Influence of simvastatin on LDL-subtypes in patients with heterozygous familial hypercholesterolemia and in patients with diabetes mellitus and mixed hyperlipoproteinemia[*]

Summary

This study evaluates the influence of simvastatin on lipid concentrations and on LDL-subtype distribution in patients with heterozygous familial hypercholesterolemia and in patients with type 2 diabetes and mixed hyperlipoproteinemia.

Nine patients with familial hypercholesterolemia (LDL-cholesterol: 7.1 ± 1.1 mmol/L, triglycerides: 1.3 ± 0.4 mmol/L) and 8 patients with type 2 diabetes mellitus and mixed hyperlipoproteinemia (HbA1c 6.8 ± 1.1%, LDL-cholesterol: 4.8 ± 0.7 mmol/L, triglycerides: 2.5 ± 1.1 mmol/L) were examined. Cholesterol concentration was determined in 7 LDL-subfractions isolated by density gradient ultracentrifugation before and during simvastatin treatment (10-20 mg/d, 4 weeks).

Simvastatin decreased LDL-cholesterol (- 34%/- 30%, all p < 0.05) and triglycerides (- 2%, n.s./- 25%, p < 0.05), but had little effect on HDL-cholesterol (+ 7%/+ 2%, n.s.) in patients with familial hypercholesterolemia and diabetes mellitus, respectively. In both groups a significant reduction of cholesterol in each LDL-subfraction was observed. Large-buoyant (LDL-1, LDL-2) and intermediate-dense (LDL-3, LDL-4) LDL were reduced more than small-dense (LDL-5-LDL-7) LDL-subtypes (- 36%/- 38%/- 23%, respectively) in patients with familial hypercholesterolemia, while in diabetic patients cholesterol reduction was uniform in all LDL-subtypes (- 29%/- 27%/- 31%, respectively).

Simvastatin decreases cholesterol concentration in all LDL-subfractions in patients with familial hypercholesterolemia and in patients with diabetes mellitus with mixed hyperlipoproteinemia. However, the relative reduction of individual LDL-subtypes differed between both groups. This suggests that the effect of simvastatin on LDL-subtype distribution depends on the type of underlying hyperlipoproteinemia.

Diabetes mellitus - Familial hypercholesterolemia - LDL-subfractions - LDL-subtypes - Simvastatin

