Initiation of a sodium–glucose cotransporter-2 (SGLT2) inhibitor is frequently accompanied by an acute initial decline in the estimated glomerular filtration rate (eGFR), which can prompt the physician to discontinue the drug. Appropriate candidates may not receive the benefit of long-term reduction in the risk of adverse cardiovascular outcomes.
In the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, which involved patients with heart failure and reduced ejection fraction, initial eGFR decline >10% was associated with a lower risk of adverse cardiovascular outcomes among participants assigned to dapagliflozin, compared with those on the placebo arm who had a similar decline in eGFR.
Now, Scott D. Solomon, MD, Edward D. Frohlich distinguished chair in Cardiovascular Pathophysiology in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital, Finnian McCausland, MD, of the Renal Division at the Brigham, and colleagues have expanded the knowledge base to patients with heart failure and mildly reduced or preserved ejection fraction.
Reporting in JAMA Cardiology on a prespecified analysis of the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, they report an initial decline in eGFR on initiation of dapagliflozin was not associated with adverse cardiovascular or kidney outcomes and did not appear to alter the long-term trajectory of eGFR decline.
Methods
DELIVER enrolled adults 40 years or older who had symptomatic heart failure and left ventricular ejection fraction (LVEF) >40%, elevated N-terminal pro–brain natriuretic peptide concentrations, and structural heart disease. Patients were randomly assigned 1:1 to dapagliflozin 10 mg once daily or matching placebo.
This analysis included only the 5,788 trial participants who had serum creatinine and eGFR measurements at baseline and month 1. An exclusion criterion in DELIVER was eGFR <25 mL/min/1.73 m2 at enrollment.
Initial Decline in eGFR
During the first month of treatment, development of a decline in eGFR >10% occurred in:
- Placebo arm—25% of patients
- Dapagliflozin arm—40% (OR, 1.9; P<0.001)
The median change in eGFR from baseline to month 1 was −6% with dapagliflozin and −1% with placebo (P<0.001).
Dapagliflozin was associated with a higher risk of initial eGFR decline across all baseline characteristics.
Cardiovascular Outcomes
The primary cardiovascular outcome in DELIVER was the composite of cardiovascular death or hospitalization/urgent visit due to worsening heart failure. Initial eGFR decline >10% was associated with a higher risk of the outcome in the placebo arm but not the dapagliflozin group:
- Placebo arm—22% of patients who had eGFR decline >10% and 17% of those who did not (adjusted HR [aHR], 1.33; 95% CI, 1.10–1.62)
- Dapagliflozin arm—15% and 16% (aHR, 0.90; 95% CI, 0.74–1.09)
Kidney Outcomes
The researchers evaluated a post hoc kidney composite outcome consisting of the first occurrence of ≥50% decline in eGFR relative to the month 1 value, development of end-stage kidney disease, or death due to kidney causes. In contrast to patients assigned to placebo, patients on dapagliflozin were not at higher risk of the kidney outcome:
- Placebo arm—2.3% of patients who experienced eGFR decline >10% and 1.8% of those who did not (aHR, 1.62; 95% CI, 0.90–2.89)
- Dapagliflozin arm—1.3% and 1.3% (aHR, 0.94; 95% CI, 0.49–1.82)
For cardiovascular and kidney outcomes, similar patterns were noted in analyses that examined alternative thresholds of decline in eGFR.
Longer-term Change in eGFR
In Kaplan–Meier analysis, the eGFR slope was examined from month 4 to month 36. The overall rate of eGFR decline was faster in the placebo group than in the dapagliflozin group, and the changes did not depend on the presence or absence of an initial decline in eGFR >10%.
Guidance for Clinicians
These data are reassuring that with appropriate monitoring, an SGLT2 inhibitor can be continued in most patients with heart failure and LVEF >40% despite the initial decline in eGFR. Clinicians should carefully consider the adverse cardiovascular and kidney risks of patients in this population who do not use one of these medications.