Risk for thiazide-induced hyponatremia greater than indicated on drug labels

Key takeaways:

• The cumulative incidence of hyponatremia was about 1.4 percentage points higher for thiazide diuretics than other antihypertensive drugs.
• The results contrast to hyponatremia frequencies listed on drug labels.

Initiating treatment with thiazide diuretics was linked to increased incidences of low blood sodium below 130 mmol/L, also known as hyponatremia, compared with non-thiazide antihypertensive drugs, according to researchers.

“Although thiazide diuretics are considered effective, low-cost, and generally well tolerated and hence a rational choice for first-line treatment of uncomplicated hypertension, they may cause significant adverse effects, such as hyponatremia,” Niklas Worm Andersson, a PhD student at Statens Serum Institut in Copenhagen, and colleagues wrote in Annals of Internal Medicine.

They added, however, “the exact burden of thiazide-induced hyponatremia is unclear.”

So, the researchers conducted two target trials: one comparing new use of bendroflumethiazide (BFZ) with a calcium-channel blocker (CCB) in 82,749 adults and the other comparing new use of hydrochlorothiazide plus a renin-angiotensin system inhibitor (HCTZ-RASi) vs. a RASi alone in 97,727 adults.

The participants were aged 40 years and older and had no prior prescription for an antihypertensive drug, no past hyponatremia and were eligible for the evaluated antihypertensive treatments.

The researchers reported that the 2-year cumulative incidences of hyponatremia were:

• 3.83% for BFZ; and
• 3.51% for HCTZ-RASi.

The risk differences, meanwhile, were:

• 1.35% (95% CI, 1.04%-1.66%) between BFZ and CCB; and
• 1.38% (95% CI, 1.01%-1.75%) between HCTZ-RASi and RASi.

“The [risk differences] of hyponatremia were higher with older age and greater comorbidity burden,” Andersson and colleagues noted.

Additionally, HRs between BFZ and CCB and HCTZ-RASi and RASi, respectively, were:

• 3.56 (95% CI, 2.76-4.6) and 4.25 (95% CI, 3.23-5.59) during the first 30 days of treatment initiation; and
• 1.26 (95% CI, 1.09-1.46) and 1.29 (95% CI, 1.05-1.58) after 1 year.

“The cumulative incidences of moderate to severe hyponatremia (sodium level less than 130 mmol/L) were approximately 3.5% for the thiazides we studied ... about 1.4 percentage points higher than the cumulative incidences with a CCB and a RASi alone,” the researchers wrote.

The results are a “remarkable contrast” to the inconsistent hyponatremia frequencies provided on thiazide labels, according to Andersson and colleagues.

“The frequency of this adverse event is most often recognized as unknown or uncommon to very rare,” they wrote.

The researchers highlighted several limitations to the study. For example, because the participants were new users, the results may not be applicable to drugs used as add-on therapy. Additionally, a filled prescription was assumed to be drug use, which may have led to conservative estimates.

Ultimately, the findings “highlight the continued need for clinical awareness as well as monitoring of this adverse drug reaction,” the researchers concluded.