hypolipidemic drugs. a. introduction over 93% of the fat that is consumed in the diet is in the form...

Hypolipidemic drugs

A. Introduction

• Over 93% of the fat that is consumed in the diet is in the form of triglycerides (TG).

• Dietary TGs are packaged by the liver into a lipoprotein known as very low density lipoprotein (VLDL).

• This lipoprotein delivers the TG to adipose tissue to be stored.

• Excess dietary carbohydrates are converted into triglycerides and also stored in adipose tissue.

• Dietary intake supplies only about 20 – 25% of the cholesterol needed everyday to build cell membranes,

• synthesize bile acids/salts,

• synthesize hormones of the adrenal glands (aldosterone, cortisol)

• and synthesize the sex hormones.

• The other 75 – 80% of our daily need for cholesterol is synthesized in the liver.

• The primary function of low density lipoprotein (LDL) is the transport of this cholesterol synthesized in the liver.

• As it travels through the circulation LDL reacts with LDL receptors on various nonhepatic cells.

• Once binding occurs, endocytosis brings the LDL complex inside the cell.

• A high dietary intake of saturated fat, as well as a genetic predisposition to synthesize LDL in the liver, results in elevated levels of LDL in the bloodstream.

• Dietary saturated fat in particular is one of the primary dietary determinants of hypercholesterolemia, as demonstrated by numerous studies (Keys et al, 1966; Wilson et al (The Framingham Study), 1980; Steinburg, 2004 and 2005).

• These studies illustrate the importance of substituting unsaturated fat for saturated fat in the diet.

• Saturated fats raise LDL cholesterol by decreasing the synthesis of LDL receptors.

• The genetic predisposition involves dysfunction of LDL receptors. An absence of LDL receptors is found in many individuals, so receptor deficiency may be both dietary and genetic.

• In some cases there is an LDL receptor, but a mutation alters the binding site in such a way that LDL is no longer able to bind to the cell.

• A third type of defect involves LDL binding to the receptor, but cannot be brought into the cell.

• The overall results are about the same, no matter which defect you consider, cholesterol is not removed from the circulation

• LDL cholesterol that does not react with a LDL receptor continues to circulate.

• It is able to penetrate injured endothelial cells that line artery walls.

• These cells are damaged by infections, smoking, diabetes, and high blood pressure.

• Injured endothelial cells become inflamed, resulting in the release of numerous inflammatory cytokines (TNF, interleukins, oxygen radicals).

• Macrophages adhere to injured endothelium via vascular cell adhesion molecules (VCAM) and release enzymes that create oxidative stress and oxidize LDL.

• The oxidation of LDL is an important step in atherogenesis as it activates further immune and inflammatory responses (i.e. entry of monocytes across endothelium).

• These monocytes differentiate into macrophages, which then engulf the LDL, becoming foam cells

• These LDL laden foam cells accumulate in significant amounts, forming lesions called fatty streaks.

• Once formed, fatty streaks produce more toxic oxygen radicals and cause immunologic and inflammatory changes (production of more cytokines) resulting in progressive damage to the vessel wall.

• It has been demonstrated by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) studies that coronary artery disease begins decades before clinical complications manifest, with 15 year olds often exhibiting early lesions.

• Generally, coronary artery disease doesn’t manifest clinically until thirty or more years later with the appearance of angina, coronary thrombosis and/or sudden death.

B. Risk factors for CAD

• Risk factors can be categorized as:

• conventional nonmodifiable

• conventional modifiable

• nontraditional

1. Conventional nonmodifiable risk factors for CAD include

• a. advanced age

•

• b. male gender or women after menopause

• c. family history of heart disease

2. Conventional modifiable risk factors for CAD include:

• a. hyperlipidemia

• b. hypertension

• c. cigarette smoking

• d. Type 2 diabetes and insulin resistance

• e. obesity, particularly central obesity

• f. sedentary life style

• g. atherogenic diet

• In individuals with known CAD, 80-90% will have the risk factors of smoking, diabetes, dyslipidemia or hypertension, and many people will have several of these risks

3. Nontraditional risk factors for CAD include

• a. increased serum markers for inflammation and thrombosis

• Of the numerous markers of inflammation that have been linked to an increase in CAD risk, C- reactive protein (CRP) has been explored in the greatest depth.

