Levothyroxine Treatment of Subclinical Hypothyroidism and the Risk of Adverse Cardiovascular Events

Abstract

Importance: There is uncertainty as to whether treatment of subclinical hypothyroidism (SCH) is associated with cardiovascular outcomes. Objectives: To determine whether levothyroxine replacement therapy decreases the risk of major adverse cardiovascular events (MACE) among individuals with SCH defined as having a thyrotropin (TSH) level between 5 and 10 mU/L. Design: We conducted a population-based cohort study using a prevalent new-user design. Setting: The study utilized data from the United Kingdom Clinical Practice Research Datalink. Participants: We identified a base cohort of individuals aged ≥18 years with incident SCH defined as having at least two TSH levels between 5 and 10 mU/L within one year between 1998 and 2018. We matched 76,946 levothyroxine treated to 76,946 untreated individuals based on age, sex, calendar time, duration of SCH, and time-conditional propensity score. We compared individuals with SCH treated with levothyroxine with individuals with no treatment. Exposure: Levothyroxine treatment versus no treatment. Main Outcome Measures: The primary outcome, MACE, was defined as a composite of nonfatal myocardial infarction, nonfatal ischemic stroke, and cardiovascular-related mortality. Results: The mean age of the study cohort was 62.8 years, and 76.5% were women. During a median follow-up time of 1.6 years (interquartile range: 0.5-4.2), the incidence rate for MACE among individuals treated with levothyroxine was 12.8 per 1000 person-years; confidence interval (CI): 12.2-13.3 and 13.9 per 1000 person-years; CI: 13.4-14.3 among nontreated individuals. Levothyroxine treatment was associated with a small decreased risk of MACE (hazard ratio: 0.88; CI: 0.83-0.93). Conclusions: Levothyroxine treatment of SCH was associated with a small decreased risk of MACE. However, given the observational nature of the study, residual confounding should be considered in the interpretation of this finding.

Keywords: cardiovascular outcomes; levothyroxine; subclinical hypothyroidism.