"If 3 point achieves statistical significance,... are we not a done deal,.. in the sense we have a drug that works,.. no matter what it is that is driving it or in what combination,..? As all 3 points are profitable,..no,...?"

The are contemporary CVOT examples from the past few years that have all met the primary 3-point MACE statistical threshhold and cover pretty much all of the possible combinations of individual components. All of the drug classes below have been hailed as great achievments in CVD risk reduction, with the caveat that canakinumab recently got its FDA application rejected.

For the PCSK9s, Evolocumab in FOURIER achieved a 20% RRR in 3-point MACE, but was due to significant reductions in  non-fatal stroke and non-fatal MI with no effect whatsoever on CVD death. However, Alirocumab in ODYSSEY achieved a 13.5% RRR in 3-point MACE due to significant reductions in non-fatal stroke and non-fatal MI AND had a non-significant trend for reducing CVD death (and a significant reduction in all-cause mortality). Sub-group analysis in ODYSSEY showed that patients with baseline LDL-C ≥100 mg/dl appeared to show the most robust decrease in CVD eath and all-cause mortality.

For the SGLT2s, Empagliflozin in EMPA-REG OUTCOMES achieved a 14% RRR in 3-point MACE, primarily due to a whopping 38% reduction in CVD death, a non-significant reduction in non-fatal MI and a non-significant increase in non-fatal stroke. Canagliflozin in CANVAS achieved a 14% RRR in 3-point MACE due to a 10-15% reductions in each of CVD death, non-fatal MI and non-fatal stroke. Dopagliflozin will report full data from DECLARE-TIMI on Nov 10th at AHA.

The GLP-1R agonists have also shown heterogeneity in their CVOT results. Liraglutide in LEADER achieved a 13% RRR in 3-point MACE primarily due to a 22% reduction in CVD death but also non-significant 11-12% reductions in non-fatal MI or non-fatal stroke. Semaglutide in SUSTAIN 6 achieved a 26% RRR in 3-point MACE primaril due to a significant 39% reduction in non-fatal stroke and a non-significant 26% RRR in non-fatal, but had absolutely no effect on CVD death. Albiglutide in HARMONY recently announced a 22% RRR in 3-point MACE primarily due to a significant 25% reduction in non-fatal, a non-significant 7% reduction in CVD death and a non-significant 14% reduction in non-fatal stroke.  

The anti-IL1B antibody canakinumab in CANTOS achieved ~15% RRR primarily due to significant reductions in heart attacks with non-significant trends for reduced CVD death and stroke.

Lots of possible combinations. Most combinations are good. Some are better than others. In my experience following market/analyst reactions, it is great to have reductions in CVD death and even better if CVD death and non-fatal MI/stroke are reduced. However, reductions on only non-fatal MI/stroke without reduced CVD death aren't as well received. 

BDAZ