No Effect of Levothyroxine on Hemoglobin in Older Adults With Subclinical Hypothyroidism

Pooled Results From 2 Randomized Controlled Trials

Robert S. Du Puy; Rosalinde K. E. Poortvliet; Simon P. Mooijaart; David J. Stott; Terry Quinn; Naveed Sattar; Rudi G. J. Westendorp; Patricia M. Kearney; Vera J. C. McCarthy; Stephen Byrne; Nicolas Rodondi; Oliver Baretella; Tinh-Hai Collet; Diana van Heemst; Olaf M. Dekkers; J. Wouter Jukema; Johannes W. A. Smit; Jacobijn Gussekloo; Wendy P. J. den Elzen

Disclosures

J Clin Endocrinol Metab. 2022;107(6):e2339-e2347.

Abstract and Introduction

Abstract

Context: Subclinical thyroid dysfunction and anemia are common disorders, and both have increasing prevalence with advancing age.

Objective: The aim of this study was to assess whether levothyroxine treatment leads to a rise in hemoglobin levels in older persons with subclinical hypothyroidism.

Methods: This preplanned combined analysis of 2 randomized controlled trials included community-dwelling persons aged 65 years and older with subclinical hypothyroidism who were randomly assigned to levothyroxine or placebo treatment. The levothyroxine dose was periodically titrated aiming at thyroid stimulating hormone (TSH) level within the reference range, with mock titrations in the placebo group. The main outcome measure was the change in hemoglobin level after 12 months.

Results: Analyses included 669 participants (placebo n = 337, levothyroxine n = 332) with a median age of 75 years (range, 65–97) and mean baseline hemoglobin of 13.8 ± 1.3 g/dL. Although levothyroxine treatment resulted in a reduction in TSH from baseline after 12 months of follow-up compared with placebo, the change in hemoglobin level was not different between the levothyroxine and the placebo groups (−0.03 g/dL [95% CI, −0.16 to 0.11]). Similar results were found in stratified analyses including sex, age, or TSH levels. No difference in change of hemoglobin levels after 12 months was identified in 69 participants with anemia at baseline (−0.33 g/dL [95% CI, −0.87 to 0.21]).

Conclusion: In persons aged 65 years and older with subclinical hypothyroidism, treatment with levothyroxine does not lead to a rise in hemoglobin levels, regardless of the presence of anemia.

Introduction

Subclinical thyroid dysfunction and anemia are common disorders, and both have increasing prevalence with advancing age.^[1–4] The symptoms of both subclinical hypothyroidism and anemia are frequently nonspecific and of similar nature (e.g., fatigue, malaise, shortness of breath, and exercise intolerance).

A number of studies have suggested a potential causal relationship between thyroid dysfunction and hematopoiesis.^[5–8] Lower hemoglobin levels have been observed in persons with (subclinical) hypothyroidism compared with their euthyroid counterparts and small cohort studies have shown increases in hemoglobin and erythropoietin levels after treatment of overt hypothyroidism.^[8–17]

We reported earlier the results of an individual participant data meta-analysis using data from 16 independent observational cohort studies including more than 42 000 participants. In participants with both overt and subclinical hypothyroidism, we demonstrated a higher anemia prevalence.^[18] In addition, reduced thyroid function at baseline was associated with an increased risk of anemia during follow-up. To date, however, there is a lack of experimental evidence of the effect of levothyroxine treatment on hemoglobin levels in older persons with subclinical hypothyroidism.

