Effects of dapagliflozin on urinary output, fluid balance, and biochemistry in critically ill patients: a post-hoc secondary analysis of the DEFENDER trial

Abstract

Background: Sodium-glucose cotransport-2 inhibitors (SGLT2i) have established benefits in diabetes mellitus, heart failure, and chronic kidney disease, but their physiological effects during critical illness remain unclear. We explored whether dapagliflozin affected urinary output, fluid balance, and other physiological parameters in critically ill patients with acute organ dysfunction.

Methods: This secondary analysis of the DEFENDER trial included 401 critically ill patients with acute organ dysfunction randomized to receive dapagliflozin 10 mg daily or standard care. We analyzed urinary output, fluid balance, electrolytes, acid-base status, glycemia, and vasopressor requirements over the first five days using Bayesian models.

Results: Dapagliflozin progressively increased urinary output (day 5: + 157 mL/day, 95% CrI -90 to 386, probability 90%) and decreased fluid balance (day 5: -290 mL/day, 95% CrI -564 to -27, probability 98%). Furosemide use was lower in the dapagliflozin group (overall -3%, 95% CrI -7% to 1%, probability 90%). Dapagliflozin had minimal effects on creatinine and electrolytes but was associated with progressive small decreases in pH (day 5: -0.02, probability 96%). Maximum glucose levels were consistently lower with dapagliflozin (-9 mg/dL overall, probability 83%). Norepinephrine requirements showed a time-dependent increase in the dapagliflozin group, with the expected dose difference reaching 0.034 mcg/kg/min by day 5 (probability 94%), and heterogeneity analysis revealed larger effects in patients with sepsis or on mechanical ventilation.

Conclusion: This exploratory analysis suggests dapagliflozin may enhance diuresis and reduce loop diuretic requirements in critically ill patients, potentially at the cost of increased vasopressor needs. Glucose levels were likely slightly lower with dapagliflozin. Given the study's limitations and heterogeneous treatment effects, these findings should be considered hypothesis-generating pending confirmation in prospective trials.

Fig. 1

Differences in urinary output,nfluid balance, and furosemide use Dapagliflozin − Control Posterior distributions of treatment effects (dapagliflozin minus control) from Bayesian mixed models adjusted for baseline characteristics. (A) Urinary output (mL/day): Progressive increase in effect from day 1 to day 5, with posterior distributions shifting rightward over time. (B) Fluid balance (mL/day): Increasingly negative fluid balance (favorable effect) with dapagliflozin, shown by leftward shift of distributions. (C) Furosemide use (probability difference): Consistent reduction in furosemide requirements with dapagliflozin across all days. Shaded areas represent posterior density distributions for each day, with darker shades indicating earlier days. Vertical dashed lines indicate no effect. All models adjusted for baseline vasopressor use, admission type, mechanical ventilation, and creatinine levels

Fig. 2

Posterior Distributions of Treatment Effects on Laboratoy Parameters by Day. Baseline−adjusted analyses; vertical dashed line indicates no effect.Posterior distributions of baseline-adjusted treatment effects by day from Bayesian mixed models. (A) Creatinine: Minimal effects across all days with distributions centered near zero. (B) Sodium: Slight trend toward higher values with dapagliflozin, most pronounced by day 5. (C) Potassium: No clinically meaningful differences between groups. (D) pH: Progressive decrease with dapagliflozin treatment, with distributions shifting leftward from day 3 onward. (E) Base excess: Time-dependent pattern shifting from higher values early to lower values by day 5, consistent with mild metabolic acidosis. All models adjusted for baseline admission type, mechanical ventilation, and vasopressor use. Vertical dashed lines indicate no effect

Fig. 3

Posterior Distributions of Difference in Glucose Values Vertical dashed line indicates no effect. Effects of dapagliflozin on glucose parameters. (A) Posterior distribution of differences in maximum glucose levels (mg/dL) between dapagliflozin and control groups by day. Distributions are consistently shifted to the left of zero, indicating lower maximum glucose values with dapagliflozin across all days. (B) Posterior distribution of differences in minimum glucose levels (mg/dL)

Fig. 4

Hurdle Model Analysis of Norepinephrine Requirements Dapagliflozin vs Control (Adjusted for baseline characteristics).Hurdle model analysis of norepinephrine requirements. Panel A shows the overall expected dose difference, combining both the probability of requiring norepinephrine and the dose when required. This effect increased progressively from day 1 (0.007 mcg/kg/min, 65% probability of increase) to day 5 (0.034 mcg/kg/min, 94% probability). The hurdle model decomposition reveals two contributing mechanisms: Panel B shows that dapagliflozin increased the probability of requiring norepinephrine (up to 7% absolute difference by day 5), while Panel C demonstrates that among patients receiving norepinephrine, those in the dapagliflozin group required progressively higher doses