Semaglutide cut albuminuria 52% in non-diabetic kidney disease trial

The SMART trial found that weekly semaglutide 2.4 mg reduced a key marker of kidney damage in adults who had chronic kidney disease along with overweight or obesity, but not diabetes. The results were published online on Oct. 25, 2024, in Nature Medicine ^[1][2].

Over 24 weeks, urine albumin-to-creatinine ratio (UACR) fell by a placebo-adjusted 52.1% in the semaglutide group ^[1][2]. UACR measures how much albumin, a blood protein, leaks into urine; higher levels signal kidney damage and are used to track risk of kidney disease getting worse ^[2].

The trial screened 125 people and randomized 101: 51 to semaglutide 2.4 mg by injection once weekly and 50 to placebo ^[1]. It was a double-blind, placebo-controlled phase 3 study run at sites in the Netherlands, Germany, Spain and Canada ^[2]. Participants had an estimated glomerular filtration rate (eGFR) of at least 25 mL/min/1.73 m², a UACR between 30 and 3,499 mg/g, and a body mass index of at least 27 kg/m² ^[1][2].

Their average age was 55.8 years, 39.6% were female, median UACR was 251 mg/g, mean eGFR was 65.0 and mean BMI was 36.2 ^[1]. The most common kidney disease causes were chronic glomerulonephritis (25 participants) and hypertensive CKD (27) ^[1].

UACR fell 48.6% from baseline in the semaglutide group while rising 7.4% in the placebo group, producing the placebo-corrected difference of 52.1% (P < 0.0001) ^[2]. The two sources describe the confidence interval for that figure slightly differently: Nature Medicine's abstract gives −65.5% to −33.4%, while the PACE-CME summary gives −65.2% to −34.1% ^[1][2]. Subgroup analyses found the effect was consistent across age, sex, kidney disease cause, BMI, eGFR, albuminuria level and use of SGLT2 inhibitors ^[2].

Placebo-corrected changes at 24 weeks also included body weight down 9.1 kg, waist circumference down 4.4 cm, systolic blood pressure down 6.3 mmHg and hs-CRP (a marker of inflammation) down 37.9% ^[2]. There were no significant differences between groups in eGFR, in GFR measured directly with iohexol clearance, or in diastolic blood pressure ^[2].

Adverse events were reported by 75% of the semaglutide group and 64% of the placebo group; serious adverse events occurred in 2% and 4% respectively ^[2]. Nature Medicine's abstract reports gastrointestinal adverse events in 30 people on semaglutide versus 15 on placebo, including nausea, diarrhea and constipation ^[1][2]. The authors said the safety profile was consistent with earlier studies in patients with overweight or obesity ^[2].

Why it matters for patients

Most of the evidence linking GLP-1 drugs to kidney protection comes from people who have type 2 diabetes. This trial tested semaglutide specifically in adults with CKD who do not have diabetes, a group where obesity itself can drive kidney damage ^[2].

Albuminuria is used as a treatable target in kidney care, and the authors describe their results as adding to evidence that GLP-1 effects are independent of, and possibly additive to, SGLT2 inhibitors, a standard CKD drug class ^[2]. Participants in this trial could keep taking an SGLT2 inhibitor ^[2].

Several limits are worth noting. The trial lasted 24 weeks and enrolled 101 people, and it measured a laboratory marker rather than outcomes such as dialysis, transplant or kidney failure. Whether a 52% drop in UACR translates into fewer of those events over years has not been reported here. Kidney filtration rate did not change significantly over the 24 weeks ^[2]. Whether the marker stays down after the drug is stopped has not been reported; the trial included a 4-week washout period, but those results are not described in these sources ^[2]. It also has not been reported whether regulators have reviewed semaglutide for non-diabetic CKD, and this article gives no dosing or prescribing guidance.

What happens next

The results were published online on Oct. 25, 2024, ahead of print in Nature Medicine ^[2]. The trial is registered as NCT04889183, and its data are available through the University of Groningen's data catalog ^[1]. The study design was 24 weeks of treatment followed by a 4-week washout ^[2].

The related FLOW trial tested semaglutide in people with type 2 diabetes and CKD, and the SELECT trial examined kidney outcomes in people with overweight or obesity and cardiovascular disease but no diabetes ^[2]. Any further trials in non-diabetic CKD have not been reported.