Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Regular Article
Seasonal Variation in Diuretic-Induced Dehydration Using Spontaneous Reports of Adverse Events
Satoshi Nakao, Mika Maezawa, Kohei Shiota, Fumiya Goto, Koumi Miyasaka, Sakiko Hirofuji, Kiyoka Matsumoto, Moe Yamashita, Nanaka Ichihara, Yuka Nokura, Kana Sugishita, Tomofumi Yamazaki, Hideyuki Tanaka, Hirofumi Tamaki, Kazuhiro Iguchi, Mitsuhiro Nakamura
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キーワード: diuretic, dehydration, seasonal variation, adverse event, Japanese Adverse Drug Event Report database
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2025 年 48 巻 9 号 p. 1335-1342

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Abstract

Diuretics have long been central to the treatment of heart failure (HF) and hypertension, and are widely used in clinical settings. Herein, we performed a retrospective analysis of seasonal variations in diuretic-induced dehydration (DID) using the Japanese Adverse Drug Event Report (JADER) database, a platform that presents data on real-world clinical practice. A total of 11 diuretics prescribed in Japan, categorized into six groups, were included. The monthly reporting ratio (RR) of DID in the JADER database was determined from January 2003 to December 2023. DID was most common in January, followed by August. Furthermore, it was frequently reported during the winter months of December, January, and February. It is important for healthcare providers to understand that DID is common in both winter and summer, and thus recommend adequate water intake even in the former for patients taking diuretics. These findings can contribute to the management of dehydration in patients taking diuretics and are beneficial to healthcare professionals involved in the treatment of HF and hypertension.

INTRODUCTION

Diuretics regulate fluid volume and improve symptoms in diseases such as heart failure (HF), hypertension, kidney disease, liver cirrhosis with ascites, and acute pulmonary edema.1–5) They are classified first, by their primary site of action along the nephron and second, by the mechanism by which they inhibit transport.6)

Diuretics have been reported to cause various adverse events,6) making the management of diuretic-related adverse events important in clinical practice. The major side effects of loop diuretics include hypersensitivity reactions, extracellular fluid volume depletion, hypokalemic alkalosis, hypomagnesemia, and ototoxicity.6) Those of thiazide diuretics include hyponatremia, hypokalemic alkalosis, hyperglycemia/diabetes, hyperuricemia/gout, and hypomagnesemia.6) Potassium-sparing diuretics may cause hyperkalemia due to their mechanism of action.7) Tolvaptan has been reported to cause dehydration-related adverse events (thirst, polyuria, nocturia, and polydipsia due to the excretion of water without electrolytes) with increased aquaresis.8) In summary, increased urinary excretion by any diuretic can lead to dehydration.

Because dehydration is associated with increased morbidity and mortality in the elderly, its diagnosis and treatment are important.9) Dehydration has been implicated in acute kidney injury, thrombosis, thromboembolism, and delirium, and is a major factor in the prognosis of the elderly.10) It is associated with decreased water intake due to decreased thirst sensation, impaired renal function, and decreased water content in the body in this patient population, the latter being exacerbated by the use of diuretics.11) Because dehydration is related to sweating and the amount of water ingested,12) the risk of developing it varies with season. Matsumoto et al. investigated the risk of dehydration in patients taking sodium-glucose co-transporter 2 (SGLT2) inhibitors on a seasonal basis.13) Similarly, it is important to consider and address the risk of diuretic-induced seasonal dehydration in patients using these agents.

Although healthcare providers are likely to be aware of diuretic-induced dehydration (DID), the effect of season on dehydration-related adverse events in real-world clinical practice remains unclear. The Japanese Adverse Drug Event Report (JADER) database, made public by the Pharmaceutical and Medical Devices Agency (PMDA), is a collection of spontaneous adverse event reporting data from actual clinical practice in Japan, in which information on the date of the occurrence of adverse events is entered. We previously revealed seasonal variations in drug-induced photosensitivity using the JADER database.14) Similarly, Marrero et al. analyzed various adverse event reports using the FDA Adverse Event Reporting System (FAERS) to identify seasonal and regional variations, including photosensitivity.15) In this study, we analyzed seasonal variations in DID by diuretic category using the JADER database. The investigation aimed to verify whether dehydration-related adverse events associated with diuretics are adequately managed, and to alert the public of possible occurrences if necessary.

