Sodium-glucose co-transporter 2 inhibitors (SGLT2i), when combined with metformin (COMBI), offer multi-organ protective effects in patients with type 2 diabetes (T2D), particularly those at high risk of cardiovascular or renal complications. However, the underlying molecular mechanisms remain poorly understood. We profiled 303 targeted serum metabolites in 1494 participants of the KORA study, including T2D patients treated with COMBI therapy, metformin monotherapy, or no glucose-lowering medication. Additionally, metabolomic profiling was quantified on seven tissues (plasma, liver, adrenal glands, adipose tissue, testis, lung, and cerebellum), and related hepatic transcripts were evaluated in 40 mice. Multivariable linear regression analyses, adjusted for age, sex, BMI, lifestyle, glycemic, and cardiovascular risk factors, were applied to human data; tissue-specific regression analyses were conducted for murine samples. Identified metabolites were further investigated using biochemical pathway analyses and literature review. COMBI therapy was associated with significant changes in metabolite profiles. In humans, 10 metabolites were significantly altered compared to metformin monotherapy. In mice, 82 altered metabolites were identified in plasma, 52 in liver, 30 in adrenal glands, 12 in adipose tissue, seven in testis, seven in lung, and six in cerebellum. COMBI therapy lowered threonine concentrations in both human serum and murine plasma but raised threonine, glycine, and urea cycle metabolites (citrulline, asymmetric dimethyl arginine (ADMA), and ornithine) in murine liver. This was accompanied by enhanced hepatic expression of Slc38a2, a threonine transporter gene. In humans, urea cycle metabolites correlated strongly with the fibrosis-4 index, a marker of liver fibrosis. Additionally, COMBI therapy elevated ketone body markers, such as hydroxybutyrylcarnitine, across murine liver, plasma, adrenal glands, adipose tissue, and testis. COMBI therapy modulates amino acid metabolism, the urea cycle, and ketone body production, suggesting potential mechanisms underlying its protective effects against liver fibrosis and male subfertility. These findings provide novel insights into the systemic metabolic actions of COMBI therapy and highlight its translational potential to improve clinical outcomes in T2D patients.

BACKGROUND:The nonsteroidal mineralocorticoid receptor antagonist finerenone has been reported to improve kidney and cardiovascular outcomes in persons with type 2 diabetes and chronic kidney disease (CKD). The efficacy and safety of finerenone in persons with type 1 diabetes and CKD are unknown. METHODS:We conducted a phase 3 trial involving adults who had type 1 diabetes, CKD (estimated glomerular filtration rate [eGFR], 25 to <90 ml per minute per 1.73 m2 of body-surface area), and albuminuria (urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams], 200 to <5000) and were receiving an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensin-receptor blocker. Participants were randomly assigned to receive finerenone (10 or 20 mg per day, depending on the eGFR) or matching placebo. The primary outcome was the relative change in the urinary albumin-to-creatinine ratio over a period of 6 months. RESULTS:A total of 242 participants underwent randomization. The median urinary albumin-to-creatinine ratio decreased from 574.6 at baseline to 373.5 at 6 months among all the participants assigned to receive finerenone and from 506.4 to 475.6 among those assigned to receive placebo. Over a period of 6 months, the urinary albumin-to-creatinine ratio decreased by 34% with finerenone (geometric mean ratio to baseline, 0.66; 95% confidence interval [CI], 0.60 to 0.73) and 12% with placebo (geometric mean ratio to baseline, 0.88; 95% CI, 0.79 to 0.98), which corresponded to a 25% greater reduction with finerenone than with placebo (geometric mean ratio for finerenone vs. placebo, 0.75; 95% CI, 0.65 to 0.87; P<0.001). The most common adverse event was hyperkalemia (in 12 participants [10.1%] with finerenone and in 4 [3.3%] with placebo); 2 participants (1.7%) discontinued finerenone because of hyperkalemia. At 6 months, the change in the eGFR was -5.6 ml per minute per 1.73 m2 with finerenone and -2.7 ml per minute per 1.73 m2 with placebo (difference, -2.9 ml per minute per 1.73 m2; 95% CI, -5.1 to -0.7); eGFR values approached baseline levels during the washout period. CONCLUSIONS:In adults with type 1 diabetes and CKD, finerenone resulted in a significantly greater decrease in the urinary albumin-to-creatinine ratio than placebo. (Funded by Bayer; FINE-ONE ClinicalTrials.gov number, NCT05901831.).

