Beyond Statins: Dr. Payal Kohli on Modern Lipid Therapy

In this wide-ranging discussion, Payal Kohli, MD, emphasizes the importance of considering non-statin lipid-lowering therapies—particularly in high-risk groups such as patients with ASCVD and high-risk diabetics—for optimal cardiovascular risk reduction. She explains the relative efficacy and roles of agents like PCSK9 inhibitors, ezetimibe, and bempedoic acid, stressing that while statins remain first-line, additional tools are crucial for patients not reaching LDL targets. Moreover, Dr. Kohli advocates for broader lipoprotein(a) screening, referencing its genetic determinism and strong link to atherosclerosis and aortic stenosis, and urges clinicians to adopt a multidimensional approach to risk that includes inflammation, triglycerides, obesity, and thrombosis. As access to newer agents improves, she calls for a shift in mindset from short-term drug costs to long-term population health benefits, including heart attack and stroke prevention.

Transcript:

Cardio Care Today: What patient populations benefit most from adding non-statin agents (e.g., ezetimibe, PCSK9 inhibitors, bempedoic acid) to statin therapy?

Dr. Payal Kohli:

It’s so important to think about non-statin agents in pretty much all our patients, but there are some patients where they tend to be higher risk, and those are the populations that benefit the most. You get more bang for your buck if the patient’s underlying risk level is high. And specifically, I’m thinking of secondary prevention patients, patients with ASCVD, atherosclerotic cardiovascular disease, who aren’t at their LDL thresholds and are considered high risk, as well as high-risk primary prevention patients. So these are, for example, diabetics with additional cardiovascular risk factors or patients who just have a lot of what I call target signs on them. So, these are the two populations where the absolute risk is high; therefore, the return from your investment on a non-statin agent is also quite high. But again, I would implore you to think about even your statin-intolerant patients, even your sort of bread and butter primary prevention patients who aren’t at the target that they need to be at for their LDL cholesterol, because these are also patients who would benefit from having these non-statin agents added.

How do the LDL-C lowering effects of bempedoic acid compare to ezetimibe and PCSK9 inhibitors in real-world populations?

Yeah, we’ve got a lot of tools in our toolbox, and we have to figure out which tool we’re going to reach for, depending on what we’re trying to do. My first thought is always efficacy. What lowers LDL, and how much does it lower your LDL? So your general statin will give you about 30 to 40%. And then every doubling, every statin only gives you an additional 6% LDL reduction. So that’s when you start to reach for these non-statin agents. And the biggest tool in our toolbox, or the big guns, are the PCSK9 inhibitors because they can reliably lower your LDL, about 63% from wherever you started, and they’re monoclonal antibodies, so they’re very targeted. It’s very unlikely to have PCSK9 resistance.

But next, you have ezetimibe. That’s an oral agent. It’s been around for a while, and it’s inexpensive. These are all the advantages of it. We’ve seen some outcomes data and improvements at trial as well, but that only gives you about a 20% LDL reduction on a good day. It’s not quite as potent as those PCSK9 inhibitors. And then you have bempedoic acid, which I like to say is a little bit wimpy, but if your bases are loaded and you need to bring your man home, it can get you through the finish line. So it gives you about a 17% to 21% LDL reduction, depending on whether you have a background statin or not. So if you have a background statin, I call it statin’s lazy friend, because it doesn’t do as much work, because it works in the same pathway as a statin, but when statins are not around, you can get up to a 21% LDL reduction. Some of the earlier trials of bempedoic acid saw perhaps even a slightly higher LDL reduction.

Now remember, bempedoic acid does reduce your high sensitivity CRP as well, just like statins do, because it works in the same pathway, whereas PCFK9 inhibitors reduce the life of protein A. They don’t work in the same pathway as statins. So they have no effect on high-sensitivity CRP. So it’s always a dealer’s choice when it comes to which tool you’re going to use, but you need to weigh efficacy. You need to weigh safety, tolerability, and cost.

In the age of high-cost biologics, how do we determine cost-effectiveness and accessibility of PCSK9 inhibitors and inclisiran for patients?

