Vicadrostat ± Empagliflozin: Consistent Albuminuria Reduction Across CKD Risk Subgroups

Written by Agavriloaei Bogdan Dumitru

Reviewed by @ Sophia Ambruso, Priya John.

The question: Does the aldosterone synthase inhibitor vicadrostat consistently reduce albuminuria across the CKD risk strata represented in the study, including patients with uncontrolled hypertension or those receiving diuretics?

To respond, we have the next article: https://www.sciencedirect.com/science/article/pii/S2468024926027774 

Background: The Renin-Angiotensin-Aldosterone System (RAAS) 

The renin-angiotensin-aldosterone system (RAAS) is a primary target for the most widely used classes of antihypertensive medications: angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and direct renin inhibitors (Valentini et al, 2025)

The RAAS cascade evolutionarily exists to defend the hypovolemic state and begins with the release of renin from juxtaglomerular cells in the setting of low effective arterial blood volume, stimulated in part by sympathetic nervous system activation of β1-adrenergic receptors. Renin converts hepatic angiotensinogen into angiotensin I, which is subsequently converted by angiotensin-converting enzyme (ACE) into angiotensin II,  a potent vasoconstrictor that also stimulates aldosterone secretion from the adrenal zona glomerulosa. Aldosterone acts on the distal convoluted tubule and collecting duct, promoting sodium retention and potassium excretion, thereby contributing to elevated blood pressure (Rajapaksha et al 2021). However, in the sodium avid state, aldosterone drives sodium retention, hypertension, inflammation, and fibrosis in CKD.

Limitations of Conventional RAAS Blockade

Despite the availability of multiple drugs targeting different components of the RAAS, contributors such as inadequate systemic and renal vasodilation, inflammation, endothelial dysfunction, and aldosterone excess continue to pose challenges in the adequate treatment of resistant hypertension. A notable issue is the phenomenon of aldosterone breakthrough in which angiotensin II and aldosterone levels rebound after an initial suppression induced by ACE inhibitors/ARBs, even while RAAS blockade is maintained. This phenomenon partly explains why conventional RAAS blockade fails to fully control blood pressure in some patients, particularly those with resistant hypertension (Prasad et al, 2026). .Beyond its hemodynamic effects, dysregulated aldosterone signaling may directly contribute to kidney damage. Aldosterone exerts genomic effects through activation of the mineralocorticoid receptor (MR), promoting pro-inflammatory and profibrotic pathways. In addition, aldosterone can exert rapid non-genomic effects that are independent of classical MR-mediated gene transcription and may further contribute to vascular and renal injury. Thus, persistent aldosterone bioactivity may promote cardiorenal damage beyond its effects on sodium retention, volume expansion, and blood pressure (Fioretti el al, 2025).

These limitations have opened the door to additional therapeutic targets that complement classical RAAS blockade:

• Aldosterone synthase (CYP11B2) inhibitors — such as vicadrostat, baxdrostat and lorundrostat — which block aldosterone synthesis directly at the adrenal level, in contrast to MRAs, which only block the mineralocorticoid receptor.By reducing aldosterone production upstream of the MR, these agents may inhibit both genomic and non-genomic effects of aldosterone, which contribute to vascular smooth muscle cell hypertrophy, vascular fibrosis, and renal interstitial fibrosis. 

• Small interfering RNA (siRNA) targeting angiotensinogen (zilebesiran) — which reduces hepatic production of angiotensinogen, the initial substrate of the entire RAAS cascade, providing sustained antihypertensive effects with quarterly or semiannual dosing (Desai et al, 2023). Overview of RAAS is presented in figure 1.

• MRAs versus ASIs: receptor blockade versus aldosterone suppression. MRAs have established cardiorenal benefits in selected patient populations, whereas ASIs offer a promising upstream approach by directly suppressing aldosterone synthesis. Whether ASIs should replace or complement MRAs in clinical practice remains to be established through comparative and long-term outcome trials.

