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Drugs in R&D

, Volume 16, Issue 1, pp 53–68 | Cite as

Comorbidities, Concomitant Medications, and Diet as Factors Affecting Levothyroxine Therapy: Results of the CONTROL Surveillance Project

  • Marjorie McMillanEmail author
  • Keith S. Rotenberg
  • Kevin Vora
  • Arnold B. Sterman
  • Lionel Thevathasan
  • Michael F. Ryan
  • Munish Mehra
  • Walter Sandulli
Open Access
Original Research Article

Abstract

Background

The CONTROL Surveillance Project was a comprehensive patient-based survey conducted among hypothyroid patients undergoing treatment. The primary objective of the study was to specifically quantify the prevalence of factors adversely affecting levothyroxine therapy.

Methods

Participants were selected from a large proprietary database. Those eligible for the study completed a 21-question survey.

Results

Of the eligible hypothyroid patients, 925 (92.5 %) were being treated with levothyroxine monotherapy. The mean age was 60.4 years; 755 (81.6 %) were female and 168 (18.2 %) were male. Almost half of those receiving levothyroxine (435, 47.0 %) had at least one comorbid condition that could adversely affect its absorption: gastroesophageal reflux disease (33.8 % of patients), irritable bowel syndrome (9.7 %), lactose intolerance (7.8 %), or a history of gastric bypass surgery or bowel resection (3.0 %). Other factors reported by many patients that could adversely affect levothyroxine absorption included use of prescription medications (20.6 %) and over-the-counter medications (34.3 %) used to treat comorbid gastrointestinal (GI) conditions; use of dietary supplements (51.8 %, primarily calcium and iron); and intake of foods/beverages high in fiber, iodine, or soy (68.0 %). Of the 13.4 % who reported difficulty controlling their hypothyroid symptoms, significantly more patients with comorbid GI conditions reported such difficulty (7.8 versus 5.6 %, P < 0.01). Frequent changes in levothyroxine dosing (two or more dose changes in the past year) were reported by 8.0 % of survey participants. Those with GI comorbidities were nearly twice as likely to have such changes (5.0 versus 3.0 %, P < 0.01).

Conclusion

Better initial workup of patients, including identification of relevant GI comorbidities and allergies, may help in the early detection of factors that may affect the performance of levothyroxine.

Keywords

Irritable Bowel Syndrome Hypothyroidism Levothyroxine Subclinical Hypothyroidism Hypothyroid Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Key Points

This study documented the prevalence in hypothyroid patients of factors known to affect levothyroxine efficacy and tolerability.

The results suggest that there is room for improved dialogue between physicians and patients regarding the proper administration of levothyroxine and the avoidance of foods and drugs that complicate its use.

For patients receiving higher-than-recommended doses of levothyroxine, a complete patient re-evaluation is recommended to determine the presence of factors that affect the ability of levothyroxine to achieve desired therapeutic results.

Adopting these steps may improve patients’ quality of life and reduce the financial burden placed on the healthcare system, resulting from the frequent physician and pharmacy visits, medication adjustments, laboratory tests, and poor compliance associated with levothyroxine therapy.

1 Introduction

1.1 Background and Study Rationale

Hypothyroidism often results from autoimmune thyroid disease or thyroid resection [1, 2]. In the majority of cases, hypothyroidism can be treated effectively by oral thyroid hormone supplementation, most commonly with levothyroxine. Typically, patients require 1.6–1.8 μg of levothyroxine per kilogram of body weight, although lean body mass is a better criterion for dosing, with typical doses being 2–3 μg/kg [3, 4, 5, 6].

Key factors adversely affecting levothyroxine performance have been widely reported in the clinical literature. They include comorbid conditions and their treatments, diet, tolerability of medication, and compliance with instructions for administration [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18].

When levothyroxine is taken in a fasting state, up to 80 % of it can be absorbed [19].

However, the absorption of levothyroxine can be limited by a variety of diseases of the gastrointestinal (GI) tract, including inflammatory bowel disease (IBD), atrophic gastritis, celiac disease, Helicobacter pylori infection, gastroesophageal reflux disease (GERD), lactose intolerance, and gastroparesis, among others. The presence of these conditions may adversely affect levothyroxine absorption and thereby affect its dose requirements [7, 8, 9, 10, 11, 12, 15, 16, 17, 18, 20].

Additional factors that have been shown to affect levothyroxine absorption and performance—some of which may be related to the diseases of the GI tract noted above—include excess body weight; poor compliance with therapy; diet; gastric bypass surgery (reduced or delayed absorption); and use of certain nutritional supplements, vitamins, and medications, such as proton pump inhibitors, histamine receptor blockers, cholestyramine, and motility-modifying agents [7, 8, 12, 13, 14, 15, 16, 17].

1.2 Study Objectives

The primary objective of the CONTROL Surveillance Project was to specifically quantify the prevalence of factors that are known to adversely affect levothyroxine performance, including:
  • The prevalence of GI conditions known to affect drug absorption.

  • Sensitivity to inactive ingredients contained in tablet drug formulations (i.e., excipients).

  • Consumption of prescription and non-prescription medications, vitamins, foods, and beverages known to interfere with levothyroxine therapy.

  • Patient understanding and compliance with levothyroxine administration guidelines (e.g., timing before and after meals).

