2B-05 - The association between GLP-1 RA initiation and cardiovascular events among patients treated with levothyroxine: A target trial emulation

Background:
GLP-1 receptor agonists (GLP-1RA) are effective therapies for patients with type 2 diabetes (T2D), offering benefits across key clinical outcomes, including weight loss. Hypothyroidism frequently co-occurs with T2D, with levothyroxine as the standard therapy. However, the narrow therapeutic range of levothyroxine increases the risk of iatrogenic hyperthyroidism and may lead to cardiovascular events. In patients receiving levothyroxine, initiation of GLP-1RA may alter their levothyroxine dose given weight reduction, leading to thyroid hormone over-replacement, which can elevate the risk of atrial fibrillation/flutter (AF/Aflutter) and stroke. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are ideal comparators because they share similar cardiometabolic indications with GLP-1RA but have minimal impact on weight loss, thyroid hormone absorption, or AF/Aflutter risk.


Objectives:
To investigate the impact of GLP-1RA initiation, compared to SGLT2 inhibitors, on risks of AF/Aflutter and stroke in patients with T2D treated with levothyroxine.


Methods:
We emulated an incident new-user design trial using 15% of U.S. Medicare beneficiaries from 01/01/2011 to 12/31/2020. Patients entered the base cohort once diagnosed with T2D, and then they were assigned to initiate GLP-1RA (exposure group) or SGLT2 inhibitors (control group). Eligible patients were aged > 65 years, continuously received a stable dose of levothyroxine for ≥6 months, with continuous Medicare enrollment and without malignant cancer during 1 year before the index date. We used 1:1 propensity score matching to balance covariates between study arms and mimic randomization. The primary outcome was AF/Aflutter, and secondary outcome was stroke, including ischemic stroke or transient ischemic attack. We assessed the per-protocol effect of using GLP-1RA vs. SGLT2 inhibitors on outcomes using weighted Cox proportional hazards models.


Results:
After matching, we included 2,384 patients in both GLP-1RA and SGLT2 groups with mean age (SD): 73.3 (5.9) vs. 73.2 (5.8), and 71.5% and 71.8% of female. The mean follow-up time was 0.75 years. The incidence rate of AF/Aflutter was significantly higher in the GLP-1RA group than SGLT2 group (0.74 vs. 0.71/100 person-years; HR: 1.46; 95%CI: 1.28–1.67). In contrast, no significant difference was observed between the two groups for stroke (0.74 vs. 0.49/100 person-years; HR: 1.17; 95% CI: 0.98–1.39).


Conclusions:
In patients with T2D treated with stable doses of levothyroxine, GLP-1RA initiation was associated with a higher risk of AF/Aflutter. These findings emphasize the urgent need for proactive thyroid monitoring and timely levothyroxine adjustment to reduce cardiovascular risk.