AIMS:Chronic obstructive pulmonary disease (COPD) is associated with worse outcomes in heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). A post hoc analysis of TOPCAT suggested that the effectiveness of the steroidal mineralocorticoid receptor antagonist (MRA), spironolactone, may be modified by pulmonary disease, with a greater benefit in patients with COPD/asthma. We examined the effects of the non-steroidal MRA, finerenone, compared to placebo, according to COPD status in a prespecified analysis of FINEARTS-HF. METHODS AND RESULTS:A history of COPD was investigator-reported. The primary outcome was the composite of cardiovascular death and total worsening HF events. Of the 6001 patients randomized in FINEARTS-HF, 773 patients (12.9%) had COPD. Compared to patients without COPD, those with COPD had more adverse clinical features, including worse New York Heart Association class and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, more prior HF hospitalization, atrial fibrillation/flutter, obesity, peripheral artery disease, and hypertension, as well as elevated high-sensitivity troponin T levels. Patients with COPD had a higher risk of the primary endpoint (adjusted rate ratio [RR] 1.44, 95% confidence interval [CI] 1.21-1.71). The benefit of finerenone on the primary outcome was consistent irrespective of COPD status (no COPD: RR 0.84 [95% CI 0.73-0.97]; COPD: 0.84 [95% CI 0.61-1.16]; pinteraction = 0.93). Consistent effects were also observed for all secondary outcomes. Finerenone improved KCCQ total symptom score from baseline to 12 months to a similar extent in patients with and without COPD (pinteraction = 0.46). CONCLUSION:In patients with HFmrEF/HFpEF, the beneficial effects of finerenone on clinical events and symptoms were consistent, regardless of COPD status. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov ID NCT04435626.

BACKGROUND:Mapping clinical, biomarker, and diuretic dosing trajectories before adverse clinical outcomes in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) may inform population monitoring approaches. OBJECTIVES:The authors assessed temporal patterns of 2 biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP] and estimated glomerular filtration rate [eGFR]), physician assigned functional status (NYHA functional class), a patient-reported outcome (Kansas City Cardiomyopathy Questionnaire-Total Symptom Score [KCCQ-TSS]), and diuretic dosing leading up to a clinical event. METHODS:FINEARTS-HF was a double-blind, randomized clinical trial testing finerenone vs placebo in 6,001 patients with symptomatic HF and a left ventricular ejection fraction of ≥40%. Key variables including NT-proBNP, eGFR, NYHA functional class, KCCQ-TSS, and diuretic dosing (expressed as furosemide equivalents) were serially assessed until the occurrence of cardiovascular death, first HF event, or the end of the follow-up period. Each variable was plotted relative to the number of months before an event or the end of follow-up. Patients who experienced a clinical event were compared with a control population who remained alive and free of hospitalization during follow-up. RESULTS:Over a median 2.7-year follow-up period, 1,343 cardiovascular deaths or first HF events occurred. At baseline, the participants who experienced a clinical event had higher NT-proBNP values, lower eGFR, higher NYHA functional class, lower KCCQ-TSS, and higher diuretic doses compared with the control population. The eGFR declined by about 5 mL/min/1.73 m2 (from a mean of ∼57 to ∼52 mL/min/1.73 m2), and the NT-proBNP level increased by approximately 70% to 80%, in the 12 to 18 months leading up to an event; these markers remained relatively stable in the control group. NYHA functional class showed a sharp deterioration in the 6 to 9 months before an event, and KCCQ-TSS declined by approximately 6 points (from a mean of ∼68 to ∼62) during this period, reflecting worsening functional class and patient-reported symptoms, respectively. Finally, diuretic doses increased in the 6 months preceding the event, from ∼50 to ∼60 mg/day of furosemide equivalents. CONCLUSIONS:In a large HFmrEF/HFpEF trial population, clinically meaningful changes in readily available biomarkers, functional status, and patient-reported health status were observed in the months leading up to a clinical event. Monitoring these parameters may help identify patients at high risk for near-term adverse clinical events. (Finerenone Trial to Investigate the Efficacy and Safety Superior to Placebo in Patients With Heart Failure [FINEARTS-HF]; NCT04435626).