2 Methods

2.1 Survey Development/Selection of Patients

The survey’s content was developed as a cooperative effort between Akrimax Pharmaceuticals, LLC (Cranford, NJ, USA; the study sponsor) and Healthcare Research and Analytics, LLC (HRA; Parsippany, NJ, USA). HRA programmed the questionnaire into an online instrument via its Confirmit tool.

Prior to the full launch of the survey, it was tested to ensure that recording of data was consistent with the survey’s questions and screening criteria. All survey responses were recorded confidentially, with the study sponsor being blinded to the responses of individual participants.

Participants were selected from a large proprietary database from Research Now®. Research Now® identified individuals with a self-reported diagnosis of primary hypothyroidism and recruited potential survey respondents for this online quantitative study via e-mail invitations from their proprietary “By-Invitation-Only®” panel. Each person contacted was assigned an individual ID for recording his or her entire survey participation history, including “Did not meet inclusion/exclusion criteria”.

Those who accepted the invitation to take part in the survey were provided with a link to access the survey web page, where they were provided with information about the project, the anonymity of the survey’s findings, an outline of what study subjects were required to do, and the time required. Subjects were informed that every attempt would be made to ensure the confidentiality of their data, and they were given a statement indicating that participation was voluntary and that withdrawal from the survey was possible at any stage.

Qualified subjects then completed the 21-question survey online (see “Appendix”). Subjects received an honorarium or gratuity (as termed by Research Now®) of US$20, based on the length of time a subject took to complete the survey online and the sample type, in keeping with the panel membership policies of Research Now®. The honorarium or gratuity did not exceed the agreed-upon amount set by the study sponsor or exceed the industry standards for market research among this sample type. Respondents received their honoraria/gratuities upon completion of the survey.

The survey was initiated on March 27, 2015, and completed on April 8, 2015.

2.2 Sample Size and Inclusion/Exclusion Criteria

The study was designed to be exploratory, and all statistical tests were performed to provide hypotheses for future research. The primary intent of the study was to gather data through a patient survey for better understanding of the prevalence of factors that are known to affect the performance of levothyroxine therapy. A pre-survey power analysis determined that a sample size of 1000 subjects would be sufficient to obtain estimates of prevalence rates that reflect the prevalence of certain GI conditions in the target population, with a 95 % confidence interval. For conditions such as GERD and H. pylori infection, whose prevalence in the general population is relatively high (15–40 %) [9, 10, 13], a sample size of 1000 subjects would provide an estimated 95 % confidence interval of ±2–3 %. For conditions with a low prevalence (e.g., a condition with a 0.75 % prevalence reported in the literature), such as Crohn’s disease or ulcerative colitis [13], a sample size of 1000 subjects would provide an estimated 95 % confidence interval of ±0.53 %.

2.2.1 Inclusion Criteria

Each subject was required to meet all of the following criteria:
  • Being treated with prescription medication for hypothyroidism.

  • At least 19 years of age.

  • US resident.

  • Voluntary agreement to provide informed consent.

  • Able to read English.

  • Willing and able to complete the survey.

2.2.2 Exclusion Criteria

Any subject who met the following criterion was excluded:
  • Not taking prescription medication to treat hypothyroidism.

2.3 Survey Completion and Quality Assurance

Patients entered their answers online. If a patient did not complete the survey, i.e., did not progress to the last question and enter an answer, his or her survey was recorded as incomplete and the answers were not included in the results. Incomplete surveys were categorized separately from survey terminations (patients disqualified through screening questions). More information regarding the survey completion and quality assurance process is presented in Table 1.
Table 1

Survey completion and quality assurance features

Feature

Personal computers used by patients

Clicking on survey link = unique respondent

Answers required for each question before proceeding

Return to previous questions not allowed

Survey exit without completing all questions = incomplete

Following survey submission, return to survey not allowed

Assignment of unique ID plus RVID programming prevented further access from same computer

RVID relevant ID

2.4 Data Management, Tabulations, and Statistical Analyses

The survey questions incorporated multiple choice/closed-ended questions, either “single punch/single select” or “multiple punch/select all that apply”. Some questions included an open-ended option, “Other (specify: …)”. Coding of all answers, data checks, summary tabulations, and statistical analyses of the data, including tests of significance for hypothesis testing, were performed by HRA. All were exploratory in nature, and no adjustments for multiple comparisons were made. The Quantum software package (IBM, Armonk, NY, USA) was used for all phases of data processing, online data collection sources, and SPSS®-generated data.

For continuous data, the number of subjects, mean, standard deviation, median, minimum, and maximum were calculated. Where appropriate, statistical tests were performed for hypothesis-testing purposes. Demographic data for the sample are presented by age, gender, and race.

2.5 Study Ethics

The protocol and appropriate related documents were reviewed and approved by IntegReview IRB (Austin, TX, USA), constituted and functioning in accordance with US federal guidelines [21].

The study was conducted in accordance with the standard operating practices of the study sponsor, Akrimax, which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines [21].

Each subject was informed that participation in the study was voluntary and that he or she could withdraw from the study at any time. A waiver of informed consent was issued by IntegReview IRB, in accordance with US federal guidelines [22].

