Chinese researchers are set to launch a multicenter clinical trial investigating whether levothyroxine treatment can reduce cardiovascular disease risk in older adults with subclinical hypothyroidism (SCH). The study will be the first to use age-specific thyroid-stimulating hormone (TSH) reference ranges for diagnosing SCH in elderly patients.
The open-label, randomized controlled trial will recruit 230 participants aged 65 and older from three medical institutions in Jiangsu Province, China. Recruitment is scheduled to begin in December 2024 and continue through November 2025.
Study Design and Methodology
Participants will be randomly assigned to either receive levothyroxine (Merck Euthyrox®) or undergo observation only. The treatment group will start with a daily dose of 50 μg (or 25 μg for those weighing less than 50 kg), with adjustments made based on TSH levels throughout the 48-week follow-up period.
"This is the first multicenter trial using age-specific TSH reference ranges to accurately identify subclinical hypothyroidism in older adults," said the research team. "Previous studies may have misdiagnosed elderly patients by applying standard adult reference ranges."
The trial will use population-specific TSH reference values established in previous research: 0.65–5.51 mIU/L for ages 65–69, 0.85–5.89 mIU/L for ages 70–79, and 0.78–6.70 mIU/L for those 80 and older.
Primary and Secondary Endpoints
The primary endpoint will be changes in carotid intima-media thickness (CIMT) and maximum plaque thickness between baseline and the final visit at 48 weeks. CIMT is considered a validated surrogate marker for cardiovascular disease risk, with research showing that a reduction of 10 μm per year correlates with a 16% decrease in relative cardiovascular risk.
Secondary endpoints include:
- Incidence of fatal and non-fatal cardiovascular events
- Changes in blood lipid profiles (total cholesterol and LDL-C)
- Changes in bone mineral density at the lumbar spine and femoral neck
"Using CIMT as our primary endpoint allows us to assess cardiovascular risk with a much smaller sample size than would be required for clinical cardiovascular events," the researchers explained. "A 10-μm reduction in CIMT over one year would suggest meaningful cardiovascular risk reduction."
Clinical Significance
Subclinical hypothyroidism affects a significant portion of the elderly population, but its diagnosis and management remain controversial. Current guidelines often apply the same TSH reference ranges to all adults, potentially leading to overdiagnosis in older individuals whose TSH levels naturally increase with age.
The researchers note that in iodine-adequate areas, the 97.5th percentile reference value for TSH increases by approximately 0.3 mIU/L for every decade after age 30. When using age-specific reference ranges, the prevalence of SCH in older adults drops dramatically from nearly 20% to just 3.3%.
This study builds upon the TRUST trial, which was previously the largest RCT examining levothyroxine therapy in elderly SCH patients. However, TRUST did not use age-adjusted TSH thresholds and was unable to fully assess cardiovascular outcomes due to reduced sample size.
Comprehensive Assessment
The trial will include thorough baseline and follow-up assessments, including:
- Vascular ultrasound to measure CIMT and plaque burden
- Dual-energy X-ray absorptiometry (DXA) scans for bone mineral density
- Blood tests for thyroid function and lipid profiles
- Comorbidity assessment using the Charlson Comorbidity Index
- Nutritional status evaluation including urinary iodine-to-creatinine ratio
Participants will be closely monitored with follow-up visits at 4, 8, 12, 24, and 48 weeks. SMS and email reminders will be sent every two weeks to improve adherence, and medication compliance will be assessed using pill counts.
Safety Monitoring
An independent data and safety monitoring committee will oversee the trial, with adverse events graded according to the Common Terminology Criteria for Adverse Events. The researchers will monitor for potential complications including heart failure, arrhythmias, myocardial infarction, stroke, and hyperthyroid crisis.
The study has been approved by the ethics committees of the Affiliated Suqian Hospital of Xuzhou Medical University and the Affiliated Nanjing University of Chinese Medicine Nanjing Integrated Traditional Chinese and Western Medicine Hospital. It is registered on the Chinese Clinical Trial Registry (ChiCTR2400092634).
Looking to the Future
The findings from this trial could significantly impact clinical practice by providing evidence-based guidance for the diagnosis and treatment of subclinical hypothyroidism in older adults.
"Our results will help determine whether levothyroxine therapy provides cardiovascular benefits in elderly patients with subclinical hypothyroidism when diagnosed using age-appropriate criteria," the researchers stated. "This could lead to more precise and personalized treatment approaches for this common condition."
The researchers acknowledge some limitations, including the inability to perform subgroup analyses due to sample size constraints and the focus on Chinese participants, which may limit generalizability to other ethnicities. Nevertheless, this study represents an important step toward optimizing thyroid management in the elderly population.
