PPM2 Lipid Lowering Agents

“Three new drugs for hyperlipidemia.” The Medical Letter. Vol. 45, #1151. (March 3, 2003) pp. 17-19.

For patients with known cardiovascular disease (secondary prevention), cholesterol lowering leads to a reduction in total mortality in men and women and in middle-aged patients and older patients. Among patients without cardiovascular disease (primary prevention), the data are less conclusive, with heart disease mortality and all-cause mortality differing among studies. Nonetheless, treatment algorithms have been designed to assist clinicians in selecting patients for cholesterol-lowering therapy based on their lipid levels and their overall risk of developing cardiovascular disease.

The two main lipids in blood are cholesterol and triglyceride. They are carried in lipoproteins, globular particles that also contain proteins known as apoproteins. Cholesterol is an essential element of all animal cell membranes and forms the backbone of steroid hormones and bile acids; triglycerides are important in transferring energy from food into cells. Why lipids are deposited into the walls of large and medium-sized arteries—an event with potentially lethal consequences—is not known.

Lipoproteins are usually classified on the basis of density, which is determined by the amounts of triglyceride (which makes them less dense) and apoproteins (which makes them more dense). The least dense particles, known as chylomicrons, are normally found in the blood only after fat-containing foods have been eaten. They rise as a creamy layer when nonfasting serum is allowed to stand. The other lipoproteins are suspended in serum and must be separated using a centrifuge. The densest (and smallest) family of particles consists mainly of apoproteins and cholesterol and are called high-density lipoproteins (HDL). Somewhat less dense are the low-density lipoproteins (LDL). Least dense are the large, very-low-density lipoproteins (VLDL), consisting mainly of triglyceride. In fasting serum, most of the cholesterol is carried on LDL particles and is therefore referred to as LDL cholesterol; most of the triglyceride is found in VLDL particles. Specific apoproteins are associated with each lipoprotein class.

Chylomicrons are made in the gut and travel via the portal vein into the liver and via the thoracic duct into the circulation. They are normally completely metabolized, transferring energy from food into muscle and fat cells. The liver manufactures VLDL particles from its own stores of fat and carbohydrate. VLDL particles transfer triglyceride to cells; after losing enough, they eventually become LDL particles, which provide cholesterol for cellular needs. Excess LDL particles are taken up by the liver, and the cholesterol they contain is then excreted into the bile. HDL particles are made in the liver and intestine and appear to facilitate the transfer of apoproteins among lipoproteins. They also participate in reverse cholesterol transport, either by transferring cholesterol into other lipoproteins or directly into the liver.

The plaques in the arterial walls of patients with atherosclerosis contain large amounts of cholesterol. The higher the level of LDL cholesterol, the greater the risk of atherosclerotic heart disease; conversely, the higher the HDL cholesterol, the lower the risk of coronary heart disease (CHD). This is true in men and women, in different racial and ethnic groups, and at all ages up to age 75. Because most cholesterol in serum is LDL, high total cholesterol levels are also associated with an increased risk of CHD. Middle-aged men whose serum cholesterol levels are in the highest quintile for age (above about 230 mg/dL) have a risk of coronary death before age 65 of about 10%; men in the lowest quintile (below about 170 mg/dL) have a 3% risk. Death from CHD before age 65 is less common in women, with equivalent risks one-third those of men. In men, each 10-mg/dL increase in cholesterol (or LDL cholesterol) increases the risk of CHD by about 10%; each 5-mg/dL increase in HDL reduces the risk by about 10%. The effect of HDL cholesterol is greater in women, whereas the effects of total and LDL cholesterol are smaller. All of these relationships diminish with age.

The exact mechanism by which LDL particles result in the formation of atherosclerotic plaques—or the means whereby HDL particles protect against their formation—is not known. The model of LDL carrying cholesterol into the walls of arteries with HDL removing it is simple but not established. The natural oxidation of LDL particles may be particularly atherogenic. Receptors on the surface of macrophages within atherosclerotic plaques bind and accumulate oxidized LDL. The formation of antibodies to oxidized LDL may also be important in plaque formation. The size of the LDL molecule may also influence atherogenesis; at the same LDL concentrations, individuals with large numbers of smaller particles appear to be at higher risk for CHD.

The relationship of VLDL cholesterol to atherogenesis is less certain. The number, size, or subtype of VLDL particles—in addition to the total amount in serum—may be important. In addition, HDL and VLDL levels are inversely related. Patients with a high VLDL level are likely to have a low HDL level and thus be at increased risk for CHD for that reason alone.

