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. 2024 Jan 2;149(1):28-35.
doi: 10.1161/CIRCULATIONAHA.123.066213. Epub 2023 Nov 6.

Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13 970 Contemporary High-Risk Patients With Statin Intolerance

Paul M Ridker  1 , Lei Lei  2 , Michael J Louie  2 , Tariq Haddad  3 , Stephen J Nicholls  4 , A Michael Lincoff  5 , Peter Libby  1 , Steven E Nissen  5 ; CLEAR Outcomes Investigators
Affiliations

Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13 970 Contemporary High-Risk Patients With Statin Intolerance

Paul M Ridker et al. Circulation. .

Abstract

Background: 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 13 970 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.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993406.

Keywords: C-reactive protein; atherosclerosis; cholesterol; clinical trials as topic; inflammation.

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Conflict of interest statement

Disclosures Dr Ridker has received institutional research grant support from Kowa, Novartis, Amarin, Pfizer, Esperion, NovoNordisk, and the National Heart, Lung, and Blood Institute; has served as a consultant to Novartis, Flame, Agepha, Ardelyx, AstraZeneca, Janssen, Civi Biopharm, Glaxo Smith Kline, SOCAR, Novo Nordisk, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer-Ingelheim, RTI; Zomagen, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute (Boston, MA). Drs Lei and Louie are employees of Esperion Therapeutics. Dr Haddad reports no conflicts. Dr Nicholls has received research support from AstraZeneca, New Amsterdam Pharma, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, Fauna Bio and LipoScience and is a consultant for AstraZeneca, Amarin, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim, Vaxxinity, Sequiris, Silence Therapeutics. Dr Lincoff has received institutional research grant support from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion, Novartis and has served as a consultant to Akebia, Ardelyx, Becton-Dickson, Eli Lilly, Endologix, Fibrogen, GlaxoSmithKline, Medtronic, Neovasc, Novo Nordisk, Provention Bio, and ReCor. Dr Libby is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. He is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech, Inc. Dr Libby’s laboratory has received research funding the past 2 years from Novartis, Novo Nordisk, and Genentech and receives current funding support from National Heart, Lung, and Blood Institute (1R01HL134892 and 1R01HL163099-01), the RRM Charitable Fund and the Simard Fund. He is on the Board of Directors of XBiotech, Inc. Dr Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics. Dr Libby’s interests were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. Dr Nissen reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen, Bristol Myers Squibb, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics. Dr Nissen is involved in these clinical trials but receives no personal remuneration for his participation.

Figures

Figure 1.
Figure 1.
Relative impact of inflammation and cholesterol as independent determinants of risk for cardiovascular death. Increasing quartiles of inflammatory risk (as assessed by hsCRP; left) and increasing quartiles of cholesterol risk (as assessed by LDLC; right) as predictors of cardiovascular death among 13 970 statin-intolerant patients. Hazard ratios and 95% CIs adjusted for age, sex, ethnicity, region, diabetes, body mass index, estimated glomerular filtration rate, blood pressure, alcohol use, smoking status, known atherosclerotic disease, and randomized treatment assignment. hsCRP indicates high-sensitivity C-reactive protein; and LDLC, low-density lipoprotein cholesterol.
Figure 2.
Figure 2.
Inflammation determines risk of cardiovascular death at both high and low levels of LDLC. Joint analysis of hsCRP (≥ or <2 mg/L) and LDLC (≥ or <130 mg/dL) as predictors of cardiovascular death among 13 970 statin-intolerant patients. Hazard ratios and 95% CIs adjusted for age, sex, ethnicity, region, diabetes, body mass index, estimated glomerular filtration rate, blood pressure, alcohol use, smoking status, known atherosclerotic disease, and randomized treatment assignment. hsCRP indicates high-sensitivity C-reactive protein; and LDLC, low-density lipoprotein cholesterol.
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