Levothyroxine Ineffective for Subclinical Hypothyroidism in Seniors

Thyroid replacement therapy lowered thyrotropin levels in elderly patients, but treatment did not relieve any symptoms of hypothyroidism.

Written by Katie Estes PhD

Interviews with David Stott, MB ChB, MD, and Tim Korevaar, MD, PhD

Findings from the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism (TRUST) trial,1 a randomized placebo-controlled study, established that levothyroxine, provided for thyroid replacement therapy, offered no benefit to older patients with subclinical hypothyroidism; the results were published online by the New England Journal of Medicine.1

Subclinical hypothyroidism is characterized by an elevated serum thyrotropin level and a defined range of serum free thyroxine (TSH).2

Although patients with subclinical hypothyroidism rarely show any symptoms, there is evidence to suggest that they may be at an increased risk of coronary heart disease.3 The Thyroid Studies Collaboration found that subclinical hypothyroidism is associated with increased coronary heart disease and mortality (TSH > 7mU/L) and a higher risk of coronary heart disease (CHD) (TSH > 10mU/L).3

“We should accept treatment of older subjects with mild subclinical hypothyroidism (TSH 4.6-10) is not justified on basis of current evidence,” lead author, David Stott, MB ChB, MD, told EndocrineWeb.

TRUST Evaluates Thyroid Replacement Therapy

While the research team set out to determine whether any cardiovascular benefit would be gained from levothyroxine supplementation in older individuals with subclinical hypothyroidism, recruitment fell short so only quality of life parameters could be assessed.1

The study participants were 65 years or older (mean age 74.4 years) and 54% were women with persistent subclinical hypothyroidism, defined as having an elevated thyrotropin level on at least two occasions (4.60 to 19.99 mIU per liter).1 The treatment target for this study was a TSH of 0.40 to 4.60 mU/L.

A total of 737 community-dwelling seniors were given 50 mg of levothyroxine or a placebo daily (or 25 mg if they weighed less than 50 kg or had known CVD).1 The outcome desired was to achieve a thyrotropin level of 0.40 to 4.59 mIU per liter; dosage adjustments were made accordingly.

To assess the effect of levothyroxine treatment after 12 months, patients were evaluated using the Thyroid-Related Quality-of-Life Patient-Reported Outcome (ThyPRO) Hypothyroid Symptoms score4 and a Tiredness score.

After 12 months, the mean thyrotropin level difference between the levothyroxine and placebo groups was significant.1 The between-group difference was 1.92 mIU per liter (P<0.001), with a mean thyrotropin level in the levothyroxine group of 3.63 ± 2.11 mIU per liter, and 5.48 ± 2.48 mIU per liter in the placebo group.

Need to Update Treatment Guidelines for Elderly

In contrast to the thyrotropin levels, the results of the Hypothyroid Symptoms score and Tiredness score after 12 months were not significantly different between the levothyroxine and placebo groups. There was also no difference in these measurements at 6 to 8 weeks into the study.

Dr. Stott said, “our study concludes this treatment provides no apparent benefits for older adults and should therefore no longer be started routinely for this condition. An update of the guidelines is necessary.”

Tim Korevaar, MD, PhD, offered commentary on the study in Clinical Thyroidology.5 In speaking to EndocrineWeb, Dr. Korevaar said, “the strengths of this study were its randomization and multicenter design. It was set up as the first large study to investigate the potential benefits of levothyroxine treatment in the elderly.

The study1 was originally designed to look not only at hypothyroidism symptoms but also the cardiovascular events previously identified as a risk factor for patients with subclinical hypothyroidism,2 said Dr. Korevaar.

“Unfortunately, the study had to be scaled down due to problems in recruiting so further research in this area would be of use,” he said.

When asked where he would focus future research, Dr. Korevaar said, “similar to the original plan, I would focus on cardiovascular events and mortality because that is a major outcome for which observational studies indicate that there is a higher risk.”  

Looking Ahead, Need Better Risk Assessment Techniques

Going forward, finding a better way to identify patients with subclinical hypothyroidism who are at higher risk for cardiovascular events may be the key,1 according to the authors. One avenue may be identifying genetic markers that offer a clue to who these high-risk individuals are.

“Large studies investigating thyroid-related genes are currently ongoing, and may help to identify what TSH concentration is normal for each individual,” Dr. Korevaar told EndocrineWeb, “Gaining that information may be useful in identifying if a high TSH concentration should be considered as too high for that individual, and could also help to identify a more optimal treatment goal.”


  1. Stott DJ, Rodondi N, Kearney PM, et al, for the TRUST Study Group. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med. April 3, 2017. [Epub ahead of print]
  2. Rugge JB, Bougatsos C, Chou R. Screening for and Treatment of Thyroid Dysfunction: An Evidence Review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014.
  3. Rodondi N, den Elzen WP, Bauer DC, et al, for the Thyroid Studies Collaborative. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010;304(12):1365-1374.
  4. Watt T, Hegedüs L, Groenvold M, et al. Validity and reliability of the novel thyroid-specific quality of life questionnaire, ThyPRO. Eur J Endocrinol. 2010;162(1):161-167.
  5. Korevaar TIM, Stott DJ, Rondondi N, et al, for the TRUST Study Group. Levothyroxine does not lower hypothyroidism symptoms in older adults with mild subclinical hypothyroidism. Clin Thyroidol. 2017;29(6):224-228.

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American Thyroid Association Guideline: Treatment of Hypothyroidism Other Than Levothyroxine Monotherapy