BOSTON — Whether or not to add liothyronine (LT3) to levothyroxine (LT4) for patients with hypothyroidism experiencing residual symptoms with LT4 alone was the subject of a debate between two esteemed thyroid experts at the ENDO 2024: The Endocrine Society Annual Meeting.
A minority of patients with hypothyroidism treated with LT4 experienced persistent symptoms and reduced qualify of life despite normalization of thyroid-stimulating hormone (TSH) levels. Possible explanations include the presence of comorbid conditions with overlapping symptoms — including menopause — the effects of autoimmunity itself, inadequate restoration of thyroid axis physiology, or discordant expectations.
Numerous randomized controlled trials comparing the use of LT3 in combination with LT4 or desiccated thyroid extract vs LT4 alone in the treatment of hypothyroidism have shown no objective differences in alleviating symptoms. However, the combination is generally safe, and patients often say they prefer it to LT4 monotherapy. In the real world, patients may seek out providers who will prescribe LT3 to them.
Recent guidelines from the Joint British Thyroid Association/Society and earlier recommendations from the American Thyroid Association both said that a trial of the combination is acceptable for patients with persistent symptoms but maintained that LT4 monotherapy replacement should remain the standard of care for most patients.
At the Endocrine Society's annual meeting, Antonio C. Bianco, MD, PhD, professor of medicine at The University of Chicago, Illinois, argued in favor of combination LT3+LT4 therapy. On the other side, Simon H. Pearce, MD, professor of endocrinology at Newcastle University, Newcastle Upon Tyne, England, argued against it.
Combination Therapy: Safe and Preferred
Bianco noted that persistent symptoms among a minority of LT4-treated patients can be significant, including cognitive impairment, low energy, mood disturbance, and weight gain. Some of these individuals don't actually have hypothyroidism, or their TSH levels have not been normalized despite the LT4 treatment. However, even beyond those reasons, in some patients, there is incomplete normalization of thyroid hormone signaling so that some patients treated with LT4 have a relative deficiency of T3 and a relative excess of T4.
He pointed to recently published data from the ELSA-Brasil study, for which he was a coauthor. Among 186 adults who initiated LT4 treatment during the 8-year study, initiation was associated with an 11%-19% increase in TSH, an approximate 19% increase in free T4, and a 7% reduction in free T3 levels. Among another 243 who took LT4 continuously over the study period, 47% had at least one serum-free T4 level above the control reference range, and 16% had at least one serum-free T3 level below the reference range, all despite normal TSH levels.
The initiation of treatment with LT4 was associated with an increase in triglyceride levels despite an increase in the use of cholesterol-lowering medications.
"The way we know how to fix this is to give patients a combination of T4 and T3…If you have a patient taking levothyroxine who has normal levels of TSH, what you do is lower the dose of levothyroxine and add a small dose of LT3. TSH must remain in the normal range," Bianco said.
He also reviewed two meta-analyses examining the effect of combination LT4+LT3 vs LT4 monotherapy, both including 18 randomized trials. One was published in 2022 in Clinical Endocrinology and the other in 2021 in Thyroid. Both showed that while there were no overall differences in psychological or physical health, the combination was safe, and patients more often preferred the combination. This was true even in the blinded studies, he noted.
The reason for the overall lack of difference in symptoms, Bianco said, is that most of these studies were done in all comers, not specifically in those who continue to experience symptoms while on LT4 monotherapy with normalized TSH. He was a coauthor of another study, published in 2021 in The Journal of Clinical Endocrinology & Metabolism, in which 75 patients were randomized to LT4 monotherapy, LT4+LT3, or desiccated extract for 22 weeks. While again there was no overall difference in symptoms, those with the highest tertile of symptoms showed improvement on several symptom measures.
"If they had very little symptoms on levothyroxine, the changes to a combination therapy didn't do anything…If they were more symptomatic on levothyroxine, this is when switching to combination therapy really exhibited decreased residual symptoms. If you look at the whole cohort, you wouldn't see that. But if you focus on those symptomatic only on thyroxine, those are the ones that really benefit from combination therapy," Bianco said.
