Effects of once-weekly subcutaneous semaglutide on kidney function and safety in patients with type 2 diabetes: a post-hoc analysis of the SUSTAIN 1–7 randomised controlled trials

Background: Patients with type 2 diabetes have a high risk of developing chronic kidney disease. We examined the effects of semaglutide on kidney function and safety in a large, broad type 2 diabetes population. Methods: We did a post-hoc analysis of 8416 patients with type 2 diabetes enrolled in the SUSTAIN 1–5 and SUSTAIN 7 randomised controlled trials, and the SUSTAIN 6 cardiovascular outcomes trial, to examine the effects of once-weekly subcutaneous semaglutide 0·5 mg and 1·0 mg versus comparators (active treatments or placebo) on estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and kidney adverse events. Data from SUSTAIN 1–5 and SUSTAIN 7 were pooled. eGFR and UACR were also analysed by kidney function and albuminuria status. Findings: In SUSTAIN 1–5 and SUSTAIN 7, eGFR decreased from baseline to week 12 with all active treatments; estimated treatment differences (ETDs) versus placebo were −2·15 (95% CI −3·47 to −0·83) mL/min per 1·73 m² with semaglutide 0·5 mg and −3·00 (−4·31 to −1·68) mL/min per 1·73 m² with semaglutide 1·0 mg; after week 12, eGFR plateaued. In SUSTAIN 1–5 and SUSTAIN 7, from baseline to end of treatment the decline in eGFR was greater with semaglutide than with placebo (ETD −1·58 [95% CI −2·92 to −0·25] mL/min per 1·73 m² with semaglutide 0·5 mg and −2·02 [–3·35 to −0·68] mL/min per 1·73 m² with semaglutide 1·0 mg). In SUSTAIN 6, the decline in eGFR was greater with semaglutide than with placebo from baseline to week 16 (ETD −1·29 [95% CI −2·07 to −0·51] mL/min per 1·73 m² with semaglutide 0·5 mg and −1·56 [–2·33 to −0·78] mL/min per 1·73 m² with semaglutide 1·0 mg), but not from week 16 to week 104 (1·29 [0·30 to 2·28] mL/min per 1·73 m² with semaglutide 0·5 mg and 2·44 [1·45 to 3·44] mL/min per 1·73 m² with semaglutide 1·0 mg). Overall (ie, from baseline to week 104), the eGFR decline in SUSTAIN 6 was similar between semaglutide and placebo (ETD 0·07 [95% CI −0·92 to 1·07] mL/min per 1·73 m² with semaglutide 0·5 mg and 0·97 [–0·03 to 1·97] mL/min per 1·73 m² with semaglutide 1·0 mg). In SUSTAIN 1–5, UACR ratios at end of treatment to baseline were 0·917 with semaglutide 0·5 mg, 0·836 with semaglutide 1·0 mg, and 1·239 with placebo; at end of treatment, greater reductions in UACR were observed with semaglutide versus placebo (estimated treatment ratios 0·74 [95% CI 0·64 to 0·85] for semaglutide 0·5 mg and 0·68 [0·59 to 0·78] for semaglutide 1·0 mg). In SUSTAIN 6, UACR ratios at end of treatment (week 104) to baseline were 0·973 with semaglutide 0·5 mg, 0·858 with semaglutide 1·0 mg, and 1·302 with placebo; at week 104, greater reductions in UACR were observed with semaglutide versus placebo (estimated treatment ratios 0·75 [95% CI 0·66 to 0·85] for semaglutide 0·5 mg and 0·66 [0·58 to 0·75] for semaglutide 1·0 mg). In SUSTAIN 1–7, eGFR initially declined in patients with normal kidney function (and in those with mild kidney impairment with semaglutide 1·0 mg in SUSTAIN 6), but overall (ie, by week 30 for SUSTAIN 1–5 and SUSTAIN 7, and week 104 for SUSTAIN 6), eGFR did not differ between semaglutide and placebo. In SUSTAIN 1–6, UACR decreased in patients with pre-existing microalbuminuria or macroalbuminuria at baseline; it did not change or increased in those with normoalbuminuria at baseline. Kidney adverse events were balanced between treatment groups. Interpretation: Across the SUSTAIN 1–7 trials, semaglutide was associated with initial reductions in eGFR that plateaued, and marked reductions in UACR. This post-hoc analysis suggests no increase in the risk of kidney adverse events with semaglutide versus the active comparators used across SUSTAIN 1–7. Funding: Novo Nordisk.