Download PDF
Exp Clin Endocrinol Diabetes 2004; 112(5): 241-247
DOI: 10.1055/s-2004-817970
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Qualitative Effect of Fenofibrate and Quantitative Effect of Atorvastatin on LDL Profile in Combined Hyperlipidemia with dense LDL

K. Winkler1 , P. Weltzien2 , I. Friedrich1 , H. Schmitz2 , H.-H. Nickell1 , P. Hauck3 , M. M. Hoffmann1 , M. W. Baumstark4 , H. Wieland1 , W. März5
  • 1Department of Clinical Chemistry, University of Freiburg, Germany
  • 2Fournier Pharma GmbH, Sulzbach, Germany
  • 3Internistische Praxis, Weisshoferstraße 26, Bretten, Germany
  • 4Department of Sports Medicine, University of Freiburg, Germany
  • 5Department of Clinical Chemistry, University of Graz, Austria
Further Information

Publication History

Received: May 21, 2003 First decision: July 7, 2003

Accepted: October 30, 2003

Publication Date:
14 May 2004 (online)

Also available at
    Permissions and Reprints

Abstract

Introduction: The association of elevated plasma triglyceride concentrations, decreased HDL-cholesterol, and dense LDL (dLDL) is referred to as the atherogenic lipoprotein phenotype. dLDL particularly plays a role in the metabolic syndrome and type 2 diabetes and may be one of the factors responsible for the increased risk for coronary artery disease in these patients. The effect of fenofibrate and atorvastatin on the LDL subfraction profile in patients with combined hyperlipidemia and a preponderance of dLDL was studied in a sequential design.

Methods: Six male patients with combined hyperlipidemia and dLDL received 160 mg/die supra-bioavailable fenofibrate. After a washout phase of 8 weeks all patients received 10 mg/die atorvastatin for another 8 weeks. At baseline, after fenofibrate, and after atorvastatin treatment LDL subfractions were analyzed by equilibrium density gradient ultracentrifugation,

Results: Treatment with atorvastatin and fenofibrate reduced serum cholesterol by 30 % and 21 % (p = 0.046) (p-values for differences between treatment groups), triglycerides by 32 % and 45 %, LDL cholesterol by 28 % and 16 %, and increased HDL cholesterol by 3 % and 6 %, respectively. Atorvastatin and fenofibrate treatment resulted in the following changes of apoB and LDL subfractions: LDL-1 (1.019 - 1.031 kg/L) - 31 % and + 15 % (p = 0.028); LDL-2 (1.031 - 1.034 kg/L) - 14 % and + 57 % (p = 0.028); LDL-3 (1.034 - 1.037 kg/L) - 20 % and + 30 % (p = 0.028); LDL-4 (1.037 - 1.040 kg/L) - 25 % and - 6 %; LDL-5 (1.040 - 1.044 kg/L) - 29 % and - 38 %; and LDL-6 (1.044 - 1.063 kg/L) - 39 % and - 55 % (p = 0.028). As a consequence, fenofibrate reduced LDL density significantly (p = 0.028 versus atorvastatin).

Conclusions: Atorvastatin decreased all LDL-subfractions to a similar extent (quantitative effect) whereas fenofibrate reduced predominantly dLDL and changed the LDL profile towards medium dense LDL-particles (qualitative effect). Since medium dense LDL have a higher affinity to the LDL-receptor fenofibrate may have a higher antiatherogenic potential than assessed by the reduction of total LDL-cholesterol and triglycerides alone.

