Drug administration as a factor affecting levothyroxine therapy—results of the CONTROL surveillance II study

Introduction

Background

The standard of care for treating hypothyroidism is levothyroxine, a synthetic form of thyroxine (T4), which is the body’s natural thyroid hormone (1). Levothyroxine is a medication with a narrow therapeutic index. Ensuring proper dosage and maximum absorption is critical to therapeutic success.

Initial doses can range from 25–50 µg in individuals with milder forms of hypothyroidism, to larger doses of 88–175 µg (2). The American Thyroid Association (ATA) recommends taking levothyroxine 30–60 minutes before breakfast or before bedtime with at least a 3-hour interval from the evening meal (3).

Levothyroxine absorption can be influenced by many factors. When taken in a fasting state, up to 80% of levothyroxine can be absorbed (4). However, the absorption of levothyroxine can be limited by a variety of diseases of the gastrointestinal (GI) tract, including but not limited to inflammatory bowel disease, atrophic gastritis, celiac disease, H. pylori infection, gastroesophageal reflux disease (GERD), and gastroparesis (5). Other conditions which negatively affect the epithelium in the stomach or small intestine will also reduce or slow the absorption of levothyroxine (6).

Foods, beverages, dietary/nutritional supplements and medications such as proton pump inhibitors (PPIs), histamine receptor blockers, cholestyramine, and motility-modifying agents can adversely affect levothyroxine absorption (7). Patient behavior regarding the timing and administration of levothyroxine may also contribute to suboptimal levothyroxine absorption (8).

Levothyroxine requires adherence to strict administration guidance to achieve targeted thyroid stimulating hormone (TSH) levels and control of hypothyroid symptoms. This poses a challenge to both caregivers and patients. A common clinical approach often used to manage this challenge is physician-recommended dose changes. However, many clinicians do not fully appreciate the ill effects associated with frequent levothyroxine dose changes, especially the risk associated with excessive levothyroxine exposure. Data from multiple studies have demonstrated that exposure to supratherapeutic doses of levothyroxine is common, ranging from 14% to 22% of all patients (9). Excessive levothyroxine exposure has been associated with an increase in cardiovascular conditions such as atrial fibrillation, tachycardia, left ventricular hypertrophy, and poor diastolic relaxation (10). It has also been associated with unnecessary overutilization of healthcare resources (11), as well as significantly less patient satisfaction (12).

A deeper understanding of the factors that can influence patient adherence to levothyroxine’s strict administration guidance, and strategies that can enhance adherence, may help reduce unnecessary dose changes and overexposure, leading to better clinical outcomes.

Rationale and knowledge gap

The CONTROL Study program was conceived to describe the utilization of levothyroxine in clinical practice in the United States. The first of four studies, CONTROL Surveillance, surveyed 925 randomly selected patients taking levothyroxine for hypothyroidism (13). The primary objective was to quantify the prevalence of factors known to contribute to poor levothyroxine performance, which was defined by the number of dose titrations experienced by patients during a prior 12-month period. Almost one-third (31.8%) of respondents reported experiencing one or more dose changes; 8.3% reported more than two dose changes. Almost half of respondents reported having at least one comorbid condition that could adversely affect levothyroxine absorption [e.g., GERD, irritable bowel syndrome (IBS), lactose intolerance, or a history of gastric bypass surgery or bowel resection]. While most branded formulations do not contain lactose, varying generic formulations do contain lactose as an excipient with which tolerability issues might arise (14). Other interfering factors reported included the use of prescription medications (20.6%), or the consumption of foods (68.0%) and dietary supplements (51.8%) that are known to interfere with levothyroxine absorption.

Correlations were demonstrated between the presence of these interfering factors and levothyroxine dose changes.

Among the most important findings of the CONTROL Surveillance Study were those regarding how patients take levothyroxine. Up to 21% of participants reported taking levothyroxine within 30 minutes of eating breakfast; and 26.6% reported using over-the-counter (OTC) or prescription acid blockers that can influence the dissolution and absorption of levothyroxine tablet therapies (13). Other findings include the prevalent use of medications, vitamins, and supplements known to interfere with levothyroxine, such as calcium, or iron or foods such as soy or dairy products. Current Food and Drug Administration (FDA) guidance recommends avoiding coadministration of foods, supplements and drugs known to interfere with levothyroxine absorption. FDA labelling also cautions against concomitant use of levothyroxine tablet and capsule formulations with acid-reducing drugs such as PPIs, as this may result in incomplete drug absorption (15).

