Over- and Undertreatment With Levothyroxine

Findings of the Population-Based Rhineland Study

Background: Levothyroxine is a very commonly prescribed drug, and treatment with it is often insufficient or excessive. Nonetheless, there have been only a few reports on the determinants of inadequate levothyroxine treatment.

Methods: Data from 2938 participants in the population-based Rhineland Study were analyzed. Putative determinants of inadequate levothyroxine treatment (overtreatment, thyrotropin level <0.56 mU/L; undertreatment, thyrotropin level >4.27 mU/L) were studied with logistic regression. The determinants of the levothyroxine dose were assessed with linear regression.

Results: Overall, 23% of the participants (n = 662) stated that they were taking levothyroxine. Among these participants, 18% were overtreated and 4% were undertreated. Individuals over 70 years of age and above were four times as likely to be overtreated (OR = 4.05, 95% CI [1.20; 13.72]). Each rise in the levothyroxine dose by 25 µg was associated with an increased risk of overtreatment (OR = 1.02, 95% CI [1.02; 1.03]) and of undertreatment (OR = 1.02, 95% CI [1.00; 1.03]). Well-controlled participants (normal thyrotropin levels 0.56–4.27 mU/L) received a lower levothyroxine dose (1.04 ± 0.5 µg/kg/d) than overtreated (1.40 ±0.5 µg/kg/d) or undertreated (1.37 ±0.5 µg/kg/d) participants. No association was found between sociodemographic factors or comorbidities and the levothyroxine dose. Iodine supplementation was associated with a lower daily dose (β = −0.19, 95% CI [−0.28; −0.10]), while three years or more of levothyroxine exposure was associated with a higher daily dose (β = 0.24, 95% CI [0.07; 0.41]).

Conclusion: Levothyroxine intake was high in our sample, and suboptimal despite monitoring. Our findings underscore the need for careful dosing and for due consideration of deintensification of treatment where appropriate.

Levothyroxine (LT4), the linchpin of thyroid hormone replacement therapy, is highly effective, inexpensive, and easy to administer (1, 2). LT4 use is increasing in many countries (3), most likely due to the increase in treatment of mild subclinical hypothyroidism (4, 5). In 2019, LT4 was the fourth most prescribed drug in Germany, with almost nine million prescriptions (6). A population-based study in Germany (age range 20 to > 80 years) reported a prevalence of LT4 use of 11%, while the Rhineland Study (age range 30–95 years) stated a prevalence of 24% (7, 8, 9). Studies in other European countries have reported prevalence rates of only 3–5% (10, 11, 12). These discrepancies may be attributable partly to regional differences in thyroid function parameters, thyroid diseases, or treatment protocols (13, 14).

The LT4 dosage is usually based on the serum level of thyrotropin (TSH). TSH must be monitored closely to avoid overtreatment, which causes high healthcare costs and adverse effects, or undertreatment, which has little clinical benefit (15, 16). Importantly, TSH levels outside the reference range are associated with adverse health outcomes, e.g., iatrogenic hyperthyroidism, increased cardiovascular morbidity/mortality, elevated fracture risk, and cognitive dysfunction (17, 18, 19). This is particularly true in older patients with suppressed TSH (20).

Despite the potential health risks, high rates of overtreatment (14–20%) and undertreatment (10–27%) have been described (10, 11, 12). However, these reports come from countries with a low prevalence of LT4 use compared with Germany. To date, only two studies have examined the quality of LT4 treatment in Germany. One of these (data from the period 1997–2001) reported over- and undertreatment rates of 19.5% and 10%, respectively (21), while the other (data from the years 2005–2018) reported only the cumulative risk (overtreatment 1.3%, undertreatment 3%) (22). The prevalence, however, was not reported, so the current burden in Germany remains unclear (22). A German study published in 2020 found that TSH levels are poorly monitored in LT4 users. Investigation of the current extent of over- and undertreatment is therefore needed (8).

