We read with interest the State-of-the-Art Review by Kumar et al.1 on glucagon-like peptide-1 receptor agonists (GLP-1RAs) in cardiovascular-kidney-metabolic syndrome.
Although the review convincingly highlights the pleiotropic benefits of GLP-1RAsacross organ systems, greater emphasis on the metabolic heterogeneity of obesity could further refine the interpretation of cardiovascular risk and treatment effects.
In this context, the distinction between metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUHO) has been proposed, based on the absence or presence of obesity-related metabolic abnormalities such as diabetes, hypertension, or dyslipidaemia.2, 3, 4, 5 Importantly, cardiovascular risk associated with obesity differs markedly according to both metabolic status and clinical outcome.2 For atherosclerotic events, multiple large cohort studies have shown that individuals with MHO have little or no excess risk of myocardial infarction or ischemic stroke compared with metabolically healthy normal-weight individuals, whereas MUHO is consistently associated with a substantially increased risk. This pattern supports the concept that ischemic risk is largely driven by metabolic dysfunction rather than adiposity itself. In contrast, heart failure and atrial fibrillation display a different risk profile. Even in the absence of overt metabolic abnormalities, MHO is associated with a persistently higher risk of incident heart failure and atrial fibrillation, albeit lower than in MUHO, suggesting weight-related hemodynamic load, cardiac remodeling, and adipose tissue distribution as dominant mechanisms.2 Accordingly, the cardiovascular benefit of GLP-1RAs on ischemic outcomes appears most pronounced in MUHO, whereas observational data show more modest or nonsignificant associations in MHO, particularly for atrial fibrillation.4
These distinctions have direct therapeutic implications. In MUHO, GLP-1RAs may reduce cardiovascular events predominantly through improvement of metabolic abnormalities that drive atherosclerosis and adverse outcomes. In MHO, where baseline ischemic risk is lower but risks of heart failure and atrial fibrillation remain elevated, the role of GLP-1RAs may be more preventive, aimed at delaying progression to metabolic unhealthiness rather than producing immediate reductions in myocardial infarction or stroke.3,4 Explicitly integrating MHO and MUHO phenotypes—and recognizing outcome-specific risk patterns—within the cardiovascular-kidney-metabolic framework could therefore help personalize GLP-1RA use, align expectations regarding cardiovascular benefit, and strengthen the clinical applicability of this otherwise comprehensive review.
Footnotes
Dr Fauchier has received consultant or speaker fees of small amounts for AstraZeneca, Bayer, BMS/Pfizer, Boehringer Ingelheim, Boston Scientific, Medtronic and Novo Nordisk outside of this work. Dr Morel has received grants supporting investigator-initiated studies from AstraZeneca, Medtronic, and Boehringer Ingelheim, all outside the submitted work.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
- 1.Kumar S., Anderson J.E., Coviello A., Lopez-Jimenez F., Bakris G.L. The role of glucagon-like Peptide-1 receptor agonists in the treatment of cardiovascular-kidney-metabolic syndrome. JACC Adv. 2026;5 doi: 10.1016/j.jacadv.2025.102465. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Fauchier G., Bisson A., Bodin A., et al. Metabolically healthy obesity and cardiovascular events: a nationwide cohort study. Diabetes Obes Metab. 2021;23:2492–2501. doi: 10.1111/dom.14492. [DOI] [PubMed] [Google Scholar]
- 3.Copur S., Tanriover C., Yavuz F., Tuttle K.R., Kanbay M. Tirzepatide and potential use for metabolically healthy obesity. Eur J Intern Med. 2023;113:1–5. doi: 10.1016/j.ejim.2023.05.012. [DOI] [PubMed] [Google Scholar]
- 4.Bucci T., Alam U., Fauchier G., et al. GLP-1 receptor agonists and cardiovascular events in metabolically healthy or unhealthy obesity. Diabetes Obes Metab. 2025;27:2418–2429. doi: 10.1111/dom.16238. [DOI] [PubMed] [Google Scholar]
- 5.Fauchier L., Guglieri M., Fauchier G. The need for metabolic health stratification in global obesity forecasts. Lancet (London, England) 2026;406:2923. doi: 10.1016/S0140-6736(25)01234-6. [DOI] [PubMed] [Google Scholar]