• CRP is a protein mostly synthesized in the liver, whose plasma concentration increases shortly after infarction as part of the systemic inflammatory response.

• CRP is an indirect measure of atherosclerotic plaque and is an important indicator of CAD risk.

• The high-sensitivity C-reactive protein (hs-CRP) test assesses the connection between high CRP levels and risk of cardiovascular disease.

• Low CV disease risk < 1.0 mg/L• Moderate CV disease risk 1.5 – 3.0 mg/L• High CV disease risk > 3 mg/L

b. hyperhomocysteinemia

• This occurs because of a genetic lack of the enzyme that breaks down homocysteine or because of a nutritional deficiency (folate, vitamin B12 and vitamin B6 ).

• In addition to vitamin deficiencies, several therapeutic drugs (methotrexate, theophylline, cyclosporine and most anticonvulsants)

• and chronic disease states (liver and renal disease, hypothyroidism and malignancies) can lead to moderate hyperhomocysteinemia.

• Studies have demonstrated that for every 5 μmol/L increase in homocysteine the risk for developing heart disease increases by 20%.

• Normal: 5 – 15 μmol/L• Moderate risk: 16 – 30 μmol/L• Intermediate risk: 31 – 100 μmol/L• Severe risk: > 100 μmol/L

• The mechanisms by which homocysteine contribute to CAD include:

• increased biosynthesis of cholesterol in the liver

• decreases in endogenous vasodilators (i.e. NO)

3. infection

• There is emerging evidence that infection may play a role in CAD risk. Studies have found that several microorganisms, especially Chlamydia pneumoneae and Helicobacter pylori are often present in atherosclerotic lesions.

C. Treatments

• The primary target of cholesterol-lowering therapy is LDL cholesterol.

• The reason for this is that research from experimental animals, laboratory investigations, epidemiology and genetic forms of hypercholesterolemia indicate that elevated LDL cholesterol is a major cause of CAD and that clinical trials show that LDL-lowering therapy reduces the risk for CAD.

• The American Heart Association provides a set of guidelines for fasting LDL levels, in mg/dl, and risk for heart disease:

• Optimal (reduced risk): < 100 • Near optimal/above optimal: 100 –

129 • Borderline high: 130 – 159 • High: 160 –

189 • Very high (highest increased risk): 190

• The American Heart Association provides a set of guidelines for fasting HDL levels, in mg/dl, and risk for heart disease:

• Low, heightened risk for heart disease: < 40 for men; < 50 for women

• Medium: 40 – 59

• Optimal: protective against heart disease: > 60

• In the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) the following classifications were given for Total cholesterol and triglycerides:

• Total cholesterol

• Desirable: < 200

• Borderline high: 200-239

• High: 240

• Triglyceride  

• Normal: < 150 mg/dL

• Borderline-high: 150 – 199 mg/dL

• High: 200 – 499 mg/dL

• Very high: 500 mg/dL or >

• There are 5 major categories of drugs used in the treatment of CAD.

1. HMG-CoA reductase inhibitors

• The HMG-CoA reductase inhibitors, or statins are a class of hypolipidemic agents that are competitive inhibitors of HMG-CoA reductase.

• HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate. This is the rate-limiting step in the synthesis of cholesterol by the liver.

• They are considered to be the most potent cholesterol-lowering agents, lowering LDL-cholesterol between 20–60%.

• They also lower triglycerides, lower CRP, and modestly raise HDL cholesterol (5-10%).

• The JUPITER trial, published in 11/2008 NEJM involved 18,000 people from 25 countries with average cholesterol levels but elevated CRP.

• They were randomized to receive either a statin (Crestor) or placebo.