There are several genetic disorders that provide insight into the pathogenesis of lipid-related diseases. Most important—but rare in the homozygous state (about one per million)—is a condition in which the cell-surface receptors for the LDL molecule are absent or defective, familial hypercholesterolemia, resulting in unregulated synthesis of LDL. Patients with two abnormal genes (homozygotes) have extremely high levels—up to eight times normal—and present with atherosclerotic disease in childhood. Homozygotes may require liver transplantation to correct their severe lipid abnormalities. Those with one defective gene (heterozygotes) have LDL concentrations twice normal; persons with this condition may develop CHD in their 30s or 40s.

Another rare condition is caused by an abnormality of lipoprotein lipase, the enzyme that enables peripheral tissues to take up triglyceride from chylomicrons and VLDL particles. Patients with this condition, one cause of familial hyperchylomicronemia, have marked hypertriglyceridemia with recurrent pancreatitis and hepatosplenomegaly in childhood.

Numerous other genetic abnormalities of lipid metabolism are named for the abnormality noted when serum is electrophoresed (eg, dysbetalipoproteinemia) or from combinations of lipid abnormalities in families (eg, familial combined hyperlipidemia). Thus, family members of patients with severe lipid disorders are appropriately studied. Other patients have abnormalities in the production of apoproteins, such as increased apoprotein B and its affiliated lipoproteins, LDL and VLDL; reduced apoprotein AII and its affiliated particle; or excess lipoprotein(a). Other mutations occur in lipoprotein lipase and in the gene encoding for cholesterol efflux regulatory protein.

In fasting serum, cholesterol is carried primarily on three different lipoproteins—the VLDL, LDL, and HDL molecules. Total cholesterol equals the sum of these three components:

Most clinical laboratories measure the total cholesterol, the total triglycerides, and the amount of cholesterol found in the HDL fraction, which is easily precipitated from serum. Most triglyceride is found in VLDL particles, which contain five times as much triglyceride by weight as cholesterol. The amount of cholesterol found in the VLDL fraction can be estimated by dividing the triglyceride by 5:

Because the triglyceride level is used as a proxy for the amount of VLDL, this formula only works in fasting samples. Furthermore, it only works when the triglyceride level is less than 400-500 mg/dL. At higher triglyceride levels, LDL and VLDL cholesterol levels can be determined after ultracentrifugation or by direct chemical measurement.

The total cholesterol is reasonably stable over time; however, measurements of HDL and especially triglycerides may vary considerably because of analytic error in the laboratory and biologic variation in a patient's lipid level. Thus, the LDL should always be estimated as the mean of at least two determinations; if those two estimates differ by more than 10%, a third lipid profile is obtained and is estimated as follows:

Understanding the relationships of the different lipid fractions leads to a more accurate understanding of a patient's lipid-related coronary risk than the total cholesterol. Two persons with the same total cholesterol of 275 mg/dL may have very different lipid profiles. One may have an HDL cholesterol of 110 mg/dL with a triglyceride of 150 mg/dL, giving an estimated LDL cholesterol of 135 mg/dL; the other may have an HDL cholesterol of 25 mg/dL with a triglyceride of 200 mg/dL and an LDL cholesterol of 210 mg/dL. The second would have more than a tenfold higher CHD risk than the first, assuming no differences in other factors. Because of high HDL cholesterol levels in women, many with apparently high total cholesterol levels have favorable lipid profiles. Thus, evaluation of the lipid fractions is essential before therapy is initiated.

Some authorities use the ratio of the total to HDL cholesterol as an indicator of lipid-related coronary risk: the lower this ratio is, the better. (In the example above, the first person would have a ratio of 275 ÷ 110 = 2.5, while the second would have a much less favorable ratio of 275 ÷ 25 = 11.) Although ratios are useful predictors within populations of patients, they may obscure important information in individual patients. (A total cholesterol of 300 mg/dL and an HDL of 60 mg/dL results in the same ratio of 5 as a total cholesterol of 150 mg/dL with an HDL of 30 mg/dL.) Moreover, errors in the measurement of HDL cholesterol are common in many laboratories, and the total cholesterol-to-HDL cholesterol ratio magnifies their importance.

There is no true "normal" range for serum lipids. In Western populations, cholesterol values are about 20% higher than in Asian populations and exceed 300 mg/dL in nearly 5% of adults. About 10% of adults have LDL cholesterol levels above 200 mg/dL. Total and LDL cholesterol levels tend to rise with age in persons who are otherwise in good health.

Declines are seen in acute illness, and lipid studies in such patients are of little value with the exception of the serum triglyceride level in a patient with pancreatitis. Cholesterol levels (even when expressed as an age-matched percentile rank, such as the highest 20%) do not remain constant over time, especially from childhood through adolescence and young adulthood. Thus, children and young adults with relatively high cholesterol may have lower levels later in life, whereas those with low cholesterol may show increases.

Most studies of the effect of cholesterol lowering have distinguished between primary and secondary prevention. The important distinction is that primary prevention trials enroll healthy subjects who have relatively low rates of coronary disease but in whom other causes of morbidity and mortality are proportionately more common. Secondary prevention trials, on the other hand, follow patients who have a high rate of subsequent coronary disease; other causes of mortality are relatively less important.

