1. Prophylaxis of Coronary Heart Disease: Drugs That Help Normalize Cholesterol and Triglyceride Levels

2. Prophylaxis of Coronary Heart Disease (CHD)  Cholesterol  Plasma lipoproteins  Role of LDL cholesterol in atherosclerosis  Detection, evaluation, and treatment of high cholesterol: recommendations from ATP III  Drugs and other products used to improve plasma lipid levels ATP = Adult Treatment Panel; LDL = low-density lipoprotein.

3. Cholesterol  Component of all cell membranes and membranes of intracellular organelles  Required for synthesis of certain hormones and bile salts  Deposited in stratum corneum of the skin  Comes from dietary sources  Manufactured by cells, primarily in the liver  Increased dietary cholesterol produces only a small increase in cholesterol in the blood (inhibits endogenous cholesterol production)

4. Plasma Lipoproteins  Structure and function of lipoproteins  Function  Basic structure  Apolipoproteins Recognition sites for cell-surface receptors Recognition sites for cell-surface receptors Activate enzymes that metabolize lipoproteins Activate enzymes that metabolize lipoproteins Increase the structural stability of lipoproteins Increase the structural stability of lipoproteins

5. Plasma Lipoproteins  Classes of lipoproteins  Six major classes of plasma lipoproteins  Three relevant to coronary atherosclerosis Very-low-density lipoproteins (VLDLs) Very-low-density lipoproteins (VLDLs)  Triglycerides Low-density lipoproteins (LDLs) Low-density lipoproteins (LDLs)  Cholesterol primary core lipid  Greatest contributor to coronary heart disease (CHD) High-density lipoproteins (HDLs) High-density lipoproteins (HDLs)  Cholesterol

6. Role of LDL Cholesterol in Atherosclerosis  LDLs initiate and fuel development of atherosclerosis  Process begins with transport of LDLs from the arterial lumen into endothelial cells, then into the space underlying the arterial epithelium

7. Atherogenesis  More than just deposit of lipids  Now considered primarily a chronic inflammatory process  Infiltration of macrophages, T lymphocytes, and other inflammatory mediators

8. Detection, Evaluation, and Treatment of High Cholesterol  Cholesterol screening  Every 5 years for adults over the age of 20 years  Total cholesterol HDL cholesterol HDL cholesterol  Less than 40 mg/dL: low to undesirable LDL cholesterol LDL cholesterol  Less than 100 mg/dL: desirable  Triglycerides (TGs)

9. CHD Risk Assessment  Factors in risk assessment  Identifying CHD risk factors  Calculating 10-year CHD risk  Identifying CHD risk equivalents Diabetes Diabetes Atherosclerotic disease other than CHD Atherosclerotic disease other than CHD Framingham risk score greater than 20% Framingham risk score greater than 20%  Identifying an individual’s CHD risk category Each type of dyslipidemia a patient has contributes independently to CHD risk Each type of dyslipidemia a patient has contributes independently to CHD risk

10. Treatment of High-LDL Cholesterol  Therapeutic lifestyle changes (TLCs)  Smoking cessation  The TLC diet  Exercise

11. Drug Therapy: Not First-Line Therapy  Drugs should be used only if TLCs fail  HMG-CoA reductase inhibitors  Bile-acid sequestrants  Nicotinic acid (niacin)  Fibrates (reduce levels of TGs, not LDLs) HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A.

12. Secondary Treatment Targets  Metabolic syndrome  High blood glucose  High triglycerides  High apolipoprotein B  Low high-density lipoprotein (HDL)  Small LDL particles  Prothrombotic state  Proinflammatory state  Hypertension  High triglycerides  Levels above 150 mg/dL

13. Treatment Goals for Metabolic Syndrome  Reduce the risk for atherosclerotic disease  Reduce the risk for type 2 diabetes  Increase physical activity

14. Drugs and Other Products to Alter Plasma Lipid Levels  High LDL: contributes most to cardiovascular disease  Also consider  High total cholesterol  Low HDL cholesterol  High triglycerides  Drugs can improve lipid profiles, but not all improve clinical outcomes

15. HMG-CoA Reductase Inhibitors (Statins)  Most effective drugs for lowering LDL  Reduction of LDL cholesterol  Elevation of HDL cholesterol  Reduction of triglyceride levels  Nonlipid beneficial cardiovascular actions  Promote plaque stability  Reduce the risk for cardiovascular (CV) events  Increased bone formation

