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hs-CRP and LDL-C Levels as Predictors of Cardiovascular Events Among High-Risk Patients With Statin Intolerance
TAKE-HOME MESSAGE
- The multinational CLEAR-Outcomes trial involving 13,970 statin-intolerant patients found that 180 mg of oral bempedoic acid daily reduced the median levels of hs-CRP and LDL-C by 21.6% and 21.1%, respectively, at 6 months compared with placebo. Bempedoic acid consistently reduced cardiovascular risk across varying hs-CRP and LDL-C levels. A high hs-CRP level was significantly correlated with adverse outcomes, regardless of the LDL-C level.
- In statin-intolerant patients, bempedoic acid showed efficacy in reducing inflammation-related cardiovascular risk. This study also highlights elevated a hs-CRP level as a risk predictor for future cardiovascular events and death.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDLC). Whether these relationships are present among statin-intolerant patients with higher LDLC levels is uncertain but has implications for the choice of preventive therapies, including bempedoic acid, an agent that reduces both LDLC and hsCRP.
METHODS
The multinational CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) randomly allocated 13970 statin-intolerant patients to 180 mg of oral bempedoic acid daily or matching placebo and followed them for a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and for all-cause mortality. Quartiles of increasing baseline hsCRP and LDLC were assessed as predictors of future adverse events after adjustment for traditional risk factors and randomized treatment assignment.
RESULTS
Compared with placebo, bempedoic acid reduced median hsCRP by 21.6% and mean LDLC levels by 21.1% at 6 months. Baseline hsCRP was significantly associated with the primary composite end point of major cardiovascular events (highest versus lowest hsCRP quartile; hazard ratio [HR], 1.43 [95% CI, 1.24-1.65]), cardiovascular mortality (HR, 2.00 [95% CI, 1.53-2.61]), and all-cause mortality (HR, 2.21 [95% CI, 1.79-2.73]). By contrast, the relationship of baseline LDLC quartile (highest versus lowest) to future events was smaller in magnitude for the primary composite cardiovascular end point (HR, 1.19 [95% CI, 1.04-1.37]) and neutral for cardiovascular mortality (HR, 0.90 [95% CI, 0.70-1.17]) and all-cause mortality (HR, 0.95 [95% CI, 0.78-1.16]). Risks were high for those with elevated hsCRP irrespective of LDLC level. Bempedoic acid demonstrated similar efficacy in reducing cardiovascular events across all levels of hsCRP and LDLC.
CONCLUSIONS
Among contemporary statin-intolerant patients, inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidemia assessed by LDLC. Compared with placebo, bempedoic acid had similar efficacy for reducing cardiovascular risk across hsCRP and LDLC strata.
Additional Info
Disclosure statements are available on the authors' profiles:
Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13970 Contemporary High-Risk Patients With Statin Intolerance
Circulation 2023 Nov 06;[EPub Ahead of Print], PM Ridker, L Lei, MJ Louie, T Haddad, SJ Nicholls, AM Lincoff, P Libby, SE NissenFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
A recent analysis of 31,245 contemporary statin-treated patients in the PROMINENT, REDUCE-IT, and STRENGTH trials demonstrated that residual inflammatory risk (assessed by hs-CRP) was a more powerful predictor of future cardiovascular events than was residual cholesterol risk (assessed by LDL-C).1 However, not all patients can tolerate statin therapy, and the contemporary relationships of hs-CRP and LDL-C to cardiovascular risk are uncertain for those not taking statins.
Completion of the CLEAR Outcomes trial (N = 13,970) comparing bempedoic acid with placebo among statin-intolerant patents with, or at high risk for, ASCVD afforded the opportunity to evaluate the contemporary relationships of hs-CRP and LDL-C with the incidence of future major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality. The main findings of the new analysis are almost identical to the prior data; namely, that residual inflammatory risk was again a stronger determinant of risk for future cardiovascular events than residual cholesterol risk, this time among individuals who were statin-intolerant. Moreover, the risks associated with hs-CRP were particularly high for large catastrophic events resulting in cardiovascular death. Bempedoic acid, an agent that lowers both LDL-C and hs-CRP, reduced cardiovascular risk in a similar manner across all LDL-C and hs-CRP thresholds.
The take-home message for clinicians is that we can’t treat what we don’t measure.
Just like we universally assess LDL-C and blood pressure, we should be widely measuring hs-CRP among our atherosclerosis patients to identify patients with residual inflammatory risk who might well benefit from targeted anti-inflammatory therapy. Based on the results of the landmark LoDoCo2 and COLCOT trials, the US FDA recently approved low-dose colchicine (0.5 mg orally daily) as the first targeted anti-inflammatory therapy for chronic atherosclerotic disease. Thus, among patients without serious kidney or liver disease (where colchicine is relatively contraindicated), clinicians now have a proven method not just to lower hs-CRP but also to reduce event rates due to vascular inflammation by 25% to 30%.
Diet, exercise, and smoking cessation all lower hs-CRP and reduce event rates. Similarly, low-dose colchicine, statins, bempedoic acid, GLP-1R agonists, and SGLT2 inhibitors all lower hs-CRP and all are associated with lower risks of future cardiovascular events. As such, “lower is better” appears to be true for inflammation just as it is for LDL-C.
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