Thiazide diuretics for hypertension pose more hyponatremia risk than labeling indicates
Incidence of moderate to severe hyponatremia was significantly higher with new use of bendroflumethiazide or hydrochlorothiazide plus a renin-angiotensin system (RAS) inhibitor than with a calcium-channel blocker or a RAS inhibitor alone, two Danish target trials found.
Thiazide diuretics may pose a more substantial risk for hyponatremia than indicated by drug labeling, particularly during the first months of treatment, a study found.
To estimate the increase in the cumulative incidence of hyponatremia using thiazide diuretics compared with nonthiazide antihypertensive drugs in routine clinical practice, researchers in Denmark emulated a population and register-based cohort study from January 2014 to October 2018 among patients ages 40 years or older who had no recent prescription for any antihypertensive drug and no previous hyponatremia.
The first target trial emulation compared new use of bendroflumethiazide (n=37,786) to a calcium-channel blocker (CCB) (n=44,963). The second compared new use of a combination pill of hydrochlorothiazide plus a renin-angiotensin system (RAS) inhibitor (n=11,943) to a RAS inhibitor alone (n=85,784). The primary outcome was two-year cumulative incidence of sodium levels less than 130 mmol/L. Results were published Dec. 19 by Annals of Internal Medicine.
The two-year cumulative incidences of hyponatremia were 3.83% for bendroflumethiazide and 3.51% for hydrochlorothiazide plus a RAS inhibitor. The risk differences were 1.35% (95% CI, 1.04% to 1.66%) between the thiazide and CCB and 1.38% (95% CI, 1.01% to 1.75%) between hydrochlorothiazide plus a RAS inhibitor and a RAS inhibitor alone. Risk differences were higher with older age and higher comorbidity burden. In the first 30 days, the hazard ratio for hyponatremia were 3.56 (95% CI, 2.76 to 4.60) with bendroflumethiazide and 4.25 (95% CI, 3.23 to 5.59) with hydrochlorothiazide; at one year, they were 1.26 (95% CI, 1.09 to 1.46) and 1.29 (95% CI, 1.05 to 1.58), respectively.
The study authors concluded that hyponatremia is a common adverse drug reaction to thiazide and emphasized the importance of clinical awareness and monitoring. They cautioned that the study assumed that filled prescriptions equaled drug use, so residual confounding is possible.
Still, “Our results are in remarkable contrast to the frequencies of hyponatremia provided in the product labels for thiazide diuretics,” they wrote. “Thiazide-induced hyponatremia is currently reported with inconsistent frequency across existing drug labels; the frequency of this adverse event is most often recognized as unknown or uncommon to very rare (that is, <1 in 10000 to <1 in 100; time periods not reported).”