Physiologic Effects of Levothyroxine and Liothyronine in the in Older Individuals With Persistent Subclinical Hypothyroidism: A Randomized, Double-Blind, Cross-Over Study

Background: Subclinical hypothyroidism is common in older individuals, but the physiologic responses to treatment with levothyroxine (LT4) and liothyronine (LT3) are not well defined in this age group. Methods: We conducted a randomized, double-blind, cross-over study of LT4 and LT3 treatment in men and women aged 70 years and over without anti-thyroid peroxidase antibodies with persistent subclinical hypothyroidism, defined as having a TSH level between 4.5 and 19.9 µIU/mL with a normal free thyroxine (FT4) level at two consecutive time points. Physiologic outcome measures assessed after achieving a TSH level of 0.5-1.5 µIU/mL with each therapy included vital signs, weight and body composition, bone mineral content and bone density, lipids, resting energy expenditure (REE), cognitive function, quality of life, and thyroid symptoms. Results: Thirteen participants [mean (SD) age 77 (5) years], 4 women and 9 men, completed the study. Baseline mean TSH was 4.84 (1.29) µIU/mL. The mean LT4 dose was 105 (36) µg/day [1.4 (0.5) µg/kg/day] and LT4 dose was 34 (9) µg/day [0.4 (0.1) µg/kg/day]. Mean time on LT4 was 200 days and on LT3 was 231 days, with a 28 day washout period. Compared with baseline, participants had an average weight loss of 1.1 kg on LT4 (p<0.02) and 2.5 kg on LT3 (p<0.001), which was significantly different between the two treatments (p=0.01). Fat mass decreased by an average of 0.7 kg on LT4 (p=0.03 vs. baseline) and 1.5 kg on LT3 (p<0.01 vs. baseline) and differed between treatments (p=0.01). There was a significant difference in total cholesterol of 13.3 mg/dL (p<0.001) and in low-density lipoprotein cholesterol (LDL) of 10.8 mg/dL (p<0.001) between LT4 and LT3 treatment arms; for both, the levels were lower on LT3 than LT4. No differences were seen in the other assessed outcomes. Conclusions: In a cross-over study of treatment of LT4 or LT3 in persistent subclinical hypothyroidism, participants lost fat mass and weight after each treatment, with a greater decrease after treatment with LT3. These findings support different physiologic responses to LT4 compared with LT3.