To T3 or Not: What's the Story on Combo Therapy in Hypothyroidism?

Nancy A Melville

December 18, 2014

"To T3 or not to T3?" That was the question posed in the title of a talk at the 2014 Annual Meeting of the American Thyroid Association addressing the group's new hypothyroidism guidelines and one of their key controversial issues — combination therapy.

The conclusion — that evidence is still insufficient to choose 'to T3' — specifically, to routinely combine triiodothyronine (L-T3) with synthetic thyroxine and levothyroxine (L-T4) in the treatment of hypothyroidism — was not, in the minds of some, the nobler of choices, and the ATA subsequently found itself the target of more than a few slings and arrows.

The use of combination therapy is clearly a very emotive issue.

"The use of combination therapy is clearly a very emotive issue," said presenter Jacqueline Jonklaas, MD (Georgetown University Medical Center, Washington, DC), head of the ATA task force on the new hypothyroidism guidelines, underscoring her point with a sampling of postings on the ATA's Facebook page following the recommendation: some calling the decision "shameful," others accusing the ATA of being in the pockets of the pharmaceutical industry, and at least one battle cry for a class-action lawsuit.

Dr Jacqueline Jonklaas

Dr Jonklaas noted that even some of the guidelines' own reviewers questioned the decision. She shared a couple of their comments, including: "I do not understand why the authors would not recommend a therapeutic trial of low-dose T3, even though the benefits may be unproven," and "I (personally) think that not mentioning a therapeutic trial with low doses of T3 is unnecessarily rigid, if these guidelines are for practicing physicians."

In a stance seen as somewhat bolder than the ATA, the European Thyroid Association (ETA) has specifically addressed combination therapy in guidance published in 2012 (Eur Thyroid J. 2012;1:55–71) , which opened the door for L-T4 and L-T3 combination therapy "as an experimental treatment modality" for hypothyroidism in compliant L-T4–treated hypothyroid patients who have persistent complaints despite serum thyroid-stimulating-hormone (TSH) values within the reference range.

Guidelines Recommend Only Against "Routine" Use of Combo

Dr Antonio Bianco

But among the most important phrases in the new ATA guidelines that should be underscored — loud and clear — is that they "recommend only against the routine use of combination therapy," said ATA president elect Antonio C Bianco, MD, PhD (chief, division of endocrinology and metabolism; executive vice chair, department of internal medicine, Rush University Medical Center, Chicago, Illinois), who cochaired the hypothyroidism task force along with Dr Jonklaas.

"At the same time, there are multiple instances in which combination therapy is supported," he told Medscape Medical News.

Those instances include when patients' serum TSH levels are normal but they are still symptomatic — which is when most clinicians are likely to consider the option.

In such cases, "acknowledgment of the patients' symptoms and evaluation for alternative causes is recommended," the guidelines state.

With L-T4 monotherapy effective in treating approximately 80% to 90% of hypothyroid patients, however, the recommendation that monotherapy should stand as the routine treatment in primary hypothyroidism is reasonable, Dr Bianco stressed.

Dr Jonklaas agrees and defended the stance taken by the 11-member task force, explaining that evidence is weak regarding combination therapy: few studies have directly compared the two regimens of combination and monotherapy, and the 13 combination-therapy trials that were evaluated had too many inconsistencies to collectively provide the kind of conclusive support needed for a recommendation for routine use.

"The studies included diverse causes of hypothyroidism, different dosing recommendations, different outcomes measures, and different durations of treatment," she explained.

Some studies also had flaws such as nonvalidated outcome measures, and the studies did not address the important concern of overtreatment when L-T3 is combined with L-T4.

"We don't have a good sense of how many people are over- or undertreated in these combination-therapy regimens," Dr Jonklaas said. "We also do know there were some reports of side effects and concern about cardiac arrhythmia, with one report of atrial fibrillation."

"All of these are reasons arguing against 'just giving people L-T3.' "

Dr Bianco concurs: "Given that this is a lifelong therapy, ideally we would like to know that this is safe [and] that it [will not harm] patients in 10, 20, or 30 years before we make the recommendation that all patients can routinely use combination therapy. In contrast, safety data do exist for L-T4 tablets."

The take-home message, Dr Jonklaas told Medscape Medical News, is that "levothyroxine remains the best therapy that we have for patients with hypothyroidism; however, we should not be complacent, as we want 100% of our patients to feel well."

"We definitely need more research. We should try to design better studies that examine benefits and risks in both male and female patients of all ages and that examine these benefits and risks over longer periods of treatment."