Reducing cholesterol levels in healthy middle-aged men without CHD (primary prevention) reduces their risk in proportion to the reduction in LDL cholesterol and the increase in HDL cholesterol. Treated patients have statistically significant and clinically important reductions in the rates of myocardial infarctions, new cases of angina, and need for coronary artery bypass procedures. The West of Scotland Study showed a 31% decrease in myocardial infarctions in middle-aged men treated with pravastatin compared with placebo. The AFCAPS/TexCAPS study showed similar results with lovastatin. As with any primary prevention interventions, large numbers of healthy patients need to be treated to prevent a single event. The numbers of patients needed to treat (NNT) to prevent a nonfatal myocardial infarction or a coronary artery disease death in these two studies were 46 and 50, respectively.

Primary prevention studies have found a less consistent effect on total mortality. Although the West of Scotland study found a 20% decrease in total mortality, tending toward statistical significance, the AFCAPS/TexCAPS study with lovastatin showed no difference in total mortality. The recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) also showed no reduction either in all-cause mortality or in CHD events when pravastatin was compared with usual care.

In patients with CHD, the benefits of cholesterol lowering are more clear. Major studies with statins have shown significant reductions in cardiovascular events, cardiovascular deaths, and all-cause mortality in men and women with coronary artery disease. The numbers of patients needed to treat (NNT) to prevent a nonfatal myocardial infarction or a coronary artery disease death in these three studies were between 12 and 34. Aggressive cholesterol lowering with these agents causes regression of atherosclerotic plaques in some patients, reduces the progression of atherosclerosis in saphenous vein grafts, and can slow or reverse carotid artery atherosclerosis. Meta-analysis suggests that this latter effect results in a significant decrease in strokes. Results with other classes of medications have been less consistent. For example, gemfibrozil treatment subjects had fewer cardiovascular events, but there was no benefit in all-cause mortality when compared with placebo.

The disparities in results between primary and secondary prevention studies highlight several important points. The benefits and adverse effects of cholesterol lowering appear to be specific to each type of drug; the clinician cannot assume that the effects will generalize to other classes of medication. Second, the net benefits from cholesterol lowering depend upon the underlying risk of CHD and of other disease. In patients with atherosclerosis, morbidity and mortality rates associated with CHD are high, and measures that reduce it are more likely to be beneficial even if they have no effect—or even slightly harmful effects—on other diseases. Third, the full effects of cholesterol lowering in women and in older and younger men are uncertain.

Role of cholesterol – Hypercholesterolemia contributes to the pathogenesis of atherosclerosis and has been causally associated with CAD and other atherosclerotic vascular diseases. Oxidized cholesterol accumulates in and around macrophages (foam cells) and muscle cells that have proliferated following damage to the endothelium.

HDL’s – serve to transport cholesterol from atheromas and peripheral tissues to the liver. “reverse cholesterol transport”.

LDL’s – high cholesterol concentration, transport this cholesterol to nascent atheromas and contribute to the development of atherosclerosis.

Cholesterol is a steroid that circulates in the blood stream bound to proteins of various densities (Stedman’s 27^th ed. Pg 340) When cholesterol is transported on LDL it can be picked up by atheromas (which are oxidized cholesterol that adheres to damaged endothelial lining). HDL is a carrier lipoprotein that actually attracts cholesterol from atheromas and other peripheral tissue and transports it back to the liver. Therefore LDL contributes to plaque formation and HDL helps to prevent it.

A) Lipoproteins- Lipids are insoluable in serum and must be transported by proteins. These proteins that bind to lipids and solubalize them for serum transport are collectively called Lipoproteins.

1. Chylomicrons- transport dietary lipids from the gut to the adipose tissue and liver

2. LDL- these transport cholesterol to peripheral tissues for incorporation into cell membranes and steroids

3. HDL- these are small lipoproteins that are secreted by the gut and liver and transport cholesterol from

B) The plaques in arterial walls of patients with atherosclerosis contain large amounts of cholesterol.

3. High total cholesterol levels are also associated with increased risk of atherosclerotic disease

Patients with very high levels of serum triglycerides are at risk of pancreatitis. The pathophysiology is not certain, since some patients with very high levels never develop pancreatitis. Most patients with congenital abnormalities in triglyceride metabolism present in childhood; hypertriglyceridemia-induced pancreatitis first presenting in adults is more commonly due to an acquired problem in lipid metabolism.

Although there are no clear triglyceride levels that predict pancreatitis, most clinicians are uncomfortable with fasting levels above 500 mg/dL. The risk of pancreatitis may be more related to the triglyceride level following consumption of a fatty meal. Because postprandial increases in triglyceride are inevitable if fat-containing foods are eaten, fasting triglyceride levels in persons prone to pancreatitis should be kept well below that level.

