Semaglutide reduces albuminuria in patients with overweight/obesity and non-diabetic CKD

Semaglutide treatment for 24 weeks reduced albuminuria, body weight, and systolic blood pressure compared with placebo in CKD patients with overweight or obesity but no diabetes, and it was overall well tolerated.

This summary is based on the publication of Apperloo EM, Gorriz JL, Soler MJ, et al. - Semaglutide in patients with overweight or obesity and chronic kidney disease without diabetes: a randomized double-blind placebo-controlled clinical trial. Nat Med. 2024 Oct 25 [Online ahead of print]. doi: 10.1038/s41591-024-03327-6

Introduction and methods

Background

Obesity can lead to kidney impairment, through diabetes-related and also non-diabetes–related pathophysiological mechanisms [1,2]. Despite advances in CKD treatment due to the availability of RAASis and SGLT2 inhibitors [3,4], many patients are still at risk of progressive kidney function loss and adverse CV events. As this remaining risk is associated with increased albuminuria [5-7], there is a need for therapies that can simultaneously reduce body weight and albuminuria, such as GLP-1RAs [8,9]. In the recently published FLOW trial, semaglutide reduced the risk of clinically important kidney outcomes and all-cause mortality in patients with T2D and CKD [10]. Furthermore, in the SELECT trial, the GLP-1RA slowed down the onset of persistent macroalbuminuria in patients with overweight or obesity and established CVD, but no diabetes [11].

Aim of the study

The authors examined the efficacy and safety of semaglutide in patients with CKD but no diabetes.

Methods

The SMART (SeMaglutide and Albuminuria Reduction Trial in Obese Individuals Without Diabetes) trial was a multicenter, investigator-initiated, placebo-controlled, double-blind, phase 3 RCT conducted in the Netherlands, Germany, Spain, and Canada. In this trial, 101 adults with CKD (eGFR ≥25 mL/min/1.73 m² and urinary albumin-to-creatinine ratio (UACR) 30–3,499 mg/g), BMI ≥27 kg/m², but no diabetes were randomized to subcutaneous semaglutide 2.4 mg once weekly or placebo for 24 weeks, followed by a 4-week washout period.

Outcomes

The primary endpoint was percentage change in UACR from baseline to 24 weeks. Secondary endpoints included changes from baseline to 24 weeks in eGFR, GFR measured with iohexol clearance, body weight, waist and hip circumferences, systolic and diastolic blood pressures, and hs-CRP level. Safety assessment included investigator-reported adverse events and serious adverse events.

Main results

Efficacy

• At 24 weeks, the geometric mean percentage change in UACR from baseline was −48.6% (95%CI: −60.9% to −32.3%) in patients treated with semaglutide (n=51) and 7.4% (95%CI: −8.7% to 26.2%) in placebo-treated patients (n=50). This corresponded with a placebo-corrected geometric mean percentage change of −52.1% (95%CI: –65.2% to −34.1%; P<0.0001).

• Subgroup analyses showed the treatment effects of semaglutide versus placebo on this primary endpoint were consistent across prespecified subgroups stratified by baseline characteristics such as age, sex, CKD etiology (chronic glomerulonephritis, hypertensive nephropathy, obesity-related glomerulopathy, or other/unknown), BMI, eGFR, albuminuria, and SGLT2 inhibitor use (all P for interaction>0.05).

• Significant mean placebo-corrected changes from baseline to 24 weeks with semaglutide were also observed for body weight (−9.1 kg; 95%CI: −11.0 to −7.2; P<0.0001), waist circumference (−4.4 cm; 95%CI: −8.4 to −0.3; P=0.04), systolic blood pressure (−6.3 mmHg; 95%CI: −10.9 to −1.7; P=0.01), and hs-CRP level (−37.9% 95%CI: −57.4 to −9.2; P=0.01).

• There were no significant differences in the change in iohexol-measured GFR, eGFR based on creatinine clearance, and diastolic blood pressure between the semaglutide and placebo groups (all P>0.05).

Safety

• The frequency of adverse events was similar in the semaglutide and placebo groups (75% vs. 64%), as was the frequency of serious adverse events (2% vs. 4%).

• Gastrointestinal adverse events, including nausea, diarrhea, and constipation, were more often reported in the semaglutide group than the placebo group.

• Overall, the safety profile of semaglutide was consistent with that in earlier studies in patients with overweight or obesity.

Conclusion

The SMART trial showed 24-week treatment with semaglutide 2.4 mg resulted in clinically relevant reductions in albuminuria, body weight, and systolic blood pressure compared with placebo in patients with overweight or obesity and non-diabetic CKD. There were no new safety concerns. According to the authors, their “results add to a growing body of evidence demonstrating that the effects of GLP-1RAs are independent and possibly additive to SGLT2 inhibitors.”

Find this article online at Nat Med.

References

1. Jiang, Z. et al. Obesity and chronic kidney disease. Am. J. Physiol. Endocrinol. Metab. 324, E24–E41 (2023).
2. Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity, kidney dysfunction and hypertension: mechanistic links. Nat. Rev. Nephrol. 15, 367–385 (2019).
3. Kidney Disease: Improving Global Outcomes CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the evaluation and management of chronic kidney disease. Kidney Int. 105, S117–S314 (2024). 
4. Kidney Disease: Improving Global Outcomes Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for diabetes management in chronic kidney disease. Kidney Int. 102, S1–S127 (2022).
5. Oshima, M. et al. Early change in albuminuria with canagliflozin predicts kidney and cardiovascular outcomes: a post hoc analysis from the CREDENCE trial. J. Am. Soc. Nephrol. 31, 2925–2936 (2020).
6. De Zeeuw, D. et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 65, 2309–2320 (2004).
7. Heerspink, H. J. et al. Is a reduction in albuminuria associated with renal and cardiovascular protection? A post hoc analysis of the ALTITUDE trial. Diabetes Obes. Metab. 18, 169–177 (2016).
8. Michos, E. D., Bakris, G. L., Rodbard, H. W. & Tuttle, K. R. Glucagon-like peptide-1 receptor agonists in diabetic kidney disease: a review of their kidney and heart protection. Am. J. Prev. Cardiol. 14, 100502 (2023).
9. Muskiet, M. H. A. et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat. Rev. Nephrol. 13, 605–628 (2017).
10. Perkovic, V. et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N. Engl. J. Med. 391, 109–121 (2024).
11. Colhoun, H. M. et al. Long-term kidney outcomes of semaglutide in obesity and cardiovascular disease in the SELECT trial. Nat. Med. 30, 2058–2066 (2024).