Effect of semaglutide on MACE by baseline kidney function in participants with type 2 diabetes and high risk of cardiovascular disease: SUSTAIN 6 and PIONEER 6 post hoc analysis

Presented at the EASD annual meeting 2022 by: Prof. Peter Rossing, MD - Copenhagen, Denmark

Introduction and methods

Previous studies have shown that the GLP-1RA semaglutide lowers blood glucose across eGFR levels, and reduces the risk of MACE compared with placebo. This post hoc analysis of the SUSTAIN 6 and PIONEER 6 trials was aimed to examine the association between baseline kidney function and risk of MACE. The effect of semaglutide on the risk of MACE by baseline kidney function, and the absolute risk for first MACE and NNT for kidney function subgroups was investigated as well. MACE was defined as CV death, non-fatal MI, or non-fatal stroke.

A total of 6,480 patients with T2DM and at high CV risk who received semaglutide or placebo were included in this analysis. Participants were categorized according to baseline eGFR (≥60 [reference]; ≥45-<60; <45 mL/min/1.73 m²) and UACR (<30 [reference]; ≥30-≤300; >300 mg/g). Baseline data on UACR was only available from participants in the SUSTAIN 6 trial (n=3,238).

Main results

- Risk of MACE was higher in patients with impaired kidney function compared to those with normal kidney function. With eGFR ≥60 mL/min/1.73 m² as reference, HR for MACE was 1.36 (95% CI 1.04-1.76; P = 0.022) in patients with eGFR ≥45-<60 mL/min/1.73 m², and 1.52 (95% CI 1.15-1.99; P = 0.0026) in those with eGFR<45 mL/min/1.73 m². With UACR <30 mg/g as reference, The HR for MACE in patients with values of ≥30-≤300 mg/g was 1,53 (95% CI 1.14-2.04; P=0.0043), and 2.52 (95% CI 1.84-3.42) in patients with UACR >300 mg/g.

- Semaglutide reduced the risk of MACE in the total population compared with placebo (HR 0.76, 95% CI 0.62-0.92). This benefit was consistent across the eGFR strata and UACR strata, with no significant interaction between the treatment and the strata.

- The absolute risk reductions in those with baseline eGFR ≥60, ≥45-<60, and <45 mL/min/1.73 m² were 0.98% (95% CI: 0.23 to 1.72), 1.12% (-0.80 to -3.05) and 1.03%, respectively, (-1.35 to 3.41) with NNT of 102, 89, and 97, respectively.

- The absolute risk reductions across UACR subgroups of <30, ≥30-≤300, and >300 mg/g were 2.68% (0.71 to 4.66), 0.91% (-2.53 to 4.34) and 3.24% (-3.05 to 9.52), respectively, with NNT of 37, 110, and 31, respectively.

Conclusion

This pooled post hoc analysis of SUSTAIN 6 and PIONEER 6 showed that among patients with T2DM who are at high CV risk, the risk of MACE is higher in those with impaired kidney function compared to patients with normal kidney function. Moreover, the analysis showed that semaglutide consistently reduced the risk of MACE across eGFR and UACR subgroups. The FLOW and SOUL clinical outcome trials are currently ongoing that investigate the effects of semaglutide on kidney and CV outcomes. Results of these trials are expected in 2024.

• Our reporting is based on the information provided at the EASD annual meeting -