Highlights
- The 2022 AHA/ACC/HFSA heart failure (HF) staging system, incorporating biomarkers, identifies high-risk asymptomatic patients (Stage B) who comprise the majority (62%) of the diabetic kidney disease (DKD) population.
- Asymptomatic Stage B (‘Pre-HF’) is associated with a 2-fold increase in cardiovascular events and a 5-fold increase in kidney-specific outcomes compared to Stage A.
- Sotagliflozin, a dual SGLT1/2 inhibitor, demonstrates a consistent relative risk reduction (26%) in cardiovascular death and HF events regardless of baseline HF stage.
- The absolute clinical benefit of sotagliflozin increases with disease severity, offering the greatest event-rate reduction in Stage C/D and significant renoprotection in Stage B.
Background
The intersection of type 2 diabetes (T2D), chronic kidney disease (CKD), and heart failure (HF) represents the most significant challenge in modern cardiorenal-metabolic medicine. For decades, heart failure management was largely reactive, triggered by the onset of clinical symptoms such as dyspnea or edema (NYHA class). However, subclinical cardiac structural changes and biomarker elevations often precede these symptoms, particularly in high-risk groups like those with DKD. The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guidelines shifted this paradigm by introducing a four-stage classification (A through D) that utilizes cardiac biomarkers—N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin (hs-cTnT)—to identify patients in a ‘Pre-HF’ state (Stage B).
Despite this new classification, there has been limited evidence regarding its prognostic utility in the specific population of patients with both diabetes and moderate renal impairment. Furthermore, while sodium-glucose cotransporter inhibitors (SGLTis) have become the cornerstone of therapy, whether their efficacy remains uniform across these newly defined stages remained a critical knowledge gap. The SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) trial provided a unique dataset to explore these associations post hoc.
Key Content
The 2022 AHA/ACC/HFSA Staging Framework
The revised staging system redefines the transition from health to disease. Stage A includes patients at risk but without current or prior symptoms and without structural heart disease or biomarker evidence of stretch or injury. Stage B (Pre-HF) is characterized by the absence of symptoms but presence of structural heart disease (e.g., reduced ejection fraction, hypertrophy) or increased filling pressures indicated by elevated NT-proBNP (≥125 pg/mL) or hs-cTnT (≥14 ng/L). Stages C and D represent symptomatic and refractory heart failure, respectively.
Prognostic Insights from the SCORED Post Hoc Analysis
In the post hoc analysis of the SCORED trial, 10,584 participants were categorized based on these criteria. The distribution revealed a stark reality: only 7% of patients with T2D and CKD were in Stage A. A staggering 62% were in Stage B (asymptomatic Pre-HF), and 31% were in Stage C/D. This distribution underscores that the clinical ‘absence’ of heart failure in DKD patients is often a misnomer, as most harbor subclinical evidence of myocardial stress or injury.
The association between stage and outcome was linear and profound. In the placebo arm, moving from Stage A to Stage C/D was associated with a 2- to 4-fold increase in the primary composite endpoint (cardiovascular death, HF hospitalizations, and urgent HF visits) and major adverse cardiovascular events (MACE). Perhaps most striking was the kidney-specific composite (≥50% decline in eGFR, kidney failure, or kidney death). Stage B patients faced a 5-fold higher risk of renal decline than Stage A patients, with risk levels nearly identical to those in Stage C/D. This suggests that biomarker-defined ‘Pre-HF’ is as much a marker of renal vulnerability as it is of cardiac risk.
Therapeutic Efficacy of Sotagliflozin Across Stages
Sotagliflozin is unique as a dual SGLT1 and SGLT2 inhibitor. While SGLT2 inhibition promotes glycosuria and natriuresis in the kidney, SGLT1 inhibition in the gastrointestinal tract may provide additional benefits, such as reducing postprandial glucose excursions and potentially influencing GLP-1 secretion. In the SCORED analysis, the relative benefit of sotagliflozin was remarkably consistent. The hazard ratio (HR) for the primary endpoint was 0.74 (95% CI, 0.63–0.88), with no significant interaction by HF stage (P-interaction = 1.00).
