Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Chapter 50

Prophylaxis of Coronary Heart Disease: Drugs That Help Normalize Cholesterol

and Triglyceride Levels

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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.

3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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)

4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Plasma Lipoproteins

Structure and function of lipoproteins Function Basic structure Apolipoproteins

• Recognition sites for cell-surface receptors• Activate enzymes that metabolize lipoproteins• Increase the structural stability of lipoproteins

5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Plasma Lipoproteins

Classes of lipoproteins Six major classes of plasma lipoproteins Three relevant to coronary atherosclerosis

• Very-low-density lipoproteins (VLDLs) Triglycerides

• Low-density lipoproteins (LDLs) Cholesterol primary core lipid Greatest contributor to coronary heart disease (CHD)

• High-density lipoproteins (HDLs) Cholesterol

6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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

7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Atherogenesis

More than just deposit of lipids Now considered primarily a chronic

inflammatory process Infiltration of macrophages, T lymphocytes,

and other inflammatory mediators

8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Detection, Evaluation, and Treatment of High Cholesterol

Cholesterol screening Every 5 years for adults over the age of 20 years Total cholesterol

• HDL cholesterol Less than 40 mg/dL: low to undesirable

• LDL cholesterol Less than 100 mg/dL: desirable

Triglycerides (TGs)

9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

CHD Risk Assessment

Factors in risk assessment Identifying CHD risk factors Calculating 10-year CHD risk Identifying CHD risk equivalents

• Diabetes• Atherosclerotic disease other than CHD• 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

10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Treatment of High-LDL Cholesterol

Therapeutic lifestyle changes (TLCs) Smoking cessation The TLC diet Exercise

11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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.

12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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

13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Treatment Goals for Metabolic Syndrome

Reduce the risk for atherosclerotic disease Reduce the risk for type 2 diabetes Increase physical activity

14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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

15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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

16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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

17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

HMG-CoA Reductase Inhibitors (Statins)

Adverse effects Common

• Headache• Rash• GI disturbances

Rare • Myopathy/rhabdomyolysis• Hepatotoxicity

18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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

19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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

20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Nicotinic Acid (Niacin)

Adverse effects Skin (flushing, itching)

• Intense flushing initially; can pretreat with aspirin• Decreased with SR version of niacin

Gastrointestinal Hepatotoxicity Hyperglycemia Gouty arthritis Can raise blood levels of uric acid

21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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

22Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Bile-Acid Sequestrants

Colesevelam (cont’d) Reduction in LDL cholesterol Increased VLDL levels in some patients Mechanism of action

• Increases LDL receptors on hepatocytes• Prevents reabsorption of bile acids

Therapeutic use• Reduces LDL cholesterol (in conjunction with modified

diet and exercise) Adverse effects

• Constipation

23Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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

24Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Ezetimibe

Adverse effects Myopathy Rhabdomyolysis Hepatitis Pancreatitis Thrombocytopenia

Drug interactions Statins Fibrates Bile-acid sequestrants Cyclosporine

25Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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)

26Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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

27Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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)

28Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Other Products Used to Alter Plasma Lipid Levels

Fenofibrate Fenofibric acid Drug combinations

Niacin/lovastatin Simvastatin/niacin, simvastatin/ezetimibe Pravastatin/aspirin Atorvastatin/amlodipine

29Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Other Products Used to Alter Plasma Lipid Levels

Lovaza Fish oil Plant stanol and sterol esters Estrogen Cholestin