Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Fast track – JSH2025 Tokyo: Current evidence and perspectives for hypertension management in Asia
  • Published:

SGLT2 inhibitor requires co-administration with diuretics to effectively reduce interstitial fluid retention: the DAPA-BODY trial

Hypertension Research (2025)Cite this article

Abstract

We previously demonstrated that combining a sodium–glucose cotransporter 2 (SGLT2) inhibitor with diuretics significantly reduces interstitial fluid volume without excessive depletion of circulating plasma volume or activation of the renin–angiotensin–aldosterone system (RAAS). However, the differential effects of SGLT2 inhibitor monotherapy versus combination therapy with diuretics on fluid dynamics in patients with pre-existing fluid retention remain unclear. This study included patients with fluid retention, defined by an extracellular water to total body water (ECW/TBW) ratio > 0.400, as measured by bioimpedance analysis. We evaluated 6-month changes in body fluid status and serum copeptin levels, a surrogate marker for vasopressin, between two groups: patients receiving SGLT2 inhibitor dapagliflozin monotherapy (SGLT2i group, n = 13; estimated glomerular filtration rate [eGFR] 25.0 ± 8.5 mL/min/1.73 m2) and those receiving dapagliflozin in combination with loop or thiazide diuretics (SGLT2i + diuretic group, n = 18; eGFR 29.8 ± 15.2 mL/min/1.73 m2). Changes in systolic blood pressure and estimated plasma volume did not significantly differ between groups. However, reductions in ECW/TBW, TBW, and interstitial fluid were significantly greater in the combination group than in the monotherapy group. Moreover, the increase in serum copeptin was significantly suppressed in the SGLT2i + diuretic group. No significant intergroup differences were observed in renin and aldosterone changes. These findings suggest that co-administration of SGLT2 inhibitor with diuretics can more effectively reduce interstitial fluid retention without inducing excessive plasma volume reduction or RAAS activation.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Vallon V. How can inhibition of glucose and sodium transport in the early proximal tubule protect the cardiorenal system? Nephrol Dial Transpl. 2024;39:1565–73.

    Article  CAS  Google Scholar 

  2. Rieg T, Masuda T, Gerasimova M, Mayoux E, Platt K, Powell DR, et al. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Ren Physiol. 2014;306:F188–93.

    Article  CAS  Google Scholar 

  3. Nuffield Department of Population Health Renal Studies G, Consortium SiM-AC-RT. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400:1788–801.

    Article  Google Scholar 

  4. Masuda T, Nagata D. Fluid homeostasis induced by sodium-glucose cotransporter 2 inhibitors: novel insight for better cardio-renal outcomes in chronic kidney disease. Hypertens Res. 2023;46:1195–201.

    Article  CAS  PubMed  Google Scholar 

  5. Hallow KM, Helmlinger G, Greasley PJ, McMurray JJV, Boulton DW. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diab Obes Metab. 2018;20:479–87.

    Article  CAS  Google Scholar 

  6. Asakura-Kinoshita M, Masuda T, Oka K, Ohara K, Miura M, Morinari M, et al. Sodium-glucose cotransporter 2 inhibitor combined with conventional diuretics ameliorate body fluid retention without excessive plasma volume reduction. Diagnostics. 2024;14.

  7. Masuda T, Yoshida M, Onaka T, Nagata D. Water and sodium conservation response induced by SGLT2 inhibitor ipragliflozin in Dahl salt-sensitive hypertensive rats. Hypertens Res. 2024;47:3173–81.

    Article  CAS  PubMed  Google Scholar 

  8. Masuda T, Watanabe Y, Fukuda K, Watanabe M, Onishi A, Ohara K, et al. Unmasking a sustained negative effect of SGLT2 inhibition on body fluid volume in the rat. Am J Physiol Ren Physiol. 2018;315:F653–64.

    Article  CAS  Google Scholar 

  9. Masuda T, Ohara K, Murakami T, Imai T, Nakagawa S, Okada M, et al. Sodium-glucose cotransporter 2 inhibition with dapagliflozin ameliorates extracellular volume expansion in diabetic kidney disease patients. POJ Diab Obes. 2017;1:1–8.

    Google Scholar 

  10. Masuda T, Ohara K, Vallon V, Nagata D. SGLT2 inhibitor and loop diuretic induce different vasopressin and fluid homeostatic responses in nondiabetic rats. Am J Physiol Ren Physiol. 2022;323:F361–69.

    Article  CAS  Google Scholar 

  11. Masuda T, Muto S, Fukuda K, Watanabe M, Ohara K, Koepsell H, et al. Osmotic diuresis by SGLT2 inhibition stimulates vasopressin-induced water reabsorption to maintain body fluid volume. Physiol Rep. 2020;8:e14360.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Oka K, Masuda T, Ohara K, Miura M, Morinari M, Misawa K, et al. Fluid homeostatic action of dapagliflozin in patients with chronic kidney disease: the DAPA-BODY Trial. Front Med (Lausanne). 2023;10:1287066.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ohara K, Masuda T, Morinari M, Okada M, Miki A, Nakagawa S, et al. The extracellular volume status predicts body fluid response to SGLT2 inhibitor dapagliflozin in diabetic kidney disease. Diabetol Metab Syndr. 2020;12:37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hung SC, Lai YS, Kuo KL, Tarng DC. Volume overload and adverse outcomes in chronic kidney disease: clinical observational and animal studies. J Am Heart Assoc 2015;4.