Key words

PPAR-alpha agonists - LDL-subfractions - atherogenic lipoprotein phenotype - triglycerides - high density lipoproteins

References

  • 2 Anber V, Griffin B A, McConnell M, Packard C J, Shepherd J. Influence of plasma lipid and LDL-subfraction profile on the interaction between low density lipoprotein with human arterial wall proteoglycans.  Atherosclerosis. 1996;  124 261-271
    CrossrefPubMedGoogle Scholar
  • 3 Athyros V G, Papageorgiou A A, Athyrou V V, Demitriadis D S, Kontopoulos A G. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia.  Diabetes Care. 2002;  25 1198-1202
    CrossrefPubMedGoogle Scholar
  • 4 Austin M A, Breslow J L, Hennekens C H, Buring J E, Willett W C, Krauss R M. Low-density lipoprotein subclass patterns and risk of myocardial infarction.  J Am Med Ass. 1988;  260 1917-1921
    CrossrefPubMedGoogle Scholar
  • 5 Austin M A, Edwards K L. Small, dense low density lipoprotein, and insulin resistance syndrome and noninsulin-dependent diabetes.  Curr Opin Lipidol. 1996;  7 167-171
    PubMedGoogle Scholar
  • 6 Austin M A, King M-C, Vranizian K M, Krauss R M. Atherogenic Lipoprotein Phenotype: A proposed Genetic Marker for Coronary Heart Disease Risk.  Circulation. 1990;  82 495-506
    CrossrefPubMedGoogle Scholar
  • 7 Bairaktari E T, Tzallas C S, Tsimihodimos V K, Liberopoulos E N, Miltiadous G A, Elisaf M S. Comparison of the efficacy of atorvastatin and micronized fenofibrate in the treatment of mixed hyperlipidemia.  J Cardiovasc Risk. 1999;  6 113-116
    PubMedGoogle Scholar
  • 8 Baumstark M W, Kreutz W, Berg A, Frey I, Keul J. Structure of human low-density lipoprotein subfractions, determined by X-ray small-angle scattering.  Biochim Biophys Acta. 1990;  1037 48-57
    PubMedGoogle Scholar
  • 9 Berk II P, Hoogerbrugge N, Stolk R P, Bootsma A H, Jansen H. Atorvastatin dose-dependently decreases hepatic lipase activity in type 2 diabetes: effect of sex and the LIPC promoter variant.  Diabetes Care. 2003;  26 427-432
    PubMedGoogle Scholar
  • 10 Bilheimer D W, Grundy S M, Brown M S, Goldstein J L. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes.  Proc Natl Acad Sci. 1983;  80 4124-4128
    PubMedGoogle Scholar
  • 11 Bocher V, Pineda-Torra I, Fruchart J C, Staels B. PPARs: transcription factors controlling lipid and lipoprotein metabolism.  Ann N Y Acad Sci. 2002;  967 7-18
    PubMedGoogle Scholar
  • 12 Bredie S J, de Bruin T W, Demacker P N, Kastelein J J, Stalenhoef A F. Comparison of gemfibrozil versus simvastatin in familial combined hyperlipidemia and effects on apolipoprotein-B-containing lipoproteins, low-density lipoprotein subfraction profile, and low-density lipoprotein oxidizability.  Am J Cardiol. 1999;  75 348-353
    PubMedGoogle Scholar
  • 13 Bruckert E, Dejager S, Chapman M J. Ciprofibrate therapy normalizes the atherogenic low-density lipoprotein subspecies profile in combined hyperlipidemia.  Atherosclerosis. 1993;  100 91-102
    CrossrefPubMedGoogle Scholar
  • 14 Campos H, Genest J JJ, Blijlevens E, McNamara J R, Jenner J L, Ordovas J M, Wilson P W, Schaefer E J. Low density lipoprotein particle size and coronary artery disease.  Arterioscler Thromb Vasc Biol. 1992;  12 187-195
    PubMedGoogle Scholar
  • 15 Campos H, Moye L A, Glasser S P, Stampfer M J, Sacks F M. Low-density lipoprotein size, pravastatin treatment, and coronary events.  J Am Med Ass. 2001;  286 1468-1474
    CrossrefPubMedGoogle Scholar
  • 16 Campos H, Roederer G O, Lussier-Cacan S, Davignon J, Krauss R M. Predominance of large LDL and reduced HDL2 cholesterol in normolipidemic men with coronary artery disease.  Arterioscler Thromb Vasc Biol. 1995;  15 1043-1048