Unlike mineralocorticoid receptor antagonists, which block the aldosterone receptor, vicadrostat inhibits CYP11B2 to directly suppress aldosterone production (Gashaw et al, 2026). It is being studied either alone or in combination with empagliflozin (VicaEmpa). Overview of mineralocorticoid receptor antagonists is presented in Figure 2.

Figure 2. Overview of mineralocorticoid receptor antagonists

Mechanism of action of Vicadrostat:

Vicadrostat is a potent and highly selective aldosterone synthase inhibitor (ASI) that inhibits CYP11B2, the enzyme responsible for the final steps of aldosterone synthesis in the adrenal zona glomerulosa. By selectively inhibiting CYP11B2, vicadrostat directly suppresses aldosterone production. Vicadrostat displays approximately 250-fold selectivity for CYP11B2 over CYP11B1, allowing suppression of aldosterone production while preserving cortisol synthesis (Merlo et al, 2026). Dedicated steroid profiling further demonstrated the pharmacodynamic selectivity of vicadrostat. Aldosterone suppression persisted for approximately 4 weeks after treatment discontinuation, whereas precursor concentrations returned toward baseline within approximately 1 week (Gashaw et al, 2026).

The resulting reduction in aldosterone is expected to decrease renal sodium and water retention and extracellular volume, contributing to blood pressure reduction. The mechanism of action of vicadrostat is presented in Figure 3.

Figure 3. Vicadrostat -  mechanism of action

What was already known:

Blood pressure control is not merely a cardiovascular concern, it directly influences glomerular hemodynamics and, consequently, albuminuria. Elevated systemic blood pressure is transmitted to the glomerular capillaries, particularly in the context of impaired renal autoregulation, increasing intraglomerular pressure and driving progressive proteinuria and nephron injury. As such, blood pressure reduction is a central therapeutic lever not only for cardiovascular risk reduction but also for slowing the proteinuria-mediated pathway of CKD progression.

Notably, even modest reductions in blood pressure can translate into clinically meaningful benefits: reductions in the range of approximately 5 to 10 mm Hg systolic blood pressure, similar in magnitude to what a single antihypertensive agent can achieve, have been associated with meaningful decreases in cardiovascular and kidney outcomes across clinical trials (Rahimi et al, 2021). This underscores that even incremental blood pressure improvements,  such as those observed with add-on therapies targeting the RAAS or aldosterone pathway,  may carry disproportionate clinical relevance for both cardiovascular protection and kidney outcomes, including proteinuria reduction. 

Other aldosterone synthase inhibitors have shown promising effects in CKD. In patients with CKD and uncontrolled hypertension, baxdrostat reduced systolic blood pressure by approximately 8 mmHg versus placebo and reduced UACR by approximately 55% across pooled doses, although hyperkalemia was more frequent at higher doses (Dwyer et al, 2026). Similarly, in the Explore-CKD crossover study, lorundrostat produced a placebo-adjusted reduction of 7.5 mmHg in AOSBP and 25.6% in UACR in patients with CKD and uncontrolled hypertension receiving background RAS and SGLT2 inhibition. A modest decline in eGFR was observed with lorundrostat, while three participants discontinued treatment because of adverse events, including hyperkalemia with worsening CKD, acute kidney injury, and retinal detachment (Weir et al, 2026).  Vicadrostat differs in that its CKD development program prospectively incorporated empagliflozin from the outset through a factorial run-in design, allowing the effects of aldosterone synthase inhibition alone and in combination with SGLT2 inhibition to be evaluated within the same trial.

The parent phase 2 trial (n = 586) used a two-stage randomized design to evaluate vicadrostat alone and in combination with empagliflozin in patients with CKD. During an 8-week run-in period, participants were randomized to empagliflozin 10 mg or placebo. They were then re-randomized in a 1:1:1:1 ratio to vicadrostat 3 mg, 10 mg, 20 mg, or placebo for 14 weeks. The primary endpoint was the change in first-morning-void UACR from baseline to week 14. Vicadrostat reduced UACR by up to 40% alone and up to 61% when combined with empagliflozin, supporting complementary albuminuria-lowering effects of aldosterone synthase and SGLT2 inhibition. UACR reduction is presented in Figure 4.

