All patients in BETonMACE must be type 2 diabetics with ACS events within 7-90 days and meet low HDL cut-offs. The primary outcome for BETonMACE is 3-point MACE indicidence in all apabetalone patients vs. all placebo patients. The hope is for a 30% RRR for 3-point MACE primary outcome in the total patient population. But what if the %RRR for 3-point MACE elicited by apabetalone is even greater in certain patient subgroups?

In a post-hoc subgroup analysis of the Liraglutide LEADER trial published today, they compared the liraglutide vs. placebo effect on 3-point MACE separately for those with baseline eGFR<60 mL/min and eGFR>60 mL/min. In the total population, liraglutide achieved a 13% RRR in 3-point MACE (14.9% placebo event rate vs. 13.0% liraglutide event rate at median follow up 3.8 years). If they just looked at those patients with baseline eGFR<60 mL/min, they observed a 31% RRR (21.4% placebo event rate vs. 15.4% liraglutide event rate). In those with baseline eGFR>60 mL/min, they observed a 6% RRR (13.0% placebo event rate vs. 12.3% liraglutide event rate). The %RRR was ~2.5X higher in the low eGFR group than in the total population!

BETonMACE has pre-specified several sub-group comparisons for the 3-point MACE primary outcome listed below, including the same eGFR split as investigated for LEADER. If BETonMACE achieves 30% RRR in the total population, imagine what some of these sub-groups might show!

1) Rosuvastatin separate from atorvastatin. Will the rosuvastatin combo show the synergism with apabetalone for MACE like it did with plaque reduction and have an even more astronomical %RRR MACE reduction for the rosuvastatin/apabetalone combo? Or does type of statin not matter?

2) ACS < 30 days separate from ACS > 30 days. As I've stated recently, out of all of the DPP4 inhibitor, SGLT2 inhibitor and GLP1-R agonist T2D trials, only two have required recent ACS event. Both the ELIXA trial (ACS event w/i 180 days for lixisenatide) and EXAMINE trial (ACS event w/i 90 days for alogliptin) failed to reduce 3-point MACE incidence. BETonMACE succeeding in the entire population would be huge to begin with, but what if the effect was even greater in those with ACS w/i 30 days? New standard of care?

3) eGFR <60mL/min separate from eGFR > 60mL/min. See LEADER example above. And see Dr. Kalantar-Zadeh's presentation on CVD risk in those with kidney disease. T2D patients with kidney disease are super high cardiovascular risk and the apabetalone %RRR for MACE could be massive for those with eGFR<60 mL/min. Also, keep in mind that changes in alkaline phosphatase and eGFR are secondary enpoints in the trial. 

4) HbA1c below median separate from HbA1c above median. This one is interesting. There is some evidence that apabetalone improves glucose control from the SUSTAIN/ASSURE post-hoc data. But it might be a stretch to call apabetalone a diabetes drug from an insulin and glucose perspective until we see BETonMACE data on secondary endpoints of HbA1C, fasting glucose, fasting insulin over time. Regardless, do those with the highest HbA1c (worst diabetes) benefit the most from apabetalone? Hopefully benefits are seen in both groups, which could help provide evidence that apabetalone's effects aren't dependent on severe diabetes.

5) HDL below median vs. HDL above median. BETonMACE already has the low-HDL requirement, but what if the MACE reduction is even more pronounced in those with VERY low HDL? Hopefully apabetalone works in both groups, with an amplified effect in the VERY low HDL group. Having evidence that apabetalone works even in those with HDL above the median could help provide evidence that apabetalone's effects aren't dependent on low-HDL.

6) LDL below median vs. LDL above median. This will be very informative in showing that even in patients with low LDL's managed by statins or possibly PCSK9s, that apabetalone can still be effective at MACE reduction. Also, it could provide evidence that apabetalone works to reduce MACE even better than PCSK9 inhibitors, etc for those not yet at their LDL-C goal. I guess what we want is for apabetalone to work regardless of LDL-C level.

7) TG below median vs. TG above median. Amarin's Vascepa wowed everybody and its target population was those with mildly elevated TG. It would be great if apabetalone was shown to work in those both with low and elevated TG levels. And wouldn't it be something if apabetalone was shown to have an even better %RRR than Vascepa for those with elevated TG?

This is in addition to all of the secondary/exploratory outcomes listed below beyond the 3-point MACE primary outcome.

A ton of data to come in 2019!

- Time to first occurrence of adjudication-confirmed broadly defined MACE (CV death, non-fatal MI, hospitalization for CVD events, or stroke)

- Group difference in all-cause mortality

- Percent change in apoA-I, apoB, LDL-C, HDL-C and TG concentration 

- Change in HbA1C, fasting glucose, fasting insulin over time

- Change in alkaline phosphatase (ALP)

- Change in estimated glomerular filtration rate (eGFR) 

- Percent change in hsCRP within and between treatment groups

- Percent change in fibrinogen within and between treatment groups

- Transcription (messenger RNA [mRNA]) change in whole blood 

- Health Related Quality of Life (HRQOL) as measured using the EQ-5D-5L 

- Montreal Cognitive Assessment (MoCA) test on all patients 70 and over (~18% of patients). Cognition subgroup is those with MoCA < 25 (~275 patients).

- Incidence of AEs and Serious AEs within and between treatment groups