BACKGROUND:Estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio are complementary domains of kidney disease staging and independently associated with heart failure (HF) progression. OBJECTIVES:The purpose of this study was to evaluate whether the efficacy and safety of finerenone varies according to kidney risk among patients with HF with mildly reduced or preserved ejection fraction. METHODS:In this prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure), clinical outcomes and treatment effects of finerenone on the primary endpoint (cardiovascular death and total [first and recurrent] HF events) and key secondary endpoints were evaluated according to baseline KDIGO (Kidney Disease: Improving Global Outcomes) risk category (low, moderately increased, and high or very high). Key exclusion criteria in FINEARTS-HF were eGFR <25 mL/min/1.73 m2 or serum potassium >5.0 mmol/L. RESULTS:Overall, 5,797 (97%) FINEARTS-HF participants had classifiable KDIGO risk category at baseline, of whom 2,022 (35%), 1,688 (29%), and 2,087 (36%) were low, moderate, and high/very high risk, respectively. Over a median follow-up of 2.7 years, higher kidney risk was associated with a higher rate of primary outcome events, with similar findings for other key endpoints, including the composite kidney outcome, new-onset atrial fibrillation, and vascular events. Benefits of finerenone vs placebo on the primary endpoint (Pinteraction = 0.24) and Kansas City Cardiomyopathy Questionnaire-Total Symptom Score at 12 months (Pinteraction = 0.36) were consistent irrespective of baseline kidney risk category. Participants with higher kidney risk experienced greater reductions in urine albumin-to-creatinine ratio after 6 months (Pinteraction = 0.031), without differences in eGFR slope. Risks of safety events, including hyperkalemia, with finerenone vs placebo were not enhanced among participants with higher kidney risk. CONCLUSIONS:Finerenone appears to consistently improve clinical outcomes, HF-related health status, and albuminuria across a broad spectrum of kidney risk in patients with HF with mildly reduced or preserved ejection fraction. (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure [FINEARTS-HF]; NCT04435626).

Importance:The mode of death in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) remains poorly understood and may vary by EF. Objective:To evaluate the mode of death according to EF and the treatment effect of finerenone on cause-specific mortality in patients with HFmrEF/HFpEF. Design, Setting, and Participants:This was a prespecified secondary analysis of the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) randomized clinical trial, which evaluated clinical outcomes in 6001 patients with HF and EF greater than or equal to 40% randomly assigned to finerenone or placebo. The mode of death in relation to baseline EF categories (<50%, ≥50-<60%, and ≥60%) was examined, and the effect of randomized treatment on cause-specific death in Cox regression models was assessed. Data analysis was conducted between September 2024 and January 2025. Interventions:Finerenone vs placebo. Main Outcomes and Measures:Mode of death as centrally adjudicated by a clinical end points committee. Results:Of 1013 patients (16.9%; median [IQR] age, 76 [69-82] years; 594 male [58.6%]) who died during median (IQR) follow-up of 32 (23-36) months, mode of death was ascribed to cardiovascular causes in 502 (49.6%), noncardiovascular causes in 368 (36.3%), and undetermined cause in 143 (14.1%). Of cardiovascular deaths, 215 (42.8%) were due to sudden death, 163 (32.4%) to HF, 48 (9.6%) to stroke, 25 (5.0%) to myocardial infarction, and 51 (10.2%) to other cardiovascular causes. The proportion of all-cause, cardiovascular, and sudden death was higher in those with EF less than 50%. The proportion of deaths related to HF was similar across EF categories, and the proportion of deaths due to myocardial infarction, stroke, and other cardiovascular causes was low regardless of EF. Randomization to finerenone did not significantly reduce death or cause-specific death compared with placebo in any EF category. Conclusions and Relevance:Among patients with HFmrEF/HFpEF in the FINEARTS-HF randomized clinical trial, higher proportions of cardiovascular and overall mortality in those with EF less than 50% were related principally to higher proportions of sudden death. A clear treatment effect of finerenone on cardiovascular or cause-specific mortality was not identified, although the trial was likely underpowered for these outcomes. Trial Registration:ClinicalTrials.gov Identifier: NCT04435626.