Objective

The current study sought to confirm the earlier findings from the CONTROL Surveillance Study and to further explore the reasons why patients adhere or do not adhere to FDA-recommended administration guidance for levothyroxine. The primary objective was to quantify the prevalence of improper drug administration, specifically how patients take levothyroxine, including the timing of administration and the co-ingestion of foods, beverages, vitamins, and supplements known to interfere with levothyroxine absorption. Secondary objectives included assessment of the information given by prescribers to patients relative to proper levothyroxine administration and the role of patient counselling in influencing patient adherence to such guidance. Correlation between levothyroxine administration adherence, therapy persistence and patient satisfaction with therapy was also analyzed. We present this article in accordance with the SURGE reporting checklist (available at https://aot.amegroups.com/article/view/10.21037/aot-2025-7/rc).

Methods

Primary methods

IBSA Pharma USA was the sponsor of the study. In conjunction with the Study Administrator, Way to Goal Inc., it developed the survey and was responsible for all aspects of the study. Survey questions were reviewed by board-certified endocrinology experts. Participants were selected from proprietary panel research of subjects maintained by Harmon Research Inc. of Anaheim, California. Each subject had previously agreed and consented to be a part of a panel to take surveys on various health-related topics. Recruitment into the panel is conducted across multiple digital channels, including major social media platforms such as LinkedIn, Facebook, Instagram, and TikTok, as well as through Google Ads. This multichannel approach allows Harmon to reach a broad and diverse population. (More information can be obtained by visiting https://www.harmonresearch,com). Study participants were informed of their data’s confidentiality and were given a statement indicating that their participation was voluntary and that withdrawal from the survey was possible at any point. The sponsor did not have access to patient-identifying information. The study enrolled 1,000 patients between the ages of 19 and 90 years old who self-reported to have been diagnosed with hypothyroidism by their clinician. Participants were chosen randomly. The invitation process incorporates randomization by selecting every nth eligible record to receive an email alert about a new survey opportunity. Once notified, panel members can log into their personal portal where they see a list of available surveys for which they may qualify, typically four to five surveys at any given time. This method of randomized email distribution and participant self-selection is a standard practice among commercial research panels and is designed to balance reach, feasibility, and diversity of response within target demographic criteria. Those who indicated interest were sent a link to a set of screening questions that evaluated their qualification for study inclusion. Participant identity was verified via double opt-in, digital fingerprinting, and validation of contact information. Respondents were provided all pertinent information related to the study including estimated survey duration, technology requirements such as a mobile phone, tablet or desktop/laptop, and honoraria for survey completion. Once qualified, respondents had the option to participate in the study and could click on a link that provided access. Participants could opt out at any time. Each was assigned a unique ID, and their entire participation history was recorded including inclusion and exclusion criteria. Duplicates were not allowed. Post-survey responses underwent manual review to ensure data quality, geographic eligibility, and the absence of duplicates or suspicious patterns. Persons who partially completed the survey were allowed to resume at any time. Prospective study subjects completed 9 screener questions. If a participant passed the screening criteria, he/she was asked to answer approximately 20 study questions (see Appendix 1). Time to complete the online survey was approximately 12–15 minutes. Quality control included pre-survey identity verification, in-survey screening for bots and low-effort responses, and post-survey manual review to remove incomplete, invalid, or duplicate entries. The survey was initiated in December 2023 and was completed in January 2024.

Compensation

Subjects were paid an honorarium of $25 upon completion of the survey and confirmation of contact information.

Inclusion criteria

A subject must have met the following criteria: (I) 19–90 years of age; (II) formally diagnosed with hypothyroidism by a healthcare provider; (III) currently taking levothyroxine monotherapy to treat hypothyroidism; (IV) taking levothyroxine for ≥1 year; (V) not currently pregnant; (VI) a US resident; (VII) voluntary agreement to provide informed consent.

Exclusion criteria

Any subject who met the following criteria were excluded: (I) not taking levothyroxine to treat hypothyroidism; (II) taking prescription medication to treat hypothyroidism for ≤1 year; (III) taking cytomel or generic liothyronine in addition to levothyroxine; (IV) currently pregnant.

Statistical methods

Demographic characteristics were presented using frequency and descriptive statistics. Frequency and descriptive statistics were also used to analyze categorical and continuous response sets. Cross-tabulation tables were created to present pertinent data across multiple survey questions of interest. Parametric and non-parametric between-subject analyses were performed in an exploratory fashion.

