Thiazide-induced metabolic adverse events common in older adults

Among veterans with hypertension aged 65 years and older, a new prescription for a thiazide-type diuretic was associated with a higher rate of metabolic adverse events at 9 months, according to a new report.

“The risks related to thiazide diuretics are well known, but they haven’t been well quantified in older adults in real-world clinical practice, where patients treated with a thiazide may be more frail and may have a greater burden of other diseases than patients enrolled in clinical trials,” Anil N. Makam, MD, MAS, told Cardiology Today. “What our research adds is to quantify what this risk is, and to look at which types of older adults are at greatest risk. We also looked at surveillance patterns to see if patients started on thiazides were being properly monitored for these adverse events.”

Anil N. Makam

Makam, assistant professor of medicine at the University of Texas Southwestern Medical Center, and colleagues at the University of California, San Francisco, conducted an observational cohort study using merged national Veterans Affairs pharmacy, laboratory and administrative data and Medicare administrative data from fiscal years 2007 and 2008.

They analyzed veterans aged 65 years and older who had essential hypertension but were not prescribed a first-line antihypertensive medication during a 9-month baseline period leading up to the index date. A first-line antihypertensive medication was defined as a thiazide-type diuretic, ACE inhibitor, angiotensin II receptor blocker or beta-blocker.

During a 6-month period from July to December 2007, the researchers identified 1,060 participants who were newly prescribed a thiazide-type diuretic and 1,060 propensity-matched participants who remained untreated with a first-line antihypertensive medication. They were followed for 9 months after the index date (date of initial outpatient prescription for thiazide users; date of randomly selected outpatient visit for nonusers) for the occurrence of metabolic adverse events.

The primary outcome was a composite of hyponatremia (sodium <135 mEq/L), hypokalemia (potassium <3.5 mEq/L) and decrease in estimated glomerular filtration rate (eGFR) of >25% from the baseline rate. Secondary outcomes included severe adverse events, including sodium <130 mEq/L, potassium <3 mEq/L or decrease in eGFR of >50% from the baseline rate.

During follow-up, 14.3% of new thiazide users developed a metabolic adverse event compared with 6% of nonusers (number needed to harm=12; 95% CI, 9-17). Severe metabolic adverse events occurred in 1.8% of new thiazide users vs. 0.6% of nonusers (number needed to harm=82; P=.008). Hospitalization for a metabolic adverse event occurred in 3.8% of new thiazide users vs. 2% of nonusers (number needed to harm=56; P=.02), according to the results.

The researchers noted that one limitation of the study is that its population was overwhelmingly male. However, previous studies have not demonstrated any difference in the rates of hypokalemia and decline in eGFR between men and women, but did show that the rate of hyponatremia is higher in women than in men, Makam told Cardiology Today. “For hyponatremia, we think we’re underestimating the adverse event rates because more than 95% of our sample was male. It would be hard to extrapolate our findings to females, but if anything, our findings for hyponatremia are an underestimate.”

The risk for metabolic adverse events did not vary by age, but those with at least five comorbidities were far more likely to have a metabolic adverse event compared with those whose only comorbidity was hypertension (OR=3; 95% CI, 1.4-6.2), Makam and colleagues found.

Laboratory monitoring was low, with only 42% of thiazide users monitored within 90 days after initiation of therapy, according to the researchers.

That finding was surprising, Makam said, because “these risks should be well known to providers prescribing these medications.” – by Erik Swain

For more information:

Makam AN. J Am Geriatr Soc. 2014;doi:10.1111/jgs.12839.

Anil N. Makam, MD, MAS, can be reached at 5323 Harry Hines Blvd., Mail Code 9169, Dallas, TX 75390; email: anil.makam@utsouthwestern.edu.

Disclosure: The study was funded by the National Institute on Aging and a federal training grant from the National Research Service Award. Makam reports no relevant financial disclosures.