Evidence on the determinants of over- and undertreatment and LT4 dose is also limited. Longer LT4 exposure duration and higher LT4 dose were associated with overtreatment, while men and younger persons were more likely to be undertreated (12). Age, sex, and body weight were associated with LT4 dosage, but these studies were conducted in older, obese patients or in patients who had undergone thyroidectomy (23, 24, 25).

The aim of the study described herein was to investigate the prevalence and determinants of LT4 over- and undertreatment, together with the determinants of LT4 dose, in a large-scale population-based study. Furthermore we evaluated information on the initiation, duration, and monitoring of treatment among LT4 users.

Methods

Study population

We used data from the Rhineland Study, a community-based cohort (eMethods, eTable 1). All residents (≥ 30 years) of two geographically defined areas in Bonn, Germany were invited to take part. The sole inclusion criterion was possession of sufficient German language skills to provide informed consent. The baseline data of the first 3000 participants (March 2016 to February 2020) with measured serum TSH were used. We excluded 62 participants due to incomplete TSH measurements (n = 2), missing medication data (n = 54), or because they were taking drugs that affected thyroid hormone levels (amiodarone/lithium; n = 6), so 2938 persons were included in the analyses. We also conducted a brief online survey in 2022 to obtain additional information on regular LT4 users (eMethods, eTable 2).

eTable 1

Definition of demographic and clinical characteristics

eTable 2

Prevalence of self-reported thyroid disease ever diagnosed by a doctor

TSH assessment

Blood samples were taken in the morning after a 10-hour fast. The laboratory defined the reference range of TSH as 0.56–4.27 mU/L (26). Details of blood collection and TSH measurement/reference range can be found in the eMethods.

LT4 treatment

All participants were asked to bring the original packaging of all medications they were currently using and had taken as needed in the past year. Data were collected by interview, documenting name, dosage, and current prescription status (9, 27). LT4 treatment status was categorized by TSH levels: adequate, i.e., controlled (0.56–4.27 mU/L), or inadequate, i.e. overtreatment (< 0.56 mU/L) or undertreatment (> 4.27 mU/L).

Statistical analysis

The participants’ characteristics were summarized using descriptive statistics. Group differences were calculated using logistic regression (adjusted for age and sex). Multinomial logistic regression was performed to identify possible determinants (eTable 1) of over- and undertreatment in LT4 users (reference group: controlled participants) in a fully adjusted model. Multivariable linear regression was then used to identify predictors of LT4 dose (µg/kg/d) in a fully adjusted model. Statistical analyses were conducted using RStudio (version 4.1.1).

Results

Study population

The participants’ characteristics are presented in Table 1 and eTable 2. The persons included (n = 2938) were on average 55 ± 14.4 years old (range 30–95; 56.5% women) and did not differ significantly from those who were excluded (n = 62) in terms of age (57 ± 14.9 years, range 30–87; p = 0.187) or sex ratio (women n = 34, 54.8%; p = 0.417).

Table 1

Characteristics of the study population

Overtreatment and undertreatment with LT4

Regular LT4 use was reported by 22.5% of the participants. Users were older than non-users (58.3 vs. 54.1 years; p < 0.001), and prevalence was higher in women than in men (33.3% vs. 8.6%; p < 0.001). Among LT4 users (n = 662), 78.2% were controlled (n = 518), while 21.8% (n = 144) were inadequately treated, of whom 17.7% (n = 117) were overtreated and 4.1% (n = 27) were undertreated.

Logistic regression showed that persons aged ≥ 70 years were four times more likely to be overtreated (odds ratio 4.05; 95% confidence interval [1.20; 13.72]) than those who were younger, and that increasing the LT4 dose by 25 µg/d increased the likelihood of both overtreatment (OR 1.02; [1.02; 1.03]) and undertreatment (OR 1.02; [1.00; 1.03]) (Table 2).

