Cabel,

Keep in mind the difference between 3-point MACE composite %RRR values and %RRR for individual compoenents (i.e. cardiovascular death, non-fatal stroke, non-fatal MI). Amarin's REDUCE-IT achieved a very significant 26% RRR for 3-point MACE composite secondary outcome and very significant 25% RRR for 5-pont MACE primary outcome. Additionally, REDUCE-IT acheived a significant 20% RRR (p=0.03) in cardiovasclar death. As described below for PIONEER-6, that trial actually failed to meet its 3-point MACE primary outcome with statistical significance and therefore the validity of the reported %RRRs for cardiovascular death and all-cause mortality is questionable.

The semaglutide story is interesting.......

In the SUSTAIN-6 trial for injectable semaglutide, a significant 26% RRR in 3-point MACE was observed (8.9% vs. 6.6% at median follow up 2.1 years; 4.44 vs. 3.24 events per 100 patient years). However, there was no effect on cardiovascular death. The 26% RRR in 3-point MACE was due to a 26% RRR in non-fatal MI (p=0.12) and 39% RRR in non-fatal stroke (p=0.04).

In the more recent PIONEER-6 trial for oral semaglutide, a non-significant 21% RRR in 3-point MACE was observed, driven by a 51% reduction in cardiovascular death (p=0.03) and a 26% reduction in non-fatal stroke (not significant), while non-fatal MI risk increased by 18% (non-significant). In addition, all-cause mortality (not part of the primary outcome or 3-point MACE composite) was reduced by 49% (p=0.008). Importantly, the failure to meet statistical significance for the 21% RRR primary outcome means that PIONEER-6 failed to meet its primary outcome. Therefore the statistical validity and claim of success for subsequent analyses is questionable/invalid. Usually in these cases, subsequent statistical analyses are considered exploratory only and don't carry the weight of proof of success. This becomes an interesting challenge for Novo Nordisk as they file their NDA for oral semaglutide. I wonder what kind of spin they will put on this........

Also, for anyone interested here is a link to a nice powerpoint presentation by Dr. Richard Pratley "New Treatments for Type 2 Diabetes: Implications of Cardiovascular Outcome Trials" that does a great job of covering the recent diabetes CVOTs and provides some great contemporary examples of how MACE data is presented. 

BearDownAZ