Research Now® and HRA followed all national, regional, and local laws with respect to privacy and data protection. Research Now® ensured that the survey complied with all applicable industry standards set by the Council of American Survey Research Organizations (USA) and the Market Research Association (USA).

Secure servers at Research Now® were used to carry out the collection of survey data. Personal information was fully protected. Sampling teams did not have direct access to the database that might have revealed the identity of users. The survey remained anonymous and linked to the subject database using numeric IDs to ensure protection of the identity of each subject, and, as discussed above, to prevent unauthorized access to the survey and multiple participations by individual subjects.

3 Results

3.1 Survey Completion Rates

Sixty-six percent of invited subjects (1000/1506) qualified for, and completed, the survey. Such a high percentage was most likely attributable to the ability of Research Now® to target subjects who had been previously self-identified as hypothyroid patients. There were 320 incomplete surveys and 186 survey terminations.

3.2 Demographics

Of the 1000 patients who completed the survey, 925 (92.5 %) were receiving levothyroxine monotherapy. Others were being treated either with a combination of levothyroxine and other hypothyroid medications or with non-levothyroxine therapies. The mean age of patients receiving levothyroxine monotherapy was 60.4 years (range 19 to >75 years; 8 % were aged ≥75 years, 30 % were aged 65–74 years, 37 % were aged 55–64 years, and 15 % were aged 45–54 years). Most respondents [755 (81.6 %)] were female; only 168 (18.2 %) were male (two respondents declined to specify gender). Over 90 % of respondents were Caucasian (Table 2). Nearly two-thirds (62.9 %) had been taking hypothyroid medication for more than 10 years.
Table 2

Racial and ethnic distribution of survey participants

 

Total [n (%)]

Hypothyroidism w/o GI condition [n (%)]

Hypothyroidism w/GI condition [n (%)]

Total

925

490

435

Non-Hispanic White or Euro-American

867 (94)

454 (93)

413 (95)

Black, Afro-Caribbean, or African American

13 (1)

5 (1)

8 (2)

Latino or Hispanic American

17 (2)

8 (2)

9 (2)

East Asian or Asian American

13 (1)

11 (2)

2 (*)

South Asian or Indian American

4 (*)

3 (1)

1 (*)

Middle Eastern or Arab American

3 (*)

3 (1)

– (–)

Native American or Alaskan Native

5 (1)

2 (*)

3 (1)

Mixed race

2 (*)

2 (*)

– (–)

Prefer not to answer

9 (1)

6 (1)

3 (1)

Total mentions

933

494

439

Some respondents specified more than one category

w/GI with gastrointestinal, w/o GI without gastrointestinal

* <1 %

3.3 Prevalence of Relevant Comorbid Diseases/Conditions and Use of Concomitant Medications

The prevalence of comorbid diseases or conditions that could adversely affect the absorption of levothyroxine was substantial and generally consistent with that reported in the medical literature for the population at large [9, 10, 11, 12, 13, 16, 23] (Table 3).
Table 3

Prevalence of relevant concomitant diseases/conditions in hypothyroid patient population receiving levothyroxine (n = 925)

Concomitant disease/condition

n (%)

Acid reflux or GERD

313 (33.8)

IBS

90 (9.7)

Food allergies

85 (9.2)

Lactose intolerance

72 (7.8)

Gastric bypass or bowel resection

28 (3.0)

H. pylori infection

19 (2.1)

Gastroparesis

15 (1.6)

Celiac disease

10 (1.1)

Ulcerative colitis

10 (1.1)

Crohn’s disease

6 (0.6)

Atrophic gastritis

1 (0.0)

Othera

157 (17.0)

None of the above

488 (52.8)

Because patients could specify more than one concomitant disease or condition, the total for the last column exceeds 100 %

GERD gastroesophageal reflux disease, IBS irritable bowel syndrome

aOther = numerous gastrointestinal and non-gastrointestinal conditions

A substantial number of hypothyroid patients reported taking medications for comorbid GI conditions—either prescription medications (20.6 %) or over-the-counter (OTC) medications (34.3 %)—that could also adversely affect the absorption of levothyroxine (Tables 4, 5).
Table 4

Hypothyroid patients on levothyroxine (n = 925) receiving medication for relevant concomitant diseases/conditions

Concomitant disease/condition

n (%)

Acid reflux or GERD

246 (26.6)

IBS

28 (3.0)

Food allergies

11 (1.2)

Lactose intolerance

9 (1.0)

Gastric bypass or bowel resection

8 (0.9)

Gastroparesis

7 (0.8)

Ulcerative colitis

6 (0.6)

Crohn’s disease

5 (0.5)

Atrophic gastritis

1 (0.1)

Celiac disease

1 (0.1)

H. pylori infection

1 (0.1)

Othera

139 (15.0)

None of the above

607 (65.6)

Because patients could specify medication for more than one concomitant disease or condition, the total for the last column exceeds 100 %

GERD gastroesophageal reflux disease, IBS irritable bowel syndrome

aOther = numerous gastrointestinal and non-gastrointestinal conditions

Table 5

Numbers of hypothyroid patients on levothyroxine (n = 925) who were taking antacids or acid reducers >2 times/week

Antacid or acid reducer

n (%)

Prescription acid reducer

– (–)

 Proton pump inhibitora

180 (19.5)

 Histamine (H2)-receptor blockerb

0 (0.0)