Table 2

Determinants of LT4 overtreatment and undertreatment

LT4 dose

Controlled persons had lower daily doses of LT4 (1.04 ± 0.5 µg/kg/d) than overtreated (1.40 ± 0.5 µg/kg/d) and undertreated (1.37 ± 0.5 µg/kg/d) persons, but adjustment for age and sex revealed no significant differences (Table 1). Figure 1 illustrates the LT4 doses (µg/kg/d) in relation to the TSH levels (mU/L) and shows individuals with very high and very low doses in all treatment groups. We found no association of sociodemographic factors or comorbidities with the daily LT4 dose. Iodine supplementation (β = –0.19; [–0.28; –0.10], p < 0.001) was associated with lower LT4 dose, and LT4 exposure duration (β= 0.24; [0.07; 0.41), p = 0.001) of ≥ 3 years was associated with a higher dose (Table 3).

Figure

LT4 dose (µg/kg/d) compared with TSH (mU/L), stratified by treatment status

Table 3

Determinants of LT4 dose

Online survey

The results of the survey are shown in eTable 3. The LT4 users who were included (n = 456; mean age 56.0 ± 13.0 years, range 30–94; 83.1% women) did not differ from those who were excluded (n = 206; mean age 56.0 ± 12.4 years, range 31–88; 84.4% women) in terms of age (p = 0.913) or sex (p = 0.613). Participants were predominantly long-term users (21.3 ± 12.2 years) and 60.4% reported having their TSH levels monitored every 6–12 months.

eTable 3

Results of the online survey

Discussion

We investigated the prevalence and determinants of overtreatment, undertreatment, and LT4 dosage in a large population-based cohort. A high proportion of participants, mainly women (women 33%; men 9%), reported taking LT4 (23%). Of these, 18% were overtreated and 4% undertreated. Older age was associated with overtreatment, while higher LT4 dose was associated with both overtreatment and undertreatment. Iodine supplementation was associated with lower LT4 dosage, whereas longer LT4 intake (≥ 3 years) was associated with higher doses.

LT4 is the most commonly used drug in our cohort (9). The frequency of use was higher in women than in men and increased with age, which was to be expected based on the prevalence of thyroid disease in these groups (11, 17, 28, 29). Importantly, the adverse health consequences of overtreatment are most pronounced in the elderly (20).

An increase in LT4 prescriptions has been observed worldwide, apparently mainly due to increased treatment of subclinical hypothyroidism with mild TSH elevation (30). Although treating mildly elevated TSH levels (< 10 mIU/L) is not recommended in the current guidelines (31), an American study found a median TSH of 5.3 mIU/L in 9331 patients newly started on LT4 treatment (5). This is worrying and shows how remarkable it is that the prevalence of LT4 use in our study is seven times higher than in other European studies (3.1–4.4%) (10, 11, 12) and more than twice as high as in other German population-based studies (~11%) (7, 8). Possible reasons for the differences between our study and other German studies are the period of data collection (2000–2016), different age and sex distributions, and regional variations in prescribing patterns, iodine availability, or thyroid disease (7, 8, 13, 14).

One explanation for the overall high prevalence of LT4 use in Germany may be the frequent use of TSH measurement and thyroid ultrasound (8). In Germany, there appears to be a strong focus on the thyroid both in detection of morphological changes and in drug therapy.

Indeed, the annual rate of thyroid surgery (109/100 000) is high compared with England (27/100 000) or the Netherlands (16/100 000), and thyroid hormone prescriptions increased by 40% between 2010 and 2019, when almost 9 million prescriptions were issued (6, 32). Additionally, a case-based survey found that German general practitioners were more likely to prescribe LT4 for patients with subclinical hypothyroidism than their colleagues in other European countries (33).

Approximately 18% of LT4 users were overtreated and 4% undertreated. Although the prevalence of LT4 use in our study is higher than in other studies, our results are comparable regarding overtreatment (14–20%), though not for undertreatment (10–27%) (10, 11, 12, 21). Given the high use of LT4 in our population, we expected higher rates of overtreatment. Perhaps we underestimate the prevalence of overtreatment (Figure 1), because controlled persons with low LT4 doses and low TSH levels could be overtreated as TSH levels would probably remain within the reference range after LT4 discontinuation. Whether these individuals require treatment cannot be conclusively established on the basis of our data. In some cases, e.g., patients with thyroid cancer (34), very low TSH is desirable so the levels are deliberately kept low. However, no individuals in our sample self-reported thyroid cancer, so the high prevalence of overtreatment cannot be justified in this way.

