Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) have a residual risk of CKD progression despite current therapies, which tends to worsen with more advanced CKD. Finerenone, a novel, selective, nonsteroidal mineralocorticoid receptor antagonist, decreased the risk of kidney and cardiovascular (CV) outcomes in phase III trials for patients with CKD and T2D. Combining finerenone with other CKD in T2D therapies, such as sodium-glucose co-transporter-2 inhibitors (SGLT-2is) is of interest, but more data are needed.

Abstract Background/Introduction Chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) is associated with an increased risk of cardiovascular (CV) events. The modifiability of CKD-associated CV risk in patients with T2D across a spectrum of CKD stages remains unknown. Purpose To test whether CKD, as defined jointly by estimated glomerular filtration rate (eGFR) and albuminuria (urine albumin-to-creatinine ratio [UACR]), is a modifiable CV risk factor in patients with T2D. Furthermore, to estimate the population-wide reduction in first CV events in the US if all eligible patients were treated with finerenone. Methods We estimated the incidence rates of CV events (composite of CV death, non-fatal stroke, non-fatal myocardial infarction, or hospitalisation for heart failure) over a median follow-up of 3.0 years in 13,026 patients with CKD and T2D, treated with finerenone or placebo, in a joint analysis by eGFR and UACR categories. Patients were from FIDELITY, a prespecified pooled analysis of two phase III trials, and had an eGFR ≥25 ml/min/1.73 m2 and UACR 30–5000 mg/g at screening.The potential impact of finerenone treatment on the US population was evaluated by simulating the number of first CV events that could be prevented per year with finerenone, using incidence rates from FIDELITY and prevalence rates of CKD in patients with T2D from the National Health and Nutrition Examination Survey (NHANES). Results Lower eGFR and higher UACR categories were associated with higher incidences of CV events in finerenone and placebo recipients (Figure). Finerenone reduced CV risk versus placebo (hazard ratio 0.86; 95% CI 0.78–0.95; p=0.0018) without evidence of moderation of risk reduction by combined eGFR and UACR categories (p interaction = 0.66; Figure 1). Using NHANES, a total of 6.4 million treatment-eligible individuals with CKD and T2D were identified; 75% had CKD with an eGFR ≥60 ml/min/1.73 m2 and 25% had CKD with an eGFR <60 ml/min/1.73 m2. Simulations using this NHANES population projected that 1 year of finerenone treatment could prevent 38,359 CV events in US patients with CKD and T2D, with 66% of events prevented in patients with eGFR ≥60 ml/min/1.73 m2. Conclusions Higher albuminuria and lower eGFR are associated with increased CV risk in patients with T2D. Across a range of eGFR and albuminuria categories, CV risk is modifiable. Therefore, CKD is a modifiable CV risk factor in part mediated by mineralocorticoid receptor overactivation. UACR screening to identify patients with T2D and albuminuria with an eGFR ≥60 ml/min/1.73 m2 is likely to provide a significant opportunity for population benefits. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer AG

