The HMG-CoA Reductase Inhibitor Cerivastatin Lowers Advanced Glycation End Products in Patients with Type 2 Diabetes

Abstract

Although the association between type 2 diabetes mellitus (DM) and cardiovascular diseases is well-documented, current knowledge regarding reasons for the increased prevalence of atherosclerosis in DM is incomplete. Advanced glycosylation end-products (AGE) may play an important role in the development of atherosclerosis in diabetic patients. We examined the effect of the HMG-CoA reductase inhibitor (HMGRI) cerivastatin on serum concentration of AGE-CML in patients with elevated fasting glucose, impaired glucose tolerance or DM. The study was a multicenter, double-blind, randomized, parallel-group comparison of cerivastatin at 0.4 mg daily for 12 weeks (n=34) and placebo (n=35). Patients were characterized by combined hyperlipoproteinemia and the preponderance of dense LDL. Primary objective of the study was the effect of cerivastatin on the concentration of dense LDL subfractions. Here we report on the effect of cerivastatin on the concentration of AGE-CML. After 12 weeks of treatment cerivastatin reduced cholesterol, apolipoprotein B, LDL cholesterol and the concentration of dense LDL. Furthermore, cerivastatin significantly lowered the concentration of AGE-CML by 21% (P=0,005; compared to -7,5% in the placebo group). The effect on AGE-CML was correlated with the reduction in LDL cholesterol (r=0.355, P=0.003) and LDL apoB (r=0.239, P=0.05). In addition to the lipid-lowering effects of HMGRI, the reduction of AGE-CML observed in our study may entail an improvement of the cardiovascular prognosis in patients with chronic hyperglycemia.

HMG-CoA reductase inhibitor - advanced glycation end products - type 2 diabetes

References

• 1 Akira K, Amano M, Okajima F, Hashimoto T, Oikawa S. Inhibitory effects of amlodipine and fluvastatin on the deposition of advanced glycation end products in aortic wall of cholesterol and fructose-fed rabbits.  Biol Pharm Bull. 2006;  29 75-81
• 2 Balletshofer BM, Goebbel S, Rittig K, Enderle M, Schmolzer I, Wascher TC, Ferenc Pap A, Westermeier T, Petzinna D, Matthaei S, Haring HU. Intense cholesterol lowering therapy with a HMG-CoA reductase inhibitor does not improve nitric oxide dependent endothelial function in type-2-diabetes-a multicenter, randomised, double-blind, three-arm placebo-controlled clinical trial.  Exp Clin Endocrinol Diabetes. 2005;  113 324-330
• 3 Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes.  Cardiovasc Res. 2004;  63 582-592
• 4 Baumstark MW, 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
• 5 Boehm BO, Schilling S, Rosinger S, Lang GE, Lang GK, Kientsch-Engel R, Stahl P. Elevated serum levels of n(epsilon)-carboxymethyl-lysine, an advanced glycation end product, are associated with proliferative diabetic retinopathy and macular oedema.  Diabetologia. 2004;  47 1376-1379
• 6 Bucala R. Lipid and lipoprotein modification by advanced glycosylation end-products: role in atherosclerosis.  Exp Physiol. 1997;  82 327-337
• 7 Bucala R, Makita Z, Vega G, Grundy S, Koschinsky T, Cerami A, Vlassara H. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency.  Proc Natl Acad Sci USA. 1994;  91 9441-9445
• 8 Bucala R, Mitchell R, Arnold K, Innerarity T, Vlassara H, Cerami A. Identification of the major site of apolipoprotein B modification by advanced glycosylation end products blocking uptake by the low density lipoprotein receptor.  J Biol Chem. 1995;  270 10828-10832
• 9 Cheung BM, Lauder IJ, Lau CP, Kumana CR. Meta-analysis of large randomized controlled trials to evaluate the impact of statins on cardiovascular outcomes.  Br J Clin Pharmacol. 2004;  57 640-651
• 10 Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (CARDS): multicentre randomised placebo-controlled trial.  Lancet. 2004;  364 685-696
• 11 Costa J, Borges M, David C, Vaz Carneiro A. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials.  BMJ. 2006;  332 1115-1124
• 12 Forster LF, Stewart G, Bedford D, Stewart JP, Rogers E, Shepherd J, Packard CJ, Caslake MJ. Influence of atorvastatin and simvastatin on apolipoprotein B metabolism in moderate combined hyperlipidemic subjects with low VLDL and LDL fractional clearance rates.  Atherosclerosis. 2002;  164 129-145
• 13 Geiss HC, Schwandt P, Parhofer KG. 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
• 14 Hoff HF, Whitaker TE, O'Neil J. Oxidation of low density lipoprotein leads to particle aggregation and altered macrophage recognition.  J Biol Chem. 1992;  267 602-609
• 15 Holvoet P, Vanhaecke J, Janssens S, Van de Werf F, Collen D. Oxidized LDL and malondialdehyde-modified LDL in patients with acute coronary syndromes and stable coronary artery disease.  Circulation. 1998;  98 1487-1494
• 16 Marz W, Scharnagl H, Abletshauser C, Hoffmann MM, Berg A, Keul J, Wieland H, Baumstark MW. Fluvastatin lowers atherogenic dense low-density lipoproteins in postmenopausal women with the atherogenic lipoprotein phenotype.  Circulation. 2001;  103 1942-1948
• 17 Okamoto T, Yamagishi S, Inagaki Y, Amano S, Koga K, Abe R, Takeuchi M, Ohno S, Yoshimura A, Makita Z. Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin.  Faseb J. 2002;  16 1928-1930
• 18 Pietsch A, Erl W, Lorenz RL. Lovastatin reduces expression of the combined adhesion and scavenger receptor cd36 in human monocytic cells.  Biochem Pharmacol. 1996;  52 433-439
• 19 Pontrelli L, Parris W, Adeli K, Cheung RC. Atorvastatin treatment beneficially alters the lipoprotein profile and increases low-density lipoprotein particle diameter in patients with combined dyslipidemia and impaired fasting glucose/type 2 diabetes.  Metabolism. 2002;  51 334-342
• 20 Pyorala K, Ballantyne CM, Gumbiner B, Lee MW, Shah A, Davies MJ, Mitchel YB, Pedersen TR, Kjekshus J. Reduction of cardiovascular events by simvastatin in nondiabetic coronary heart disease patients with and without the metabolic syndrome: subgroup analyses of the scandinavian simvastatin survival study (4S).  Diabetes Care. 2004;  27 1735-1740
• 21 Scharnagl H, Winkler K, Mantz S, Baumstark MW, Wieland H, Marz W. Inhibition of HMG-CoA reductase with cerivastatin lowers dense low density lipoproteins in patients with elevated fasting glucose, impaired glucose tolerance and type 2 diabetes mellitus.  Exp Clin Endocrinol Diabetes. 2004;  112 269-277
• 22 Schiekofer S, Galasso G, Andrassy M, Aprahamian T, Schneider J, Rocnik E. Glucose control with insulin results in reduction of NF-ιB-binding activity in mononuclear blood cells of patients with recently manifested type 1 diabetes.  Diabetes Obes Metab. 2006;  8 473-482
• 23 Winkler K, Abletshauser C, Hoffmann MM, Friedrich I, Baumstark MW, Wieland H, Marz 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

Correspondence