• Those receiving the statin had a significant decrease in both their LDL cholesterol levels (which were not elevated to begin with) and their CRP levels.

• The statins include:

a. lovastatin (Mevacor, Altocor) Merck

• Lovastatin was the first statin approved by the FDA (August 1987).

•

• The dosage is 20-80 mg and should be taken in the evening with food. Typical results: a 25-40% reduction in LDL.

b. simvastatin (Zocor) Merck

• Simvastin was approved in the late 1980’s.

• The dosage is 20-80 mg and should be taken in the evening.

• Typical results: a 35-50% reduction in LDL.

• Simvastatin is highly lipophilic, and there tends to be more insomnia with the lipophilic statins (unknown mechanism).

c. pravastatin (Pravachol) Bristol Meyer Squibb

• Pravastatin was “discovered” in Japan in 1979, produced by a chemical modification of lovastatin.

• This involved a fermentation reaction performed by the bacterium Nocardia autotrophica.

• Pravastatin received FDA approval in 1991, and was introduced to the US market by Bristol-Myers Squibb.

• In terms of clinical trials, pravastatin is the most studied statin.

• The dosage is 20-80 mg and should be taken in the evening, with or without food.

• Typical results: a 20-35% reduction in LDL

• Pravastatin is less lipophilic than simvastatin and is also less likely to cause insomnia.

d. fluvastatin (Leschol) Novartis

• Fluvastatin received FDA approval in 1993.

• The dosage is 20-80 mg

• 20-35% reduction in LDL

e. atorvastatin (Lipitor) Pfizer

• Atorvastation received FDA approval in 1997 and by 2004 was the best selling drug in the world with sales of $10.9 billion.

• The dosage is 10-80 mg.

• Typical results: a 35-60% reduction in LDL

• One of the advantages of Lipitor is that it can be taken with or without food at any time of the day.

f. Rosuvastatin (Crestor) Astra Zeneca

• Crestor received FDA approval in August 2003, and since 2004 has been approved in 67 countries.

• The dosage is 5-40 mg.

• It may be taken with or without food any time of the day.

• Typical results: a 46-52% reduction in LDL

g. pitavastatin (Livalo)

• The “newest” statin in the U.S., receiving FDA approval in 8/2009.

• The dosage is 2 – 4 mg.

Adverse effects of statins elevated liver enzymes

• Within 6 weeks of the onset of statin therapy the patient should have a blood test to determine the concentration of the liver enzymes aspartate aminotransferase, AST (normal concentration is 0 – 35 U/L) and alanine transaminase, ALT(normal concentration is 4 – 36 U/L).

• Of these, the AST test is the most sensitive marker of the impact of statin therapy. If it is elevated more than 2-3 times the upper limit of normal, therapy should be terminated.

• A fatty liver is the most common cause of elevated AST and ALT in patients on statin therapy.

normal liver, fatty liver and cirrhosis

muscle pain

• The most commonly reported adverse effect with statin use is muscle pain. There is a serious, but rare complication associated with the breakdown of muscle proteins called rhabdomyolysis.

• These muscle proteins, especially myoglobin, are released into the circulation, and result in the potentially life-threatening complications of myoglobinuric acute renal failure and cardiac arrest.

• The most common symptoms of rhabdomyolysis include: dark urine (typically brown);

• swollen, tender muscles of the thighs, calves, and lower back.

• Creatine phosphokinase (CPK) elevation is one of the most important diagnostic criteria of rhabdomyolysis. A value above the upper limit of normal (range of 30 – 200 U/ L), indicates a problem.

GI problems

• Common GI problems with statin therapy, which generally resolve within a couple of weeks of initiating therapy include: nausea, diarrhea, constipation, excessive flatulence.

Other effects

• Headache, dizziness, taste alterations, insomnia, and photosensitivity are other reported effects.

2. Bile acid sequestrants

• Bile acid sequestrants are a group of medications which bind bile in the GI tract. By binding bile they prevent its reabsorption, increasing its removal.