However, while the relative risk reduction was stable, the absolute benefit scaled with disease severity. The number of events prevented per 1000 patient-years was significantly higher in Stage C/D compared to Stage B, and higher in Stage B compared to Stage A. For kidney-specific outcomes, the absolute benefit of sotagliflozin was similarly robust in both Stage B and Stage C/D, highlighting that even in the absence of clinical HF symptoms, these patients derive significant renoprotection from dual SGLT1/2 inhibition.
Integration of Broader Evidence: GLP-1 and Lifestyle Factors
Recent prospective cohort data from the US Veterans Affairs’ Million Veteran Program suggests that the integration of pharmacotherapy with lifestyle modification is synergistic. For instance, adherence to a healthy lifestyle combined with GLP-1 receptor agonists (GLP-1 RAs) resulted in a 43% lower risk of MACE. While SCORED focused on sotagliflozin, the emerging ‘triple therapy’ (SGLT inhibitor, GLP-1 RA, and RAS inhibitor) appears to be the ultimate goal for patients in Stage B and C. Mechanistically, as hypothesized in recent literature, concurrent RAS inhibition may redirect amylin-induced activation toward protective alternative pathways, further enhancing the cardiorenal benefits seen in trials like SCORED and ATTAIN-2 (orforglipron).
Expert Commentary
The SCORED post hoc analysis provides a critical validation of the 2022 HF staging system. For the clinician, the most actionable finding is the ‘Hidden Danger’ of Stage B. In patients with T2D and CKD, a simple biomarker screen can identify a population (the 62%) who are often treated as ‘standard’ diabetic patients but who actually possess a 5-fold higher risk of kidney failure than their biomarker-negative counterparts.
One controversy remains: the cost-effectiveness and implementation of routine NT-proBNP and troponin screening in primary care. However, given that the absolute benefit of sotagliflozin is so high in Stage B, these biomarkers act as a precision medicine tool, identifying those who need aggressive therapy the most. Furthermore, the similarity in kidney outcomes between Stage B and Stage C/D patients suggests that ‘Pre-HF’ might be better understood as a ‘Cardio-Renal Stress Syndrome,’ where the heart and kidney are in a deleterious feedback loop long before the first gasp of breathlessness occurs.
The consistency of sotagliflozin’s effect across stages also simplifies clinical decision-making. Physicians should not wait for symptomatic HF to initiate dual SGLT1/2 or selective SGLT2 inhibition. The ‘legacy effect’ of metabolic memory and inflammatory stress—discussed in the context of redefining success in Type 1 Diabetes—likely applies to T2D as well; early intervention in Stage A or B is essential to preserve ‘physiological resilience’ and prevent the irreversible structural damage seen in Stage D.
Conclusion
The application of the 2022 AHA/ACC/HFSA HF staging to the SCORED trial participants reveals that the majority of patients with diabetes and kidney disease are already in a state of subclinical heart failure (Stage B). This stage is not benign; it carries a massive increase in the risk of both cardiovascular and renal failure. Sotagliflozin provides a potent, consistent relative risk reduction across the entire spectrum of heart failure stages. Future clinical practice should prioritize biomarker-based risk stratification to identify asymptomatic Stage B patients, ensuring early initiation of therapy to maximize absolute clinical benefits and halt the progression of the cardiorenal-metabolic syndrome.
References
- Odutayo A, Bhatt DL, et al. Association Between the 2022 AHA/ACC/HFSA Heart Failure Staging and Cardiovascular and Kidney Outcomes in Patients With Diabetes and Kidney Disease: A Post Hoc Analysis of the SCORED Randomized Controlled Trial. Circulation. Heart failure. 2026;19(3):e013054. PMID: 41569429.
- Bhatt DL, Szarek M, et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med. 2021;384(2):129-139. PMID: 33200891.
- Heidenreich PA, Bozkurt B, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145(18):e895-e1032. PMID: 35363499.
- Koya D, et al. Combined associations of GLP-1 receptor agonists and a healthy lifestyle with cardiovascular outcomes among individuals with type 2 diabetes. Lancet Diabetes Endocrinol. 2026;14(4):317-326. PMID: 41763234.
