Highlights
- Up to 61% of US adults (approximately 148 million) meet FDA-approved indications for at least one of three novel CKM therapy classes: GLP-1RAs, SGLT2is, or nsMRAs.
- GLP-1 receptor agonist eligibility is the most prevalent, encompassing over 50% of the population, driven largely by expanded indications for obesity and cardiovascular risk reduction.
- Nearly 12 million adults qualify for ‘triple therapy’ (all three medication classes), signifying a complex population with multi-organ risk profiles.
- Significant disparities in eligibility exist between general population surveys and ambulatory healthcare samples, highlighting a massive ‘implementation gap’ in clinical practice.
Background
The convergence of obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), and cardiovascular disease (CVD) has led the American Heart Association (AHA) to formally define the Cardiovascular-Kidney-Metabolic (CKM) syndrome. This syndrome reflects the pathophysiological interconnectedness of metabolic dysregulation and target organ damage. As the global prevalence of obesity and metabolic dysfunction continues to rise, the therapeutic landscape has undergone a paradigm shift with the emergence of three pivotal medication classes: glucagon-like peptide 1 receptor agonists (GLP-1RAs), sodium-glucose cotransporter-2 inhibitors (SGLT2is), and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs).
While clinical trials—such as SELECT, EMPA-KIDNEY, and FIDELIO-DKD—have demonstrated profound benefits in reducing major adverse cardiovascular events (MACE) and progression to end-stage kidney disease, the actual burden of eligibility within the United States population remained poorly quantified until recently. Understanding the scale of eligibility across different healthcare settings—national surveys, community cohorts, and ambulatory clinics—is essential for health systems planning, resource allocation, and addressing health inequities.
Key Content
The Pharmacological Pillars of CKM Management
The current management of CKM syndrome is anchored by three classes of drugs that have transcended their original indications as glucose-lowering agents.
- GLP-1 Receptor Agonists (GLP-1RAs): Originally for T2D, these agents (e.g., semaglutide, tirzepatide) now have broad indications for chronic weight management and MACE reduction in patients with established CVD and obesity.
- SGLT2 Inhibitors (SGLT2is): These agents (e.g., empagliflozin, dapagliflozin) have become foundational therapy for heart failure (across the spectrum of ejection fraction) and CKD, regardless of diabetes status.
- Nonsteroidal Mineralocorticoid Receptor Antagonists (nsMRAs): Finerenone, the primary agent in this class, is indicated for reducing the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and non-fatal MI in adults with CKD associated with T2D.
Synthesizing Evidence of Population Eligibility
Recent high-impact evidence, notably the cross-sectional analysis by Mounsey et al. (JAMA Cardiology, 2026), provides a comprehensive map of medication eligibility. By utilizing the National Health and Nutrition Examination Survey (NHANES), pooled community cohorts (including FHS and ARIC), and large ambulatory samples (BIDMC and MGB), researchers have established a clear hierarchy of eligibility.
1. GLP-1RA Eligibility: The Dominant Class
In the NHANES sample, 56% of US adults (representing 137.1 million people) were eligible for GLP-1RA therapy. This high prevalence is attributed to the expansion of indications to include obesity (BMI ≥30 or ≥27 with comorbidities) and the recent inclusion of patients with overweight/obesity and established CVD (as per the SELECT trial criteria). In ambulatory healthcare settings, this figure remained high at 41% to 46%, suggesting that nearly half of the patients walking into a primary care or specialty clinic meet the criteria for these agents.
2. SGLT2i and nsMRA Eligibility
SGLT2i eligibility was found in approximately 24% of the NHANES population (57.9 million adults) and 33% of pooled community cohorts. The higher prevalence in community cohorts likely reflects the older age of those participants (mean age 63 vs 47 in NHANES), who have a higher burden of CKD and heart failure. Eligibility for nsMRAs remains more niche but significant, at approximately 5% of the population (11.7 million adults), primarily constrained by the requirement for co-existing CKD and T2D.
