Q&A: GLP-1 Receptor Agonists and the Advent of CKM Syndrome, With Lawrence Leiter, MD

GLP-1 receptor agonists entered clinical practice as glucose-lowering agents, but the therapeutic rationale for their use has expanded well beyond glycemia. Cardiovascular outcomes trials established mortality and MACE benefits in high-risk patients with type 2 diabetes, and subsequent data have extended the evidence base to include chronic kidney disease, metabolic dysfunction-associated steatohepatitis, obstructive sleep apnea, and osteoarthritis. Most recently, a cluster of real-world analyses presented at the 2026 ASCO Annual Meeting suggested GLP-1 RAs may reduce metastatic progression across 4 obesity-related tumor types — lung, breast, colorectal, and liver — with patients on GLP-1 RAs 38% to 50% less likely to progress to stage IV disease compared with those on DPP-4 inhibitors.¹

The expanding benefit profile of incretin-class agents coincides with a long-overdue reconceptualization of how comorbidities cluster in clinical practice. In 2023, the AHA issued a presidential advisory formally defining cardiovascular-kidney-metabolic (CKM) syndrome, and in June 2026, the ACC, AHA, ADA, and ASN jointly published the first-ever clinical practice guideline for its prevention and management — with staging recommendations applicable to both adults and youth. The guideline reflects a shift away from siloed organ-specific treatment and toward integrated, multidisciplinary management of interconnected cardiometabolic risk. GLP-1 RAs, with demonstrated benefits across multiple components of CKM syndrome, are well-positioned as a potential foundational therapy within this framework — addressing polypharmacy concerns while targeting several comorbidities simultaneously.²

Lawrence A. Leiter, MD, FRCPC, FACP, professor of medicine and nutritional sciences at the University of Toronto and director of the Lipid Clinic at St. Michael's Hospital, spoke with HCPLive at the 10th Annual Heart in Diabetes Conference in Philadelphia to discuss the evolution of incretin-class agents and their role in CKM syndrome management.

Q&A: GLP-1 Receptor Agonists and the Advent of CKM Syndrome, With Lawrence Leiter, MD

HCPLive: Are incretin-based therapies still understood primarily as glucose-lowering agents with pleiotropic effects, or more as systemic metabolic regulators that transcend glycemic control as the primary endpoint?

Lawrence Leiter, MD: Our understanding of the GLP-1 RAs and other GLP-1-like drugs has evolved over the years. They were originally developed as glucose lowering agents, and then we recognized that they can be associated with significant weight loss. Now, of course, we have evidence for cardiovascular risk reduction, for improvements in kidney disease, improvements in liver disease, sleep apnea, osteoarthritis, and the list goes on and on. Currently, there's a suggestion that their anti-inflammatory effects may have other beneficial, have other benefits. At the recent cancer meeting, there were 40 different papers talking about the potential benefits of GLP-1 RAs against cancer, so these are remarkable agents, and we're just learning more and more about their potential benefits.

HCPLive: Does the breadth of clinical benefit observed with incretins suggest a shift away from disease-specific treatment paradigms towards more integrated cardiometabolic risk modification?

Lawrence Leiter, MD: Recently, there has been a long overdue recognition that we shouldn't be treating individual diseases – they cluster together. Finally, the AHA has now come out with statements on the CKM - cardio kidney metabolic - syndrome, and very recently specific guidelines to treat that. I think one of the potential benefits of the incretin class is that they will treat many disorders within this CKM syndrome. Our patients are pushing back against polypharmacy, and here we have agents that can improve many of the comorbidities associated with the CKM syndrome.

HCPLive: Do you see incretins becoming foundational across metabolic disease management in the same way we viewed statins as the de facto first line therapy in cardiology?

Lawrence Leiter, MD: Again, I think there has been an evolution in how we use the incretin agents, and if you look at our guidelines, you know our diabetes guidelines used to say start with metformin, and then, if necessary, add another agent. Now our guidelines, of course, say that, in certain groups of patients with diabetes, so if patients have cardiovascular disease, have kidney disease, have heart failure, you start the GLP-1 RA as a first step. I think this is going to continue to broaden, and I think more and more patients will have GLP-1 RAs as very early therapy, as you know what one could call a potentially foundational agent.

Editors’ Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

References:

1. Orland MD, et al. Can GLP-1 receptor agonists mitigate cancer progression? A propensity-matched analysis across seven solid tumors. Presented at: 2026 ASCO Annual Meeting; May 29–June 2, 2026; Chicago, IL. Abstract 3143.

2. Writing Committee Members; ACC/AHA Joint Committee on Clinical Practice Guidelines. 2026 AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic Syndrome. J Am Coll Cardiol. 2026. doi:10.1016/j.jacc.2026.03.056.