REPORT

Redefining Risk for CKM Syndrome

ARTICLE   |   A CKM Syndrome Perspective, informed by ESC Congress 2026

Redefining Risk for CKM Syndrome

A Roadmap from Guideline to Clinical Practice

Authors:
Geoff Catalano, VP, Medical Director, Medical Strategy & Scientific Affairs, BGBx
Amanda Eckel, SVP, Client Partnership & Innovation, BGBx
Samema Sarowar, AVP, Medical Director, Medical Strategy & Scientific Affairs, BGBx 

Executive Summary

CKM (cardiovascular-kidney-metabolic) syndrome was defined three years ago. Today, somewhere between 80 and 90% of US adults already meet criteria for stage 1 or higher, meaning true cardiovascular, renal, and metabolic health, stage 0, is now the exception rather than the norm. What has changed only in the last two years is not the biology, but the toolkit: a formal joint guideline, a validated staging and risk system, and therapies built to treat the interconnected condition directly, not just its individual pieces. The clinical case for CKM syndrome is closed. What is still being written is the operational one: whether care delivery, reimbursement, and the teams behind them reorganize around a framework that now spans three specialties at once. This paper is a roadmap for that work.

Section 1: Three Years Old, Just Getting Real

CKM syndrome is not a new idea dressed up for 2026. The American Heart Association first defined it in its 2023 presidential advisory¹, drawing a formal line between cardiovascular disease, chronic kidney disease, and metabolic dysfunction that clinicians had long treated as separate problems. What arrived in 2026 is not the concept, but the infrastructure: a joint AHA/ACC/ADA/ASN guideline², a validated staging system, and a body of therapeutic evidence substantial enough to act on. The three-year gap between definition and guideline was not a knowledge problem. It reflects how long it actually takes a field to build consensus around a new way of organizing risk, and it is worth keeping in mind as this paper turns to what still has to happen next. 

The scale makes this more than an academic reclassification. National data puts stage 0 prevalence, true cardiovascular, renal, and metabolic health, in the low teens among all adults, and in the single digits among adults 45 and older². CKM syndrome is not a subgroup. It is the new norm. 

It is also easy to misread the guideline as describing only its most severe cases, patients with cardiovascular disease, kidney disease, and metabolic dysfunction all present at once. That is stage 4, the last of five². Stage 1 requires nothing more than excess or dysfunctional adiposity, with no cardiovascular, kidney, or glycemic abnormality present yet. Most of the patients captured by this framework are early in the continuum, not at its far end, which is exactly why early intervention, not late-stage management, is the guideline’s central argument. Reading it as a narrow, late-stage framework undersells both its reach and its urgency. 

Have We Been Here Before?

Metabolic syndrome, proposed in 2001, took nearly a decade to reach a harmonized definition, and the WHO later questioned its practical clinical value. 3,4 CKM syndrome arrives with something metabolic syndrome never had – a joint guideline, a staging tool, and drugs that treat the whole picture at once. 

Section 2: A Common Language for Risk

A shared diagnosis needs a shared vocabulary, and that is what the five-stage system provides. Before this framework, a cardiologist, a nephrologist, and an endocrinologist could examine the same patient and describe three different risk profiles, none of them wrong, none of them complete. The staging system gives all three a common reference point: 

  • Stage 0: No risk factors present. 
  • Stage 1: Excess or dysfunctional adiposity. 
  • Stage 2: Metabolic risk factors and CKD. 
  • Stage 3: Subclinical cardiovascular disease. 
  • Stage 4: Clinical cardiovascular disease. 

Mortality rises step-wise across these stages.2 Cohort data shows a clear gradient from stage 0 through stage 4, which is what makes the framework clinically actionable rather than purely descriptive. A stage is not just a label, it is a predictor. The PREVENT risk equations5 extend that logic into a quantification standard for stages 0 through 3, giving clinicians a number to act on well before disease is clinically established. 

The integrated risk framework reflected in CKM staging is increasingly relevant as obesity and diabetes threaten progress against cardiovascular disease. At ESC 2026, experts emphasized earlier detection across the life course, while a new ESC cardiovascular health-check initiative brings cardiovascular, metabolic, adiposity, and kidney measures together to identify risk earlier. A decade of ESC Atlas data documenting the scale and inequalities of cardiovascular disease helped catalyze the EU Safe Hearts Plan—turning population-level risk data into a coordinated framework for earlier identification and prevention across Europe.6,7

Staging tells a clinician where a patient sits. It does not explain why CKM prevalence and severity cluster the way they do, and the original 2023 advisory was explicit that social determinants of health, not biology alone, drive much of that variation1. Where a patient lives, what care they can access, and what resources they have to manage a chronic, multi-domain condition all shape whether stage 1 becomes stage 4.

