitors may be continued unless creatinine increases by more than 30%, at which point dose reduction or withdrawal should be considered 1
Monitoring Protocol
Check serum creatinine and potassium within 2-4 weeks of initiation or dose changes: 1
- Measure baseline creatinine before starting therapy 1
- Recheck at 2-4 weeks after initiation 1
- Calculate the percentage change from baseline 1
- Continue monitoring if increase is <30% 1
When to Continue Therapy
Continue both medications if: 1
- Creatinine increase is ≤30% from baseline 1
- No symptomatic hypotension is present 1
- Potassium remains controlled (generally <5.5 mEq/L) 2
- Patient is adequately volume-replete 1
When to Reduce Dose or Discontinue
Reduce dose or temporarily discontinue if: 1
- Creatinine increases >30% from baseline 1
- Symptomatic hypotension develops 1
- Uncontrolled hyperkalemia occurs despite interventions 1
- Evidence of volume depletion is present 1
Special Considerations for Combined Therapy
The combination of Entresto and Jardiance appears safe regarding renal function: 3
A 2020 study of 108 patients with heart failure and type 2 diabetes showed that co-administration of sacubitril/valsartan and empagliflozin did not result in significant worsening of renal function compared to either agent alone 3
When both agents are initiated simultaneously, GFR trajectories remain stable without statistically significant decline 3
SGLT2 inhibitors like Jardiance may initially cause small GFR decreases through hemodynamic effects, but this is not associated with increased AKI risk in clinical trials 1
Common Pitfalls to Avoid
Do not discontinue therapy prematurely for minor creatinine elevations: 1
- A 10-20% creatinine increase is expected and indicates the drugs are exerting their desired renoprotective effects 1
- Premature discontinuation denies patients the mortality and morbidity benefits of these medications 1
Assess for volume depletion before attributing creatinine rise to the medications: 1
- Diuretic-induced intravascular volume depletion is the most common avoidable reason for creatinine elevation 1
- Consider reducing diuretic doses if volume depletion is suspected 1
Ensure patients are not taking NSAIDs or other nephrotoxic agents: 2
- Concomitant NSAIDs can precipitate acute renal failure in patients on RAS blockers 1, 2
- Review all medications for potential nephrotoxic interactions 2
Clinical Context from FDA Label
During the PARADIGM-HF trial run-in periods: 2
- 1.7-1.8% of patients discontinued due to renal dysfunction during both enalapril and sacubitril/valsartan run-in phases 2
- In the double-blind period, approximately 16% of both sacubitril/valsartan and enalapril-treated patients had serum creatinine increases >50% 2
- These increases were similar between groups, indicating this is a class effect of RAS blockade 2
Long-Term Renal Outcomes
Maintaining therapy despite initial creatinine increases provides long-term renal protection: 1, 4