In this prospective study of individuals with CKD and T2D receiving finerenone treatment in routine clinical practice, at baseline most participants were classified as high or very high risk per the KDIGO risk categories [9]. Relative to FIDELITY [19], FINE-REAL included a greater proportion of participants in the moderate KDIGO risk category, fewer participants in the high-risk category, and a similar number of participants in the very high-risk category at baseline at the time of this pre-specified interim analysis. This trend suggests that in routine clinical practice, physicians are increasingly treating patients with earlier stage CKD compared with participants in the randomized clinical trials.

UACR is a sensitive and early indicator of kidney damage and can be routinely used to accurately assess CKD stage and monitor kidney health [26]. The American Diabetes Association and KDIGO work group recommend that all patients with T2D be screened for CKD at least annually through the measurement of UACR and eGFR [9, 20, 27]. In FINE-REAL, a total of 71.8% of participants had UACR measurements, suggesting that patients are often screened for CKD in accordance with guideline recommendations [9, 20, 27]. Whilst guidelines recommend that patients undergo annual UACR screening [9, 20, 27], it is not a requirement, according to the prescribing information, for starting treatment with finerenone [15, 16]. Nevertheless, the prevalence of UACR screening in FINE-REAL is much higher than currently available real-world data suggest; one retrospective study reported that urine protein assessment (including UACR) was only conducted in approximately 30% of patients with CKD and T2D in the US in 2019 [28]. Early detection of CKD enables the timely administration of appropriate treatment, which is essential for preventing disease progression in patients. Treatment guidelines recommend UACR should be reduced by ≥ 30% in patients with CKD and UACR ≥ 300 mg/g [20]. Moreover, the availability of SGLT2 inhibitors and GLP-1 receptor agonists, medications in addition to ACEis and ARBs that reduce UACR [29, 30][Supplementary reference 31], may contribute to clinicians being more inclined to assess UACR.

While UACR screening is always relevant, it is clearly very important in patients treated with finerenone. A recent mediation analysis demonstrated that UACR reduction in the FIDELIO-DKD and FIGARO-DKD studies accounted for 84% of the effect of finerenone in reducing the risk of the composite kidney endpoint (onset of kidney failure, a sustained decrease in eGFR ≥ 57% over at least 4 weeks or kidney-related death) [Supplementary reference 32]. These results provide evidence supporting measuring UACR for the identification of patients eligible for finerenone therapy (both in high-risk patients and in moderate-risk patients with relatively preserved eGFRs) and the monitoring of subsequent response to treatment. The use of agents that act on the renin–angiotensin–aldosterone system, SGLT2 inhibitors, GLP-1 receptor agonists, and a nsMRA (finerenone) are described as the four pillars of treatment to reduce cardiorenal outcomes in people with T2D and CKD [Supplementary reference 33]. These agents have distinct mechanisms of action from each other, providing further evidence supporting their combinability, yet research confirming their potentially additive benefits is lacking. The FINE-REAL study will provide supporting evidence from a real-word perspective on the utilization of these pharmacological pillars for disease management.

Finerenone was continuously administered in most (92.3%) participants. Following a pause in treatment, finerenone was restarted in 27 patients. Furthermore, only five participants permanently discontinued treatment. These data suggest good tolerance as well as adherence to finerenone treatment in the study cohort. Serious TEAEs were reported in 27 (5.4%) participants, while concomitant medications to manage AEs were only administered to 11 (2.2%) participants. Moreover, this interim analysis, at a median follow-up duration of 7 months, showed that the occurrence of hyperkalemia in the real-world setting was low (5.0%), with no hyperkalemia leading to dialysis, hospitalization or death. In FIDELITY, finerenone was associated with an increase from baseline in serum potassium of 0.21 mmol/L at 4 months; thereafter, mean serum potassium levels remained stable for the remaining duration of the follow-up period [19]. Pre-specified annual analyses from FINE-REAL will provide insight on TEAE and hyperkalemia occurrences when more study participants have completed the full follow-up period.