  15. Tai R, Ohashi Y, Mizuiri S, Aikawa A, Sakai K. Association between ratio of measured extracellular volume to expected body fluid volume and renal outcomes in patients with chronic kidney disease: a retrospective single-center cohort study. BMC Nephrol. 2014;15:189.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tsai YC, Tsai JC, Chen SC, Chiu YW, Hwang SJ, Hung CC, et al. Association of fluid overload with kidney disease progression in advanced CKD: a prospective cohort study. Am J Kidney Dis. 2014;63:68–75.

    Article  PubMed  Google Scholar 

  17. Kanbay M, Yilmaz S, Dincer N, Ortiz A, Sag AA, Covic A, et al. Antidiuretic hormone and serum osmolarity physiology and related outcomes: What Is Old, What Is New, and What Is Unknown? J Clin Endocrinol Metab. 2019;104:5406–20.

    Article  PubMed  Google Scholar 

  18. Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem. 2006;52:112–9.

    Article  CAS  PubMed  Google Scholar 

  19. Scholtes RA, Muskiet MHA, van Baar MJB, Hesp AC, Greasley PJ, Hammarstedt A, et al. The adaptive renal response for volume homeostasis during 2 weeks of dapagliflozin treatment in people with type 2 diabetes and preserved renal function on a sodium-controlled diet. Kidney Int Rep. 2022;7:1084–92.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Berton AM, Parasiliti-Caprino M, Prencipe N, Bioletto F, Lopez C, Bona C, et al. Copeptin adaptive response to SGLT2 inhibitors in patients with type 2 diabetes mellitus: The GliRACo study. Front Neurosci. 2023;17:1098404.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Huang X, Dorhout Mees E, Vos P, Hamza S, Braam B. Everything we always wanted to know about furosemide but were afraid to ask. Am J Physiol Ren Physiol. 2016;310:F958–71.

    Article  CAS  Google Scholar 

  22. Channavajjhala SK, Bramley R, Peltz T, Oosthuyzen W, Jia W, Kinnear S, et al. Urinary extracellular vesicle protein profiling and endogenous lithium clearance support excessive renal sodium wasting and water reabsorption in thiazide-induced hyponatremia. Kidney Int Rep. 2019;4:139–47.

    Article  PubMed  Google Scholar 

  23. InBody Co., Ltd. InBody S10 User’s manual. 2015.

  24. Kim CR, Shin JH, Hwang JH, Kim SH. Monitoring volume status using bioelectrical impedance analysis in chronic hemodialysis patients. ASAIO J. 2018;64:245–52.

    Article  PubMed  Google Scholar 

  25. Zheng K, Lu J, Liu X, Ji W, Liu P, Cui J, et al. The clinical application value of the extracellular-water-to-total-body-water ratio obtained by bioelectrical impedance analysis in people with advanced cancer. Nutrition. 2022;96:111567.

    Article  CAS  PubMed  Google Scholar 

  26. Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–46.

    Article  CAS  PubMed  Google Scholar 

  27. Wheeler DC, Toto RD, Stefansson BV, Jongs N, Chertow GM, Greene T, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int. 2021;100:215–24.

    Article  CAS  PubMed  Google Scholar 

  28. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.

    Article  CAS  PubMed  Google Scholar 

  29. Flannery AH, Ortiz-Soriano V, Li X, Gianella FG, Toto RD, Moe OW, et al. Serum renin and major adverse kidney events in critically ill patients: a multicenter prospective study. Crit Care. 2021;25:294.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Rieder M, Wirth L, Pollmeier L, Jeserich M, Goller I, Baldus N, et al. Serum ACE2, angiotensin II, and aldosterone levels are unchanged in patients with COVID-19. Am J Hypertens. 2021;34:278–81.

    Article  CAS  PubMed  Google Scholar 

  31. Strauss MB, Davis RK, Rosenbaum JD, Rossmeisl EC. Water diuresis produced during recumbency by the intravenous infusion of isotonic saline solution. J Clin Invest. 1951;30:862–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kaplan AA. A simple and accurate method for prescribing plasma exchange. ASAIO Trans. 1990;36:M597–99.

    CAS  PubMed  Google Scholar 

  33. Retzlaff JA, Tauxe WN, Kiely JM, Stroebel CF. Erythrocyte volume, plasma volume, and lean body mass in adult men and women. Blood. 1969;33:649–61.

    Article  CAS  PubMed  Google Scholar 

  34. Ohara K, Masuda T, Murakami T, Imai T, Yoshizawa H, Nakagawa S, et al. Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on fluid distribution: a comparison study with furosemide and tolvaptan. Nephrology. 2019;24:904–11.

    Article  CAS  PubMed  Google Scholar 

  35. Masuda T, Ohara K, Nagayama I, Matsuoka R, Murakami T, Nakagawa S, et al. Impact of serum albumin levels on the body fluid response to tolvaptan in chronic kidney disease patients. Int Urol Nephrol. 2019;51:1623–9.