Frequency and percentage statistics were used to analyze the survey questions using categorical and “select all that apply” response sets. Descriptive statistics (mean, median, standard deviation, and interquartile range) were used for questions using continuous level response sets, such as a five-point scale. Cross-tabulation tables were created to present the frequencies and percentages of survey responses across multiple questions of interest. Parametric [independent samples t-test, one-way analysis of variance (ANOVA), and post hoc tests] and/or non-parametric (chi-square, Mann-Whitney U, Kruskal-Wallis, and Dunn’s test) between-subjects analyses were performed based on the meeting of statistical assumptions. These inferential analyses were all exploratory in nature. No adjustments were made to account for multiple comparisons. The frequency, descriptive, and inferential statistics were presented in tabular and visual formats. All analyses were performed using Q Professional Version 5.16.4.0 and statistical significance was assumed at a non-adjusted, two-sided alpha value of 0.05.

Sample size

Using a 95% confidence interval, a 3% margin of error, and a prevalence of 15–40% in the general population for GERD and H. pylori infections (7,13,16,17), a total sample size of 1,000 participants was needed to have adequate statistical power for purposes of yielding a generalizable measure of prevalence within the population of interest. There were no a priori hypotheses stipulated for the proposed inferential analyses.

Reporting of results

Way to Goal organized and analyzed the results, highlighting relevant research findings and implications.

Study ethics

Institutional review board

The protocol and appropriate related documents were reviewed and approved by Advarra of Columbia, MD, which was constituted and is functioning in accordance with International Council on Harmonization (ICH) E6, Section 3.

A signed letter of study approval from the Institutional Review Board (IRB) Chairman was sent to the Study Administrator (Way to Goal Business Insights) with a copy sent to the Sponsor (IBSA) prior to study initiation.

Ethical conduct of the study

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was conducted in accordance with the standard operating practices of IBSA, which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines.

Subject information and consent

Each subject was informed that participation in the study was voluntary and that he/she may withdraw from the study at any time. A waiver of informed consent was issued by Advarra.

Confidentiality of information

Way to Goal and IBSA followed all national, regional, and local laws with respect to privacy and data protection to ensure that the survey complied with all applicable industry standards. This included observing the following guidelines, among others:

• Voluntary cooperation of subjects;
• Protection of researchers’ and respondents’ identities;
• Terms & Conditions and privacy policies compliant with local laws;
• State-of-the-art data security policies and measures;
• Reliable and validated data procedures;
• Strict adherence to rules governing the interviewing of children and young people.

Results

Survey completion rates

More than three thousand respondents (3,029) requested to take the survey. Of these, 58% (1,759) did not meet the study’s inclusion criteria. Of the 1,270 who met the study’s criteria and initiated the survey, 79% (1,000) successfully completed it.

Demographics

Respondents to the survey were predominantly female (74%). Non-Hispanic whites represented 84% of study participants; Hispanic and black non-Hispanics represented 14%, and 2% reported as “other”. Most respondents were under the care of a primary care physician (PCP) for the treatment of their hypothyroidism (70%), followed by those treated by an endocrinologist (19%) or a mid-level practitioner such as a nurse practitioner or physician assistant (9%), or a thyroid specialist (2%). The majority (81%) reported taking levothyroxine to treat their hypothyroidism for 6 years or more; 61% for more than 10 years. About half are taking branded levothyroxine tablets (51%); the remainder reported taking generic levothyroxine tablet therapies (49%) (Figure 1). The median age of participants was 62 years. A description of the study population appears in Table 1.

Figure 1 About half are taking branded levothyroxine tablets (51%); the remainder reported taking generic levothyroxine tablet therapies (49%).

Comorbidities

Consistent with the initial CONTROL Surveillance Study, the prevalence of comorbid diseases or conditions, some of which could adversely affect the absorption of levothyroxine, was observed (18). Among study participants, 54% reported having GI comorbidities (Figure 2). Participants with GI comorbidities were more likely to report changes in levothyroxine dosing than those without such conditions (74% vs. 48%, P<0.05). These comorbidities were generally consistent with prevalence rates reported in the medical literature for the population at large (7,13,16-18) and included GERD/acid reflux (30%), IBS (8%), lactose intolerance, food allergies/sensitivities and celiac disease (7%), ulcerative colitis (3%), gastric bypass or bowel resection (3%), gastroparesis (2%) or Crohn’s disease (1%) (Figure 2). Results of the study did not specify who of the 3% selected gastric bypass or bowel resection. Ulcerative colitis is representative of inflammatory bowel disease, affecting the large bowel. Some data have shown that the associated inflammation may decrease levothyroxine absorption by increasing small intestinal permeability (19).

