"The Pioneer trial drug seems to be after the same (almost) patient population as ABL. Their 21% RRR announced seems pretty good,... will this be our future competitor...?"

Yes, the various SGLT2 inhibitor and GLP1-R agonist classes of drugs have shown their merit for not only managing blood glucose levels in type 2 diabetics (T2D), but also for lowering risk of cardiovascular events in recent CVOT trials. Since BETonMACE population is T2D patients, then yes I agree that the MACE reduction achieved by BETonMACE will be measured against the MACE reduction already achieved by these two classes of drugs in their various CVOTs.

The patient populations between BETonMACE and PIONEER 6 (and most other T2D CVOTs) are different. Although these SGLT2 and GLP1-R agonist CVOTs were done in T2D patients, none of these trials required a recent ACS event except for ELIXA for the GLR1-R agonist Lixisenatide that required ACS event w/i 180 days. BETonMACE requires a recent ACS event within 90 days. I rambled on this subject in a recent post that also brought in the DPP4 inhibitor trial EXAMINE. Other than ELIXA and EXAMINE, no DPP4/SGLT2 inhibitor/GLP1-R agonist T2D CVOT has required recent ACS event that I know of. Many of them, including PIONEER 6 and REWIND exclude patients with ACS event within 60 days. Additionally, BETonMACE has a low-HDL requirement that none of the DPP4/SGLT2 inhibitor/GLP1-R agonist T2D CVOTs required.

Lastly, PIONEER 6 was a small study designed to assess cardiovascular safety of oral semaglutide for registration. The main point of the trial was to demonstrate non-inferiority for incidence of 3-point MACE compared to placebo. It was not powered to show superiority to placebo and did not achieve statistical signficance. The 21% RRR in 3-point MACE was not significant. Novo Nordisk is hoping to avoid having to do another CVOT for oral semaglutide to show superiority for MACE reduction by having the FDA also consider the significant MACE reduction achieved by injectable semaglutide in their previous SUSTAIN-6 CVOT. From their news release:

"As announced in August 2018, Novo Nordisk has since the approval of Ozempic® (once-weekly injectable semaglutide) engaged in a constructive dialogue with the US FDA (Food and Drug Administration) on minimising the need for additional separate large cardiovascular outcomes trials (CVOTs) to obtain a cardiovascular (CV) indication for semaglutide in different formulations Following the results of the PIONEER 6 trial, Novo Nordisk is now evaluating the potential to obtain a CV indication for Ozempic® based on the already obtained clinical data from the CVOT SUSTAIN 6 in combination with the CVOT PIONEER 6 with oral semaglutide. Novo Nordisk will continue these discussions with the FDA." 

The really interesting and complicating detail is in the MACE distribution betwen oral and injectable semaglutide. Injectable semaglutide in SUSTAIN-6 achieved significant 26% RRR in 3-point MACE but had no effect on CV death. It achieved a 26% RRR in non-fatal MI (non-significant p=0.12) and 39% RRR in non-fatal stroke (significant p=0.04). Oral semaglutide in PIONEER 6 achieved a non-significant 21% RRR in 3-point MACE that was "driven by a statistically significant reduction in cardiovascular death of 51% (HR 0.49, p=0.03), while non-fatal myocardial infarction (HR 1.18, non-significant) or non-fatal stroke (HR 0.74, non-significant) were broadly similarly distributed between the two treatment arms." So both oral and injectable semaglutide reduced non-fatal stroke. But for CV death, oral in PIONEER 6 reduced CV death but injectable in SUSTAIN 6 had no effect. For non-fatal MI, injectable in SUSTAIN 6 reduced non-fatal MI but oral in PIONEER 6 increased non-fatal MI by 18%. This may complicate matters with the FDA and force Novo Nordisk to run another CVOT for oral semaglutide to show superiority.

BDAZ