Abstract
We investigated the factors influencing triglycerides (TG) reduction during ezetimibe, alone or combined with orlistat, administration. Eighty-six obese hypercholesterolemic subjects were prescribed a low-fat diet and were randomized to ezetimibe (E group), orlistat (O group), or both (OE group) for 6 months. Plasma TG and apolipoprotein (apo) C-III reduction was significantly greater in the combination group compared with monotherapy. Multivariate analysis showed that in E group apoC-III reduction and baseline TG levels were independently positively correlated, whereas baseline apoC-II levels were negatively correlated, with TG lowering. In OE group apoC-III reduction was the only independent contributor to TG reduction.
Similar content being viewed by others
Abbreviations
- apo:
-
Apolipoprotein
- apoA-I:
-
Apolipoprotein A-I
- apoB:
-
Apolipoprotein B
- apoC-II:
-
Apolipoprotein C-II
- apoC-III:
-
Apolipoprotein C-III
- apoE:
-
Apolipoprotein E
- BMI:
-
Body mass index
- CVD:
-
Cardiovascular disease
- Group O:
-
Orlistat group
- Group E:
-
Ezetimibe group
- Group OE:
-
Orlistat plus ezetimibe group
- HDL:
-
High density lipoproteins
- HDL-C:
-
High density lipoprotein cholesterol
- HL:
-
Hepatic lipase
- HOMA:
-
Homeostasis model assessment
- LDL-C:
-
Low density lipoprotein cholesterol
- LPL:
-
Lipoprotein lipase
- MetS:
-
Metabolic syndrome
- TG:
-
Triglycerides
- TC:
-
Total cholesterol
- VLDL:
-
Very low density lipoproteins
References
Jong MC, Hofker MH, Havekes LM (1999) Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler Thromb Vasc Biol 19:472–484
Wang CS (1991) Structure and functional properties of apolipoprotein C-II. Prog Lipid Res 30:253–258
Chan DC, Chen MM, Ooi EM, Watts GF (2008) An ABC of apolipoprotein C-III: a clinically useful new cardiovascular risk factor? Int J Clin Pract 62:799–809
Filippatos TD, Mikhailidis DP (2009) Lipid-lowering drugs acting at the level of the gastrointestinal tract. Curr Pharm Des 15:490–516
Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, Crona JH, Davis HR Jr, Dean DC, Detmers PA, Graziano MP, Hughes M, Macintyre DE, Ogawa A, O’Neill KA, Iyer SP, Shevell DE, Smith MM, Tang YS, Makarewicz AM, Ujjainwalla F, Altmann SW, Chapman KT, Thornberry NA (2005) The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci USA 102:8132–8137
Kiortsis DN, Filippatos TD, Elisaf MS (2005) The effects of orlistat on metabolic parameters and other cardiovascular risk factors. Diabetes Metab 31:15–22
Filippatos TD, Derdemezis CS, Gazi IF, Nakou ES, Mikhailidis DP, Elisaf MS (2008) Orlistat-associated adverse effects and drug interactions: a critical review. Drug Saf 31:53–65
Filippatos T, Derdemezis C, Elisaf M (2009) Effects of orlistat, alone or combined with hypolipidemic drugs, on cardiovascular risk factors. Clin Lipidol 4:331–341
Filippatos TD, Gazi IF, Liberopoulos EN, Athyros VG, Elisaf MS, Tselepis AD, Kiortsis DN (2007) The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis 193:428–437
Filippatos TD, Kiortsis DN, Liberopoulos EN, Georgoula M, Mikhailidis DP, Elisaf MS (2005) Effect of orlistat, micronised fenofibrate and their combination on metabolic parameters in overweight and obese patients with the metabolic syndrome: the FenOrli study. Curr Med Res Opin 21:1997–2006
Filippatos TD, Liberopoulos EN, Kostapanos M, Gazi IF, Papavasiliou EC, Kiortsis DN, Tselepis AD, Elisaf MS (2008) The effects of orlistat and fenofibrate, alone or in combination, on high-density lipoprotein subfractions and pre-beta1-HDL levels in obese patients with metabolic syndrome. Diabetes Obes Metab 10:476–483
Nakou ES, Filippatos TD, Georgoula M, Kiortsis DN, Tselepis AD, Mikhailidis DP, Elisaf MS (2008) The effect of orlistat and ezetimibe, alone or in combination, on serum LDL and small dense LDL cholesterol levels in overweight and obese patients with hypercholesterolaemia. Curr Med Res Opin 24:1919–1929
Nakou ES, Filippatos TD, Kiortsis DN, Derdemezis CS, Tselepis AD, Mikhailidis DP, Elisaf MS (2008) The effects of ezetimibe and orlistat, alone or in combination, on high-density lipoprotein (HDL) subclasses and HDL-associated enzyme activities in overweight and obese patients with hyperlipidaemia. Expert Opin Pharmacother 9:3151–3158