    Article  CAS  PubMed  Google Scholar 

  36. Durante W, Behnammanesh G, Peyton KJ. Effects of sodium-glucose co-transporter 2 inhibitors on vascular cell function and arterial remodeling. Int J Mol Sci 2021; 22.

  37. Herat LY, Magno AL, Rudnicka C, Hricova J, Carnagarin R, Ward NC, et al. SGLT2 inhibitor-induced sympathoinhibition. A Nov Mechanism Cardiorenal Prot JACC Basic Transl Sci. 2020;5:169–79.

    Google Scholar 

  38. Sugiyama S, Jinnouchi H, Kurinami N, Hieshima K, Yoshida A, Jinnouchi K, et al. The SGLT2 inhibitor dapagliflozin significantly improves the peripheral microvascular endothelial function in patients with uncontrolled type 2 diabetes mellitus. Intern Med. 2018;57:2147–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Packer M. SGLT2 inhibition: neither a diuretic nor a natriuretic. J Am Coll Cardiol. 2024;83:1399–402.

    Article  CAS  PubMed  Google Scholar 

  40. Marton A, Saffari SE, Rauh M, Sun RN, Nagel AM, Linz P, et al. Water conservation overrides osmotic diuresis during SGLT2 inhibition in patients with heart failure. J Am Coll Cardiol. 2024;83:1386–98.

    Article  CAS  PubMed  Google Scholar 

  41. Onishi A, Fu Y, Patel R, Darshi M, Crespo-Masip M, Huang W, et al. A role for tubular Na(+)/H(+) exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin. Am J Physiol Ren Physiol. 2020;319:F712–28.

    Article  CAS  Google Scholar 

  42. Kario K, Hoshide S, Mogi M. Hypertension treatment up-date on World Hypertension Day 2024: current status and future prospects in Asia. Hypertens Res. 2024;47:1763–5.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the data entry support of Naoko Ishikawa and the technical support provided by the clinical engineers at the Shin-Oyama City Hospital and Nasu Minami Hospital. We thank Shinji Asakura (Oyama Suginoki Clinic) for his critical comments and support, as well as the laboratory technicians at Jichi Medical University, Shin-Oyama City Hospital, and Nasu Minami Hospital. We also thank Editage (www.editage.jp) for English language editing.

Funding

This research was supported by the Kidney Foundation, Japan (Grant number JKFB21-18 to TM) and the Jichi Medical University Young Investigator Awards (to TM and KOh).

Author information

Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

    Takahiro Masuda, Maki Asakura-Kinoshita, Kentaro Oka, Ken Ohara, Masato Sakai, Kyohei Misawa, Keiji Hirai, Tetsu Akimoto, Daisuke Nagata & Yoshiyuki Morishita

  2. Department of Nephrology, Shin-Oyama City Hospital, Tochigi, Japan

    Marina Miura

  3. Department of Cardiology, Nasu Minami Hospital, Tochigi, Japan

    Masato Morinari

  4. Department of Cardiology, Shin-Oyama City Hospital, Tochigi, Japan

    Kazuyuki Shimada

Authors
  1. Takahiro Masuda
    View author publications

    Search author on:PubMed Google Scholar

  2. Maki Asakura-Kinoshita
    View author publications

    Search author on:PubMed Google Scholar

  3. Kentaro Oka
    View author publications

    Search author on:PubMed Google Scholar

  4. Ken Ohara
    View author publications

    Search author on:PubMed Google Scholar

  5. Masato Sakai
    View author publications

    Search author on:PubMed Google Scholar

  6. Marina Miura
    View author publications

    Search author on:PubMed Google Scholar

  7. Kyohei Misawa
    View author publications

    Search author on:PubMed Google Scholar

  8. Keiji Hirai
    View author publications

    Search author on:PubMed Google Scholar

  9. Masato Morinari
    View author publications

    Search author on:PubMed Google Scholar

  10. Tetsu Akimoto
    View author publications

    Search author on:PubMed Google Scholar

  11. Kazuyuki Shimada
    View author publications

    Search author on:PubMed Google Scholar

  12. Daisuke Nagata
    View author publications

    Search author on:PubMed Google Scholar

  13. Yoshiyuki Morishita
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Conceptualization: TM and MAK; Data curation: TM, KOk, KOh, MMi and MMo; Formal analysis: TM, MAK, and KOk; Investigation: TM, MAK, and KOk; Writing—original draft: TM; Writing—review and editing: MAK, KOk, KOh, MS, MMi, KM, MS, MM, KH, TA, KS, DS, and YM; Funding acquisition: TM and KOh; Validation: KH, TA, KS, DN and YM. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Takahiro Masuda.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Masuda, T., Asakura-Kinoshita, M., Oka, K. et al. SGLT2 inhibitor requires co-administration with diuretics to effectively reduce interstitial fluid retention: the DAPA-BODY trial. Hypertens Res (2025). https://doi.org/10.1038/s41440-025-02388-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41440-025-02388-5

Keywords

Search

Advanced search

Quick links