Non-prescription acid reducer

– (–)

 Proton pump inhibitora

83 (9.0)

 Histamine (H2)-receptor blockerb

53 (5.7)

Non-prescription antacidsc

168 (18.2)

Other non-prescription antacid or acid reducerd

13 (1.4)

Other prescription antacid or acid reducere

11 (1.2)

None of the above

543 (58.7)

Because patients could specify more than one medication, the total for the last column exceeds 100 %

aEsomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole

bCimetidine, ranitidine

cMultiple brands

dOther non-prescription antacids or acid reducers = generics of multiple products

eOther prescription antacids or acid reducers = generics of multiple products

3.4 Other Key Factors Affecting Levothyroxine Performance

Certain dietary supplements are known to cause malabsorption of levothyroxine [7, 8, 13, 15, 17]. Overall, 51.8 % of patients indicated that they frequently take one or more such dietary supplements, with calcium supplements (47.5 %) and iron supplements (11.9 %) being most frequently reported.

A majority (68.0 %) of patients indicated that they frequently (more than twice weekly) eat food or consume beverages that are known to cause malabsorption of levothyroxine. These include high-fiber foods (bran flakes, broccoli, fiber bars, fiber drinks), foods high in iodine (dried seaweed, cranberries, lobster, cod, plain yogurt), and soy-based foods.

More than 20 % of patients reported taking levothyroxine during breakfast or later in the day, including during lunch or dinner. Many patients (21.5 %) reported taking levothyroxine less than the recommended 30 min before eating.

Of the 925 patients who were receiving levothyroxine, 112 (12.1 %) reported experiencing GI upset (nausea, stomach cramps, or diarrhea) when taking it.

Overall, 15.2 % of patients receiving levothyroxine reported allergies to one or more excipients that are known to be included in most tablet drug formulations. Those most frequently reported were allergies to lactose (11.9 %), gluten (3.78 %), and food dyes and sucrose (1–2 % each).

3.5 Control of Symptoms

Lack of hypothyroid symptom control was reported by survey respondents. Of the 124 patients (13.4 %) reporting difficulty controlling their hypothyroid symptoms, significantly more patients with comorbid GI conditions who were taking levothyroxine reported difficulty with symptom control, versus those without such conditions (P < 0.01) [Table 6].
Table 6

Patients indicating their level of agreement with the statement “It’s hard to control my hypothyroid symptoms”

 

Hypothyroidism w/o GI condition [n (%)]

Hypothyroidism w/GI condition [n (%)]

Total [n (%)]

Completely or somewhat agree

52 (5.6)

72 (7.8)

124 (13.4)

Slightly agree or disagree

438 (47.4)

363 (39.2)

801 (86.6)

Total

490 (53.0)

435 (47.0)

925

Chi-square test P value: <0.01

w/GI with gastrointestinal, w/o GI without gastrointestinal

3.6 Changes in Hypothyroid Medication/Changes in Levothyroxine Dose

More than 80 % of surveyed patients reported having had at least one change in their prescribed hypothyroid medication since beginning therapy. Many patients (16.0 %) reported 5–10 changes, and 6.1 % reported having >10 changes. As presented in Fig. 1, the overall number of self-reported changes in hypothyroid medication since the beginning of treatment with levothyroxine was comparable between those with and those without comorbid GI conditions.
Fig. 1

Total number of changes in hypothyroid medication since initiation of therapy

While many participants in the CONTROL Surveillance Project had been on levothyroxine for several years, many (31.4 %) reported a change in levothyroxine dose within the past year. Among patients experiencing ≥2 levothyroxine dose changes during the past year, those with self-reported GI comorbidities had nearly twice the prevalence of the other patients (P < 0.01) [Fig. 2].
Fig. 2

Number of changes in dose of levothyroxine in the past year

3.7 Quality-of-Life Factors and Self-Reported Patient Satisfaction

While the CONTROL Surveillance Project was not designed to measure quality of life, nearly 11 % of respondents indicated that their thyroid condition “reduced their quality of life” and “rendered them unable to do the things they used to do”. Similarly, 28.4 % of all respondents indicated that their thyroid condition limited their ability to “take on any activity or task”. Overall, 16.6 % of patients indicated that they have been “unable to live life normally since undergoing treatment for hypothyroidism”.

A minority of respondents reported ever discussing with their physician topics such as the proper administration of hypothyroid medication (44.4 %), concomitant use of prescription medications (29.5 %), concomitant use of OTC medications (12.6 %), use of dietary or food supplements (10.9 %), or the presence of stomach or GI conditions (10.0 %) or food allergies (4.1 %) that may interfere with levothyroxine therapy.

Overall, 19.6 % of patients stated that they are not fully satisfied with their hypothyroid treatment. Significantly more patients with comorbid GI conditions reported dissatisfaction with their thyroid treatment, versus those without such conditions (P < 0.05) (Table 7).
Table 7

Patients indicating their level of agreement with the statement “I am satisfied with my hypothyroid treatment”

 

Hypothyroidism w/o GI condition [n (%)]

Hypothyroidism w/GI condition [n (%)]

Total [n (%)]

Completely or somewhat agree

407 (44.0)

337 (36.4)

744 (80.4)

Slightly agree or disagree

83 (9.0)

98 (10.6)

181 (19.6)

Total

490 (53.0)

435 (47.0)

925

Chi-square test P value: <0.05

w/GI with gastrointestinal, w/o GI without gastrointestinal

4 Discussion

Many factors contribute directly or indirectly to the failure of levothyroxine therapy. These can adversely affect treatment satisfaction and can lead to unnecessary consumption of healthcare resources in the form of increased physician and pharmacy visits, laboratory costs, and medication adjustments [24, 25, 26, 27, 28, 29, 30, 31, 32, 33].

