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Initial Decline in eGFR With Dapagliflozin in HFrEF
Quick Takes
- In patients with HFrEF, dapagliflozin initiation is associated with an early decline or dip in eGFR followed by a partial improvement or rebound.
- Interestingly, this early decline in eGFR was associated with improved CV and HF outcomes.
- Routine discontinuation of dapagliflozin or other HF therapies due to an early decline in eGFR is not supported based on the findings of this study.
Study Questions:
In patients with heart failure with reduced ejection fraction (HFrEF) being started on the sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin, what are the frequency and associated outcomes of an early decline in estimated glomerular filtration rate (eGFR) after medication initiation?
Methods:
DAPA-HF was a multicenter, international, randomized, and double-blind trial of dapagliflozin compared to placebo in patients with symptomatic HFrEF already on standard HF therapies. Key exclusion criteria included type 1 diabetes mellitus, symptomatic hypotension, and an eGFR <30 ml/min/1.73 m2. The primary outcome was a composite of worsening HF (hospitalization or an urgent visit resulting in intravenous therapy for HF) or cardiovascular (CV) death. There were several important CV and renal secondary outcomes. This current study is a post hoc analysis exploring the relationship between dapagliflozin initiation and an early decline, or dip, in eGFR. An early decline in eGFR was defined as a >10% decrease between baseline and 14 days. The frequency and magnitude of early eGFR decline as well as predictors, associated CV outcomes, and trends of eGFR change were explored.
Results:
Baseline eGFR was comparable between the placebo and dapagliflozin groups, with a mean (standard deviation) of 65.5 (19.3) and 66.0 (19.6) ml/min/1.73 m2, respectively. Mean eGFR change between 0 and 14 days was -1.1 ml/min/1.73 m2 (95% confidence interval [CI], 1.5 to -0.7) in the placebo group compared to -4.2 ml/min/1.73 m2 (95% CI, -4.6 to -3.9) in the dapagliflozin group. This resulted in a placebo-corrected difference of 3.1 ml/min/1.73 m2 (95% CI, 2.6-3.7). There was no interaction between baseline eGFR and effect of dapagliflozin on absolute eGFR change.
At day 14, 38.2% of patients in the dapagliflozin group and 21.0% in the placebo group had an eGFR decline of >10% (odds ratio, 2.36; 95% CI, 2.07-2.69; p < 0.001). Greater eGFR declines of >20% and >30% were seen in 12.6% and 3.4% of patients in the dapagliflozin group and 6.4% and 1.3% in the placebo group, respectively. In a multivariable logistic regression model, baseline predictors of an early eGFR decline for patients receiving dapagliflozin were older age, presence of type 2 diabetes, high left ventricular ejection fraction, and lower eGFR.
With respect to outcomes, the hazard ratio (HR) for the primary outcome in the placebo group comparing those with a >10% eGFR decline vs. ≤10% change was 1.45 (95% CI, 1.19-1.78). For the dapagliflozin group, the HR for the primary outcome was 0.73 (95% CI, 0.59-0.91). This suggests an association between worse outcomes with an early eGFR decline in the placebo group but better outcomes with an early eGFR decline in the dapagliflozin group. Similar findings were seen in the key secondary outcomes of CV death, total HF hospitalizations and CV death, and all-cause mortality. Long term rate-of-decline of renal function, assessed between day 60 and day 720, was slower for patients on dapagliflozin with an early decline in eGFR of >10% (slope -0.7 ml/min/1.73 m2 per year) compared to patients with a stable or increase in early eGFR (slope -2.3) and a decline up to 10% (slope -1.7).
Conclusions:
An early decline in eGFR was more common in patients initiated on dapagliflozin compared to placebo, though the absolute mean changes were small for both groups. Interestingly, for patients on dapagliflozin, an early eGFR decline was associated with better outcomes. The opposite was observed with the placebo group, with an early eGFR decline associated with worse outcomes.
Perspective:
SGLT2 inhibitors are now the fourth pillar of HFrEF management and have been incorporated into the new 2022 AHA/ACC/HFSA HF guidelines. Despite evidence of benefit, complex barriers still exist to initiating and titrating these life-saving medications, which includes variations and declines in kidney function. This can lead to discontinuation of HFrEF medical therapies including SGLT2 inhibitors. The results of this study are highly important in that it acknowledges early declines in renal function with dapagliflozin are common but usually modest and are often partially reversed. In addition, there seems to be a link to better CV outcomes in those with this early decline in eGFR, though the exact reasons for this are still unclear. Long-term renal outcomes also do not seem to be worse in those with an early eGFR decline. Understanding all the limitations that come with a post hoc analysis, this study does give clinicians additional evidence to support continuation of SGLT2 inhibitors in most patients despite an early eGFR decline. This is one more step toward getting all patients with HFrEF on maximally tolerated medical therapies.
Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure
Keywords: Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Heart Failure, Metabolic Syndrome, Outcome Assessment, Health Care, Renal Insufficiency, Secondary Prevention, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume, Ventricular Function, Left
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