    PubMedGoogle Scholar
  • 17 Cheung M C, Austin M A, Moulin P, Wolf A C, Cryer D, Knopp R H. Effects of pravastatin on apolipoprotein-specific high density lipoprotein subpopulations and low density lipoprotein subclass phenotypes in patients with primary hypercholesterolemia.  Atherosclerosis. 1993;  102 107-119
    CrossrefPubMedGoogle Scholar
  • 18 Coresh J, Kwiterovich Jr P O, Smith H H, Bachorik P S. Association of plasma triglyceride concentration and LDL particle diameter, density, and chemical composition with premature coronary artery disease in men and women.  J Lipid Res. 1993;  34 1687-1697
    PubMedGoogle Scholar
  • 19 de Graaf J, Demacker P N, Stalenhoef A F. The effect of simvastatin treatment on the low-density lipoprotein subfraction profile and composition in familial hypercholesterolaemia.  Neth J Med. 1993 a;  43 254-261
    PubMedGoogle Scholar
  • 20 de Graaf J, Hendriks J C, Demacker P N, Stalenhoef A F. Identification of multiple dense LDL subfractions with enhanced susceptibility to in vitro oxidation among hypertriglyceridemic subjects. Normalization after clofibrate treatment.  Arterioscler Thromb. 1993 b;  13 712-719
    PubMedGoogle Scholar
  • 21 Franceschini G, Cassinotti M, Vecchio G, Gianfranceschi G, Pazzucconi F, Murakami T, Sirtori M, D'Acquarica A L, Sirtori C R. Pravastatin effectively lowers LDL cholesterol in familial combined hyperlipidemia without changing LDL subclass pattern.  Arterioscler Thromb. 1994;  14 1569-1575
    PubMedGoogle Scholar
  • 22 Frost R J, Otto C, Geiss H C, Schwandt P, Parhofer K G. Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia.  Am J Cardiol. 2001;  87 44-48
    PubMedGoogle Scholar
  • 23 Galeano N F, Al-Haideri M, Keyserman F, Rumsey S C, Deckelbaum R J. Small dense low density lipoprotein has increased affinity for LDL-receptor-independent cell surface binding sites: a potential mechanism for increased atherogenicity.  J Lipid Res. 1998;  39 1263-1273
    PubMedGoogle Scholar
  • 24 Gardner C D, Fortmann S P, Krauss R M. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.  J Am Med Ass. 1996;  276 875-881
    CrossrefPubMedGoogle Scholar
  • 25 Geiss H C, Otto C, Schwandt P, Parhofer K G. Effect of atorvastatin on low-density lipoprotein subtypes in patients with different forms of hyperlipoproteinemia and control subjects.  Metabolism. 2001;  50 983-988
    CrossrefPubMedGoogle Scholar
  • 26 Geiss H C, Schwandt P, Parhofer K G. Influence of simvastatin on LDL-subtypes in patients with heterozygous familial hypercholesterolemia and in patients with diabetes mellitus and mixed hyperlipoproteinemia.  Exp Clin Endocrinol Diabetes. 2002;  110 182-187
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Griffin B A, Freeman D J, Tait G W, Thomson J, Caslake M J, Packard C J, Shepherd J. Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk.  Atherosclerosis. 1994;  106 241-253
    CrossrefPubMedGoogle Scholar
  • 28 Guerin M, Bruckert E, Dolphin P J, Turpin G, Chapman M J. Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic, dense LDL profile in combined hyperlipidemia.  Arterioscler Thromb Vasc Biol. 1996;  16 763-772
    PubMedGoogle Scholar
  • 29 Guerin M, Dolphin P J, Talussot C, Gardette J, Berthezene F, Chapman M J. Pravastatin modulates cholesteryl ester transfer from HDL to ApoB-containing lipoproteins and lipoprotein subspecies profile in familial hypercholesterolemia.  Arterioscler Thromb Vasc Biol. 1995;  15 1359-1368
