Better cardiorenal protection for patients with CKD and type 1 diabetes

In 2025, it is estimated that ∼9.5 million persons worldwide suffer from type 1 diabetes (T1D) [1]. The projected global prevalence of T1D for 2040 is expected to be increased up to 14.7 million persons [1]. In observational studies, an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g is identified in approximately one of three patients with T1D [2], indicating that chronic kidney disease (CKD) is a common comorbidity in this population. The co-existence of T1D and CKD substantially magnifies the risk for adverse cardiorenal events, as happens in those with CKD associated with type 2 diabetes (T2D) [3]. Over the last 7 years, several novel therapies have been developed for the improvement of cardiorenal outcomes in patients with CKD and T2D, such as sodium-glucose co-transporter type 2 inhibitors (SGLT2is), the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone and the glucagon-like peptide-1 receptor agonist semaglutide [4]. These therapies have received a strong indication for cardiorenal protection in recently released international guidelines [5]. Furthermore, a recent trial has provided direct evidence that in patients with albuminuric CKD and T2D who are already receiving standard-of-care treatment with a renin–angiotensin system (RAS) blocker, the simultaneous initiation of finerenone with empagliflozin is superior to either monotherapy in lowering albuminuria [6]. These data are supporting the notion that combination therapy results in maximal cardiorenal protection, possibly with fewer adverse events (Fig. 1). Randomized controlled trials demonstrating the safety and efficacy of novel therapies in improving cardiorenal outcomes in patients with CKD and T2D. CI: confidence interval; CKD: chronic kidney disease; CREDENCE: Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD: Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; EMPA-KIDNEY: Study of Heart and Kidney Protection with Empagliflozin; FIDELIO-DKD: Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease; FIGARO-DKD: Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease; FLOW: Evaluate Renal Function with Semaglutide Once Weekly; HR: hazard ratio; T2D: type 2 diabetes. For patients with CKD and T1D, landmark trials conducted approximately three decades ago demonstrated that improvement in glycemic and blood pressure (BP) control together with the administration of the angiotensin-converting enzyme inhibitor (ACEi) captopril are effective pharmacological interventions in retarding the progression of CKD to kidney failure [7,8]. Unfortunately, the standard-of-care therapy for these patients has not been modified thereafter. Until now, the aforementioned puzzle of four pillars of therapy that has been built for patients with CKD and T2D is not applicable to people living with T1D. The main reason is the absence of trials to demonstrate the safety and efficacy of these pillars of therapy specifically in patients with type 1 diabetic nephropathy [3]. In the following sections of this article, we explore the potential role of the non-steroidal MRA finerenone as a cardiorenal protective therapy in patients with CKD and T1D. We critically evaluate the design and main findings of the recently published FINE-ONE [9] (Finerenone Efficacy and Safety in Chronic Kidney Disease and Type One Diabetes) trial and we conclude with perspectives for future research in this important scientific field. Despite the pharmacological blockade of the RAS with an ACEi or an angiotensin receptor blocker, there is often a rebound elevation in the plasma aldosterone levels over 6–12 months after the initiation of therapy. The aldosterone breakthrough phenomenon is not innocent. In contrast, studies conducted specifically in patients with CKD and T1D have shown that aldosterone excess despite the administration of an RAS blocker is associated with a more rapid deterioration of kidney function over time [10]. Accordingly, mineralocorticoid receptor (MR) antagonism appears to be a mechanistically plausible target of therapy in patients with CKD and T1D. Most importantly, two parallel, phase 3 trials involving a total of 13 026 patients with T2D and a broad spectrum of CKD demonstrated that relative to placebo, the addition of the non-steroidal MRA finerenone to standard-of-care therapy with maximum-labeled or maximally tolerated doses of an RAS blocker is effective in improving long-term cardiovascular and kidney outcomes [11]. This large phase 3 clinical-trial program also demonstrated the safety of this intervention. Serious hyperkalemic events leading to permanent discontinuation of therapy occurred in a small subset of patients [11]. However, patients with CKD and T1D were a priori excluded from these trials. Consequently, the question whether the positive benefit–risk profile of finerenone is also applicable to patients with CKD and T1D has remained unanswered. The aforementioned scientific gap has been covered with the design of the FINE-ONE (Table 1) [9], a phase 3 trial involving 242 adult patients with T1D and albuminuric CKD. Similarly with the trials conducted in patients with CKD and T2D, the design of the FINE-ONE trial predetermined that patients should receive optimal background therapy with an RAS blocker before randomization. Patients fulfilling the prespecified eligibility criteria were randomized in a 1:1 ratio to double-blind therapy with finerenone (10–20 