Growing CONFIDENCE in co-prescribing of SGLT2 inhibitors and non-steroidal MRAs

Since the findings of the CREDENCE (Canagliflozin and Renal Events in Type 2 Diabetes with Established Nephropathy Clinical Evaluation) were published in 2019, landmark trials of sodium–glucose co-transporter 2 inhibitors (SGLT2i) have consistently shown that these agents delay the progression of chronic kidney disease (CKD) and reduce adverse renal and cardiovascular outcomes in people with type 2 diabetes.^1–3 In 2020 and 2021, respectively, 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 found that treatment with the non-steroidal selective mineralocorticoid receptor antagonist (nsMRA) finerenone in patients with a broad spectrum of CKD and type 2 diabetes also improved cardiorenal outcomes.^4,5 

None of the participants in the CREDENCE, EMPA-KIDNEY or DAPA-CKD trials were taking finerenone, and only a small minority of patients in FIDELIO-CKD and FIGARO-DKD (4.6 and 8.4%, respectively) were on treatment with SGLT2i.^1–5 A pooled analysis of FIDELIO-CKD and FIGARO-DKD did show that concomitant treatment with finerenone and SGLT2i did not increase rates of renal adverse events, nor did it alter the cardiorenal benefits of finerenone treatment.⁶ The safety and synergy of combining nsMRA and SGLT2i in people type 2 diabetes and CKD, however, warranted robust evaluation. 

These were the key motivations behind CONFIDENCE (Combination Effect of Finerenone and Empagliflozin in Participants with Chronic Kidney Disease and Type 2 Diabetes).⁷ This was a multicentre, international, double-blind, active-comparator, randomised controlled trial of finerenone 10–20 mg/day monotherapy, empagliflozin 10 mg/day monotherapy, or the combination of both finerenone and empagliflozin in patients with type 2 diabetes and albuminuric CKD (defined as an estimated glomerular filtration rate (eGFR) of 30–90 mL/min/1.73 m² and urinary albumin-to-creatinine ratio of 100–5000 mg/g). All subjects must have been on established renin–angiotensin–aldosterone system (RAAS) inhibitor therapy for at least one month before enrolment. Key exclusion criteria were: recent use of SGLT2i or potassium-binding drugs, type 1 diabetes, chronic heart failure with reduced ejection fraction, persistent hyperkalaemia (defined as serum potassium >4.8 mmol/L), myocardial infarction, stroke or heart failure hospitalisation within three months. The primary efficacy outcome measure was change in mean urinary albumin-to-creatinine ratio at 180 days. Safety outcome measures included change in eGFR from baseline to day 30, acute kidney injury, hyperkalaemia, symptomatic hypotension and ketoacidosis. 

The final study group included 800 participants (269 received combination therapy, 264 finerenone and 267 empagliflozin), although only 749 completed follow-up. Mean age was 67±10 years, 25% were females, mean HbA_1c was 7.3±1.3%, mean eGFR 54±17 mL/min/1.73 m² and median urinary albumin-to-creatinine ratio (uACR) 579 (IQR, 292–1092). At 180 days, the reduction from baseline uACR with combined finerenone and empagliflozin therapy was 29% greater than with finerenone monotherapy and 32% greater than empagliflozin monotherapy. More than half of those patients who received combination treatment achieved a >50% reduction in uACR, as compared to around a third with either finerenone or empagliflozin monotherapy. Discontinuation of treatment at 180 days was associated with steep returns to near baseline levels of uACR and eGFR at day 210, in all three arms.

Rates of adverse events leading to treatment discontinuation were comparably low (~3.5%) in all three treatment arms. Although the occurrence of hyperkalaemia was more than twice as likely (~10% versus 3.8%) in those who received finerenone (either in combination with empagliflozin or as monotherapy) compared to those treated with empagliflozin alone, treatment discontinuation associated with hyperkalaemia only occurred in one participant in each trial arm. An average 7.4 mmHg reduction in systolic blood pressure was observed in those treated with combination therapy, which was twice the reduction associated with either finerenone or empagliflozin monotherapy.⁷

In summary, in patients with albuminuric CKD and type 2 diabetes, combination therapy with the nsMRA finerenone and the SGLT2i empagliflozin was associated with early and sustained reductions in albuminuria beyond that achieved with either agent alone. These synergistic effects were not at the expense of significant safety concerns. This raises the exciting potential that nsMRA and SGLT2i combination therapy could translate to substantial reductions in hard clinical kidney outcomes and become a new pillar of management in CKD, alongside RAAS inhibitors (and possibly glucagon-like peptide-1 receptor agonists).

Whilst the prospect of combination therapies to improve kidney outcomes in diabetic kidney disease is tantalising, only a small minority of patients are likely to receive all appropriate guideline-directed medical therapies. Recent US estimates suggest that over 2 million people would be eligible for treatment with finerenone based upon the FIDELIO-DKD and FIGARO-DKD trial inclusion criteria, the majority of whom are also likely to warrant SGLT2i therapy.⁸ In the UK, however, a recent cross-sectional analysis of primary care data in over 6.5 million people (comprising over half a million people with CKD and a third with co-existing type 2 diabetes), SGLT2i were only prescribed in 17% of those eligible.⁹ Prescribing patterns of finerenone are, as yet, unknown but are likely to be much lower than SGLT2i given its relatively recent introduction. Even if future kidney guidelines advocate combination therapy with nsMRA and SGLT2i, barriers to implementation will need to be identified and urgently addressed to ensure higher proportions of patients receive all appropriate disease trajectory-modifying drugs. Nevertheless, the CONFIDENCE trial gives us more confidence that finerenone and empagliflozin can (and should) be co-prescribed in diabetic albuminuric kidney disease. 

A digest of the study can be read here.

References

1. Perkovic V, Jardine MJ, Neal B et al; CREDENCE Trial Investigators (2019) Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 380: 2295–306
2. Heerspink HJL, Stefansson BV, Correa-Rotter R et al; DAPA-CKD Trial Committees and Investigators (2020) Dapagliflozin in patients with chronic kidney disease. N Engl J Med 383: 1436–46
3. The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C et al (2023) Empagliflozin in patients with chronic kidney disease. N Engl J Med 388: 117–27
4. Bakris GL, Agarwal R, Anker SD et al; FIDELIO-DKD Investigators (2020) Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 383: 2219–29
5. Pitt B, Filippatos G, Agarwal R et al; FIGARO-DKD Investigators (2021) Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med 385: 2252–63
6. Rossing P, Anker SD, Filippatos G et al; FIDELIO-DKD, FIGARO-DKD Investigators (2022) Finerenone in patients with chronic kidney disease and type 2 diabetes by sodium-glucose cotransporter 2 inhibitor treatment: The FIDELITY analysis. Diabetes Care 45: 2991–8
7. Agarwal R, Green JB, Heerspink HJL et al; CONFIDENCE Investigators (2025) Finerenone with empagliflozin in chronic kidney disease and type 2 diabetes. N Engl J Med 5 Jun [Epub ahead of print]
8. Chiu N, Aggarwal R, Bakris GL et al (2022) Generalizability of FIGARO-DKD and FIDELIO-DKD trial criteria to the US population eligible for finerenone. J Am Heart Assoc 11: e025079
9. Forbes AK, Hinton W, Feher MD et al (2024) Implementation of chronic kidney disease guidelines for sodium-glucose co-transporter-2 inhibitor use in primary care in the UK: a cross-sectional study. EClinicalMedicine 68: 102426