The year 2025 marked a transformative period for incretin-based therapies, with glucagon-like peptide-1 (GLP-1) receptor agonists and the dual GIP/GLP-1 agonist tirzepatide demonstrating unprecedented multisystem benefits beyond glycemic control and weight loss [1][2][3][4][5].
The SURPASS-CVOT trial demonstrated tirzepatide's cardiovascular non-inferiority to dulaglutide in patients with type 2 diabetes and atherosclerotic cardiovascular disease, with a hazard ratio of 0.92 for the composite primary endpoint [1]. Real-world evidence further revealed tirzepatide's superiority over both liraglutide and semaglutide in reducing major adverse cardiovascular events (MACE) in patients with obstructive sleep apnea and type 2 diabetes [2]. Cost-effectiveness analyses projected that tirzepatide could prevent 20,854 incident diabetes cases and 10,655 cardiovascular disease cases per 100,000 individuals over a lifetime, though current pricing remains a barrier to widespread adoption [3].
Unexpectedly, retrospective cohort data suggested potential neuroprotective effects, with GLP-1 receptor agonist use associated with lower risks of dementia, Parkinson disease, and stroke in adults with type 2 diabetes and obesity [4]. Meta-analyses confirmed that GLP-1 and GIP/GLP-1 receptor agonists reduce MACE and all-cause mortality even in overweight or obese adults without diabetes, expanding their clinical utility beyond traditional diabetic populations [5].
Why it matters:
For clinicians: GLP-1-based therapies represent a paradigm shift from treating isolated metabolic parameters to addressing comprehensive cardiometabolic risk. Tirzepatide's superior weight loss (up to 21.4% body weight) combined with cardiovascular and potential neuroprotective benefits provides a compelling option for patients with obesity and related comorbidities. However, gastrointestinal side effects and high costs require careful patient selection and shared decision-making.
For researchers: The mechanistic basis for neuroprotective and cardioprotective effects beyond weight loss warrants dedicated randomized controlled trials. Understanding the differential effects of GLP-1 versus dual GIP/GLP-1 agonism could inform next-generation therapeutic design and identify patient populations most likely to benefit from specific mechanisms.
References
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. N Engl J Med. 2025;393(24):2409-2420. doi: 10.1056/NEJMoa2505928
PubMed: https://pubmed.ncbi.nlm.nih.gov/41406444/ - Henney AE, Riley DR, Anson M, et al. Comparative Efficacy of Tirzepatide, Liraglutide, and Semaglutide in Reduction of Risk of Major Adverse Cardiovascular Events in Patients with Obstructive Sleep Apnea and Type 2 Diabetes: Real-World Evidence. Ann Am Thorac Soc. 2025;22(7):1042-1052. doi: 10.1513/AnnalsATS.202409-923OC
PubMed: https://pubmed.ncbi.nlm.nih.gov/40590655/ - Hwang JH, Laiteerapong N, Huang ES, Kim DD. Lifetime Health Effects and Cost-Effectiveness of Tirzepatide and Semaglutide in US Adults. JAMA Health Forum. 2025;6(3):e245586. doi: 10.1001/jamahealthforum.2024.5586
PubMed: https://pubmed.ncbi.nlm.nih.gov/40085108/ - Lin HT, Tsai YF, Liao PL, Wei JCC. Neurodegeneration and Stroke After Semaglutide and Tirzepatide in Patients With Diabetes and Obesity. JAMA Netw Open. 2025;8(7):e2521016. doi: 10.1001/jamanetworkopen.2025.21016
PubMed: https://pubmed.ncbi.nlm.nih.gov/40663350/ - Tang H, Lu Y, Zhang B, et al. Cardiovascular and kidney outcomes of GLP-1 receptor agonists in adults with obesity: A target trial emulation study. Diabetes Obes Metab. 2025;27(11):6527-6536. doi: 10.1111/dom.70054
PubMed: https://pubmed.ncbi.nlm.nih.gov/40874398/