Professor Hong Tianpei: Looking back on 70 years of levothyroxine and looking forward to the future of hypothyroidism management

Introduction It has been more than 170 years since humans first recognized hypothyroidism (referred to as hypothyroidism), and levothyroxine (LT4) has also gone through 70 years in the treatment of hypothyroidism
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At the recent Merck Forum, Professor Hong Tianpei from the Department of Endocrinology, Peking University Third Hospital reviewed the 70-year history of LT4 in the treatment of hypothyroidism with colleagues, and made an in-depth interpretation of the following four hot topics in the clinical management of hypothyroidism
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Looking back on the past: 70 years of levothyroxine in the treatment of hypothyroidism 1 Professor Hong Tianpei pointed out that in 1850, Curling first reported the existence of thyroid deficiency in the autopsy reports of two children with growth retardation, which is the first time that humans have realized that the thyroid has a role in health.
important impact
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Since then, scholars such as Fagge, Gull, and Kocher have successively reported clinical manifestations related to hypothyroidism, which has made people gradually realize the causal relationship between thyroid and hypothyroidism
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LT4 was successfully developed in 1949, which overcomes the problem of poor intestinal absorption of thyroxine (T4), and was widely used soon after it was launched in Europe and the United States
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Since 2012, LT4 monotherapy has become the standard regimen for hypothyroidism replacement therapy recommended by domestic and foreign guidelines
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When LT4 was first launched, it did not require the supervision of the national drug regulatory authority.
Since then, the global regulation of LT4 content standards in LT4 tablets has gradually begun.
90%-105%) of the regulatory process (Figure 1), China raised the LT4 quality standard to 95%-105% in 2013
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In 2019, through the improvement of the formula, the content of the active ingredients has been increased to 95%-105%, which meets the strict quality standards in China, allowing more patients with hypothyroidism to achieve accurate and stable treatment, allowing more patients with hypothyroidism to achieve accurate and stable treatment.
benefit from it
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Figure 1.
Evolution of quality regulatory standards for levothyroxine tablets Looking to the future: Focus on a hot topic in hypothyroidism management 2 Is SCH related to CVD? Numerous studies have shown that there is a significant correlation between subclinical hypothyroidism (SCH) and cardiovascular disease (CVD), but what impact does SCH have on CVD? Professor Hong Tianpei pointed out: ✦ Effects on cardiovascular risk factors: Compared with the control group with normal thyroid function, whether it was SCH with thyroid stimulating hormone (TSH) < 10 mIU/L or SCH with TSH ≥ 10 mIU/L, Dyslipidemia such as elevated total cholesterol, elevated low-density lipoprotein cholesterol (LDL-C), and increased carotid intima-media thickness (CIMT) were also seen
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In addition, there is an increased risk of hypertension and insulin resistance in the SCH population
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✦ Impact on coronary heart disease risk: stratified by age, there is strong evidence that SCH is associated with an increased risk of coronary heart disease in young and middle-aged (<65 years old); in the elderly (≥65 years old), with a history of cardiovascular disease Or high-risk factors, TSH ≥10 mIU/L SCH subgroup, may increase the risk of coronary heart disease
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Stratified by TSH, among thyroid peroxidase antibody (TPOAb)-negative SCH patients, the risk of coronary heart disease increased with elevated TSH levels (test for trend, P = 0.
002) (Figure 2)
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Figure 2.
The effect of SCH with different TSH levels on the risk of coronary heart disease Increased risk; stratified by TSH, the SCH subgroup with TSH ≥10 mIU/L had an increased risk of heart failure
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In addition, in patients with established heart failure, SCH was associated with an increased risk of cardiovascular death or hospitalization for heart failure, suggesting that thyroid function may be a predictor of heart failure prognosis
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✦ Effects on the risk of cardiovascular death or all-cause mortality: stratified by age, in the young and middle-aged population, there is good evidence that SCH is associated with an increased risk of death; in the elderly population, SCH is not associated with an increased risk of death.
, only individual studies found an increased risk of death in high-risk subgroups of patients (Figure 3)
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Figure 3.
Association of SCH with Cardiovascular or All-Cause Death in Different Age Groups Should LT4 be considered for SCH? The question of whether SCH should intervene has been debated for 40 years
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Professor Hong Tianpei pointed out that the existing evidence shows: ✦ For young and middle-aged SCH populations: Studies have shown that LT4 treatment can improve cardiac function and reduce the risk of cardiovascular events in young and middle-aged SCH populations
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A meta-analysis showed that LT4 treatment also reduced the risk of all-cause mortality in young and middle-aged SCH populations (Figure 4)
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Figure 4.
The effect of LT4 treatment on the risk of all-cause mortality in different age groups with SCH Several studies have observed that LT4 can improve cardiac function in patients with chronic heart failure and SCH
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In addition, LT4 was not observed to reduce the risk of all-cause mortality
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✦ Effects on blood lipids: Current evidence shows that LT4 can reduce total cholesterol and LDL-C levels in patients with SCH, and may also reduce triglyceride levels, but the impact on high-density lipoprotein cholesterol (HDL-C) levels is currently unknown.