16. HMG-CoA Reductase Inhibitors (Statins)  Mechanism of cholesterol reduction  Clinical trials  Therapeutic uses  Hypercholesterolemia  Primary and secondary prevention of CV events  Post-MI therapy  Diabetes  Potential uses

17. HMG-CoA Reductase Inhibitors (Statins)  Adverse effects  Common Headache Headache Rash Rash GI disturbances GI disturbances  Rare Myopathy/rhabdomyolysis Myopathy/rhabdomyolysis Hepatotoxicity Hepatotoxicity

18. HMG-CoA Reductase Inhibitor (Statins)  Drug interactions  Most other lipid-lowering drugs (except bile acid sequestrants)  Drugs that inhibit CYP3A4  Use in pregnancy  Dosing should be once daily in the evening  Endogenous cholesterol synthesis increases during the night  Statins have greatest impact when given in the evening

19. Nicotinic Acid (Niacin)  Reduces LDL and TG levels  Increases HDL levels more effectively than any other drug  Effect on plasma lipoproteins  Lowering TG levels  Raising HDL cholesterol

20. Nicotinic Acid (Niacin)  Adverse effects  Skin (flushing, itching) Intense flushing initially; can pretreat with aspirin Intense flushing initially; can pretreat with aspirin Decreased with SR version of niacin Decreased with SR version of niacin  Gastrointestinal  Hepatotoxicity  Hyperglycemia  Gouty arthritis  Can raise blood levels of uric acid

21. Bile-Acid Sequestrants  Previously were first-line drugs  Now primarily used as adjuncts to statins  Cholestyramine  Colestipol  Colesevelam  Newest and better-tolerated drug  Does not decrease uptake of fat-soluble vitamins (as other bile sequestrants do)  Does not significantly reduce the absorption of statins, warfarin, digoxin, and most other drugs studied

22. Bile-Acid Sequestrants  Colesevelam (cont’d)  Reduction in LDL cholesterol  Increased VLDL levels in some patients  Mechanism of action Increases LDL receptors on hepatocytes Increases LDL receptors on hepatocytes Prevents reabsorption of bile acids Prevents reabsorption of bile acids  Therapeutic use Reduces LDL cholesterol (in conjunction with modified diet and exercise) Reduces LDL cholesterol (in conjunction with modified diet and exercise)  Adverse effects Constipation Constipation

23. Ezetimibe  Mechanism of action and impact on plasma lipids  Inhibits cholesterol absorption  Therapeutic use  Reduces total cholesterol, LDL cholesterol, and apolipoprotein B  Approved for monotherapy and combined use with statins

24. Ezetimibe  Adverse effects  Myopathy  Rhabdomyolysis  Hepatitis  Pancreatitis  Thrombocytopenia  Drug interactions  Statins  Fibrates  Bile-acid sequestrants  Cyclosporine

25. Fibric Acid Derivatives (Fibrates)  Most effective drugs available for lowering TG levels  Can raise HDL cholesterol  Little or no effect on LDL cholesterol  Can increase the risk for bleeding in patients on warfarin  Can increase the risk for rhabdomyolysis in patients taking statins  Three drugs in the United States  Gemfibrozil (Lopid)  Fenofibrate (Tricor, others)  Fenofibric acid (TriLipix)

26. Gemfibrozil  Effects on plasma lipoproteins  Decreases plasma TG content  Lowers VLDL levels  Can raise HDL cholesterol  Mechanism  Appears to interact with a specific receptor subtype (PPAR alpha)  Drug interactions  Displaces warfarin from plasma albumin  Measure INR frequently

27. Gemfibrozil  Therapeutic uses  Reduces high levels of plasma triglycerides (VLDLs)  Treatment reserved for patients who have not responded to diet modification  Less effective than statins in reducing LDL  Can raise HDL (not approved for this use)  Adverse effects  Rashes  Gastrointestinal disturbances  Gallstones  Myopathy  Liver injury (hepatotoxic)

28. Other Products Used to Alter Plasma Lipid Levels  Fenofibrate  Fenofibric acid  Drug combinations  Niacin/lovastatin  Simvastatin/niacin, simvastatin/ezetimibe  Pravastatin/aspirin  Atorvastatin/amlodipine

29. Other Products Used to Alter Plasma Lipid Levels  Lovaza  Fish oil  Plant stanol and sterol esters  Estrogen  Cholestin