Vasopressin-mediated water conservation overrides the osmotic-diuretic effect of glucosuria during SGLT2 inhibition in patients with chronic heart failure (DAPA-Shuttle1: a mechanistic placebo-controlled, randomized trial)
Authors: Marton Adriana , Saffari Seyed Ehsan , Rauh Manfred , Nagel Armin , Linz Peter , Lim Tzy Tiing , Minegishi-Takase Kaoru 
Published: May 2024

Background: SGLT2 inhibitors may improve cardiac outcomes due to their osmotic-diureticpotential. We prospectively tested the hypothesis that vasopressin-driven urine concentration overrides the osmotic-diuretic driving force of dapagliflozin-induced glucosuria.Methods: DAPA-Shuttle1 was an investigator-initiated, mechanistic, single-center, randomized controlled trial at the National Heart Centre, Singapore. Eligible participants with heart failure NYHA classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10mg daily or placebo (1:1) for 4 weeks. Participants, investigators, and study personnel were masked to assignment throughout the trial. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels, solute free water clearance (FWC), and tissue Na+ content.Results: Between November 2019 and September 2021 forty participants were enrolled. Thirty three randomized, SGLT2 inhibitors naïve participants started the treatment intervention and completed the study, of which (placebo: n=14; dapagliflozin: n=15) provided accurate 24h urine collections (mean age 59±14 years, LVEF 31±9%). Dapagliflozin treatment increased glucosuria by 3.3 mmol/kg/d ([95%CI 2.51,4.04], p<0.0001) within 48h (early); this effect persisted after 4 weeks (late; 2.7 mmol/kg/d [95%CI 1.98,3.5], p<0.0001). Dapagliflozin treatment neither increased natriuresis (early: P=0.68; late: P=0.64), nor changed tissue Na+ content (early: P=0.62; late: P=0.90). Despite sustained glucosuria, urine volume did not significantly increase with dapagliflozin (mean difference early: +2.8 ml/kg/d [95%CI -1.97,7.48], P=0.25; late: +0.9ml/kg/d [95%CI -3.83,5.62], P=0.70). Dapagliflozin treatment increased plasma copeptin early (+5.5 pmol/L [95%CI 0.45,10.5], p<0.05) and late (+7.8 pmol/L [95%CI 2.77,12.81], p<0.01), leading to proportional reductions in FWC (early: -9.1 ml/kg/d [95%CI -14, -4.12], p<0.001; late: -11.0 ml/kg [95%CI -15.94, -6.07], p<0.0001) and increases in urine concentration (late: +134 mmol/L [95%CI 39.28, 229.12], p<0.01). This physiological-adaptive water conservation mechanism prevented a glucose-driven increase 70 in urine volume of approximately ≍10 ml/kg/d · 75 kg = 750 ml/d.Conclusions: SGLT2 inhibition with dapagliflozin caused relevant glucosuria, but adaptive physiological, vasopressin-driven water conservation virtually eliminated the expected osmotic diuretic potential of the drug. Therefore, the presented mechanistic-experimental evidence does not support the hypothesis that the beneficial effects of SGLT2 inhibitors in patients with heart failure are attributable to chronic cardiac decongestion. The DAPA-Shuttle1 study was an investigator-initiated trial funded by Astra Zeneca via the Externally sponsored scientific research program (ESR-18-13712). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.