Similar to another German study (8), almost 60% of LT4 users in the Rhineland Study reported having their TSH levels monitored every 6–12 months, with no noticeable difference between controlled and inadequately treated persons (eTable 3). This demonstrates that frequent monitoring does not necessarily prevent inadequate treatment.

The likelihood of overtreatment was high in individuals ≥ 70 years, which is unsurprising as it has been reported that overtreatment is common in the elderly (35). Complex LT4 treatment regimens, with varying dosages across weekdays to achieve optimal titration, can become challenging with increasing age, especially as non-adherence rises with age (17). Among the LT4 users with suppressed TSH levels, 27% were aged ≥ 70 years. Importantly, suppressed TSH is particularly strongly associated with adverse health outcomes in the elderly (20). This makes the finding that 23% of all participants used LT4 all the more important.

Reducing the number of unnecessary LT4 prescriptions may improve health status and reduce healthcare costs. Future studies should aim to understand what factors contribute to use of LT4 by this extremely high proportion of people. In agreement with another study (12), the probability of over- and undertreatment rose with increasing LT4 dose. One can only speculate about the possible reasons for undertreatment despite high dosage. One possible explanation is lack of adherence to treatment, or reluctance on the part of physicians to increase the dose beyond a certain point for fear of adverse events. In contrast to a previous study, we did not find that men were more often undertreated than women, but we did observe a trend in that direction (12). This could be because thyroid disease is more common in women, and women more frequently receive TSH tests (8).

Both overtreated and undertreated participants had higher mean daily doses than controlled users. No associations were found between either sociodemographic factors or comorbidities and LT4 dosage. However, iodine supplementation was associated with lower daily doses, while LT4 exposure duration of ≥ 3 years was associated with higher daily doses.

Although there was no significant association between age and LT4 dose, younger persons tended to receive higher doses and older persons to receive lower doses, which is consistent with recent evidence that older persons should start with a low dose (24, 36).

Iodine, an important micronutrient, is known to control thyroid function by reducing the thyroid gland’s response to TSH. In high concentrations, iodine inhibits thyroid hormone secretion. Especially in persons with pre-existing thyroid disease, iodine can induce hypo- or hyperthyroidism (37). Therefore, correct dose adjustment in iodine supplementation is all the more important.

One possible reason for the association between the duration of LT4 intake and higher dosage is that treatment for thyroid hormone deficiency is usually started at a low dose and then increased by dose titration to achieve target TSH levels. Alternatively, thyroid function may decline progressively in patients who initially have subclinical hypothyroidism.

Strengths and limitations

One of the strengths of our study is the examination of both overtreatment and undertreatment in a large population-based cohort. Our extensive data allowed us to analyze various determinants, and self-reported medication data may better reflect actual use than secondary data. Although self-reported medication data may introduce reporting bias, we validated the reliability of our data (27).

Potential limitations include the fact that treatment adherence could not be considered. Furthermore, as is often the case in epidemiological studies (21), only one TSH measurement time point was available, so that our results cannot account for any TSH fluctuations (38). We did not have detailed information on whether and when dose adjustments were made. According to participants’ reports, however, the last dose adjustment had taken place on average 6 years earlier. Moreover, we do not have longitudinal data, so we could not follow changes in TSH levels or general health. Finally, our population may be “healthier,” which would limit the generalizability of our results. However, the prevalences of hypertension and polypharmacy and the age and sex distributions are all comparable with the German population (9, 27).

The prevalence of LT4 use in our population was very high and was suboptimal in almost a quarter of the participants despite frequent TSH monitoring. This high proportion of LT4 use is probably due to overtreatment in the vast majority of participants and, assuming that 18% of participants have suppressed TSH, will contribute to adverse health outcomes.

Conclusion

Our report suggests that the focus should be not only on intensification of treatment, but also on deintensification. Furthermore, the strategy for monitoring should be reconsidered, as it does not appear to lead to high-quality care at present.

