Initiation of GLP-1 receptor agonists (GLP-1RA) was associated with a 46% higher risk of compared to sodium-glucose cotransporter 2 (SGLT2) inhibitors.
The study involved 2,384 Medicare beneficiaries aged over 65, all on stable doses.
Mean age of participants was approximately 73 years, with a majority being female (71.5% in GLP-1RA group and 71.8% in SGLT2 group).
Median follow-up time for participants was 1.05 years.
No statistically significant difference in stroke risk was found between GLP-1RA and SGLT2 inhibitors (HR: 1.17; 95% CI: 0.98-1.39).
Sensitivity analyses confirmed the higher risk of AF/Aflutter associated with GLP-1RA initiation.
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BACKGROUND: Initiation of Glucagon-Like Peptide-1 receptor agonists (GLP-1RA) in patients with type 2 diabetes (T2D) treated with may decrease the required levothyroxine dose due to weight loss or enhance levothyroxine absorption through delayed gastric emptying. These changes may cause thyroid hormone over-replacement and increased risk of (AF/Aflutter) and stroke. Our study aims to investigate the impact of GLP-1RA initiation on risks of AF/Aflutter and stroke in patients with T2D treated with levothyroxine, compared to sodium-glucose cotransporter 2 (SGLT2) inhibitors.
METHODS: Leveraging the target trial emulation framework, we conducted a retrospective study using observational data to emulate a new user, active comparator trial examining the effects of initiating GLP-1RA (exposure group) versus SGLT2 inhibitors (control group), with random treatment assignment emulated by propensity score matching with 1:1 ratio. We used a 15% nationally representative sample of U.S. Medicare beneficiaries to identify participants > 65 years, continuously on stable dose of levothyroxine for ≥ 6 months before the index date (i.e., GLP-1RA or SGLT2 inhibitor initiation), with continuous Medicare enrollment, without malignant cancer or palliative care during 1 year before the index date. The primary outcome was AF/Aflutter, and secondary outcome was stroke, including ischemic stroke or transient ischemic attack. We assessed the per-protocol effects of GLP-1RA vs. SGLT2 inhibitors using inverse-probability-censoring weighted Cox proportional hazards models.
RESULTS: After matching, the study cohort included 2,384 participants 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 median follow-up time was 1.05 years. Compared to SGLT2 inhibitors, initiation of GLP-1RA was associated with higher risk of AF/Aflutter (HR: 1.46; 95% CI: 1.28-1.67), while no statistically significant difference was observed between the two groups for stroke (HR: 1.17; 95% CI: 0.98-1.39). Sensitivity analyses showed consistent results, including restricting outcomes to inpatient visits, conducting an intention-to-treat analysis, applying a prevalent new user design, and substituting SGLT2 inhibitors with dipeptidyl peptidase-4 (DPP4) inhibitors as the active comparator.
CONCLUSIONS: In patients with T2D historically treated with stable doses of levothyroxine, GLP-1RA initiation was associated with a higher risk of AF/Aflutter. Further research is warranted to investigate the potential roles of weight loss, TSH fluctuations, and levothyroxine dose adjustment after GLP-1RA in mediating the cardiovascular risk.
Key numbers
1.46
Increase in Risk
comparing to
2,384 participants
Study Cohort Size
Participants in both and groups after matching
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