3. The Intersection: Overlapping Eligibility and Triple Therapy
A critical finding in the synthesized data is the degree of overlap. Between 12% and 17% of adults are eligible for both GLP-1RA and SGLT2i therapies. Furthermore, approximately 1% to 5% of the total US adult population—representing 11.7 million individuals—meet FDA indications for all three classes simultaneously. This subset of patients represents the highest-risk group, characterized by T2D, CKD, and high cardiovascular risk, where the synergistic benefits of these therapies are most desperately needed.
Methodological Advances in Assessing CKM Burden
The use of multi-source data (survey vs. cohort vs. EHR) highlights important nuances in CKM epidemiology. While NHANES provides a snapshot of the general public, ambulatory healthcare samples (like Mass General Brigham) reflect the “real-world” population that is actively seeking care. Interestingly, the lower eligibility for SGLT2is in ambulatory samples (14%) compared to NHANES (24%) may point to differences in how CKD and heart failure are coded or diagnosed in clinical practice versus standardized survey measurements.
Expert Commentary
The findings presented by Mounsey et al. underscore a staggering reality: the majority of the US adult population is now a candidate for specialized cardiometabolic pharmacotherapy. However, several clinical and systemic controversies remain.
The Implementation-Access Gap
While 148 million adults may be eligible, only a fraction currently receive these medications. Barriers include high out-of-pocket costs, prior authorization requirements, and “clinical inertia” among providers. For nsMRAs and SGLT2is in particular, there is a persistent gap in prescribing even for those with clear-cut indications like CKD and HFrEF.
Mechanistic Synergy and Polypharmacy
From a biological perspective, the rationale for triple therapy is strong. SGLT2is provide hemodynamic and metabolic benefits; GLP-1RAs offer potent weight loss and anti-inflammatory effects; and nsMRAs specifically target the pro-fibrotic and pro-inflammatory pathways of the mineralocorticoid receptor. However, we lack large-scale RCTs specifically looking at the “triple-pillar” combination’s safety regarding hyperkalemia (nsMRA) and acute kidney injury (SGLT2i). Clinicians must balance the benefits against the risks of complex polypharmacy and potential drug-drug interactions.
Health Equity and Policy
The high cost of GLP-1RAs poses a significant risk of widening health disparities. If eligibility is universal but access is stratified by socioeconomic status, we may see a divergence in cardiovascular outcomes between the most and least affluent populations. Health policy must evolve to categorize CKM syndrome as a public health priority rather than a collection of individual lifestyle diseases.
Conclusion
The evolution of CKM syndrome management marks a new era in preventative medicine. With approximately 60% of the population meeting FDA indications for novel therapies, the focus must shift from identifying *who* to treat to determining *how* to deliver these treatments equitably and effectively. The potential for 11.7 million Americans to benefit from triple therapy offers a massive opportunity to reduce the burden of dialysis, heart failure hospitalizations, and cardiovascular death. Future research should prioritize implementation science and the long-term safety of combined CKM therapies to translate these population-level eligibility figures into tangible clinical outcomes.
References
- Mounsey LA, et al. Cardiovascular-Kidney-Metabolic Medication Eligibility Across National Survey, Community-Based, and Ambulatory Healthcare Samples. JAMA Cardiol. 2026;11(3):250-258. PMID: 41604173.
- Ndumele CE, et al. A Scientific Statement From the American Heart Association: Cardiovascular-Kidney-Metabolic Health. Circulation. 2023;148(20):1606-1635. PMID: 37811810.
- Lincoff AM, et al. Semaglutide and Cardiovascular Outcomes in Patients with Overweight or Obesity who do not have Diabetes. N Engl J Med. 2023;389(24):2221-2232. PMID: 37952131.
- Herrington WG, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. PMID: 36331190.
- Bakris GL, et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;383(23):2219-2229. PMID: 33091221.