In contrast, results from a retrospective observational study of 224,100 individuals who were documented to have initiated a steroidal MRA in the Healthcare Integrated Research Database (identified comorbidities were categorized by heart failure, CKD, or other) suggest that discontinuation of steroidal MRAs occurs more frequently in clinical practice, with 73% of individuals discontinuing treatment after a median of 90 days [Supplementary reference 34]. Steroidal MRAs are associated with a risk of hyperkalemia and do not have a label indication for reducing kidney disease progression in people with CKD and T2D [Supplementary references 35–38]. The KDIGO 2024 clinical practice guideline for the management of CKD states that a steroidal MRA may be used for heart failure, hyperaldosteronism, or refractory hypertension, but may cause hyperkalemia or a reversible decline in eGFR, especially in people with a low eGFR [Supplementary reference 39]. A systematic review and meta-analysis of 33,048 patients with diabetic kidney disease across 31 randomized controlled trials reported that hyperkalemia occurred more frequently with steroidal MRAs than finerenone when added to ACEis/ARBs; the pooled risk ratio for steroidal MRA + ACEi/ARB vs ACEi/ARB was 5.42 (95% CI 2.15–13.67) and for finerenone + ACEi/ARB vs ACEi/ARB was 2.05 (95% CI 1.84–2.28) [Supplementary reference 40]. In the phase 2 ARTS trial (NCT01807221), people with heart failure with reduced ejection fraction and mild or moderate CKD were randomized to multiple doses of finerenone or spironolactone. In this study, hyperkalemia occurred less frequently in those randomized to finerenone compared with those randomized to spironolactone (pooled finerenone vs spironolactone; 5.3 vs 12.7%, respectively) [Supplementary reference 41]. Similarly, in an indirect comparison study of finerenone and spironolactone using data from FIDELITY and the AMBER study (NCT03071263), there were fewer treatment discontinuations due to hyperkalemia with finerenone (0.3%) compared to spironolactone + patiromer (6.8%), and spironolactone + placebo (23.0%) [Supplementary reference 42].

ACEis or ARBs were prescribed to 71.8% of participants at baseline in FINE-REAL, and despite guideline recommendations, 28.2% of participants did not receive a concomitant ACEi or ARB. This may be due to multiple factors such as clinical inertia (failure to initiate or intensify treatment) and a lack of patient compliance. A recent retrospective analysis indicated that the use of concomitant medications is somewhat similar in finerenone users across two US databases; including use of concomitant ACEis/ARBs (70.5% vs 70.4%), SGLT2 inhibitors (42.5% vs 53.3%), and GLP-1 receptor agonists (35.1% vs 42.1%) [22]. However, these results must be interpreted cautiously and considered in the context of additional real-world studies of finerenone. FINE-REAL is the first global, prospective, observational study investigating the use of a nsMRA in routine clinical care in patients with CKD and T2D. These findings, and future data from this ongoing study, will help to inform decision-making with respect to initiation of finerenone in patients with CKD and T2D. As more participants are enrolled in FINE-REAL, it may be possible to analyze how finerenone initiation varies across different nations, particularly when more low- and middle-income countries are included. Moreover, FINE-REAL will likely provide information on the treatment of patients with multimorbidity, including cardiovascular comorbidities, both in terms of the multidisciplinary management (i.e. cardiologists, endocrinologists, and nephrologists) involved in their care as well as the different classes of treatments prescribed (i.e. ACEis/ARBs, SGLT2 inhibitors, GLP-1 receptor agonists, and MRAs). The American Diabetes Association/KDIGO consensus guidelines advocate for comprehensive, multidisciplinary care for patients in recognition of the need for primary and secondary prevention of diabetes-related heart and kidney complications [9].

The FINE-REAL study has several strengths. Firstly, the findings can be generalized due to the global nature of the study. Secondly, FINE-REAL enrolls a more heterogeneous patient population than the randomized clinical trials of finerenone, particularly as patients were recruited across nephrology, endocrinology, cardiology, and primary care settings. Thirdly, the study provides insights into clinical practice following the approval of finerenone. The limitations of this interim analysis of FINE-REAL include the short follow-up time and the observational nature of the study, meaning the findings cannot be used to demonstrate causality. Some analyses could not be reported/performed due to short follow-up time and/or small sample sizes, including longitudinal data on eGFR or UACR and the association of participant characteristics with TEAEs.

In conclusion, finerenone was initiated across various clinical settings and populations with CKD and T2D in routine clinical practice; treatment discontinuation and occurrence of hyperkalemia in this finerenone-prescribed cohort were low, consistent with clinical trial data.