Figure 2 In addition to their levothyroxine, hypothyroid patients most commonly use prescription medication to treat GERD/acid reflux (30%), irritable bowel syndrome (8%), lactose intolerance/food allergies/celiac disease (7%), ulcerative colitis (3%), and gastric bypass or bowel resection (3%). GERD, gastroesophageal reflux disease.

Timing of levothyroxine administration

In the CONTROL Surveillance II study, 36% of participants reported taking levothyroxine outside of FDA-recommended guidance: daily on an empty stomach at least 30 minutes before eating breakfast. This includes 18% who take levothyroxine ≤30 minutes before eating, 7% who take levothyroxine inconsistently at different times of the day, 2% who take levothyroxine while eating and 9% who take levothyroxine <2 hours after eating (Figure 3). Most (93%) reported taking their levothyroxine consistently at the same time each day or on most days. When asked about the difficulty of taking levothyroxine each morning on an empty stomach at least 30 minutes before breakfast, most participants (77%) reported that they “have no problem” adhering to this regimen. However, 24% of study participants reported some degree of difficulty in adhering to this guidance.

Figure 3 36% of participants reported taking levothyroxine outside of FDA-recommended guidance: daily on an empty stomach at least 30 minutes before eating breakfast. This includes 7% who take levothyroxine at different times of day every day, 18% who take levothyroxine ≤30 minutes before eating, 2% who take levothyroxine while eating and 9% who take levothyroxine <2 hours after eating. FDA, Food and Drug Administration.

Administration of levothyroxine with water

In CONTROL Surveillance II, most participants (81%) reported taking levothyroxine with water; 16% with other liquids. These other liquids include black coffee (3% of respondents), coffee with milk/cream/non-dairy creamer (4%), tea (2%), juice (3%), soda (2%), and milk (2%). No respondents reported taking levothyroxine with soy milk (Figure 4).

Figure 4 A majority of participants (81%) reported taking levothyroxine with water; 16% with other liquids.

Ingestion of interfering foods/dietary supplements

Overall, 49% of study participants indicated that they take dietary supplements; 33% reported that they do so “always” or “often”. The most widely used vitamins and supplements cited were calcium (30% of respondents), iron (15%), potassium (15%) and selenium (5%). A majority reported using multivitamins (57%) or miscellaneous vitamins/ minerals (25%). Many of these products contain calcium, iron or other ingredients that are known to interfere with the absorption of levothyroxine and should be separated from levothyroxine by at least 4 hours (Figure 5) (15, 18). As many as 33% of study participants reported that they ingest vitamins and supplements “always” or “often” while taking levothyroxine.

Figure 5 The most widely used vitamins and supplements cited were calcium (30%), iron (15%), potassium (15%) and selenium (5%); a majority (57%) reported using multivitamins or miscellaneous vitamins/minerals (25%).

Use of interfering medication

In CONTROL Surveillance II, participants reported taking prescription or over-the-counter antacids (15%) or acid reducers (39%) on a frequent basis (Figure 6). The effects of these drugs on the performance of levothyroxine are well known. While both agents maintain different mechanisms of action, they may produce hypochlorhydria, affecting intragastric pH (15).

Figure 6 The majority (54%) reported taking prescription and over-the-counter antacids and/or acid reducers while 46% do not take any antacid or acid reducers frequently. Among those who take antacids or acid reducers, 54% reported taking prescription acid reducers and 67% use over-the-counter acid reducing medications on a frequent basis.

Gastric pH is required to dissolve levothyroxine tablets (18), and variability in the dissolution of T4 products can impact the oral absorption and bioavailability of T4 and may result in bioequivalence problems between various available products (20). All levothyroxine products, with the exception of one liquid formulation, have a class label that states that proton pump inhibitors may decrease T4 absorption. Only two subjects who participated in Control Surveillance II reported taking this formulation (Figure 1).

Changes in levothyroxine formulation or dose

The results of CONTROL Surveillance II were highly concordant, with 34% of respondents reporting having experienced one levothyroxine dose change in the prior 12 months; 15% reported ≥2 dose changes.

Like the original CONTROL Surveillance Study, participants who reported having concomitant GI disease were more likely to report changes in levothyroxine dosage. The frequent consumption of antacids and acid-reducing drugs was also correlated with more frequent dose changes (64% vs. 50%, P≤0.05). Patients who reported never consuming vitamins and supplements at the same time as levothyroxine were less likely to experience frequent levothyroxine dose changes (55% vs. 43%; P≤0.05).

Effectiveness of prescriber provided education

In CONTROL Surveillance II a significant number of patients (28%) did not recall prescriber instructions to take levothyroxine with water on an empty stomach ≥30 minutes before breakfast.