MATERIALS AND METHODS

Data Source

The publicly available JADER dataset, including information recorded between April 2004 and December 2023 (Fig. 1), was downloaded from the PMDA website (www.pmda.go.jp). The JADER database comprises four tables: (1) DEMO (patients’ demographic information); (2) DRUG (drug information); (3) REAC (adverse event information); and (4) HIST (primary disease information). In the DRUG table, each drug is assigned a code according to its association with adverse drug reactions, namely, “suspected drug,” “concomitant drug,” and “interacting drug.” It was difficult to confirm the criteria used to define dehydration (PT code: 10012174) events and drugs by volunteers at the time of reporting. However, the reports in the JADER database are reported by healthcare professionals; therefore, we believe that analyses restricted to “suspected drugs” provide the most robust results regarding the association of certain drugs with dehydration (PT code: 10012174) events. Consequently, first, our analysis was restricted to reports in which the drugs were recorded as “suspected drug.” Nonetheless, the use of a diuretic as a concomitant drug or interacting drug may also have been associated with dehydration. Therefore, we incorporated “concomitant drug” and “interacting drug” into the “suspected drug” category, and the same analysis was conducted. The results are summarized in the Supplementary Data (Supplementary Tables S1–S4, Supplementary Figs. S1, S2). We built a relational database that integrated the data tables using FileMaker Pro version 20.3.2 (Claris International Inc., Santa Clara, CA, U.S.A.).

Fig. 1. Flowchart Depicting the Process of Data Analysis

Drug Selection

One carbonic anhydrase inhibitor (acetazolamide), one osmotic diuretic (concentrated glycerin fructose), three loop diuretics (azosemide, furosemide, and torasemide), three thiazide diuretics (hydrochlorothiazide, indapamide, and trichlormethiazide), two potassium-sparing diuretics (eplerenone and spironolactone), and one vasopressin receptor antagonist (tolvaptan) used in Japan as of 2024 were included (Fig. 1). The route of administration of these drugs was also considered.

Adverse Events Selection

Adverse events in the JADER database were defined based on the Medical Dictionary for Regulatory Activities (MedDRA; www.meddra.org/how-to-use/support-documentation/japanese) version 27.0 (Fig. 1). To extract cases from the JADER database, the preferred term (PT) for dehydration (PT code: 10012174) with an occurrence date from January 2003 to December 2023 was used (Fig. 1). In this study, dehydration was strictly defined using PT codes to ensure the robustness of the results. Other PTs related to dehydration, such as “specific gravity urine increased” (PT code: 10050773), were preliminarily examined, with four reports identified throughout the study period. However, “specific gravity urine increased” (PT code: 10050773) was excluded from the analysis.

Patient Background Survey

Sex, age, and reason for diuretic use in DID reports were analyzed from DEMO and DRUG tables. Diuretics are administered for a variety of purposes, including HF, hypertension, and fluid retention. Owing to this, reasons for diuretic use were extracted and analyzed to explore patients’ underlying medical conditions in cases of DID.

Time Series Analysis

The reporting ratio (RR) was calculated as the number of adverse events of dehydrations reported for each target drug per month divided by the total number of adverse events reported per month. Temperatures used were the 10-year monthly average temperatures for Tokyo from 2014 to 2023, as published by the Japan Meteorological Agency.16) JMP Pro version 17 (SAS Institute Inc., Cary, NC, U.S.A.) was used to visualize the time-series data.

