Assessing the Cardiovascular Effects of Levothyroxine Use in an Ageing United Kingdom Population (ACEL-UK): Cohort Study.

Levothyroxine therapy was associated with a protective effect against cardiovascular events in adults over 50 with subclinical hypothyroidism.

• Adjusted time-varying hazard ratio for CV events with LT4 use: HR 0.91 (95% CI, 0.87-0.97; P < .001)
• CV events were defined as angina, myocardial infarction, peripheral vascular disease, stent procedures, or stroke
• Study included 53,899 patients; 19,952 (37%) received LT4 and 33,947 (63%) did not
• Baseline median age was 67 years (IQR: 59-76 years); 68.5% female; median TSH 4.6 mU/L (IQR: 4.1-5.4 mU/L)

Levothyroxine therapy was associated with increased risk of bone events in adults over 50 with subclinical hypothyroidism.

• Adjusted time-varying hazard ratio for bone events with LT4 use: HR 1.21 (95% CI, 1.14-1.28; P < .001)
• Bone events were defined as fragility fractures or osteoporosis
• The increased bone risk was observed despite adjustment for relevant confounding factors
• Median follow-up duration was 10 years (IQR: 5.5-10.0 years)

Levothyroxine therapy was associated with increased all-cause mortality in adults over 50 with subclinical hypothyroidism.

• Adjusted time-varying hazard ratio for all-cause mortality with LT4 use: HR 1.17 (95% CI, 1.13-1.22; P < .001)
• This association persisted after adjustment for relevant factors in the time-varying Cox model
• The cohort was drawn from UK Primary Care patients in the Health Improvement Network (THIN) database
• The study was retrospective in design

TSH levels in the study population were in the subclinical hypothyroidism range with a relatively narrow distribution, reflecting a population near the upper limit of standard reference intervals.

• Median TSH at baseline was 4.6 mU/L (IQR: 4.1-5.4 mU/L)
• Standard TSH reference intervals do not reflect the tendency for TSH to rise with age, potentially leading to overdiagnosis of subclinical hypothyroidism in older adults
• The study population was predominantly female (68.5%) with a median age of 67 years
• The authors note this distribution may reflect overdiagnosis of SCH in ageing individuals whose elevated TSH may be physiologically normal

The study was a large retrospective cohort study of older UK primary care patients with subclinical hypothyroidism followed for a median of 10 years.

• Total cohort: 53,899 patients identified from the Health Improvement Network (THIN) UK primary care database
• Median follow-up was 10 years (IQR: 5.5-10.0 years)
• Inclusion criteria required age older than 50 years with subclinical hypothyroidism
• Time-varying hazard ratios were used to account for changes in LT4 prescribing status over follow-up, adjusted for relevant factors