Larence Leiter, MD, is the director of the Lipid Clinic and associate director of the Clinical Nutrition and Risk Factor Modification centre at St. Michael’s Hospital in Toronto.

Lawrence Leiter, MD

Lawrence Leiter, MD | Image Credit: University of Toronto

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.

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.

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 

 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?

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?

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?

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.

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.

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.

Articles

GLP-1 receptor agonists have progressed from glucose-lowering drugs to pleiotropic metabolic therapies with evidence for weight loss and reductions in CV events, CKD, MASH, OSA, and osteoarthritis. Real-world ASCO 2026 analyses suggested 38%–50% lower odds of progression to stage IV disease versus DPP-4 inhibitors across obesity-associated lung, breast, colorectal, and liver cancers. Concurrently, CKM syndrome has been formalized by AHA and codified in 2026 ACC/AHA/ADA/ASN guidelines, favoring integrated care and positioning GLP-1 RAs as polypharmacy-sparing foundational agents. Anti-inflammatory mechanisms and broader oncologic signals remain under active study.

Leiter discusses the growth of incretin-based therapies through all aspects of the cardio-kidney-metabolic syndrome space.

Intensive LDL-C lowering has reshaped secondary prevention over the past decade, with large randomized trials consistently demonstrating incremental cardiovascular benefit as achieved 

 falls below previously accepted thresholds. The FOURIER trial enrolled 27,564 patients with established 

atherosclerotic cardiovascular disease (ASCVD)

 on background statin therapy and randomized them to the PCSK9 inhibitor evolocumab or placebo, reducing median LDL-C to 30 mg/dL and reducing the risk of major adverse cardiovascular events. Long-term follow-up data from FOURIER-OLE, extending some patients' exposure to nearly 8 years, showed sustained event reduction including, for the first time with this drug class, a significant reduction in cardiovascular death.

The evidence now points toward earlier, more aggressive intervention. A 2024 meta-analysis of 60 randomized controlled trials found the hazard ratio per 1 mmol/L LDL-C reduction was more favorable in primary prevention (0.74) than in secondary prevention (0.80), suggesting greater proportional event reduction is achievable before atherosclerotic burden accumulates. For patients with 

, the risk calculus is further complicated by persistent residual cardiovascular risk: the ADA's 2026 Standards of Care reaffirm LDL-C lowering as central to ASCVD risk reduction in this population, with benefit directly proportional to the magnitude of LDL-C reduction across statin and nonstatin regimens.

Lawrence A. Leiter, MD, director of the Lipid Clinic and associate director of the Clinical Nutrition and Risk Factor Modification Centre at St. Michael's Hospital in Toronto, has contributed to multiple FOURIER analyses and brings particular expertise to the intersection of lipid management and diabetes. In the following interview, Lawrence A. Leiter, MD, spoke with HCPLive at the 

 in Philadelphia about LDL-C target achievement, sequencing of nonstatin therapies, and multifactorial risk reduction in patients with diabetes.

Q&A: Intensive LDL Lowering and Cardiovascular Prevention Strategies, With Lawrence Leiter, MD

HCPLive: In high-risk patients with diabetes who do not have established ASCVD, what defines the threshold for moving to PCSK9 inhibition rather than intensifying conventional lipid-lowering therapy?

I think the key point, what the evidence shows us, is that intensive LDL lowering and getting to targets lower than had been previously recommended is associated with significant cardiovascular benefit. The training, the VESALIUS-CV trial I was involved with, we used a PCSK9 inhibitor, evolocumab, in patients who had elevated LDL, despite optimized statin therapy. But when we translate in the real world, I think the key is the achievement of a lower LDL target, not the drugs that were specifically used. If patients aren't starting off with as high LDL as we had in VESALIUS-CV, often one can get them to a target of <55 or 40, as we did in the trial mix per deciliter with statins plus or minus ezetimibe plus or minus bempedoic acid, and only if you don't get them there with those agents, is it necessary to move on to a PCSK9 inhibitor?

HCPLive: Do you see the expanding use of PCSK9 inhibition in high-risk diabetes as a shift towards preemptive ASCVD disease modification?

Well, I think we know it's easier to prevent disease than it is to treat it when it's already present. First of all, looking at the big picture, there are far too many patients we see whose first symptom is their last symptom. Patients who had unrecognized atherosclerosis have an MI and may pass away as a result of that. We cannot wait until people have significant atherosclerotic burden and only start to treat then – we need to prevent it earlier. I think we now know that for the same magnitude of LDL cholesterol reduction you're going to see greater event reduction in people who have not yet had an event, so-called primary prevention population, than those who already did. That's presumably because it's easier to prevent plaque from occurring rather than waiting until a person has significant plaque in their coronary arteries and only then intervening.

HCPLive: Are we approaching a point in which lipid lowering in diabetes is viewed as a foundational risk reprogramming?

Well, our patients with diabetes continue to have increased cardiovascular risk, and even the latest data would show that our patients with diabetes continue to have twice the cardiovascular risk as people without diabetes, and there isn't going to be a single intervention that is going to reduce that risk. We really need a multifactorial risk reduction strategy. It's difficult, and patients will push back against polypharmacy, and often it's a negotiation for each additional drug we need to add. But to me, optimizing all the risk factors is foundational. We have to improve their glucose, improve blood pressure, optimize lipids, use other evidence-based therapies, SGLT2 inhibitors, GLP-1 RAs, aspirin as appropriate. There are many things we need to do to significantly reduce the risk in our patients with diabetes.

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. 

Brouwers JJWM, Koopal M, Visseren FLJ, et al. Course of the effects of LDL-cholesterol reduction on cardiovascular risk over time: a meta-analysis of 60 randomized controlled trials. Atherosclerosis. 2024;395:118540. 

doi:10.1016/j.atherosclerosis.2024.118540

American Diabetes Association. 10. Cardiovascular disease and risk management: standards of care in diabetes—2026. Diabetes Care. 2026;49(Suppl 1):S216-S266. 

https://pubmed.ncbi.nlm.nih.gov/41358899/

Intensive LDL-C lowering to levels near 30 mg/dL with PCSK9 inhibition has delivered sustained MACE reductions and, with prolonged exposure, cardiovascular mortality benefit. Meta-analytic data indicate larger proportional risk reductions in primary versus secondary prevention, supporting earlier intervention before plaque burden accrues. In diabetes, persistent residual ASCVD risk makes LDL-C lowering a central, dose-responsive strategy across statin and nonstatin regimens. Practical sequencing emphasizes achieving stringent LDL-C targets (eg, <55 or <40 mg/dL) using statins, ezetimibe, and bempedoic acid before escalating to PCSK9 inhibitors.

Leiter discusses the importance of earlier and more dramatic lipid-lowering interventions in patients with diabetes at risk of cardiovascular disease.