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Randomized Controlled Trial
. 2022 Aug;24(8):1578-1587.
doi: 10.1111/dom.14729. Epub 2022 Jun 1.

Effects of dapagliflozin on volume status and systemic haemodynamics in patients with chronic kidney disease without diabetes: Results from DAPASALT and DIAMOND

Taha Sen  1 , Rosalie Scholtes  2 , Peter J Greasley  3 , David Z I Cherney  4 , Claire C J Dekkers  1 , Marc Vervloet  5 , Alexander H J Danser  6 , Sean J Barbour  7 , Cecilia Karlsson  8 , Ann Hammarstedt  8 , Qiang Li  9 , Gozewijn D Laverman  10 , Petter Bjornstad  11   12 , Daniel H van Raalte  2 , Hiddo J L Heerspink  1   9
Affiliations
Randomized Controlled Trial

Effects of dapagliflozin on volume status and systemic haemodynamics in patients with chronic kidney disease without diabetes: Results from DAPASALT and DIAMOND

Taha Sen et al. Diabetes Obes Metab. 2022 Aug.

Abstract

Aims: To assess the effect of sodium-glucose cotransporter-2 inhibitor dapagliflozin on natriuresis, blood pressure (BP) and volume status in patients with chronic kidney disease (CKD) without diabetes.

Materials and methods: We performed a mechanistic open-label study (DAPASALT) to evaluate the effects of dapagliflozin on 24-hour sodium excretion, 24-hour BP, extracellular volume, and markers of volume status during a standardized sodium diet (150 mmol/d) in six patients with CKD. In parallel, in a placebo-controlled double-blind crossover trial (DIAMOND), we determined the effects of 6 weeks of dapagliflozin on markers of volume status in 53 patients with CKD.

Results: In DAPASALT (mean age 65 years, mean estimated glomerular filtration rate [eGFR] 39.4 mL/min/1.73 m2 , median urine albumin:creatinine ratio [UACR] 111 mg/g), dapagliflozin did not change 24-hour sodium and volume excretion during 2 weeks of treatment. Dapagliflozin was associated with a modest increase in 24-hour glucose excretion on Day 4, which persisted at Day 14 and reversed to baseline after discontinuation. Mean 24-hour systolic BP decreased by -9.3 (95% confidence interval [CI] -19.1, 0.4) mmHg after 4 days and was sustained at Day 14 and at wash-out. Renin, angiotensin II, urinary aldosterone and copeptin levels increased from baseline. In DIAMOND (mean age 51 years, mean eGFR 59.0 mL/min/1.73 m2 , median UACR 608 mg/g), compared to placebo, dapagliflozin increased plasma renin (38.5 [95% CI 7.4, 78.8]%), aldosterone (19.1 [95% CI -5.9, 50.8]%), and copeptin levels (7.3 [95% CI 0.1, 14.5] pmol/L).

Conclusions: During a standardized sodium diet, dapagliflozin decreased BP but did not increase 24-hour sodium and volume excretion. The lack of increased natriuresis and diuresis may be attributed to activation of intra-renal compensatory mechanisms to prevent excessive water loss.

Keywords: SGLT2 inhibitor; adaptive response; dapagliflozin; kidney.

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Conflict of interest statement

T. Sen, R. Scholtes, C.C.J. Dekkers, Q. Li, S. Barbour and A.H.J. Danser have nothing to disclose. P.J Greasley, C. Karlsson and A. Hammarstedt are AstraZeneca employees and shareholders. D.Z.I.C has received honoraria from Boehringer Ingelheim‐Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi‐Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, CSL‐Behring, Otsuka, Novartis and Novo‐Nordisk, and has received operational funding for clinical trials from Boehringer Ingelheim‐Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo‐Nordisk. M. Vervloet has received consulting fees from Amgen, Vifor Fresenius Medical Care Renal Pharma, Medice, Cablon Medical, Otsuka and Kyowa Kirin. G.D. Laverman has served on advisory boards of Boehringer Ingelheim, Eli Lilly Alliance, Sanofi, Novo Nordisk, AstraZeneca and Vifor Pharma, and received research grants from AstraZeneca, Sanofi, Novo Nordisk, Vifor Pharma. P. Bjornstad. has acted as a consultant for AstraZeneca, Bayer, Bristol‐Myers Squibb, Boehringer Ingelheim, Eli‐Lilly, LG Chem, Sanofi, Novo Nordisk and Horizon Pharma. P.B. serves on the advisory boards for AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk and XORTX. D.H. van Raalte serves on advisory boards of Boehringer Ingelheim, Eli Lilly Alliance, Sanofi, Merck Sharp & Dohme (MSD) and Bayer, and received research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Sanofi and MSD. H.J.L. Heerspink has served as a consultant for AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Fresenius, Gilead, Janssen, Merck, Mundipharma, Mitsubishi Tanabe and Retrophin, and has received grant support from AbbVie, AstraZeneca, Boehringer Ingelheim and Janssen.

Figures

FIGURE 1
FIGURE 1
Mean (standard deviation) 24‐hour sodium (A), glucose (B), volume (C) and fractional lithium excretion (D) at baseline, start of treatment, end of treatment and follow‐up of the DAPASALT trial participants. Fractional lithium excretion was >2 times the upper limit of normal in one participant at baseline, which could not be explained by concomitant use of medication or other circumstances. At 4 days a large decrease in fractional lithium excretion was observed. The baseline lithium excretion in this participant was considered to be an outlying value and the patient was removed from the fractional lithium excretion analysis
FIGURE 2
FIGURE 2
Mean (standard deviation) systolic (A) and diastolic (B) blood pressure at baseline, start of treatment, end of treatment and follow‐up of the DAPASALT trial participants
FIGURE 3
FIGURE 3
Mean (standard deviation) extracellular (A) and intracellular (B) fluid and total body water (C) at baseline, start of treatment, end of treatment and follow‐up of the DAPASALT trial participants
See this image and copyright information in PMC

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