AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Baseline Characteristics and Interim Analysis of the DEFEND Study: SGLT2 Inhibition in Patients with a Fontan
By Jacobsen R, Kelly SL, Sauceda H et al.
Introduction: DEFEND (Dapagliflozin or Empagliflozin for Fontan Exercise, Quality of Life [QoL], and Ketone Body Levels) is a multicenter observational prospective study to investigate SGLT2-inhibitors (SGLT2i) in individuals with Fontan circulation with limited exercise capacity. A proposed mechanism of SGLT2i efficacy in HF is promotion of ketone body production by the liver in the form of beta-hydroxybutyrate (B-OHB). We hypothesize that SGLT2i treatment will result in increased circulating B-OHB (primary outcome), improved exercise capacity, NTpro-BNP, and QoL. We report baseline characteristics and available interim 6-month follow up for DEFEND, which is currently enrolling. Methods: Inclusion: Fontan, age 10-40 yrs and max VO ₂ < 70% predicted. Exclusion: treatment or prior discontinuation of SGLT2i for adverse event, pregnancy, diabetes. Type of SGLT2i, dosing, and decision to treat are at the discretion of the treating cardiologist; goal enrollment is 55 participants per intention to treat cohort (No SGLT2i or SGLT2i). Continuous variables were analyzed using t-tests or Mann-Whitney U tests and categorical variables by chi-square or Fisher's exact test based on normality assessment; paired analyses used paired t-tests or Wilcoxon signed-rank tests. QoL results have not been analyzed and paired 6-month B-OHB values were available in too few participants to support meaningful between-group comparisons and therefore neither are reported in this interim analysis. Results: . As of May 2026, 75 participants were enrolled (No SGLT2i: n=40, SGLT2i: n=35 [64% goal enrollment]). Cohorts were well-matched for sex (28% vs 29% female, p=1.00), race, ethnicity, and insurance type. The SGLT2i cohort was older (median 21 yrs [IQR 18-28] vs 18 yrs [14-24], p=0.011). Baseline % predicted max VO ₂ (54.1±9.5% vs 57.7±8.2%, p=0.105) and NT-proBNP (199 pg/mL [76-331] vs 108 pg/mL [56-172], p=0.175) did not differ. Pre-treatment B-OHB was higher in the SGLT2i cohort (median 0.17 mmol/L [0.11-0.37] vs 0.09 mmol/L [0.07-0.17], p=0.004; Fig A ). Limited 6-month follow-up data are available for 24 participants (No SGLT2i: n=14, SGLT2i: n=10). The % predicted max VO ₂ improved in the SGLT2i cohort (median Δ+9.0% [4.0-16.0%], p=0.034) and was unchanged in No SGLT2i (p=0.138; Fig B) . NT-proBNP increased significantly in the No SGLT2i cohort (median Δ+8.1 pg/mL [1.3-73.8], p=0.049), while remaining stable in the SGLT2i cohort (p=0.766; Fig C ). Conclusions: . Fontan patients selected for SGLT2i therapy were older and exhibited significantly higher pre-treatment ketone levels, suggesting they may be more hemodynamically stressed at baseline. Despite this disadvantage, the SGLT2i cohort demonstrated a significant improvement in exercise capacity (unchanged in No SGLT2i) and stable NT-proBNP (increased in No SGLT2i) at 6 months. These preliminary findings support continued enrollment in DEFEND.