Similarly, 55% of participants did not recall being advised to avoid the coadministration of vitamins and supplements. Only 40% recalled discussion about the effects that acid-reducing drugs like PPIs can have on levothyroxine absorption (Figure 7).

Figure 7 While most patients (72%) recall their physician’s instructions to take levothyroxine with water on an empty stomach ≥30 minutes before breakfast, 28% report not receiving or don’t recall such instruction. Similarly, 55% do not recall being advised to avoid the coadministration of levothyroxine with vitamins and supplements; 60% do not recall being told about the inhibitory effects that acid reducing drugs like PPIs can have on levothyroxine absorption. PPIs, proton pump inhibitors.

Lack of awareness of proper levothyroxine administration was consistent among study participants, regardless of treating physician type. Among patients being treated by PCPs, 19% reported not being fully aware of important levothyroxine administration considerations. This compares with 17% of study participants who reported being treated by an endocrinologist/thyroid specialist. Despite this feedback, most respondents reported that they felt that interactions with their physicians were “positive”, “provided sufficient information”, and were “clear”.

Levothyroxine administration, treatment satisfaction and therapy persistence

CONTROL Surveillance II explored the role that levothyroxine administration guidelines may have on treatment satisfaction and therapy persistence. Participants who reported difficulty adhering to levothyroxine administration guidance were more likely to express dissatisfaction with their therapy versus those who did not have such difficulty (73% vs. 65%; P≤0.05). Similarly, participants who reported difficulty adhering to levothyroxine administration guidance were more likely to report stopping their prescribed medication for >1 month versus those who did not report difficulty adhering to medication administration guidance (25% vs. 10%; P≤0.05) (Table 2).

Other findings

In CONTROL Surveillance II most study participants (85%) expressed a desire to take an active role in decisions regarding their hypothyroidism treatment. Only a minority (15%) reported taking whatever medication their physician recommends. Many (53%) expressed a willingness to try alternative formulations of levothyroxine in lieu of oral solid versions of the drug. Patients who experienced frequent levothyroxine dose changes predictably reported being more open to such alternatives versus those who had not experienced dose changes (67% vs. 44%; P≤0.05). Those who reported difficulty adhering to FDA-approved levothyroxine administration guidance were also more likely to be receptive to alternative levothyroxine formulations (36% vs. 23%; P≤0.05) (Table 3).

Discussion

CONTROL Surveillance II is the first study to comprehensively assess patient knowledge of and compliance with levothyroxine administration guidance. It documents the widespread lack of patient adherence to such guidance and suggests a previously non-described link between patients’ ability to adhere to levothyroxine administration guidance, frequent levothyroxine dose and formulation changes, patient satisfaction with therapy and drug discontinuation. Equally important, it measures patient perceptions about the information provided by healthcare providers about levothyroxine.

Important findings

CONTROL Surveillance II confirms prior findings regarding the prevalence of GI conditions that may interfere with the absorption of levothyroxine tablet therapies. The rates of GERD/acid reflux, IBS, ulcerative colitis, lactose intolerance and gastric surgery observed in CONTROL Surveillance II mirror those observed in CONTROL Surveillance. Participants with underlying GI comorbidities were more likely to report changes in levothyroxine dosing than those without such conditions (74% vs. 48%, P<0.05).

The lack of reported awareness of the effects of PPIs on levothyroxine among study participants is particularly concerning. In a retrospective study of 1,491 levothyroxine-taking patients, Irving et al. demonstrated that the use of PPIs increased serum TSH concentrations by 0.12 mU/L (P<0.01) over a period of 6 months (21). Given the widespread availability of non-prescription PPI therapy, patient education about its effects on levothyroxine absorption would appear to be critical. However, managing levothyroxine in a world with non-prescription PPI therapy can be challenging. In a recent survey, only 58% of patients reported discussing their use of OTC drugs with their physicians (22).

Given the challenges that OTC drug use can pose, prescribers may wish to consider alternatives to levothyroxine tablet formulations. In a crossover comparison study with 15 healthy subjects who were administered IV esomeprazole 80 mg 30 minutes following administration of either a levothyroxine capsule or a branded levothyroxine tablet, levothyroxine drug levels were found to be 16% higher in patients taking the capsule formulation (23). In a single center, comparative bioavailability, open-label, randomized, single-dose, 3-period crossover pharmacokinetic study among patients administered omeprazole and a levothyroxine liquid administered in a monodose ampule, no statistically significant differences were found in the blood levels of levothyroxine when the liquid formulation was administered in the presence or absence of PPI therapy (24). Based on the results of this study, the FDA granted a labelling change for the liquid formulation studied, which removed cautionary language about its use in the presence of PPIs. Patients who demonstrate difficulty adhering to the FDA label guidance around levothyroxine use with interfering medications such as PPIs might benefit from a liquid formulation (25).

