Patients prefer combined therapy for hypothyroidism, but data reveal few added benefits
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Key takeaways:
- More than half of adults with hypothyroidism say they prefer combined liothyronine and levothyroxine therapy.
- Most studies find no difference in outcomes between combination therapy and levothyroxine alone.
BOSTON — Most adults with hypothyroidism prefer combination therapy with liothyronine plus levothyroxine over levothyroxine alone, but most trials find combination therapy provides limited added benefit, according to two speakers.
During a debate at ENDO 2024, Antonio C. Bianco, MD, PhD, professor of medicine in the section of adult and pediatric endocrinology, diabetes and metabolism at the University of Chicago, said many adults with hypothyroidism may be able to resolve their symptoms with levothyroxine monotherapy, but combination therapy may be necessary for adults with clinically relevant residual symptoms.
“All of the major guidelines have [changed] over the last 10 years,” Bianco said during the debate. “They all accept that we should start patients with levothyroxine. If the patient does not fully benefit from that treatment, a trial with combination therapy should be done.”
In contrast, Simon H. Pearce, MD, FRCP, professor of endocrinology at Newcastle University in the U.K., said data from numerous randomized controlled trials have found no difference in clinical outcomes between adults receiving combination therapy and those receiving levothyroxine monotherapy, and a placebo effect may be leading adults to prefer combination therapy.
Patients prefer combination therapy
Levothyroxine typically resolves hypothyroidism symptoms for most adults, but some continue to report cognitive impairment, low energy level, poor quality of life, mood issues and difficulty maintaining body weight, according to Bianco. There may be several causes for residual symptoms, but levothyroxine alone may not be able to normalize thyroid hormone signaling. Signaling may be fixed with combination therapy, Bianco said.
Data from 12 randomized controlled trials with about 1,900 participants found combination therapy with liothyronine and levothyroxine was associated with similar normalization of thyroid-stimulating hormone and resolution of patient-reported symptoms as levothyroxine alone. There was also no difference in safety outcomes between the two therapies.
In nine randomized controlled trials with about 660 adults with hypothyroidism, participants were asked which therapy they preferred. Of the respondents, 52% said they preferred combination therapy with liothyronine and levothyroxine, whereas 24% preferred levothyroxine monotherapy and 24% had no preference.
Since both therapies have similar efficacy, providers should take a patient’s preference into account when making treatment decisions, Bianco said.
“You don’t want to give levothyroxine to patients that prefer combination therapy,” Bianco said. “In the same way, you don’t want to give combination therapy to patients that prefer levothyroxine. You want to listen to the patient; you want to give what they are preferring if both treatments are indeed similar.”
One trial found more benefits with combination therapy compared with levothyroxine monotherapy. In a randomized double-blind crossover trial published in The Journal of Clinical Endocrinology & Metabolism in 2021, adults experienced fewer high-intensity symptoms with combination therapy compared with levothyroxine.
Bianco said providers should use shared decision-making and consider combination therapy for some adults with hypothyroidism.
“It’s important that we learn from the vast data that’s published that treatment with combination therapy is effective, is safe, and patients prefer the treatment,” Bianco said.
Limited data on benefits
Pearce questioned how many adults needed any sort of levothyroxine therapy, let alone combination therapy. A study published in JAMA Internal Medicine in 2021 found 28% of U.S. adults receiving levothyroxine in 2018 had normal thyroid function when they began treatment. Pearce attributed some of this number to unconscious bias from providers who may attribute symptoms, such as fatigue, to hypothyroidism.
“Among most non-endocrinology health care professionals and lots of the public, [unconscious bias] is absolutely huge,” Pearce said.
Another misconception, according to Pearce, is the belief that prescribing more thyroid hormone will make a person feel better. A double-blind study published in The Journal of Clinical Endocrinology & Metabolism in 2018 assessed changes in quality of life, mood and cognition for adults on long-term levothyroxine therapy who received changes in dose. The study found no difference in thyroid disease symptoms or quality of life between dose amounts. Additionally, adults could not distinguish how much levothyroxine they were taking.
“Fine-tuning levothyroxine to attempt optimal symptom control is not evidence-based,” Pearce said. “Also, contrary to the popular narrative, more thyroid hormone does not make you feel better.”
Combination therapy with liothyronine and levothyroxine was not associated with any difference in clinical outcomes compared with levothyroxine alone in the majority of 17 randomized controlled trials conducted from 1999 to 2024. Among four trials with more than 100 participants, there were no differences in outcomes between adults receiving combination therapy and those receiving levothyroxine.
Pearce acknowledged some studies show patients prefer combination therapy; however, he said, taking thyroid hormones could lead to a placebo effect. A study published in The Journal of Clinical Endocrinology & Metabolism found adults receiving levothyroxine alone had similar quality of life and thyroid symptom improvements as adults receiving combination therapy. Another study published in Thyroid in 2018 examined patient satisfaction for adults receiving combination therapy compared with levothyroxine alone. There was no difference in satisfaction regarding weight, fatigue, mood or memory between the two groups.
References:
Brito JP, et al. JAMA Intern Med. 2021;doi:10.1001/jamainternmed.2021.2686.
Peterson SJ, et al. Thyroid. 2018;doi:10.1089/thy.2017.0681.
Samuels MH, et al. J Clin Endocrinol Metab. 2018;doi:10.1210/jc.2018-01203.
Saravanan P, et al. J Clin Endocrinol Metab. 2005;doi:10.1210/jc.2004-1672.
Shakir MKM, et al. J Clin Endocrinol Metab. 2021;doi:10.1210/clinem/dgab478.
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Bianco A, et al. D01. Presented at: ENDO annual meeting; June 1-4, 2024; Boston.
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