Explore-CKD: lorundrostat added to an SGLT2 inhibitor lowered blood pressure and albuminuria

Design

Randomised, double-blind, placebo-controlled crossover phase 2 trial

Population

59 adults with uncontrolled hypertension, CKD and albuminuria on an SGLT2 inhibitor

Primary outcome

Change in automated office systolic blood pressure

Effect

Placebo-adjusted -7.5 mmHg (95% CI -12.3 to -2.7); UACR -25.6% (-37.7 to -11.2)

Aldosterone contributes to hypertension and CKD. Lorundrostat is an investigational aldosterone synthase inhibitor. Explore-CKD was a randomised, double-blind, placebo-controlled crossover trial in 59 adults with uncontrolled hypertension, CKD and albuminuria, all on stable renin-angiotensin blockade and an SGLT2 inhibitor. Mean age was 64.6, 76% had type 2 diabetes, baseline office systolic pressure was 149 mmHg, geometric mean UACR 517 mg/g and eGFR 43. Participants received lorundrostat 25 mg daily or placebo for 4 weeks each, separated by a 4-week washout.

Office systolic pressure fell by 9.3 mmHg with lorundrostat and 1.8 with placebo (placebo-adjusted -7.5, 95% CI -12.3 to -2.7). UACR fell by 25.6% on a placebo-adjusted basis (-37.7 to -11.2). eGFR drifted from 42.9 to 40.1 with lorundrostat and to 42.1 with placebo. Three participants stopped for adverse events: hyperkalaemia with CKD worsening, acute kidney injury and retinal detachment.

Four weeks is too short to show kidney outcomes. The authors say longer studies are needed to learn whether the albuminuria reduction translates to durable kidney or cardiovascular benefit.

• Lorundrostat is investigational; it is not a prescribing option from this trial.
• Placebo-adjusted systolic pressure fell by 7.5 mmHg on top of an SGLT2 inhibitor and renin-angiotensin blockade.
• Albuminuria fell by about a quarter, with a small additional eGFR dip.
• Hyperkalaemia and AKI led to discontinuation in two of 59 participants.
• The trial lasted 4 weeks per period and does not address kidney outcomes.

Why it matters

Residual aldosterone effects may persist after SGLT2 inhibitor and renin-angiotensin therapy, and this probes a new way to address them.

Don't overread it

Phase 2, four-week periods, 59 participants and surrogate end points: blood pressure and albuminuria are not kidney failure or death.

The statistics, in plain English

A placebo-adjusted fall of 7.5 mmHg with an interval of -12.3 to -2.7 means the true effect could be as small as about 3 mmHg or as large as 12. A crossover trial uses each person as their own control, which is efficient but vulnerable to carry-over; the washout period is meant to limit it.

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