The CONTROL Surveillance Project is one of the most comprehensive patient-based surveys ever conducted among hypothyroid patients. It has helped to document the prevalence of factors that can complicate levothyroxine therapy. Unlike previous community-based surveys or retrospective analyses of patient medical records [3, 34, 35], CONTROL Surveillance attempted to measure the influences that diet, OTC medication use, and the degree of adherence to levothyroxine administration guidelines (before or after meals) may have on levothyroxine therapy. Such information is rarely, or only sporadically, recorded in patient records.

The results of the CONTROL Surveillance Project quantify the prevalence of GI disorders that can inhibit the absorption of levothyroxine and necessitate frequent levothyroxine dose adjustments. Of the 925 hypothyroid patients surveyed who were currently taking levothyroxine, 435 (47.0 %) had at least one commonly prevalent GI disease or condition. The prevalence rates of GERD, irritable bowel syndrome (IBS), gastroparesis, and a history of gastric bypass surgery or bowel resection were generally consistent between those found in the CONTROL Surveillance Project and those reported in the literature for general patient populations [9, 10, 11, 12, 13, 16, 23]. It should be noted that the age range (from 19 to >75 years) and mean age (60.4 years) of the patient population in this survey mirror those of the hypothyroid population reported in the medical literature and in clinical practice [36], which would be expected with such a large sample of patients who self-identified as having this condition.

In comparison with all other patients in this study, significantly more of those who had such GI disorders reported difficulty achieving control of their hypothyroid symptoms (P < 0.01). Similarly, a relationship between these commonly prevalent GI conditions and the need for levothyroxine dose adjustment was noted. Participants experiencing ≥2 levothyroxine dose changes in the past year were more likely to have one or more of these conditions.

Hypothyroid patients requiring increased doses of levothyroxine have been well documented in the medical literature and in clinical practice [37]. Data from five different studies have shown that non-optimal levothyroxine therapy, resulting in thyroid-stimulating hormone (TSH) levels above (or below) the reference range, is common, ranging from 32 to 48 % of patients [38, 39, 40, 41, 42].

In a study by Vaisman et al. [42], questionnaires were used to evaluate levothyroxine replacement treatment in patients with primary hypothyroidism being followed in referral centers in Brazil. Among all patients taking thyroid medication, 42.7 % had an abnormal serum TSH level (28.3 % were undertreated and 14.4 % were overtreated). The investigators concluded that a significant number of patients taking thyroid hormones are not in the therapeutic range, on the basis of TSH assays. Clinicians should, therefore, consider monitoring patients on thyroid replacement more frequently and provide patients with more precise recommendations about proper use of levothyroxine.

Vigário et al. [43] performed a cross-sectional study involving 2057 patients receiving levothyroxine replacement for primary hypothyroidism at four referral centers in Brazil. The results showed that a total of 14.4 % of patients were overtreated (13.0 % with subclinical hyperthyroidism and 1.4 % with overt hyperthyroidism). The prevalence of undertreatment was 25.9 % (21.5 % with subclinical hypothyroidism and 4.4 % overt hypothyroidism). The investigators concluded that undertreatment of hypothyroidism is associated with poor patient health-related quality of life (especially physical and emotional aspects), and adequate levothyroxine therapy should always be given to maintain serum TSH levels within the reference range.

It is also interesting to note that more than 20 % of patients in our survey reported taking levothyroxine during breakfast or later in the day, including during lunch or dinner. Many patients (21.5 %) reported taking levothyroxine less than the recommended 30 min before eating. Inappropriate timing of ingestion may have contributed to less-than-optimal levothyroxine performance in these patients.

In a randomized, double-blind, crossover trial involving 90 patients, however, Bolk et al. [44] found that levothyroxine taken at bedtime rather than in the morning significantly improved thyroid hormone levels. These investigators recommended that clinicians consider prescribing levothyroxine intake at bedtime.

Regarding gastric bypass surgery, its impact on the absorption of levothyroxine can vary, depending on the procedure [23]. Rubio et al. [45] evaluated the absorption of levothyroxine in morbidly obese patients before (n = 15) and after (n = 15) a Roux-en-Y surgical procedure. Although bypass surgery did not diminish the absorption of levothyroxine in this study, a small but significant delay in the absorption of levothyroxine was observed in patients following surgery.