BACKGROUND:Limited evidence exists to support the simultaneous initiation of sodium-glucose cotransporter-2 inhibitors and finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in persons with chronic kidney disease and type 2 diabetes. METHODS:We randomly assigned participants with chronic kidney disease (estimated glomerular filtration rate [eGFR], 30 to 90 ml per minute per 1.73 m2 of body-surface area), albuminuria (a urinary albumin-to-creatinine ratio of 100 to ≤5000 [with albumin measured in milligrams and creatinine measured in grams]), and type 2 diabetes, who were already taking a renin-angiotensin system inhibitor, in a 1:1:1 ratio to receive finerenone (with empagliflozin-matching placebo) at a dose of 10 or 20 mg per day, empagliflozin at a dose of 10 mg per day (with finerenone-matching placebo), or a combination of finerenone and empagliflozin. The primary outcome was the relative change in the log-transformed mean urinary albumin-to-creatinine ratio from baseline to 180 days. Safety was assessed. RESULTS:At baseline, the urinary albumin-to-creatinine ratio was similar among the participants in the three groups; the median value was 579 (interquartile range, 292 to 1092) among those with available data (265 in the combination-therapy group, 258 in the finerenone group, and 261 participants in the empagliflozin group). At day 180, the reduction in the urinary albumin-to-creatinine ratio with combination therapy was 29% greater than that with finerenone alone (least-squares mean ratio of the difference in the change from baseline, 0.71; 95% confidence interval [CI], 0.61 to 0.82; P<0.001) and 32% greater than that with empagliflozin alone (least-squares mean ratio of the difference in the change from baseline, 0.68; 95% CI, 0.59 to 0.79; P<0.001). Neither agent, alone or in combination, led to unexpected adverse events. Symptomatic hypotension, acute kidney injury, and hyperkalemia leading to drug discontinuation were uncommon. CONCLUSIONS:Among persons with both chronic kidney disease and type 2 diabetes, initial therapy with finerenone plus empagliflozin led to a greater reduction in the urinary albumin-to-creatinine ratio than either treatment alone. (Funded by Bayer; CONFIDENCE ClinicalTrials.gov number, NCT05254002.).

BACKGROUND:Patients with heart failure (HF) with mildly reduced or preserved ejection fraction face heightened long-term risks of morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal mineralocorticoid receptor antagonist finerenone have both been shown to reduce the risk of cardiovascular events in this population, but the effects of their combined use are not known.METHODS:FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction >= 40%. Baseline SGLT2i use was a prespecified subgroup. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. We first assessed for evidence of treatment heterogeneity on the basis of baseline SGLT2i use. We further examined SGLT2i uptake during the trial and evaluated the treatment effects of finerenone accounting for baseline and during-trial use of SGLT2i in time-varying analyses.RESULTS:Among 6001 participants, 817 (13.6%) were treated with an SGLT2i at baseline. During 2.6 years median follow-up, treatment with finerenone similarly reduced the risk of the primary outcome in participants treated with an SGLT2i (rate ratio, 0.83 [95% CI, 0.60-1.16]) and without an SGLT2i at baseline (rate ratio, 0.85 [95% CI, 0.74-0.98]; Pinteraction=0.76). In follow-up, 980 participants initiated SGLT2i, which was less frequent in the finerenone arm compared with placebo (17.7% versus 20.1%; hazard ratio, 0.86 [95% CI, 0.76-0.97]). Time-updated analyses accounting for baseline and subsequent use of SGLT2i did not meaningfully alter the treatment effects of finerenone on the primary end point.CONCLUSIONS:The treatment benefits of the nonsteroidal mineralocorticoid receptor antagonist finerenone were observed irrespective of concomitant use of an SGLT2i. These data suggest that the combined use of SGLT2i and a nonsteroidal mineralocorticoid receptor antagonist may provide additive protection against cardiovascular events in patients with HF with mildly reduced or preserved ejection fraction.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626.