Could Genetic Variation Play a Role in Response to Therapy?

One theory as to why some patients may indeed continue to experience hypothyroid symptoms such as fatigue, weight gain, and "brain fog" despite achieving normal TSH levels with L-T4 monotherapy was recently proposed with the discovery of common variations in the deiodinase 2 (DIO2) gene (J Clin Endocrinol Metab. 2009;94:1623-1629). The latter was found to be associated with reduced ability to convert T4 to T3, potentially leading to a lack of response to monotherapy with T4.

According to Leonard Wartofsky, MD (Georgetown University School of Medicine, Washington Hospital Center, Washington, DC), this information could make a big difference in improving hypothyroidism treatment.

"Although our professional organizations continue to recommend L-T4 alone for the treatment of hypothyroidism, the possibility of a DIO2 gene polymorphism should be considered in patients on L-T4 monotherapy who continue to complain of fatigue in spite of dosage-achieving low-normal serum thyroid-stimulating-hormone levels," he wrote in an editorial last year (Curr Opin Endocrinol Diabetes Obes. 2013;20:460-466).

One place to look for such evidence could be in patients' free T4 and free T3 levels, he added. "A…clue to the presence of this polymorphism could be a higher-than-normal free-T4/free-T3 ratio."

Dr Wartofsky told Medscape Medical News that while he recognized the ATA's need to make the recommendation it did on combination therapy, he personally leans more toward the ETA guidelines, which allow greater experimentation.

I think that the ATA guidelines' recommendation regarding combination therapy is appropriately cautious.

"I think that the ATA guidelines' recommendation regarding combination therapy is appropriately cautious," given the available data on this, said Dr Wartofsky. "But because the data from studies ostensibly showing no benefit of combination therapy may be viewed as flawed, I personally consider the ETA guidelines on this particular issue to be both more reasonable and patient-centered."

The ATA task force did address the genetic data in its guidelines, agreeing that controlled confirmatory studies are needed.

But the task force noted that genetic testing for the specific deiodinase polymorphisms is currently available only in a research setting, and it added that there is likely much more to the picture than is realized.

"The small effect of the type 2 deiodinase gene variants identified so far that do affect thyroid-hormone concentrations suggests that other factors (eg, yet-unidentified genetic variants) may play a far greater role in determining an individual patient's thyroid-hormone concentrations," the task force noted.

Meanwhile, Desiccated Thyroid Lives On

While the debate among clinicians continues over combined therapy, online posting and blogs from patients and patient advocates show a continued interest in treatment with desiccated-thyroid extracts, despite their being generally considered obsolete since the introduction of synthetic formulations during the early 1960s.

Containing a combination of T4 and T3, desiccated thyroid, made from porcine thyroid and also referred to as natural desiccated thyroid, is currently available under such brand names as Armour (Forest Laboratories) or Naturethroid (RLC Labs).

Long the first-line treatment for hypothyroidism, the treatment still represents, for some, the ideal combination therapy.

"I suggest Armour to patients because it's economical and it's simple," said Gary Pepper, MD (Palm Beach Diabetes and Endocrinology Specialists, Jupiter, Florida), a strong proponent of the use of desiccated thyroid.

I suggest Armour to patients because it's economical and it's simple.

"One problem with combination therapy [with synthetic T4 and T3] is that people find it to be very hard to take three pills a day, and you only have to take one Armour," he told Medscape Medical News.

"Furthermore, the synthetic T3 is very expensive, so I'm really looking at it from a more practical point of view."

In a study he published this year, Dr Pepper described satisfaction ratings among 154 of his own patients who were still symptomatic while on L-T4 for hypothyroidism and who were switched to Armour (J Endocrinol Diabetes Obes. 2014;2:1055).

After a minimum of 4 weeks on Armour, 78% expressed a preference for Armour compared with L-T4, with no serious adverse events noted, even with 30 of the subjects aged 65 years or older.

Dr Gary Pepper

"The key is, if you pinpoint the subgroup of patients who still have symptoms while taking T4 in your research, you get a more accurate picture of efficacy," Dr Pepper explained.

The only randomized, double-blind trial to compare desiccated thyroid with L-T4 therapy for hypothyroidism, a crossover study published last year, showed that about half of patients preferred the desiccated-thyroid therapy (J Clin Endocrinol Metab. 2013;98:1982-1990).

The study involved 70 patients, aged 18 to 65, who were treated for 16 weeks with either desiccated-thyroid extract or L-T4 and then crossed over for the same duration.