Sakurabayashi I, Saito Y, Kita T, Matsuzawa Y, Goto Y (2001) Reference intervals for serum apolipoproteins A-I, A-II, B, C-II, C-III, and E in healthy Japanese determined with a commercial immunoturbidimetric assay and effects of sex, age, smoking, drinking, and Lp(a) level. Clin Chim Acta 312:87–95
Ooi EM, Barrett PH, Chan DC, Watts GF (2008) Apolipoprotein C-III: understanding an emerging cardiovascular risk factor. Clin Sci (Lond) 114:611–624
Yamamoto M, Morita SY, Kumon M, Kawabe M, Nishitsuji K, Saito H, Vertut-Doi A, Nakano M, Handa T (2003) Effects of plasma apolipoproteins on lipoprotein lipase-mediated lipolysis of small and large lipid emulsions. Biochim Biophys Acta 1632:31–39
Wang CS, McConathy WJ, Kloer HU, Alaupovic P (1985) Modulation of lipoprotein lipase activity by apolipoproteins: effect of apolipoprotein C-III. J Clin Invest 75:384–390
Ginsberg HN, Le NA, Goldberg IJ, Gibson JC, Rubinstein A, Wang-Iverson P, Norum R, Brown WV (1986) Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest 78:1287–1295
Jong MC, Rensen PC, Dahlmans VE, van der Boom H, van Berkel TJ, Havekes LM (2001) Apolipoprotein C-III deficiency accelerates triglyceride hydrolysis by lipoprotein lipase in wild-type and apoE knockout mice. J Lipid Res 42:1578–1585
McConathy WJ, Gesquiere JC, Bass H, Tartar A, Fruchart JC, Wang CS (1992) Inhibition of lipoprotein lipase activity by synthetic peptides of apolipoprotein C-III. J Lipid Res 33:995–1003
Kalogirou M, Tsimihodimos V, Gazi I, Filippatos T, Saougos V, Tselepis AD, Mikhailidis DP, Elisaf M (2007) Effect of ezetimibe monotherapy on the concentration of lipoprotein subfractions in patients with primary dyslipidaemia. Curr Med Res Opin 23:1169–1176
Derdemezis C, Filippatos T, Tselepis A, Mikhailidis D, Elisaf M (2008) Effects of ezetimibe, either alone or in combination with atorvastatin, on serum visfatin levels: a pilot study. Expert Opin Pharmacother 9:1829–1837
Kostapanos MS, Milionis HJ, Filippatos TD, Nakou ES, Bairaktari ET, Tselepis AD, Elisaf MS (2007) A 12-week, prospective, open-label analysis of the effect of rosuvastatin on triglyceride-rich lipoprotein metabolism in patients with primary dyslipidemia. Clin Ther 29:1403–1414
Bradley WA, Hwang SL, Karlin JB, Lin AH, Prasad SC, Gotto AM Jr, Gianturco SH (1984) Low-density lipoprotein receptor binding determinants switch from apolipoprotein E to apolipoprotein B during conversion of hypertriglyceridemic very-low-density lipoprotein to low-density lipoproteins. J Biol Chem 259:14728–14735
Brown SA, Via DP, Gotto AM Jr, Bradley WA, Gianturco SH (1986) Apolipoprotein E-mediated binding of hypertriglyceridemic very low density lipoproteins to isolated low density lipoprotein receptors detected by ligand blotting. Biochem Biophys Res Commun 139:333–340
Packard CJ, Demant T, Stewart JP, Bedford D, Caslake MJ, Schwertfeger G, Bedynek A, Shepherd J, Seidel D (2000) Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions. J Lipid Res 41:305–318
Caslake MJ, Packard CJ (2004) Phenotypes, genotypes and response to statin therapy. Curr Opin Lipidol 15:387–392
Tremblay AJ, Lamarche B, Cohn JS, Hogue JC, Couture P (2006) Effect of ezetimibe on the in vivo kinetics of apoB-48 and apoB-100 in men with primary hypercholesterolemia. Arterioscler Thromb Vasc Biol 26:1101–1106
Masuda D, Nakagawa-Toyama Y, Nakatani K, Inagaki M, Tsubakio-Yamamoto K, Sandoval JC, Ohama T, Nishida M, Ishigami M, Yamashita S (2009) Ezetimibe improves postprandial hyperlipidaemia in patients with type IIb hyperlipidaemia. Eur J Clin Invest 39:689–698
Wang CS, Downs D, Dashti A, Jackson KW (1996) Isolation and characterization of recombinant human apolipoprotein C-II expressed in Escherichia coli. Biochim Biophys Acta 1302:224–230
Fojo SS, Brewer HB (1992) Hypertriglyceridaemia due to genetic defects in lipoprotein lipase and apolipoprotein C-II. J Intern Med 231:669–677
