Levothyroxine (LT4) treatment was not associated with an increased risk for cardiovascular (CV) events among midlife and older women with hypothyroidism, and it may reduce CV risk in subclinical hypothyroidism in the broader adult population, found two studies presented at the American Thyroid Association (ATA) 2025 Meeting in Scottsdale, Arizona.

In the first study, researchers sought to evaluate the cardiac risks associated with possible unintended LT4 treatment-related fluctuations in circulating thyroid hormones in women transitioning through menopause, explained Matthew D. Ettleson, MD, an assistant professor of medicine in the Section of Endocrinology, Diabetes, and Metabolism at the University of Chicago, Chicago, and first author of both studies.

“The concern is that women with hypothyroidism are overtreated and undertreated at various times over the long course of LT4 treatment,” Ettleson told Medscape Medical News. The researchers hypothesized that these periods, evidenced by abnormal thyroid-stimulating hormone (TSH) levels, might increase the risk for CV events, particularly in women after menopause into early old age, he said.

To investigate, Ettleson and colleagues turned to the SWAN, a hallmark, multicenter, multiethnic, longitudinal study of midlife and older women.

Their study involved 2647 women, of whom 421 (15.9%) had LT4-treated hypothyroidism. The remainder were untreated control individuals without thyroid disease.

Significant differences between those with and without hypothyroidism included a higher rate of non-Hispanic White individuals (63% vs 44.7%) and higher median TSH levels (3.2 vs 1.8 mIU/L). Participants completed up to 17 follow-up visits over the course of the study.

Researchers found no significant differences between the treated and untreated groups in the primary outcome of CV events, defined as fatal and nonfatal myocardial infarction, stroke, heart failure, percutaneous coronary intervention, and coronary artery bypass graft surgery.

After a multivariate adjustment, LT4-treated hypothyroidism was not associated with an increased risk for any CVD event, fatal or nonfatal.

To take a closer look at those who may have been overtreated or undertreated, the researcher conducted a sensitivity analysis of the LT4-treated patients who had at least one abnormal TSH level (< 0.1 mIU/L or > 10 mIU/L). It showed an elevated risk for CV events among those patients; however, the difference did not reach statistical significance.

“In a diverse sample of women with long-term follow-up through the menopause transition, we observed no difference in the incidence of CVD events between those with LT4-treated hypothyroidism and those without thyroid disease,” the researchers concluded.

LT4’s Effect in Subclinical Hypothyroidism

In the second study, Ettleson and colleagues sought to evaluate whether LT4 treatment affects the increased CVD risk in subclinical hypothyroidism that was identified in other research.

They used the TriNetX Global Collaborative Network database to identify patients who had at least one TSH level between 4.5 and 10 mIU/L (the parameters for subclinical hypothyroidism) between 2005 and 2023. Patients prescribed LT4 within 1 year of the index event were assigned to the treated cohort. Those with no LT4 prescription and with a second TSH level between 4.5 and 10 mIU/L within 2 years were assigned to the control cohort.

Researchers performed 1:1 propensity score matching based on age, sex, race, ethnicity, BMI, TSH levels, type 2 diabetes, hypertension, and dyslipidemia. After matching, 46,153 patients were included in each cohort (LT4 group: mean age, 53 years; 65% women and no LT4 group: mean age, 54 years; 63% women).

Over a median follow-up of 6 years, those in the LT4 group had a reduced risk for all-cause mortality (hazard ratio [HR], 0.94), atrial fibrillation (HR, 0.84), major adverse cardiac events (HR, 0.91), and heart failure (HR, 0.89) compared with the no LT4 group.

LT4 use was associated with an increased risk for fractures (HR, 1.096) and a decreased risk for diabetes (HR, 0.84), dyslipidemia (HR, 0.91), and hypertension (HR, 0.84).

Treatment with LT4 was further associated with a reduced risk for all-cause mortality among women (HR, 0.895) and individuals younger than 65 years (HR, 0.87).

“The data supports a personalized approach to subclinical hypothyroidism treatment, with an emphasis on treatment in those under 65 years of age,” Ettleson said. “When we looked at older individuals, the benefit really wasn’t there.”

While controversy remains regarding the treatment of subclinical hypothyroidism, particularly with some reports that up to 30% of patients start LT4 despite having normal thyroid levels, the findings nevertheless suggest treatment benefits, notably for those younger than 65 years and for women, Ettleson said. He noted, however, that “reduction of CVD risk is just one part of making the decision to treat.”

“The findings really aren’t so different from current guidelines, but they add evidence from a large real-world dataset,” Ettleson added.

Findings Are ‘Reassuring’

Commenting on the research, David S. Cooper, MD, a professor of medicine and radiology in the Division of Endocrinology, Diabetes, and Metabolism at the Johns Hopkins University School of Medicine, Baltimore, noted that, in general, “the findings from both studies are reassuring that LT4 therapy may be of benefit and may not pose much harm.”

The potential effects on CV health of LT4 overtreatment examined in the SWAN research are “a big concern, since many studies have shown that a sizeable fraction of persons treated with LT4 end up being overtreated,” Cooper said. “This is especially true in the older population.”

Regarding the study of patients with subclinical hypothyroidism, the findings are potentially important because there are little data on CV outcomes with LT4 therapy in this patient population, Cooper noted.

“What is surprising are all of the other possible benefits — diabetes, hypertension, osteoporosis, etc.,” he said. “One wonders whether the treated group somehow was receiving a different intensity of medical care than the nontreated group, something that cannot be excluded completely by propensity score matching.”

Prospective, randomized trials are needed to confirm the findings, Cooper added.

“My personal opinion is to treat persons with subclinical hypothyroidism under age 65, especially those with serum TSH levels above 7 or 8 mIU/L, but to monitor thyroid function carefully to prevent iatrogenic hyperthyroidism,” he said. “Whether LT4 therapy in these patients should be stopped after age 65 or 70 years is an unanswered question.”

Ettleson and Cooper reported having no disclosures.