Moreover, preliminary data from a double-blind, randomized, controlled trial of LT4+LT3 vs LT4+placebo in 38 patients who had undergone total thyroidectomy for low-grade thyroid cancer showed that the combination resulted in improved diastolic function without any cardiovascular events.
Long-term safety has also been demonstrated in at least three trials, including one lasting a median 9.3 years, which found no differences in atrial fibrillation, cardiovascular disease, or fractures.
Bianco concluded, "I think we should really pause and give a chance for shared decision-making in the treatment of hypothyroidism. We should listen and if all things are equal, I think this is an opportunity for us to see what the patient is telling us, and if they really prefer combination therapy, we should give it a try."
Are We Sure It's Not a Placebo Effect?
Pearce agreed with Bianco that some patients with hypothyroidism have persistent symptoms on LT4 and that patients taking LT4 have lower serum T3 levels. However, he questioned Bianco's assertions that T3 deficiency is associated with persistent symptoms and that randomized trials show any benefit of combination therapy.
He noted a strong "thyroid bias" in prescribing, particularly given the high rates of obesity, that has led to over-prescribing of LT4 for people who don't actually have overt hypothyroidism, as a 2021 publication showed. The linkage of excess body weight with hypothyroidism "is an unconscious bias…if your patient on levothyroxine comes in saying I don't feel great on levothyroxine, they might not even need it," Pearce said.
Moreover, he pointed to two studies, one published in The New England Journal of Medicine showing no benefit of LT4 in older adults with subclinical hypothyroidism and the other in The Journal of Clinical Endocrinology & Metabolism, finding that small changes in LT4 doses don't significantly change hypothyroid symptoms or quality of life, despite the expected changes in serum TSH.
"So maybe tight TSH control doesn't actually affect how you feel," Pearce commented.
And, in the JCEM study, when the participants who were blinded to the LT4 dose they received were asked to choose which dose they preferred, a third preferred the lowest dose, while the rest were about evenly split among the higher doses or no preference. "I didn't believe the results of this study when I first read it because it was counter to my clinical observations…We think people feel a little bit better with a little more levothyroxine," he said.
But then another study found the same thing. Yet again, there were no differences in symptoms, well-being, or quality of life among patients randomized and blinded to three different LT4 doses with three different TSH target ranges in or near the reference range.
The participants were unable to guess what doses they'd been given. However, when asked what dose they preferred, a majority who guessed their dose had been increased from baseline said they preferred that dose, while nearly all who thought their dose had been decreased said they preferred their original dose.
"People like the idea that more thyroid hormones will be better for them. But there's no objective evidence. So, the clinical practice of fine-tunning the levothyroxine to attempt optimal symptom control is not evidence based…I have to say I still spend time in my clinic doing it, but at least I'm cognizant that it's not evidence based," Pearce said.
And as for adding LT3, there have been 17 randomized controlled trials comparing the combination to LT4 monotherapy, of which just two showed a benefit of the combination. There have also been six meta-analyses showing no benefit except for patient preference.
The preference, Pearce said, is likely because the participants weren't actually masked to their allocated therapy. Evidence for that includes the fact that patients taking LT3 often describe a "hit" followed by a later "drop." In addition, the package label for LT3 in the United Kingdom warns of tachycardia, anxiety, tremor, insomnia, sweating, facial flushing, and other telltale signs. What's more, desiccated thyroid extract has been described as smelling like pork, at least in the United Kingdom.
In another blinded study comparing LT4+LT3 with LT4 monotherapy, there was a 39% improvement in General Health Questionnaire scores at 3 months in the group that had received added placebo rather than LT3, sustained at 1 year. "So patients do prefer LT3 when they're asked, but the placebo effect is strong."
Overall, "There's not one solution for this patient group, but the answer is probably something else for many of these patients," Pearce concluded.
Bianco is a consultant for AbbVie, Acella, Aligos, and Synthonics and received research funding from the National Institute of Diabetes and Digestive and Kidney Diseases. Pearce received speaker fees from Berlin-Chemie, IBSA, and Merck and does consulting for Apitope/Worg and Roivant/Immunovant.
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape Medical News, with other work appearing in the Washington Post, NPR's Shots blog, and Diatribe. She is on X: @MiriamETucker.