For Medical Affairs, that has a direct operational consequence. It should inform where scientific exchange happens and which communities field teams prioritize, not just which specialists they target. 

Insights from ESC Congress 2026

ESC Congress 2026 reinforced that cardiovascular risk and outcomes are geographically patterned, not uniformly distributed. A decade of ESC Atlas data has exposed persistent differences in disease burden, access to specialist care, and health-system capacity across communities. The Atlas shows that middle-income ESC countries have roughly twice the CVD mortality of high-income countries, while healthy life-years lost to CVD are approximately threefold higher. This supports a shift from simply identifying high-risk patients to identifying the places where gaps in prevention and care are greatest.8

Section 3. Treating the Syndrome, Not the Symptom

Metabolic syndrome never had this problem solved for it. When it was proposed in 2001, there was no drug built to treat the syndrome as a syndrome, only individual medications for individual risk factors. CKM syndrome arrives with therapies that already treat the interconnected biology directly, which is the strongest evidence yet that this is a real, mechanistically grounded condition and not just a new label for a familiar cluster of comorbidities. The evidence now spans three therapeutic classes: 

  • SGLT2 inhibitors, originally approved for glycemic control in patients with type 2 diabetes (T2D), as established cardiorenal-protective anchors. DAPA-CKD showed dapagliflozin reduced the composite risk of kidney disease progression or cardiovascular (CV)/renal death by 39% across a broad CKD population, with and without T2D.9 EMPA-KIDNEY extended similar findings for empagliflozin to a broader CKD population regardless of glycemic status.10 In patients with HF, irrespective of LVEF, dapagliflozin reduced the composite of HF hospitalization or CV death in the DAPA-HF and DELIVER trials.11,12 Similarly, empagliflozin reduced HF hospitalization and CV death risk, regardless of LVEF, in the EMPEROR-Reduced (HFrEF) and EMPEROR-Preserved (HFpEF) trials.13,14 
  • Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, as a second established cardiorenal anchor. FIDELIO-DKD and FIGARO-DKD demonstrated reduced cardiovascular and kidney composite outcomes in patients with type 2 diabetes and CKD.15 FIND-CKD extended the benefit to patients with CKD without diabetes, where finerenone reduced kidney disease progression and a composite of cardio-kidney outcomes.16 FINEARTS-HF demonstrated a reduction in the risk of HF hospitalization and CV death in patients with heart failure with LVEF ≥40%.17  
  • Dual GLP-1/GIP and GLP-1 receptor agonists as the mechanistic proof point, spanning weight, glycemic, cardiovascular, and renal endpoints. SELECT showed a 20% reduction in major adverse cardiovascular events with semaglutide in adults with overweight or obesity and established cardiovascular disease, without diabetes, plus a kidney sub-study showing a reduced composite kidney outcome.18 FLOW, in patients with type 2 diabetes and CKD, was stopped early for efficacy on cardiovascular and kidney outcomes.19   SUMMIT showed tirzepatide’s benefit in adults with obesity and HFpEF ; subsequent analyses showed these benefits were maintained in patients with CKD.20 SURPASS-CVOT demonstrated that tirzepatide was noninferior to the GLP-1RA dulaglutide for major adverse cardiovascular events in patients with T2D and established CVD.21   
  • Triple GIP/GLP-1/glucagon receptor agonism represents the next emerging incretin-based class. Retatrutide has demonstrated substantial weight and glycemic effects across multiple Phase 3 trials, including in patients with established CVD. Dedicated Phase 3 studies are now evaluating whether these metabolic effects translate into CV and kidney outcome benefits, potentially extending triple agonism across the CKM spectrum.22,23

Insights from ESC Congress 2026

New mechanisms are also emerging that target biology spanning traditional CKM domains. At ESC 2026, the Phase 2b LUMINARA trial provided early evidence of target engagement with AZD5462, the first oral RXFP1 relaxin-receptor agonist, with favorable effects on cardiac remodeling and vascular resistance across chronic heart failure phenotypes.24 These data beg the question of whether an effect would be seen in CKD, although a Phase 1 trial in patients with HF and CKD was terminated, suggesting that pathways are not always connected in ways we easily understand.

Furthermore, Phase 3 SHASTA-3 and SHASTA-4 data at ESC 2026 showed that plozasiran, an RNAi therapeutic targeting APOC3, reduced triglycerides by approximately 80% and acute pancreatitis events by 78% in severe hypertriglyceridemia; illustrating the emergence of molecularly targeted therapies directed at specific pathways underlying metabolic risk.25 This study and others suggest that precision metabolic therapeutics are beginning to emerge as a broader development category, with multiple RNA-based programs targeting APOC3 and other regulators of lipid metabolism.