Strengths and limitations

The CONTROL Surveillance II Study was controlled and powered to determine statistically meaningful results and to provide key insights into the prevalence and causes of patient non-adherence to FDA-recommended administration guidance for levothyroxine. 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 the interpretation of results. Additionally, the self-reported data collected did not include the patient’s body weight and levothyroxine dosage; therefore, it is not possible to determine if any patients were on supratherapeutic doses. Because of the exclusion of important patient populations, the results of the trial cannot be generalized to the entire levothyroxine-taking population. CONTROL Surveillance II did not record whether patients were taking levothyroxine for thyroid hormone replacement or TSH suppression. It has been postulated that patients who have experienced thyroidectomy are more likely to remain adherent to levothyroxine therapy than those who have not experienced thyroidectomy (26).

Likewise, pregnant patients were also excluded from the study. While pregnant patients represent a small percentage of the total hypothyroid population, their treatment with levothyroxine can be challenging. This is particularly true considering the varying and rapid hormonal changes, weight fluctuations and GI disturbances that happen in pregnancy. Properly powered studies are warranted to assess levothyroxine administration adherence in both thyroidectomized and pregnant hypothyroid patients.

Comparison with previous research

Coffee and levothyroxine

In CONTROL Surveillance II most study participants reported taking levothyroxine within the FDA-recommended timeframe: 30 minutes before breakfast. Of concern are respondents who reported that current levothyroxine administration guidance is either inconvenient (10%) or impractical given their lifestyle (14%).

In CONTROL Surveillance II, 19% of respondents reported not habitually taking levothyroxine with water. When alternate liquids were consumed, coffee was their preferred choice indicated (7%) (Figure 4). Given the American tendency to consume coffee in the morning, the simultaneous consumption of levothyroxine and coffee consumption is not trivial. According to an American Coffee Association survey, up to 68% of Americans consume a cup of coffee within one hour after awakening; 28% within 15 minutes after awakening (27).

Prescribers are not always aware of the inhibitory effects of black coffee on the absorption of levothyroxine. Such an effect has been noted in the clinical literature. The proposed mechanism for this interaction is the sequestration of levothyroxine by coffee and in consequence, altered intestinal absorption of the drug (28). In a 2008 study, Benvenga et al. documented altered intestinal absorption of levothyroxine tablets caused by black coffee (29). Conversely, a subsequent study by Vita et al. demonstrated the lack of such an effect on a levothyroxine capsule formulation. During a 6-month period after switching from a daily routine of taking levothyroxine tablet therapies with water, TSH levels among patients switched to a daily regimen of taking levothyroxine capsules with black coffee were shown to be equivalent pre- and post-switch (0.34±0.30 vs. 0.41±0.46 mU/L (P=0.90) (30).

The use of vitamins and nutritional supplements with levothyroxine

Control Surveillance II confirms the widespread use of vitamins and nutritional supplements among patients taking levothyroxine. Many are unaware of the potential of these products to interfere with their thyroid medication. Only 45% of study participants reported having a discussion with their healthcare provider relative to the need to administer levothyroxine in the absence of certain vitamins and nutritional supplements. As with over-the-counter drugs, patients often overlook providing prescribers with details of their over-the-counter supplement use. In a survey of 31,044 patients, only 33.4% reported telling a conventional healthcare provider about their herb or nutritional supplement use (31).

The widespread use of multivitamins was also observed in CONTROL Surveillance II with more than half of study participants (57%) reporting consuming multivitamins ≥2 times per week (Figure 5).

Many multivitamins contain calcium or iron, nutrients known to interfere with levothyroxine. The prevalent use of these products among study participants is not surprising. In an analysis of NHANES 2003–2006, a nationally representative, cross-sectional survey, Bailey et al. estimated that multivitamins are the most widely consumed dietary supplement in the United States, with more than one-third of the population reporting daily use (32).

