Low-dose tolvaptan for the treatment of Syndrome of Inappropriate Antidiuretic Hormone-associated hyponatremia: a systematic review, meta-analysis, and meta-regression analysis of clinical effectiveness and safety

TY - JOUR

T1 - Low-dose tolvaptan for the treatment of Syndrome of Inappropriate Antidiuretic Hormone-associated hyponatremia

T2 - a systematic review, meta-analysis, and meta-regression analysis of clinical effectiveness and safety

AU - Llewellyn, David C.

AU - Nuamek, Thitikorn

AU - Oštarijaš, Eduard

AU - Logan Ellis, Hugh

AU - Drakou, Eftychia E

AU - Aylwin, Simon JB

AU - Dimitriadis, Georgios K

N1 - Publisher Copyright: © 2025 AACE

PY - 2025/7/31

Y1 - 2025/7/31

N2 - Objective: Tolvaptan at the licensed dose of 15 mg effectively treats syndrome of inappropriate antidiuresis (SIAD)–associated hyponatremia. However, concerns about overcorrection and osmotic demyelination syndrome have limited its adoption. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of lower tolvaptan doses (<15 mg) for treating SIAD-associated hyponatremia. Methods: We systematically searched MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov, and Scopus from inception to February 2024. The primary outcomes were change in serum sodium and overcorrection rates. The secondary outcomes included adverse effects, hospital length of stay, and quality-of-life measures. We conducted meta-analyses using mean differences for efficacy and proportions for safety outcomes, with dose-based subgroup analyses and meta-regression. Results: From 968 identified studies, 18 met inclusion criteria, comprising 495 patients. Initial doses below 15 mg increased the serum sodium level by 7.2 mmol/L (95% CI, 6.0-8.4) within 24 hours. In the 7.5-mg subgroup (n = 286), the mean increase was 7.8 mmol/L (95% CI, 6.2-9.4). The overcorrection rates were 31% (95% CI, 15%-53%) for an increase of ≥10 mmol/L and 10% (95% CI, 3%-20%) for an increase of ≥12 mmol/L in 24 hours. In the 3.75-mg subgroup, the mean increase was 7.1 mmol/L (95% CI, 4.7-9.6). There were insufficient data to review overcorrection rates. No cases of osmotic demyelination syndrome were reported. The secondary outcome data were insufficient for meta-analysis. Conclusion: Low-dose tolvaptan (3.75-7.5 mg) effectively increases the serum sodium level in SIAD-associated hyponatremia. We recommend initiating tolvaptan at 7.5 mg, or 3.75 mg in high-risk patients, with close monitoring of sodium levels. These findings support a lower starting dose than currently licensed, although randomized controlled trials are needed to confirm optimal dosing strategies.

AB - Objective: Tolvaptan at the licensed dose of 15 mg effectively treats syndrome of inappropriate antidiuresis (SIAD)–associated hyponatremia. However, concerns about overcorrection and osmotic demyelination syndrome have limited its adoption. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of lower tolvaptan doses (<15 mg) for treating SIAD-associated hyponatremia. Methods: We systematically searched MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov, and Scopus from inception to February 2024. The primary outcomes were change in serum sodium and overcorrection rates. The secondary outcomes included adverse effects, hospital length of stay, and quality-of-life measures. We conducted meta-analyses using mean differences for efficacy and proportions for safety outcomes, with dose-based subgroup analyses and meta-regression. Results: From 968 identified studies, 18 met inclusion criteria, comprising 495 patients. Initial doses below 15 mg increased the serum sodium level by 7.2 mmol/L (95% CI, 6.0-8.4) within 24 hours. In the 7.5-mg subgroup (n = 286), the mean increase was 7.8 mmol/L (95% CI, 6.2-9.4). The overcorrection rates were 31% (95% CI, 15%-53%) for an increase of ≥10 mmol/L and 10% (95% CI, 3%-20%) for an increase of ≥12 mmol/L in 24 hours. In the 3.75-mg subgroup, the mean increase was 7.1 mmol/L (95% CI, 4.7-9.6). There were insufficient data to review overcorrection rates. No cases of osmotic demyelination syndrome were reported. The secondary outcome data were insufficient for meta-analysis. Conclusion: Low-dose tolvaptan (3.75-7.5 mg) effectively increases the serum sodium level in SIAD-associated hyponatremia. We recommend initiating tolvaptan at 7.5 mg, or 3.75 mg in high-risk patients, with close monitoring of sodium levels. These findings support a lower starting dose than currently licensed, although randomized controlled trials are needed to confirm optimal dosing strategies.

UR - https://www.scopus.com/pages/publications/105006596455

U2 - 10.1016/j.eprac.2025.04.012

DO - 10.1016/j.eprac.2025.04.012

M3 - Article

SN - 1530-891X

VL - 31

SP - 956

EP - 964

JO - Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists

JF - Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists

IS - 7

ER -