ROCHESTER, MN — An ongoing problem in treating hypothyroidism is dealing with patients who fall into the sub-clinical category. The result is that more than half of U.S. patients initiating levothyroxine therapy in a 10-year period failed to meet the threshold for benefit, according to a new study.
The research published in JAMA Internal Medicine is significant because levothyroxine is one of the most commonly prescribed drugs in the United States. In fact, about 7% of the population estimated to have an active prescription.1
Yet, pointed out researchers from the Mayo Clinic, Yale School of Medicine and colleagues, no clinically relevant benefits have been established for levothyroxine replacement in terms of quality of life or thyroid-related symptoms for non-pregnant adults with sub-clinical hypothyroidism—thyrotropin level elevated but ≤10 mIU/L and normal free thyroxine [FT4] levels. Researchers from the Central Arkansas Veterans Healthcare System in Little Rock participated in the study.
The authors advised that their results “suggest substantial overuse of levothyroxine during the entire duration of the study, suggesting opportunities to improve care.”
The issue is especially challenging for health systems such as VHA, which treats a more elderly population. A Danish study in Frontiers in Endocrinology pointed out, “The elderly population is growing, and increasing incidence and prevalence of hypothyroidism with age are observed globally. Elderly people have more comorbidities compared to young patients, complicating correct diagnosis and management of hypothyroidism.”2
Of foremost concern, according to the authors, is that cardiovascular complications can compromise the usual start dosage and upward titration of L-T4 due to higher risk of decompensating cardiac ischemia and function, adding, “It, therefore, takes more effort and care from the clinician, and the maintenance dose may have to be lower in order to avoid a cardiac incidence.”
Researchers advised, however, that L-T4 has a beneficial effect on cardiac function by increasing performance and is used to help with conditions such as cardiac ischemia.
“The endocrinologist is obliged to collaborate with the cardiologist on prophylactic cardiac measures by invasive cardiac surgery or medical therapy against cardiac ischemic angina,” they added.
The study team also noted that management of mild (sub-clinical) hypothyroidism often is extremely complex in the elderly because comorbidities often result in non-thyroidal illness, resembling mild hypothyroidism both clinically and biochemically.
In an analysis that included many older patients, the Mayo Clinic-led study team sought to better understand the use of levothyroxine in the United States by analyzing national data for commercially insured and Medicare Advantage beneficiaries
To do that, the researchers conducted a retrospective analysis of de-identified administrative claims data linked with laboratory results from OptumLabs Data Warehouse. Included were adults with new levothyroxine prescriptions which they filled between Jan.1, 2008, and Dec. 31, 2018, and who had a thyrotropin level measured within 3 months prior to levothyroxine initiation. Ultimately, the study focused on 110,842 patients who started on levothyroxine treatment between 2008 and 2018.
Using a subsample with thyrotropin and thyroxine levels available, the study team defined thyroid function as:
- overt hypothyroidism (elevated thyrotropin and low free or total thyroxine [FT4 or T4] levels),
- sub-clinical hypothyroidism (elevated thyrotropin and normal FT4 or T4 levels), and
- normal thyroid function (normal thyrotropin and FT4 or T4 levels).
Also analyzed were mild subclinical hypothyroidism (thyrotropin level of 4.5 mIU/L to <10 mIU/L with normal FT4 or T4), moderate sub-clinical hypothyroidism (thyrotropin level of 10-19.9 mIU/L), and severe subclinical hypothyroidism (thyrotropin level > 19.9 mIU/L).
Median thyrotropin level at treatment initiation did not significantly change: 5.8 mIU/L in 2008 to 5.3 mIU/L in 2018, the authors note, adding that, in the subset of 58 706 patients with thyrotropin and FT4 or T4 levels available, levothyroxine was initiated for overt hypothyroidism (4948 [8.4%]), sub-clinical hypothyroidism (35 814 [61.0%]), and normal thyroid levels (17 944 [30.5%]).
Results indicated that, during the 10-year period, the proportion of adults with overt hypothyroidism increased (7.6% to 8.4%; P = 0.02); the proportion with sub-clinical hypothyroidism did not change (59.3% to 65.7%; P = 0.36); and the proportion with normal thyroid function did not change (32.9% to 26.2%; P = 0.84).
Among patients with subclinical hypothyroidism, meanwhile, no significant change was documented in patients with mild sub-clinical hypothyroidism (48.2% to 57.9%; P = 0.73) and moderate subclinical hypothyroidism (8.5% to 6.4%; P = .16), while the proportion with severe subclinical hypothyroidism decreased (2.5% to 1.3%; P = 0.02).
“We found that levothyroxine treatment was commonly initiated for mildly increased thyrotropin levels, and this did not change significantly over time,” researchers wrote. “Among patients for whom full thyroid function test results were available, 60% initiated levothyroxine for treatment of sub-clinical hypothyroidism (mostly for mild sub-clinical hypothyroidism) and 30% for normal thyroid function, without significant change in these patterns over time.”
The authors emphasized that the practice “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.”
- Brito JP, Ross JS, El Kawkgi OM, Maraka S, Deng Y, Shah ND, Lipska KJ. Levothyroxine Use in the United States, 2008-2018. JAMA Intern Med. 2021 Jun 21. doi: 10.1001/jamainternmed.2021.2686. Epub ahead of print. PMID: 34152370.
- Effraimidis G, Watt T, Feldt-Rasmussen U. Levothyroxine Therapy in Elderly Patients With Hypothyroidism. Front. Endocrinol., 12 March 2021 | https://doi.org/10.3389/fendo.2021.641560