Effects of Dapagliflozin on Volume Status When Added to Renin–Angiotensin System Inhibitors

Eickhoff, Mie K.; Dekkers, Claire C. J.; Kramers, Bart J.; Laverman, Gozewijn Dirk; Frimodt-Møller, Marie; Jørgensen, Niklas Rye; Faber, Jens; Danser, A. H. Jan; Gansevoort, Ron T.; Rossing, Peter; Persson, Frederik; Heerspink, Hiddo J. L.

doi:10.3390/jcm8060779

Open AccessArticle

Effects of Dapagliflozin on Volume Status When Added to Renin–Angiotensin System Inhibitors

by

Mie K. Eickhoff

^1,†,

Claire C. J. Dekkers

^2,†

,

Bart J. Kramers

³,

Gozewijn Dirk Laverman

⁴

,

Marie Frimodt-Møller

¹

,

Niklas Rye Jørgensen

⁵,

Jens Faber

^6,8

,

A. H. Jan Danser

⁷,

Ron T. Gansevoort

³,

Peter Rossing

^1,8,

Frederik Persson

¹ and

Hiddo J. L. Heerspink

^2,*

¹

Complications Research, Steno Diabetes Center Copenhagen, 2820 Gentofte, Denmark

²

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands

³

Department of Nephrology, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands

⁴

Department of internal medicine, Ziekenhuisgroep Twente, 7600 SZ Almelo, The Netherlands

⁵

Department of Clinical Biochemistry, Rigshospitalet, 2100 Copenhagen Ø, Denmark

⁶

Department of Endocrinology, Herlev & Gentofte Hospital, 2730 Herlev, Denmark

⁷

Department of Internal Medicine, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands

⁸

Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

J. Clin. Med. 2019, 8(6), 779; https://doi.org/10.3390/jcm8060779

Submission received: 29 April 2019 / Revised: 20 May 2019 / Accepted: 27 May 2019 / Published: 31 May 2019

(This article belongs to the Section Pharmacology)

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Abstract

Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart and kidney failure in patients with type 2 diabetes, possibly due to diuretic effects. Previous non-placebo-controlled studies with SGLT2 inhibitors observed changes in volume markers in healthy individuals and in patients with type 2 diabetes with preserved kidney function. It is unclear whether patients with type 2 diabetes and signs of kidney damage show similar changes. Therefore, a post hoc analysis was performed on two randomized controlled trials (n = 69), assessing effects of dapagliflozin 10 mg/day when added to renin–angiotensin system inhibition in patients with type 2 diabetes and urinary albumin-to-creatinine ratio ≥30 mg/g. Blood and 24-h urine was collected at the start and the end of treatment periods lasting six and 12 weeks. Effects of dapagliflozin compared to placebo on various markers of volume status were determined. Fractional lithium excretion, a marker of proximal tubular sodium reabsorption, was assessed in 33 patients. Dapagliflozin increased urinary glucose excretion by 217.2 mmol/24 h (95% confidence interval (CI): from 155.7 to 278.7, p < 0.01) and urinary osmolality by 60.4 mOsmol/kg (from 30.0 to 90.9, p < 0.01), compared to placebo. Fractional lithium excretion increased by 19.6% (from 6.7 to 34.2; p < 0.01), suggesting inhibition of sodium reabsorption in the proximal tubule. Renin and copeptin increased by 46.9% (from 21.6 to 77.4, p < 0.01) and 33.0% (from 23.9 to 42.7, p < 0.01), respectively. Free water clearance (FWC) decreased by −885.3 mL/24 h (from −1156.2 to −614.3, p < 0.01). These changes in markers of volume status suggest that dapagliflozin exerts both osmotic and natriuretic diuretic effects in patients with type 2 diabetes and kidney damage, as reflected by increased urinary osmolality and fractional lithium excretion. As a result, compensating mechanisms are activated to retain sodium and water.

Keywords: SGLT2 inhibitor; dapagliflozin; diabetic nephropathy; heart failure

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MDPI and ACS Style

Eickhoff, M.K.; Dekkers, C.C.J.; Kramers, B.J.; Laverman, G.D.; Frimodt-Møller, M.; Jørgensen, N.R.; Faber, J.; Danser, A.H.J.; Gansevoort, R.T.; Rossing, P.; et al. Effects of Dapagliflozin on Volume Status When Added to Renin–Angiotensin System Inhibitors. J. Clin. Med. 2019, 8, 779. https://doi.org/10.3390/jcm8060779

AMA Style

Eickhoff MK, Dekkers CCJ, Kramers BJ, Laverman GD, Frimodt-Møller M, Jørgensen NR, Faber J, Danser AHJ, Gansevoort RT, Rossing P, et al. Effects of Dapagliflozin on Volume Status When Added to Renin–Angiotensin System Inhibitors. Journal of Clinical Medicine. 2019; 8(6):779. https://doi.org/10.3390/jcm8060779

Chicago/Turabian Style

Eickhoff, Mie K., Claire C. J. Dekkers, Bart J. Kramers, Gozewijn Dirk Laverman, Marie Frimodt-Møller, Niklas Rye Jørgensen, Jens Faber, A. H. Jan Danser, Ron T. Gansevoort, Peter Rossing, and et al. 2019. "Effects of Dapagliflozin on Volume Status When Added to Renin–Angiotensin System Inhibitors" Journal of Clinical Medicine 8, no. 6: 779. https://doi.org/10.3390/jcm8060779

APA Style

Eickhoff, M. K., Dekkers, C. C. J., Kramers, B. J., Laverman, G. D., Frimodt-Møller, M., Jørgensen, N. R., Faber, J., Danser, A. H. J., Gansevoort, R. T., Rossing, P., Persson, F., & Heerspink, H. J. L. (2019). Effects of Dapagliflozin on Volume Status When Added to Renin–Angiotensin System Inhibitors. Journal of Clinical Medicine, 8(6), 779. https://doi.org/10.3390/jcm8060779

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Effects of Dapagliflozin on Volume Status When Added to Renin–Angiotensin System Inhibitors

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