Torcetrapib Does Not Reduce Atherosclerosis Beyond Atorvastatin and Induces More Proinflammatory Lesions Than Atorvastatin
Although cholesteryl ester transfer protein (CETP) inhibition is regarded as a promising strategy to reduce atherosclerosis by increasing high-density lipoprotein cholesterol, the CETP inhibitor torcetrapib given in addition to atorvastatin had no effect on atherosclerosis and even increased cardiov...
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| Veröffentlicht in: | Circulation (New York, N.Y.) N.Y.), 2008-05, Vol.117 (19), p.2515-2522 |
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| creator | DE HAAN, Willeke DE VRIES-VAN DER WEIJ, Jitske RENSEN, Patrick C. N VAN DER HOORN, José W. A GAUTIER, Thomas VAN DER HOOGT, Caroline C WESTERTERP, Marit ROMIJN, Johannes A JUKEMA, J. Wouter HAVEKES, Louis M PRINCEN, Hans M. G |
| description | Although cholesteryl ester transfer protein (CETP) inhibition is regarded as a promising strategy to reduce atherosclerosis by increasing high-density lipoprotein cholesterol, the CETP inhibitor torcetrapib given in addition to atorvastatin had no effect on atherosclerosis and even increased cardiovascular death in the recent Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial. Therefore, we evaluated the antiatherogenic potential and adverse effects of torcetrapib in humanized APOE*3-Leiden.CETP (E3L.CETP) mice.
E3L.CETP mice were fed a cholesterol-rich diet without drugs or with torcetrapib (12 mg x kg(-1) x d(-1)), atorvastatin (2.8 mg x kg(-1) x d(-1)), or both for 14 weeks. Torcetrapib decreased CETP activity in both the absence and presence of atorvastatin (-74% and -73%, respectively; P |
| doi_str_mv | 10.1161/CIRCULATIONAHA.107.761965 |
| format | Article |
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E3L.CETP mice were fed a cholesterol-rich diet without drugs or with torcetrapib (12 mg x kg(-1) x d(-1)), atorvastatin (2.8 mg x kg(-1) x d(-1)), or both for 14 weeks. Torcetrapib decreased CETP activity in both the absence and presence of atorvastatin (-74% and -73%, respectively; P<0.001). Torcetrapib decreased plasma cholesterol (-20%; P<0.01), albeit to a lesser extent than atorvastatin (-42%; P<0.001) or the combination of torcetrapib and atorvastatin (-40%; P<0.001). Torcetrapib increased high-density lipoprotein cholesterol in the absence (30%) and presence (34%) of atorvastatin. Torcetrapib and atorvastatin alone reduced atherosclerotic lesion size (-43% and -46%; P<0.05), but combination therapy did not reduce atherosclerosis compared with atorvastatin alone. Remarkably, compared with atorvastatin, torcetrapib enhanced monocyte recruitment and expression of monocyte chemoattractant protein-1 and resulted in lesions of a more inflammatory phenotype, as reflected by an increased macrophage content and reduced collagen content.
