Treating Subclinical Hypothyroidism With Levothyroxine: Is There Evidence of Benefit?

Authors:
Eric A. Dietrich, PharmD, BCPS, and Kyle Davis, PharmD, BCPS

Citation:
Dietrich EA, Davis K. Treating subclinical hypothyroidism with levothyroxine: is there evidence of benefit? Consultant. 2017;57(8):504-505.

Hypothyroidism is estimated to occur in approximately 1 in 300 Americans, and its prevalence increases significantly with age. Hypothyroidism is most often caused by failure of the thyroid gland itself, and it also may result from insufficient stimulation of the thyroid gland by the pituitary gland or the hypothalamus. The most common symptoms of hypothyroidism are fatigue, weight gain, depression, myalgias, and concentration difficulties. Treatment of hypothyroidism revolves around thyroid hormone replacement therapy, most commonly with levothyroxine, which is well-tolerated with minimal adverse events when administered correctly.¹

Subclinical hypothyroidism is an elevation in thyroid-stimulating hormone (TSH) concentrations, with free thyroxine (FT₄) and free triiodothyronine (FT₃) concentrations within the reference range, with or without signs or symptoms of hypothyroidism. Subclinical hypothyroidism is believed to affect as much as 12% of the adult population, and its prevalence is growing significantly.² Given the tolerability of thyroid hormone replacement therapy, subclinical hypothyroidism traditionally has been treated with medication. But does evidence exist to support such a strategy?

Patient Case

PM, a 71-year-old woman with a history of osteopenia and prediabetes, presented for her annual follow-up visit. She had continued to do well taking alendronate, 70 mg once weekly, and calcium with vitamin D, 650 mg/400 IU twice daily, and adhering to your diet and exercise recommendations to maintain her optimal weight and blood glucose levels. She had no health concerns at the visit. The results of laboratory tests completed 1 week prior to her visit had shown a glycated hemoglobin level of 6.1%, a serum creatinine level of 0.67 mg/dL, an estimated glomerular filtration rate greater than 60 mL/min, and a TSH level of 7.3 mIU/L. Given the elevated TSH level, FT₄ and FT₃ tests were ordered, the results of which returned as normal. You ask her to repeat the thyroid function panel (TSH, FT₄, and FT₃) in 2 months to confirm the original abnormal TSH findings.

At a return visit 2 months later, PM reports that she continues to remain relatively asymptomatic, with some mild myalgias and fatigue from time to time, although these rarely impact her quality of life. Results of the repeated thyroid panel show a TSH level of 7.2 mIU/L, with her FT₄ and FT₃ remaining within normal limits. Based on the elevated TSH level but normal FT₄ and FT₃ levels confirmed with thyroid function tests 8 weeks apart, she receives a diagnosis of subclinical hypothyroidism. Will PM benefit from beginning levothyroxine therapy?

The Evidence

The authors of a 2007 Cochrane Review³ evaluated 12 trials (11 of which were placebo-controlled) aimed at determining the effect of levothyroxine on patients with subclinical hypothyroidism. Of the 7 studies that evaluated mood, symptoms, and quality of life, none showed a significant benefit of levothyroxine therapy. None of the 12 studies evaluated cardiovascular morbidity or mortality, and only 1 demonstrated an improvement in cognitive function. The Cochrane Review authors concluded that the use of levothyroxine did not significantly improve symptoms or quality of life in patients with subclinical hypothyroidism.

More recently, Stott and colleagues⁴ evaluated the efficacy of levothyroxine in older adults with subclinical hypothyroidism in a prospective, randomized, placebo-controlled study. Patients older than 65 years with subclinical hypothyroidism were randomly assigned to either 25 to 50 µg of levothyroxine or placebo. Following 1 year of therapy, the TSH level was significantly lower in the levothyroxine group (3.63 mIU/L vs 5.48 mIU/L; P < .001). However, no difference was observed in hypothyroid symptoms score or tiredness score in patients receiving thyroid replacement therapy compared with those receiving placebo. The authors concluded that levothyroxine was not associated with a significant benefit in elderly patients with subclinical hypothyroidism.

Clinical Application

PM’s laboratory test results confirm the diagnosis of subclinical hypothyroidism. She occasionally experiences mild symptoms that do not significantly impact her quality of life. Traditionally, she may have been considered a candidate for thyroid replacement therapy, but the body of evidence suggests that PM has little to gain from such treatment. The large meta-analysis and recent randomized controlled study discussed above confirmed that thyroid replacement therapy did not improve patients’ symptoms or quality of life; fortunately, patients who did receive treatment did not appear to experience a statistically higher rate of serious adverse events such as cardiovascular morbidity or mortality. However, patients who would be started on treatment would be required to undergo laboratory monitoring, have follow-up visits for monitoring, and purchase the thyroid replacement medication, which would greatly increase costs. While the studies did not show a statistically significant difference in the rate of adverse events with treatment, a patient taking any medication has a higher risk for adverse events than does a patient not taking a medication. Given the lack of benefit, it seems prudent to not treat, since any rate of adverse events, no matter how low, would exceed the benefit to be gained.

Furthermore, the strict administration requirements with levothyroxine may burden the patient. PM is also taking alendronate, which has its own specific administration requirements; attempting to coadminister alendronate and levothyroxine would create a difficult scenario each week, since both medications must be administered on an empty stomach prior to other medications. While the administration overall may not be equally burdensome in every patient, it must be weighed against the potential for benefit. Given that the potential for benefit appears negligible, any level of burden would exceed the benefit to be gained.

If PM were to develop overt hypothyroidism—that is, an elevated TSH level, a low FT₄ level, and more-significant symptoms of hypothyroidism, the benefits of treatment would increase greatly and would likely outweigh the burdens of administration and the costs of treatment. But because she currently has subclinical hypothyroidism, the evidence does not support treatment at this time.

Outcome of the Case

After discussing the potential advantages and disadvantages of beginning treatment for her newly diagnosed subclinical hypothyroidism, PM elects to defer treatment at this time. She is counseled to monitor for the signs and symptoms (such as excessive fatigue, cold intolerance, and weight gain) that may signal a further decline in her thyroid function to overt hypothyroidism. She will continue to have her TSH level monitored at scheduled intervals for additional surveillance for conversion to overt hypothyroidism.

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.

REFERENCES:

1. Gaitonde DY, Rowley KD, Sweeney LB. Hypothyroidism: an update. Am Fam Physician. 2012;86(3):244-251.
2. Portillo-Sanchez P, Rodriguez-Gutierrez R, Brito JP. Subclinical hypothyroidism in elderly individuals—overdiagnosis and overtreatment? A teachable moment. JAMA Intern Med. 2016;176(12):1741-1742.
3. Villar HCCE, Saconato H, Valente O, Atallah ÀN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007;(3):​CD003419. doi:10.1002/14651858.CD003419.pub2.
4. Stott DJ, Rodondi N, Kearney PM, et al; TRUST Study Group. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376(26):2534-2544.