Serum sodium ion level influenced by daily salt intake after administration of sodium-glucose cotransporter 2 inhibitors

Accepted Manuscript Serum sodium ion level is influenced by daily salt intake after administration of sodium–glucose cotransporter 2 inhibitors Eijiro Yamada, MD, PhD, Aya Osaki, MD, PhD, Tsugumichi Saito, MD, PhD, Yawara Niijima, MD, Junichi Okada, MD, Shuichi Okada, MD, PhD, Masanobu Yamada, MD, PhD PII:

S0899-9007(17)30104-1

DOI:

10.1016/j.nut.2017.05.008

Reference:

NUT 9964

To appear in:

Nutrition

Received Date: 9 February 2017 Revised Date:

1 May 2017

Accepted Date: 15 May 2017

Please cite this article as: Yamada E, Osaki A, Saito T, Niijima Y, Okada J, Okada S, Yamada M, Serum sodium ion level is influenced by daily salt intake after administration of sodium–glucose cotransporter 2 inhibitors, Nutrition (2017), doi: 10.1016/j.nut.2017.05.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Serum sodium ion level is influenced by daily salt intake after administration of

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sodium–glucose cotransporter 2 inhibitors

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Eijiro Yamadaa MD, PhD, Aya Osaki MD, PhD, Tsugumichi Saito MD, PhD, Yawara

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Niijimab MD, Junichi Okadaa MD, Shuichi Okadaa* MD,PhD, Masanobu Yamadaa MD,PhD

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Department of Medicine and Molecular Science, Gunma University Graduate School

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of Medicine,

3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan Kan-etsu Chuo Hospital, 71 Kitahara, Takasaki, Gunma 370-3513, Japan

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author: Shuichi Okada

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*Correspondence

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan TEL.: +81-27-220-8501, FAX: +81-27-220-8136, E-MAIL: [email protected] A statement of all funding: This study was not supported by a grant. Conflicts of interests: none

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ABSTRACT

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Although sodium–glucose cotransporter 2 (SGLT2) inhibitors increase the excretion of sodium into urine, hyponatraemia is rare, consequent averse effect. In this study, we examined whether salt (sodium ion) intake affects serum sodium levels in 20 patients

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with type 2 diabetes mellitus after receiving SGLT2 inhibitors. The patients underwent

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regular follow-up examinations at one-month interval during which blood glucose, serum sodium and HbA1c levels were assessed, and daily salt intake was estimated according to Tanaka’s formula. The samples from before and after starting canagliflozin

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(100mg/day) were compared. The data showed significant positive correlation between the changes in serum sodium levels and daily salt intake in patients after receiving

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SGLT2 inhibitors. This indicates that patients who reduce their daily salt intake while

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under SGLT2 inhibitor medication may experience hyponatraemia. Although salt restriction is important to treat patients with type 2 diabetes mellitus and hypertension, daily salt intake should be considered carefully when SGLT2 inhibitors are administered.

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Keywords; Daily salt intake, Sodium-glucose cotransporter 2 inhibitor, type 2 diabetes

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mellitus, Hyponatraemia

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Although sodium–glucose cotransporter 2 (SGLT2) inhibitors increase the

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excretion of sodium into urine, hyponatraemia is rare, consequent adverse side effect caused by SGLT2 inhibitors. This could be regulated due to compensation mechanisms such as an increase in sodium reabsorption in the loop of Henle and regulation of the

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distal tubule by aldosterone1. Given this, we hypothesized that daily salt (sodium ion)

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intake affects serum sodium levels in patients with type 2 diabetes mellitus who receives SGLT2 inhibitors. To investigate this, we conducted a clinical study that included 20 patients with type 2 diabetes mellitus (11 men and 9 women; median age,

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69 years), who visited Kan-etsu Chuo Hospital once a month for a regular follow-up examination during which glucose concentrations in plasma, serum sodium and HbA1c

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levels were assessed. We estimated daily salt intake according to Tanaka’s formula2.

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Data from before and after starting SGLT2 inhibitor, canagliflozin (100mg/day), were compared. SPSS version 10.0 software (IBM-SPSS, Inc., Chicago, IL, USA) was used for all statistical analyses, and p < 0.05 was considered statistically significant. The study protocol was reviewed and approved by our hospital review board, and the study was conducted in accordance with the principles of the Declaration of Helsinki. Written

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informed consent was obtained from each patient. The patients had the following

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characteristics and mean data: body mass index, 26.3 kg/m2; systolic blood pressure, 130.0 mmHg; diastolic blood pressure, 77.3 mmHg; total cholesterol, 220.5 mg/dL; triglyceride, 135 mg/dL and uric acid, 6.1 mg/dL. The median HbA1c level changed

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from 7.8% to 7.2%, the median serum sodium levels changed from 140 meq/L to 143

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meq/L, and the median estimated daily salt intake changed from 9.3g/day to 10.9g/day from before starting SGLT2 treatment to after receiving 3 months of treatment. Three of the 20 patients were medicated with diuretics and 7 with angiotensin II receptor

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blockers. Although the sample size was small, we found a significant positive correlation between the changes in serum sodium levels and daily salt (sodium ion)

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intake following treatment with SGLT2 inhibitors (Figure 1A, p=0.0008, R2=0.4741).

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On the other hand, we did not find any correlation between serum sodium levels and daily salt intake in the case of patients with type 2 diabetes mellitus without SGLT2 inhibitors (Figure 1B, p=0.0237, R2=0.5167, N=20). These findings indicated that patients who reduce their daily salt (i.e. sodium) intake while receiving SGLT2 inhibitors may experience hyponatraemia. Although salt restriction is important to treat

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patients with type 2 diabetes mellitus and hypertension, attention needs to be given to

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daily salt intake when SGLT2 inhibitors are administered. However, it will be required to analyze a larger number of subjects to

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confirm our results.

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References

1. Chen L, LaRocque LM, Efe O, Wang J, Sands JM, Klein JD. Effect of dapagliflozin

352:517-523.

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treatment on fluid and electrolyte balance in diabetic rats. Am J Med Sci. 2016;

2. Ito T, Takeda M, Hamano T, Kijima T, Yamasaki M, Isomura M, et al. Effect of salt

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intake on blood pressure in patients receiving antihypertensive therapy: Shimane

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CoHRE Study. Eur J Intern Med. 2016 ;28:70-73.

Figure legend

Figure 1A: Correlation between the changes in serum sodium levels and daily salt intake after the administration of SGLT2 inhibitors

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The y- and x-axes represent the changes in daily salt intake and serum sodium (Na)

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from before starting SGLT2 inhibitors and after 3 months of treatment. Each point represents a patient and the calculations were based on the mean of 3 measurements.

the administration of SGLT2 inhibitors

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Figure 1B: Correlation between serum sodium levels and daily salt intake without

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The y- and x-axes represent serum sodium (Na) levels and daily salt intake without the administration of SGLT2 inhibitors. Each point represents a patient and the calculations

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were based on the mean of 3 measurements.

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