Keywords: Chronic Kidney Disease, Diabetic Nephropathy, Finerenone, Empagliflozin, SGLT2 inhibitors, Mineralocorticoid Receptor Antagonist, CONFIDENCE study
The management of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus (T2DM) remains a growing clinical challenge, with substantial morbidity, mortality, and healthcare costs. While standard therapies—such as renin-angiotensin system (RAS) inhibitors—slow disease progression, residual risk remains high.
New data from the CONFIDENCE study, presented recently, suggest that early dual therapy using finerenone and empagliflozin may offer additive kidney protection, shifting the treatment paradigm toward combination therapy from the outset.
The Pathophysiological Basis for Combination Therapy
In diabetic kidney disease (DKD), persistent hyperglycemia and hypertension drive glomerular injury through complex pathways involving glomerular hyperfiltration, oxidative stress, inflammation, and fibrosis.
- Finerenone, a non-steroidal mineralocorticoid receptor antagonist (MRA), blocks mineralocorticoid-induced inflammation and fibrosis at the cellular level.
- Empagliflozin, a SGLT2 inhibitor, reduces intraglomerular pressure and improves glycemic control, while also conferring cardiorenal protection through hemodynamic and metabolic effects.
Given their complementary mechanisms, combined use offers a biologically plausible strategy to enhance renal outcomes.
The CONFIDENCE Study: Design and Outcomes
The CONFIDENCE trial was a randomized, controlled study evaluating the efficacy of combination therapy versus monotherapy in patients with CKD and T2DM. Participants were randomized into three groups:
- Finerenone + placebo
- Empagliflozin + placebo
- Finerenone + Empagliflozin
All patients continued standard background care, including ACE inhibitors or ARBs.
The primary endpoint was the change in urinary albumin-to-creatinine ratio (UACR), a surrogate marker for renal damage and predictor of progression in diabetic kidney disease.
Key Findings
The results demonstrated a superior renal benefit with combination therapy:
| Treatment Arm | Reduction in UACR |
|---|---|
| Finerenone + Empagliflozin | 52% |
| Finerenone alone | 29% |
| Empagliflozin alone | 32% |
Importantly, the onset of effect was rapid, with significant reductions observed within two weeks of therapy initiation. This suggests a potential role for early intervention to alter disease trajectory before irreversible renal damage occurs.
Clinical Significance and Safety Profile
These findings reinforce a growing body of evidence supporting dual blockade strategies in cardio-renal-metabolic disease. While current guidelines favor stepwise intensification, the CONFIDENCE trial supports a “hit early, hit hard” approach akin to treatment models in heart failure and hypertension.
Safety Outcomes:
- Adverse events were generally mild and manageable.
- Reported effects included transient hypotension, hyperkalemia, and minor fluctuations in eGFR—all consistent with the known pharmacologic profiles of the agents used.
- Treatment discontinuation was rare.
Future Directions
While the data are encouraging, longer-term studies are required to evaluate:
- Hard renal outcomes (e.g., decline in eGFR, dialysis initiation)
- Cardiovascular event reduction
- Cost-effectiveness and implementation feasibility in diverse healthcare systems
Additionally, further research is needed to define optimal sequencing or co-initiation of these agents and to determine their efficacy in non-diabetic CKD populations.
Conclusion
The CONFIDENCE study represents an important step forward in the treatment of diabetic kidney disease. By demonstrating a synergistic effect of finerenone and empagliflozin on albuminuria reduction, it opens the door to more aggressive, early-stage intervention aimed at preserving renal function and improving long-term outcomes.
As clinical practice continues to evolve toward multifactorial, mechanism-based therapies, the early adoption of dual therapy may soon become a cornerstone in the management of CKD in patients with diabetes.
Clinical Perspective
For clinicians managing patients with T2DM and CKD, the emerging data supports a proactive approach—considering combination therapy early in the disease course, particularly in patients with persistent albuminuria despite standard care.