Comparison with prior study

The CONTROL Surveillance and CONTROL Surveillance II studies provide a comprehensive portrait of the levothyroxine-taking population in the United States. Comprehensively, these studies examined the use of levothyroxine in more than 1,900 adult hypothyroid patients. The results of both studies are highly congruent. However, some notable points of dissimilarity are worth noting. These include:

• Study population. As part of its study limitations discussion, the investigators in CONTROL Surveillance (2016) identified key population cohorts that were underrepresented in the study versus the known US hypothyroid patient population. Black and Hispanic subjects were two such groups. The greater numbers of Black and Hispanic study subjects in the CONTROL Surveillance II Study more closely represent the real-world prevalence of those patient populations. The percentage of male subjects in CONTROL Surveillance II also more closely resembles the real-world hypothyroid patient population. However, both studies overrepresent Caucasians. Knapton and Myers have reported the tendency of non-Caucasians to have lower response rates to online surveys. The reasons for this are unclear (33).
• Generic vs. brand formulations. Unlike CONTROL Surveillance I, a little more than half of study respondents in CONTROL Surveillance II (51%) reported taking branded levothyroxine formulations. This is not reflective of real-world use. In the United States, over 80% of levothyroxine prescriptions are filled with generic formulations (34).

The choice of levothyroxine formulation is of importance to many patients. In a 2021 retrospective analysis of the pharmacy records of 19,850 patients taking levothyroxine, Hennessey et al. noted that patients switched from branded to generic versions of levothyroxine were significantly more likely to experience out of range TSH levels compared with those who were maintained on their branded therapy (35). While choice of branded or generic levothyroxine may be an important clinical consideration, it is not relevant to determining patient adherence to levothyroxine administration guidance, as all levothyroxine therapies share the same product labelling. For this reason, participation in CONTROL Surveillance II was not restricted based on the use of branded or generic formulations.

Explanations of findings

The results of CONTROL Surveillance II suggest a correlation between levothyroxine administration, satisfaction with therapy, and therapy persistence. The 31% of study participants who reported levothyroxine administration to be “inconvenient” or “difficult to follow” were more likely to be dissatisfied with their treatment versus those who did not report such difficulty (73% vs. 65%; P≤0.05). The lack of therapy persistence among such patients was also noteworthy. Those who reported difficulty adhering to that levothyroxine administration were more likely to report stopping their prescribed medication for >1 month versus those who did not report such difficulty (25% vs. 10%; P≤0.05).

The correlations observed between administration guidance, treatment satisfaction and therapy persistence observed in our study are consistent with those seen in the clinical literature. In a systematic review of 20 published studies examining the link between treatment satisfaction and adherence, compliance, or persistence, Barbosa et al. observed that greater treatment satisfaction was associated with improved therapy persistence. This link was demonstrated for a large spectrum of diseases, such as osteoporosis, diabetes, psychosis, and glaucoma, in both clinical trials and observational studies. The authors also noted that greater treatment complexity, including unusual dosing or administration regimens, was correlated with lessened treatment satisfaction and poorer therapy persistence (36). The exception is Tirosint-SOL from IBSA Pharma. Only 2 participants in CONTROL Surveillance II reported taking this drug.

Implications and actions needed

Most study respondents positively rated the quality, clarity and usefulness of discussions with clinicians relative to levothyroxine therapy. However, suboptimal patient adherence to the drug’s strict administration guidelines and low patient awareness of the interaction between levothyroxine and commonly consumed foods, beverages, drugs and nutritional supplements suggest that there is significant room for improvement. In this regard, the results of CONTROL Surveillance II are congruent with those observed in other studies. A survey conducted by Shrestha et al. reported that most patients do not get enough information about their prescribed medication from their treating clinician and do not understand much of the information provided (37).

The barriers to effective clinician-patient communication have been documented extensively. For clinicians treating hypothyroidism, taking an accurate patient history is a critical first step in evaluating treatment options and improving the likelihood of therapy success. A thorough patient history should include asking patients about their use of non-prescription drugs, dietary habits and lifestyle. Identifying therapy-limiting factors early in the treatment process may help to avoid many of the frustrating problems frequently encountered with levothyroxine.

