Clinical trial NCT00106119: Thyroid and Glucose and Energy Metabolism
Official title: Peripheral Thyroid Hormone Conversion and Glucose and Energy Metabolism
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Thyroid Diseases
Keywords: Levothyroxine
Liothyronine
Lipid Metabolism
Gluconeogensis
Thyrotropin Releasing Hormone
Deiodinase
Replacement Thyroid Hormone Therapy
Thyroidectomy
Near Total Thyroidectomy
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2005-03-21
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER

Brief summary: This study will examine how two thyroid preparations-levothyroxine (T4) and liothyronine (T3)-affect fat and cholesterol metabolism, blood sugar regulation, and thyrotropin secretion in patients who have had their thyroid gland removed. Results of the study may help in the development of better therapies to optimize blood sugar and cholesterol levels in some patients.

Patients 18 years of age or older who have had most or all of their thyroid gland removed and are taking long-term thyroid hormone medication may be eligible for this study after screening.

Detailed description: Thyroid hormone action plays an important role in the regulation of many physiologic processes, among them glucose and lipid metabolism. Interestingly, the clinical presentation of thyroid dysfunction is extremely variable, with relatively poor correlation between circulating hormone levels and clinical features. This finding suggests that the local, intracellular concentration of the active hormone liothyronine (T3), regulated by peripheral conversion of the pro-hormone levothyroxine (T4), is an important determinant in the maintenance of the thyroidal homeostasis.

The aim of the present study is the evaluation of the role of peripheral thyroid hormone conversion in the regulation of glucose and lipid metabolism by assessing the differential response to T4 or T3 treatment in subjects devoid of endogenous thyroid hormone production. T3 administration bypasses peripheral metabolism and therefore will allow us to assess the role of the peripheral thyroid hormone conversion in the regulation of the hormone action at the end-organ level.

Fifty hypothyroid subjects will be initially randomized to either of the thyroid hormone replacements liothyronine (T3) or levothyroxine (T4) treatment period (one arm cross-over design, with treatment sequence randomized), aimed to maintain serum TSH levels greater than or equal to 0.5 less than or equal to 1.5 mU/L, indicating full replacement. After a 30-day period of steady-state replacement the study subjects will be admitted to the Clinical Center and, after a three-day period of stabilization and an overnight fast, will undergo the following tests: escalating dose TRH stimulation test, indirect calorimetry, graded exercise tolerance test, DEXA scan, and echocardiogram.

Patients will also undergo skeletal muscle biopsy and subcutaneous adipose tissue biopsy and microdialysis, as well as a two-step euglycemic hyperinsulinemic clamp with measurement of splanchnic gluconeogenesis. Fasting venous blood samples will be collected for the determination of the parameters of lipid, glucose and energy metabolism.

After discharge, the patients will switch to the other form of thyroid hormone replacement therapy (second period) . The therapy will be adjusted in order to achieve the same therapeutic goal for TSH concentrations (greater than or equal to 0.5 less than or equal to 1.5 mU/L), analogous to that achieved during the first phase of the study (TSH less than or equal to 0.5 mU/L difference between T3 and T4 phases). After reaching a 30-day period of steady-state replacement, study subjects will be re-admitted to the Clinical Center and the previously described evaluation procedures will be repeated.

Eligibility criteria: * INCLUSION CRITERIA:

Age greater than or equal to 18 years, male or female.

History of total or near total thyroidectomy or hypothyroidism on replacement therapy.

For non-thyroidectomized patients, at least three-year history of replacement therapy (at least 1.2 mcg/Kg LT4/body weight), and less than 5% uptake at 24H on (123)I thyroid scan while on replacement therapy.

Written informed consent.

EXCLUSION CRITERIA:

BMI less than or equal to 20 or greater than or equal to 30 kg/m(2).

Metastatic thyroid cancer or history of thyroid cancer with high risk of recurrence requiring suppressive thyroid hormone therapy (Singer 1996).

Significant thyroid residual greater than 1 mL as measured by ultrasound (limited to thyroidectomized patients) or greater than 5 percent uptake at 24H on (123)I thyroid scan while on replacement therapy (limited to hypothyroid patients not undergone total thyroidectomy).

History or symptoms compatible with cardiovascular disease, including paroxysmal supraventricular tachycardia, atrial fibrillation, syncopal episodes or use of prescription medications for heart conditions, including antihypertensives.

Allergy to lidocaine, isoproterenol, TRH, levothyroxine, liothyronine, Tylenol #3, oxycodone, nitroglycerin.

Pregnancy or unwillingness to use non-hormonal contraception during the study.

