Response to the Nephrological perspectives on the underutilization of SGLT2i in heart failure and chronic kidney disease

Abstract

Editor-in-Chief

ESC Heart Failure

We would like to thank Dr. Özant Helvacı and his colleagues for their insightful comments about our article entitled the RED-HEART study.¹ We are grateful for their letter to the editor, which raised awareness of the suboptimal use of SGLT2i in heart failure (HF) and chronic kidney disease (CKD). We would like to clarify a few points that they raised.

Dr. Helvacı and his colleagues note that the formula for estimating glomerular filtration rate (GFR) and cut-off value to define CKD are unclear. We think that the criticism mentioned above is justified in making the definitions in the article more understandable. However, due to the constraints imposed by the specified limit on the number of words permitted for scientific article writing and journal submissions, it was impossible to include all the details in the methodology section. In the RED-HEART study, we used the simplified modification of diet in renal disease equation with four variables, including age, sex, ethnicity, and serum creatinine, to estimate GFR.² The definition of CKD used in this study was based on the estimated GFR < 60 mL/min/1.73 m² (GFR categories G3a–G5) for a minimum period of 3 months.^{3, 4}

Another key point highlighted by the authors is that the evaluation of albuminuria is essential for CKD assessment. We fully agree with the authors. The definition of CKD encompasses a wide range of markers of kidney damage, extending beyond the conventional concept of reduced GFR. KDIGO 2024 guideline for the evaluation and management of CKD recommends a classification system for CKD which is based on the estimation of GFR and degree of albuminuria.⁴ However, the RED-HEART study is designed as a ‘real-world study’ and aims to demonstrate the diagnostic methodology used in daily practice for HF, CKD, and diabetes. The findings of the present study demonstrate that cardiologists practicing in Türkiye frequently use GFR as the primary diagnostic tool for CKD, frequently neglecting to incorporate the assessment of albuminuria into their routine clinical practice.¹ As cardiologists, we should be aware of the role of albuminuria in the assessment and classification of CKD.

Patients with de novo HF, acute decompensated HF, and ages <18 years were excluded from the RED-HEART study. There were not any exclusion criteria regarding advanced CKD. The median GFR value of 75 mL/min/1.73 m² among our study population is slightly higher than pivotal trials of empagliflozin and dapagliflozin, which vary between 61 and 66 mL/min/1.73 m².^5-8 The discrepancy may be explained by the mean (or median) age of the study populations. While the median age is 66 years in the RED-HEART study,¹ the mean age of study participants was 72 years in the EMPEROR-Preserved and DELIVER trials.^{7, 8} We suggest that the lower mean age of the subjects in this study may have resulted in a higher median GFR value. Another explanation for this discrepancy may be the observational design of our study. As we mentioned in the limitations section of the article, the observational design of the study may have introduced biases in patient evaluation, selection and attrition.

Dr. Helvacı and his colleagues point out the significant difference in the prevalence of CKD between the RED-HEART study and other HF clinical trials. The prevalence of CKD varies between 41% and 50% in phase-III trials of SGLT2i, while Hebert et al. reported 26% of patients had CKD in a prospective cohort of HF patients.⁹ A meta-analysis reported that the prevalence of moderate-to-severe renal impairment in the HF population is 29% like our results.¹⁰ Although randomized controlled HF trials had higher internal validity, they also had strict well-defined inclusion/exclusion criteria; thus, the translation of the results confirmed in a small number of patients selected by set criteria in randomized controlled trials to diversified actual situations that could occur in the real world would be challenging. Ideally, randomized controlled trials and real-world studies should be developed in such a manner that they complement each other, rather than being in direct competition. For this reason, we need more real-world evidence, as provided by the RED-HEART study, to deeply understand the epidemiology and clinical characteristics of patients with HF.

Finally, we support the authors' recommendation for educational initiatives and collaboration between cardiologists and nephrologists to improve adherence to guideline recommendations for the use of SGLT2i in patients with HF and CKD. We would like to thank them once again for their valuable comments, contributions and future directions. We hope that we will be involved in projects together in the near future.

There are no conflicts of interest to declare.