The aim of this study was to assess whether levothyroxine treatment for subclinical hypothyroidism leads to a rise in hemoglobin levels in older persons. We performed a preplanned secondary outcome analysis of 2 randomized controlled trials on levothyroxine treatment for subclinical hypothyroidism in older persons.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Baseline characteristics of the study participants
	Placebo group	Levothyroxine group
N	337	332
Socio-demographic characteristics:
Age, median (range)	75 (65–97)	75 (65–93)
Male, no. (%)	160 (47.5)	163 (49.1)
MMSE, median (IQR)	29 (28–30)	29 (27–29)
Barthel Index, mean (SD)	19.6 (0.9)	19.7 (0.9)
Instrumental activities of daily living score, mean (SD)	13.6 (1.1)	13.7 (0.8)
Handgrip strength, kg	27.6 (11.1)	28.3 (10.6)
Body mass index, kg/m²	27.6 (4.4)	28.1 (5.2)
Systolic blood pressure, mmHg	143.3 (19.3)	141.6 (19.0)
Diastolic blood pressure, mmHg	75.4 (11.9)	74.1 (11.6)
Current smoker, no. (%)	24 (7.1)	25 (7.5)
Current alcohol user, no. (%)^a	213 (63.2)	187 (56.3)
Comorbidities, no. (%)^b	280 (83.1)	282 (84.9)
0–1	161 (47.8)	144 (43.4)
2–4	160 (47.5)	167 (50.3)
4+	16 (4.7)	21 (6.3)
Caucasian, no. (%)	331 (98.2)	328 (98.8)
Concurrent anti-anemic medication use, no. (%)^c	21 (6.2)	26 (7.8)
Thyroid function tests
TSH, median (IQR), mIU/L	5.8 (5.1 - 6.8)	5.8 (5.1 - 7.1)
fT4, pmol/L	13.4 (1.9)	13.4 (2.0)
Hematological parameters
Hemoglobin, g/dL^d	13.8 (1.3)	13.8 (1.3)
Men	14.3 (1.3)	14.3 (1.4)
Women	13.4 (1.1)	13.4 (1.1)
Anemia status, no. (%)^e
No anemia	293 (86.9)	294 (88.6)
Mild anemia	36 (10.7)	31 (9.3)
Moderate anemia	8 (2.4)	7 (2.1)
Severe anemia	0 (0)	0 (0)

Continuous data are presented as mean (SD) and, if stated otherwise, as median (IQR); categorical data are presented as number (percentage).
Abbreviations: fT4, free thyroxine; IQR, interquartile range; MMSE, Mini-Mental State Exam; TSH, thyrotropin (thyroid stimulating hormone);
^aDefined as an average of one or more self-reported consumed units of alcohol per week.
^bComorbidity was defined as having a history of one or more of the following: myocardial infarction, angina, stroke, transient ischemic attacks, heart failure, peripheral vascular disease, revascularization, atrial fibrillation, hypertension, diabetes mellitus, epilepsy, dementia, osteoporosis, or other.
^cConcurrent medication use was defined as using one or more of the following medications: iron supplements, parenteral iron preparations, vitamin B12, folic acid, erythropoietin, or other anti-anemic drugs.
^dConversion factor of hemoglobin from g/dL to mmol/L = value*0.6206.
^eAnemia defined by World Health Organization categories: women hemoglobin [Hb] < 12.0 g/dL, men Hb < 13.0 g/dL. Anemia severity was graded as: mild (women: 11.0 ≤ Hb ≤ 11.9 g/dL, men: 11.0 ≤ Hb ≤ 12.9 g/dL), moderate (all: 8.0 ≤ Hb ≤ 10.9 g/dL), severe (all: Hb < 8.0 g/dL).

Table 2. Baseline associations between thyroid function and hematologic parameters in 669 older participants with subclinical hypothyroidism
	Estimate	95% CI	P value
Thyroid function and hemoglobin	Beta
TSH
Univariable	−0.01	−0.06 to 0.04	0.649
Multivariable	−0.01	−0.06 to 0.04	0.736
fT4
Univariable	−0.05	−0.10 to 0.00	0.065
Multivariable	−0.03	−0.07 to 0.02	0.267
Thyroid function and anemia (n = 82)	Odds ratio
TSH
Univariable	1.04	0.93 to 1.16	0.523
Multivariable	1.03	0.91 to 1.17	0.595
fT4
Univariable	1.13	1.01 to 1.26	0.041
Multivariable	1.08	0.96 to 1.22	0.200

Units: TSH mIU/L; fT4 pmol/L. Betas and corresponding confidence intervals were calculated using linear mixed effect regression models and represent the difference in hemoglobin level (g/dL) per unit increase in TSH (mIU/L) or fT4 (pmol/L), Odds ratios with corresponding confidence intervals were calculated using logistic regression models, per unit increase in TSH or fT4. Multivariable models were adjusted for possible confounders age and sex.

