CONFIDENCE trial: Dual therapy shows promise for CKD and diabetes
ISN-ACT Global Trials Focus (GTF) editorial team member Michele Provenzano summarizes the design and outcomes of the latest “Trial of the month” featured in ISN-ACT GTF.
Trial of the month:
Stronger together: Finerenone & empagliflozin boost kidney outcomes in diabetes
Finerenone with empagliflozin in chronic kidney disease and type 2 diabetes
Agarwal R, et al., N Engl J Med. 2025 Jun 5
Summary
The CONFIDENCE trial was a double-blind, randomized study enrolling 800 participants with chronic kidney disease (CKD) (eGFR 30–90 ml/min/1.73 m²), albuminuria (urinary albumin-to-creatinine ratio [UACR] 100– 5000 mg/g), and type 2 diabetes, all of whom were receiving renin–angiotensin system inhibitors.
Participants were randomly assigned in a 1:1:1 ratio to receive finerenone (10 or 20 mg daily), empagliflozin (10 mg daily), or both therapies, with matching placebos to ensure blinding. The treatment lasted for 180 days, followed by a 30-day observation period. At baseline, median UACR values were comparable across groups: 574 mg/g in the combination group, 578 mg/g in the finerenone group, and 583 mg/g in the empagliflozin group.
By day 180, combination therapy resulted in a 29% greater reduction in UACR compared to finerenone alone (least-squares mean ratio [LSMR] 0.71; 95% CI, 0.61–0.82; P<0.001) and a 32% greater reduction compared to empagliflozin alone (LSMR 0.68; 95% CI, 0.59– 0.79; P<0.001), with similar safety profiles across the groups. After treatment discontinuation, UACR increased in all groups but remained below baseline levels in all groups, with LSMR at day 210 of 1.63 (95% CI, 1.49–1.78) for combination therapy, 1.45 (95% CI, 1.32–1.59) for finerenone, and 1.44 (95% CI, 1.32–1.58) for empagliflozin.
Serious adverse events occurred in 7.1% (combination therapy), 6.1% (finerenone), and 6.4% (empagliflozin) of participants, with treatment discontinuation due to adverse events being rare (≤4.5%). A ≥30% decline in eGFR at 30 days was seen in 6.3% of the combination group, 3.8% with finerenone, and 1.1% with empagliflozin, mostly reversible upon discontinuation. Hyperkalemia was more common with finerenone (11.4%) than with combination therapy (9.3%) or empagliflozin (3.8%). Combination therapy also led to the greatest reduction in systolic blood pressure, with a mean decrease of 7.4mmHg within 30 days, compared to 5.3mmHg for finerenone and 2.6mmHg for empagliflozin.
Commentary
The CONFIDENCE trial provides evidence on the effectiveness and safety of combining empagliflozin and finerenone simultaneously for patients with CKD and type 2 diabetes.
While both medications are backed by strong evidence and included in international guidelines, data on initiating them at the same time were previously lacking. This trial fills that gap, showing that the combination is well tolerated, does not result in problems with hyperkalemia, and, as expected, does reduce albuminuria, an important marker that is associated with a decreased risk of CKD progression.
Notably, the more profound reduction on in albuminuria appears within four weeks, with the combination, than either drug alone, indicating a possible synergistic effect between the two drugs. From a safety standpoint, the simultaneous combination did not significantly increase adverse events such as acute kidney injury or hyperkalemia.
Additionally, it achieved a greater reduction in systolic blood pressure, which could improve blood pressure control in CKD patients. However, the study has limitations, including a relatively small sample size (800 patients), a short follow-up period of 180 days, and a 30-day post-treatment observation that restricts insights into long-term efficacy and safety. Furthermore, relying on UACR as a surrogate endpoint limits definitive conclusions about long-term clinical benefits. Although UACR reduction is an accepted intermediate endpoint, trials focused on clinical outcomes are necessary.
In conclusion, the CONFIDENCE trial supports early co-initiation of empagliflozin and finerenone as a promising strategy for people with diabetes and CKD, based on their additive effects on reducing albuminuria. Nonetheless, further long-term research is needed to determine whether this dual therapy provides significant clinical benefits over each medication alone in lowering risks of kidney failure, cardiovascular events, and death.
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