Can thiazide diuretics cause increases in serum glucose?
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Background
Thiazide diuretics are a class of FDA-approved medications that inhibit the reabsorption of sodium in the distal convoluted tubule of nephrons in the kidneys; inhibiting this reabsorption promotes natriuresis and diuresis to occur.1 This class of medications made their debut in the late 1950s, and since then have remained among the first-line agents to treat hypertension.1,2 The 3 most common thiazide diuretic agents utilized in the United States are hydrochlorothiazide, chlorthalidone, and indapamide. Hydrochlorothiazide and chlorthalidone are FDA-approved to treat chronic hypertension and as adjunctive therapy for edema associated with various disorders such as chronic heart failure, renal impairment, or corticosteroid therapy.3,4 Indapamide is also FDA-approved for use in treating chronic hypertension; it can also be used to treat edema in heart failure. These agents all have off-label use for calcium nephrolithiasis prevention, and additionally hydrochlorothiazide has been reported to be used off-label for diabetes insipidus.4
Evidence and Literature Review
According to tertiary drug databases such as Lexicomp, various thiazide diuretics do have hyperglycemia listed as an adverse reaction (though frequency and incidence rates are not defined).4 Package inserts for hydrochlorothiazide, chlorthalidone, and indapamide list hyperglycemia as a potential adverse reaction as well.3 Clinical trials have also regularly demonstrated undesirable metabolic biochemical changes when taking diuretics in comparison to other medications, such as an increase in serum glucose levels.5 Usually, diuretic-induced increases in serum glucose levels are small and appear to reduce over time.
The Table below summarizes recent (published 2016 to 2023) meta-analyses of randomized controlled trials that have evaluated changes in plasma glucose due to thiazide diuretic use.
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| Table. Overview of evidence examining glycemic changes with thiazide diuretic use6,7 | |||
|---|---|---|---|
| Study | Included Studies | Results | Conclusions |
| Hall et al 20206 | MA of 95 RCTs (N=76,608) comparing a thiazide or thiazide-like diuretic with any comparator reporting any measure of blood glucose | Overall, in pooled analysis, thiazide diuretics were found to marginally increase FPG (WMD, 0.20 mmol/L†; 95% CI, 0.15 to 0.25;I2=84%) Subgroup analysis of thiazides utilized as monotherapy and combination therapy demonstrated similar results (WMD, 0.17 mmol/L; 95% CI, 0.10 to 0.24; I2=83%) In studies that compared thiazides with placebo vs an active comparator, a similar effect on FPG was seen (WMD, 0.16 mmol/L; 95% CI, 0.07 to 0.25; I2 = 72%) Standard and increased doses of thiazides demonstrated similar effects on FPG: (WMD, 0.21 mmol/L; 95% CI, 0.14 to 0.28; I2 =80%) and (WMD, 0.18 mmol/L; 95% CI, 0.09 to 0.26; I2 = 80%), respectively | Authors concluded that thiazide diuretics have a small and clinically insignificant impact on FPG and results did not change substantially when considering dose or duration, comparison against placebo or an active comparator, or using thiazides as monotherapy or combination therapy |
| Zhang et al 20167 | MA of 26 RCTs (N=16,162) comparing thiazide or thiazide-like diuretics with a comparator (e.g., other hypertensive agent, placebo, nontreatment) that assessed 1 or more glycemic parameters in patients with hypertension | Overall, thiazide/ thiazide-like diuretics were found to increase FPG compared to other hypertensive agents, placebo or nontreatment (MD, 0.27 mmol/L; 95% CI, 0.15 to 0.39; p<.0001; I2=97%). In subgroup analysis, patients receiving lower doses of thiazides (hydrochlorothiazide or chlorthalidone ≤25 mg daily) had less change in FPG (MD, 0.15 mmol/L; 95% CI, 0.03 to 0.27) compared to patients receiving higher doses (MD, 0.60 mmol/L; 95% CI, 0.39 to 0.82; p=.00003) In subgroup analysis, patients who received longer duration of treatment (≥6 months) also had less glycemic change (MD, -0.01 mmol/L; 95% CI, -0.47 to 0.45) than patients with shorter treatment duration (MD, 0.50 mmol/L; 95% CI, 0.36 to 0.64; p=0.04) | Authors concluded that there were statistically significant but small magnitude of glycemic changes associated with thiazide-type diuretics in patients with hypertension |
| Abbreviations: CI: confidence interval; FPG: fasting plasma glucose; I2: heterogeneity statistic (> 75% indicates high heterogeneity between studies); MA: meta-analyses; MD: mean difference; RCT: randomized controlled trials; WMD: weighted mean difference †: 1 mmol/L = 18 mg/dL |
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Conclusion
Tertiary drug databases and individual medication package inserts have reported that various thiazide diuretics do have hyperglycemia listed as an adverse reaction. Randomized controlled trial data analyzed in meta-analyses have also demonstrated that diuretic-induced increases in serum glucose levels exist, however changes in glucose levels were of small magnitude (statistically significant but not necessarily clinically impactful).
References
- Akbari P, Khorasani-Zadeh A. Thiazide Diuretics. [Updated 2023 Jan 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532918/
- Ernst ME, Fravel MA. Thiazide and the thiazide-like diuretics: Review of hydrochlorothiazide, chlorthalidone, and indapamide. Am J Hypertens. 2022;35(7):573-586. doi:10.1093/ajh/hpac048
- DailyMed: National Library of Medicine. Accessed October 2023. https://dailymed.nlm.nih.gov/dailymed/index.cfm
- Lexicomp. Wolters Kluwer; 2023. Accessed October 2023. http://online.lexi.com/lco/action/home
- Carter BL, Einhorn PT, Brands M, et al. Thiazide-induced dysglycemia: call for research from a working group from the national heart, lung, and blood institute. Hypertension. 2008;52(1):30-36. doi:10.1161/HYPERTENSIONAHA.108.114389
- Hall JJ, Eurich DT, Nagy D, Tjosvold L, Gamble JM. Thiazide diuretic-induced change in fasting plasma glucose: A meta-analysis of randomized clinical trials. J Gen Intern Med. 2020;35(6):1849-1860. doi:10.1007/s11606-020-05731-3
- Zhang X, Zhao Q. Association of thiazide-type diuretics with glycemic changes in hypertensive patients: A systematic review and meta-analysis of randomized controlled clinical trials. J Clin Hypertens (Greenwich). 2016;18(4):342-351. doi:10.1111/jch.12679
Prepared by:
Faria Munir, PharmD, MS, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
November 2023
The information presented is current as of October 20, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.