I’m constantly hearing this from a lot of my primary care colleagues, which is that we can’t get the drugs to the patients because they’re not affordable. I think we need to take a step back and take a broader look at the picture, which is really that we’re not just counting how much the drug costs, but we have to count the lives saved, the heart attacks prevented, and the strokes prevented. I’m hoping for a couple of things. First, given that the PCSK9 inhibitors have been around nearly a decade now, hopefully the price point is going to come down, and that’s going to make them easier to access for our patients, so that we can reduce risk. But two, a bit of a culture shift where we stop thinking about just tomorrow and we think more about the 5, 10, 20 year horizon and how much we’re saving the health system by investing in these types of medications, which can reduce risk, as I’ve talked about, of cardiovascular death, MI, and stroke.

I think that we’re headed in the right direction when it comes to cost and accessibility. There is broader coverage now for PCSK9 inhibitors. When they first came out, it was very difficult to get our patients onto these medications. They had to have recurrent, multiple vascular events to do that. But now I do think it’s become a lot easier. Even some of our patients with subclinical atherosclerosis, for example, a very high calcium score, who haven’t yet had a vascular event, when you code an atherosclerotic ICD-10 code, you can get these agents covered by insurance. So I would urge you to keep trying with the insurance companies because things have changed, the cost has changed, and a lot of insurance companies have come on board, and I do expect the future to look even brighter.

What is the clinical significance of lowering lipoprotein(a), and should Lp(a) be routinely measured in intermediate-risk patients?

Lipoprotein A is a new kid on the block. We’re all talking about it. We’re trying to decide if we want to check it in. Not all of our patients are. But here’s my approach to lipoprotein A. We know that Mendelian randomization studies have told us about causality in atherosclerosis. It’s six times as atherogenic as LDL cholesterol, and it causes aortic stenosis, blood clots, and inflammation. It’s a bad guy, and it’s likely to stay because it’s largely genetically determined. So, 70% to 90% of our LPa is genetically determined. There can be some variability during pregnancy and postmenopause and what have you with some medications, but mostly it’s a genetic risk factor.

So we’re waiting to see the outcomes data from the lipoprotein A reducing agents that are out there. We have many siRNAs. We have small molecule interfering agents. We have all kinds of agents that are reducing LPA 70 to 90%, and we know that they’re safe and well tolerated based on phase two studies. The phase three data is still cooking. We’ll see if lowering lipoprotein A reduces cardiovascular events. We think it will be based on the Mendelian randomization, but that data remains to be seen.

My approach right now, before we have those large outcomes trials, is to check a one-time lipoprotein A in every single patient that walks through my door, regardless of their risk level or family history. And that’s based on the National Lipid Association guidelines from 2024, which suggest a one-time lifetime check on everyone. So I would urge you to check in on yourself, your family members, and your patients, because it does a few things that help you reclassify their LDL threshold. So I bump them down to the lower LDL threshold if their LPA is elevated. I may start primary prevention aspirin in older patients because we know that older patients with elevated lipoprotein benefit from primary prevention aspirin. I may screen their family members. And so that’s the cascade screening, and I may screen them for aortic stenosis. This is all while I’m waiting for the results of those large outcomes trials.

How should clinicians approach residual cardiovascular risk in patients who achieve LDL-C goals on statins but still have elevated triglycerides or inflammation?

I think we need to stop thinking of just one risk pathway because we know that patients, even with their LDL-C at goal, very, very low, they go on to have cardiovascular events. So we call this persistent risk or we call this residual risk, whatever you want to call it. The idea here is that there are multiple risk pathways. It’s not just the LDL. You got LDL here. You’ve got inflammation right next to it. You’ve got obesity, which could overlap with inflammation. You’ve got triglycerides that are persistently elevated. You perhaps even have thrombosis as one of the parallel pathways. So, I started to think about my patients in a parallel fashion, thinking about all of these pathways and how to reduce their risk. We also know that the pathways work by different mechanisms. We know that agents like Vascepa, as well as the GLP-1 receptor agonists, which are obesity agents and diabetes agents, all modulate atherosclerotic plaque. They change the fibrous cap thickness. They change the necrotic core. They change the plaque volume.

And we know that LDL reduction has the same effect. The lower you get your LDL, the thicker you make your fibrous cap, the less inflammation you have in the core, the more smooth muscles you have, and the more soft in you make that plaque. So I like to say they take angry plaque and turn it into happy plaque. And that’s what we need to think about: these parallel risk reduction pathways, because it’s not just about LDL, it’s about LDL and how it interacts with inflammation, with thrombosis, with your triglycerides, and with all of the other things that are involved in the pathogenesis of plaque.