    PubMedGoogle Scholar
  • 30 Halle M, Berg A, Garwers U, Baumstark M W, Knisel W, Grathwohl D, Konig D, Keul J. Influence of 4 weeks' intervention by exercise and diet on low-density lipoprotein subfractions in obese men with type 2 diabetes.  Metabolism. 1999;  48 641-644
    CrossrefPubMedGoogle Scholar
  • 31 Kontopoulos A G, Athyros V G, Papageorgiou A A, Hatzikonstandinou H A, Mayroudi M C, Boudoulas H. Effects of simvastatin and ciprofibrate alone and in combination on lipid profile, plasma fibrinogen and low density lipoprotein particle structure and distribution in patients with familial combined hyperlipidaemia and coronary artery disease.  Coron Artery Dis. 1996;  7 843-850
    PubMedGoogle Scholar
  • 32 Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais G R, Lupien P J, Despres J P. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study.  Circulation. 1997;  95 69-75
    PubMedGoogle Scholar
  • 33 Liamis G, Kakafika A, Bairaktari E, Miltiadous G, Tsimihodimos V, Goudevenos J, Achimastos A, Elisaf M. Combined treatment with fibrates and small doses of atorvastatin in patients with mixed hyperlipidemia.  Curr Med Res Opin. 2002;  18 125-128
    CrossrefPubMedGoogle Scholar
  • 34 März W, Scharnagl H, Abletshauser C, Hoffmann M M, Berg A, Keul J, Wieland H, Baumstark M W. Fluvastatin lowers atherogenic dense low-density lipoproteins in postmenopausal women with the atherogenic lipoprotein phenotype.  Circulation. 2001;  103 1942-1948
    PubMedGoogle Scholar
  • 35 McNamara J R, Jenner J L, Li Z, Wilson P W, Schaefer E J. Change in LDL particle size is associated with change in plasma triglyceride concentration.  Arterioscler Thromb. 1992;  12 1284-1290
    PubMedGoogle Scholar
  • 36 NCEP-Guidelines . Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blodd cholesterol in adults (Adult Treatment Panel III).  J Am Med Assoc. 2001;  285 2486-2497
    CrossrefPubMedGoogle Scholar
  • 37 Nigon F, Lesnik P, Rouis M, Chapman M J. Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL receptor.  J Lipid Res. 1991;  32 1741-1753
    PubMedGoogle Scholar
  • 38 Reaven G M, Chen Y-DI, Jeppesen J, Maheux P, Krauss R M. Insulin resistance and hyperinsulinemia in individuals with small, dense, low density lipoprotein particles.  J Clin Invest. 1993;  92 141-146
    PubMedGoogle Scholar
  • 39 Robins S J, Collins D, Wittes J T, Papademetriou V, Deedwania P C, Schaefer E J, McNamara J R, Kashyap M L, Hershman J M, Wexler L F, Rubins H B. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial.  J Am Med Ass. 2001;  285 1585-1591
    CrossrefPubMedGoogle Scholar
  • 40 Sacks F M. The role of high-density lipoprotein (HDL) cholesterol in the prevention and treatment of coronary heart disease: expert group recommendations.  Am J Cardiol. 2002;  90 139-143
    CrossrefPubMedGoogle Scholar
  • 41 Sasaki S, Kuwahara N, Kunitomo K, Harada S, Yamada T, Azuma A, Takeda K, Nakagawa M. Effects of atorvastatin on oxidized low-density lipoprotein, low-density lipoprotein subfraction distribution, and remnant lipoprotein in patients with mixed hyperlipoproteinemia.  Am J Cardiol. 2002;  89 386-389
    CrossrefPubMedGoogle Scholar
  • 42 Stampfer M J, Krauss R M, Ma J, Blanche P J, Holl L G, Sacks F M, Hennekens C H. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.  J Am Med Ass. 1996;  276 882-888
    CrossrefPubMedGoogle Scholar
  • 43 Superko H R, Krauss R M. Differential effects of nicotinic acid in subjects with different LDL subclass patterns.  Atherosclerosis. 1992;  95 69-76
    PubMedGoogle Scholar
