Golfyeti,

Also in the discussion of the NEJM SUSTAIN-6 paper:

"This trial was powered as a noninferiority study to exclude a preapproval safety margin of 1.8 set by the Food and Drug Administration. It was not powered to show superiority, so such testing was not prespecified. However, the treatment effect of semaglutide and the accrual of more events than estimated resulted in a significantly lower risk of the primary outcome among patients in the semaglutide group. Patients were followed for a relatively short duration (2.1 years) and were at high cardiovascular risk."

So even though SUSTAIN-6 was not powered as an efficacy/superiority study and efficacy/superiority testing was not pre-specified, the trial still showed a 26% RRR for 3-point MACE (P<0.001 for noninferiority; P=0.02 for superiority). They probably did not expect a %RRR of that magnitude and were happily surprised to have seen an unexpected P=0.02 for superiority. 

In SUSTAIN-6  for injectable semaglutide, the 3-point MACE primary outcome occurred in 108 of 1648 semaglutide patients (6.6%) and 146 of 1649 placebo patients (8.9%) over a median follow up period of 2.1 years. The PIONEER-6 trial for oral semaglutide was also designed to test for non-inferiority, not superiority, and only accumulated a total of 137 MACE events over median 16 month follow up time. Most other recent type 2 diabetes CVOTs for the DPP4 inhibitors, SGLT2 inhibitors and GLP1-R agonists all accumulated many more 3-point MACE events than SUSTAIN-6 and PIONEER-6.

What sets BETonMACE (a relatively low 250 MACE event target) apart from most other T2D CVOTs is that: 1) it is in a very high risk patient pool whose placebo event rate will likely be higher than any of the previous DPP4 inhibitors, SGLT2 inhibitors and GLP1-R agonist CVOTs; and 2) it is expecting a ~30% RRR in 3-point MACE. Because of #1, the absolute risk reduction in BETonMACE will be much greater than any of these other trials if it acheives ~30% RRR. These parameters should allow BETonMACE to achieve the statistical power needed with a smaller sampler size than other CVOTs.

BearDownAZ