CETP inhibition by torcetrapib per se reduces atherosclerotic lesion size but does not enhance the antiatherogenic potential of atorvastatin. However, compared with atorvastatin, torcetrapib introduces lesions of a less stable phenotype.</description><identifier>ISSN: 0009-7322</identifier><identifier>EISSN: 1524-4539</identifier><identifier>DOI: 10.1161/CIRCULATIONAHA.107.761965</identifier><identifier>PMID: 18458167</identifier><identifier>CODEN: CIRCAZ</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Animals ; Atherosclerosis (general aspects, experimental research) ; Atherosclerosis - drug therapy ; Atherosclerosis - pathology ; Atorvastatin Calcium ; Biological and medical sciences ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Cholesterol Ester Transfer Proteins - antagonists & inhibitors ; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous ; Drug Synergism ; Heptanoic Acids - pharmacology ; Heptanoic Acids - therapeutic use ; Inflammation - chemically induced ; Medical sciences ; Mice ; Mice, Inbred Strains ; Pyrroles - pharmacology ; Pyrroles - therapeutic use ; Quinolines - pharmacology ; Quinolines - therapeutic use</subject><ispartof>Circulation (New York, N.Y.), 2008-05, Vol.117 (19), p.2515-2522</ispartof><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-919b976711a0b4bae936db36d86c70cb9605637b9e591e348b0e820506b2b6b53</citedby><cites>FETCH-LOGICAL-c439t-919b976711a0b4bae936db36d86c70cb9605637b9e591e348b0e820506b2b6b53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3674,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20351400$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18458167$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>DE HAAN, Willeke</creatorcontrib><creatorcontrib>DE VRIES-VAN DER WEIJ, Jitske</creatorcontrib><creatorcontrib>RENSEN, Patrick C. N</creatorcontrib><creatorcontrib>VAN DER HOORN, José W. A</creatorcontrib><creatorcontrib>GAUTIER, Thomas</creatorcontrib><creatorcontrib>VAN DER HOOGT, Caroline C</creatorcontrib><creatorcontrib>WESTERTERP, Marit</creatorcontrib><creatorcontrib>ROMIJN, Johannes A</creatorcontrib><creatorcontrib>JUKEMA, J. Wouter</creatorcontrib><creatorcontrib>HAVEKES, Louis M</creatorcontrib><creatorcontrib>PRINCEN, Hans M. G</creatorcontrib><title>Torcetrapib Does Not Reduce Atherosclerosis Beyond Atorvastatin and Induces More Proinflammatory Lesions Than Atorvastatin</title><title>Circulation (New York, N.Y.)</title><addtitle>Circulation</addtitle><description>Although cholesteryl ester transfer protein (CETP) inhibition is regarded as a promising strategy to reduce atherosclerosis by increasing high-density lipoprotein cholesterol, the CETP inhibitor torcetrapib given in addition to atorvastatin had no effect on atherosclerosis and even increased cardiovascular death in the recent Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial. Therefore, we evaluated the antiatherogenic potential and adverse effects of torcetrapib in humanized APOE*3-Leiden.CETP (E3L.CETP) mice.
E3L.CETP mice were fed a cholesterol-rich diet without drugs or with torcetrapib (12 mg x kg(-1) x d(-1)), atorvastatin (2.8 mg x kg(-1) x d(-1)), or both for 14 weeks. Torcetrapib decreased CETP activity in both the absence and presence of atorvastatin (-74% and -73%, respectively; P<0.001). Torcetrapib decreased plasma cholesterol (-20%; P<0.01), albeit to a lesser extent than atorvastatin (-42%; P<0.001) or the combination of torcetrapib and atorvastatin (-40%; P<0.001). Torcetrapib increased high-density lipoprotein cholesterol in the absence (30%) and presence (34%) of atorvastatin. Torcetrapib and atorvastatin alone reduced atherosclerotic lesion size (-43% and -46%; P<0.05), but combination therapy did not reduce atherosclerosis compared with atorvastatin alone. Remarkably, compared with atorvastatin, torcetrapib enhanced monocyte recruitment and expression of monocyte chemoattractant protein-1 and resulted in lesions of a more inflammatory phenotype, as reflected by an increased macrophage content and reduced collagen content.
