Common Diuretic Pauses Atherosclerosis in CKD, T2D

AUSTIN, Texas -- The diuretic spironolactone stopped the progression of atherosclerosis in people with type 2 diabetes and chronic kidney disease (CKD), according to the MAGMA trial.

Among 79 patients with stages 3 to 4 CKD, those randomized to received 25 mg/day of the mineralocorticoid receptor antagonist saw a significantly smaller change in thoracic aorta wall volume at 12 months (average 0.5% vs 7.3% with placebo, P<0.05) -- meeting the study's primary endpoint, found Matthew Weir, MD, of the University of Maryland in Baltimore, and colleagues.

"We are now finally moving into an era where we have more choices," said Weir during a presentation of the late-breaking findings at the National Kidney Foundation Spring Clinical Meeting. "And I think [mineralocorticoid receptor] blockade certainly is one to come and be considered in many of our patients."

As for secondary outcomes, patients on daily spironolactone also saw decreases in three other measures of atherosclerosis that only increased for those on placebo:

• Thoracic aorta total wall volume change: -0.04 vs 1.2 cm³ for placebo (P<0.05)
• Left ventricular mass index change: -3.5 vs 2.1 g/m² (P<0.001)
• Left ventricular myocardial T1 times change: -10.3 vs 17.1 ms (P<0.05)

"Progressive increase in native T1 values likely reflects increasing fibrosis and was attenuated with spironolactone," Weir pointed out.

On top of that, 24-hour ambulatory blood pressure also dropped across the board. There was a 5.95 and 2.00 mm Hg change in systolic blood pressure for the spironolactone and placebo groups, respectively, and a significantly different 4.00 and 2.00 mm Hg change for diastolic blood pressure.

"Our mediation analysis so far suggests that this effect on atherosclerosis is a lot more than just blood pressure reduction," Weir added. "Proteomic profile reveals significant downregulation of pathways involved in inflammation, cytokine activation, and immunity."

Outcomes looking at several tertiary endpoints, like transcriptomic profile and assay for transposase-accessible chromatin with sequencing, are to come later this year, said Weir.

Session moderator Joseph Vassalotti, MD, of the Icahn School of Medicine at Mount Sinai in New York City, questioned how spironolactone fits into the bigger picture with other agents in CKD like finerenone (Kerendia).

"Certainly the data from the FIDELTY program would indicate [the finerenone] dose to utilize for clinical benefits. If the patients don't have access to finerenone, then certainly I would say that spironolactone 25 [mg] would be an alternate consideration," Weir responded.

Finerenone, the first non-steroidal, selective mineralocorticoid receptor antagonist, was approved in July 2021 to reduce the risk of sustained estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adults with CKD associated with type 2 diabetes.

In MAGMA, following a 2-week placebo run-in phase, 37 patients were titrated up to receive 25 mg per day of spironolactone over a 4-week dose-escalation phase. This was followed by a 48-week treatment phase.

MRI was used at the start of the dose-escalation phase to measure the aorta, and was performed again at the end of the treatment phase. The researchers measured a series of sagittal sections on the imaging to calculate the percentage of thoracic aorta wall volume.

All participants had to be over the age of 45, have type 2 diabetes with an HbA1c below 9%, a GFR below 90 mL/min/1.73 m² with proteinuria or below 60 regardless of proteinuria. Everyone also had to check off at least one of several pre-specified cardiovascular-related risk factors. All were also on a stable angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy.

Weir noted that they initially started with one of the key exclusion criteria as a GFR below 30 but then later dropped it down to 20 based on a protocol adjustment. Some other exclusion criteria included uncontrolled hypertension, "out of control lipids," hyperkalemia, and known atherosclerotic events in the prior 6 months.

At baseline, the average age was 64, most were male, and most participants were Black patients. Nearly all were on statins at baseline, and most were also taking aspirin and RAS inhibitors. Mean GFR was around 46, potassium was 4.3 mmol/L, and LDL cholesterol was 74 mg/dL.

Throughout the trial, potassium levels "surprisingly" didn't change that much, as they expected to have to use more potassium binders in patients, said Weir. This was likely due to the low daily dose of spironolactone used. Overall, the side effects of spironolactone were "minimal," according to him.

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