Diabetes
Elizabeth Briand
More than one out of every 10 Americans has diabetes, according to CDC. For these millions of individuals, their condition puts them at high risk of developing CKD, with roughly one in three adults with diabetes also contending with CKD.
With the deep connections between the two diseases, researchers have been seeking new ways to manage CKD for patients with T2D. The CONFIDENCE trial sought to determine whether simultaneous initiation of finerenone and empagliflozin reduced urinary albumin-to-creatinine ratio (UACR) more than either agent alone in adults with CKD and T2D.
Trial results, which were published in the August 7, 2025, edition of NEJM, revealed that the combination therapy led to a 29% to 32% greater reduction in UACR compared to either monotherapy at 180 days, with a safety profile similar to monotherapy.
According to lead author Rajiv Agarwal, MD, the results were not unexpected but are clinically significant and may signal the emergence of a new treatment option.
“These findings could influence patient care by supporting earlier and simultaneous initiation of both agents in high-risk CKD and type 2 diabetes, rather than the traditional stepwise approach,” said Agarwal. “This may accelerate albuminuria reduction and potentially improve long-term renal and cardiovascular outcomes.”
The CONFIDENCE trial was a double-blind, randomized, active-controlled trial of finerenone alone, emplagflozin alone, or a combination of the two therapies administered to 798 people with CKD with albuminuria and T2D.
Promising combination
The motivation for investigating the combination of finerenone and empagliflozin, according to Agarwal, stemmed from the complementary mechanisms of action: Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, and empagliflozin, an SGLT-2 inhibitor, both reduce cardiorenal risk but via distinct pathways.
“Prior analyses suggested additive benefits, but robust evidence for simultaneous initiation was lacking. Both drugs have shown independent efficacy in reducing albuminuria and slowing CKD progression, and preclinical and subgroup data suggested potential for greater benefit and possibly reduced hyperkalemia risk when used together,” said Agarwal, who is emeritus professor of medicine at Indiana University School of Medicine.
Hyperkalemia involves abnormally high levels of potassium in the blood and is important to individuals with CKD because damaged kidneys are unable to properly filter and remove excess potassium from the body. It is a common condition for people with CKD.
Patients enrolled in the study were already on a renin–angiotensin system inhibitor.
Researchers honed in on UACR because of its use as a common kidney function test for detection of kidney damage. The noninvasive test is especially helpful in monitoring kidney health for people with diabetes or high BP who are at higher risk for kidney disease.
New standard?
Authors of an August 7, 2025, NEJM editorial about the trial noted that it had “several limitations, the most notable of which was that a surrogate marker was used as the primary end point rather than a direct measure of clinical events such as kidney failure or cardiovascular outcomes.”
Although more research may be needed to confirm the effect of this combination of medications, it may offer a better option than stepwise therapy, which the trial study authors noted “may prolong the time to effective treatment and can lead to clinical inertia,” adding that “in clinical practice, follow-up testing to assess the urinary albumin-to-creatinine ratio is infrequently performed, which may in turn underestimate the ongoing risk and add to clinical inertia.”
Agarwal noted that while monitoring for hyperkalemia, BP, and eGFRs remain important in preserving and protecting kidney function, the results of this study demonstrate that the combination of finerenone and empagliflozin could offer a manageable safety profile.
“Early combination therapy may become a new standard for high-risk patients,” he said. ■