|Year : 2018 | Volume
| Issue : 2 | Page : 89-93
A comparative study on effect of evening versus morning intake of levothyroxine in patients of hypothyroidism
Sajjad Hossain1, Manasi Banerjee1, Shirsendu Mondal1, Animesh Maiti2
1 Department of Pharmacology, Medical College, Kolkata, West Bengal, India
2 Department of Endocrinology, Medical College, Kolkata, West Bengal, India
|Date of Web Publication||17-Jul-2018|
Department of Pharmacology, Medical College, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
Background: Levothyroxine sodium is widely prescribed to treat primary hypothyroidism. Conventionally, levothyroxine is asked to be taken in the morning on an empty stomach. A pilot study showed that levothyroxine intake at bedtime significantly decreased thyrotropin levels and increased free thyroxine (fT) and total triiodothyronine levels. Till date, no large randomized trial investigating the best time of levothyroxine intake, including quality-of-life evaluation has been performed.
Materials and Methods: The primary objective of this study was to compare the serum thyroid stimulating hormone and fT4level between patients taking evening dose of levothyroxine with patients taking morning dose. The secondary objectives were to compare lipid profile between patients of the two groups.
Results: A total of 147 patients were recruited and randomized into either of the study groups (73 in Group A and 72 in Group B). A total of 58 patients in Group A and 57 patients in Group B were considered for statistical evaluation. There was no statistical difference in achievement of euthyroidism and improvement of thyroid profile between the two groups. Changes in values of total cholesterol, triglyceride, low-density lipoprotein (LDL), very LDL and high-density lipoprotein were not significantly different between the groups.
Conclusions: Levothyroxine taken at bedtime improved thyroid hormone level. Serum lipid levels showed no significant changes with bedtime versus morning intake. Clinicians may consider prescribing levothyroxine at bedtime as an alternative to the conventional morning dose.
Keywords: Hypothyroidism, levothyroxine, morning and evening dose
|How to cite this article:|
Hossain S, Banerjee M, Mondal S, Maiti A. A comparative study on effect of evening versus morning intake of levothyroxine in patients of hypothyroidism. Thyroid Res Pract 2018;15:89-93
|How to cite this URL:|
Hossain S, Banerjee M, Mondal S, Maiti A. A comparative study on effect of evening versus morning intake of levothyroxine in patients of hypothyroidism. Thyroid Res Pract [serial online] 2018 [cited 2018 Nov 22];15:89-93. Available from: http://www.thetrp.net/text.asp?2018/15/2/89/236939
| Introduction|| |
Hypothyroidism is a common endocrine disorder in general population, resulting from a deficiency of thyroid hormone. The prevalence of hypothyroidism in India is high, affecting approximately one in 10 adults in the study population. Female gender and older age are found to have a significant association with hypothyroidism. Biochemical changes in hypothyroidism are increased serum thyroid-stimulating hormone (TSH), decreased free thyroxine (fT), T3. The risk of developing hypothyroidism in women with positive antibodies and elevated TSH was higher than in those with either alone. Other abnormal laboratory findings in hypothyroidism may include elevated cholesterol and triglycerides. The treatment of choice in both primary and secondary hypothyroidism is thyroxine (levothyroxine sodium). It is used for replacement therapy due to its consistent potency and prolonged duration of action. On oral administration, absorption of thyroxine occurs in the stomach and small intestine and is incomplete. About 80% is absorbed, and it is slightly increased when taken in empty stomach. Interference with absorption has been seen with sucralfate, iron sulfate, calcium preparations, aluminum antacids, activated charcoal, food items, and herbal remedies.,, Fiber-enriched diet also shows reduced bioavailability of levothyroxine. Conventionally, the drug is advised to be taken on empty stomach at least half an hour before breakfast. For many patients with hypothyroidism, it may be inconvenient to take the drug in the morning because of their lifestyle; For example, for Muslims in the month of Ramadan and intake of multiple other drugs in the morning due to comorbidity. They often request their physicians to prescribe the drug at some alternate time of the day. The results of the study conducted by Bolk et al. showed a significant improvement in the thyroid hormone profile of patients after switching from morning to the evening dose. The study showed that changing the timing of thyroxine ingestion does not affect quality-of-life variables and plasma lipid levels provided it is taken on empty stomach.