RESULTS

The total number of JADER reports from April 2004 to December 2023 was 894123. For suspected drug, the number of dehydration reports for acetazolamide, concentrated glycerin fructose, azosemide, furosemide, torasemide, hydrochlorothiazide, indapamide, trichlormethiazide, eplerenone, spironolactone, and tolvaptan was 2, 1, 40, 107, 13, 25, 8, 23, 15, 75, and 71, respectively (Table 1). The number of dehydration reports for the six diuretic categories (carbonic anhydrase inhibitor, osmotic diuretic, loop diuretics, thiazide diuretics, potassium-sparing diuretics, and vasopressin receptor antagonist) was 2, 1, 160, 56, 90, and 71, respectively (Table 1). Regarding the route of administration, furosemide and tolvaptan were reported to be administered through multiple routes, viz. oral (per os: p.o.) and intravenous (i.v.) administration (Table 1). The sex and age distribution of patients with reported DID in the JADER database were analyzed (Table 2). The proportion of men and women reporting DID was nearly equal; however, DID reports were more frequent among elderly individuals compared with younger ones (Table 2). The purpose of diuretic use in DID cases was also examined (Table 3). Loop diuretics and potassium-sparing diuretics were predominantly prescribed for HF, edema, and hypertension, whereas thiazide diuretics were primarily used for hypertension (Table 3). Furthermore, vasopressin receptor antagonists were most commonly administered for the management of HF and fluid retention (Table 3).

Table 1. The Number of Dehydration Reports for Diuretics

Category of diuretic Drug Administration route Case (n)
Carbonic anhydrase inhibitor 2
Acetazolamide p.o.† 2
Osmotic diuretic 1
Concentrated glycerin fructose i.v.‡ 1
Loop diuretics 160
Azosemide p.o.† 39
Unidentified 1
Furosemide p.o.† 93
i.v.‡ 7
Unidentified 7
Torasemide p.o.† 12
Unidentified 1
Thiazide diuretics 56
Hydrochlorothiazide p.o.† 25
Indapamide p.o.† 6
Unidentified 2
Trichlormethiazide p.o.† 23
Potassium-sparing diuretics 90
Eplerenone p.o.† 13
Unidentified 2
Spironolactone p.o.† 71
Unidentified 4
Vasopressin receptor antagonist 71
Tolvaptan p.o.† 66
i.v.‡ 2
Unidentified 3

†p.o.: per os; ‡i.v.: intravenous

Table 2. The Number of Diuretic-Induced Dehydration Reports Stratified by Sex and Age

Total DID† case (n) Reporting ratio (%)
Total 894123 232 0.026
Sex
 Male 432514 120 0.028
 Female 418256 111 0.027
 Unidentified 43353 1 0.002
Age
 0–9 years 32149 4 0.012
 10–19 years 23153 0 0.000
 20–29 years 28561 4 0.014
 30–39 years 44628 1 0.002
 40–49 years 64094 11 0.017
 50–59 years 101079 21 0.021
 60–69 years 174273 24 0.014
 70–79 years 210782 59 0.028
 80–89 years 108893 83 0.076
 90–99 years 16307 20 0.123
 ≥100 years 373 1 0.268
 Unidentified 89831 4 0.004

† DID: diuretic-induced dehydration

Table 3. Breakdown of Reasons for Diuretic Use

Category of diuretic Reasons for diuretic use Case (n) (%)
Carbonic anhydrase inhibitor
Epilepsy 1 50.0
Glaucoma 1 50.0
Others 0
Unidentified 0
Total 2
Osmotic diuretic
Unidentified 1 100.0
Total 1
Loop diuretics
Heart failure 38 23.5
Edema 20 12.3
Hypertension 18 11.1
Fluid retention 9 5.6
Ascites 6 3.7
Others 19 11.7
Unidentified 52 32.1
Total 162
Thiazide diuretics
Hypertension 36 64.3
Heart failure 3 5.4
Others 5 8.9
Unidentified 12 21.4
Total 56
Potassium-sparing diuretics
Hypertension 21 22.8
Heart failure 18 19.6
Edema 10 10.9
Fluid retention 7 7.6
Ascites 3 3.3
Others 6 6.5
Unidentified 27 29.3
Total 92
Vasopressin receptor antagonist
Heart failure 30 37.0
Fluid retention 16 19.8
Edema 7 8.6
Hepatic cirrhosis 4 4.9
Ascites 3 3.7
Congenital cystic kidney disease 3 3.7
Others 8 9.9
Unidentified 10 12.3
Total 81

The number of reported DID per diuretic category for each month and the average temperature for each month were investigated (Table 4). Figure 2 shows the monthly RR for diuretic category use. The dehydration percentage reported for all drugs was highest in the summer months of July and August. DID was the most common in January, followed by August. DID was also frequently reported during the winter months of December, January, and February. The “suspected drug” plus “concomitant drug” categories were used for the analysis and the percentage of DID reports was calculated (Supplementary Tables S1, S2, Supplementary Fig. S1). We further expanded the analysis to include “interacting drugs” and calculated the percentage of DID reports (Supplementary Tables S3, S4, Supplementary Fig. S2). When the analysis was expanded to include concomitant and interacting drugs, as in the case of suspected drugs only, DID was most common in January, followed by July and August.