There are inconsistent and even conflicting findings
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✦ Effects on carotid intima-media thickness (CIMT): Available evidence suggests that LT4 can reduce CIMT in young and middle-aged SCH populations, suggesting that it may slow or prevent atherosclerosis progression
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✦ Effects on symptoms related to hypothyroidism: In the SCH population, data on the effect of LT4 on symptoms related to hypothyroidism are limited, and the results are conflicting
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✦ Effects on quality of life: Evidence from studies on the effect of LT4 on quality of life in SCH is limited and results are conflicting
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Nonetheless, existing quality-of-life scoring tools may not be sensitive enough to detect the modest effect of LT4 on quality of life in elderly patients with SCH
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Therefore, the current domestic and foreign guidelines and core reviews recommend LT4 for the treatment of SCH as follows: For SCH patients with TSH <10 mIU/L, individualized treatment decisions should be made according to the different clinical characteristics or special needs of the patients and the age of the patients.
; For SCH patients with TSH ≥10 mIU/L, LT4 therapy is recommended (Figure 5)
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Figure 5.
Are LT4/LT3 combination therapy considered in the current domestic and foreign guidelines and core review recommendations regarding SCH receiving LT4 therapy? Among patients with hypothyroidism whose TSH has been controlled within the normal range, 5% to 12% still have symptoms similar to hypothyroidism.
The most common symptoms are fatigue, lethargy, difficulty in weight control, and memory loss
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So should LT4/LT3 combination therapy be considered for such patients? Professor Hong Tianpei pointed out that, by summarizing the existing research data, compared with LT4 single-agent replacement therapy, whether LT4/LT3 combination therapy has additional benefits has conflicting results in different studies, mainly because the existing LT4/LT3 combination therapy.
Randomized controlled trials (RCTs) comparing treatment head-to-head with LT4 monotherapy have a number of design issues, including subject population, sample size, intervention regimen, duration of follow-up, and study endpoints
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Therefore, in 2021, the three major thyroid societies in the United States, Europe, and the United Kingdom jointly published an expert consensus, pointing out that future RCTs designing LT4/LT3 combination therapy should pay attention to three aspects: inclusion criteria, intervention program, and endpoint design (Figure 6)
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Figure 6.
Relevant considerations for expert consensus on designing future RCTs of LT4/LT3 combination therapy.
Impact of long-term LT4 therapy on bone metabolism in patients with clinical hypothyroidism or SCH? At present, there are few studies on the effect of clinical hypothyroidism or SCH on bone mineral density, and the conclusions of the studies are uncertain
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There seems to be some difference in the effects of clinical hypothyroidism and SCH on fracture risk.
Patients with clinical hypothyroidism have an increased fracture risk, while SCH is not associated with fracture risk
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So what are the effects of long-term LT4 treatment on bone mineral density and fracture risk in patients with clinical hypothyroidism or SCH? Professor Hong Tianpei pointed out: ✦ The effect of LT4 on bone mineral density: There is currently a lack of high-quality RCT studies in patients with clinical hypothyroidism, and the conclusions cannot be determined, but LT4 may accelerate the rate of bone turnover
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In SCH patients, recent studies suggest that LT4 does not affect bone mineral density
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✦ The effect of LT4 on fracture risk: There is a lack of high-quality RCT studies, and the conclusions are uncertain
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However, insufficient or excessive LT4 replacement therapy may increase fracture risk (Fig.
7)
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Figure 7.
Summary of the effect of long-term LT4 treatment on fracture risk in patients with hypothyroidism.
Through Professor Hong Tianpei’s wonderful explanation, we can understand that after 70 years of long development of LT4, LT4 has become the standard recommended replacement therapy for hypothyroidism.
, The State Food and Drug Administration's quality supervision standards for LT4 tablets also tend to be stricter, stipulating that the active ingredient LT4 content should reach 95%-105%
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In addition, Professor Hong Tianpei made targeted answers by summarizing the existing research evidence on some hot topics in the clinical management of hypothyroidism at this stage
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Although there are still some unresolved issues, it is believed that clearer answers will be obtained in the near future
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Expert profile Hong Tianpei Peking University Third Hospital ✫ Director of the Department of Endocrinology, Peking University Third Hospital, second-level professor, chief physician, doctoral tutor ✫ Vice-chairman of Chinese Medical Association Endocrinology Branch (CSE) ✫ Vice-chairman of Endocrinology and Metabolism Branch of Chinese Medical Doctor Association, etc.
✫ Served as Chinese Journal of Diabetes, Chinese Journal of Endocrinology and Metabolism, and International Journal of Endocrinology and Metabolism Deputy Editor-in-Chief of 6 other journals ✫ Lead the formulation of the People's Republic of China health industry standard "Diabetes Screening and Diagnosis" ✫ Main research directions are basic and clinical research on diabetes, stem cell differentiation research, endocrine and reproductive health research ✫ He has been in charge of national level And more than 20 provincial and ministerial scientific research projects, including 9 National Natural Science Foundation projects (7 general projects, 1 key project, 1 major research plan) ✫ More than 300 papers published in Chinese core journals
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JAMA and other well-known journals published more than 80 SCI papers✫ Won the 2018 National Famous Doctor-Excellent Achievement Award, 2017 CSE Outstanding Contribution Award-Kang Ankun Award, etc.
Source: Thyroid Academy