Tirzepatide use linked to lower mortality, improved cardiometabolic outcomes vs semaglutide in obese patients with hypothyroidism
Presenter: Andrew Cecil, DO, MS, Advocate Aurora Health Care
Cardiovascular, metabolic, and mortality outcomes with semaglutide versus tirzepatide in obese patients with hypothyroidism: a real-world analysis. Presented April 23, 2026.
Tirzepatide was linked to lower all-cause mortality and lower rates of multiple cardiometabolic events than semaglutide in obese adults with hypothyroidism, according to a real-world analysis presented at AACE 2026.1
The retrospective cohort study matched 42,940 patients per treatment group drawn from the TriNetX Global Collaborative Network and followed them for up to 5 years, comparing all-cause mortality and a range of cardiometabolic, renal, skeletal, and cerebrovascular endpoints.
Hypothyroidism and obesity frequently co-occur, compounding cardiovascular risk through mechanisms that include dyslipidemia and hypertension. Pivotal trials of glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists have not specifically examined outcomes in patients with hypothyroidism, leaving clinicians to extrapolate from broader populations.
“Clinicians are already prescribing these drugs in this population, so we wanted to generate some real-world outcomes data to possibly help guide the decision,” said Andrew Cecil, DO, MS, of Advocate Aurora Health Care.
Investigators identified adults aged 18 years and older with obesity (body mass index ≥ 30 kg/m²) and hypothyroidism who initiated either semaglutide or tirzepatide. After 1:1 propensity score matching, the two cohorts were well balanced by demographics (mean age 57.8 vs 57.6 years; 78.9% vs 79.1% female).
At 5 years, tirzepatide was associated with superior outcomes across multiple domains, with statistically significantly lower incidence rates of:
- All-cause mortality—0.7% with tirzepatide vs 1.2% with semaglutide
- Heart failure—1.7% vs 2.2%
- New-onset hypertension—6.1% vs 7.7%.
- Type 2 diabetes—3.9% vs 4.8%
- Cerebrovascular disease—1.5% vs 1.9%
- Chronic kidney disease—2.6% vs 2.9%
- Pulmonary embolism—0.4% vs 0.5%.
However, myocardial infarction (MI) and osteoporosis outcomes were comparable between the two groups, with P values greater than .05.
Dr. Cecil said the divergence between cardiorenal outcomes and MI risk may be attributable to the GIP component of tirzepatide. He noted that the SURPASS-CVOT study showed tirzepatide was noninferior, but not superior, to dulaglutide on a three-point major adverse cardiovascular event composite endpoint, while a post hoc analysis using a six-component endpoint showed a 16% reduction in cardiorenal events.2
The SUMMIT trial3 showed tirzepatide cut worsening heart failure events by nearly half in obese patients with heart failure with preserved ejection fraction, he added.
“GIP receptors are abundant in epicardial adipose tissue, and GIP agonism may suppress local inflammation and reduce volume overload,” Dr. Cecil said. “These are mechanisms that would have a much greater impact on heart failure and kidney outcomes than on atherothrombotic events like MI.”
Dr. Cecil also flagged a practical concern for endocrinologists prescribing incretin-based therapies to patients on stable levothyroxine: meaningful weight loss can shift thyroid hormone requirements, and weight-loss-driven over-replacement can go undetected if thyroid-stimulating hormone (TSH) is not rechecked. He pointed to a recent target trial emulation in Medicare beneficiaries that found GLP-1 receptor agonist initiation in patients on stable levothyroxine was associated with a higher risk of atrial fibrillation compared with sodium-glucose cotransporter-2 inhibitor initiation.4
“It may be beneficial to recheck TSH within a few months of starting either agent and be prepared to adjust the levothyroxine dose,” Dr. Cecil said.
The investigators acknowledged that the retrospective design and potential residual confounding warrant cautious interpretation, and that TSH changes and levothyroxine dose adjustments were not captured in the TriNetX database. Prospective studies are needed to confirm the findings and better define the comparative role of incretin-based therapies in patients with hypothyroidism and obesity, the authors noted.
Dr. Cecil characterized the results as hypothesis-generating rather than practice-changing. “Both drugs are effective, but our data suggest tirzepatide may offer broader cardiometabolic protection in obese hypothyroid patients, particularly around heart failure, kidney outcomes, and mortality,” he said. “For a patient with obesity, hypothyroidism, and heart failure risk factors or chronic kidney disease, tirzepatide may be the better choice.”
Disclosures
Dr. Cecil reported no disclosures.
References
- Cecil A, Essien E, Agyekum A, Amoako G. Cardiovascular, metabolic, and mortality outcomes with semaglutide versus tirzepatide in obese patients with hypothyroidism: a real-world analysis. Endocrine Pract 2026; 32(suppl). https://doi.org/10.1016/j.eprac.2026.03.054
- Nissen SE, Wolski K, D'Alessio D, et al. Cardiorenal outcomes with tirzepatide compared with dulaglutide in patients with diabetes and cardiovascular disease: a post hoc analysis of the SURPASS-CVOT randomized clinical trial. JAMA Cardiol. Published online March 28, 2026. doi:10.1001/jamacardio.2026.0767
- Packer M, Zile MR, Kramer CM, et al; SUMMIT Trial Study Group. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med 2025; 392(5):427–437. doi:10.1056/NEJMoa2410027
- Du F, Singh Ospina NM, Chen Y, et al. Glucagon-like peptide-1 receptor agonists and risk for cardiovascular events in older adults treated with levothyroxine: a target trial emulation. Cardiovasc Diabetol 2025; 24(1):459. doi:10.1186/s12933-025-02971-7