Table 4. The Number of Diuretic-Induced Dehydration Reports per Diuretic Category for Each Month and Average Temperature for Each Month

Month Total reports* All diuretics Carbonic anhydrase inhibitor Osmotic diuretic Loop diuretics Thiazide diuretics Potassium-sparing diuretics Vasopressin receptor antagonist Temperature
Case (n) Case (n) Reporting ratio (%) Case (n) Reporting ratio (%) Case (n) Reporting ratio (%) Case (n) Reporting ratio (%) Case (n) Reporting ratio (%) Case (n) Reporting ratio (%) Case (n) Reporting ratio (%) (°C)
January 69454 29 0.0418 0 0.0000 0 0.0000 22 0.0317 6 0.0086 12 0.0173 13 0.0187 5.74
February 69526 20 0.0288 0 0.0000 0 0.0000 15 0.0216 7 0.0101 8 0.0115 5 0.0072 6.76
March 78829 13 0.0165 0 0.0000 1 0.0013 7 0.0089 1 0.0013 5 0.0063 7 0.0089 10.87
April 80887 13 0.0161 0 0.0000 0 0.0000 7 0.0087 1 0.0012 7 0.0087 7 0.0087 14.97
May 86466 23 0.0266 0 0.0000 0 0.0000 14 0.0162 7 0.0081 10 0.0116 4 0.0046 19.83
June 91719 15 0.0164 0 0.0000 0 0.0000 12 0.0131 3 0.0033 5 0.0055 1 0.0011 22.62
July 86775 24 0.0277 0 0.0000 0 0.0000 20 0.0230 8 0.0092 9 0.0104 3 0.0035 26.44
August 81739 28 0.0343 0 0.0000 0 0.0000 16 0.0196 8 0.0098 11 0.0135 8 0.0098 27.76
September 75588 17 0.0225 1 0.0013 0 0.0000 8 0.0106 4 0.0053 5 0.0066 6 0.0079 23.86
October 78245 14 0.0179 1 0.0013 0 0.0000 10 0.0128 2 0.0026 5 0.0064 3 0.0038 18.33
November 73489 14 0.0191 0 0.0000 0 0.0000 4 0.0054 3 0.0041 6 0.0082 4 0.0054 13.51
December 68856 23 0.0334 0 0.0000 0 0.0000 14 0.0203 6 0.0087 7 0.0102 10 0.0145 8.08

*JADER 2003.1–2023.12

Fig. 2. Rader Chart of the Reporting Ratio of Diuretic-Induced Dehydration and Average Temperatures in Japan

DISCUSSION

Dehydration is a typical adverse event associated with diuretics, and has been reported for all diuretics in the JADER database. In the present study, the percentage of reported dehydration tended to be higher in summer and winter.

In general, dehydration involves the withdrawal of water through perspiration12) and there are seasonal differences in its risk. Living in hot climates increases water loss and the risk of dehydration.17) In Japan, the Ministry of Health, Labor and Welfare, Ministry of the Environment, and Japan Meteorological Agency have issued warnings to be careful of heat stroke and dehydration during the summer season. In winter, water withdrawal due to sweating is thought to be less frequent, which may explain the decrease in water consumption. Nevertheless, a decreased water intake can cause dehydration.12)

