Wegovy Cut Albuminuria by Half in Non-Diabetic CKD

SAN DIEGO — Semaglutide (Wegovy) reduced albuminuria in patients with overweight or obesity and chronic kidney disease (CKD) but without type 2 diabetes, a randomized trial showed.

Among 101 patients, those who received 2.4-mg semaglutide for 24 weeks had a 52.1% (95% CI -65.5 to -33.4, P<0.0001) reduction in urine albumin-to-creatinine ratio (UACR) compared with those who received placebo, reported Hiddo J.L. Heerspink, PhD, of University Medical Center Groningen in the Netherlands, at the American Society of Nephrology Kidney Week meeting.

“The albuminuria level step-wise decreased at each dose titration step and reached the maximum effect after 24 weeks,” he said. “This effect was sustained throughout the 4-week washout period.”

The findings, which were also published in Nature Medicine, add to a growing body of evidence demonstrating semaglutide’s renal benefits, though prior studies have focused on patients with type 2 diabetes.

For instance, the phase III FLOW trial, which enrolled patients with type 2 diabetes and CKD, reported a 24% risk reduction in a composite kidney outcome with 1-mg semaglutide (Ozempic). Additionally, the STEP-2 trial in type 2 diabetes and obesity reported a 28% drop in albuminuria compared with placebo.

In the current trial, known as SMART, the investigators randomized 51 patients to semaglutide and 50 to placebo. Average age was 56, 40% were women, and 91% were white. The mean estimated glomerular filtration rate (eGFR) was 65 mL/min/1.73 m², baseline body mass index (BMI) was 36.2, and median UACR was 251 mg/g.

The reduction in albuminuria with semaglutide was consistent across most subgroups, including when stratified by baseline HbA1c (<5.6% vs ≥5.6%), baseline BMI (≤35 vs >35), baseline UACR (<300 mg/g vs ≥300 mg/g), and baseline eGFR (<60 vs ≥ 60 mL/min/1.73 m²).

Of note, the reduction in albuminuria only reached significance in those not taking an SGLT2 inhibitor at baseline and those with a CKD etiology of ischemic/hypertensive nephrology or other/unknown cases. Patients with chronic glomerulonephritis or obesity glomerulopathy had a trend towards a reduction, but this didn’t meet significance.

As expected, those on semaglutide had a significant reduction in body weight, as well as other metabolic improvements, compared with placebo:

• Body weight: -20.1 lb (P<0.0001)
• Waist circumference: -4.4 cm (P=0.04)
• High-sensitivity C-reactive protein level: -37.9% (P=0.01).
• Systolic blood pressure: -6.3 mm Hg (P=0.01)

The effects of semaglutide on body weight had not plateaued by week 24, the investigators noted.

While there was an initial decrease in creatinine-estimated eGFR in the semaglutide group at week 8 (mean difference compared with placebo -4.3 mL/min/1.73m²), levels were similar at week 24. There were no changes observed in cystatin C-estimated eGFR or iohexol-measured GFR between the groups.

“No correlations were observed between changes in body weight and eGFR during 24-week treatment with semaglutide regardless of whether eGFR was estimated with creatinine or cystatin C or measured with iohexol clearance,” the researchers wrote.

Heerspink posited that there may not have been enough weight loss to see a correlation with eGFR change, adding that there was also no correlation between weight loss and change in cystatin C- or creatinine-estimated eGFR with similar drugs like tirzepatide (Mounjaro, Zepbound).

However, the investigational triple-hormone receptor agonist retatrutide, which yielded up to a 24.2% weight loss within 48 weeks, had a correlation between change in body weight and eGFR, “so maybe 9 kg [weight loss seen here] isn’t enough to see that correlation, and you need more profound reductions in body weight before you see it,” said Heerspink.

Consistent with the GLP-1 receptor agonist class, there were higher rates of gastrointestinal side effects with semaglutide, including nausea (31.4% vs 4% of placebo patients), diarrhea (21.6% vs 4%), and constipation (15.7% vs 8%). Rates of serious adverse events were comparable between the groups (one event vs two events).

“This study supports a larger and longer study in CKD patients,” Heerspink concluded.

When session co-moderator Swapnil Hiremath, MD, of the University of Ottawa in Canada, asked if semaglutide should be tested in people with a lower BMI and CKD without diabetes, Heerspink emphatically responded “yes,” but warned against using this drug in those with too low of a BMI due to the weight-loss effects.

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