Study funding

This work was supported by a grant provided by the Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany (V-15646/68502/2014–2016 and V-17746/68502/2018–2020).

Data sharing

The datasets for this manuscript are not publicly available because of data protection regulations. Access to data can, however, be provided to scientists in accordance with the Rhineland Study’s Data Use and Access Policy. Requests to access the datasets should be directed to Prof. Dr. Dr. Monique M.B. Breteler, [e-mail].

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 1 March 2023, revised version accepted on 7 August 2023.

Corresponding author

Dr. Folgerdiena M. de Vries
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)

Venusberg-Campus 1, Gebäude 99

53127 Bonn, Germany

Cite this as:
Alaeddin N, Jongejan RMS, Stingl JC, de Rijke YB, Peeters RP, Breteler MMB, de Vries FM: Over- and undertreatment with levothyroxine—findings of the population-based Rhineland Study. Dtsch Arztebl Int 2023; 120: 711–8. DOI: 10.3238/arztebl.m2023.0192

►Supplementary material
eMethods, eTables:
www.aerzteblatt.de/m2023.0192

References

1. Chaker L, Bianco AC, Jonklaas J, et al.: Hypothyroidism. Lancet 2017; 390: 1550–62

2. Eligar V, Taylor PN, Okosieme OE, et al.: Thyroxine replacement: a clinical endocrinologist’s viewpoint. Ann Clin Biochem 2016; 53: 421–33

3. Rodriguez-Gutierrez R, Maraka S, Ospina NS, et al.: Levothyroxine overuse: time for an about face? Lancet Diabetes Endocrinol 2017; 5: 246–8

4. Taylor PN, Iqbal A, Minassian C, et al.: Falling threshold for treatment of borderline elevated thyrotropin levels—balancing benefits and risks. JAMA Intern Med 2014; 174: 32

5. Brito JP, Ross JS, El Kawkgi OM, et al.: Levothyroxine use in the United States, 2008–2018. JAMA Intern Med 2021; 181: 1402–5

6. Schwabe U, Wolf-Dieter Ludwig: Arzneiverordnungs-Report 2020. Springer Berlin Heidelberg, 2020, 825–31

7. Khattak RM, Ittermann T, Nauck M, et al.: Monitoring the prevalence of thyroid disorders in the adult population of Northeast Germany. Popul Health Metr 2016; 14: 39

8. Kiel S, Ittermann T, Völzke H, et al.: Frequency of thyroid function tests and examinations in participants of a population-based study. BMC Health Serv Res 2020; 20: 70

9. de Vries FM, Stingl JC, Breteler MMB: Polypharmacy, potentially inappropriate medication and pharmacogenomics drug exposure in the Rhineland Study. Br J Clin Pharmacol 2021; 87: 2732–56

10. Wouters HJCM, Slagter SN, Muller Kobold AC, et al.: Epidemiology of thyroid disorders in the Lifelines Cohort Study (the Netherlands). PLoS One 2020; 15: e0242795

11. Janett-Pellegri C, Wildisen L, Feller M, et al.: Prevalence and factors associated with chronic use of levothyroxine: a cohort study. PLoS One 2021; 16: e0261160

12. Okosieme OE, Belludi G, Spittle K, et al.: Adequacy of thyroid hormone replacement in a general population. Qjm 2011; 104: 395–401

13. Girschik C, Muchalla P, Kowall B, et al.: [Regional Differences in Thyroid Function Parameters: A Comparison of European Cohort Studies]. Gesundheitswesen 2023; 85: 175–80

14. Meisinger C, Ittermann T, Wallaschofski H, et al.: Geographic variations in the frequency of thyroid disorders and thyroid peroxidase antibodies in persons without former thyroid disease within Germany. Eur J Endocrinol 2012; 167: 363–71

15. Lyu H, Xu T, Brotman D, et al.: Overtreatment in the United States. PLoS One 2017; 12: 1–11

16. Kearney M, Treadwell J, Marshall M: Overtreatment and undertreatment: time to challenge our thinking. Br J Gen Pract 2017; 67: 442–3