4.1 Comparisons with Prior Patient Surveys

The CONTROL Surveillance Project extends the findings of two earlier, more limited, surveys among treated hypothyroid patients [34, 35]. In 1977, the Whickham Survey [34] determined the prevalence of overt hypothyroidism to be 1.4–1.9 % in females and 0.1 % in males in a general population of 2779 (mean age 47 years) in County Durham, England. In 2006, Wilson et al. [35] conducted another community-based, cross-sectional survey in the UK, involving 5690 subjects aged 65 years and older—the Birmingham Elderly Survey. The investigators reported prevalence rates of 0.4 % for overt hypothyroidism and 2.9 % for subclinical hypothyroidism. In obtaining subject demographic information, the investigators reported the overall prevalence rates of GI diseases to be 0 % in subjects with overt hypothyroidism and 1.8 % in subjects with subclinical hypothyroidism. However, the sample sizes of the two groups were small (n = 23 and n = 168, respectively), and the GI diseases were not categorized systematically. In both surveys, there was no attempt to document the prevalence of factors [such as diet, medication consumption (prescription and non-prescription), and patient behaviors] that are known to affect the performance of levothyroxine.

4.2 Study Limitations

The CONTROL Surveillance Project was controlled and powered to determine statistically meaningful results and to provide key insights into important issues surrounding levothyroxine treatment in hypothyroid patients. But, given the lack of control over patient inclusion by race, among other reasons, its findings should be considered more hypothesis generating than conclusive. Because this was a patient survey with no access to patient records, certain data, such as thyroid hormone levels, were not available to assist in interpretation of the results. The high percentage of Caucasian respondents in CONTROL Surveillance is not consistent with the racial mix of the hypothyroid population at large reported in the published literature [46]. However, the overrepresentation of Caucasians is consistent with the results reported in other patient survey panels. Knapton and Myers [46] have reported the tendency of many non-Caucasians to have lower response rates to online surveys; the reasons for it are unclear.

5 Conclusion

Levothyroxine has been the “gold standard” treatment for hypothyroidism for over 60 years. It is one of the most frequently used medications in the USA, with over 115 million prescriptions dispensed in 2013 [47]. Notwithstanding the ubiquitous use of levothyroxine, there have been few surveys that address the prevalence of commonly cited reasons for its frequently suboptimal performance.

The CONTROL Surveillance Project documents the prevalence of factors that are well known to affect levothyroxine efficacy and tolerability. GI comorbidities, concomitant drug use, and dietary habits that complicate levothyroxine therapy may be more prevalent among treated hypothyroid patients than is generally understood. Similarly, allergies to excipient ingredients found in most tablet drug formulations may also be more common than is generally perceived. The frequency of levothyroxine dose changes, the need for unexpectedly high doses, and the inability of levothyroxine to control the symptoms of hypothyroidism have been shown to correlate with the presence of these factors [48].

The results of the CONTROL Surveillance Project suggest that there is room for improved dialogue between physicians and patients regarding the proper administration of levothyroxine and the avoidance of foods and drugs that complicate its use. In particular, better initial workup of patients (including identification of relevant comorbidities and allergies) may help to detect factors that can lead to suboptimal efficacy or tolerability of levothyroxine. For patients already on levothyroxine therapy who are receiving doses that are higher than those recommended by current treatment guidelines [49], a complete patient re-evaluation is recommended to determine the presence of factors that affect the ability of levothyroxine to achieve desired therapeutic results [50, 51, 52]. Adopting these additional steps may improve the quality of life for patients and reduce the financial burden placed on the healthcare system that results from the frequent physician and pharmacy visits, medication adjustments, laboratory tests, and poor compliance associated with levothyroxine therapy.

Notes

Acknowledgments

The authors would like to thank Lisa Rowe and Brenda Kiminyo-Bode at Healthcare Research and Analytics, LLC (Parsippany, NJ, USA) and Aesculapius Consulting, Inc. (East Brunswick, NJ, USA) for their editorial support.

Compliance with Ethical Standards

Conflicts of interest

All potential conflicts of interest and financial considerations are provided in the “Disclosures” section below.

Author participation

Each of the authors participated in the data collection, data organization, and/or writing of this manuscript.

Disclosures

This study was funded by Akrimax Pharmaceuticals, LLC (Cranford, NJ, USA). Marjorie McMillan, MPH (McMillan Survey Research and Statistical Consulting, Memphis, TN, USA) was contracted by Akrimax for survey research consulting services. Keith S. Rotenberg, PhD, Kevin Vora, RPh, and Walter Sandulli, MBA, are employees of Akrimax. Arnold B. Sterman, MD, has been a consultant for Akrimax and Newron Sweden. Lionel Thevathasan, MD, owner of LT Associates Ltd (Paris, France), has been a consultant for Akrimax, AstraZeneca, Bayer, Daiichi-Sankyo, Medscape, Roche, and Sanofi. Michael F. Ryan, PhD (Medical/Marketing Decisions, LLC, Bridgewater, NJ, USA) was contracted by Akrimax for survey research and writing services. Munish Mehra, PhD (Quantum Change Group, LLC, Gaithersburg, MD, USA) was contracted by Akrimax for statistical services.