mg/day) or placebo. FINE-ONE truly enrolled patients at high risk for CKD progression (mean eGFR at baseline: 58.9 ml/min/1.73 m2; median UACR at baseline: 549 mg/g). During a follow-up period of 6 months, the proportional reduction in the levels of UACR was 25% greater in finerenone-treated than in placebo-treated patients [geometric mean ratio for the difference between groups: 0.75; 95% confidence interval (CI): 0.65–0.87] [9]. With respect to the safety of therapy, the most commonly recorded adverse event was hyperkalemia (incidence rate: 10.1% with finerenone vs. 3.3% with placebo). However, the vast majority of hyperkalemic events were mild. The discontinuation rate of finerenone owing to hyperkalemia was low (1.7%) [9]. Furthermore, over 6 months of treatment, finerenone was associated with a greater decline in the levels of eGFR than the change in eGFR seen with placebo. However, after a 30-day long washout period, the eGFR levels approached again the baseline values [9], evidence suggestive of an acute, hemodynamically mediated and potentially reversible effect of finerenone. The design and main findings of the FINE-ONE trial. CKD: chronic kidney disease; CI: confidence interval; eGFR: estimated glomerular filtration rate; FINE-ONE: Finerenone Efficacy and Safety in Chronic Kidney Disease and Type One Diabetes; RAS: renin–angiotensin system; T1D: type one diabetes; UACR: urinary albumin-to-creatinine ratio. FINE-ONE was a short-term study, in which changes in albuminuria over a follow-up period of 6 months were a priori selected as the primary efficacy outcome of the trial [9]. The albuminuria-lowering effect of finerenone over the course of the FINE-ONE trial is similar in magnitude with the early reduction in albuminuria that was observed in two prior phase 3 trials involving patients with CKD and T2D [11]. Specifically, a secondary analysis of the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trials showed that an early ≥30% reduction in UACR was observed in 53.2% of finerenone-treated patients and in 27% of placebo-treated patients [12]. This initial albuminuria-lowering action mediated 87% of the long-term benefit of finerenone relative to placebo on the composite clinical endpoint of kidney failure, sustained ≥57% decrease in the levels of eGFR from baseline or renal death [12]. In an updated 2026 meta-analysis incorporating individual patient-level data from 48 trials with a total of 85 681 participants, each 30% placebo-subtracted reduction in the levels of UACR with active treatment over the first 6 months of follow-up was associated with a relative risk reduction of 19% in the long-term clinical endpoint of kidney failure or doubling in the serum creatinine concentration [13]. Taken together, despite the fact that FINE-ONE was not originally designed to investigate treatment effects of finerenone on “hard” clinical endpoints [9], we have reasons to believe that a cardiorenal protective effect possibly exists. Strong evidence supports the notion that changes in albuminuria can be used as a valid surrogate endpoint in CKD trials [13], mainly when the design of large outcome trials is not feasible. FINE-ONE showed that the safety profile of finerenone in patients with CKD and T1D does not substantially differ from the safety that was demonstrated over the course of the FIDELIO-DKD and FIGARO-DKD trials [11]. In the FINE-ONE trial [9], finerenone provoked a modest placebo-subtracted reduction in office BP (-0.9 and -1.3 mmHg for the systolic and diastolic component, respectively). However, the early, acute, and reversible changes in the eGFR levels indicate that finerenone may induce stronger intra-glomerular hemodynamic effects. With respect to the risk of hyperkalemia, the proportion of patients who required permanent discontinuation of finerenone due to hyperkalemia was low [9]. However, it has to be noted that this risk is real. Accordingly, serum creatinine and potassium concentrations should be closely monitored for the prevention of adverse events in daily clinical practice. In conclusion, can we offer better cardiorenal protection with the use of novel therapies in patients with CKD and T1D? The answer to this question is now positive. After approximately three decades from the publication of landmark trials that established the current standard-of-care therapy for this high-risk population [7,8], the FINE-ONE trial provides important data that the non-steroidal MRA finerenone is safe and effective in lowering UACR in patients with albuminuric CKD and T1D [9]. In our point of view, this is an important first step forward. Possibly, in the future, additional novel therapies may be added to our therapeutic armamentarium. For example, the SUGARNSALT (Sotagliflozin to Slow Kidney Function Decline in Persons with Type 1 Diabetes and Diabetic Kidney Disease) is an ongoing clinical trial aiming to investigate whether the dual SGLT1i and SGLT2i sotagliflozin is more effective than placebo in slowing the rate of eGFR decline in patients with T1D and moderate-to-advanced CKD (NCT06217302). SUGARNSALT is planning to recruit 150 patients and the completion of this promising trial is anticipated in 2029. This article was not supported by any source and represents an original effort of the authors. Conceptualization: P.I.G.; Writing—original draft: P.I.G.; Writing—review & editing: A.R. and V.L.; Supervision: V.L. All authors have no conflicts of interest relevant to this work to disclose.