17. Effraimidis G, Watt T, Feldt-Rasmussen U: Levothyroxine therapy in elderly patients with hypothyroidism. Front Endocrinol (Lausanne) 2021; 12: 1–12

18. Blum MR, Bauer DC, Collet TH, et al.: Subclinical thyroid dysfunction and fracture risk. JAMA 2015; 313: 2055

19. Collet TH, Gussekloo J, Bauer DC, et al.: Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med 2012; 172: 1–7

20. Biondi B, Cooper DS: Subclinical hyperthyroidism. N Engl J Med 2018; 378: 2411–9

21. Hannemann A, Friedrich N, Haring R, et al.: Thyroid function tests in patients taking thyroid medication in Germany: results from the population-based Study of Health in Pomerania (SHIP). BMC Res Notes 2010; 3: 227

22. Kostev K: Frequency of over- and under-treatment with levothyroxine in primary care in Germany. Eur J Endocrinol 2022; 186: L5

23. Mele C, Tagliaferri MA, Pagano L, et al.: Levothyroxine replacement in obese Adults: the role of metabolic variables and aging on thyroid testing abnormalities. J Clin Endocrinol Metab 2019; 104: 6265–74

24. Jonklaas J: Sex and age differences in levothyroxine dosage requirement. Endocr Pract 2010; 16: 71–9

25. Devdhar M, Drooger R, Pehlivanova M, et al.: Levothyroxine replacement doses are affected by gender and weight, but not age. Thyroid 2011; 21: 821–7

26. Pellikaan K, Snijders F, Rosenberg AGW, et al.: Thyroid function in adults with prader—Willi Syndrome; a Cohort study and literature review. J Clin Med 2021; 10: 3804

27. Alaeddin N, Stingl JC, Breteler MMB, et al.: Validation of self-reported medication use applying untargeted mass spectrometry-based metabolomics techniques in the Rhineland study. Br J Clin Pharmacol 2022; 88: 2380–95

28. Canaris GJ, Manowitz NR, Mayor G, et al.: The colorado thyroid disease prevalence study. Arch Intern Med 2000; 160: 526–34

29. Åsvold BO, Vatten LJ, Bjøro T: Changes in the prevalence of hypothyroidism: the HUNT study in Norway. Eur J Endocrinol 2013; 169: 613–20

30. Bekkering GE, Agoritsas T, Lytvyn L, et al.: Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ 2019; 365: l2006

31. Peeters RP: Subclinical hypothyroidism. N Engl J Med 2017; 376: 2556–65

32. Verburg FA: Is thyroid surgery performed too often in Germany? Nuklearmedizin 2015; 54: 101–5

33. den Elzen WPJ, Lefèbre-van de Fliert AA, Virgini V, et al.: International variation in GP treatment strategies for subclinical hypothyroidism in older adults: a case-based survey. Br J Gen Pract 2015; 65: e121–32

34. Haugen BR, Alexander EK, Bible KC, et al.: 2015 American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016; 26: 1–133

35. Somwaru LL, Arnold AM, Joshi N, et al.: High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over. J Clin Endocrinol Metab 2009; 94: 1342–5

36. Gottwald-Hostalek U, Razvi S: Getting the levothyroxine (LT4) dose right for adults with hypothyroidism: opportunities and challenges in the use of modern LT4 preparations. Curr Med Res Opin 2022; 38: 1865–70

37. Leung AM, Braverman LE: Iodine-induced thyroid dysfunction. Curr Opin Endocrinol Diabetes Obes 2012; 19: 414–9

38. Weeke J, Gundersen HJ: Circadian and 30 minutes variations in serum TSH and thyroid hormones in normal subjects. Acta Endocrinol (Copenh) 1978; 89: 659–72

39. Schübel J, Voigt K, Uebel T Erhöhter TSH-Wert in der Hausarztpraxis S2k-Leitlinie. DEGAM Dtsch Gesellschaft für Allg und Fam eV 2023, (last accessed on 4 August 2023).