References

  1. 1.
    Dar RA, Chowdri NA, Parray FQ, Wani SH. An unusual case of Hashimoto’s thyroiditis with four lobed thyroid gland. N Am J Med Sci. 2012;4:151–3.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Yaturu S, Fontinot J, Rowland T. Mixed medullary thyroid cancer and follicular cancer. Am J Case Rep. 2011;12:1–4.CrossRefGoogle Scholar
  3. 3.
    Robertson HM, Narayanaswamy AK, Pereira O, et al. Factors contributing to high levothyroxine doses in primary hypothyroidism: an interventional audit of a large community database. Thyroid. 2014;24:1765–71.CrossRefPubMedGoogle Scholar
  4. 4.
    Santini F, Pinchera A, Marsili A, et al. Lean body mass is a major determinant of levothyroxine dosage in the treatment of thyroid disease. J Clin Endocrinol Metab. 2005;90:124–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Roos A, Linn-Rasker SP, van Domburg RT, Tijssen JP, Berghout S. The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med. 2005;165:1714–20.CrossRefPubMedGoogle Scholar
  6. 6.
    Mandel SJ, Brent GA, Larscn PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med. 1993;119:492–502.CrossRefPubMedGoogle Scholar
  7. 7.
    Khandelwal D, Tandon N. Overt and subclinical hypothyroidism: who to treat and how. Drugs. 2012;72:17–33.CrossRefPubMedGoogle Scholar
  8. 8.
    Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine absorption. Best Pract Res Clin Endocrinol Metab. 2009;23:781–92.CrossRefPubMedGoogle Scholar
  9. 9.
    Badillo R, Francis D. Diagnosis and treatment of gastroesophageal reflux disease. World J Gastrointest Pharmacol Ther. 2014;5:105–12.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Cohen E, Bolus R, Khanna D, et al. GERD symptoms in the general population: prevalence and severity versus care-seeking patients. Dig Dis Sci. 2014;59:2488–96.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Fasano A, Catassi C. Clinical practice: celiac disease. N Engl J Med. 2012;367:2419–26.CrossRefPubMedGoogle Scholar
  12. 12.
    Miller AD, Smith KM. Medication and nutrient administration considerations after bariatric surgery. Am J Health Syst Pharm. 2006;63:1852–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Ward LS. The difficult patient: drug interaction and the influence of concomitant diseases on the treatment of hypothyroidism. Arq Bras Endocrinol Metabol. 2010;54:435–42.CrossRefPubMedGoogle Scholar
  14. 14.
    Groener JB, Lehnhoff D, Piel D, et al. Subcutaneous application of levothyroxine as successful treatment option in a patient with malabsorption. Am J Case Rep. 2013;14:48–51.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Gaitonde DY, Rowley KD, Sweeney LB. Hypothyroidism: an update. Am Fam Physician. 2012;86:244–51.PubMedGoogle Scholar
  16. 16.
    Cellini M, Santaguida MG, Gatto I, et al. Systematic appraisal of lactose intolerance as cause of increased need for oral thyroxine. J Clin Endocrinol Metab. 2014;99:E1454–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Ianiro G, Mangiola F, Di Rienzo TA, et al. Levothyroxine absorption in health and disease, and new therapeutic perspectives. Eur Rev Med Pharmacol Sci. 2014;18:451–6.PubMedGoogle Scholar
  18. 18.
    Benvenga S. When thyroid hormone replacement is ineffective? Curr Opin Endocrinol Diabetes Obes. 2013;20:467–77.CrossRefPubMedGoogle Scholar
  19. 19.
    Hasselström K, Siersbaek-Nielsen K, Lumholtz IB, Faber J, Kirkegaard C, Friis T. The bioavailability of thyroxine and 3,5,3′-triiodothyronine in normal subjects and in hyper- and hypothyroid patients. Acta Endocrinol (Copenh). 1985;110:483–6.PubMedGoogle Scholar
  20. 20.
    Checchi S, Montanaro A, Pasqui L, et al. l-Thyroxine requirement in patients with autoimmune hypothyroidism and parietal cell antibodies. J Clin Endocrinol Metab. 2008;93:465–9.CrossRefPubMedGoogle Scholar
  21. 21.
    US Food and Drug Administration. International Conference on Harmonisation; good clinical practice: consolidated guideline; availability. Federal Register. 1997;62:25692–709.Google Scholar
  22. 22.
    US Department of Health and Human Services. Code of Federal Regulations. Title 45 Public Welfare. Section 46.116.7–8. US Department of Health and Human Services. 2009. http://www.hhs.gov/ohrp/policy/ohrpregulations.pdf. Accessed 10 Dec 2015.
  23. 23.
    Padwal R, Brocks D, Sharma AM. A systematic review of drug absorption following bariatric surgery and its theoretical implications. Obes Rev. 2010;11:41–50.CrossRefPubMedGoogle Scholar
  24. 24.
    McMillan C, Bradley C, Razvi S, Weaver J. Psychometric evaluation of a new questionnaire measuring treatment satisfaction in hypothyroidism: the ThyTSQ. Value Health. 2006;9:132–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Quinque EM, Villringer A, Kratzsch J, Karger S. Patient-reported outcomes in adequately treated hypothyroidism—insights from the German versions of ThyDQoL, ThySRQ and ThyTSQ. Health Qual Life Outcomes. 2013;11:68.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Virili C, Santaguida MG, Cellini M, Del Duca SC, Gargano L, Centanni M. Pilot study with softgel thyroxine preparation in the treatment of patients with T4 malabsorption due to gastric disorders. Endocr Rev. 2013;34:Abstract OR50-4.Google Scholar
  27. 27.