Background Obesity is associated with excessive adipocyte-derived aldosterone secretion, independent of the classical renin-angiotensin-aldosterone cascade, and mineralocorticoid receptor antagonists may be more effective in patients with heart failure (HF) and obesity. Objectives This study sought to examine the effects of the nonsteroidal mineralocorticoid receptor antagonist finerenone compared with placebo, according to body mass index (BMI) in FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure). Methods A total of 6,001 patients with HF with NYHA functional class II, III, and IV, a left ventricular ejection fraction of ≥40%, evidence of structural heart disease, and elevated natriuretic peptide levels were randomized to finerenone or placebo. BMI (kg/m2) was examined using World Health Organization categories, namely, underweight/normal weight (<25.0 kg/m2; n = 1,306); overweight (25.0-29.9 kg/m2; n = 1,990); obesity class I (30.0-34.9 kg/m2; n = 1,546); obesity class II (35.0-39.9 kg/m2; n = 751); and obesity class III (≥40 kg/m2; n = 395). The primary outcome was cardiovascular death and total worsening HF events. Results Data on baseline BMI were available for 5,988 patients (median: 29.2 kg/m2; Q1-Q3: 25.5-33.6 kg/m2). Compared with patients who were underweight/normal weight, those with obesity class II or III had a higher risk of the primary outcome (underweight/normal weight, reference; overweight, unadjusted rate ratio: 0.96 [95% CI: 0.81-1.15]; obesity class I: 1.04 [95% CI: 0.86-1.26]; obesity class II-III: 1.26 [95% CI: 1.03-1.54]). The effect of finerenone on the primary outcome did not vary by baseline BMI (underweight/normal weight, rate ratio: 0.80 [95% CI: 0.62-1.04]; overweight: 0.91 [95% CI: 0.72-1.15]; obesity class I: 0.92 [95% CI: 0.72-1.19]; obesity class II-III: 0.67 [95% CI: 0.50-0.89]; Pinteraction = 0.32). However, when BMI was examined as a continuous variable, the beneficial effect of finerenone seemed to be greater in those with a higher BMI (Pinteraction = 0.005). A similar pattern was observed for total worsening HF events. Consistent effects across baseline BMI were observed for cardiovascular and all-cause death and improvement in the Kansas City Cardiomyopathy Questionnaire scores. Conclusions In patients with HF with mildly reduced/preserved ejection fraction, the beneficial effects of finerenone on clinical events and symptoms were consistent, irrespective of BMI at baseline, possibly with a greater effect on the primary outcome in patients with higher BMI. (FINEARTS-HF [FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure]; NCT04435626)

BACKGROUND:Pooling data from participants with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) from all completed outcomes trials evaluating finerenone to date may enhance understanding of its safety and efficacy in this high-risk and heterogeneous population. OBJECTIVES:In this prespecified participant-level pooled analysis of the FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF trials (FINE-HEART), we evaluated the safety and efficacy of finerenone in individuals with HFmrEF/HFpEF. METHODS:The treatment effects of finerenone vs placebo on cardiovascular death or heart failure hospitalization were evaluated using Cox proportional hazards regression models stratified by trial. Additional endpoints included cardiovascular death, HF hospitalization, new-onset atrial fibrillation, and all-cause death. RESULTS:Among 18,991 pooled trial participants, 7,008 (36.9%) had HFmrEF/HFpEF (mean age, 71 ± 10 years; 44% female). Over a median follow-up of 2.5 years, finerenone reduced cardiovascular death or heart failure hospitalization compared with placebo (HR: 0.87 [95% CI: 0.78-0.96]; P = 0.008). Consistent effects were observed across trials (Pinteraction = 0.24), key subgroups, and baseline estimated glomerular filtration rate (Pinteraction = 0.47), urine albumin-to-creatinine ratio (Pinteraction = 0.62), and glycated hemoglobin (Pinteraction = 0.93). Finerenone additionally appeared to reduce heart failure hospitalization (HR: 0.84 [95% CI: 0.74-0.94]; P = 0.003) and new-onset atrial fibrillation (HR: 0.75 [95% CI: 0.58-0.97]; P = 0.030), but did not statistically significantly decrease cardiovascular death or all-cause death. Hyperkalemia was more common, and hypokalemia was less common, with finerenone vs placebo. Serious adverse events were similar between the treatment arms. CONCLUSIONS:This participant-level pooled analysis of 3 large-scale outcomes trials supports the use of finerenone in individuals with HFmrEF/HFpEF across a broad range of cardiovascular-kidney-metabolic risk. (FINE-HEART: An Integrated Pooled Analysis of Finerenone across 3 Phase III Trials of Heart Failure and Chronic Kidney Disease and Type 2 Diabetes; CRD42024570467).

