An intriguing new CCTA study called the Essence-TIMI 73b (which sounds like part of the Complement Cascade from Immunology class) was presented of Olezarsen (Tryngolza), an ApoC3 inhibitor currently approved for Familial Chylomicronemia (which, to this point, has shown impressive reductions in not only triglycerides, but more importantly, pancreatitis for that population).  And given some genetic studies showing that folks with ApoC3 loss-of-function have decreased triglycerides AND cardiovascular risk, some have speculated that ApoC3 inhibition could perhaps have broader applications beyond those with severe hypertriglyceridemia (sHTG).

Briefly, ApoC3 is the “Great Inhibitor” of hepatic ApoB-lipoprotein uptake as well as an inhibitor of lipoprotein lipase (LPL).  Quite the double whammy, and the decreased LPL activity is particularly relevant in states of severe hypertriglyceridemia.  Additionally, if ApoC3 is present on an ApoB particle (such as an LDL), it is not readily cleared by the LDL receptor and instead can be cleared by minority pathways such as syndecan-1 (very inefficient).  Ergo, these ApoC3 particles tend to “loiter” and longer plasma residence times typically increase risk of those guys ending up in your arterial wall. (For more on this topic, check out Chapter 4 of the “Deep End of the Community Pool” in the Remixed 2nd Edition of The Home Security System and the Lipid Neighborhood).

So this study looked at CCTA plaque changes in a population with more subtle elevations in triglycerides (median 249 mg/dL).  468 patients were enrolled, with 349 in the Olezarsen arm, and the primary endpoint was change in non-calcified plaque volume (NCPV).

There was virtually no change from baseline in LDL-C in both groups.  But, despite a 63.9% reduction in triglycerides, a 16% drop in ApoB (a particle measurement of potentially atherogenic particles), and a 22.9% decrease in non-HDL-C (a popular surrogate for “remnant” cholesterol), there was also NO CHANGE in plaque characteristics from baseline to 12 month follow-up!

The placebo arm started with an NCPV of 130.7 mm3 and the treatment arm at 122.7 mm3 (for reference, the DISCO-CT trial patients had a baseline NCPV of 413 mm3…you can read about that study HERE).  And the total plaque volume (TPV) of these folks was between 163-181 mm3 (below the “high-risk” threshold of 238.5 mm3, but still a decent amount of coronary plaque).

The TPV went up a smidge in the Olezarsen group, and it went down a little bit in the placebo arm…and the changes in other plaque features (such as low-attenuation plaque, which is a high-risk feature) were also negligible. 

So to summarize, the changes in plaque were as negligible as the changes in LDL-C (as this basically was unchanged from baseline).  We all love ApoB…but maybe we need to tip our hats to the “LDL Crowd” here…or maybe ApoC3 isn’t a great target for plaque modification…or maybe it’s the type of ApoB particle that matters…or maybe we just have a lot more to learn and lipids are humbling!

So we know the robust effects of other interventions on coronary plaque (see Chapter 8 in my book). But as for ApoC3 inhibition?  Great for FCS and sHTG, but for now let’s pump the brakes on speculations that it could be a PROMINENT additional tool for ASCVD (6 people worldwide will get that joke…you know you’ve arrived at a special place in the world when your stand-up comedy routine involves failed fibrate trials)😊