Understanding Cholesterol Synthesis and Absorption Is the Key to Achieving Cholesterol Targets

Login or register to view PDF.
Citation
Asia Pacific Cardiology - Volume 1 Issue 1;2007:1(1):7-10

Pages

The importance of plasma cholesterol reduction in the attenuation of cardiovascular (CV) risk has been clearly demonstrated in large clinical trials using statins. However, despite the clear risks of hyperlipidaemia and the proven benefits of lipid-lowering therapies, only a minority of patients currently achieve recommended low-density lipoprotein (LDL) cholesterol treatment goals in clinical practice.1,2 More patients are being treated for lipid reduction than ever before, but there remains a substantial degree of undertreatment. This is due to a number of factors, including patient non-compliance, tolerability issues, variable physician follow-up, patients not receiving adequate dosages of the lipid-lowering drugs available and the drugs themselves not being optimal.
Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary artery disease. However, the benefit of treatment varies between patients. Genetic variation can contribute to inter-individual variations in the clinical efficacy of drug therapy, and significant progress has been made in identifying common genetic polymorphisms that influence responsiveness to statin therapy. To date, more than 30 candidate genes related to the pharmacokinetics and pharmacodynamics of statins have been investigated as potential determinants of drug responsiveness in terms of LDL cholesterol lowering.3
An important link also exists between dietary cholesterol absorption and cholesterol production. Inhibiting cholesterol synthesis with statins increases cholesterol absorption, and decreasing cholesterol absorption increases cholesterol synthesis. This partially explains why it is difficult to achieve LDL targets in many patients. The intestinal pool of cholesterol is also an important source of blood cholesterol and is derived from biliary secretion and the diet. Approximately half of intestinal cholesterol is absorbed into the bloodstream. The absorption of excess cholesterol can increase the amount of cholesterol stored in the liver, resulting in increased very-low-density lipoprotein (VLDL) secretion and LDL cholesterol formation and downregulation of LDL receptor activity, leading to increased plasma LDL cholesterol levels. Genetic variation at gene loci that affect intestinal cholesterol absorption include apolipoprotein (apo) E4; adenosine triphosphate-binding cassette transporters G5 and G8; cholesterol production such as 3-hydroxy-3-methylglutaryl co-enzyme A (HMGCoa) reductase; and lipoprotein catabolism such as apoB and the LDL receptor. All may play a role in modulating responsiveness as well as genes involved in the metabolism of statins such as cytochrome P450.3

Pages

References
  1. García Ruiz FJ, Marín Ibáñez A, Pérez Jiménez F, et al., and the REALITY Study Group, Current lipid management and low cholesterol goal attainment in common daily practice in Spain. The REALITY Study, Pharmacoeconomics, 2004;22:1–14.
  2. Krobot KJ, Yin DD, Alemao E, Steinhagen-Thiessen E, Realworld effectiveness of lipid-lowering therapy in male and female outpatients with CHD: relation to pre-treatment LDLcholesterol, pre-treatment CHD risk and other factors, Eur J Cardiovasc Prev Rehabil, 2005;1:37–450.
  3. Kouji K, Akao H, Polisecki E, Schaefer E, Pharmacogenomics of statin responsiveness, Am J Cardiol, 2005;96:65–7.
  4. Sehayek E, Nath C, Heinemann T, et al., U-shaped relationship between change in dietary cholesterol absorption and plasma lipoprotein responsiveness and evidence for extreme interindividual variation in dietary cholesterol absorption in humans, J Lipid Res, 1998;39(12):2415–22.
  5. Miettinen TA, Kesaniemi YA, Cholesterol absorption: regulation of cholesterol synthesis and elimination and within-population variations of serum cholesterol levels, Am J Clin Nutr, 1989;49(4):629–35.
  6. McNamara DJ, Effects of fat-modified diets on cholesterol and lipoprotein metabolism, Annu Rev Nutr, 1987;7:273–90.
  7. McNamara DJ, Kolb R, Parker TS, et al., Heterogeneity of cholesterol homeostasis in man. Response to changes in dietary fat quality and cholesterol quantity, J Clin Invest, 1987;79(6):1729–39.
  8. Kern F Jr, Normal plasma cholesterol in an 88-year-old man who eats 25 eggs a day. Mechanisms of adaptation, N Engl J Med, 1991;324:896–9.
  9. Ostlund RE Jr, Bosner MS, Stenson WF, Cholesterol absorption efficiency declines at moderate dietary doses in normal human subjects, J Lipid Res, 1999;40:1453–8.
  10. Biss K, Taylor CB, Lewis LA, et al., Atherosclerosis and lipid metabolism in the Masai of East Africa, Afr J Med Sci, 1971;2:249–57.
  11. 4S. Randomised trial of cholesterol lowering in 4,444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet, 1994;344:1383–9.
  12. Pedersen TR, Faergeman O, Kastelein JJ, et al., High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomised controlled trial, JAMA, 2005;294:2437–45.
  13. Miettinen TA, Strandberg TE, Gylling H, Non-cholesterol Sterols and Cholesterol Lowering by Long-Term Simvastatin Treatment in Coronary Patients: Relation to Basal Serum Cholestanol, Arterioscler Thromb Vasc Biol, 2000;20:1340–46.
  14. Miettinen TA, Gylling H, Lindbohm N, et al., Serum noncholesterol sterols during inhibition of cholesterol synthesis by statins, J Lab Clin Med, 2003;141:131–7.
  15. Miettinen TA, Gylling H, Synthesis and absorption markers of cholesterol in serum and lipoproteins during a large dose of statin treatment, Europ J Clin Invest, 2003;33:976–82.
  16. Pazzucconi F, Dorigotti F, Gianfranceschi G, et al., Therapy with HMG CoA reductase inhibitors: characteristics of the long-term permanence of hypocholesterolemic activity, Atherosclerosis, 1995;117:189–98.
  17. Farkkila M, Tilvis R, Miettinen T, Raised plasma cholesterol precursors in patients with gut resections, Gut, 1988;29:188–95.
  18. Sudhop T, Lutjohann D, Kodal A, et al., Intestinal Cholesterol Absorption by Ezetimibe in Humans, Circulation, 2002;106:1943–8.
  19. Vanhanen HT, Blomqvist S, Ehnholm C, et al., Serum cholesterol, cholesterol precursors and plant sterols in hypercholesterolemic subjects with different apoE phenotypes during dietary sitostanol ester treatment, J Lipid Res, 1993;34: 1535–44.
  20. Gylling H, Miettinen TA, Baseline intestinal absorption and synthesis of cholesterol regulate its response to hypolipidaemic treatments in coronary patients, Atherosclerosis, 2002;160:477–81.
  21. Gylling H, Miettinen TA, The effect of cholesterol absorption inhibition on low density lipoprotein cholesterol level, Atherosclerosis, 1995;117:305–8.
  22. Miettinen TA, Gylling H, Strandberg T, Sarna S, Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study, BMJ, 1998;316:1127–30.
  23. Ziajka PE, Reis M, Kreul S, King H, Initial low-density lipoprotein response to statin therapy predicts subsequent lowdensity lipoprotein response to the addition of ezetimibe, Am J Cardiol, 2004;93:779–80.
  24. Parker TS, McNamara DJ, Brown CD, et al., Plasma mevalonate as a measure of cholesterol synthesis in man, J Clin Invest, 1984;74:795–804.
  25. O’Neill FH, Patel DD, Knight BL, et al., Determinants of variable response to statin treatment in patients with refractory familial hypercholesterolemia, Arterioscler Thromb Vasc Biol, 2001;21:832–7.