CETP inhibition by torcetrapib per se reduces atherosclerotic lesion size but does not enhance the antiatherogenic potential of atorvastatin. However, compared with atorvastatin, torcetrapib introduces lesions of a less stable phenotype.</description><subject>Animals</subject><subject>Atherosclerosis (general aspects, experimental research)</subject><subject>Atherosclerosis - drug therapy</subject><subject>Atherosclerosis - pathology</subject><subject>Atorvastatin Calcium</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Cardiology. Vascular system</subject><subject>Cholesterol Ester Transfer Proteins - antagonists & inhibitors</subject><subject>Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous</subject><subject>Drug Synergism</subject><subject>Heptanoic Acids - pharmacology</subject><subject>Heptanoic Acids - therapeutic use</subject><subject>Inflammation - chemically induced</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred Strains</subject><subject>Pyrroles - pharmacology</subject><subject>Pyrroles - therapeutic use</subject><subject>Quinolines - pharmacology</subject><subject>Quinolines - therapeutic use</subject><issn>0009-7322</issn><issn>1524-4539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkF9LwzAUxYMobk6_gsQHHzuTpkmaxzr_bFA3Gd1zSdKMVdpmJJ0wP70ZG8oe7r3cw-9cuAeAB4zGGDP8NJktJ6s8K2aLeTbNxhjxMWdYMHoBhpjGSZRQIi7BECEkIk7ieABuvP8KKyOcXoMBThOaYsaH4KewTpveyW2t4Is1Hs5tD5em2mkDs35jnPW6OfTaw2ezt10VZOu-pe9lX3dQBmHWHXAPP6wz8NPZuls3sm1l4PYwN762nYfFRnZn1ltwtZaNN3enOQKrt9diMo3yxftskuWRTojoI4GFEpxxjCVSiZJGEFapUCnTHGklGKLhLSUMFdiQJFXIpDGiiKlYMUXJCIjjXR2-8M6sy62rW-n2JUblIc_yPM8g8_KYZ_DeH73bnWpN9e88BRiAxxMgvZbN2slO1_6PixGhOEGI_AK-hYHT</recordid><startdate>20080513</startdate><enddate>20080513</enddate><creator>DE HAAN, Willeke</creator><creator>DE VRIES-VAN DER WEIJ, Jitske</creator><creator>RENSEN, Patrick C. N</creator><creator>VAN DER HOORN, José W. A</creator><creator>GAUTIER, Thomas</creator><creator>VAN DER HOOGT, Caroline C</creator><creator>WESTERTERP, Marit</creator><creator>ROMIJN, Johannes A</creator><creator>JUKEMA, J. Wouter</creator><creator>HAVEKES, Louis M</creator><creator>PRINCEN, Hans M. G</creator><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20080513</creationdate><title>Torcetrapib Does Not Reduce Atherosclerosis Beyond Atorvastatin and Induces More Proinflammatory Lesions Than Atorvastatin</title><author>DE HAAN, Willeke ; DE VRIES-VAN DER WEIJ, Jitske ; RENSEN, Patrick C. N ; VAN DER HOORN, José W. A ; GAUTIER, Thomas ; VAN DER HOOGT, Caroline C ; WESTERTERP, Marit ; ROMIJN, Johannes A ; JUKEMA, J. Wouter ; HAVEKES, Louis M ; PRINCEN, Hans M. 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Miscellaneous</topic><topic>Drug Synergism</topic><topic>Heptanoic Acids - pharmacology</topic><topic>Heptanoic Acids - therapeutic use</topic><topic>Inflammation - chemically induced</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred Strains</topic><topic>Pyrroles - pharmacology</topic><topic>Pyrroles - therapeutic use</topic><topic>Quinolines - pharmacology</topic><topic>Quinolines - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DE HAAN, Willeke</creatorcontrib><creatorcontrib>DE VRIES-VAN DER WEIJ, Jitske</creatorcontrib><creatorcontrib>RENSEN, Patrick C. N</creatorcontrib><creatorcontrib>VAN DER HOORN, José W. A</creatorcontrib><creatorcontrib>GAUTIER, Thomas</creatorcontrib><creatorcontrib>VAN DER HOOGT, Caroline C</creatorcontrib><creatorcontrib>WESTERTERP, Marit</creatorcontrib><creatorcontrib>ROMIJN, Johannes A</creatorcontrib><creatorcontrib>JUKEMA, J. Wouter</creatorcontrib><creatorcontrib>HAVEKES, Louis M</creatorcontrib><creatorcontrib>PRINCEN, Hans M. G</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Circulation (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>DE HAAN, Willeke</au><au>DE VRIES-VAN DER WEIJ, Jitske</au><au>RENSEN, Patrick C. N</au><au>VAN DER HOORN, José W. A</au><au>GAUTIER, Thomas</au><au>VAN DER HOOGT, Caroline C</au><au>WESTERTERP, Marit</au><au>ROMIJN, Johannes A</au><au>JUKEMA, J. Wouter</au><au>HAVEKES, Louis M</au><au>PRINCEN, Hans M. G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Torcetrapib Does Not Reduce Atherosclerosis Beyond Atorvastatin and Induces More Proinflammatory Lesions Than Atorvastatin</atitle><jtitle>Circulation (New York, N.Y.)