No Thyroid-Function Benefits With T4/T3 Combo in Crossover Study

Nancy A Melville

October 27, 2015

ORLANDO, Florida — In the ongoing debate over the treatment of hypothyroidism with a combination of levothyroxine (T4) and triiodothyronine (T3), a new randomized, crossover study shows safety but no significant overall clinical benefits, using such a fixed combination.

The double-blind study, presented last week at the 2015 International Thyroid Congress and Annual Meeting of the American Thyroid Association (ITC/ATA), involved 32 adults with primary hypothyroidism, including 30 females, who had been treated with T4 for 6 months or more.

"There is still controversy regarding whether the combination therapy is safe and effective," lead author Gilberto Paz-Filho, MD, of the Australian National University, Canberra, told Medscape Medical News.

"Our study sought to evaluate whether a unique, fixed dose of T4 plus T3 [Novothyral, Merck] could improve the well-being of patients with hypothyroidism, and while the evaluated formulation of combination therapy was safe, it was not better than T4 monotherapy [Euthyrox, Merck]."

As previously reported by Medscape Medical News, ATA guidelines issued last year recommend against the routine use of combination T4 plus T3 therapy, although they did indicate that, at the discretion of the practitioner, therapy with T3 could be attempted. This advice sparked a huge debate.

Asked to comment on the new study, session comoderator Marco Centanni, MD, of the University of Rome, Medicosurgical Sciences and Biotechnologies, Italy, said he supports the ATA guidelines on combination therapy.

"Combination T4/T3…is not a first choice in the treatment of hypothyroidism, [and this study] confirms [previously reported] negative results," he told Medscape Medical News.

Findings in Concordance with the Literature

Dr Paz-Filho reported that the patients in this new study were randomized to either continued treatment with T4 (n=17) or to start treatment with the combination of T4 and T3 (75 μg plus 15 μg per day, n=15).

After 8 weeks of treatment, the regimens were switched and treatment continued for another 8 weeks.

When researchers looked at measures of thyroid function, as well as lipid profiles, plasma glucose, body mass index (BMI) and other measures, the only significant difference at final assessments was in free T4 levels, which were significantly lower when patients were treated with combination therapy compared with T4 alone (in group one, 1.07 ng/dL at week 16 vs 1.65 ng/dL at week 8; in group two, 0.97 ng/dL at week 8 vs 1.63 ng/dL at week 16; P < .001 for both groups).

While group one also showed a significant difference in mean thyroid-stimulating-hormone (TSH) levels (P < .05), overall there were no differences in median TSH or T3 levels between the treatment regimens.

More patients showed T3 levels that were above the upper limit while on combination therapy compared with T4 alone, however (15% vs 3%).

Dr Centanni noted that a caveat of the current study was in the dosing. "The timing of treatment was insufficient," he said. "At least three administrations of T3 per day are required."

While an increase in heart rate was associated with combination-therapy use, there were no significant changes on ECG or in arterial blood pressure, and no other differences were observed in terms of body weight and quality-of-life measures such as energy, well-being, and mood complaints, Dr Paz-Filho noted.

He added, however, that more patients reported reductions in shortness of breath while on the combination therapy.

"Most of our findings are in concordance with the literature, but we were surprised to see while patients were on the combination therapy, they referred to less shortness of breath, in comparison with being on T4 monotherapy," he said. "This is an unspecific finding, with clinical significance that is unclear."

The combination therapy involved a commercially available formulation that offered some convenience and potential added measure of safety, Dr Paz-Filho added.

"This [formulation] eliminates the need for compounding the medication, which adds several confounding factors, such as dosing errors."

Still a Need for Future Studies

Explaining the rationale behind combination therapy, Dr Paz-Filho explained that patients frequently report continued symptoms of hypothyroidism after treatment with T4 alone.

"Many patients with primary hypothyroidism do not improve with the standard T4 monotherapy, despite achieving normal thyroid-hormone levels in the blood. This may occur because levothyroxine alone does not restore normal thyroid levels in tissues such as muscle and liver."

While animal studies have shown that the combination therapy can effectively restore euthyroidism in most tissues, evidence in humans has been less conclusive.

With many patients continuing to report greater improvements with combination T4 and T3 therapy, research should continue in exploring the reasons for this, Dr Paz-Filho stressed.

"In the clinics, patients empirically treated with the combination therapy refer to some improvements and prefer that type of therapy," he said.

"Therefore, there is still need for future studies with longer follow-up, evaluating the effect of long-acting, slow-release forms of T3, in patients with relatively low T3, and with polymorphisms in genes affecting thyroid economy."

Merck provided the Novothyral (T4/T3) and Euthyrox (T4) capsules used in the study. Dr Paz-Filho and Dr Centanni reported they have no relevant financial relationships.

2015 International Thyroid Congress and Annual Meeting of the American Thyroid Association; Orlando, Florida. Abstract 7, presented October 19, 2015.

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