Dr. Payal Kohli: Rethinking LDL Strategy

In this expert commentary, Payal Kohli, MD, breaks down the latest findings from LDL-lowering trials like FOURIER and ODYSSEY, emphasizing that “lower is better, faster, and for longer.” She explains how earlier and sustained reductions in LDL lead to greater cardiovascular risk reduction, even when patients eventually reach the same cholesterol levels. Dr. Kohli addresses challenges such as statin-related nocebo effects, medication resistance, and the underuse of combination therapy in high-risk patients with atherosclerotic cardiovascular disease. Furthermore, Dr. Kohli explores future directions in lipid management, including inclisiran, CRISPR-based gene editing, and shifting global guidelines—all pointing toward a more aggressive and patient-centered approach to prevention.

Transcript

What are the key takeaways from recent outcomes trials (e.g., FOURIER, ODYSSEY OUTCOMES, CLEAR Outcomes) regarding the use of non-statin therapies?

Dr. Payal Kohli: There is a clear message from FOURIER ODYSSEY outcomes and many of the other recent LDL reduction trials,… which is [that] lower is better for longer and faster. The lower you get your LDL [low-density lipoprotein cholesterol], the more you reduce your risk, the more bang for your buck you get for longer. We’re talking about a concept of cholesterol years of exposure where it’s not just, okay, we reduce your LDL in your 50s or 60s. You start treating in your 20s and 30s before that atherosclerotic plaque has deposited, or even in your 40s, again when you’re going through life transition and starting to hit menopause and such, and earlier.

We know that in the FOURIER open-label extension trial, the patients that started on placebo and then switched to evolucomab versus those that started on evolucomab and stayed on evolucomab—the ones that started on the medication, the PCSK9 inhibitor—they got a head start because they got another 2.2 years of median LDL reduction, and that gave them a head start in terms of their cardiovascular event reduction. Even though they both ended up at the same LDL after 8 years of follow-up, the guys that started earlier with their LDL reduction did better with respect to their major adverse cardiovascular event. My mantra has become “Lower is better, faster, and for longer.” That’s really the takeaway message from all of these trials. We know that the pathogenesis of much of this is through plaque modulation. They [the medications] change plaque volume; they actually stabilize the plaque so that it’s less likely to rupture and cause an acute coronary syndrome.

How can we differentiate between true statin intolerance and nocebo effect in clinical practice?

This is a tough one, and we really do need to start recognizing the importance of [the] nocebo effect in our clinical practice, especially with people on social media all day long and Dr. Google doing all the things that Dr. Google does. If somebody types in “statin side effects,” and they see “myalgias,” they’re more likely to feel myalgias. That’s what a nocebo effect is—that you have an adverse relationship with the drug, and that actually creates the side effects, or the perceived side effects, from that drug.

There are a few things you can try. The first is de-escalation and re-challenge. You can actually take them [the patient] off the statin, put them back on a statin, [and] see if the side effects come back, or [you can] try a different statin. We know that atorvastatin is lipophilic, [and] rosuvastatin is hydrophilic. Sometimes if people get a myalgia [in response] to one, they may not get it [in response] to the other. You can suggest adding something like CoQ10 [coenzyme Q10] to see if it counteracts the nocebo effect or if it provides relief from the myalgias. You can even think about checking AceK [acesulfame potassium] to make sure that it’s not a real reaction. But one thing I’ve seen done sometimes—which you may want to talk to your patient about—is something called  a blinded challenge. … You give them a pill, and they don’t know if it’s a statin or a placebo, and [you] have them take it and see if they still have those types of reactions. Of course, if it turns out to be a placebo, then a lot of that is coming from the nocebo effect, their perceptions.

At the end of the day, I would suggest sitting down and talking to your patient and reframing their relationship with medications. A lot of patients have what I call an adversarial relationship with medications. They’re resistant to them. They fight them. They think it’s a loss, or they don’t want to be on a medicine for the rest of their life. …[You can say,] “LDL-reducing medicines reduce your risk of stroke, which we all worry about. They reduce your risk of vascular dementia, which we all worry about. They reduce your risk of erectile dysfunction, which many men worry about.” Actually imploring them to understand better that the medicine is making them live better and [that] it’s their friend, not their enemy—that really helps.

Should inclisiran’s twice-yearly dosing model change how we manage long-term adherence in lipid-lowering therapy?

The fact that inclisiran is twice a year, I find really fascinating because compliance is such a big problem when it comes to lipid lowering, right? Because [if] you think about it, our cholesterol doesn’t cause symptoms unless it causes that heart attack or that stroke. It’s an asymptomatic condition. I don’t usually have patients coming to my office saying, “Dr. Kohli, please treat my cholesterol.” On top of that, it’s an unsexy thing to treat because you don’t see the immediate effects. So both from a patient perspective and a physician perspective, there’s an attrition. There’s a clinical inertia around treating cholesterol because you have so many other fires to put out, and the patients have so many other things they actually want to get treated, like their weight or what have you, that nobody wants to treat cholesterol. A way around that is to change the frequency of dosing to twice a year to achieve a better benefit.

