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Combined Therapy with Levothyroxine and Liothyronine in Two Ratios, Compared with Levothyroxine Monotherapy in Primary Hypothyroidism: a Double-Blind, Randomized, Controlled Clinical Trial

Departments of Endocrinology and Metabolism (B.C.A., E.F., W.M.W.), Psychiatry (E.M.W., A.H.S., J.H.), Cardiology (J.G.P.T.), Clinical Chemistry (E.E.), and General Practice (H.C.P.M.v.W.), Academic Medical Centre, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Bente C. Appelhof, M.D., Academic Medical Center of the University of Amsterdam, Department of Endocrinology and Metabolism, F5-161, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: b.c.appelhof{at}amc.uva.nl.

Controversy remains about the value of combined treatment with levothyroxine (LT₄) and liothyronine (LT₃), compared with LT₄ alone in primary hypothyroidism. We compared combined treatment with LT₄ and LT₃ in a ratio of 5:1 or 10:1 with LT₄ monotherapy. We conducted a double-blind, randomized, controlled trial in 141 patients (18–70 yr old) with primary autoimmune hypothyroidism, recruited via general practitioners. Inclusion criteria included: LT₄ treatment for 6 months or more, a stable dose for 6 wk or more, and serum TSH levels between 0.11 and 4.0 µU/ml (mU/liter). Randomization groups were: 1) continuation of LT₄ (n = 48); 2) LT₄/LT₃, ratio 10:1 (n = 46); and 3) LT₄/LT₃, ratio 5:1 (n = 47). Subjective preference of study medication after 15 wk, compared with usual LT₄, was the primary outcome measure. Secondary outcomes included scores on questionnaires on mood, fatigue, psychological symptoms, and a substantial set of neurocognitive tests. Study medication was preferred to usual treatment by 29.2, 41.3, and 52.2% in the LT₄, 10:1 ratio, and 5:1 ratio groups, respectively (² test for trend, P = 0.024). This linear trend was not substantiated by results on any of the secondary outcome measures: scores on questionnaires and neurocognitive tests consistently ameliorated, but the amelioration was not different among the treatment groups. Median end point serum TSH was 0.64 µU/ml (mU/liter), 0.35 µU/ml (mU/liter), and 0.07 µU/ml (mU/liter), respectively [ANOVA on ln(TSH) for linear trend, P < 0.01]. Mean body weight change was +0.1, –0.5, and –1.7 kg, respectively (ANOVA for trend, P = 0.01). Decrease in weight, but not decrease in serum TSH was correlated with increased satisfaction with study medication. Of the patients who preferred combined LT₄/LT₃ therapy, 44% had serum TSH less than 0.11 µU/ml (mU/liter). Patients preferred combined LT₄/LT₃ therapy to usual LT₄ therapy, but changes in mood, fatigue, well-being, and neurocognitive functions could not satisfactorily explain why the primary outcome was in favor of LT₄/LT₃ combination therapy. Decrease in body weight was associated with satisfaction with study medication.

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