Stepwise intensification of guideline-directed medical therapy is associated with reduced major adverse kidney events in patients with HFpEF and diabetes

Background Diabetes mellitus is the leading cause of chronic kidney disease and is strongly associated with cardiovascular and all-cause mortality. Heart failure with preserved ejection fraction (HFpEF) frequently coexists with diabetes and confers high cardiorenal risk. Contemporary management of diabetic kidney disease is based on four pillars of guideline-directed medical therapy (GDMT): renin–angiotensin system inhibitors, sodium–glucose cotransporter-2 inhibitors, mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists. Although these agents are increasingly used in combination, the impact of the number of GDMT classes implemented on renal outcomes in HFpEF remains unclear. Aims To evaluate whether the number of GDMT classes prescribed is associated with renal outcomes in patients with HFpEF. Methods In this multicentre study, 1,125 hospitalized patients with HFpEF (median age 79 years; 62.1% male) were categorized according to the number of GDMT classes prescribed: 0 (Group A), 1 (Group B), 2 (Group C), and 3–4 drugs (Group D). The primary endpoint was kidney disease progression, defined as estimated Glomerular Filtration Rate (eGFR) <10 mL/min/1.73 m², sustained ≥40% decline in eGFR, or initiation of maintenance dialysis. The median follow-up was 415 days. Cumulative incidence was compared using Gray’s test, and multivariable Fine–Gray competing-risk regression was performed. Results The distribution was: Group A, 276 (24.5%); Group B, 429 (38.1%); Group C, 310 (27.6%); and Group D, 110 (9.8%). The primary endpoint occurred in 205 patients (18.2%). Events included eGFR <10 mL/min/1.73 m² in 32 patients, ≥40% eGFR decline in 165, and maintenance dialysis in 8. The cumulative incidence of renal events decreased stepwise with increasing GDMT classes (Gray’s test P = 0.017). In multivariable competing risk analysis, compared with Group A (0 drug), the risk of the primary endpoint was significantly lower in Group B (sHR 0.633, 95% CI 0.43–0.93, P = 0.020), Group C (sHR 0.627, 95% CI 0.41–0.97, P = 0.034), and Group D (sHR 0.531, 95% CI 0.29–0.99, P = 0.046), demonstrating a significant dose–response relationship (Figure). In subgroup analyses stratified by body mass index (BMI), the relative benefit appeared attenuated in patients with BMI <20 kg/m². Conclusions Incremental implementation of GDMT was associated with reduced risk of renal events in patients with HFpEF. Even when full implementation was not feasible, addition of each GDMT class conferred incremental renoprotective benefit. These findings support stepwise optimization of GDMT for cardiorenal protection.