Background: Elevated lipoprotein(a) (Lp(a)) levels are causally and independently associated with increased cardiovascular (CV) risk due to increased inflammation and macrophage uptake. Levels of oxidized Lp(a) were more predictive of CV events and endothelial dysfunction in type 2 diabetes than non-oxidized Lp(a). Atorvastatin reduces CV risk in diabetes and is metabolized by cytochrome P450 3A4 to the active hydroxylated metabolite (ATM) that has intrinsic antioxidant properties. We compared the effects of ATM and rosuvastatin on lipid oxidation in plasma samples enriched with Lp(a) under conditions of high glucose.
Methods: Lp(a) was enriched to 41% of total ApoB-containing particles from patients with elevated levels by isopycnic centrifugation. Samples of Lp(a) were incubated under high glucose (200 mg/dL) conditions at 37°C for 30 min with multiple concentrations of ATM and/or rosuvastatin (5 and 10 µM) and Trolox (10 µM), a water-soluble analog of Vitamin E. Samples were then subjected to copper sulfate-induced oxidation monitored by formation of malondialdehyde.
Results: Lp(a)-enriched plasma underwent increased oxidation, peaking at 4 hr by 32-fold after (0.37 ± 0.04 vs 12.27 ± 0.61, p<0.001) under conditions of high glucose. ATM significantly inhibited Lp(a) oxidation in a time- and dose-dependent manner; after 4 h, ATM at 5 and 10 µM inhibited oxidation by 75% and 81%, respectively (p<0.001) while rosuvastatin showed no significant activity. These effects of ATM were superior to Trolox.
Conclusions: Under high glucose conditions, ATM inhibited oxidation of Lp(a) enriched plasma in a dose-dependent fashion compared to rosuvastatin. The activity of ATM is attributed to its distinct lipophilic properties and direct scavenging activity compared to rosuvastatin. The potent antioxidant activity of atorvastatin active metabolites may contribute to reduced CV risk in patients with diabetes and elevated Lp(a).
S.C.R. Sherratt: None. P. Libby: Consultant; Amgen Inc., AstraZeneca, Baim Institute, Beren, ESPERION Therapeutics, Inc., Genentech, Inc., Kowa Pharmaceuticals America, Inc., Medimmune, Merck & Co., Inc., Moderna, Inc., Novo Nordisk, Novartis AG, Pfizer Inc., Sanofi-Regeneron. Advisory Panel; Amgen Inc., Caristo, Cartesian, CSL Behring, DalCor, Dewpoint, Eulicid, Kancera, Kowa Pharmaceuticals America, Inc., Olatec, Medimmune, Novartis AG, PlaqueTec, TenSixteen Bio, Soley Therapeutics, XBiotech, Inc. Other Relationship; Novartis, Novo Nordisk, Genentech, XBiotech. D.L. Bhatt: Advisory Panel; Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed,. Board Member; American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock);. Consultant; Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene. Other Relationship; Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute, Boston Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai, Novartis, Popul, ACC, Arnold and Porter Law Firm, Baim Institute, Belvoir Publications, CSL Behring, Cowen and Company, Duke Clinical Research Institute, HMP Global, Journal of the ACC, K2P, Level Ex, Medtelligence/Re, Population Health Research Institute, Wiley, Clinical Cardiology, Lexicon Pharmaceuticals, Inc. Research Support; Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scienti, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Mode, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio. Other Relationship; Elsevier (Editor, Braunwald’s Heart Disease), Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions, American College of Cardiology, FlowCo. Stock/Shareholder; Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock). R. Mason: Research Support; Viatris Inc., Amarin Corporation, Lexicon Pharmaceuticals, Inc., ESPERION Therapeutics, Inc.
Viatris