BACKGROUND:Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitors (SGLT2is) both reduce chronic kidney disease (CKD) progression and improve kidney/cardiovascular (CV) outcomes. The CONFIDENCE (COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with chronic kidney disease and type 2 diabetes using a UACR Endpoint) study (NCT05254002; EudraCT 2021-003037-11) hypothesis is that early combination of finerenone and empagliflozin, an SGLT2i, is superior to either drug alone in reducing urine albumin-to-creatinine ratio (UACR) over 6 months. METHODS:CONFIDENCE is an ongoing, fully enrolled, randomized, controlled, double-blind, multicentre phase 2 clinical trial in adults (≥18 years of age) with CKD and type 2 diabetes (T2D), estimated glomerular filtration rate (eGFR) of 30-90 mL/min/1.73 m2 and UACR of ≥100 to <5000 mg/g. Participants taking the clinically maximum tolerated dose of a renin-angiotensin system inhibitor for >1 month at screening were eligible. Participants were randomized 1:1:1 to once-daily finerenone plus empagliflozin, finerenone plus placebo, or empagliflozin plus placebo; doses were 10 mg once daily for empagliflozin and 10 or 20 mg once daily for finerenone, depending on eGFR at baseline. Randomization was stratified by eGFR (<60 or ≥60 mL/min/1.73 m2) and UACR (≤850 or >850 mg/g). The primary efficacy outcome is the relative change in UACR from baseline at Day 180. RESULTS:There were 818 participants randomized across 143 sites from 14 countries between July 2022 and August 2024. Mean (standard deviation) eGFR was 54.2 (17.1) mL/min/1.73 m2. Median (interquartile range) UACR was 583 (292, 1140) mg/g. Mean (standard deviation) HbA1c was 7.3 (1.2)%. Mean systolic/diastolic blood pressure was 135.2/77.3 mmHg. Glucagon-like peptide-1 receptor agonists and insulin were used by 182 (23%) and 313 (39%) participants, respectively. Atherosclerotic CV disease, diabetic retinopathy and a history of heart failure were present in 223 (28%), 126 (16%) and 30 (4%) participants, respectively. CONCLUSIONS:The CONFIDENCE trial enrolled a diverse population with CKD and T2D, and will determine the impact of simultaneous initiation of combination finerenone and an SGLT2i versus individual therapy on potentially mitigating the progression of CKD in people with T2D. TRIAL REGISTRATION NUMBER:ClinicalTrials.gov NCT05254002; EudraCT 2021-003037-11.

