For Thyroid, Right Medication at the Right Time Makes a Difference

Abstract & Commentary

By Rahul Gupta, MD, MPH, FACP, Clinical Assistant Professor, West Virginia University School of Medicine, Charleston, WV. Dr. Gupta reports no financial relationship to this field of study.

Synopsis: Clinicians should consider prescribing levothyroxine at bedtime since this study demonstrates significantly improved thyroid hormone levels compared to morning intake.

Source: Bolk N, et al. Effects of evening vs morning levothyroxine intake: A randomized double-blind crossover trial. Arch Intern Med 2010;170:1996-2003.

Levothyroxine remains one of the most commonly prescribed medications for a common disease, primary hypothyroidism. This treatment is administered with the aim of restoring clinical euthyroidism and maintaining normal serum levels of thyroid-stimulating hormone (TSH). While there exist other choices for treatment, levothyroxine monotherapy at an appropriate daily dose provides uniform levels of both thyroxine and triiodothyronine in the circulation without diurnal variation and, therefore, is the medication of choice in most patients with hypothyroidism.

Since about 70%-80% of the drug is absorbed, mostly in the small bowel, there is consensus that levothyroxine should be taken in the morning before breakfast to prevent interference in its intestinal absorption.1 Interference with levothyroxine absorption has been documented for several drugs including raloxifene, antacids, cholestyramine resin, colestipol hydrochloride, sucralfate, iron sulfate, activated charcoal, foods, and herbal remedies.2-4 Therefore, the drug manufacturers' prescribing information directs patients to take levothyroxine once daily on an empty stomach, 30 minutes to 1 hour before breakfast. However, it has not been adequately and systematically studied whether intestinal absorption is better when the stomach is empty in the morning or at night. Since many patients are regularly prescribed multiple medications, it would make more sense to know which method of dosing would be more effective clinically.

Bolk et al conducted a randomized double-blind crossover trial among 105 consecutive patients with primary hypothyroidism visiting a Dutch hospital clinic between April 1, 2007, and Nov. 30, 2008. Patients who were pregnant or had a gastrointestinal tract disorder or thyroid cancer were excluded from the study. Patients were instructed during 6 months to take 1 capsule in the morning and 1 capsule at bedtime (one containing levothyroxine and the other a placebo), with a switch after 3 months. Patients were instructed to take the morning capsule on an empty stomach half an hour before breakfast and the bedtime capsule at night just before going to bed. Plasma thyrotropin, FT4, T3, creatinine, and lipid levels were monitored as well as blood pressure, heart rate, body weight, and quality-of-life variables.

Of the 90 patients who completed the trial and were available for analysis, the authors found that compared with morning intake, when levothyroxine was taken at bedtime, it significantly improved thyroid hormone levels. However, quality-of-life variables and plasma lipid levels showed no significant changes with levothyroxine intake at bedtime vs in the morning. Interestingly enough, after the study was completed, and the patients were given a choice, more than half of the patients decided to continue with bedtime intake of levothyroxine. The authors state that the conditions of chronic illness and obesity may be more to blame for the lack of thyroid hormone level changes translating into quality-of-life changes. Additionally, there may be other factors affecting quality-of-life in patients with hypothyroidism such as the newly discovered thyroid hormone metabolite thyronamine (not replaced by levothyroxine treatment) or the presence of an autoimmune disorder (such as Hashimoto's disease).

Commentary

Comparative effectiveness research (CER) is designed to inform health care decisions by providing evidence on the effectiveness, benefits, and harms of different treatment options. Where evidence does not sufficiently exist, CER may be helpful in identifying new and emerging clinical interventions. Such is the case with the study mentioned above. The authors present data supporting the change in dosing of levothyroxine from morning to bedtime. While the sample size of the study was relatively small, it is a well-designed study and raises an important question: How many of our own patients are truly directed to or actually take levothyroxine on an empty stomach 30 minutes to 1 hour before breakfast?

There is another big picture question to be answered as experts and our political leaders embrace the idea of funding CER at unprecedented levels. As more timely and relevant research is conducted under CER and the results favoring more effective clinical treatment options are disseminated, who will decide when to pull the trigger and incorporate those changes into existing practices, which may often be in direct contrast with the conventional recommendations and guidelines?5 Will there be the same delays in changing recommendations and practice guidelines as those that exist today? For the concept of CER to be successful, it is vital that not only research data are available, but also that mechanisms are developed to translate those findings in a timely manner into clinical practice. For example, based on the results of the above study, clinicians should direct patients to take levothyroxine at bedtime instead of mornings, provided that it is taken on an empty stomach. But I would have to think twice prior to changing my practice since giving this advice today would place me in direct opposition to the manufacturers' prescribing information.

References

1. Wenzel KW, Kirschsieper HE. Aspects of the absorption of oral levothyroxine in normal man. Metabolism 1977;26:1-8.

2. Siraj ES, et al. Raloxifene causing malabsorption of levothyroxine. Arch Intern Med 2003;163:1367-1370.

3. Singh N, et al. Effect of calcium carbonate on the absorption of levothyroxine. JAMA 2000;283:2822-2825.

4. Benvenga S, et al. Altered intestinal absorption of L-thyroxine caused by coffee. Thyroid 2008;18:293-301.

5. Atkins D, Kupersmith J. Implementation research: A critical component of realizing the benefits of comparative effectiveness research. Am J Med 2010;123:e38-45.