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

Abstract Context Thyrotropin (TSH) levels tend to rise with age, but standard reference intervals do not reflect this, potentially leading to overdiagnosis of subclinical hypothyroidism (SCH) and excessive levothyroxine (LT4) prescriptions in older adults. Objective This work aimed to compare outcomes in adults older than 50 years with SCH who were either prescribed or not prescribed LT4. Methods A retrospective cohort study was conducted using data from UK Primary Care patients from the Health Improvement Network. The primary outcome was cardiovascular (CV) events (angina, myocardial infarction, peripheral vascular disease, stent procedures, or stroke). Secondary outcomes included bone events (fragility fractures or osteoporosis) and all-cause mortality. Time-varying hazard ratios (HRs) adjusted for relevant factors were estimated. Results This study included 53 899 patients (baseline median age 67 years (interquartile range [IQR]: 59-76 years); 68.5% female; median TSH 4.6 mU/L (IQR: 4.1-5.4 mU/L). Median follow-up duration was 10 years (IQR: 5.5-10.0 years). Of these, 19 952 (37%) received LT4 and 33 947 (63%) did not. LT4 therapy showed a protective effect against CV events (HR: 0.91; 95% CI, 0.87-0.97; P < .001) but increased risk of bone events (HR: 1.21; 95% CI, 1.14-1.28; P < .001) and all-cause mortality (HR: 1.17; 95% CI, 1.13-1.22; P < .001). Conclusion Our data suggest that LT4 therapy in older individuals with SCH is associated with a trade-off between the potentially beneficial effect on CV risk and the deleterious relationship with bone health and mortality risk. These risks need to be considered, mitigated, and discussed when LT4 therapy is being deliberated in older patients with SCH.