UKMi Q&A xx - SPS



What clinical evidence is there to support the use of desiccated thyroid extract products?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

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Date prepared: November 2018

Background

The aim of treatment for hypothyroidism is to render the patient ‘euthyroid’, or with a normal thyroid state. (1) The Royal College of Physicians (RCP), the British Thyroid Association (BTA) and the European Thyroid Association (ETA) recommend that synthetic levothyroxine (tetra-iodothyronine, or T4) monotherapy is the standard treatment for hypothyroidism, due to the robust evidence supporting its use. (1-3)

Levothyroxine has a long half-life (1 week), giving relatively stable blood levels with minimal daily fluctuations in T4 (4). It is converted into liothyronine (T3) in the body and so a preparation of levothyroxine should provide T3 in an appropriate concentration. (4). Liothyronine has a quicker onset (a few hours) and shorter duration of action (half-life is about 24 hours) than levothyroxine. (2;5-8)

Desiccated thyroid extracts (DTE), such as Armour® Thyroid, NP Thyroid® and Nature-Throid®, are natural preparations derived from porcine (pig) thyroid glands. One grain of thyroid contains 38 micrograms (mcg) levothyroxine and 9mcg liothyronine per 65mg of the labelled amount of thyroid (5-7), but this can be variable between batches. (3) Pigs have 2-3 times more T3 (relative to T4) than humans so a consistent effect cannot be guaranteed with DTE products. (9)

DTE products are not licensed in the UK and can cost the NHS twenty times more than a prescription of levothyroxine with no obvious benefit. (9) While they are available in the US, (5-7) they have not been approved by the US FDA as licensed drugs and have therefore not undergone rigorous clinical trials evaluating safety and efficacy.

The RCP, the BTA and the ETA all state routine use of natural thyroid extracts is not generally recommended as they are inconsistent with normal physiology, have not been unequivocally proven to be of any benefit to patients and may be harmful in the long term. There is some concern that symptoms of hyperthyroidism can occur with high T3 levels post-dose, due to the shorter half-life of natural thyroid extracts. Furthermore, as the dose cannot be adjusted easily in the combination product, patients are likely to be receiving higher doses, particularly of T3, leading to a risk of osteoporosis and arrhythmia, in addition to unknown risks from long term use. (1-3;9)

A recently published NHS England document ’Items which should not be routinely prescribed in primary care’ advises against the use of liothyronine (including Armour® Thyroid) except under exceptional circumstances when levothyroxine has failed and use is supported by a consultant NHS endocrinologist. (10) Subsequently the Regional Medicines Optimisation Committee (RMOC) published guidance which advised against the use of combination products containing DTE (e.g. Armour® Thyroid) and gave further guidance to prescribers around exceptional circumstances, criteria and responsibilities for liothyronine prescribing. (11)

This Q&A summarises the published clinical evidence for DTE products.

Answer

Few robust studies of desiccated thyroid have been carried out in the last 10 years. Most data are pre-1980 and many studies date from the 1950s to 1970s. These tend to be uncontrolled, open-label studies which compared desiccated thyroid with levothyroxine, not in terms of efficacy and safety but comparative potency, onset and duration of action, and effects on serum lipids; these have not been included in this Q&A. (12-15) It is not clear whether studies comparing levothyroxine alone with levothyroxine/T3 combination can be extrapolated to desiccated thyroid. These studies have not been reviewed because they do not provide information supporting the clinical effectiveness of natural DTE.

Randomised, double-blind trial

There is only one randomised, prospective, double-blind study comparing the effectiveness of DTE with levothyroxine (n=70). (16) Patients with primary hypothyroidism on a stable dose of levothyroxine were randomised to treatment with either DTE or levothyroxine in identical appearing capsules. Each grain (65mg) of DTE (as Armour® Thyroid) provided 38mcg levothyroxine and 9mcg liothyronine. The initial desiccated thyroid dose was based on the conversion: 1mg DTE = 1.667mcg levothyroxine. After 6 weeks of study medication, thyroid stimulating hormone (TSH) levels were checked and medication adjusted to maintain TSH between 0.5 and 3.0microIU/mL. Once the TSH was within range, medication was continued for at least another 12 weeks. Patients were then crossed over to the other treatment arm for 16 weeks, with TSH checked at 6 weeks as during the first treatment period.

The primary outcome measures were the changes from baseline to endpoint of a number of assessments, including the Thyroid Symptom Questionnaire (TSQ), the quality of life General Health Questionnaire (GHQ)-12, the Wechsler memory scale (WMS-IV) and the Beck Depression Inventory (BDI). The WMS-IV included the auditory memory index (AMI) and the visual working memory index (VWMI). Subgroup analyses were carried out on patients who preferred desiccated thyroid or levothyroxine or who had no preference. A sample size of 67 was required to provide 80% power to detect a difference of 8 points on the TSQ.

a) Primary outcome measures. Overall, the patients showed no difference in symptom scores, general health questionnaires or neuropsychological testing. During the DTE treatment period, there was a trend towards greater improvements in GHQ-12, TSQ and AMI and there was a reduction of 2.86lb in weight (p ................
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