Table 3. Changes in TSH, fT4, and hemoglobin levels in relevant subgroups in older participants with subclinical hypothyroidism on levothyroxine treatment, compared with placebo
	N	Baseline		12-month follow-up
	N	Placebo	Levothyroxine	Placebo	Levothyroxine	Treatment effect (95% CI)^a	P value
Effect on thyroid hormone levels ^b
TSH, mIU/L^b	660	6.3 (1.7)	6.5 (2.1)	5.5 (2.5)	3.6 (2.1)	−1.98 (−2.30 to −1.66)	<0.001
fT4, pmol/L ^b	177	13.4 (1.9)	13.4 (2.0)	12.4 (1.7)	14.7 (2.8)	2.33 (1.87 to 2.80)	<0.001
Effect on hemoglobin levels
Sex
Men	298	14.3 (1.3)	14.3 (1.4)	14.2 (1.5)	14.2 (1.5)	−0.05 (−0.26 to 0.15)	0.599
Women	320	13.4 (1.1)	13.4 (1.1)	13.4 (1.3)	13.4 (1.1)	0.01 (−0.16 to 0.17)	0.950
Age
< 80 years	466	14.0 (1.2)	13.9 (1.3)	14.0 (1.3)	13.8 (1.3)	−0.06 (−0.20 to 0.08)	0.412
≥ 80 years	152	13.4 (1.4)	13.6 (1.4)	13.3 (1.5)	13.5 (1.5)	0.10 (−0.23 to 0.44)	0.540
TSH
4.60 – 5.10	157	13.8 (1.2)	13.8 (1.3)	13.6 (1.3)	13.6 (1.4)	−0.09 (−0.32 to 0.13)	0.418
5.11 – 5.76	152	13.8 (1.4)	13.9 (1.2)	13.8 (1.7)	13.9 (1.3)	−0.03 (−0.35 to 0.29)	0.863
5.77 – 6.99	158	13.9 (1.2)	13.8 (1.3)	13.8 (1.5)	13.9 (1.4)	0.16 (−0.08 to 0.41)	0.188
> 7.0	151	13.8 (1.3)	13.8 (1.5)	13.8 (1.2)	13.8 (1.3)	−0.13 (−0.40 to 0.14)	0.336
Hemoglobin quartiles split by sex
Men
9.35 – 13.70	67	12.4 (0.8)	12.3 (1.1)	12.5 (1.2)	12.5 (1.4)	−0.26 (−0.95 to 0.44)	0.455
13.71 – 14.50	93	14.2 (0.3)	14.1 (0.3)	14.3 (0.7)	14.0 (0.7)	−0.20 (−0.70 to 0.30)	0.419
14.51 – 15.20	60	15.0 (0.2)	14.9 (0.2)	14.4 (1.5)	14.8 (0.7)	−0.09 (−0.52 to 0.34)	0.680
15.21 – 17.24	73	15.8 (0.4)	15.8 (0.5)	15.5 (0.8)	15.4 (1.1)	0.03 (−0.30 to 0.35)	0.877
Women
9.67 – 12.73	79	11.9 (0.8)	12.1 (0.5)	12.0 (1.3)	12.1 (0.9)	0.04 (−0.35 to 0.43)	0.842
12.74 – 13.40	84	13.1 (0.2)	13.2 (0.2)	13.0 (0.8)	13.3 (0.6)	0.02 (−0.21 to 0.25)	0.858
13.41 – 14.02	76	13.8 (0.2)	13.7 (0.2)	13.8 (0.5)	13.7 (0.7)	−0.19 (−0.55 to 0.18)	0.317
14.03 – 16.30	81	14.7 (0.4)	14.7 (0.6)	14.6 (0.9)	14.4 (0.8)	−0.13 (−0.55 to 0.29)	0.540
Anemia at baseline
No anemia	549	14.1 (1.0)	14.1 (1.1)	14.0 (1.2)	14.0 (1.2)	0.01 (−0.12 to 0.15)	0.886
Anemia	69	11.6 (0.8)	11.6 (0.8)	11.9 (1.3)	11.8 (1.2)	−0.33 (−0.87 to 0.21)	0.233

^aTreatment effects were calculated using linear mixed effect regression models adjusting for study site, study, treatment dose at randomization, age and sex and represent the additional change in hemoglobin level (g/dL) after 12 months of treatment with levothyroxine, compared with placebo. In stratified analysis the stratifying variable was not an adjusting variable for that analysis.
^bTreatment effects represent the additional change in TSH (mIU/L) or fT4 (pmol/L) after 12 months of treatment with levothyroxine, compared with placebo. Anemia defined by World Health Organization categories: Women hemoglobin (Hb) < 12.0 g/dL, men Hb < 13.0 g/dL.