Urine specific gravity is a good biomarker for evaluating hydration status in free-living conditions.18,19) Stavrinou et al. investigated the relationship between season and drinking water volume to dehydration in Cypriot adolescents.20) In their study, the temperatures ranged from 10 to 15°C in winter and 26 to 30°C in summer.20) Cyprus has a Mediterranean climate characterized by mild winters and hot summers. It is reasonable to assume that the high temperatures during summer may contribute to an increased risk of dehydration.21) In the aforementioned study, adolescents had a significantly higher mean urine specific gravity in winter than in summer: 1.026 (SD 0.007) versus 1.023 (SD 0.007), respectively (p = 0.002),20) but there was no difference in the total water intake between summer and winter. The authors hypothesized that high temperatures during the summer can lead to increased water loss through sweating and increased thermal stress, which is typically expected with a higher fluid intake. Nevertheless, adolescents in Cyprus showed higher urine specific gravity during the winter than in the summer, despite similar total water intake. However, physiologically, dehydration can occur due to passive exposure to a hot environment, physical exertion, or water restriction.22) A possible explanation is that adolescents (children) may be more physically active during the school term in winter, when temperatures are approximately 15°C, whereas physical activity levels could decline in hotter weather,23) particularly in Mediterranean climates.24)

On the other hand, the average minimum temperature in Tokyo, Japan in January 2024 was 2.9°C and the average maximum temperature in August 2024 was 33.6°C.16) The climate in Japan is hot in summer and cold in winter, which affects sweating and drinking behaviors. It is generally known that dehydration is a common concern during the summer months due to increased water loss from perspiration. During high summer temperatures, blood vessels on the skin surface dilate, which strains the cardiovascular system’s thermoregulation, in turn increasing the risk of dehydration.25,26) It remains unclear whether the tendency for increased physical activity in winter applies to Japan.

Unlike in the study by Stavrinou et al. on adolescents, the reports of patients with DID in the present study were predominantly those of the elderly (Table 2). Elderly individuals with reduced muscle mass experience progressive decreases in total body water and intracellular water content.27) As a result, they are at increased risk for mild chronic dehydration.27) According to a report on the habitual water intake of 242 Japanese adults (30–76 years old), male and female, using the 16-d semi-weighed dietary record method, the average intake was 2121 g/d for those aged 30–49 years and 2324 g/d for those aged 50–76 years.28) The total water intake averaged 2331 g/d in summer and 2134 g/d in winter.28)

There was a bimodality in the relative risk of dehydration between the two seasons in the present study. It is reasonable to assume that DID is more common in winter due to a decrease in total water intake, in addition to the effects of diuretics. In winter, dehydration is difficult to detect and awareness of water intake is lower than in summer. Therefore, healthcare providers must take adequate precautions against dehydration caused by diuretics not only in summer but also in winter.

In recent years, SGLT2 inhibitors have been used not only for the treatment of diabetes but also for the treatment of HF. They have diuretic properties and require dehydration management. Matsumoto et al. used the JADER database to investigate seasonal variations in SGLT2 inhibitor-induced dehydration and found that the relative risk of dehydration increased in summer and winter.13) The seasonal variation in DID observed in the present study exhibits a trend consistent with previous findings. Due to the potential concomitant use of SGLT-2 inhibitors and diuretics, we preliminarily conducted an investigation into the concurrent administration of these two agents. Among the 233 DID reports analyzed herein, 47 involved the concomitant use of SGLT2 inhibitors. Furthermore, we performed a time series analysis on 186 DID reports that did not involve concomitant use of SGLT2 inhibitors (Supplementary Table S5 and Supplementary Fig. S3). In the DID reports that did not include SGLT2 inhibitors, the RR was highest in January, followed by December, August, and February (Supplementary Table S5 and Supplementary Fig. S3). These results suggest that DID has seasonal patterns not only for SGLT2 inhibitors, but also for diuretics alone without SGLT2 inhibitors, indicating that it is more likely to occur in winter and summer. The evaluation of the combined effects of the two drugs remains a subject for future investigation.

Loop diuretics have been used to alleviate volume overload in acute HF for more than 50 years and are recommended in the ESC HF guidelines to reduce the signs and/or symptoms of congestion in patients with HF with reduced ejection fraction.29,30) They compete with chloride ions to bind to and inhibit the sodium-potassium-chloride co-transporter on the apical membrane of the thick ascending limb of the loop of Henle.31)

Thiazide diuretics have been shown to reduce cardiovascular mortality and morbidity in systolic and diastolic hypertension and are commonly used in the treatment of hypertension.32) In the DID reports in this study, most thiazide diuretics were used for hypertension (Table 3). Thiazide diuretics are sometimes combined with loop diuretics for HFs that are resistant to loop diuretics.33) They block the sodium-chloride channel in the proximal segment of the distal convoluted tubule of nephrons, causing natriuresis and diuresis.34,35)

