Combination Therapy No Better Than T4 Alone for Primary Hypothyroidism

Laurie Barclay, MD

December 09, 2003

Dec. 9, 2003 — Combination therapy for primary hypothyroidism offers no additional benefit over levothyroxine alone, according to the results of a randomized controlled trial published in the Dec. 10 issue of The Journal of the American Medical Association. The editorialist puts this finding in clinical perspective.

"Standard therapy for patients with primary hypothyroidism is replacement with synthetic thyroxine, which undergoes peripheral conversion to triiodothyronine, the active form of thyroid hormone," write Patrick W. Clyde, MD, from the National Naval Medical Center in Bethesda, MD, and colleagues. "Within the lay population and in some medical communities, there is a perception that adding synthetic triiodothyronine, or liothyronine, to levothyroxine improves the symptoms of hypothyroidism despite insufficient evidence to support this practice."

This double-blind, placebo-controlled trial was conducted from May 2000 to February 2002 at a military treatment facility serving active duty and retired military personnel and members of their families. Forty-six patients aged 24 to 65 years with at least a six-month history of treatment with levothyroxine for primary hypothyroidism were randomized to treatment with either their usual dose of levothyroxine or with combination therapy, in which their usual levothyroxine dose was reduced by 50 µg/d and substituted with liothyronine, 7.5 µg, taken twice daily for four months.

In both groups, serum thyrotropin levels remained similar and within the normal range from baseline to four months, and body weight and serum lipid levels remained stable. Scores on a hypothyroid-specific health-related quality-of-life (HRQL) questionnaire improved in both the levothyroxine alone group (23%; P < .001) and the combination therapy group (12%; P = .02), but these changes were not significantly different ( P = .54).

Although performance on 12 of 13 neuropsychological tests was similar in both groups after treatment, the levothyroxine alone group performed better than the combination therapy group on the Grooved Peg Board test.

"Compared with levothyroxine alone, treatment of primary hypothyroidism with combination levothyroxine plus liothyronine demonstrated no beneficial changes in body weight, serum lipid levels, hypothyroid symptoms as measured by a HRQL questionnaire, and standard measures of cognitive performance," the authors write. "New guidelines for patients receiving therapy for primary hypothyroidism recommend a target TSH level between 0.3 and 3.0 mIU/L or between 0.5 and 2.0 mIU/L [and] using only levothyroxine when treating hypothyroidism. This study supports these guidelines by providing sound evidence that levothyroxine alone continues to be the most appropriate therapy for patients with primary hypothyroidism."

The Clinical Investigation Program of the National Naval Medical Center in Bethesda, Maryland, funded this study.

In an accompanying editorial, David S. Cooper, MD, from the Sinai Hospital of Baltimore, Maryland, notes that the marked placebo effect in the control group makes it difficult to interpret these negative results. However, two other recent studies also failed to confirm the benefits of combination therapy.

"Until studies are performed in thyroidectomized individuals using a combination of drugs formulated at the correct ratio containing a slow-release form of T3, the hypothesis that combination therapy might be superior to T4 monotherapy cannot be completely rejected," he writes. "Before another century elapses, let us hope that the optimum treatment for all hypothyroid patients will be revealed by additional well-designed clinical trials using novel thyroid hormone preparations that precisely mirror normal thyroid physiology."

JAMA. 2003;290:2952-2958, 3002-3004

Reviewed by Gary D. Vogin, MD

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