Breastfeeding

Use of hormonal contraceptives or estrogen replacement therapy.

Use of tobacco (smoking, chewing) for the two weeks preceding the hospital admissions (metabolic testing)

Diabetes mellitus, either type I or II.

Hypercholesterolemia (serum levels greater than or equal to 240 mg/dL), hypertriglyceridemia (plasma levels greater than or equal to 220 mg/dL) and/or use of antilipemic therapy.

Liver disease or ALT serum level greater than two fold the upper laboratory reference limit.

Renal insufficiency or estimated creatinine clearance less than or equal to 50 mL/min.

Use of medications/supplements/alternative therapies known to alter thyroid function.

Current history or symptoms compatible with psychosis including major depression (including history of hospitalization for depression, history of attempted suicide, history of suicidal ideation).

Use of antipsychotic medications

History of drug or alcohol abuse within the last 5 years; current use of drugs or alcohol (CAGE greater than 3).

Keloid formation (relative to skeletal muscle and subcutaneous adipose tissue biopsies).

Current or previous clinically significant (requiring medical/surgical intervention) extrathyroidal manifestations of autoimmune thyroid disease (dermopathy, ophthalmopathy, arthropathy).

Primary outcomes:
measure: Insulin-mediated Glucose Disposal Rate at Levothyroxine Treatment Phase
timeFrame: One month of therapy.
measure: Insulin-mediated Glucose Disposal Rate at Liothyronine Treatment Phase
timeFrame: One month of therapy
Secondary outcomes:
measure: Total Cholesterol at Levothyroxine Treatment Phase
timeFrame: One month of therapy.
measure: Total Cholesterol at Liothyronine Treatment Phase
timeFrame: One month of therapy.
measure: Triglycerides at Levothyroxine Treatment Phase
timeFrame: One month of therapy.
measure: Triglycerides at Liothyronine Treatment Phase
timeFrame: One month of therapy.
measure: Resting Energy Expenditure at Levothyroxine Treatment Phase
timeFrame: One month of therapy.
measure: Resting Energy Expenditure at Liothyronine Treatment Phase
timeFrame: One month of therapy.
measure: Left Ventricle Mass Index at Levothyroxine Treatment Phase
timeFrame: One month of therapy.
measure: Left Ventricle Mass Index at Liothyronine Treatment Phase
timeFrame: One month of therapy.
measure: Apolipoprotein A-I at Levothyroxine Treatment Phase
timeFrame: One month of therapy.
measure: Apolipoprotein A-I at Liothyronine Treatment Phase
timeFrame: One month of therapy.
measure: Apolipoprotein B at Levothyroxine Treatment Phase
timeFrame: One month of therapy.
measure: Apolipoprotein B at Liothyronine Treatment Phase
timeFrame: One month of therapy.
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Kong Y Chen, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Bakker SJ, ter Maaten JC, Popp-Snijders C, Slaets JP, Heine RJ, Gans RO. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab. 2001 Mar;86(3):1206-11. doi: 10.1210/jcem.86.3.7324.
citation: Bartha T, Kim SW, Salvatore D, Gereben B, Tu HM, Harney JW, Rudas P, Larsen PR. Characterization of the 5'-flanking and 5'-untranslated regions of the cyclic adenosine 3',5'-monophosphate-responsive human type 2 iodothyronine deiodinase gene. Endocrinology. 2000 Jan;141(1):229-37. doi: 10.1210/endo.141.1.7282.
citation: Yavuz S, Linderman JD, Smith S, Zhao X, Pucino F, Celi FS. The dynamic pituitary response to escalating-dose TRH stimulation test in hypothyroid patients treated with liothyronine or levothyroxine replacement therapy. J Clin Endocrinol Metab. 2013 May;98(5):E862-6. doi: 10.1210/jc.2012-4196. Epub 2013 Apr 12.
citation: Celi FS, Zemskova M, Linderman JD, Smith S, Drinkard B, Sachdev V, Skarulis MC, Kozlosky M, Csako G, Costello R, Pucino F. Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine. J Clin Endocrinol Metab. 2011 Nov;96(11):3466-74. doi: 10.1210/jc.2011-1329. Epub 2011 Aug 24.
citation: Celi FS, Zemskova M, Linderman JD, Babar NI, Skarulis MC, Csako G, Wesley R, Costello R, Penzak SR, Pucino F. The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross-over study in thyroidectomized patients. Clin Endocrinol (Oxf). 2010 May;72(5):709-15. doi: 10.1111/j.1365-2265.2009.03700.x.