Introduction and methods

Reduction in the rate of eGFR decline with semaglutide vs placebo: a post-hoc pooled analysis of SUSTAIN 6 and PIONEER 6

Presented at ERA-EDTA during the virtual meeting by Katherine Tuttle (Spokane, WA, USA)

The GLP-1 receptor agonist semaglutide may result in nephroprotective effects, as indicated in the SUSTAIN 6 CV outcomes trial, that evaluated semaglutide in patients with T2DM and high CV risk. The more recent PIONEER 6 CVOT evaluated the effect of oral semaglutide on CV outcomes and demonstrated CV safety. Both had similar designs and patient populations. In SUSTAIN 6, 3297 patients were randomized to subcutaneous semaglutide or placebo and followed for maximal duration of 104 weeks. 3183 Patients were enrolled in PIONEER 6 and randomized to oral semaglutide or placebo. Median follow-up was 69 weeks.

An analysis of pooled data from SUSTAIN 6 and PIONEER 6 was undertaken to evaluate the effects of semaglutide on kidney function compared to placebo. Data of 6480 patients was included and pooled into two groups: semaglutide and placebo. Kidney function was examined between semaglutide and placebo groups, overall and in subgroups by baseline eGFR ((≥30–<60 or ≥60 mL/min/1.73 m²).

Kidney function was assessed by annual change in estimated glomerular filtration rate (eGFR). A previous meta-analysis of 47 studies observed a strong association between treatment effects of eGFR slope and on clinical endpoints. Therefore, eGFR slope was considered a viable surrogate for renal clinical endpoints.

Main results

• In the semaglutide group, annual rate of eGFR change was 0.60 mL/min/1.73 m² (95%CI: 0.31-0.90, P<0.0001) lower than in the placebo group in year 1.
• In the subgroup with baseline eGFR ≥60 mL/min/1.73 m², estimated treatment difference for semaglutide vs placebo at year 1 was 0.48 mL/min/1.73 m² (95%CI: 0.13-0.82). This was 1.07 mL/min/1.73 m² (95%CI: 0.46-1.68) for the subgroup of baseline eGFR ≥30–<60 mL/min/1.73 m2. There was a numerically larger difference in estimated treatment difference between the subgroups, but this was not statically significant (Pinteraction=0.21).

Conclusions

Treatment with the GLP-1RA semaglutide resulted in a smaller decline of eGFR compared to placebo in a pooled analysis of SUSTAIN 6 and PIONEER 6 trials. This effect was observed in the total population and across different subgroups of baseline eGFR.

Discussion

Katherine Tuttle briefly presented the design of the FLOW trial, an ongoing renal outcomes trial in T2DM patients with DKD and eGFR between 25 and 75 mL/min/1.73 m². The primary outcome is a composite of CKD endpoints (≥50% eGFR decline, persistent eGFR <15 mL/min/1.73 m², initiation of chronic kidney replacement therapy, kidney disease death and CV death).

- Our reporting is based on the information provided at the ERA-EDTA congress -