Patients treated with desiccated thyroid had an average weight loss of 3 lb, and there was no difference in thyroid-function blood tests between the two groups after treatment.

In terms of patient satisfaction, 48% of patients expressed preference for the desiccated-thyroid extract over L-T4.

Dr Thanh D Hoang

"It was interesting to find out that nearly half of the study patients preferred desiccated-thyroid extract over L-T4 therapy, and desiccated-thyroid extract caused modest weight loss," lead author Thanh D Hoang, DO (Naval Medical Center, San Diego, California) told Medscape Medical News.

"No study patient experienced significant adverse effects from desiccated-thyroid extract or L-T4; therefore, desiccated-thyroid–extract therapy can be considered for some hypothyroid patients who do not do well with L-T4," he noted.

This study is important in light of the fact that patients clearly are continuing to look for alternative therapies and are turning to desiccated thyroid, and it is not clear whether studies comparing synthetic T4 and synthetic T4/T3 combination "can be extrapolated to desiccated thyroid," he added.

"Therefore, it is imperative to further investigate the effects and efficacy of desiccated thyroid in hypothyroid patients."

ATA Task Force: More Evidence Needed for Desiccated Thyroid

The ATA guidelines acknowledge Dr Hoang's study on desiccated thyroid and have removed a recommendation that products such as Armour "should not be used."

But they still "strongly recommend" levothyroxine over the use of desiccated-thyroid extracts in the routine care of primary hypothyroidism.

"Although there is preliminary evidence from a short-duration study that some patients may prefer treatment using thyroid extracts, high-quality controlled long-term outcome data are lacking to document superiority of this treatment [over] levothyroxine therapy."

And desiccated-thyroid formulations present two key safety concerns, the guidelines assert — the first being that their ratio of T4 to T3 is 4.2 to 1, significantly lower than the 14:1 ratio the human thyroid normally secretes.

"This relative excess of T3 leads to supraphysiologic levels of T3," the guidelines state.

In addition, a shorter half-life of T3 results in peak levels after dosing followed by fluctuations throughout the day, thereby posing a risk for thyrotoxicosis if the therapy isn't adjusted to serum TSH levels.

Dr Pepper, who regularly treats patients with Armour — but underscored that he has no relationship with the makers — responded that the T4:T3 ratio is not as fixed a ratio as the guidelines suggest.

"It's important to remember that the ratio is just an average, and anyone who has done research on this knows that the ratio doesn't apply to everyone," he said. "There are some, particularly patients who don't create T3 as well, who don't fit into those margins, so the argument is extremely weak.

"Furthermore, we are specialists, after all," he added. "You monitor the patient's blood levels and adjust the dose as is appropriate."

The same applies to the risk for thyrotoxicosis, Dr Pepper said.

"Regarding the theory that it could be dangerous — where are the case reports of people getting sick? You will not find a single scientific paper stating any real danger from desiccated thyroid, and as far as I'm concerned, the [medical societies] are scaring people away from this."

"I have patients who are 60 and 70 years old who are taking this medication, and I can tell you they are delighted with it."

ATA President Elect: Thyroid Community Voices Should Be Heard

Whether the topic is desiccated thyroid, combination therapy, or the host of other hypothyroid issues raised by the often-outspoken online thyroid community, the opinions deserve recognition, Dr Bianco stressed.

[Some] patients are very vocal about this, and I can only sympathize with them. They are symptomatic, sometimes depressed, and actively seeking a way to improve quality of life.

"I agree that (some) patients are very vocal about this, and I can only sympathize with them," he said. "They are symptomatic, sometimes depressed, and actively seeking a way to improve quality of life."

"Physicians, professional societies, and pharmaceutical companies should listen and help."

Dr Jonklaas noted that she and coinvestigator Kenneth D Burman, MD, have conducted a study of a T3 product funded by IPE; however, the study was designed only to look at blood levels of T3, and the product was not discussed in the guidelines. Dr Bianco is director of a research laboratory at Rush University Medical Center funded exclusively by the National Institutes of Health and the ATA to study thyroid-hormone metabolism and action. He is on a board of scientific counselors of the National Institute of Diabetes and Digestive and Kidney Diseases and from 2013 to 2014 he was on the scientific board for Fondazione Institut Biochimique for scientific research. Dr Wartofsky is the editor in chief of the Journal of Clinical Endocrinology & Metabolism. He is a consultant for Asurogen, Genzyme, and IBSA and is on the speaker's bureau for Genzyme. Dr Pepper and Dr Hoang report they have no relevant financial relationships.

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