Now with inclisiran—the nice thing about it being twice a year is that makes it easy in terms of compliance. It allows you to have a patient visit. I have personally and anecdotally seen some heterogeneity in response to inclisiran. Some patients are not dropping that 52% that we saw in the ORION trials that most people drop. There’s a wide variability. That could potentially be one issue. The second could be if the patient does get lost to follow-up, then they’re not at home taking their medicine every day; they just don’t come in for their medicine; they end up missing it. Then of course, [there is the} cost. The twice-a-year hospital-administered or office-administered agent goes through part B … instead of part D…, and so that ends up, for some patients, being more costly.

But it raises an important question in preventive cardiology, which is should we change the paradigm? Should we do, for example, an annual vaccination for your LDL? Or let’s take it a step further: should we edit your genes in your teens, 20s, and 30s to turn off your LDL—excuse me, turn off your PCSK9 gene so that you have a lifelong reduction in LDL? Because remember I said cholesterol years of exposure area under the curve, and this is a concept being explored by some startup companies, including Verve Therapeutics…. They’ve actually already presented data at the American Heart Association [scientific session] on using CRISPR technology, which puts a typo into your PCSK9 gene. Now, of course, they’re studying this in FH [familial hypercholesterolemia] patients because those are the highest-risk patients right now. It hasn’t come into the general population, but the future of LDL lowering may look very different from an oral medicine every day. Or it may lean towards more combination therapy.

How do guidelines differ in their approach to LDL-C targets and combination therapy?

Overall, the guidelines are relatively consistent that lower is better, but you do see some heterogeneity amongst them. The ACCH [American College of Cardiology/American Heart Association] guidelines use thresholds. They use LDL thresholds, and they use that delta 50% of lowering your LDL at least 50% as sort of the benchmarks. But they only …propose combination therapy after statins as a first-line agent if your threshold has not been met and if your threshold suggests that you need escalation of therapy. On the other hand, the European guidelines are a bit more aggressive, and they do propose, many of them, upfront combination therapy. Some even propose potentially lower LDL targets, and [for the] highest-risk patients in Europe, for example, [they] do propose an LDL target less than 40 milligrams per deciliter.

The DCRM [diabetes, cardiorenal, and/or metabolic] guidelines also propose less than 40 milligrams per deciliter for some of the highest-risk patients, whereas the ACCH guidelines are more around that 55 milligrams per deciliter mark. If you look at countries like India, you see that every patient hitting the door of the cath lab actually is being titrated to an LDL less than 30 milligrams per deciliter. The overall theme is very consistent here. Lower is better. Where exactly that low point falls is where there are some slight differences. How early to start that combination therapy also may have some differences because the American guidelines are a bit more focused on cost than some of these other ones, but they’re all very consistent.

Are we underutilizing combination therapy in high-risk ASCVD patients—and if so, why?

It drives me crazy how much we’re underutilizing combination therapy in high- risk ASCVD [arteriosclerotic cardiovascular disease] patients. We have the recipe. We know that lipids are one of the greatest population-attributable contributors to ASCVD risk, and yet we have this apathy towards it, and I don’t quite understand it. It’s clinical inertia. It’s the fact that the LDLC [low-density lipoprotein cholesterol] is asymptomatic until it declares itself with a ruptured plaque. But when it comes to blood pressure, for example, if somebody walks into your office with a blood pressure 190 over 110, you would never reach for a single-agent therapy. You would always give them a combination therapy of a thiazide plus an ARB [angiotensin-receptor blocker] or [a] calcium channel blocker plus an ARB.

But in lipids, we do this all the time, and then what we do is we burn out the patients because we keep having to check blood tests over and over again. We make the patient more reluctant for polypharmacy because a lot of patients are like, “No, [not] another medicine, another medicine for an asymptomatic condition.” I really implore us to start …doing a culture shift here, where if your patient walks into your office, they need a 50% LDL reduction or 70% LDL reduction because of their threshold of 55 milligrams per deciliter—and we know that 55 is the new 70—then you just hit them up front with combination therapy.

Now of course, insurance may force you to start the statin first, but I would say after the statin, have a very low threshold to reach for combination agents in order to get your patients to where they are. This is a paradigm for lipid lowering using multiple agents from different classes to minimize the side effects of A1c increase and myalgias that you can get with [a] statin. Maximize the statin as much as you can. But once you’ve already gotten to a high-intensity statin, doubling it from 40 to 80 or 20 to 40 …may give you a little bit benefit. But it may bump their A1c; it may give them myalgias; whereas if you’re still 40% away from your goal, then you want to reach for that PCSK9 inhibitor early.