2024 EASD | SELECT Trial: Treatment Benefits on MACE with Semaglutide Has Shown in The Presence of Impaired Kidney Function

Is semaglutide as effective at reducing major cardiovascular events in the presence of impaired kidney function in people with overweight or obesity? A prespecified analysis from the SELECT trial

H.M. Colhoun, S.E. Kahn, P.M. Brown, E.T.B. Olesen, R. Bravo, J. Deanfield, A. Goudev, G. Latkovskis, M. Lehrke, A.M. Lincoff, N. Rathor, C.-C. Wu, I. Lingvay, On behalf of the SELECT investigator group;

Background and aims: In the SELECT trial, semaglutide (sema) 2.4 mg reduced major adverse cardiovascular events (MACE) by 20% vs placebo (pbo) in participants (pts) with overweight or obesity (BMI ≥27 kg/m2) and prior CVD but without diabetes. This prespecified analysis examined if the treatment effect on MACE and a combined endpoint of MACE or death from any cause was maintained in pts with reduced eGFR or micro/macroalbuminuria.

Materials and methods: Pts were randomised to once-weekly s.c. sema 2.4 mg (n=8,803) or pbo (n=8,801). eGFR (mL/min/1.73 m2) was estimated using the serum creatinine-based CKD-EPI 2009 equation. Urinary albumin-to-creatinine ratio (UACR; mg/g) was calculated using single urine samples. MACE was a composite of death from cardiovascular causes, nonfatal MI or nonfatal stroke in a time-to-first-event analysis. Cox proportional hazard models estimated treatment effect on MACE according to eGFR and albuminuria status at randomisation. Treatment effect for the combined endpoint of MACE or death from any cause was also estimated.

Results: At randomisation, 1,908 (11%) pts had eGFR <60 and 2,281 (13%) had UACR ≥30. Median follow-up: 3.5 years. In pts with eGFR ≥60, MACE occurred in 6.0% of sema vs 7.3% of the pbo arm (HR=0.82 [95% CI 0.72-0.92]). In pts with eGFR <60, MACE occurred in 9.7% of sema vs 13.5% of the pbo arm (HR=0.69 [0.52-0.90]; p interaction=0.22) (Figure 1). For MACE or death from any cause, HRs for sema vs pbo were 0.82 (0.74-0.92) for eGFR ≥60, vs 0.67 (0.53-0.84) for eGFR <60 (p interaction=0.12). In pts with UACR <30, MACE occurred in 5.9% of sema vs 7.3% of the pbo arm (HR=0.80 [0.70-0.90]). In pts with UACR ≥30, MACE occurred in 9.9% of sema vs 12.3% of the pbo arm (HR=0.80 [0.62-1.02]; p interaction=0.97) (Figure 1). For MACE or death from any cause, HRs for sema vs pbo were 0.79 (0.71-0.89) for UACR <30 and 0.81 (0.65-1.01) for UACR ≥30 (p interaction=0.88).

Conclusion: The effect of sema in reducing MACE, and reducing MACE or death from any cause, was consistent in pts with eGFR <60 vs ≥60 mL/min/1.73 m2 or UACR <30 vs ≥30 mg/g. There was a higher rate of MACE associated with reduced eGFR and albuminuria in pts with overweight or obesity but without diabetes. Thus, the absolute treatment benefit on MACE with sema is higher in the presence of impaired kidney function.

Clinical Trial Registration Number: NCT03574597

60th EASD Annual Meeting of the European Association for the Study of Diabetes. Diabetologia 67 (Suppl 1), 1–593 (2024). https://doi.org/10.1007/s00125-024-06226-0