My name is Marc Bonaca. I'm a cardiologist and vascular medicine physician at University of Colorado in the United States.

What is the reasoning behind the CLEAR OUTCOMES trial?

So CLEAR OUTCOMES was a large, randomized trial looking at LDL lowering with a drug called bempedoic acid versus placebo in a broad range of patients, some who had atherosclerotic vascular disease, some who were high-risk primary prevention. And the reason it was done is because we know that many patients are getting to low enough LDL cholesterols, in part because they can't tolerate statins or they can't get low enough, or we have to look at other combinations of drugs to get people to very low levels.

So a trial was presented last year and was positive, showed that bempedoic acid reduced major adverse cardiovascular events in patients with primary prevention or established atherosclerotic vascular disease.

Could you tell us about the mechanism of action behind bempedoic acid?

Yeah. So I think bempedoic acid isn't well understood by a lot of clinicians, so I think there's a lot of learning to do. One of the issues with statins is that it not only gets into the liver to lower cholesterol through expression of the LDL receptor, but it gets into the muscle and other tissues, so it causes muscle side effects. It's also a diabetes signal. Bempedoic acid works a step just upstream of statins, and it's specific to the liver, so it doesn't get into muscle cells or other places. And so it works very much along the lines of a statin, but it's a different mechanism. It's a step upstream called ATP citrate lyase, and it's an inhibitor of that enzymatic step.

What was the study design and patient population?

CLEAR OUTCOMES randomized patients who were statin intolerant, and they went through a lot of work to make sure these were people that really couldn't tolerate statins and they had atherosclerotic vascular disease, including peripheral artery disease. But it could be coronary disease or cerebrovascular disease or primary prevention.

It was a large trial, randomized a lot of patients, and of those with atherosclerotic vascular disease, around 1600 of them had lower extremity peripheral artery disease. Yeah, so this analysis at AHA aimed to look at patients with peripheral artery disease, asked two questions: what was the risk of major adverse cardiovascular events, and were the effects of bempedoic acid, the benefits, the same? I think even more importantly for this population, what were the rates of major adverse limb events, things like amputation or needing revascularization for claudication? And was there effect of bempedoic acid?

What are the take-home messages for practice?

So the overall findings show that bempedoic acid reduced major adverse cardiovascular events by about 15% across the board. In [indistinct], though, they had about a 35% reduction in major adverse limb events. So people needing to go get a stent or a bypass for claudication, amputations, other things. And overall, when you combine the two, there was a large absolute risk reduction in patients with PAD.

I think the take-home message is patients with PAD are very high risk for MACE but also for limb outcomes. LDL lowering is an important target and that drugs like bempedoic acid are a really important tool in the toolkit for lowering the risk of MACE and limb outcomes in this population. So I think if you see these patients, you should think about bempedoic acid as another tool in your toolkit.

What further research is needed in this area?

Hey, I think further research with bempedoic acid, I'd like to understand a little bit more about the drivers of this really big benefit in PAD. Is it all LDL lowering? Bempedoic acid gives you about a 20% reduction in CRP. We know inflammation is bad in PAD. So is it mediated through LDL, mediated through CRP?

I think the other aspect is that we know statins have a side effect where they increase the risk of diabetes and bempedoic acid doesn't do that. So there are other metabolic benefits that are contributing to this overall vascular benefit. I think further research could help describe that.