Debate Continues on Combination Therapy for Hypothyroidism

It's "critically important" for clinicians to recognize that not all patients with hypothyroidism are fully treated with levothyroxine (LT4) and some may need combination treatment with triiodothyronine (LT3) despite normal levels of thyroid stimulating hormone (TSH), according to thyroid expert Antonio C. Bianco, MD, PhD.

Speaking to a crowded room at the recent American Association of Clinical Endocrinology (AACE) Annual Meeting 2022, Bianco summarized the history of thyroid replacement treatment, the emerging data focusing on the subset of patients remaining symptomatic on levothyroxine, and how the clinical guidelines have evolved from stating that LT4 is the one and only treatment to now acknowledging that some patients may need combination therapy.

"Treatment with LT4 will leave residual symptoms in about 10%-20% of the patients. Before planning a thyroid surgery, this issue should be discussed with patients. We used to tell patients that LT4 treatment resolves all symptoms, but this is not true for all. For those...who remain symptomatic while on LT4, physicians should attempt combination therapy," Bianco told Medscape Medical News.

The acknowledgement, he said, is "critically important because patients are greatly aggravated by the fact that physicians are satisfied with a normal serum TSH and yet they do not feel well. This comes out in every survey we and others have done." Common residual symptoms include weight gain, fatigue, and "brain fog," which clinicians sometimes dismiss as psychological, he noted.

However, Bianco cautioned that before attempting combination therapy, it's important to make sure that patients don't have other comorbidities that could explain the residual symptoms, including perimenopause/menopause, obesity, vitamin B deficiency, anemia, or other autoimmune diseases.

Bianco is professor of medicine at the University of Chicago and author of more than 80 publications on the thyroid as well as an upcoming book.

Doctors Follow Guidelines...

Asked for comment, session moderator Alex Tessnow, MD, of the University of Texas Southwestern Medical Center, Southlake, told Medscape Medical News: "I agree with him entirely. I think the biggest challenge we have now is lack of data. It's amazing how common hypothyroidism is. Almost 20% of women over age 65 have an elevated TSH."

"Levothyroxine is the number one prescribed drug in the country. And of all those trials, only three have more than one hundred patients in them. That's how unstudied this topic is. We really need to know more."

Among the reasons the topic remains controversial, Tessnow said, are that "for years the guidelines said levothyroxine is the first choice. Doctors don't want to deviate from the guidelines."

And he noted that some doctors "may be fearful of LT3 being so potent and short-acting and potentially causing cardiac arrhythmias."

"Levothyroxine is so long-acting it's easy to give. Often patients have to take LT3 more than once a day on an empty stomach. There's no combination pill as of now."

Bianco noted that two investigational slow-release LT3 molecules are currently in the pipeline and could alleviate some of these concerns.

Trials Should Focus on Those Not Doing Well on Levothyroxine Alone

Tessnow and Bianco both noted that most of the studies that have failed to show a benefit of combination LT4+LT3 treatment have included overall populations with hypothyroidism rather than focusing just on those who remain asymptomatic with LT4.

"It is possible that those individuals most likely to benefit from combination therapy may not yet have been included in trials in sufficient numbers in order to provide adequate power for detecting a response," Bianco said.

Tessnow agreed: "The sheer number of people who are doing fine on levothyroxine are going to cover up the potential benefit the combination would give those who are most symptomatic. We need to focus our studies on those patients".

In fact, this research gap was among the conclusions from an expert consensus statement published in March 2021, following a joint conference of the American Thyroid Association (ATA), the British Thyroid Association (BTA), and the European Thyroid Association (ETA). Bianco was one of the statement's authors.

This "acknowledges that the previous clinical trials were not adequately designed," says Bianco, adding, "there is a need for new clinical trials."

Many Patient Reports Document Dissatisfaction With LT4 Treatment

Numerous patient-generated publications have documented residual symptoms with LT4 treatment alone, including higher levels of symptoms on questionnaires, deficits in neurocognitive functioning, impact on psychological well-being, and "brain fog," as reported by Medscape Medical News and published in December 2021, and notably, a study from Bianco's group in 2018, which found "prominent dissatisfaction" with their treatment and their physicians.

"Some changed physicians five to ten times. We concluded there was a significant burden of unsuccessfully resolved symptoms among patients with hypothyroidism," Bianco said during his talk.

"Some say patient preference isn't a clinical outcome, but we have to consider it...To not listen to the patient in what they prefer is unfair and just gives them more reason to be mad at us," he added.

History and Physiology: Why LT4 Is Used But May Not Be Enough for Some

Treatment of hypothyroidism using implantation of a sheep's entire thyroid gland was first described in 1890, followed by subcutaneous injections of sheep's thyroid extract. A short time later, thyroid extract by mouth was introduced. In 1965, a study demonstrated efficacy of a 3.5:1 mixture of synthetic LT4 and LT3.

The shift to LT4 monotherapy happened in 1970, with a study published in the Journal of Clinical Investigation showing that T4 was converted to T3 in humans, "which all interpreted as 'no need to use thyroid extract,' then LT4 became the standard of care," Bianco said.

He then explained the physiologic basis for why some patients may not fare well with LT4 alone.

TSH in the normal range doesn't mean T3 and T4 are normal. "The thyroid is hard-wired to preserve serum T3," he said.

But once the patient develops hypothyroidism, the thyroid no longer responds to TSH, and serum T3 is only maintained via conversion of T4 to T3. Although LT4 is used to normalize serum TSH levels, that occurs before serum T3 is normalized, resulting in lower serum T3 levels and relatively higher serum T4 levels.

The lower T3 level with normal serum TSH explains the residual symptoms, Bianco explained.

"Thus, by adding small amounts of LT3 to the regimen with LT4 we can normalize serum TSH but with normal serum T4 and T3 levels," he said.

So why do most patients report feeling fine with LT4 alone? "We do not have the answer to this question. Multiple factors could explain it, including genetics," he told Medscape Medical News.

How Can Combination Therapy Be Given Safely?

The 2012 guidance from the ETA provided specific information for how combination therapy should be prescribed by reducing LT4 and replacing a small amount with LT3 in order to keep TSH within normal range.

For example, if the patient is taking 100 µg/day of LT4, drop that to 87.5 µg/day and add 5 µg/day of LT3. Similarly, 200 µg/day of LT4 should be dropped to 175 µg/day and 10 µg/day of LT3 added.

Patients should undergo enhanced follow-up, with measurement of serum T3 at baseline and 3 hours after LT3.

This approach should be avoided in patients with cardiac conditions or concomitant use of other medications that could potentiate the effects.

Indeed, while there has been concern about cardiac effects of LT3, trials following nearly 1000 patients for as long as 1 year have shown that the addition of LT3 only minimally affects serum TSH, heart rate, or blood pressure. Bone turnover markers remained within normal range in two studies.

Another large study published in 2016 also showed no long-term effects of LT3 on cardiovascular disease outcomes or fractures, although there was increased use of antipsychotic medications.

"Given the new safety data, physicians could be more liberal with this form of therapy as they treat patients with residual symptoms," he concluded.

Bianco has reported receiving consulting fees from Abbott/AbbVie, Allergan, Synthonic. Tessnow has reported receiving consulting fees from Horizon.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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