A comparative study done at Rohtak, Harayana showed no significant change in thyroid profile and quality of life parameters when levothyroxine is given to morning and evening groups. As data on comparative studies of similar type are lacking in eastern India, we aimed to compare the effect of evening versus morning dose of levothyroxine on serum TSH and fT4 in patients of hypothyroidism.
| Materials and Methods|| |
The primary objective of this study was to compare the serum TSH and fT4 level between patients taking an evening dose of levothyroxine with patients taking morning dose. The secondary objectives were to compare lipid profile between patients of the two groups. The study protocol was approved by the Institutional Ethics Committee and was done in compliance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice (GCP) guidelines, the Indian version of GCP guidelines, Declaration of Helsinki and Ethical guidelines for Biomedical Research by the Indian Council of Medical Research. Written informed consent was obtained from each patient.
This is a randomized, parallel group, open labeled, comparative study. Subjects were randomized in blocks of 10, using computer-generated random number list to either Group A (evening group) or Group B (morning group). No stratification was used. Each block was randomized in 1:1 ratio. The investigator who enrolled the participants and prescribed the study medication was different from the one who generated the random number lists. Study medication was dispensed from the hospital pharmacy. Patients were asked to maintain a study diary to assess compliance.
The study was conducted for a period of 18 months from July 2013 to December 2014. A total of 168 patients were enrolled for the study. For sample size calculation, a difference of 1 μIU/L in TSH between the two groups was taken as the primary efficacy parameter. A pilot study was done on 20 patients, and the standard deviation was found to be 2.4 in Group 'A' and 2.2 in Group 'B'. Assuming significance level (α) of 0.05 and power of the study (1-β) as 80%, the target sample size was found to be 168 (using WINPEPI version 3.85). They were randomized into two groups, 84 in each group.
Patients of either sex, aged 18–55 years with serum TSH > 4.25 μIU/L (normal value (0.3–4.25 μIU/L) and having decreased or normal serum fT4(normal value 0.7–1.24 ng/dL) attending the Endocrinology outpatient department of our tertiary care hospital in West Bengal were selected for the study. Those fulfilling the inclusion criteria and willing to participate were recruited.
Pregnant or lactating women were not included in our study. Those with thyroid malignancy, ischemic heart disease, chronic kidney disease were excluded. Patients taking medications known to interfere with the absorption of levothyroxine, such as sucralfate, iron sulfate, calcium preparations, aluminum antacids, and activated charcoal were also excluded.
Those suffering from an acute medical or surgical illness were excluded.
Baseline visit was done at recruitment. Patients were asked to come for the second visit after 3 months and third visit after 6 months. At baseline, blood samples were obtained for determination of plasma TSH, fT4, and lipid levels. The tests were repeated at subsequent visits and compliance was checked from the trial diary.
The individual study subject received levothyroxine sodium once daily. Patients in Group A were given levothyroxine minimum 2 h after dinner, and those in Group B were given the same in the morning minimum half an hour before breakfast. Initial dosage was calculated as 1.6 mcg/kg body weight, and the closest commercially available dosage was started. Provision of dose adjustment of levothyroxine was kept on 2 weekly basis based on serum TSH level. Erba Manheim, Chem-5 Plus for Analysis of serum TSH and serum fT4, Model XL-600 for analysis of serum lipid profile were done. Blood was collected for analysis of serum TSH, serum fT4 and lipid profile. Investigations were done in the Department of Biochemistry of our institution, which is the National Accreditation Board for Testing and Calibration Laboratories accredited Laboratory. Blood sample was collected in the morning after 12 h of overnight fasting.
Any participant could withdraw from the study before completion in case of any intercurrent illness, noncompliance or protocol violation.
Data were analyzed with the help of Graph Pad Instat (Graph Pad Software, San Diego) version 3. As the numerical raw data failed to pass the normality test (KS test), so the nonparametric tests were applied. Mann–Whitney test for comparison between groups and unpaired t-test was done for within group comparison. All the categorical data were compared by Fisher's exact test. P < 0.05 was taken as statistically significant.
| Results|| |
Out of 168 patients screened for this study, 12 did not meet inclusion criteria and 9 did not give written informed consent. 147 patients were recruited and randomized into either of the study groups (73 in Group A and 72 in Group B). Twelve patients from Group A and 15 from Group B were lost to follow-up. Three patients of Group A became pregnant and were excluded from the study. Data from a total of 58 patients in Group A and 57 patients in Group B were considered for statistical evaluation.
[Table 1] shows the baseline characteristics of the two groups. The mean age of patients in Group A was 36.91 ± 11.28 years and that in Group B was 35.24 ± 10.25 years. Mean weight was 62.15 ± 12.16 kg in Group A and 61.70 ± 10.38 kg in Group B at baseline.
