New Trials on T3/T4 Combination for Hypothyroidism 'Justified'

Nancy A. Melville

March 02, 2021

Amid the ongoing uncertainties over the role of combination therapy in the treatment of hypothyroidism, endocrinology experts have issued a consensus statement that new clinical trials are warranted in order to take a fresh look at this controversial issue and to evaluate new evidence on everything from genetics to sustained-release treatment formulations.

Following a joint conference of the American Thyroid Association (ATA), the British Thyroid Association, and the European Thyroid Association (ETA), the experts concluded: "We believe that there is equipoise for a new well-designed adequately powered clinical trial of combination therapy.

"Furthermore, patients and physicians have demonstrated an urgent strong interest in addressing the clinical problem of patients' dissatisfaction with the existing standard of care for thyroid hormone therapy," they underscored.

Existing Trials Have Limitations; Use Combo Therapy Sparingly in Meantime

Numerous trials have been conducted on short-acting liothyronine (LT3) in combination with the standard therapy of levothyroxine (LT4). However, the experts agreed that shortcomings in the existing studies and mounting unanswered questions need to be addressed, Jacqueline Jonklaas, MD, PhD, told Medscape Medical News.

"There was sufficient justification for new trials of our current T3 preparation based on the fact that the trials were underpowered and had other issues, such as not selecting patients with residual symptoms, short duration of the study, and once-daily dosing of T3," explained Jonklaas, a professor of medicine in the Division of Endocrinology at Georgetown University, in Washington, DC.

She noted, however, that with the evidence that is currently available, caution should be used in prescribing the combination therapy.

"The immediate implication...for the clinician is that until we have clearly shown benefits of combination therapy, there is extra caution to not use it universally and not to use it for symptoms that could be due to other conditions," she observed.

"There is also a caution to not use nonphysiological doses (high doses), to monitor for side effects, and to discontinue treatment if the patient does not experience benefits," she said.

Fourteen previous clinical trials failed to show a consistent benefit of the combination therapy, yet patients continue to report benefit from the approach. The joint conference was called to review the most up-to-date evidence and determine steps forward.

The meeting resulted in the experts identifying 10 key issues that would be the most meaningful in guiding productive clinical trials.

The full details are published jointly in Thyroid, the official journal of the ATA, and in the ETA's European Thyroid Journal.

Sustained-Release T3, Patient-Reported Outcomes

Among the key topics agreed upon is the need to evaluate a sustained-release T3 preparation. Such a preparation could overcome concern of the dissipation of circulating T3 that occurs with oral tablet formulations, which fail to achieve the relatively stable levels seen in normal individuals, Jonklaas noted.

"There was unanimous agreement that when and if a sustained-release T3 preparation became available and had undergone preliminary testing, new trials with such a preparation were definitely warranted," she said.

Preliminary testing of a new product that potentially provides sustained release of T3 has recently started, Jonklaas noted.

Patient-reported outcomes were acknowledged as essential in the full picture of understanding treatment efficacy, and the experts agreed that an emphasis on those outcomes will be important in any future trials of combination therapy.

"Outcomes that are important to patients need to be included as the main measures of whether a treatment is successful," Jonklaas emphasized.

"Also, patient preference for the therapy is another important measure," she said.

Importantly, trials should investigate patients who report residual symptoms while taking LT4 monotherapy, the experts further agreed.

Because there is evidence that genetic factors could play a role in response to hypothyroidism treatment, studies should investigate responses of patients who have genetic polymorphisms of deiodinase enzymes, which play a key role in the activation and inactivation of thyroid hormones.

Importantly, "all of these considerations would apply regardless of whether the current T3 or a new sustained-release T3 was being studied," Jonklaas noted.

Current Recommendations for Combination Therapy

Until such clinical trials provide better answers, the experts agree that LT4 therapy should be carefully optimized before clinicians consider combination therapy.

Factors that should rule out combination therapy include the presence of medical conditions that could place patients at risk. These include pregnancy; pregnant women should not be given combination therapy, owing to the developing baby's reliance on adequate T4, Jonklaas said.

"Also, if combination therapy does not benefit the patient, it should be discontinued and the dose should not be increased beyond what is considered physiologic," she concluded.

Jonklaas has disclosed no relevant financial relationships.

Thyroid. Published online February 12, 2021. Full text

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