Figure 4. Overall reduction of UACR – Vicadrostat alone and Vicadrostat with Empagliflozin

What this analysis tested: Whether these effects hold consistently across four clinically relevant subgroups (n = 503 with UACR data):

• KDIGO risk category (moderate-to-high vs. very high)

• KFRE 5-year risk (<5% vs. ≥5%)

• Uncontrolled vs. controlled hypertension

• Diuretic use at baseline

Key Results

Vicadrostat demonstrated consistent effects on albuminuria, blood pressure, and kidney function across the evaluated CKD subgroups, including KDIGO and KFRE risk categories, hypertension status, and baseline diuretic use.

Albuminuria reduction

• UACR reductions ranged from approximately 24% to 55% with vicadrostat 10 or 20 mg across subgroups.

• Reductions were generally consistent regardless of KDIGO or KFRE risk, hypertension control, or baseline diuretic use.

• Although some nominal subgroup interactions were observed, none remained statistically significant after correction for multiple comparisons.

Clinically meaningful UACR response

• A ≥30% reduction in UACR was achieved by 43–82% of participants receiving vicadrostat 10 or 20 mg across subgroups.

• Responder rates were generally numerically higher with vicadrostat plus empagliflozin (VicaEmpa) than with vicadrostat alone.

• Among participants receiving VicaEmpa, responder rates were numerically higher in those using baseline diuretics, although this pattern was not observed consistently with vicadrostat monotherapy.

Systolic blood pressure

• SBP reductions were generally consistent across KDIGO and KFRE risk categories, hypertension status, and baseline diuretic use.

• Reductions were also observed in participants with uncontrolled hypertension.

• SBP lowering tended to be greater with background empagliflozin, without evidence of significant subgroup interactions after correction for multiple comparisons.

Kidney function

• Changes in eGFR were modest overall and generally consistent across the evaluated subgroups.

• Importantly, participants classified as very high KDIGO risk or KFRE ≥5% did not experience a greater absolute eGFR decline.

• eGFR changes were also broadly comparable regardless of hypertension control or baseline diuretic use.

Overall, these subgroup findings suggest that the albuminuria- and blood pressure-lowering effects of vicadrostat, alone or combined with empagliflozin, were broadly consistent across different CKD risk profiles and clinical characteristics. However, the absence of statistically significant treatment-by-subgroup interactions should not be interpreted as proof of equivalent effects in every subgroup.

Safety

As expected for an aldosterone-pathway therapy, hyperkalemia remains an important safety consideration. In the phase II CKD trial of vicadrostat, serum potassium was 0.32 mmol/L (95% CI, 0.13–0.50) and 0.24 mmol/L (95% CI, 0.08–0.41) higher compared with placebo for the 10 and 20 mg doses, respectively, when used in combination with empagliflozin. This is relevant given that SGLT2 inhibitors have been associated with an approximately 16% reduction in the risk of serious hyperkalemia across CKD and cardiovascular outcome trials (HR 0.84).

However, the available subgroup analyses offer limited insight into who is most susceptible to hyperkalemia. The manuscript reports that overall adverse-event frequencies were similar across KDIGO risk, KFRE, hypertension, and diuretic-use subgroups, but hyperkalemia itself is not reported separately across these groups. Consequently, it remains unclear whether potassium elevations were more frequent in clinically relevant higher-risk groups, particularly patients receiving diuretics and those in the very-high KDIGO risk category with lower eGFR. This remains an important safety question for future studies of vicadrostat.

Limitations: This was a phase 2 post-hoc analysis, not powered to detect subgroup interactions; findings should be considered hypothesis-generating rather than confirmatory. KDIGO and KFRE subgroups also overlapped substantially, limiting fully independent interpretation.

Conclusion: Vicadrostat, with or without empagliflozin, reduced albuminuria and blood pressure consistently across a broad range of CKD severity, hypertension status, and diuretic use, supporting the inclusion of a broad patient population in the ongoing phase 3 EASi-KIDNEY trial (NCT06531824).