Liothyronine Use in Hypothyroidism and its Effects on Cancer and Mortality

Abstract

Background: The prescription of liothyronine (LT3) to treat hypothyroidism is increasing worldwide; however, the long-term safety of LT3 use has yet to be determined. Previous studies have suggested a possible association between LT3 use and breast cancer. The aim of this study was to examine the effects of LT3 use on cancer incidence and mortality. Methods: Our sample included the full adult population of individuals living in Sweden with at least three purchases of thyroid hormone therapy between July 2005 and December 2017. Individual-level data on drug purchases were linked to registry data on cancer incidence and mortality. There were 575,461 individuals with at least three purchases, of which 11,147 had made at least three purchases of LT3, including combinations of levothyroxine (LT4) and LT3. Individuals were followed for a median follow-up time of 8.1 years. We applied Cox regression with a time-varying exposure variable, comparing LT3 users (individuals with at least three cumulative purchases of LT3) with LT4-only users (the rest). Outcomes included breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, and breast cancer mortality. We adjusted for age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose in multivariate analyses. Results: Multivariate analyses produced a hazard ratio of 0.93 (95% confidence interval [0.75-1.15]) for breast cancer incidence (only females), 0.97 (0.87-1.08) for any cancer incidence, 0.69 (0.61-0.77) for all-cause mortality, 0.78 (0.62-0.98) for any cancer mortality, and 0.91 (0.50-1.66) for breast cancer mortality (only females). Conclusions: In this large, Swedish, long-term registry-based study, the use of LT3 did not lead to increased breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality compared with LT4 use. Somewhat surprisingly, there was evidence of lower mortality in LT3 users in models adjusting for dose, potentially an artifact of underlying associations between dose and health status/diagnosis.

Use of Thyroid Hormones in Hypothyroid and Euthyroid Patients: A 2020 THESIS Questionnaire Survey of Members of the Swedish Endocrine Society

“…Well-designed randomized clinical trials in patients with persistent symptoms after exclusion of comorbidities are required to address this issue. Although our recent large register-based study ( 21 ) provided reassuring evidence regarding the risk of cancer and mortality in L-T3 treated Swedish patients, there could still be other health risks associated with long-term L-T3 therapy warranting randomized trials examining the safety of the combined treatment. Moreover, the cost-effectiveness of the combined treatment also remains an issue, as it is more expensive than L-T4 treatment alone ( 47 ) and usually requires more frequent monitoring.…”

“…To date, a number of randomized controlled trials have studied the effect of combined L-T4+L-T3 and five systemic reviews/meta-analyses have concluded that the combined treatment is not superior to standard L-T4 treatment with respect to hypothyroid symptoms and quality of life (15)(16)(17)(18) or patient preference (19). Data on long-term safety are limited (20,21). Therefore, European guidelines restrict the recommendation of L-T3 to that of experimental treatment (2).…”

T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity

“…Observational studies lasting 9 to 17 years found no increased risk of cardiovascular disease, atrial fibrillation, or fractures in patients using T3 compared to patients using T4 [ 87 , 88 ]. The use of LT3 did not lead to increased breast cancer or any cancer incidence and mortality compared with LT4 use [ 89 ]. There was only an increased incident use of antipsychotic medication during follow-up in T3 users [ 87 ].…”

Liothyronine use in primary hypothyroidism — current concepts

“…In a long-term cohort study conducted in Sweden, the use of LT3 did not lead to an increase in the incidence of breast cancer, the incidence of any cancer, and all-cause mortality compared to the use of LT4. Surprisingly, there was evidence of lower mortality in LT3 users after dose adjustment, which was potentially attributed to an artifact of the underlying associations between dose and patient diagnosis [37].…”