Two major real-world studies presented at the 75th European Society of Cardiology (ESC) conference have provided compelling evidence for the expanded therapeutic potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in high-risk cardiovascular and renal patient populations, demonstrating superior efficacy compared to existing treatments.
Breakthrough Results in Diabetes-Kidney Disease Patients
Dr. Daiki Yoshiura presented groundbreaking real-world evidence analyzing 30,787 patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) using electronic health records from 2018 to 2021. After propensity-score matching 7,729 patients in each group, researchers found that GLP-1RAs were associated with significantly lower rates of all-cause mortality, new incidence of heart failure, severe kidney dysfunction, or hemodialysis within three years compared to sitagliptin.
"In patients with T2DM and CKD, GLP-1RAs were associated with a lower risk of death and worsening of renal function compared to sitagliptin," Yoshiura concluded. The study represents one of the largest real-world analyses examining GLP-1RA efficacy in this vulnerable patient population.
Transformative Impact in Heart Failure with Preserved Ejection Fraction
Dr. Nils Kruger presented equally impressive findings focusing on Novo Nordisk's semaglutide and Lilly's tirzepatide in patients with heart failure with preserved ejection fraction (HFpEF). The study included 58,333 patients in the semaglutide cohort and 11,257 patients in the tirzepatide cohort, demonstrating robust safety profiles with no significant increase in adverse events.
Patients initiating semaglutide or tirzepatide had more than 40% lower risk of hospitalization for heart failure or all-cause mortality compared to sitagliptin. In head-to-head comparison, tirzepatide provided no statistically significant advantage over semaglutide (HR = 0.86, 95% CI 0.70-1.06).
Clinical Trial Data Reinforces Real-World Findings
The real-world evidence aligns with robust clinical trial data. In the STEP-HFpEF program, semaglutide significantly improved Kansas City Cardiomyopathy Questionnaire scores, reduced body weight by 7.8%-13.3%, enhanced exercise capacity as measured by 6-minute walk distance, and decreased inflammatory markers like C-reactive protein by over 40%.
Tirzepatide demonstrated even more robust outcomes in the SUMMIT trial, reducing the composite risk of cardiovascular death or worsening heart failure events by 38% (HR 0.62), with particularly striking reductions in heart failure hospitalizations by 46% (HR 0.54).
Addressing Unmet Medical Needs
The findings support expanding GLP-1 agonist use beyond traditional diabetes and obesity indications to cardiometabolic HFpEF, addressing a significant unmet medical need where conventional heart failure therapies have shown limited efficacy. GLP-1RAs, especially semaglutide, have emerged as disease-modifying agents in T2D patients with CKD, providing significant reductions in renal and cardiovascular events, and lowering mortality rates.
However, penetration in heart failure with reduced ejection fraction (HFrEF) remains limited due to neutral or adverse effects, including a four-fold arrhythmia risk. As one key opinion leader noted: "I think that probably GLP-1RAs are more effective in interfering with the mechanisms, which are responsible for heart failure, and I would see GLP-1 receptor more effective, maybe in patients with preserved ejection fraction."
Market Access Challenges Persist
Despite the compelling clinical evidence, market access remains challenging. While therapies such as GLP-1RAs address unmet needs in heart failure, they come with high price tags, and gaining market access against cheaper, generic drugs continues to be a major barrier. The ESC presentation provides compelling real-world evidence that could drive treatment guideline changes and increase market penetration, especially given the substantial unmet medical need in managing patients with both diabetes and kidney disease.
