Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Abstract

ImportanceAn initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure.ObjectiveTo examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial.Design, Setting, and ParticipantsThis was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were analyzed from February to October 2023.InterventionDapagliflozin, 10 mg per day, or placebo.Main Outcomes and MeasuresIn this prespecified analysis, the frequency of an initial eGFR decline (baseline to month 1) was compared between dapagliflozin and placebo. Cox models adjusted for baseline eGFR and established prognostic factors were fit to estimate the association of an initial eGFR decline with cardiovascular (cardiovascular death or heart failure event) and kidney (≥50% eGFR decline, eGFR<15 or dialysis, death from kidney causes) outcomes, landmarked at month 1, stratified by diabetes.ResultsStudy data from 5788 participants (mean [SD] age, 72 [10] years; 3253 male [56%]) were analyzed. The median (IQR) change in eGFR level from baseline to month 1 was −1 (−6 to 5) with placebo and −4 (−9 to 1) with dapagliflozin (difference, −3; P < .001). A higher proportion of patients assigned to dapagliflozin developed an initial eGFR decline greater than 10% vs placebo (1144 of 2892 [40%] vs 737 of 2896 [25%]; odds ratio, 1.9; 95% CI, 1.7-2.1; P difference <.001). An initial eGFR decline of greater than 10% (vs ≤10%) was associated with a higher risk of the primary cardiovascular outcome among those randomized to placebo (adjusted hazard ratio [aHR], 1.33; 95% CI, 1.10-1.62) but not among those randomized to dapagliflozin (aHR, 0.90; 95% CI, 0.74-1.09; P for interaction = .01). Similar associations were observed when alternative thresholds of initial eGFR decline were considered and when analyzed as a continuous measure. An initial eGFR decline of greater than 10% was not associated with adverse subsequent kidney composite outcomes in dapagliflozin-treated patients (aHR, 0.94; 95% CI, 0.49-1.82).Conclusions and RelevanceAmong patients with HFmrEF or HFpEF treated with dapagliflozin, an initial eGFR decline was frequent but not associated with subsequent risk of cardiovascular or kidney events. These data reinforce clinical guidance that SGLT2is should not be interrupted or discontinued in response to an initial eGFR decline.Trial RegistrationClinicalTrials.gov Identifier: NCT03619213

Application of the European Kidney Function Consortium Equation to Estimate Glomerular Filtration Rate: A Comparison Study of the CKiD and CKD-EPI Equations Using the Korea National Health and Nutrition Examination Survey (KNHANES 2008–2021)

“…Additionally, due to the limited data availability, we could neither analyze eGFR in comparison with mGFR nor extend our evaluation including cystatin-C-based eGFR equations [17,28,29]. Moreover, without in-depth clinical information and repeated sCr measurements, we could not explore the association between eGFR changes and detailed clinical outcomes in various clinical settings [30][31][32][33][34]. Nevertheless, the strength of our study is that the present data were obtained from a large number of enrolled subjects, who reflect the general Korean population.…”

Heart Failure with Mildly Reduced Ejection Fraction—A Phenotype Waiting to Be Explored

“…Additionally, SGLT2 inhibitors have shown promising results in reducing cardiovascular death or HF hospitalisation, as demonstrated in the EMPEROR-preserved study and the DELIVER trial [47][48][49][50][51], especially in patients with mildly reduced or preserved EF, irrespective of their diabetic status. Lastly, vericiguat has demonstrated its efficacy in reducing the combined primary endpoint of cardiovascular death or first HF hospitalisation, albeit less so in patients with an EF percentage between 40 and 45% [52].…”

“…The 2021 ESC guidelines, advocate for a comprehensive pharmacological approach in managing HFmrEF, recommending angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) [41], mineralocorticoid receptor antagonists (MRAs) [42], sacubitril/valsartan (ARNIs) [43,44], beta-blockers [45], and sodium-glucose cotransporter 2 inhibitors (SGLT2) [46][47][48][49][50][51] as Class 2b recommendations (Table 1).…”

Advances in Cardiorenal Medicine; the Year 2023 in Review

“…The observed rise in serum creatinine was initially considered a potential safety concern due to the natriuretic and osmotic diuretic effects of SGLT-2i. A secondary analysis of DELIVER examined the implications of the initial decline in eGFR and concluded that it was a frequent observation with dapagliflozin (40% of patients experiencing an initial drop of greater than 10%), but was not associated with subsequent risk of cardiovascular or kidney events [24]. Of note, lack of an adverse impact on the outcomes by the initial dip in eGFR had previously been reported in HF with reduced ejection fraction [25].…”