</jtitle><addtitle>Circulation</addtitle><date>2008-05-13</date><risdate>2008</risdate><volume>117</volume><issue>19</issue><spage>2515</spage><epage>2522</epage><pages>2515-2522</pages><issn>0009-7322</issn><eissn>1524-4539</eissn><coden>CIRCAZ</coden><abstract>Although cholesteryl ester transfer protein (CETP) inhibition is regarded as a promising strategy to reduce atherosclerosis by increasing high-density lipoprotein cholesterol, the CETP inhibitor torcetrapib given in addition to atorvastatin had no effect on atherosclerosis and even increased cardiovascular death in the recent Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial. Therefore, we evaluated the antiatherogenic potential and adverse effects of torcetrapib in humanized APOE*3-Leiden.CETP (E3L.CETP) mice.
E3L.CETP mice were fed a cholesterol-rich diet without drugs or with torcetrapib (12 mg x kg(-1) x d(-1)), atorvastatin (2.8 mg x kg(-1) x d(-1)), or both for 14 weeks. Torcetrapib decreased CETP activity in both the absence and presence of atorvastatin (-74% and -73%, respectively; P<0.001). Torcetrapib decreased plasma cholesterol (-20%; P<0.01), albeit to a lesser extent than atorvastatin (-42%; P<0.001) or the combination of torcetrapib and atorvastatin (-40%; P<0.001). Torcetrapib increased high-density lipoprotein cholesterol in the absence (30%) and presence (34%) of atorvastatin. Torcetrapib and atorvastatin alone reduced atherosclerotic lesion size (-43% and -46%; P<0.05), but combination therapy did not reduce atherosclerosis compared with atorvastatin alone. Remarkably, compared with atorvastatin, torcetrapib enhanced monocyte recruitment and expression of monocyte chemoattractant protein-1 and resulted in lesions of a more inflammatory phenotype, as reflected by an increased macrophage content and reduced collagen content.
CETP inhibition by torcetrapib per se reduces atherosclerotic lesion size but does not enhance the antiatherogenic potential of atorvastatin. However, compared with atorvastatin, torcetrapib introduces lesions of a less stable phenotype.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>18458167</pmid><doi>10.1161/CIRCULATIONAHA.107.761965</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0009-7322 |
| ispartof | Circulation (New York, N.Y.), 2008-05, Vol.117 (19), p.2515-2522 |
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| source | Journals@Ovid Ovid Autoload; MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Atherosclerosis (general aspects, experimental research) Atherosclerosis - drug therapy Atherosclerosis - pathology Atorvastatin Calcium Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cholesterol Ester Transfer Proteins - antagonists & inhibitors Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Drug Synergism Heptanoic Acids - pharmacology Heptanoic Acids - therapeutic use Inflammation - chemically induced Medical sciences Mice Mice, Inbred Strains Pyrroles - pharmacology Pyrroles - therapeutic use Quinolines - pharmacology Quinolines - therapeutic use |
| title | Torcetrapib Does Not Reduce Atherosclerosis Beyond Atorvastatin and Induces More Proinflammatory Lesions Than Atorvastatin |
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