Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials

Abstract

Background Semaglutide is a glucagon-like peptide-1 (GLP-1) analog treatment for type 2 diabetes (T2D) available in subcutaneous (s.c.) and oral formulations. Two cardiovascular (CV) outcomes trials showed that in subjects with T2D at high risk of CV events there were fewer major adverse CV events (MACE; defined as CV death, non-fatal stroke, non-fatal myocardial infarction) with semaglutide than with placebo (hazard ratio [95% CI]: 0.74 [0.58;0.95] for once-weekly s.c. semaglutide and 0.79 [0.57;1.11] for once-daily oral semaglutide). However, there is little evidence for an effect of semaglutide on MACE in subjects not at high risk of CV events. This post hoc analysis examined CV effects of semaglutide in subjects across a continuum of baseline CV risk. Methods Data from the s.c. (SUSTAIN) and oral (PIONEER) semaglutide phase 3a clinical trial programs were combined according to randomized treatment (semaglutide or comparators) and analyzed to assess time to first MACE and its individual components. A CV risk model was developed with independent data from the LEADER trial (liraglutide vs placebo), considering baseline variables common to all datasets. Semaglutide data were analyzed to assess effects of treatment as a function of CV risk predicted using the CV risk prediction model. Results The CV risk prediction model performed satisfactorily when applied to the semaglutide data set (area under the curve: 0.77). There was a reduced relative and absolute risk of MACE for semaglutide vs comparators across the entire continuum of CV risk. While the relative risk reduction tended to be largest with low CV risk score, the largest absolute risk reduction was for intermediate to high CV risk score. Similar results were seen for relative risk reduction of the individual MACE components and also when only placebo comparator data were included. Conclusion Semaglutide reduced the risk of MACE vs comparators across the continuum of baseline CV risk in a broad T2D population. Trial registrations ClinicalTrials.gov identifiers: NCT02054897, NCT01930188, NCT01885208, NCT02128932, NCT02305381, NCT01720446, NCT02207374, NCT02254291, NCT02906930, NCT02863328, NCT02607865, NCT02863419, NCT02827708, NCT02692716, NCT02849080, NCT03021187, NCT03018028, NCT03015220.

Recent developments in GLP‐1RA therapy: A review of the latest evidence of efficacy and safety and differences within the class

“…Until very recently, it seemed implausible that the complex interactions between the GLP‐1 peptide and the extracellular domain of its receptor could be achieved by small non‐peptide molecules 82 . However, at least three such GLP‐1RAs are now in development (TT‐OAD2, LY3502790 and PF‐06882961) and one of these has reported data from a 4‐week Phase 1 study during the scientific sessions of the American Diabetes Association in June 2020 83 .…”

Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: An exploratory analysis of cardiovascular outcomes with semaglutide

“…These findings reinforce other post hoc analyses of the SUSTAIN and PIONEER CV outcome and glycaemic efficacy trials, in which semaglutide appears to reduce the risk of MACE across a broad continuum of CV risk. 4,5 Indeed, in a recent meta-analysis of CV outcomes trials of GLP-1 RAs, which included 56 004 patients, the reduction in risk of MACE was not significantly different between patients with established CVD and patients with CV risk factors only, 6 demonstrating a favourable protective effect of the GLP-1 RA class across the CV risk continuum.…”

Therapie des Typ-2-Diabetes

“…Dabei zeigte Semaglutid im Vergleich zu Vergleichstherapien eine signifikante absolute und relative Risikoreduktion von MACE (kardiovaskulärer Tod, nicht tödlicher Herzinfarkt, nicht tödlicher Schlaganfall) über das gesamte Spektrum des kardiovaskulären Risikos. Dies fand sich auch bei den einzelnen Komponenten von MACE [176].…”