Jong MC, Havekes LM (2000) Insights into apolipoprotein C metabolism from transgenic and gene-targeted mice. Int J Tissue React 22:59–66
Baggio G, Manzato E, Gabelli C, Fellin R, Martini S, Enzi GB, Verlato F, Baiocchi MR, Sprecher DL, Kashyap ML et al (1986) Apolipoprotein C-II deficiency syndrome clinical features, lipoprotein characterization, lipase activity, and correction of hypertriglyceridemia after apolipoprotein C-II administration in two affected patients. J Clin Invest 77:520–527
Reina M, Brunzell JD, Deeb SS (1992) Molecular basis of familial chylomicronemia: mutations in the lipoprotein lipase and apolipoprotein C-II genes. J Lipid Res 33:1823–1832
Shachter NS, Hayek T, Leff T, Smith JD, Rosenberg DW, Walsh A, Ramakrishnan R, Goldberg IJ, Ginsberg HN, Breslow JL (1994) Overexpression of apolipoprotein CII causes hypertriglyceridemia in transgenic mice. J Clin Invest 93:1683–1690
Kowal RC, Herz J, Weisgraber KH, Mahley RW, Brown MS, Goldstein JL (1990) Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein. J Biol Chem 265:10771–10779
Clavey V, Lestavel-Delattre S, Copin C, Bard JM, Fruchart JC (1995) Modulation of lipoprotein B binding to the LDL receptor by exogenous lipids and apolipoproteins CI, CII, CIII, and E. Arterioscler Thromb Vasc Biol 15:963–971
Lucas CP, Boldrin MN, Reaven GM (2003) Effect of orlistat added to diet (30% of calories from fat) on plasma lipids, glucose, and insulin in obese patients with hypercholesterolemia. Am J Cardiol 91:961–964
Reitsma JB, Castro Cabezas M, de Bruin TW, Erkelens DW (1994) Relationship between improved postprandial lipemia and low-density lipoprotein metabolism during treatment with tetrahydrolipstatin, a pancreatic lipase inhibitor. Metabolism 43:293–298
Tan KC, Tso AW, Tam SC, Pang RW, Lam KS (2002) Acute effect of orlistat on post-prandial lipaemia and free fatty acids in overweight patients with Type 2 diabetes mellitus. Diabet Med 19:944–948
Filippatos T, Tsimihodimos V, Kostapanos M, Kostara C, Bairaktari E, Kiortsis D, Elisaf M (2008) Analysis of the 6-month effect of orlistat, alone or in combination with fenofibrate, administration on triglyceride-rich lipoprotein metabolism in overweight and obese patients with metabolic syndrome. J Clin Lipidol 2:279–284
Fernandez ML, Metghalchi S, Vega-Lopez S, Conde-Knape K, Lohman TG, Cordero-Macintyre ZR (2004) Beneficial effects of weight loss on plasma apolipoproteins in postmenopausal women. J Nutr Biochem 15:717–721
Gervaise N, Garrigue MA, Lasfargues G, Lecomte P (2000) Triglycerides, apo C3 and Lp B:C3 and cardiovascular risk in type II diabetes. Diabetologia 43:703–708
Lee SJ, Campos H, Moye LA, Sacks FM (2003) LDL containing apolipoprotein CIII is an independent risk factor for coronary events in diabetic patients. Arterioscler Thromb Vasc Biol 23:853–858
Gerber Y, Goldbourt U, Segev S, Harats D (2003) Indices related to apo CII and CIII serum concentrations and coronary heart disease: a case-control study. Prev Med 37:18–22
Luc G, Fievet C, Arveiler D, Evans AE, Bard JM, Cambien F, Fruchart JC, Ducimetiere P (1996) Apolipoproteins C-III and E in apoB- and non-apoB-containing lipoproteins in two populations at contrasting risk for myocardial infarction: the ECTIM study. Etude Cas Temoins sur ‘Infarctus du Myocarde. J Lipid Res 37:508–517
Hodis HN, Mack WJ, Azen SP, Alaupovic P, Pogoda JM, LaBree L, Hemphill LC, Kramsch DM, Blankenhorn DH (1994) Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin. Circulation 90:42–49
Sacks FM, Alaupovic P, Moye LA, Cole TG, Sussex B, Stampfer MJ, Pfeffer MA, Braunwald E (2000) VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the cholesterol and recurrent events (CARE) trial. Circulation 102:1886–1892
Conflict of interest statement
None.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Nakou, E.S., Filippatos, T.D., Agouridis, A.P. et al. The Effects of Ezetimibe and/or Orlistat on Triglyceride-Rich Lipoprotein Metabolism in Obese Hypercholesterolemic Patients. Lipids 45, 445–450 (2010). https://doi.org/10.1007/s11745-010-3409-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11745-010-3409-0