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Initial Decline in eGFR After Dapagliflozin Initiation and Its Associated Outcomes in Patients With HFrEF
TAKE-HOME MESSAGE
- In this post hoc analysis of the DAPA-HF trial including more than 4000 participants with HFrEF, the mean changes in estimated glomerular filtration rate (eGFR) between days 0 and 14 were –1.1 mL/min/1.73 m2 and –4.2 mL/min/1.73 m2 with placebo and dapagliflozin, respectively. Overall, 38.2% of patients — with older age, lower baseline eGFR, higher LVEF, and type 2 diabetes — experienced a >10% early decline in eGFR with dapagliflozin compared with placebo (OR, 2.36). In the dapagliflozin group, a >10% initial decline in eGFR was associated with a 27% reduced risk of the primary outcome compared with those with a ≤10% decline (HR, 0.73).
- These findings highlight that an early decline in eGFR following dapagliflozin initiation is common, small, and associated with better clinical outcomes in patients with HFrEF.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBackground
In a post hoc analysis, the frequency of occurrence of an early decline ("dip") in estimated glomerular filtration rate (eGFR) after initiation of dapagliflozin, and its association with outcomes, was evaluated in patients with heart failure and reduced ejection fraction (HFrEF) randomized in the Dapagliflozin and Prevention of Adverse outcomes in Heart Failure trial.Methods
HFrEF patients with or without type 2 diabetes and an eGFR ≥30 mL/min/1.73m2 were randomized to placebo or dapagliflozin 10mg daily. The primary outcome was the composite of worsening heart failure or cardiovascular death. The extent of the dip in eGFR between baseline and 2 weeks, patient characteristics associated with a >10% decline, and cardiovascular outcomes and eGFR slopes in participants experiencing this decline were investigated. Time-to-event outcomes were assessed in Cox regression from 14 days; eGFR slopes were assessed using repeated measure mixed effect models.Results
The mean change in eGFR between day 0 and 14 was -1.1 ml/min/1.73m2 (95% CI -1.5,-0.7) with placebo and -4.2 ml/min/1.73m2 (-4.6,-3.9) with dapagliflozin, giving a between treatment difference of 3.1 (2.6, 3.7) ml/min/1.73m2. The proportions of patients randomized to dapagliflozin experiencing a >10%, >20% and >30% decline in eGFR were: 38.2%, 12.6%, and 3.4%, respectively; for placebo they were 21.0%, 6.4% and 1.3%, respectively. The odds ratio for a >10% early decline in eGFR with dapagliflozin, compared with placebo, was 2.36 (95%CI 2.07-2.69), P<0.001. Baseline characteristics associated with a >10% decline in eGFR on dapagliflozin were older age, lower eGFR, higher ejection fraction, and type 2 diabetes. The hazard ratio for the primary outcome in patients in the placebo group experiencing a >10% decline in eGFR, compared with ≤10% decline in eGFR was 1.45 (95% CI 1.19-1.78). The corresponding hazard ratio in the dapagliflozin group was 0.73 (95% CI 0.59-0.91), P-interaction <0.001. A >10% initial decline in eGFR was not associated with greater long-term decline in eGFR or more adverse events.Conclusions
The average dip in eGFR after starting dapagliflozin was small and associated with better clinical outcomes, compared with a similar decline on placebo in patients with HFrEF. Large declines in eGFR were uncommon with dapagliflozin.
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Circulation
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Initial Decline ("dip") in Estimated Glomerular Filtration Rate Following Initiation of Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction: Insights from DAPA-HF
Circulation 2022 Apr 20;[EPub Ahead of Print], C Adamson, KF Docherty, HJL Heerspink, RA de Boer, K Damman, SE Inzucchi, L Køber, MN Kosiborod, FA Martinez, MC Petrie, P Ponikowski, MS Sabatine, M Schou, SD Solomon, S Verma, O Bengtsson, AM Langkilde, M Sjöstrand, M Vaduganathan, PS Jhund, JJV McMurrayFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The hyperfiltration theory of progressive kidney damage is one of the most seminal hypothesis in nephrology.1 This theory is one of the major mechanisms purported to be operative in renoprotection mediated by antagonists of the renin-angiotensin-aldosterone system, in which a decrease in angiotensin-mediated vasoconstriction of the efferent arteriole results in reductions in intraglomerular pressures. While first abruptly lowering glomerular filtration rate (GFR) in some, it results in long-term improvement in kidney outcomes.2 Sodium–glucose cotransporter-2 inhibitors (SGLT2i) have also been shown to improve intraglomerular pressures, partially mediated through tubuloglomerular feedback and vasoconstriction of the afferent arterioles.3
In the post hoc analysis of the DAPA-HF trial, average estimated GFR (eGFR) dips, and association of dichotomized dips (>10% decline in eGFR) in the placebo and dapagliflozin arms with the clinical outcomes were examined.4 As shown repeatedly in literature, patients with HFrEF undergo acute declines in eGFR, whether due to RAAS antagonists, aggressive decongestion, or now due to SGLT2i. The “treatment-induced declines” in eGFR are well-tolerated, and often are associated with better outcomes.5
What is remarkable in this analysis of the DAPA-HF trial is that >10% decrease in eGFR (38% of dapa-treated), >20% decrease (13% of dapa-treated), and >25% decrease (7% in dapa-treated)—changes that in clinical practice may cause clinicians to react with panic and potentially discontinue the SGLT2i due to “hypercreatinemia-phobia”—were associated with 18% to 39% reduction in risk in the primary outcome. While mechanisms to explain why this profound protection would occur with lowering of GFR (eg, improvements in metabolic demand, oxygenation of kidney tissue, mitochondrial function), it serves as yet another example to practice a “zen-like” approach to medicine and allow permissive hypercreatinemia prevail in the treatment of high-risk patients to allow for improved clinical outcomes.6
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