Martins et al. reported that the blood pressure-lowering effect of thiazides increased at higher doses and was enhanced by their association with potassium-sparing diuretics.36) The potassium-sparing diuretics further mitigated potassium depletion induced by thiazide diuretics.36) Potassium-sparing diuretics inhibit sodium-potassium cotransporters in the distal convoluted tubule, which increases sodium excretion and reduces potassium excretion.31)

Tolvaptan is a loop aquaretic that functions as a selective and competitive vasopressin receptor 2 antagonist; it inhibits inappropriate vasopressin elevation and mediates water retention.37) In addition, it improves free water excretion by selectively inhibiting the vasopressin V2 receptor.37) Tolvaptan is primarily used to treat fluid retention in patients with inadequate response to other diuretics, and Samsca®︎, an oral formulation of tolvaptan, is indicated for controlling the progression of autosomal dominant polycystic kidney disease.38) In the DID reports in this study, tolvaptan was also used in three cases of congenital cystic kidney disease (Table 3).

Similar to other diuretics, vasopressin receptor antagonists were associated with increased reports of dehydration in December and January. However, reports of summer dehydration were lower than those for other diuretics. The reason behind this finding is unknown; however, one justification may be that vasopressin receptor antagonists, unlike other diuretics, discharge only water without accompanying electrolyte changes. Vasopressin receptor antagonists inhibit the binding of vasopressin to its receptor and the translocation of aquaporin 2, which is involved in water reabsorption, to the cell surface, resulting in diuretic effects.39) Water and sodium withdrawal are thought to increase during the summer months because of increased sweating. Diuretics other than vasopressin receptor antagonists cause additional sodium loss, whereas vasopressin receptor antagonists do not. This may explain why the reported rate of dehydration was not higher in the summer months with vasopressin receptor antagonists. Vasopressin receptor antagonists may increase serum sodium concentrations because they drain only water. Thirst was reported at a high frequency with the use of tolvaptan,38) which may have led to increased water consumption behavior and prevented dehydration.

The limitations of this study should be highlighted. Herein, we utilized reporting rates that are simple to calculate and easy to verify to assess seasonal trends in dehydration. By contrast, Nakao et al. investigated seasonal variation in photosensitivity and attempted to account for background factors such as reporting month, reporting year, and gender by employing multiple logistic regression, thereby obtaining an adjusted reporting odds ratio (ROR).14) The authors observed similar trends in seasonal variation in both the reported percentage and the adjusted ROR measures. The Autoregressive Integrated Moving Average (ARIMA) model is commonly used to analyze periodicity in time-series data, such as seasonal variations.40,41) However, in the present dataset, ARIMA failed to detect clear periodicity, likely due to the small number of reports in each reporting year (data not shown). If the number of adverse event reports was sufficient and the events exhibited periodicity, a time-series analysis method such as ARIMA would have been preferable. The applicability of this approach thus remains a subject for future investigation.

In addition, duplicate reports of the same patient are known to exist in JADER, making it challenging to accurately identify and classify them in the dataset published by PMDA. Nevertheless, our findings suggest that the observed bimodal pattern of dehydration symptoms associated with diuretics, peaking in summer and winter, is a plausible result. This pattern is likely attributable to the pharmacological effects of diuretics and their actual applications in clinical practice.

Winter dehydration is often overlooked due to minimal perspiration, leading to insufficient awareness among both patients and healthcare providers. Dehydration caused by low drinking water consumption is a common chronic health condition in the elderly.10,42) In addition, the use of diuretics further promotes water loss. Therefore, educating patients taking diuretics to drink adequate amounts of water, even in winter when they are less thirsty, may help prevent DID.

CONCLUSION

In Japanese clinical practice, the RR for DID is the highest in the summer months of July and August, as well as in winter (December, January, and February). These findings are useful and informative for healthcare professionals involved in the treatment of cardiovascular diseases.

Acknowledgments

This research was partially supported by the Japan Society for the Promotion of Science KAKENHI (Grant Numbers: 21K11100, 21K06646, and 25K10049).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

REFERENCES
 
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Published by The Pharmaceutical Society of Japan

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