CONFIDENCE supports simultaneous MR, SGLT2 inhibition in CKD and T2D

The phase II CONFIDENCE* trial shows the benefit of dual therapy with the selective ns-MRA** finerenone and the SGLT2i** empagliflozin vs either agent alone in individuals with chronic kidney disease (CKD) and type 2 diabetes (T2D).

“As early as 14 days, there was a 30-percent reduction in albuminuria with simultaneous initiation of finerenone and empagliflozin. In fact, 54 percent of those who received this regimen achieved this outcome at this point,” said Dr Rajiv Agarwal from the Indiana University School of Medicine, Indianapolis, Indiana, US, who presented the efficacy and safety results at ERA 2025.

Additive reductions in UACR*** were gradually seen (35 percent by day 30; 49 percent by day 90) that by day 180, there was a 52-percent reduction in UACR with the combo regimen, noted Agarwal, amidst a roaring applause.

“The primary efficacy endpoints were met for this combination. There was a 32-percent greater reduction vs empagliflozin and 29-percent greater reduction vs finerenone,” he said.

Of note, the albuminuria gradually returned to near baseline when the regimen was stopped. [ERA 2025, abstract 116]

Seventy percent of participants receiving the combination therapy achieved the treatment target of >30-percent UACR reduction at 180 days (vs 52 percent of those on either agent). The corresponding proportions of participants achieving the >40- and >50-percent reduction target were 64 percent (vs 44 percent) and 55 percent (vs 34 percent), respectively.

“With monotherapy, the outcomes were always about ≤20 percent less. Therefore, the combination therapy, no matter how you look at it, was more efficacious in getting to treatment target,” Agarwal said.

Other outcomes

Day 14 saw increases in potassium (K+) levels with empagliflozin, more so with finerenone-based therapies, and the levels were sustained until day 180. These returned to baseline levels after the washout phase.

The proportion of participants with serum K+ >5.5 mmol/L was 18.6 percent with finerenone and 15.3 percent with the combination. “[This implies that] when you combine finerenone with empagliflozin, it makes the therapy safer in terms of K+,” explained Agarwal.

The incidence of treatment-emergent hyperkalaemia was lower with combo therapy than finerenone (9.3 percent vs 11.4 percent). Overall, none of those with hyperkalaemic episodes were hospitalized, had a serious adverse event, or died, and only three (one in each study arm) permanently stopped the study drug/s.

Systolic blood pressure dipped at day 14 across all arms, but the most profound effect was seen with the combo regimen due to the synergistic effect of both agents. This effect was sustained until day 180 and returned to baseline after washout.

The combination led to greater drops in eGFR*** than with either agent alone. This continued and plateaued at day 90. “The initial eGFR decline [with the] combination therapy was predictable and largely reversible after drug withdrawal,” Agarwal said.

He added that the return to baseline levels across most outcomes is an expected haemodynamic effect that happens because of drug withdrawal.

Overall, there were low incidences of symptomatic hypotension (three in the combo arm) and acute kidney injury (AKI; five in the combo arm and three in the finerenone arm).

Study characteristics

ACEis/ARBs**, SGLT2is, ns-MRAs, and GLP-1 RAs** are the four standard pillars of care in T2D and CKD, noted co-investigator Dr Peter Rossing from the University of Copenhagen in Denmark, who presented the study rationale at ERA 2025. “We hypothesized that a combination of finerenone and an SGLT2i could decrease albuminuria more than either treatment alone, and that it could do so safely.”

The full analysis set comprised 800 patients (mean age 67 years, 75 percent men, 46 percent Asian) with CKD (mean eGFR 54 mL/min/1.73 m², median UACR 579 mg/g) and T2D (mean HbA_1C 7.3 percent). They were randomized 1:1:1 to once-daily finerenone 10 or 20 mg + placebo, empagliflozin 10 mg + placebo, or a combination of both. They were followed for 180 days. A 30-day washout period ensued thereafter.

Ninety-eight percent of participants were on ACEis/ARBs and 23 percent were on GLP-1 RAs. The cohort was representative of a high-risk population – 88 percent were hypertensive, 28 percent had atherosclerotic cardiovascular disease, and 16 percent had diabetic retinopathy.

Combined benefits of multiple pillars of therapy

“The findings clearly show that finerenone and an SGLT2i can be initiated simultaneously,” said co-investigator Dr Johannes Mann from the Friedrich Alexander University, Erlangen, Germany, during his part at ERA 2025.

“Simultaneous initiation of finerenone and an SGLT2i provides early and additive effects on UACR reduction that are statistically and clinically significant,” said Agarwal. Symptomatic hypertension, AKI, and hyperkalaemia leading to drug discontinuation – three concerns when starting this combination – were uncommon, he added.

“The evidence shows the combined benefits of multiple pillars of therapy and that potentially greater benefits can be achieved through early and intensive intervention,” said Mann.