Inflammation predicts events more than cholesterol in high-risk statin-intolerant patients
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Key takeaways:
- In statin-intolerant patients, inflammation risk contributed more to death and CV events than cholesterol risk.
- The results suggest measuring high-sensitivity C-reactive protein could benefit patients.
PHILADELPHIA — In the CLEAR Outcomes cohort of patients with statin intolerance, inflammation predicted risk for CV events and death more strongly than cholesterol, researchers reported at the American Heart Association Scientific Sessions.
The new analysis, simultaneously published in Circulation, builds on the main results of CLEAR Outcomes, in which, as Healio previously reported, bempedoic acid (Nexletol, Esperion Therapeutics) reduced risk for major CV events by 13% compared with placebo in more than 13,000 patients with statin intolerance and CVD or at high risk for it, as well as on a pooled analysis of more than 31,000 high-risk statin-treated patients showing that residual inflammatory risk as assessed by high-sensitivity C-reactive protein better predicted CV events and death than residual cholesterol risk as assessed by LDL.
“Everybody [is] beginning to coalesce around this general idea that down the road, we need to target both hyperlipidemia and inflammation together. That has been very rewarding and quite interesting,” Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention and the Eugene Braunwald Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School, told Healio. “One of the issues that was raised by the original [pooled analysis] was, have you inadvertently somehow diminished the impact of LDL cholesterol because everybody was already on a statin? We did the original analysis with everybody on a statin because we don’t want to undermine the idea that everybody should be on a statin. The question was what should your next drug be assuming you are on a statin. Should you consider another lipid-lowering drug, or should you consider anti-inflammatory therapy? That was the structure of that paper. To address the idea of have we inadvertently diminished [the inflammation hypothesis] by looking only at statin-treated patients, we said, let’s look inside CLEAR Outcomes, because it has the same structure as the other three trials we looked at — it’s a contemporary trial, everyone is getting aggressive care — but by definition, these patients are statin-intolerant.”
For the present CLEAR Outcomes analysis, Ridker and colleagues stratified the 13,970 patients (mean age, 66 years; 48% women) into quartiles based on baseline hsCRP (median, 2.3 mg/L) and baseline LDL (median, 134.5 mg/dL).
At 6 months, bemepdoic acid reduced hsCRP by 21.6% and LDL by 21.1% compared with placebo, according to the researchers.
At a median follow-up of 40.6 months, compared with the lowest quartile of baseline hsCRP, those in the highest quartile had elevated risk for the primary endpoint of major adverse CV events, defined as MI, stroke, coronary revascularization or CV death (HR = 1.43; 95% CI, 1.24-1.65), CV death (HR = 2; 95% CI, 1.53-2.61) and all-cause mortality (HR = 2.21; 95% CI, 1.79-2.73), according to the researchers.
In contrast, compared with the lowest quartile of baseline LDL, those in the highest quartile had elevated risk for the primary endpoint to a lesser degree than that seen in the hsCRP analysis (HR = 1.19; 95% CI, 1.04-1.37) and no elevated risk for CV mortality (HR = 0.9; 95% CI, 0.7-1.17) or all-cause mortality (HR = 0.95; 95% CI, 0.78-1.16), Ridker and colleagues found.
Bempedoic acid consistently reduced risk for CV events compared with placebo across all levels of baseline hsCRP and LDL, according to the researchers.
“The fundamental finding is that we are still in this setting where the inflammation is at least as important [as cholesterol level],” Ridker told Healio. “And again, for the cardiovascular deaths, which I think is the most important issue, it’s more important. To me, this is an extension of the prior work but a very important one, and a big reminder that yes, we want to lower LDL cholesterol, but we need to move beyond that. We need to start taking inflammation inhibition very seriously.”
In June, the FDA approved low-dose (0.5 mg) colchicine (Lodoco, Agepha Pharma) as the first anti-inflammatory therapy indicated to reduce CV risk in patients with residual inflammatory risk.
“The FDA approval of low-dose colchicine is very important, because it says to the physician community, here is a drug that we are simply not using. But it has been proven in two major randomized trials to be very effective, so please consider that,” Ridker told Healio. “[Low-dose colchicine is] a drug physicians should think about to add on not as a substitute for cholesterol lowering, but as an adjunct for cholesterol lowering. It’s not a drug to be used in patients with significant kidney dysfunction or significant liver dysfunction. But there are a lot of patients out there with chronic stable atherosclerosis already on a statin, perhaps also on bempedoic acid or ezetimibe, who have elevated hsCRP levels, and assuming patients don’t have kidney or liver problems, it’s a drug people should consider to bring down risk.”
Reference:
Perspective
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This paper is another representation that baseline inflammatory status is an important predictor of CV events. This has been brought forward for several years, dating back to certain statin studies where researchers looked at the achievement of a low LDL and the achievement of hsCRP value both individually and together. Those individuals who got the lowest LDL with the lowest CRP did best. There was a modest reduction in LDL of 20% as a consequence of the use of bempedoic acid, the drug in the CLEAR Outcomes study, and there was also a reduction in CRP.
I think what we should be aware of is that there are other opportunities for treatment, particularly as many of the people in this trial had LDLs that are high in the 130s and 150s. Lowering LDL by 20% may not have offered the greatest protection from cardiovascular events going forward. So many of us might have looked to use a combination of bempedoic acid with ezetimibe that instead of 20% would've given almost double that in reduction in LDL, 38% or 39%. Or to use a PCSK9 inhibitor. That is something that would need to be looked at to make this even that much more meaningful.
I agree that you don't know what the degree of inflammation is in a certain patient without measuring it. And I think that a majority of doctors or care providers do not measure hsCRP. I think we should be measuring this biomarker in order to look at whether or not the CRP is above or below a threshold that in this case was approximately 2 mg/L.
And then comes the idea — do you treat everybody with colchicine or do you treat only those with elevated levels of CRP? I think you could interpret this as trying to get doctors to be more impressed and focused on measures of inflammation than on measures of lipids. Now, thankfully, towards the end of the paper, the researchers give a disclaimer to say, this is not an attempt to tell you that LDL is not important. And it is not an attempt to tell you that lipid-lowering therapy, typically statins, are not important. I think that the most productive take-home message would be that measures of inflammation should not be ignored. And the only way you cannot ignore them is to measure them. And then if they're elevated, act accordingly. Individuals should know that there are many things that lower CRP, which relate to CV problems. Of interest is the SELECT trial of semaglutide 2.4 mg (Wegovy, Novo Nordisk) in patients who are overweight or obese with CVD. There was about a 38% or 39% reduction in CRP, and this was on top of statins. So I think that there are multiple agents that could be considered when CRP is elevated, and that lowering CRP is more times than not a good thing to do. And that sometimes the intensity of the statin that you're going to use may predict how much CRP you're going to knock down. And while bempedoic acid does lower CRP, there may be other lipid-lowering agents that will lower it even a little more effectively.
So I think the best take-home without being lopsided in recommendations is that we should measure inflammation, be mindful of it, and try to use therapies that might be able to optimize the baseline inflammatory state and in the hope of reducing CV outcomes.
In the last 6 to 12 months, measuring hsCRP has become part of my routine blood tests. Whereas if I looked at older blood tests that I’ve drawn, it was rarely part of the included tests. Other data have changed my mind and the data from this study is just another piece that supports the decision I’ve made to include CRP in standard of care for my patients.
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Ridker PM, et al. Abstract 303. Presented at: American Heart Association Scientific Sessions; Nov. 11-13, 2023; Philadelphia.
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