Section 4. The Guideline Is a Living Document

A guideline this new should be expected to change, and it already has. The addition of MASLD as a recognized CKM domain, absent from the original 2023 staging framework, is a sign the model is still catching up to the underlying biology, not the reverse2. That is a feature of a maturing field, worth stating plainly rather than downplaying.

Insights from ESC Congress 2026

The treatment evidence is now being matched by changes in clinical practice frameworks. At ESC 2026, the Society released its first guideline dedicated to the intersection of cardiovascular disease and CKD, explicitly calling on cardiologists to identify CKD and modify cardiovascular management accordingly – another sign that organ-specific treatment silos are giving way to integrated cardiorenal care.

A Transatlantic Distinction 

ESC’s 2026 guidance on cardiovascular disease and chronic kidney disease26 is not identical in scope to the AHA’s broader CKM syndrome framework, which also encompasses obesity and diabetes as staging criteria. Worth knowing before conversations with European stakeholders. 

Reorganization is already underway, unevenly. ESC Congress 2026 listed Cardiovascular Kidney Metabolic as its own standalone session track27, a sign the field itself, not just individual guidelines, is beginning to restructure around this model. Implementation science, a distinct and increasingly active area of inquiry, is already asking the operational question this paper is built around: how does evidence-based CKM management actually reach a patient.

The staging system, the guideline, and the drug classes arrived within roughly the same two-year window. The clinic models built to act on all three at once did not. Multidisciplinary care coordinated across cardiology, nephrology, and endocrinology remains the exception rather than the standard. Reimbursement still rewards single-specialty visits over coordinated ones. And few field teams are trained to work fluently across all three domains at once. None of these gaps will close on their own and closing them is a multi-year undertaking. It requires organizations willing to build for a model that does not yet have established infrastructure behind it, a position the field’s most credible players need to take now, not once the infrastructure catches up.

Insights from ESC Congress 2026

Early care models are beginning to appear: ESC 2026 highlighted Spain’s experience with dedicated cardio-renal units designed to improve implementation of heart-failure therapy, an example of clinical infrastructure beginning to reorganize around disease overlap rather than traditional specialty boundaries.

The implementation gap is now being named explicitly: ESC 2026 programming focused on underutilized therapies and “missed opportunities” where heart, kidney and metabolic disease overlap, reinforcing that the principal challenge is increasingly not whether effective therapies exist, but whether systems can deliver them across specialty boundaries.

Section 5. What This Means For You

  • Cardiologists, Endocrinologists, Nephrologists: staging does not just describe a patient, it changes referral timing and treatment sequencing. A stage 2 patient managed within a single specialty is being under-treated relative to what the guideline now supports. 
  • Medical Affairs: scientific exchange has to span specialties instead of stopping at the boundary of a single therapeutic area. Field teams that lack cross-domain fluency will be explaining last year’s guideline to this year’s patients. 
  • Payers and Market Access: the treatable population is expanding as dual, and eventually triple, agonist economics reach further into the CKM continuum. An access strategy built around a single domain will lag a guideline that already spans three. 
  • Commercial and Brand Teams: narratives and messaging need to account for CKM staging, not single-domain positioning. A therapy indicated and promoted within two CKM domains, cardiorenal protection, for example, can be considered to have little effect on metabolic drivers but can still be considered part of the CKM conversation. Closing that gap is a commercial opportunity as much as a scientific one. 

The Next Mile

CKM syndrome now has what a chronic condition needs to move from framework to practice: a shared definition, a staging system clinicians can act on, and therapies that treat the interconnected biology rather than its individual pieces. What it does not yet have is care delivery organized to match. Closing that gap will take longer than publishing the guideline did, and it will not close on its own. 

The organizations that move first, building multidisciplinary clinic models, redesigning reimbursement around coordinated care, training field and clinical teams to work across specialties, will define what CKM management actually looks like in practice for the next decade. Everyone else will still be catching up to a guideline that is already three years old by the time they start. 

Let’s Continue the Conversation

This paper raises more questions than any single publication can answer. BGBx has spent more than two decades immersed in cardiovascular science, with parallel experience in nephrology and metabolic health – as well as many other therapeutic areas. If you’d like to think through what CKM staging means for your organization, your patients, or your commercial strategy, we’d welcome the conversation. Reach out to Amanda Eckel, SVP Client Partnership & Innovation, at : Amanda.Eckel@bgbgroup.com.