The Evaluation of Malabsorption in PATients with HYpothyroidism (EMPATHY) questionnaire, designed by Bellastella and colleagues, is a simple 7-question instrument that helps patients self-identify medical conditions and behaviors that can inhibit levothyroxine therapy. The authors validated their questionnaire in 300 newly diagnosed hypothyroid patients who were randomly assigned to two study groups. Subjects in Group 1 (n=150) were assigned to complete the EMPATHY questionnaire. Subjects in Group 2 (n=150) acted as a control and were not assigned to complete the questionnaire. The choice of thyroxine formulation and dose for each group was made based on answers provided by the questionnaire along with clinical history, or based on clinical history alone. Thyroid hormones and TSH were evaluated at enrollment and then every 2 months for 6 months. The number of the dose adjustments in the 6 months post-therapy initiation was recorded for each patient. Of the 150 patients in each group, 21 (14%) in Group 1 and 42 (28%) in Group 2 (P=0.005) needed ≥2 levothyroxine dose adjustments within 6 months. After 6 months of replacement therapy, 6 patients (4%) in Group 1 and 17 patients (11%) in Group 2 (P=0.03) did not have appropriately controlled hypothyroidism (TSH ≥2.5 mIU/L). A significantly higher levothyroxine final dose was found in Group 2 (148±33 µg/day) versus that found for Group 1 (136±28 µg/day; P=0.003). Based on these results, the authors concluded that the EMPATHY Questionnaire provides clinicians with a useful tool for pre-identifying factors that are known to interfere with levothyroxine and appropriately personalizing initial therapy to optimize therapeutic outcomes (38).

Conclusions

Levothyroxine has been the “gold standard” treatment for hypothyroidism for over 60 years. In 2020, it was the third most frequently prescribed drug in the United States with over 110 million prescriptions dispensed (34). In spite of its widespread use, therapeutic success with levothyroxine is often elusive. Its performance can be negatively affected by many patient characteristics and behaviors that are often unrecognized or underappreciated. The prevalence of these factors was reported in the original CONTROL Surveillance Study.

The CONTROL Surveillance II Study documents the prevalence of an additional factor that can negatively influence the performance of levothyroxine therapy: non-adherence to levothyroxine administration guidelines. Many patients are unaware or partially aware of how important it is to take levothyroxine within the recommended timeframe before meals, on an empty stomach with water. Likewise, many patients are unaware that their consumption of interfering foods, drugs or vitamins can negatively influence their therapy.

Our study demonstrates a correlation between the perceived complexity of levothyroxine administration, patient satisfaction with therapy and persistence to therapy. This finding is not a surprise. The relationship between drug administration complexity, patient satisfaction with therapy and therapy persistence has been noted elsewhere in the clinical literature (39). However, patient communication issues are not confined to explaining proper drug administration after a course of therapy has been determined. In the case of levothyroxine, important information often goes uncommunicated during initial patient encounters when relevant comorbidities, concomitant drug use and dietary habits can be discovered. Improved dialogue at this critical time may be aided by the use of a simple patient-administered questionnaire or other similar tools. These tools may help identify compromising patient characteristics or behaviors before therapy is initiated. Pharmacists and other healthcare professionals may also play a role in this regard by supporting the use of these tools and by counselling patients about the recommended way to take levothyroxine.

The results of CONTROL Surveillance II support the notion that clinicians should consider drug dosing and administration complexity when making hypothyroidism treatment decisions. Providing patients with multiple levothyroxine doses, every-other-day dosing, or biweekly dosing variations can negatively impact patient understanding of when and how to take their medication. For patients with known difficulty adhering to levothyroxine administration guidance, prescribers may consider a non-tablet formulation in lieu of tablet therapies.

Acknowledgments

The abstract was presented at the American Thyroid Association Annual Meeting, October 30–November 3, 2024, Chicago, Illinois, poster # 0328, and published in Thyroid. 34 (S1).

Footnote

Reporting Checklist: The authors have completed the SURGE reporting checklist. Available at https://aot.amegroups.com/article/view/10.21037/aot-2025-7/rc

Data Sharing Statement: Available at https://aot.amegroups.com/article/view/10.21037/aot-2025-7/dss

Peer Review File: Available at https://aot.amegroups.com/article/view/10.21037/aot-2025-7/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aot.amegroups.com/article/view/10.21037/aot-2025-7/coif). This study was supported by IBSA Pharma for the completion of the investigation. D.C.J., W.S. and M.C. are employees of IBSA Pharma Inc. D.G. and R.E.H. are outside consultants for IBSA Pharmaceuticals. Both Ways to Goal and Aesculapius Consulting Inc. are paid consultants of IBSA Pharmaceuticals. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was conducted in accordance with the standard operating practices of IBSA, which are designed to ensure adherence to GCP guidelines. The protocol and appropriate related documents were reviewed and approved by Advarra of Columbia, MD, which was constituted and is functioning in accordance with ICH E6, Section 3. A signed letter of study approval from the IRB Chairman was sent to the Study Administrator (Way to Goal Business Insights) with a copy sent to the Sponsor (IBSA) prior to study initiation. Each subject was informed that participation in the study was voluntary and that he/she may withdraw from the study at any time. A waiver of informed consent was issued by Advarra.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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