Most U.S. prescriptions for the thyroid hormone replacement drug levothyroxine are not appropriate for patients with mild subclinical hypothyroidism, a trend that has remained steady for a decade despite evidence showing no significant benefits for those patients, new research shows.
Dr. Juan P. Brito
“These results suggest substantial overuse of levothyroxine during the entire duration of the study, suggesting opportunities to improve care,” wrote the authors of the study published in JAMA Internal Medicine.
“There have been previous reports of increased levothyroxine overuse in the U.S., but this is the first paper to describe the nature of the drivers of the overuse,” first author Juan P. Brito, MD, of the division of endocrinology, diabetes, metabolism and nutrition, department of internal medicine, Mayo Clinic, Rochester, Minn., said in an interview.
The findings underscore the need to improve awareness of the ongoing overuse, said the authors of an accompanying editorial.
“We hope [this study] resonates as a call to action for clinicians to stop treating patients with mild subclinical hypothyroidism,” they wrote.
Only 8% of those receiving levothyroxine had overt hypothyroidism
For the study, Dr. Brito and colleagues analyzed data of adults enrolled in Medicare Advantage who filled levothyroxine prescriptions between January 2008 and December 2018 and had thyrotropin levels measured within 3 months prior to the prescription. Patients with a history of thyroid surgery, thyroid cancer, central hypothyroidism, or who were pregnant, were excluded from the study.
In the 110,842 patients who started levothyroxine during the study period, there were no significant changes in median thyrotropin levels at the time of treatment initiation, with a median level in 2008 of 5.8 mIU/L and a level in 2018 of 5.3 mIU/L (P = .79).
In a subanalysis of 58,706 patients for whom thyrotropin as well as free thyroxine (FT4 or T4) levels were available – which allowed for the determination of the level of hypothyroidism – levothyroxine was initiated for overt hypothyroidism in only 8.4% of cases.
In as many as 61.0% of cases, patients had subclinical hypothyroidism, and in 30.5% of cases, patients had normal thyroid levels.
While the proportion of adults with overt hypothyroidism initiated on levothyroxine significantly increased over the 10 years (7.6% to 8.4%; P = .02), rates of those with subclinical hypothyroidism remained unchanged (59.3% to 65.7%; P = .36), as did the proportion with normal thyroid function (32.9% to 26.2%; P = .84).
A closer look at patients specifically with subclinical hypothyroidism showed there were also no changes in the proportion with mild subclinical hypothyroidism (thyrotropin level of 4.5 mIU/L to <10 mIU/L with normal FT4 or T4) between the beginning and end of the study period (48.2% vs. 57.9%; P = .73). Rates of moderate subclinical hypothyroidism (thyrotropin level 10-19.9 mIU/L) were also similar (8.5% to 6.4%; P = .16).
No significant benefit, but ample undesirable effects
The authors underscore that levothyroxine has been shown time and again to offer no significant benefit to patients with subclinical hypothyroidism of any type, emphasized in a 2018 meta-analysis of 21 randomized, controlled trials.
“Frequent initiation of levothyroxine in these patients is at odds with evidence demonstrating no significant association of levothyroxine replacement with measures of health-related quality of life, thyroid-related symptoms, depressive symptoms, fatigue, or cognitive function,” they explained.
In addition to showing no benefit for subclinical hypothyroidism, levothyroxine is associated with a host of unwanted side effects, noted editorialists William K. Silverstein, MD, of Sunnybrook Health Sciences Centre, department of medicine, University of Toronto, and Deborah Grady, MD, of the department of medicine, University of California, San Francisco.
Some studies have shown a link between long-term levothyroxine therapy and an increased risk of cardiovascular disease, cardiac dysrhythmias, osteoporosis, and fractures, they explained.
In addition, unnecessary treatment “increases pill burden and costs, necessitates routine physician visits and blood work, and requires modification of daily routines so that patients can take medications on an empty stomach,” the editorialists wrote.
Importantly, evidence shows that once levothyroxine treatment for subclinical hypothyroidism is started, most patients will continue the therapy for life, they added.
The fact that levothyroxine is among the most commonly prescribed drugs in the United States, with about 7% of the population estimated to have an active prescription when overt hypothyroidism affects only about 0.2%-2% of the population, underscores the extent of levothyroxine overuse, Dr. Silverstein said in an interview.
“The really notable surprise was how pervasive inappropriate use of levothyroxine was,” he said. “The fact that only 8% of patients had a biochemical indication for treatment is striking.”
Potential solutions: ‘Shift the conversation’
In terms of potential solutions to the problem, Dr. Silverstein suggested laboratories change reference ranges so that only thyrotropin values greater than 10 mIU/L are reported as abnormal.
“Studies have shown that changing the thyrotropin reference range is associated with clinicians’ prescribing patterns,” he noted.
Dr. Brito agreed, noting that “there are many guidelines with different hypothyroidism thresholds, so we need to be more consistent about the message to clinicians.
“In addition, we have to come up with different approaches to symptoms that have nothing to do with levothyroxine,” Dr. Brito said.
“I try to explain to patients that it’s very unlikely that subclinical hypothyroidism would be driving significant symptoms like fatigue, weight gain, and hair loss,” Dr. Brito said. “So, one approach is to shift the conversation from how your thyroid is causing this to ‘how are we going to treat the symptoms?’ ”
The study was supported by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Dr. Silverstein has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.