DICTATE-AHF was a multicenter, prospective, randomized, open-label study with blinded event adjudication (NCT04298229); the full methods and main results have been described previously. ^, Briefly, hemodynamically stable adult patients with or without type 2 diabetes admitted to the hospital with AHF and current or planned treatment with IV loop diuretics were eligible for inclusion. Additional inclusion criteria included an eGFR ≥ 25 mL/min/1.73 m ² and at least 2 objective measures of hypervolemia. Key exclusion criteria included type 1 diabetes, serum glucose <80 mg/dL, a history of diabetic ketoacidosis, systolic blood pressure < 90 mm Hg, and a requirement for intravenous inotropic therapy at enrollment or an anticipated need for this therapy during the study period. Patients were randomized within 24 hours of presentation to either receive dapagliflozin 10 mg once daily plus structured usual care or structured usual care without an SGLT2i for 5 days or until discharge, if sooner. An IV loop diuretic titration protocol targeting a urine output of 3 to 5 L/day was used for both study arms to standardize diuretic therapy. Serum chemistries were collected daily. On study day 2, a 24-hour urine collection was completed to accurately assess sodium excretion and urine output in both treatment arms. Additionally, a spot urine sample collected approximately 2 hours after the IV diuretic dose was collected to measure the fractional excretion of sodium (FENa) at peak diuresis. At day 5 or discharge, whichever came first, natriuretic peptide concentration, final standing weight, and a congestion assessment via an orthoedema scale by a study physician blinded to treatment assignment were performed. The study protocol was approved by each Institutional Review Board. All patients provided written informed consent.

The primary outcome of DICTATE-AHF was diuretic efficiency, defined as the cumulative weight loss per cumulative loop diuretic dose from enrollment to day 5 or discharge, if sooner, expressed as kg/40 mg IV furosemide equivalents (FE). Secondary measures of diuretic efficiency included 24-hour natriuresis (expressed as mmol per 40 mg IV furosemide) and 24-hour urine output (expressed as mL per 40 mg of IV furosemide). In DICTATE-AHF, dapagliflozin’s favorable effect on the primary outcome failed to reach statistical significance, while the secondary measures of diuretic efficiency were significantly improved with dapagliflozin. In this prespecified secondary analysis, eGFR at randomization was investigated as an effect modifier between these measures of diuretic efficiency and randomized treatment assignment to dapagliflozin or structured usual care. Exploratory analyses investigated the association between changes in kidney function over the study period with both treatment assignment and diuretic efficiency.

Prerandomization and daily eGFR were calculated according to the 2021 CKD-EPI formula. Worsening kidney function was analyzed as an increase in serum creatinine (SCr) of ≥0.3 mg/dL, a decrease in eGFR by ≥20%, the change in blood urea nitrogen (BUN), and the change in the BUN to SCr ratio from randomization to the end-of-study. The diuretic efficiency was categorized as either adequate (above) or poor (below) the median cumulative weight loss of 0.195 kg/40 mg IV furosemide.

Participant characteristics were summarized using median (interquartile range [IQR]) or frequency (percent), as appropriate. The role of eGFR at randomization as an effect modifier between weight loss, urine output, and natriuresis per 40 mg IV furosemide and treatment assignment was assessed using proportional odds models treating eGFR at randomization as both a continuous exposure and dichotomized at the median. Continuous eGFR at randomization was fit with restricted cubic splines to relax the linearity assumption (3 knots), and the nonlinear term was retained in the model if the p-value was < 0.20. The proportional odds model for weight-based diuretic efficiency was adjusted for weight at randomization as in the primary analysis. The association of change in kidney function with treatment assignment and diuretic efficiency was also assessed using proportional odds models. Statistical analyses were performed by an unblinded biostatistician using the R statistical software, Version 4.4.0. All tests were 2-sided with an alpha-level of 0.05.

Of the 240 patients randomized in DICTATE-AHF, 2 patients were withdrawn from the primary study, leaving 238 patients eligible for analysis. ( Supplemental Figure S1 ) The median serum creatinine at randomization was 1.31 (IQR: 1.05-1.60) mg/dL with a median eGFR of 53 (IQR: 42 to 70) mL/min/1.73 m ²). Additional characteristics at randomization are displayed in Table 1 , dichotomized by median eGFR. As expected, patients with lower eGFR had a higher prevalence of diabetes and were less likely to receive in-hospital renin-angiotensin-aldosterone system inhibitors. The median dose of IV loop diuretics prerandomization was similar between groups. The distribution of eGFR at randomization was similar between the dapagliflozin and structured usual care treatment arms and covered a wide range of eGFR ( Supplemental Figure S2 ).

Patients with an eGFR at randomization below the median had worse diuretic efficiency measures than patients with higher eGFR ( Table 2 ). An eGFR below the median was associated with lower diuretic efficiency analyzed as weight loss/40mg IV furosemide (p = 0.008), urine output/40 mg IV furosemide (p = 0.007), and natriuresis/40 mg IV furosemide (p = 0.001). FENa/40mg IV furosemide was not different between eGFR groups, as this metric represents the “per nephron” diuretic response. eGFR at randomization, treated as a continuous or dichotomous variable, did not alter dapagliflozin’s effect on diuretic efficiency from the primary analysis. When treated as a continuous variable, eGFR at randomization did not modify the treatment effect of dapagliflozin on cumulative weight loss/40 mg IV furosemide (P interaction = 0.22), 24-hour urine output/40 mg IV furosemide (p interaction = 0.23), nor 24-hour natriuresis/40 mg IV furosemide (p interaction = 0.36) although a visual trend for diminished diuretic effect at very low eGFR exists ( Figure 1 ). Similarly, when eGFR at randomization was dichotomized by the median, the treatment effects of dapagliflozin remained unchanged for each measure of diuretic efficiency (p interaction values > 0.20 for all). After adjustment by dichotomized eGFR, dapagliflozin was still associated with a statistically significant increase in natriuresis-based (p = 0.05) and urine output-based (p = 0.006) diuretic efficiency, but dapagliflozin’s treatment effect for weight loss-based diuretic efficiency failed to reach statistical significance (p = 0.06) as in the primary analysis ( Figure 2 ).

Table 2

Diuretic efficiency by median eGFR at randomization

Diuretic efficiency	N	Above median eGFR (n = 120)	Below median eGFR (n = 118)	Combined N = 238	p-value
Total weight loss (kg)/40mg IV FE	234	0.248 (0.087, 0.591)	0.148 (0.056, 0.385)	0.195 (0.070, 0.431)	0.008
24-hour Urine-output (mL)/40mg IV FE	176 *	638 (330, 1101)	433 (217, 786)	482 (281, 896)	0.007
24-hour natriuresis (mmol of Na)/ 40mg IV FE	176 *	47 (26, 102)	32 (15, 62)	40 (22, 86)	0.001
FENa (%)/40mg IV FE	183 §	1.49 (0.80, 3.12)	1.70 (0.71, 3.02)	1.52 (0.77, 3.02)	0.61

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