Abstract Background Patients with idiopathic pulmonary fibrosis (IPF) are at increased risk of developing coronary artery disease (CAD) with a median survival of 3.5 years after diagnosis. Cardiac and pulmonary fibrosis share several common signaling pathways including TGF-β-related collagen synthesis. Pirfenidone and nintedanib were the first approved medical antifibrotic IPF therapies that inhibit TGF-β–related collagen synthesis or multiple receptor tyrosine kinases, respectively. However, the role of mineralocorticoid receptor blockade in IPF is less well understood. Purpose To test the hypothesis that the selective nonsteroidal MR antagonist finerenone has antifibrotic and anti-inflammatory activity in preclinical IPF. Methods Anti-fibrotic/anti-inflammatory efficacy was investigated in two different mouse models of pulmonary fibrosis. Lung fibrosis was induced by either intranasal application of bleomycin (1 mg/kg) or intratracheal application of silica particles (2.5 mg/mouse). Bleomycin-treated C57BL6 mice (8 weeks old male, n=10–15/group) were administered once daily orally from day 7 to 21 with vehicle (ethanol/solutol/water), finerenone (10 mg/kg) or nintedanib (60 mg/kg) in vehicle. Silica-treated C57BL6 mice (8 weeks old male, n=10–12/group) were administered once daily orally from day 7 to 30 with vehicle (ethanol/solutol/water), finerenone (1 or 10 mg/kg) or nintedanib (100 mg/kg) in vehicle, or with pirfenidone (800mg/kg/d) via chow. At day 21 and 30 respectively, histological examination of pulmonary fibrosis using immunohistochemistry (COL1A1 positive tissue area in %) and Ashcroft score as well as profibrotic and pro-inflammatory cytokine and COL1A1 protein level (ELISA) analysis in lung homogenate were performed. Results Bleomycin caused a significant increase in lung COL1A1 positive tissue area and Ashcroft Score and silica-induced lung pathology additionally showed elevated IL-1beta, IL-6, IL-10, IL-12p70, TNFalpha and COL1A1 protein levels in lung tissue. Therapeutic treatment with finerenone as well as nintedanib from day 7–21 significantly reduced the percentage of lung COL1A1 positive tissue and Ashcroft score in the bleomycin mice model without a significant difference between treatment groups. Furthermore, finerenone significantly reduced lung COL1A1 as well as IL-1beta, IL-6, IL-10, IL-12p70 and TNFalpha protein levels in lung homogenate after a therapeutic treatment from day 7–30 in the silica mice model, whereas nintedanib showed only a reduction in lung COL1A1 and IL-10 levels and treatment with pirfenidone was without significant effects. There was a significant difference in the reduction of lung IL-12p70 and TNFalpha protein levels between finerenone 10 mg/kg and nintedanib as well as pirfenidone treatment. Conclusion Nonsteroidal MR antagonism by finerenone showed anti-fibrotic/anti-inflammatory efficacy in two animal models of pulmonary fibrosis and may impact the progressive course of fibrotic diseases. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): BAYER AG

Abstract Background The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and SGLT2 inhibitors have demonstrated clinical benefits in HFrEF and CKD patients with T2D. Cardiovascular protection with finerenone and the SGLT2 inhibitor empagliflozin in combination in hypertensive cardiorenal disease is unknown. Purpose To test the hypothesis that the combination of finerenone with empagliflozin provides cardiovascular protection in preclinical hypertension-induced end-organ damage. Methods Cardiovascular morbidity and mortality was studied in hypertensive L-NAME (20 mg/L) treated renin-transgenic (mRen2)27 rats. Rats (10–11 weeks old female, n=13–17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Blood pressure (week 1, 3 and 5), urinary (week 2 and 6) and plasma parameters (week 6 and at the end of the study) were determined during the course of the study, while cardiac histology and left ventricular gene expression analysis were performed after study end. Results Empagliflozin induced a strong and dose-dependent increase in urinary glucose excretion which was not influenced by finerenone co-administration in the combination arm. Treatment with 3 mg/kg finerenone and the low dose combination significantly decreased systolic blood pressure (SBP) after 3 and 5 weeks as well as plasma uric acid after 6 weeks. SBP was significantly more reduced in the combination arm vs. the individual monotherapies after 3 weeks. Plasma NT-proBNP was reduced by empagliflozin, finerenone and the combination with similar efficacy. There was a dose-dependent protection from cardiac vasculopathy, cardiac and vascular fibrosis with both agents while low dose combination therapy was more efficient than the respective monotherapy dosages on these cardiac histology parameters. Placebo-treated rats demonstrated a ca. 50% survival rate over the course of 7 weeks while low dose combination provided the most prominent survival benefit (93%). Conclusion Non-steroidal MR antagonism by finerenone and SGLT2 inhibition by empagliflozin confer cardiovascular protection in preclinical hypertensive-induced cardiorenal disease. Combination of these two modes of action at low dosages revealed efficacious reduction in blood pressure, cardiac lesions and mortality indicating a strong potential for combined clinical use in cardiorenal patient populations. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): BAYER AG