I really love the apabetalone diagram that shows the six components that may contribute to the reduced MACE: complement pathway, coagulation pathway, vascular inflammation, vascular calcification, reverse cholesterol transport, metabolism. However, it is this last component, metabolism, that is the least understood and/or established. In the diagram, it emphasizes that there was "delayed and reduced glucose absorption and endogenous glucose production."

These statements are derived from the short trial in pre-diabetic males that treated patients for 5-weeks. However, in this study there was also a decrease in the amount of total glucose disposal and no changes in fasting plasma glucose or fasting insulin were reported. In looking at the data, the changes to these glucose kinetics parameters seem pretty modest. In addition, this 5-week long study noted some interesting safety notes:

"RVX-208 treatment increased serum creatinine by 5% (P = 0.006) with a trend for reduced estimated glomerular filtration rate (eGFR) (P = 0.051, Supplementary Table 4). There was a small, but significant reduction in circulating chloride (P = 0.04) and a corresponding trend for reduced plasma sodium (P = 0.08). The red cell count was also 2%lower (P = 0.04) after RVX-208 treatment, which may be related to a direct effect of the drug on renal function. While these differences were statistically significant, it should be noted that all measures remained within normal clinical ranges. There were no significant drug effects on LFT measures when analyzed as a group (Supplementary Table 5)."

Despite the modest changes to glucose kinetics parameters in the pre-diabetic males treated for 5 weeks, the news release that discussed post-hoc analysis of diabetic patients in the 6-month long SUSTAIN/ASSURE trials was very exciting.

"Results of analysis showed that patients with DM given RVX-208 tended to have lower blood glucose vs. placebo. But specifically in patients with DM who had low HDL, the blood glucose was significantly lower following treatment with RVX-208 vs. placebo. Furthermore, the time required for RVX-208 to reduce blood glucose was not observed until at least 12 weeks following initiation of treatment." 

BETonMACE is entirely diabetic patients with low-HDL. What kind of glucose-lowering effect could the 12-36 month treatment with apabetalone elicit? This is very exciting to think about. SGLT2 inhibitors and GLP-1R agonists are glucose lowering agents with proven MACE reducing effects. Could apabetalone not only prove its worth with MACE reduction in diabetics but also offer sufficient glucose control effects to displace the use of competing SLGT2 inhibitors and GLP-1R agonist? 

BearDownAZ