References

• 1 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 infarcation.  JAMA. 1988;  260 1917-1921
• 2 Austin M A, King M, Vranizan K M, Krauss R M. Atherogenic Lipoprotein Phenotype: a proposed genetic marker for coronary heart disease risk.  Circulation. 1990;  82 495-506
• 3 Austin M A, Mykkänen L, Kuusisto J, Edwards K L, Nelson C, Haffner S M, Pyörälä K, Laakso M. Prospective Study of small LDLs as a risk factor for non-insulin dependent diabetes mellitus in elderly men and women.  Circulation. 1995;  92 1770-1778
• 4 Blum C B. Comparison of properties of four inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.  Am J Cardiol. 1994;  73 3D-11D
• 5 Bredie S JH, de Bruin T WA, Demacker P NM, Kastelein J JP, Stalenhoef F H. Comparison of gemfibrocil 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. 1995;  75 348-353
• 6 Chapman M J, Goldstein S, Lagrange D, Laplaud P M. A density gradient ultracentrifugal procedure for the isolation of the major lipoprotein classes from human serum.  J Lipid Res. 1981;  22 339-358
• 7 Chapman M J, Guerin M, Bruckert E. Atherogenic, dense low-density lipoproteins. Pathophysiology and new therapeutic approaches.  Eur Heart J. 19 ((Suppl A)) 1998;  A24-A30
• 8 de Graaf J, Demacker P NM, Stalenhoef A FH. The effect of simvastatin treatment on the low-density lipoprotein subfraction profile and composition in familial hypercholesterolemia.  Netherlands J Med. 1993;  43 254-261
• 9 Farmer J A, Gotto A M. Dyslipidemia and other risk factors for coronary artery disease. In Braunwald E (ed) Heart Disease, 5th Edition Saunders, Philadelphia 1997: 1126-1160
• 10 Gaw A, Packard C J, Murray E F, Lindsay G M, Griffin B A, Caslake M J, Vallance B D, Lorimer A R, Shepherd J. Effects of simvastatin on apoB metabolism and LDL subfraction distribution.  Arterioscler Thromb. 1993;  13 170-189
• 11 Griffin B A, Freeman D J, Tait G W, Thompson 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.  Atheroscler. 1994;  106 241-253
• 12 Homma Y, Ozawa H, Kobayashi T, Yamaguchi H, Sakane H, Nakamura H. Effects of simvastatin on plasma lipoprotein subfractions, cholesterol esterification rate, and cholesteryl ester transfer protein in type II hyperlipoproteinemia.  Atheroscler. 1995;  114 223-234
• 13 Hoogerbrugge N, Jansen H. Atorvastatin increases low-density lipoprotein size and enhances high-density lipoprotein-cholesterol concentration in male, but not in female patients with familial hypercholesterolemia.  Atheroscler. 1999;  146 167-174
• 14 Inoue I, Takahashi K, Kikuchi C, Katayama S. LDL-apheresis reduces the susceptibility of LDL to in-vitro oxidation in a diabetic patient with hemodialysis treatment.  Diabetes Care. 1996;  19 1103-1107
• 15 Kontopoulos A G, Athyros V G, Papageorgiou A A, Hatzikonstatindou H A, Melachrini C M, Boudouls H. Effects of simvastatin and cipofibrate 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 heart disease.  Coronary Artery Dis. 1996;  7 843-850
• 16 Krauss R M, Burke D J. Identification of multiple subclasses of plasma low density lipoproteins in normal humans.  J Lipid Res. 1982;  23 97-104
• 17 Kreisberg R A. Diabetic Dyslipidemia.  Am J Cardiol. 1998;  82 67U-73U
• 18 Lagrost L, Athias A, Lemort N, Richard J-L, Desrumaux C, Châtenent-Duchêne L, Courtois M, Farnier M, Jacotot B, Braschi S, Gambert Ph. Plasma lipoprotein distribution and lipid transfer activities in patients with type II b hyperlipoproteinemia treated with simvastatin.  Atheroscler. 1998;  143 415-425
• 19 Lamarche B, Tchernof A, Moorjani S, Chantin B, Dagenais G R, Lupien P J, Després J-P. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men.  Circulation. 1997;  95 69-75
• 20 Lamon Fava S, Wilson P WF, Schaefer E J. Impact of body mass index on coronary heart disease risk factors in men and women. The Framingham offspring study.  Arterioscler Thromb Vasc Biol. 1996;  16 1509-1515
• 21 Malmström R, Packard C J, Caslake M, Bedford D, Stewart P, Yki-Järvinen H, Shepherd J, Taskinen M-R. Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM.  Diabetologia. 1997;  40 454-462
• 22 Massi-Benedetti M, Federici M O. Cardiovascular risk factors in type 2 diabetes: the role of hyperglycaemia.  Exp Clin Endocrinol Diabetes. 107 ((Suppl)) 1999;  4S120-123
• 23 McNamara J R, Jenner J L, Li Z, Wilson P WF, Schäfer E J. Change in LDL particle size is associated with change in plasma triglyceride concentration.  Arterioscler Thromb. 1992;  12 1284-1290
• 24 Millar J S, Packard Ch J. Heterogeneity of apolipoprotein B-100-containing lipoproteins: What we have learnt from kinetic studies.  Curr Opin Lipid. 1998;  9 197-202
• 25 NCEP expert panel . Summary of the second report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol levels in adults (adult treatment panel II).  JAMA. 1993;  269 3015-3023
• 26 Nigon F, Lesnik Ph, 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
• 27 Packard Ch J, Shepherd J. Lipoprotein heterogeneity and apolipoprotein B metabolism.  Arterioscler Thromb Vasc Biol. 1997;  17 3542-3556
• 28 Peeples L H, Carpenter J W, Israel R G, Barakat H A. Alterations in low-density lipoproteins in subjects with abdominal adiposity.  Metabolism. 1989;  38 1029-1036
• 29 Pyorälä K, Pedersen T R, Kjekshus J, Faergeman O, Olsson A G, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S).  Diab Care. 1997;  20 614-620
• 30 Scandianavian Simvastatin Survival Study Group . Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S).  Lancet. 1994;  344 1383-1389
• 31 Schamberger B M, Geiss H C, Ritter M M, Schwandt P, Parhofer K G. Influence of LDL-apheresis on LDL-subtypes in patients with coronary heart disease and severe hyperlipoproteinemia.  J Lipid Res. 2000;  41 727-733
• 32 Schwandt P, Geiß H C, Ritter M M, Üblacker Ch, Parhofer K G, Otto C, Laubach E, Donner M G, Haas G-M, Richter W O. The Prevention Education Program (PEP). A Prospective Study of the Efficacy of Family Oriented Life Style Modification in the Reduction of Cardiovascular Risk and Disease.  Design and Baseline Data, J Clin Epidemiol. 1999;  52 791-800
• 33 Superko H R, Haskel W L, Krauss R M. Association of lipoprotein subclass distribution with use of selective and non-selective beta blocker medications in patients with coronary heart disease.  Atheroscler. 1993;  101 1-8
• 34 Temelkova-Kurktschiev T, Henkel E, Schaper F, Koehler C, Siegert G, Hanefeld M. Prevalence and atherosclerosis risk in different types of non-diabetic hyperglycemia. Is mild hyperglycemia an underestimated evil?.  Exp Clin Endocrinol Diabetes. 2000;  108 93-99
• 35 Todd P A, Goa K L. Simvastatin. A review of pharmacological properties and therapeutic potential in hypercholesterolaemia.  Drugs. 1990;  40 583-607
• 36 Tribble D L, Holl L G, Wood P D, Krauss R M. Variations in oxidative susceptibility among 6 low density lipoprotein subfractions of differing density and particle size.  Atheroscler. 1992;  93 189-199
• 37 Twickler T HB, Dallinga-Thie G M, de Valk H W, Schreuder P CNJ, Jansen H, Cabezas M C, Erkelens D W. High dose of simvastatin normalizes postprandial remnant-like particle response in patients with heterozygous familial hypercholesterolemia.  Arterioscler Thromb Vasc Biol. 2000;  20 2422-2427
• 38 Wakatsuki A, Okatani Y, Ikenoue N. Effects of combination therapy with estrogen plus simvastatin on lipoprotein metabolism in postmenopausal women with type II a hypercholesterolemia.  Atheroscler. 2000;  150 103-111
• 39 Watts G F, Mandalia S, Brunt J N, Slavin B M, Coltart D J, Lewis B. Independent associations between plasma lipoprotein subfraction levels and the course of coronary artery disease in the St. Thomas' Atherosclerosis Regression Study (STARS).  Metabolism. 1993;  42 1461-1467
• 40 Zhao S P, Hollaar L, van't Hooft F M, Smelt A H, Gevers-Leuven J A, van der Laarse A. Effect of simvastatin on the apparent size of LDL particles in patients with type II b hyperlipoproteinemia.  Clin Chim Acta. 1991;  203 109-117

1 This article was presented in part at the 12^th international Symposium on Atherosclerosis (June 25-29, 2000, Stockholm, Sweden) and is published in abstract form in Atherosclerosis (Atheroscler 2000; 151: 37).