    Collins D, Wilcox R, Nathan M, Zubarik R. Celiac disease and hypothyroidism. Am J Med. 2012;125:278–82.CrossRefPubMedGoogle Scholar
  28. 28.
    Centanni M. Thyroxine treatment: absorption, malabsorption, and novel therapeutic approaches. Endocrine. 2013;43:8–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Dorval E, Rey JF, Soufflet C, Halling K, Barthélemy P. Perspectives on gastroesophageal reflux disease in primary care: the REFLEX study of patient–physician agreement. BMC Gastroenterol. 2011;11:25.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Walker JN, Shillo P, Ibbotson V, et al. A thyroxine absorption test followed by weekly thyroxine administration: a method to assess non-adherence to treatment. Eur J Endocrinol. 2013;168:913–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Vinagre AL, Souza MV. Levothyroxine absorption and difficult management of hypothyroid patients in the intensive care unit: two case reports and a literature review. Rev Bras Ter Intensiva. 2011;23:242–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Centanni M, Gargano L, Canettieri G, et al. Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. N Engl J Med. 2006;354:1787–95.CrossRefPubMedGoogle Scholar
  33. 33.
    Lahner E, Virili C, Santaguida MG, Annibale B, Centanni M. Helicobacter pylori infection and drugs malabsorption. World J Gastroenterol. 2014;20:10331–7.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham Survey. Clin Endocrinol (Oxf). 1977;7:481–93.CrossRefPubMedGoogle Scholar
  35. 35.
    Wilson S, Parle JV, Roberts LM, et al. Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: a community-based cross-sectional survey. J Clin Endocrinol Metab. 2006;91:4809–16.CrossRefPubMedGoogle Scholar
  36. 36.
    Vanderpump MP. The epidemiology of thyroid disease. Br Med Bull. 2011;99:39–51.CrossRefPubMedGoogle Scholar
  37. 37.
    Ramadhan A, Tamilia M. Treatment-refractory hypothyroidism. CMAJ. 2012;184:205–9.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Ross DS, Daniels GH, Gouveia D. The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid function test in an out-patient endocrine clinic. J Clin Endocrinol Metab. 1990;71:764–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. Br J Gen Pract. 1993;43:107–9.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Cararis GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160:526–34.CrossRefGoogle Scholar
  41. 41.
    Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489–99.CrossRefPubMedGoogle Scholar
  42. 42.
    Vaisman F, Coeli CM, Ward LS, et al. How good is the levothyroxine replacement in primary hypothyroidism patients in Brazil? Data of a multicentre study. J Endocrinol Invest. 2013;36:485–8.PubMedGoogle Scholar
  43. 43.
    Vigário Pdos S, Vaisman F, Coeli CM, et al. Inadequate levothyroxine replacement for primary hypothyroidism is associated with poor health-related quality of life—a Brazilian multicentre study. Endocrine. 2013;44:434–40.Google Scholar
  44. 44.
    Bolk N, Visser TJ, Nijman J, et al. Effects of evening vs morning levothyroxine intake: a randomized double-blind crossover trial. Arch Intern Med. 2010;170:1996–2003.CrossRefPubMedGoogle Scholar
  45. 45.
    Rubio IG, Galrão AL, Santo MA, Zanini AC, Medeiros-Neto G. Levothyroxine absorption in morbidly obese patients before and after Roux-En-Y gastric bypass (RYGB) surgery. Obes Surg. 2012;22:253–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Knapton K, Myers S. A study of non-response patterns. Quirks Marketing Research Media. 2005. http://www.quirks.com/articles/a2005/20050106.aspx. Accessed 10 Dec 2015.
  47. 47.
    IMS Institute for Healthcare Informatics. Medicine use and shifting costs of healthcare. Danbury: IMS Health; 2014.Google Scholar
  48. 48.
    Ruchala M, Szczepanek-Parulska E, Zybek A. The influence of lactose intolerance and other gastro-intestinal tract disorders on l-thyroxine absorption. Endokrynol Pol. 2012;63:318–23.PubMedGoogle Scholar
  49. 49.
    Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18:988–1028.CrossRefPubMedGoogle Scholar
  50. 50.
    Bevan JS, Munro JF. Thyroxine malabsorption following intestinal bypass surgery. Int J Obes (Lond). 1986;10:245–6.Google Scholar
  51. 51.
    Network Scottish Intercollegiate Guideline. Management of diabetes: a national clinical guideline 116. Edinburgh: Healthcare Improvement Scotland; 2010.Google Scholar
  52. 52.
    Green PHR, Cellier C. Celiac disease. N Engl J Med. 2007;357:1731–43.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2015

Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • Marjorie McMillan
    • 1
    Email author
  • Keith S. Rotenberg
    • 2
  • Kevin Vora
    • 2
  • Arnold B. Sterman
    • 3
  • Lionel Thevathasan
    • 4
    • 5
  • Michael F. Ryan
    • 6
  • Munish Mehra
    • 7
  • Walter Sandulli
    • 2
  1. 1.McMillan Survey Research and Statistical ConsultingMemphisUSA
  2. 2.Akrimax Pharmaceuticals, LLCCranfordUSA
  3. 3.MorristownUSA
  4. 4.LT Associates LtdParisFrance
  5. 5.Department of NeuroscienceUniversity of OxfordOxfordUK
  6. 6.Medical/Marketing Decisions, LLCBridgewaterUSA
  7. 7.Quantum Change Group, LLCGaithersburgUSA

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