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Body fluid regulation via chronic inhibition of sodium–glucose cotransporter-2 in patients with heart failure: a post hoc analysis of the CANDLE trial

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Abstract

Background

In patients with chronic heart failure (CHF) and type 2 diabetes (T2D), sodium–glucose cotransporter-2 (SGLT2) inhibition improves cardiorenal outcomes, but details of the effects on distinct subsets of body fluid volume remain incomplete.

Methods

This was a post hoc analysis of patients with CHF and T2D in the CANDLE trial (UMIN000017669), an investigator-initiated, multi-center, randomized open-label trial that compared the effect of canagliflozin (100 mg, n = 113) with glimepiride (starting dose: 0.5 mg, n = 120) on changes in N-terminal pro-brain natriuretic peptide. The estimated plasma volume (ePV, calculated with the Straus formula) and estimated extracellular volume (eEV, determined by the body surface area) were compared between treatment groups at weeks 4, 12, and 24.

Results

Among 233 patients analyzed, 166 (71.2%) had an ejection fraction (EF) > 50%. Reductions in ePV and eEV were observed only in the canagliflozin group until week 12 (change from baseline at week 12, ePV; − 7.63%; 95% confidence interval [CI], − 10.71 to − 4.55%, p < 0.001, eEV; − 123.15 mL; 95% CI, − 190.38 to − 55.92 mL, p < 0.001). While ePV stopped falling after week 12, eEV continued to fall until week 24 ([change from baseline at week 24] − [change from baseline at week 12], ePV; 1.01%; 95%CI, − 2.30–4.32%, p = 0.549, eEV; − 125.15 mL; 95% CI, − 184.35 to − 65.95 mL, p < 0.001).

Conclusions

Maintenance of a modest reduction in ePV and continuous removal of eEV via chronic SGLT2 inhibition suggests that favorable body fluid regulation contributes to the cardiorenal benefits of SGLT2 inhibitors in patients with CHF, irrespective of EF.

Trial Registration

UMIN000017669.

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Availability of data and materials

The datasets analyzed during the current study are available from the CANDLE study support office on reasonable request (candle-sub@clin-med.org).

Abbreviations

BMI:

Body mass index

CHF:

Chronic heart failure

CI:

Confidence interval

EF:

Ejection fraction

ePV:

Estimated plasma volume

eEV:

Estimated extracellular volume

eGFR:

Estimated glomerular filtration rate

GFR:

Glomerular filtration rate

Hb:

Hemoglobin

HbA1c:

Hemoglobin A1c

HF:

Heart failure

Ht:

Hematocrit

LVEF:

Left-ventricular ejection fraction

NT-proBNP:

N-terminal pro-brain natriuretic peptide

NYHA:

New York Heart Association

SBP:

Systolic blood pressure

SGLT2:

Sodium–glucose cotransporter-2

T2D:

Type 2 diabetes

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Acknowledgements

The authors thank all participants, investigators, board members, and medical staff involved in the CANDLE trial.

Funding

The work was funded by Mitsubishi Tanabe Pharma Corporation. The funders of the trial had no role in the study design, data collection, analysis or interpretation, or writing of the report.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachidori, Chuo-ku, Niigata, 951-8510, Japan

    Shinya Fujiki, Takeshi Kashimura & Takayuki Inomata

  2. Department of Cardiovascular Medicine, Saga University, Saga, Japan

    Atsushi Tanaka & Koichi Node

  3. Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Osaka, Japan

    Takumi Imai

  4. Department of Diabetes, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima, Japan

    Michio Shimabukuro

  5. Division of Cardiology, Urasoe General Hospital, Urasoe, Japan

    Hiroki Uehara

  6. Department of Cardiovascular Medicine, Saga-Ken Medical Centre Koseikan, Saga, Japan

    Ikuko Nakamura

  7. Department of Internal Medicine, Imari-Arita Kyoritsu Hospital, Matsuura, Japan

    Kazuo Matsunaga

  8. Department of Cardiology, Yokohama Minami Kyosai Hospital, Yokohama, Japan

    Makoto Suzuki

  9. Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Tohru Minamino

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  1. Shinya Fujiki
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Consortia

the CANDLE Trial Investigators

Contributions

All authors contributed to the study conception, design, and procedures. Funding acquisition for the study was carried out by KN, the principal investigator of the CANDLE trial. The data analyses were performed by SF, TakuI, AT, and KN. TakuI was responsible for the statistical analyses. The first draft of the manuscript was written by SF, and all authors reviewed subsequent drafts of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shinya Fujiki.

Ethics declarations

Conflict of interest

SF received research funding from Boehringer Ingelheim and research grants from Bayer. AT received honoraria from Boehringer Ingelheim and research funding from GlaxoSmithKline and Takeda. TakuI received lecture fees from JCR Pharmaceuticals and Kyowa Kirin; and outsourcing fees from Organization for Clinical Medicine Promotion. MS received honoraria from Astellas, Boehringer Ingelheim, Mitsubishi Tanabe, and AstraZeneca. TM has received honoraria and a research grant from Mitsubishi Tanabe Pharma. TakaI received lecture honoraria from Otsuka Pharmaceutical Co. and Daiichi-Sankyo Pharmaceutical. NK has received honoraria from MSD, Astella, AstraZeneca, Novartis Pharma, Ono Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Eli Lilly Japan, Boehringer Ingelheim Japan, Takeda Pharmaceutical; research grants from Asahi Kasei, Astellas, Mitsubishi Tanabe Pharma, Tei** Pharma, Terumo, Boehringer Ingelheim Japan, Eli Lilly and Company, Mochida Pharmaceutical, Fuji Yakuhin; and scholarships from Daiichi Sankyo Healthcare, Tei** Pharma, Medtronic, Bayer Yakuhin. All other authors declare no competing interests.

Ethics approval and consent to participate

The ethics committees of the participating institutions approved the study protocol. Written, informed consent for participation in the study was obtained from all subjects. This trial was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.

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All authors have read and approved the submission of the manuscript. The manuscript has not been published and is not being considered for publication elsewhere, in whole or in part, in any language. If the manuscript is accepted, we approve it for publication in Cardiovascular Diabetology.

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Fujiki, S., Tanaka, A., Imai, T. et al. Body fluid regulation via chronic inhibition of sodium–glucose cotransporter-2 in patients with heart failure: a post hoc analysis of the CANDLE trial. Clin Res Cardiol 112, 87–97 (2023). https://doi.org/10.1007/s00392-022-02049-4

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