Don’t TRUST Levothyroxine for Elderly Patients with Subclinical Hypothyroidism

Sandy Liu, Mercer University College of Pharmacy

Thyroid hormones have pleiotropic effects and act in the heart, brain, skeletal muscles, and bones, among other sites.  Along with body weight and energy expenditure, thyroid hormones help regulate metabolic processes necessary for normal growth and development in adults. [1]  Subclinical hypothyroidism (SCH) is when serum thyrotropin is elevated and serum levels of free thyroxine are normal with few or no hypothyroid symptoms. [2]  Some nonspecific symptoms may include tiredness, constipation, cognitive problems, and dry skin. [3]

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism [4]
Design Double-blind, randomized, placebo-controlled, parallel-group; N= 737
Objective To determine the benefits of levothyroxine replacement in elderly individuals with subclinical hypothyroidism
Study Groups Levothyroxine (n= 368); placebo (n= 369)
Methods Patients received either levothyroxine 50 mcg daily (or 25 mcg in patients with a body weight of less than 50 kg or history of coronary heart disease) or matching placebo, with stratification according to country, sex and starting dose.  Eligible patients had to be 65 years or older and have persistent subclinical hypothyroidism, defined as an elevated thyrotropin level (4.60 to 19.99 mIU per liter) that was measured on at least two occasions that were 3 months to 3 years apart, with a free thyroxine level within the reference range.  Dose adjustment in the levothyroxine group was aimed to result in a thyrotropin level within the reference range of 0.40 to 4.59 mIU per liter.
The Thyroid-Related Quality-of-Life Patient-Reported Outcome measures Hypothyroid Symptoms score (4 items) and Tiredness score (7 items); each scale ranges from 0 to 100, with higher scores indicating more symptoms and tiredness, respectively.
Duration 12 months
Primary Outcome Measure Change in Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year from baseline
Baseline Characteristics
Placebo Levothyroxine
Mean age, yrs ⁤± SD 74.8 ± 6.8 74.0 ± 5.8
Female, n (%) 198 (53.7) 198 (53.8)
White, n (%) 362 (98.1) 362 (98.4)
Previous medical conditions, n (%)
    Ischemic heart disease 50 (13.6) 50 (13.6)
    Atrial fibrillation 44 (12.0) 45 (12.4)
    Hypertension 183 (50.0) 192 (52.5)
    Diabetes mellitus 54 (14.7) 63 (17.1)
    Osteoporosis 47 (12.8) 41 (11.3)
Weight < 50 kg, n (%) 5 (1.4) 5 (1.4)
Mean thyrotropin, mIU/L ± SD 6.38 ± 2.01 6.41 ± 2.01
    Median (IQR) 5.76 (5.10-6.94) 5.73 (5.12-6.83)
    Range 4.60-17.60 4.60-17.60
    Free thyroxine, pmol/L ± SD 13.3 ± 1.9 13.4 ± 2.1
Baseline outcome measures
    Hypothyroid Symptoms, score ± SD 16.9 ± 17.9 17.5 ± 18.8
    Tiredness, score ± SD 25.5 ± 20.3 25.9 ± 20.6
Results
Placebo Levothyroxine Difference (95% CI) p-value
Mean thyrotropin, mIU/L ± SD 5.48 ± 2.48 3.63 ± 2.11 -1.92

(-2.24 to -1.59)

<0.001
Hypothyroid Symptoms, score ± SD 16.7 ± 17.5 16.6 ± 16.9 0.0

(-2.0 to 2.1)

0.99
Tiredness, score ± SD 28.6 ± 19.5 28.7 ± 20.2 0.4

(-2.1 to 2.9)

0.77
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: new-onset atrial fibrillation (3.0%); heart failure (0.8%); new diagnosis of osteoporosis (0.8%); fracture (2.4%)
Percentage that Discontinued due to Adverse Events: 22.0%
Study Author Conclusions Treatment with levothyroxine in older persons with subclinical hypothyroidism provided no symptomatic benefits.

In the United States, the typical elderly patient takes an average of 14 to 18 prescriptions each day.  The increased risk for drug-drug interactions that accompanies widespread polypharmacy among this patient population, along with the changes that come with aging, can affect medication safety and efficacy.  If levothyroxine does not provide any benefits in specific patient populations, then it may be disadvantageous to add medications to the list of prescriptive agents geriatrics use.  The funding that went into conducting a trial on a subclinical condition may have been misappropriated in that the nonspecific symptoms may be indistinguishable from increasing age.

 

References

[1] Rugge JB, Bougatsos C, Chou R. Screening and treatment of thyroid dysfunction: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162(1):35-45.

[2] Javed Z, Sathyapalan T. Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits. Ther Adv Endocrinol Metab. 2016;7(1):12-23.

[3] BioMed Central: BMC Endocrine Disorders. https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-017-0156-8. Accessed April 8, 2017.

[4] Stott DJ, Rodondi N, Kearney PM, et al. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med. 2017.

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