At first follow-up visit after 12 weeks, body weight in Group A was 61.73 ± 11.87 and 60.81 ± 9.92 in Group B. At the end of 24 weeks, the mean weight was 60.62 ± 11.77 in Group A and 60.27 ± 9.78 kg in Group B. There was no significant difference in body weight between the two groups at either 12 weeks (P = 0.524) or 24 weeks (P = 0.806).
It was seen that at the end of 12 weeks, 24 (42.10%) of patients in Group A and 30 (51.7%) of patients in Group B achieved euthyroidism. At the end of 24 weeks, 54 (94.74%) patients in Group A and 56 (96.55%) in Group B achieved euthyroidism. We observed that there was an early restoration of euthyroidism (TSH <4g.25 mIU/L) in the group receiving levothyroxine as evening dose. However, no statistically significant difference was seen at the end of 12 weeks and 24 weeks (P = 0.35 and 0.68). Improvement in thyroid profile (increase in fT4 and decrease in TSH) at 12 weeks and 24 weeks was seen both in the morning group as well as in the evening, and it was highly significant in comparison with their baseline thyroid function (P< 0.0001). However, on the intergroup comparison at the end of 12 and 24 weeks, no significant change in the thyroid profile was seen (P > 0.05) in both fT4 and TSH at the end of 24 weeks) [Figure 1] and [Figure 2].
|Figure 1: Effect on serum thyroid stimulating hormone between the two groups|
Click here to view
|Figure 2: Changes of serum free thyroxine 4 at the end of study from baseline and 12th week values. Both groups are comparable in baseline and the changes are not significantly different. P values are from Mann–Whitney test|
Click here to view
In the current study, 83.17 ± 24.12 mcg of levothyroxine was required in Group A, and 85.24 ± 24.51 mcg in Group B was required to achieve euthyroidism. There was no statistically significant difference in the amount of drug used in both the groups (P = 0.16) [Figure 3].
|Figure 3: Changes of doses of Levothyroxine to achieve euthyroidism at the end of study from baseline and 12th week values. Both groups are comparable in baseline and the changes are not significantly different. P values are from Mann-Whitney test|
Click here to view
We analyzed the secondary outcomes of the study in both of the groups. Total serum cholesterol levels decreased significantly in both of the groups at the end of 24 weeks when compared to their baseline (P< 0.05 for both of the groups). However, when Group A was compared to Group B, there was no significant statistical difference [Figure 4].
|Figure 4: Changes of serum cholesterol at the end of study from baseline and 12th week values. Both groups are comparable in baseline and the changes are not significantly different. P values are from Mann–Whitney test|
Click here to view
The study also revealed that there was a reduction in low-density lipoprotein (LDL) in both the groups. However, there was no statistical significant improvement in LDL and serum low-density lipoprotein levels when intragroup and intergroup comparison were made [Figure 5] and [Figure 6].
|Figure 5: Changes of serum low-density lipoprotein at the end of study from baseline and 12th week values. Both groups are comparable in baseline and the changes are not significantly different. P values are from Mann–Whitney test|
Click here to view
|Figure 6: Changes of serum high density lipoprotein at the end of study from baseline and 12th week values. Both groups are comparable in baseline and the changes are not significantly different. P values are from Mann-Whitney test|
Click here to view
Serum triglyceride levels were reduced significantly in both of the groups at the end of 24 weeks when compared to their baseline (P< 0.05 for both of the groups). There was no significant statistical difference between the two groups [Figure 7].
|Figure 7: Changes of serum tryglycerides at the end of study from baseline and 12th week values. Both groups are comparable in baseline and the changes are not significantly different. P values are from Mann–Whitney test|
Click here to view
Both the groups are comparable at baseline, and the changes are not significantly different at any time point. P values are from Mann–Whitney test.
| Discussion|| |
Our study showed that there was no statistically significant difference regarding changes in serum TSH and fT4 level between patients taking evening dose of levothyroxine with those taking morning dose. Changes in lipid profile over the 24 weeks period also did not show any significant difference between the two groups. Primary outcomes of this study are consistent with a similar study conducted on a western population. A study was done on Indian patients with similar results.