Authors and Disclosures

Robert S. Du Puy¹, Rosalinde K. E. Poortvliet¹, Simon P. Mooijaart^2,3, David J. Stott⁴, Terry Quinn⁴, Naveed Sattar⁵, Rudi G. J. Westendorp^6,7, Patricia M. Kearney⁸, Vera J. C. McCarthy⁹, Stephen Byrne¹⁰, Nicolas Rodondi^11,12, Oliver Baretella^11,12, Tinh-Hai Collet¹³, Diana van Heemst², Olaf M. Dekkers¹⁴, J. Wouter Jukema^15,16, Johannes W. A. Smit¹⁷, Jacobijn Gussekloo^1,2 and Wendy P. J. den Elzen^18,19

¹Department of Public Health and Primary Care, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
²Department of Internal Medicine, section Gerontology and Geriatrics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
³Institute for Evidence-based Medicine in Old age, 2333 ZA Leiden, the Netherlands
⁴Department of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G4 0SF, UK
⁵Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK
⁶Department of Public Health, University of Copenhagen, 1353 Copenhagen, Denmark
⁷Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark
⁸School of Public Health, University College Cork, Cork T12 K8AF, Ireland
⁹School of Nursing and Midwifery, University College Cork, Cork T12 AK54, Ireland
¹⁰School of Pharmacy, University College Cork, Cork, Cork T12 YT20, Ireland
¹¹Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland
¹²Institute of Primary Health Care (BIHAM), University of Bern, 3012 Bern, Switzerland
¹³Service of Endocrinology, Diabetes, Nutrition and Therapeutic Education, Geneva University Hospitals, 1205, Switzerland
¹⁴Department of Endocrinology and metabolic disorders, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
¹⁵Department of Cardiology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
¹⁶Netherlands Heart Institute, 3511 EP Utrecht, the Netherlands
¹⁷Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
¹⁸Atalmedial Diagnostics Centre, 1066 EC Amsterdam, the Netherlands
¹⁹Amsterdam UMC, Department of Clinical Chemistry, Amsterdam Public Health Research Institute, 1081 HV Amsterdam, the Netherlands

Correspondence
Rosalinde Poortvliet, Department of Public Health and Primary Care, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands. Email: r.k.e.poortvliet@lumc.nl

Author Contributions
R.S.D.P., S.P.M., D.J.S., and W.P.J.d.E. had full access to the study data and manuscript and take responsibility for the integrity of the work as a whole. Study concept and design: J.G., P.M.K., S.P.M., N.R., D.J.S., R.G.J.W. Acquisition, analysis, and interpretation of the data: R.S.D.P., W.P.J.d.E. Drafting of the manuscript: R.S.D.P., W.P.J.d.E. Critical revision of the manuscript for important intellectual content: R.P., S.P.M., D.J.S., T.Q., N.S., R.G.J.W., P.M.K., V.J.C.M., S.B. Funding European Union, Swiss National Science Foundation, and ZonMw: N.R., O.B., T.H.C., J.G., O.M.D., J.W.J., J.W.A.S., D.v.H. Statistical analysis: R.S.D.P., W.P.J.d.E. Obtained funding: J.G., S.P.M., D.J.S., N.R., R.G.J.W., P.M.K. Administrative, technical, or material support: Supervision: J.G., S.P.M., N.R., D.J.S., R.G.J.W.

Disclosures
The authors have nothing to disclose. The sponsors and funding bodies had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
N.R. received research grants from the Swiss National Science Foundation (SNSF 320030–150025 and 320030–172676), the Swiss Heart Foundation and an investigator-driven grant Velux Stiftung (grant 974a). T.C. received research grants from the Swiss National Science Foundation (PZ00P3-167826), the Swiss Society of Endocrinology and Diabetes, the Leenaards Foundation, and the Vontobel Foundation. D.v.H. received research grants from the European Union Horizon 2020 research and innovation programme (Thyrage, 666869). All other authors declare no competing interests.

Declaration of Interests
The TRUST Thyroid trial was supported by research grant (278148) from the European Union FP7-HEALTH-2011 program. Dr. Rodondi is supported to study thyroid dysfunction by research grants from the Swiss National Science Foundation (320030-172676 and 32003B_200606 to Prof. Rodondi). Other financial support for the TRUST trial in Switzerland was supplied by grants from the Swiss Heart Foundation (to Dr. Rodondi), and an investigator-driven grant from Velux Stiftung (974a to Dr. Rodondi). The IEMO 80-plus Thyroid trial was supported by research grant (627001001) from ZonMw under the ZonMw programme Evidence-based Medicine in Old age and by grants from the Swiss National Science Foundation (SNSF 320030–150025 and 320030–172676 to Dr. Rodondi). Study medication (levothyroxin and matching placebo) was supplied free of charge by Merck KGaA. Dr Collet's research is supported by grants from the Swiss National Science Foundation (PZ00P3-167826), the Swiss Society of Endocrinology and Diabetes, the Leenaards Foundation, and the Vontobel Foundation. The research of Dr. van Heemst is supported by a grant from the European Union Horizon 2020 research and innovation programme (Thyrage, 666869). All other authors declare no competing interests. The sponsors and funding bodies had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.