About the Authors

Geoff Catalano
VP, Medical Director, Medical Strategy & Scientific Affairs, BGBx

Geoff brings a deep curiosity for science and a passion for understanding how basic research and drug design translate into meaningful advances in medicine. With 15 years of experience at BGBx, his work spans medical communications and promotional advertising across US and global commercial and medical engagements. He has worked across a broad range of brands and therapeutic areas within the cardio-kidney-metabolic (CKM) landscape, including heart failure, cardiomyopathy, chronic kidney disease, acute kidney injury, dyslipidemia, and diabetes.

Amanda Eckel
SVP, Client Partnership & Innovation, BGBx

With two decades of experience, Amanda excels at the art of translating insights and data into powerful customer experience. She has worked in the US and EU across traditional HCP and consumer advertising, innovative digital marketing, and medical communications, launching multi-indication brands across all major therapeutic areas. Her work has resulted in industry award winning unbranded disease awareness and branded campaigns. After graduating with a degree in writing from Johns Hopkins University, Amanda has worked in client services, strategy, and growth roles. Her responsibilities include getting behind the “why” of everything and asking that of customers, her clients, her peers, and herself.

Samema Sarowar
AVP, Medical Director, Medical Strategy & Scientific Affairs, BGBx

Samema is a medical strategist and scientist with more than 10 years of experience translating complex clinical evidence into actionable scientific and Medical Affairs strategy. With a PhD in biochemistry, she brings deep experience in cardiorenal medicine, particularly chronic kidney disease and its intersection with cardiovascular and metabolic disease. Her work spans scientific strategy, evidence and guideline interpretation, congress intelligence, medical education, and stakeholder engagement, giving her a cross-specialty perspective well suited to the evolving CKM landscape.

About BGBx

BGBx is an independent commercial solutions partner for pharmaceutical and life science companies and their brands, combining consulting, communications, science, creativity, data, technology, innovation, and digital capabilities to deliver breakthrough results. Through BGBx Consulting and BGBx Communications, the company helps clients set strategy early, stay aligned throughout the product lifecycle, and execute through marketing and communications programs that drive impact. BGBx is Built for Breakthrough. Learn more at bgbx.com

Works Cited and Key References

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  9. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446.
  10. Herrington WG, Staplin N, Wanner C, et al; EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388:117-127.
  11. McMurray JJV, Solomon SD, Inzucchi SE, et al; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.
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  16. Heerspink HJL, Neuen BL, Agarwal R, et al; FIND-CKD Investigators. Finerenone in persons with chronic kidney disease without diabetes. N Engl J Med. 2026;395(6):533-545. doi:10.1056/NEJMoa2604625
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  18. Lincoff AM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT). N Engl J Med. 2023, with kidney sub-study, Nature Medicine, 2024.
  19. Perkovic V, et al. Semaglutide in Patients with Type 2 Diabetes and CKD (FLOW). N Engl J Med. 2024.
  20. Kosiborod MN, et al. Tirzepatide in HFpEF and Obesity, CKD subgroup analysis (SUMMIT). JACC. 2025.
  21. Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes. N Engl J Med. 2025;393(24):2409-2420.
  22. Eli Lilly and Company. 2026 Lilly ADA Investor Event. Published June 2026. https://investor.lilly.com/static-files/a2b20b4f-7944-4de2-9d10-00f384bbede2
  23. Eli Lilly and Company. Lilly’s triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C. Published July 23, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-successful-two-additional
  24. Januzzi JL, et al. Oral relaxin receptor agonist AZD5462 in participants with chronic heart failure: primary results from the LUMINARA trial. Circulation. Published online 2026. doi:10.1161/CIRCULATIONAHA.126.082763
  25. Arrowhead Pharmaceuticals, Inc. Arrowhead Pharmaceuticals presents phase 3 SHASTA-3 and SHASTA-4 data demonstrating plozasiran reduced acute pancreatitis events in patients with severe hypertriglyceridemia. Arrowheadpharma.com. Published August 30, 2026. Accessed September 1, 2026. https://arrowheadpharma.com/en-us/newsroom/arrowhead-pharmaceuticals-presents-phase-3-shasta-3-and-shasta-4
  26. European Society of Cardiology. 2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease. https://www.escardio.org/guidelines/clinical-practice-guidelines/all-esc-practice-guidelines/cvd-chronic-kidney-disease/. Accessed September 1, 2026.
  27. European Society of Cardiology. ESC Congress 2026 Programme, Cardiovascular Kidney Metabolic session track. escardio.org. https://test-digital-congress.escardio.org/esc-congress/sessions/20328. Accessed September 1, 2026.

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