The results of our study suggest a possible option of altering the time of drug intake from the conventional morning dose to an evening dose. This may prove beneficial to patients who cannot remain compliant to a daily morning dose due to their busy schedule or intake of other medications which may interfere with absorption of levothyroxine. The mean dose of levothyroxine required to achieve euthyroidism and the number of patients who achieved euthyroidism were marginally better in the evening group, although it was not significant statistically. This may be due to better absorption of drug in the evening due to noninterference with food and slow gastric motility. Evening administration of levothyroxine should be advised for the drug to be taken at least 2 h after dinner, thus providing several hours of empty stomach. Ingesting the drug in the morning, half an hour before breakfast may not result in better bioavailability. Bolk et al. also published the results of their study involving 90 patients where they compared the effects of morning versus evening administration of levothyroxine sodium. This study showed that levothyroxine taken at bedtime significantly improved thyroid hormone levels, but quality of life parameters and plasma lipids showed no significant change as compared to morning intake. These findings strengthens the observation of the present study that although bedtime administration of levothyroxine is statistically not superior to morning fasting administration, it is also not inferior to morning administration as far as total dose needed to achieve euthyroidism, number of patients achieving euthyroidism at 12 weeks and with respect to improvement in quality of life parameter and lipid profile. Strength of the present study is the fact that it involves larger number of patients compared to all previous studies, who had no earlier exposure to levothyroxine. Majority of the patients taking levothyroxine as evening/bedtime dose in the present study find it more convenient and decided to continue with evening/bedtime administration at the end of the study. An important matter of concern was impact of levothyroxine on circadian rhythm and nocturnal TSH surge when given as evening dose and whether sample for determining thyrotropin levels can be taken in the morning after nighttime administration of levothyroxine. The serum levels of TSH increase in the evening, reach a maximum near sleep-onset, and are followed by a progressive decrease during the night and low values during the day. Bolk et al. in their pilot study found no change in the circadian rhythm of TSH when switching the time of levothyroxine ingestion to bedtime. There was no significant change in T4, reverse 3,3',5'-triiodothyronine (rT3), albumin, and thyroxine binding globulin serum levels, or in the T3/rT3 ratio. The relative amplitude and time of the nocturnal TSH surge remained intact. Persani et al. showed that bioactivity of TSH has a circadian variation with less bioactive and differently glycosylated TSH molecules secreted during night. These findings bear important practical consequences in our study as the timings for blood sampling for monitoring thyroid hormones can still be done in the morning as per present norm even if the patient is taking levothyroxine as evening dose.
Our data do not allow us to conclude that ingestion of levothyroxine 2 h after the evening meal provides a sufficiently long interval to avoid the interfering effects of food on levothyroxine absorption. Limitations of our study stand that although subjects were instructed to take their levothyroxine at least 2 h after dinner, we did not collect data on the exact interval between dinner and levothyroxine ingestion in the bedtime-dosing subjects. Meal-dose intervals of >2 h may be necessary to assure an empty stomach at the time of levothyroxine ingestion, particularly when the preceding evening meal contained solid and/or fatty foods.
| Conclusion|| |
From the study, we can say that evening dose is as efficacious as morning dose in the improvement of thyroid profile, reduction in total cholesterol levels. In the modern busy life with hectic morning schedule, the results give hope for an alternate dosing regimen.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Unnikrishnan AG, Kalra S, Sahay RK, Bantwal G, John M, Tewari N. Prevalence of hypothyroidism in adults: An epidemiological study in eight cities of India. Indian J Endocrinol Metab 2013;17:647-52.
Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al.
The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;43:55-68.
Brent GA, Koenig RJ. Thyroid and anti-thyroid drugs. In: Goodman and Gillman's The Pharmacological Basis of Therapeutics. 12th
ed. New York: McGraw Hill; 2011. p. 1143.
Sherman SI, Tielens ET, Ladenson PW. Sucralfate causes malabsorption of L-thyroxine. Am J Med 1994;96:531-5.
Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong NC. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern Med 1992;117:1010-3.
Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. JAMA 2000;283:2822-5.
Liel Y, Harman-Boehm I, Shany S. Evidence for a clinically important adverse effect of fiber-enriched diet on the bioavailability of levothyroxine in adult hypothyroid patients. J Clin Endocrinol Metab 1996;81:857-9.
Bolk N, Visser TJ, Nijman J, Jongste IJ, Tijssen JG, Berghout A, et al.
Effects of evening vs. morning levothyroxine intake: A randomized double-blind crossover trial. Arch Intern Med 2010;170:1996-2003.
Rajput R, Chatterjee S, Rajput M. Can levothyroxine be taken as evening dose? Comparative evaluation of morning versus evening dose of levothyroxine in treatment of hypothyroidism. J Thyroid Res 2011;2011:505239.
Brabant G, Prank K, Ranft U, Schuermeyer T, Wagner TO, Hauser H, et al.
Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman. J Clin Endocrinol Metab 1990;70:403-9.
Persani L, Terzolo M, Asteria C, Orlandi F, Angeli A, Beck-Peccoz P. Circadian variations of thyrotropin bioactivity in normal subjects and patients with primary hypothyroidism. J Clin Endocrinol Metab 1995;80:2722-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]