• As the body loses bile acids, it converts cholesterol into bile acids, thus lowering serum cholesterol levels.

• Use of these agents has declined since the introduction of the statins. They require very large doses and need to be taken with lots of water.

• They are most often used as an adjunct to statins.

• Results are generally seen within 3-4 weeks of initiating treatment, and include a lowering of LDL (generally, no more than 20%) and a very slight elevation of HDL.

• The bile acid sequestrants include:

a. cholestyramine ( LoCHOLEST, Prevalite, Questran)

• This is the major drug in this class.

• The usual dosage of this powder is 4 - 6 g, mixed with a liquid, twice a day before meals.

• No more than 24 g/day

b. colesevelam (Welchol)

• The dosage is three 625 mg tablets, twice daily, so 6 tablets/day.

c. colestipol (Colestid)

• Dosage, if granules is 5 g, one or two times daily

• Tablets, 2 – 4 g/day, tablets are 1 g each.

adverse effects of the bile acid sequestrants

• These adverse effects are generally GI related and usually dissipate within a couple of weeks.

• They include: nausea, vomiting, heartburn, bloating, constipation (most common), flatulence, fecal impaction, fatty or black stools, and intestinal obstruction (most severe).

• Transient increases in AST, ALT and alkaline phosphatase have been observed in patients on Colestipol.

3. cholesterol absorption inhibitors

• These drugs block dietary absorption of dietary cholesterol in the small intestine, which reduces LDL cholesterol levels.

• A cholesterol inhibitor alone will generally reduce LDL between 10 – 20%. They include:

a. ezetimibe (Zetia)

• The dosage is 10 mg, once daily

•

• Adverse effects include: fatigue, coughing, nausea, diarrhea, rash, pancreatitis and angioedema.

b. ezetimibe in combination with simvastatin (Vytorin)

• This is available as 10 mg ezetimibe with either 10, 20, 40, or 80 mg of simvastatin

•

• Adverse effects include those for ezetimibe, as well as the statin adverse effects.

4. Fibrates

• The primary actions of this class of drugs is to lower triglyceride levels.

• This occurs through stimulation of lipoprotein lipase (which hydrolyzes triglycerides) and by suppression of apoprotein C-III production (this is the protein component of VLDL, the primary carrier of triglycerides from the liver to other tissues).

• These drugs were first introduced in 1962 and were widely used before the discovery of the statins.

a. gemfibrozil (Lopid)

• Dosage is 600 mg, bid at least 30 minutes before eating

b. fenofibrate (Antara, Lofibra, Tricor, Triglide)

• Antara dosage is 43 – 130 mg/day

• Lofibra dosage is 67 – 200 mg/day

• Tricor dosage is 48 – 145 mg/day

• Triglide dosage is 50 – 160 mg/day

adverse effects of fibrates

• These include GI disturbances (nausea, vomiting, diarrhea, flatulence).

• In addition, dizziness, blurred vision, muscle pain and weakness have been reported.

• Some patients taking gemfibrozil have reported gallstone formation.

• Combination therapy of gemfibrozil and a statin may be associated with an increased risk of rhabdomyolisis, according to the Committee on Safety of Medicines.

• Fenofibrate may be given with a statin, but only if statin monotherapy is insufficient (very high LDL AND very high triglycerides).

• The efficacy and safety of using a statin and a fibrate together is currently being investigated in the ACCORD trial, due to be completed by 2010.

5. Niacin (Nicotinic acid)

• Niacin is indicated for patients with very high triglycerides(> 500) who present a risk of acute pancreatitis and don’t respond to dietary control.

• This class of drugs lowers triglyceride levels by inhibiting the release of fatty acids from adipose tissue and by suppression of apoprotein C-III production in the liver.

• Dosage: 100 – 500 mg/day, increase up to 1 – 2 g tid

• Adverse effects include GI disturbances, itching, headache and flushing of the face and neck (seen in over 90% of patients).

•