Kidney Week

Abstract: FR-OR91

One-Month Treatment with Dapagliflozin Triggers Renal Water Conservation and Thus Prevents Osmotic Diuresis in Patients with Chronic Heart Failure

Session Information

• Novel Clinical Impacts on Cardiorenal Disease
  November 03, 2023 | Location: Room 103, Pennsylvania Convention Center
  Abstract Time: 04:30 PM - 04:39 PM

Category: Hypertension and CVD

• 1602 Hypertension and CVD: Clinical

Authors

• Marton, Adriana, Duke-NUS Medical School Cardiovascular & Metabolic Disorders Programme, Singapore, Singapore

Adriana Marton, MD

• Saffari, Seyed Ehsan, Duke-NUS Medical School, Singapore, Singapore

Seyed Ehsan Saffari,

• Sun, Ruo-Ning, Clinical Imaging Research Centre, Singapore, Singapore, Singapore

Ruo-Ning Sun,

• Nagel, Armin M., Universitatsklinikum Erlangen, Erlangen, Bayern, Germany

Armin M. Nagel,

• Linz, Peter, Universitatsklinikum Erlangen, Erlangen, Bayern, Germany

Peter Linz,

• Lim, Tzy Tiing, Duke-NUS Medical School Cardiovascular & Metabolic Disorders Programme, Singapore, Singapore

Tzy Tiing Lim,

• Minegishi, Kaoru, Duke-NUS Medical School Cardiovascular & Metabolic Disorders Programme, Singapore, Singapore

Kaoru Minegishi,

• Morisawa, Norihiko, Duke-NUS Medical School Cardiovascular & Metabolic Disorders Programme, Singapore, Singapore

Norihiko Morisawa,

• Yam, Wan Keat, Duke-NUS Medical School Cardiovascular & Metabolic Disorders Programme, Singapore, Singapore

Wan Keat Yam,

• Minegishi, Shintaro, Duke-NUS Medical School Cardiovascular & Metabolic Disorders Programme, Singapore, Singapore

Shintaro Minegishi,

• Totman, John J., Clinical Imaging Research Centre, Singapore, Singapore, Singapore

John J. Totman,

• Kitada, Kento, Kagawa Daigaku, Takamatsu, Kagawa, Japan

Kento Kitada,

• Wild, Johannes, Universitatsmedizin der Johannes Gutenberg-Universitat Mainz Zentrum fur Kardiologie, Mainz, Rheinland-Pfalz, Germany

Johannes Wild,

• Kovalik, Jean-Paul, Duke-NUS Medical School Cardiovascular & Metabolic Disorders Programme, Singapore, Singapore

Jean-Paul Kovalik,

• Luft, Friedrich, Max Delbruck Centrum fur Molekulare Medizin Experimental and Clinical Research Center, Berlin, Berlin, Germany

Friedrich Luft,

• Greasley, Peter J., AstraZeneca, Gothenburg, Sweden

Peter J. Greasley,

• Sim, David, National Heart Centre Singapore, Singapore, Singapore

David Sim,

• Titze, Jens, Duke-NUS Medical School Cardiovascular & Metabolic Disorders Programme, Singapore, Singapore

Jens Titze,

Background

It is unclear whether SGLT2 inhibitors improve cardiac outcomes due to their osmotic-diuretic potential. We tested the hypothesis that SGLT2 inhibition with dapagliflozin does not promote renal water excretion in patients with chronic heart failure.

Methods

DAPA-Shuttle1 was a mechanistic, double-blind, randomized trial which investigated the early (48h) and late (4 weeks) effects of dapagliflozin on urine volume generation and body solute handling. Participants with chronic heart failure NYHA classes I/II were randomly assigned to receive dapagliflozin 10mg daily or placebo for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. ClinicalTrials.gov registration NCT04080518.

Results

29 participants (placebo n=14; dapagliflozin n=15) completed the study (age 59±14 years). Dapagliflozin increased glucosuria by 3.3±0.4 mmol/kg/d (p<0.0001) within 48h; this effect persisted after 4 weeks (2.7±0.4 mmol/kg/d, p<0.0001). Dapagliflozin did not increase natriuresis (early: p=0.68; late: p=0.64), and did not change MRI-determined tissue Na⁺ content (early: p=0.62; late: p=0.90). Despite sustained glucosuria, urine volume remained stable in the dapagliflozin group after one month (+0.9±2.4 ml/kg/d, p=0.70). Dapagliflozin increased plasma copeptin (early: +5.5±2.5 pmol/L, p<0.05; late: +7.8±2.5 pmol/L, p<0.01), leading to proportional reductions in free water clearance (early: -9.1±2.5 ml/kg/d, p<0.001; late: -11.0±2.5 ml/kg/d, p<0.0001) and increases in urine concentration (late: +134±47 mmol/L; p<0.01).

Conclusion

SGLT2 inhibition with dapagliflozin triggered a vasopressin-driven water conservation response in patients with chronic heart failure, and thereby prevented a 800-1000 ml/d glucose-driven increase in urine volume. In contrast to saluretic diuretics, which promote solute excretion to increase free water excretion in the urine, SGLT2 inhibitors reduce solute-free water excretion, abolishing the osmotic-diuretic effect of glucosuria.

Funding

• Commercial Support – AstraZeneca