  • 44 Superko H R, Krauss R M, DiRicco C. Effects of Fluvastatin on Low-Density Lipoprotein Peak Particle Diameter.  Am J Cardiol. 1997;  80 78-81
    CrossrefPubMedGoogle Scholar
  • 45 Tilly-Kiesi M. The effect of lovastatin treatment on low-density lipoprotein hydrated density distribution and composition in patients with intermittent claudication and primary hypercholesterolemia.  Metabolism. 1991;  40 623-628
    CrossrefPubMedGoogle Scholar
  • 46 Tsai M Y, Yuan J, Hunninghake D B. Effect of gemfibrozil on composition of lipoproteins and distribution of LDL subspecies.  Atherosclerosis. 1992;  95 35-42
    PubMedGoogle Scholar
  • 47 Vakkilainen J, Makimattila S, Seppala-Lindroos A, Vehkavaara S, Lahdenpera S, Groop P H, Taskinen M R, Yki-Jarvinen H. Endothelial dysfunction in men with small LDL particles.  Circulation. 2000;  102 716-721
    PubMedGoogle Scholar
  • 48 van Venrooij F V, Stolk R P, Banga J D, Sijmonsma T P, van Tol A, Erkelens D W, Dallinga-Thie G M. Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes.  Diabetes Care. 2003;  26 1216-1223
    PubMedGoogle Scholar
  • 49 Vu-Dac N, Schoonjans K, Kosykh V, Dallongeville J, Fruchart J, Staels B. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor.  J Clin Invest. 1995;  96 741-750
    PubMedGoogle Scholar
  • 50 Williams P T, Superko H R, Haskell W L, Alderman E L, Blanche P J, Glines Holl L, Krauss R M. Smallest LDL particles are most strongly related to coronary disease progression in men.  Aterioscler Thromb Vasc Biol. 2003;  23 314-321
    PubMedGoogle Scholar
  • 51 Willson T, Brown P, Sternbach D, Henke B. The PPARs: from orpan receptors to drug discovery.  J Med Chem. 2000;  43 527-550
    CrossrefPubMedGoogle Scholar
  • 52 Winkler K, Friedrich I, Baumstark M W, Wieland H, März W. Pioglitazone reduces atherogenic dense low density lipoprotein (LDL) particles in patients with type 2 diabetes mellitus.  Br J Diabetes Vasc Dis. 2002;  2 143-148
    PubMedGoogle Scholar
  • 53 Winkler K, Abletshauser C, Hoffmann M M, Friedrich I, Baumstark M W, Wieland H, März W. Effect of fluvastatin slow-release on low-density lipoprotein (LDL) subfractions in patients with type 2 diabetes mellitus: baseline LDL profile determines specific mode of action.  J Clin Endocrinol Metab. 2002;  87 5485-5490
    CrossrefPubMedGoogle Scholar
  • 54 Winkler K, Konrad T, Füllert S, Friedrich I, Destani R, Baumstark M W, Krebs K, Wieland H, März W. Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension. A double-blind, placebo-controlled study.  Diabetes Care. 2003;  26 2588-2594
    CrossrefPubMedGoogle Scholar
  • 55 Winkler K, Wetzka B, Hoffmann M M, Friedrich I, Kinner M, Baumstark M W, Wieland H, März W. Low density lipoprotein (LDL) subfractions during pregnancy: Accumulation of buoyant LDL with advancing gestation.  J Clin Endocrinol Metab. 2000;  85 4543-4550
    CrossrefPubMedGoogle Scholar
  • 56 Wittke R. Effect of fluvastatin in combination with moderate endurance training on parameters of lipid metabolism.  Sports Med. 1999;  27 329-335
    PubMedGoogle Scholar
  • 57 Zambon S, Cortella A, Sartore G, Baldo-Enzi G, Manzato E, Crepaldi G. Pravastatin treatment in combined hyperlipidaemia. Effect on plasma lipoprotein levels and size.  Eur J Clin Pharmacol. 1994;  46 221-224
    PubMedGoogle Scholar

Dr. M. D. Karl Winkler

Department of Clinical Chemistry
School of Medicine
Albert-Ludwigs-University

Hugstetter Straße 55

79106 Freiburg

Germany

Phone: + 497612703759

Fax: + 49 76 12 70 34 44

Email: kwinkler@ukl.uni-freiburg.de

      >