One-Year Effects of High-Intensity Statin on Bioactive Lipids: Findings From the JUPITER Trial.

Autor: Hoshi RA; Division of Cardiovascular Medicine (R.A.H., P.M.R., H.L.-G., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Division of Preventive Medicine (R.A.H., Y.L., P.M.R., R.J.G., H.L.-G., M.V.M., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Center for Lipid Metabolomics (R.A.H., Y.L., H.L.-G., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA., Alotaibi M; Department of Medicine (M.A., J.D.W., M.J.), University of California San Diego, La Jolla.; Division of Pulmonary, Critical Care and Sleep Medicine (M.A.), University of California San Diego, La Jolla., Liu Y; Division of Preventive Medicine (R.A.H., Y.L., P.M.R., R.J.G., H.L.-G., M.V.M., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Center for Lipid Metabolomics (R.A.H., Y.L., H.L.-G., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA., Watrous JD; Department of Medicine (M.A., J.D.W., M.J.), University of California San Diego, La Jolla., Ridker PM; Division of Cardiovascular Medicine (R.A.H., P.M.R., H.L.-G., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Division of Preventive Medicine (R.A.H., Y.L., P.M.R., R.J.G., H.L.-G., M.V.M., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA., Glynn RJ; Division of Preventive Medicine (R.A.H., Y.L., P.M.R., R.J.G., H.L.-G., M.V.M., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA., Serhan CN; Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine (C.N.S.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA., Luttmann-Gibson H; Division of Cardiovascular Medicine (R.A.H., P.M.R., H.L.-G., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Division of Preventive Medicine (R.A.H., Y.L., P.M.R., R.J.G., H.L.-G., M.V.M., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Center for Lipid Metabolomics (R.A.H., Y.L., H.L.-G., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (H.L.-G.)., Moorthy MV; Division of Preventive Medicine (R.A.H., Y.L., P.M.R., R.J.G., H.L.-G., M.V.M., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA., Jain M; Department of Medicine (M.A., J.D.W., M.J.), University of California San Diego, La Jolla., Demler OV; Division of Preventive Medicine (R.A.H., Y.L., P.M.R., R.J.G., H.L.-G., M.V.M., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Center for Lipid Metabolomics (R.A.H., Y.L., H.L.-G., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Department of Computer Science, ETH Zurich, Switzerland (O.V.D.)., Mora S; Division of Cardiovascular Medicine (R.A.H., P.M.R., H.L.-G., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Division of Preventive Medicine (R.A.H., Y.L., P.M.R., R.J.G., H.L.-G., M.V.M., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Center for Lipid Metabolomics (R.A.H., Y.L., H.L.-G., O.V.D., S.M.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Jazyk: angličtina
Zdroj: Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2024 Jul; Vol. 44 (7), pp. e196-e206. Date of Electronic Publication: 2024 Jun 06.
DOI: 10.1161/ATVBAHA.124.321058
Abstrakt: Background: Statin effects extend beyond low-density lipoprotein cholesterol reduction, potentially modulating the metabolism of bioactive lipids (BALs), crucial for biological signaling and inflammation. These bioactive metabolites may serve as metabolic footprints, helping uncover underlying processes linked to pleiotropic effects of statins and yielding a better understanding of their cardioprotective properties. This study aimed to investigate the impact of high-intensity statin therapy versus placebo on plasma BALs in the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681), a randomized primary prevention trial involving individuals with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L.
Methods: Using a nontargeted mass spectrometry approach, over 11 000 lipid features were assayed from baseline and 1-year plasma samples from cardiovascular disease noncases from 2 nonoverlapping nested substudies: JUPITER discovery (n=589) and JUPITER validation (n=409). The effect of randomized allocation of rosuvastatin 20 mg versus placebo on BALs was examined by fitting a linear regression with delta values (∆=year 1-baseline) adjusted for age and baseline levels of each feature. Significant associations in discovery were analyzed in the validation cohort. Multiple comparisons were adjusted using 2-stage overall false discovery rate.
Results: We identified 610 lipid features associated with statin randomization with significant replication (overall false discovery rate, <0.05), including 26 with annotations. Statin therapy significantly increased levels of 276 features, including BALs with anti-inflammatory activity and arterial vasodilation properties. Concurrently, 334 features were significantly lowered by statin therapy, including arachidonic acid and proinflammatory and proplatelet aggregation BALs. By contrast, statin therapy reduced an eicosapentaenoic acid-derived hydroxyeicosapentaenoic acid metabolite, which may be related to impaired glucose metabolism. Additionally, we observed sex-related differences in 6 lipid metabolites and 6 unknown features.
Conclusions: Statin allocation was significantly associated with upregulation of BALs with anti-inflammatory, antiplatelet aggregation and antioxidant properties and downregulation of BALs with proinflammatory and proplatelet aggregation activity, supporting the pleiotropic effects of statins beyond low-density lipoprotein cholesterol reduction.
Competing Interests: Disclosures The parent JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) was funded by AstraZeneca (Wilmington, DE), which had no role in the current study. Quest Diagnostics and LabCorp (LipoScience) conducted assays at no additional charges. O.V. Demler received support from Kowa, not related to the current work. S. Mora has served as a consultant to Pfizer for work outside the current study. M. Jain is the founder and chief executive officer of Sapient, a private organization specialized in biotechnology research for biomarker profiling. P.M. Ridker received past investigator-initiated research grant support from AstraZeneca to conduct the JUPITER trial; has current investigator-initiated research grant support from Novartis, Novo Nordisk, Kowa, Amarin, Pfizer, Esperion, National Heart, Lung, and Blood Institute, Bristol Myers Squibb, and Operation Warp Speed; served as a consultant to Novartis, Flame, Agepha, Ardelyx, AstraZeneca, Janssen, Civi Biopharm, GlaxoSmithKline, SOCAR, Novo Nordisk, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer-Ingelheim, RTI, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; received nonmonetary research support from the Pfizer Bristol Myers Squibb Alliance and from Quidel, Inc, to conduct federally funded COVID-19 research; 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). None of these conflicts relate to the current article. The other authors report no conflicts.
Databáze: MEDLINE
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