Introduction and Objective: CKD occurs in 1 of 3 people with T1D, with substantial loss of kidney function in over half and kidney failure in nearly one fourth. Therapies to reduce these outcomes in T1D are urgently needed. The nonsteroidal mineralocorticoid receptor antagonist finerenone, on top of ACEi/ARB, reduced the risk of kidney and heart outcomes in people with CKD and T2D. The FINE-ONE trial (NCT05901831) will assess the efficacy and safety of finerenone in people with T1D and CKD. Methods: FINE-ONE is an ongoing, global, phase III trial with finerenone. Participants (n=220) with T1D and CKD (UACR ≥200-<5000 mg/g and eGFR ≥25-<90 mL/min/1.73 m2), HbA1c <10%, and serum potassium ≤4.8 mmol/L, on a stable dose of ACEi/ARB, will be randomized 1:1 to finerenone (10 or 20 mg od) or placebo. The primary efficacy outcome is the relative change in UACR from baseline over 6 months (trial duration~7.5 months). Results: At baseline, 176 randomized participants with T1D had mean HbA1c of 7.6%, mean eGFR of 60 mL/min/1.73 m2, median UACR of 536 mg/g, mean age of 51 years, and 38% were female (Table). A high proportion had a history of hypertension (82%) and 21% had CVD. The most common race was White (71%), followed by Asian (19%) and Black (7%). Conclusion: FINE-ONE will determine the efficacy and safety of finerenone in a representative population with T1D and CKD at high risk of progressive kidney function loss. H.L. Heerspink: Consultant; Alnylam Pharmaceuticals, Inc, Alexion Pharmaceuticals, Inc, AstraZeneca, Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Eli Lilly and Company, Janssen Pharmaceuticals, Inc, Novartis AG, Novo Nordisk A/S, Roche Pharmaceuticals, Traveere Pharmaceuticals, Menarini. A.L. Birkenfeld: None. D. Cherney: Consultant; Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, AMGEN, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK. Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk, Bayer. H.M. Colhoun: Advisory Panel; Novo Nordisk, Bayer Pharmaceuticals, Inc. Stock/Shareholder; Bayer Pharmaceuticals, Inc. Speaker's Bureau; Medscape. Advisory Panel; Sanofi. Research Support; Sanofi, IQVIA Inc, Roche Diagnostics. Stock/Shareholder; Roche Pharmaceuticals. L. Ji: None. C. Mathieu: Advisory Panel; Novo Nordisk, Sanofi, Eli Lilly and Company, Abbott, Medtronic, SAB Biotherapeutics, Inc, Roche Diabetes Care, Vertex Pharmaceuticals Incorporated, Biomea Fusion, Bayer Pharmaceuticals, Inc. P. Groop: Speaker's Bureau; AstraZeneca, Bayer Pharmaceuticals, Inc, Berlin-Chemie AG, Boehringer-Ingelheim. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Novo Nordisk, Menarini. R.E. Pratley: Consultant; AbbVie Inc. Stock/Shareholder; Altanine, Inc. Consultant; Amgen Inc, AstraZeneca. Other Relationship; Bayer AG, Bayer Pharmaceuticals, Inc, Biomea Fusion. Consultant; Boehringer-Ingelheim. Other Relationship; Carmot Therapeutics, Inc, Corcept Therapeutics, Dompé, Eli Lilly and Company, Endogenex. Consultant; Endogenex. Other Relationship; Fractyl Health, Inc., Gasherbrum Bio, Inc. Consultant; Genprex, Getz Pharma, Hanmi Pharm. Co., Ltd, Intas Pharmaceuticals Ltd, Lexicon Pharmaceuticals, Inc, Lilly USA LLC. Speaker's Bureau; Lilly USA LLC. Other Relationship; Metavention, Novo Nordisk, Novo Nordisk. Speaker's Bureau; Novo Nordisk. Other Relationship; Pfizer Inc, Poxel SA. Consultant; Regeneron Pharmaceuticals. Other Relationship; Sanofi. Consultant; Scholar Rock. Other Relationship; Sun Pharmaceutical Industries Ltd. S. Rosas: Other Relationship; American Diabetes Association. Research Support; Bayer Pharmaceuticals, Inc. Advisory Panel; Bayer Pharmaceuticals, Inc, Sanofi. Research Support; AstraZeneca. P. Rossing: Speaker's Bureau; Abbott. Advisory Panel; AstraZeneca, Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Gilead Sciences, Inc, Novo Nordisk. Other Relationship; Lexicon Pharmaceuticals, Inc. Speaker's Bureau; Daiichi Sankyo. J.S. Skyler: Advisory Panel; 4 Immune. Consultant; AbbVie Inc. Advisory Panel; Abvance Therapeutics. Consultant; ActoBiotics. Advisory Panel; ADOCIA. Consultant; AiTA. Board Member; Applied Therapeutics. Advisory Panel; Avotres Inc., Bayer Pharmaceuticals, Inc, Biomea Fusion. Consultant; COUR Pharmaceuticals. Board Member; Dexcom, Inc. Consultant; Eli Lilly and Company. Advisory Panel; Kriya Therapeutics, Levicure. Consultant; Novo Nordisk A/S, Quell Therapeutics. Board Member; SAB Biotherapeutics, Inc. Consultant; Sanofi, Shoreline Biosciences. Advisory Panel; Signos. Consultant; Vertex Pharmaceuticals Incorporated, vTv Therapeutics. Advisory Panel; WiNK. K.R. Tuttle: Consultant; Lilly Diabetes, Boehringer-Ingelheim, Novo Nordisk, Pfizer Inc. Other Relationship; AstraZeneca. Consultant; Bayer Pharmaceuticals, Inc, Traveere Pharmaceuticals, ProKidney. R. Lawatscheck: Employee; Bayer Pharmaceuticals, Inc. M.F. Scheerer: Employee; Bayer Pharmaceuticals, Inc. Stock/Shareholder; Bayer Pharmaceuticals, Inc, Novo Nordisk A/S, AstraZeneca, Eli Lilly and Company. J.B. McGill: Advisory Panel; Bayer Pharmaceuticals, Inc. Consultant; Jaeb Center for Health Research. Advisory Panel; Boehringer-Ingelheim, Lilly Diabetes, Novo Nordisk, MannKind Corporation. Research Support; Diagnode, Lexicon Pharmaceuticals, Inc, Biomea Fusion. J. Russell: Employee; Bayer Pharmaceuticals, Inc.

