PMID- 30561264 OWN - NLM STAT- MEDLINE DCOM- 20191119 LR - 20210109 IS - 2047-9980 (Electronic) IS - 2047-9980 (Linking) VI - 7 IP - 24 DP - 2018 Dec 18 TI - Ezetimibe in Combination With Simvastatin Reduces Remnant Cholesterol Without Affecting Biliary Lipid Concentrations in Gallstone Patients. PG - e009876 LID - 10.1161/JAHA.118.009876 [doi] LID - e009876 AB - Background In randomized trials (SHARP [Study of Heart and Renal Protection], IMPROVE -IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), combination of statin and ezetimibe resulted in additional reduction of cardiovascular events. The reduction was greater in patients with type 2 diabetes mellitus (T2 DM ), where elevated remnant cholesterol and high cardiovascular disease risk is characteristic. To evaluate possible causes behind these results, 40 patients eligible for cholecystectomy, randomized to simvastatin, ezetimibe, combined treatment (simvastatin+ezetimibe), or placebo treatment during 4 weeks before surgery, were studied. Methods and Results Fasting blood samples were taken before treatment start and at the end (just before surgery). Bile samples and liver biopsies were collected during surgery. Hepatic gene expression levels were assessed with qPCR . Lipoprotein, apolipoprotein levels, and content of cholesterol, cholesteryl ester, and triglycerides were measured after lipoprotein fractionation. Lipoprotein subclasses were analyzed by nuclear magnetic resonance. Apolipoprotein affinity for human arterial proteoglycans ( PG ) was measured. Biomarkers of cholesterol biosynthesis and intestinal absorption and bile lipid composition were analyzed using mass spectrometry. Combined treatment caused a statistically significant decrease in plasma remnant particles and apolipoprotein B (ApoB)/lipoprotein content of cholesterol, cholesteryl esters, and triglycerides. All treatments reduced ApoB-lipoprotein PG binding. Simvastatin and combined treatment modified the composition of lipoproteins. Changes in biomarkers of cholesterol synthesis and absorption and bile acid synthesis were as expected. No adverse events were found. Conclusions Combined treatment caused atheroprotective changes on ApoB-lipoproteins, remnant particles, bile components, and in ApoB-lipoprotein affinity for arterial PG . These effects might explain the decrease of cardiovascular events seen in the SHARP and IMPROVE - IT trials. Clinical Trial Registration URL : www.clinicaltrialsregister.eu . Unique identifier: 2006-004839-30). FAU - Ahmed, Osman AU - Ahmed O AD - 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden. AD - 2 Department of Biochemistry Faculty of Medicine Khartoum University Khartoum Sudan. FAU - Littmann, Karin AU - Littmann K AD - 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden. AD - 3 Function Area Clinical Chemistry Karolinska University Laboratory Function Karolinska University Hospital Stockholm Sweden. FAU - Gustafsson, Ulf AU - Gustafsson U AD - 5 Department of Surgery Karolinska Institutet at Danderyd Hospital Stockholm Sweden. FAU - Pramfalk, Camilla AU - Pramfalk C AD - 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden. FAU - Oorni, Katariina AU - Oorni K AD - 6 Wihuri Research Institute Helsinki Finland. FAU - Larsson, Lilian AU - Larsson L AD - 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden. FAU - Minniti, Mirko E AU - Minniti ME AD - 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden. FAU - Sahlin, Staffan AU - Sahlin S AD - 5 Department of Surgery Karolinska Institutet at Danderyd Hospital Stockholm Sweden. FAU - Camejo, German AU - Camejo G AD - 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden. FAU - Parini, Paolo AU - Parini P AD - 1 Division of Clinical Chemistry Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden. AD - 4 Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme Karolinska University Hospital Stockholm Sweden. AD - 7 Metabolism Unit Department of Medicine Karolinska Institutet at Karolinska University Hospital Huddinge Stockholm Sweden. FAU - Eriksson, Mats AU - Eriksson M AD - 4 Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme Karolinska University Hospital Stockholm Sweden. AD - 7 Metabolism Unit Department of Medicine Karolinska Institutet at Karolinska University Hospital Huddinge Stockholm Sweden. LA - eng PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - England TA - J Am Heart Assoc JT - Journal of the American Heart Association JID - 101580524 RN - 0 (APOB protein, human) RN - 0 (Apolipoprotein B-100) RN - 0 (Biomarkers) RN - 0 (Chylomicron Remnants) RN - 0 (Ezetimibe, Simvastatin Drug Combination) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Membrane Proteins) RN - 0 (Membrane Transport Proteins) RN - 0 (NPC1L1 protein, human) RN - 97C5T2UQ7J (Cholesterol) SB - IM MH - Apolipoprotein B-100/blood MH - Bile/*metabolism MH - Biomarkers/blood MH - Cholecystectomy MH - Cholesterol/*blood MH - Chylomicron Remnants/*blood MH - Dyslipidemias/blood/diagnosis/*drug therapy MH - Ezetimibe, Simvastatin Drug Combination/adverse effects/*therapeutic use MH - Female MH - Gallstones/diagnosis/*metabolism/surgery MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects/*therapeutic use MH - Liver/drug effects/metabolism MH - Male MH - Membrane Proteins/genetics/metabolism MH - Membrane Transport Proteins MH - Middle Aged MH - Single-Blind Method MH - Time Factors MH - Treatment Outcome PMC - PMC6405603 OTO - NOTNLM OT - ApoB-lipoproteins OT - T2DM OT - bile OT - proteoglycan binding OT - statin therapy EDAT- 2018/12/19 06:00 MHDA- 2019/11/20 06:00 PMCR- 2018/12/18 CRDT- 2018/12/19 06:00 PHST- 2018/12/19 06:00 [entrez] PHST- 2018/12/19 06:00 [pubmed] PHST- 2019/11/20 06:00 [medline] PHST- 2018/12/18 00:00 [pmc-release] AID - JAH33708 [pii] AID - 10.1161/JAHA.118.009876 [doi] PST - ppublish SO - J Am Heart Assoc. 2018 Dec 18;7(24):e009876. doi: 10.1161/JAHA.118.009876.