Heart failure (HF) with mildly reduced or preserved ejection fraction and atrial fibrillation (AF) are closely intertwined. To examine the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with HF with mildly reduced or preserved ejection fraction according to the absence or presence of AF and the type of AF (paroxysmal vs persistent or permanent). Prespecified analyses were conducted in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) randomized clinical trial. The trial was conducted across 653 sites in 37 countries. Participants were adults aged 40 years and older with symptomatic HF and left ventricular ejection fraction of 40% or greater, randomized between September 2020 and January 2023. Data analysis was conducted from September 1 to October 1, 2024. Finerenone (titrated to 20 mg or 40 mg) or placebo. The primary outcome was the composite of total HF events and cardiovascular death. New-onset AF or atrial flutter (AFL) was a prespecified exploratory outcome. Among 5984 patients (mean [SD] age, 72.0 [9.6] years; 2724 [45.5%] female) with known AF status at baseline, 1384 (23.1%) had paroxysmal AF and 1886 (31.5%) had persistent or permanent AF. Patients with both types of AF were older and had worse HF status compared with those without AF (2714 patients [45.4%]). Both types of AF were associated with a higher unadjusted risk of the primary outcome compared with no AF (event rate per 100 person-years of follow-up, 20.3 [95% CI, 17.9-23.1] with paroxysmal AF, 19.8 [95% CI, 17.8-22.0] with persistent or permanent AF, and 11.9 [95% CI, 10.7-13.3] with no AF; rate ratio [RR], 1.62 [95% CI, 1.37-1.92] with paroxysmal AF and 1.66 [95% CI, 1.43-1.93] with persistent or permanent AF vs no AF); however, the associations were attenuated after adjustment for known prognostic variables. The benefit of finerenone on the primary outcome (overall RR, 0.84 [95% CI, 0.74-0.95]) was not modified by baseline AF status (RR, 0.80 [95% CI, 0.65-0.98] with no AF, 0.83 [95% CI, 0.65-1.06] with paroxysmal AF, and 0.85 [95% CI, 0.69-1.05] with persistent or permanent AF; P for interaction = .94). New-onset AF or AFL occurred in 6.5% of patients and was associated with a higher subsequent adjusted risk of the primary outcome (rate ratio, 3.65 [95% CI, 2.57-5.18]; P < .001). The subdistribution hazard ratio for new-onset AF or AFL among those receiving finerenone vs placebo was 0.77 (95% CI, 0.57-1.04; P = .09). The efficacy of finerenone was consistent regardless of AF status. New-onset AF was associated with a substantially higher risk of subsequent outcomes. ClinicalTrials.gov Identifier: NCT04435626.

Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment.

Abstract Background Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans. Methods Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications. Results Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses. Conclusion This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.

BACKGROUND:Finerenone has kidney protective effects in patients with chronic kidney disease (CKD) with type 2 diabetes, but effects on kidney outcomes in patients with heart failure (HF) with and without diabetes and/or CKD are not known. OBJECTIVES:Examine the effects of finerenone on kidney outcomes in FINEARTS-HF, a randomized trial of finerenone vs. placebo among patients with HF with mildly reduced or preserved ejection fraction. METHODS:We explored the effects of finerenone on the secondary outcome of a sustained ≥50% eGFR decline or kidney failure (sustained eGFR decline <15 mL/min/1.73 m2; initiation of maintenance dialysis; renal transplant). In this prespecified analysis, we also report effects of finerenone on: 1) sustained ≥57% eGFR decline or kidney failure; 2) eGFR slope; 3) changes in urine albumin/creatinine ratio (UACR). RESULTS:Among 6,001 participants, mean baseline eGFR was 62 ±20mL/min/1.73m2; 48% had eGFR <60mL/min/1.73m2. Overall, 5,797 had baseline UACR data (median 18 [7,67]mg/g). Over 2.6 years median follow-up, the incidence of the composite kidney outcome (≥50% eGFR decline or kidney failure) was numerically, but non-significantly, higher for finerenone vs. placebo (75 vs. 55 events; HR 1.33; 95%CI 0.94, 1.89). Similar results were observed for the composite of ≥57% eGFR decline or kidney failure (41 vs. 31 events; HR 1.28; 95%CI 0.80, 2.05), though the overall event frequency was relatively low. During the first 3 months, finerenone led to an acute decline in eGFR of -2.9 mL/min/1.73m2 (95%CI -3.4, -2.4) but did not alter chronic (from 3 months) eGFR slope (+0.2 mL/min/1.73m2/year; 95%CI -0.1, +0.4), vs. placebo. The difference in total slope was -0.7 (95%CI -0.9 to -0.4) mL/min/1.73 m2/year. Finerenone reduced UACR by 30% (95%CI 25%, 34%) over 6 months vs. placebo, an effect that persisted throughout follow-up. Finerenone reduced the risk of new-onset of micro- and macroalbuminuria by 24% (HR 0.76; 95%CI 0.68, 0.83) and 38% (HR 0.62; 95%CI 0.53, 0.73), respectively. CONCLUSIONS:In FINEARTS-HF, a population at low risk of adverse kidney outcomes, finerenone did not significantly modify the kidney composite outcomes. Finerenone led to a greater reduction in initial eGFR, but did not result in a significant difference in chronic eGFR slope, vs. placebo. Finerenone led to early and sustained reductions in albuminuria and reduced the risk of new-onset micro- and macroalbuminuria.