The primary therapy for high triglyceride levels is dietary, avoiding alcohol and fatty foods and restricting calories. Control of secondary causes of high triglyceride levels (see Table 28-1) may also be helpful. In patients with fasting triglycerides ≥ 500 mg/dL despite adequate dietary compliance—and certainly in those with a previous episode of pancreatitis—therapy with a triglyceride-lowering drug (eg, niacin, a fibric acid derivative, or an HMG-CoA reductase inhibitor) is indicated.

Whether patients with elevated triglycerides (> 150 mg/dL) should be treated to prevent CHD is not known. Meta-analysis of 17 observational studies suggests that after adjustment for other risk factors, elevated triglycerides increased CHD risk in men by 14% and in women by 37%. Triglyceride-rich lipoproteins (partially degraded VLDL, commonly called remnant lipoproteins) have been found in human atheromas, and elevated triglycerides are associated with small dense LDL in most instances. Elevated triglycerides are also an important feature of the metabolic syndrome, found in an estimated 25% of Americans—defined by three or more of the following five abnormalities: waist circumference > 102 cm in men or > 88 cm in women, serum triglyceride level of at least 150 mg/dL, HDL level of < 40 mg/dL in men or < 50 mg/dL in women, blood pressure of at least 130/85 mm Hg, and serum glucose level of at least 110 mg/dL. Other data, however, suggest that triglyceride measurements do not improve discrimination between those with and without CHD events, and clinical trial data are not available to support the routine treatment of high triglycerides in all patients.

The recent NCEP Adult Treatment Panel III (ATP III) report, however, recommends an aggressive approach to triglyceride management. For those with borderline levels (150-199 mg/dL), emphasis is placed on calorie restriction and exercise. For patients with high triglycerides (> 200 mg/dL), the non-HDL cholesterol should be measured (total cholesterol - HDL cholesterol). The ATP III report recommends that non-HDL cholesterol should be treated with diet and medications to result in levels 30 mg/dL higher than the LDL goal. The ATP III report does not differentiate between primary and secondary prevention. A reasonable approach might be to use this approach for patients with CHD and risk equivalents for that disease but not for lower-risk patients.

The pathology is uncertain, since some pts with very high levels never develop pancreatitis.

Hypertriglyceridemia is associated with pancreatitis and is also believed to have a role in the development of atherosclerosis and heart disease in some patients, although its role in CV disorders appears to be less significant than that of hypercholesterolemia.

Breakdown of large amounts of triglycerides could result in a cytotoxic level of free fatty acids triggering acute pancreatitis.

A) Familial Hyperchylomicronemia- patients have marked hypertriglyceridemia with recurrent pancreatitis and hepatosplenomegaly in childhood.

3. State the national treatment guideline values for total cholesterol and LDL cholesterol.

Table 28-2. Framingham 10-year coronary heart disease risk projections. Calculate the number of points for each risk factor. Sum the total risk score and estimate the 10-year risk.¹

MEN
Age	Points
20-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79	-9 -4 0 3 6 8 10 11 12 13

	Points
Total Cholesterol	Age 20-39	Age 40-49	Age 50-59	Age 60-69	Age 70-79
< 160 160-199 200-239 240-279 ≥ 280	0 4 7 9 11	0 3 5 6 8	0 2 3 4 5	0 1 1 2 3	0 0 0 1 1

	Points
Age	20-39	40-49	50-59	60-69	70-79
Nonsmoker Smoker	0 8	0 5	0 3	0 1	0 1

HDL (mg/dL)	Points
≥ 60 50-59 40-49 < 40	-1 0 1 2

Systolic BP (mm Hg)	Points if Untreated	Points if Treated
< 120 120-129 130-139 140-159 ≥ 160	0 0 1 1 2	0 1 2 2 3

MEN
Point Total	10-Year Risk %
< 0	< 1
0	1
1	1
2	1
3	1
4	1
5	2
6	2
7	3
8	4
9	5
10	6
11	8
12	10
13	12
14	16
15	20
16	25
≥ 17	≥ 30
	_____% Ten-Year risk

WOMEN
Age	Points
20-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79	-7 -3 0 3 6 8 10 12 14 16

	Points
Total Cholesterol	Age 20-39	Age 40-49	Age 50-59	Age 60-69	Age 70-79
< 160 160-199 200-239 240-279 ≥ 280	0 4 8 11 13	0 3 6 8 10	0 2 4 5 7	0 1 2 3 4	0 1 1 2 2


Age	20-39	40-49	50-59	60-69	70-79
Nonsmoker Smoker	0 9	0 7	0 4	0 2	0 1

HDL (mg/dL)	Points
≥ 60 50-59 40-49 < 40	-1 0 1 2

Systolic BP (mm Hg)	Points if Untreated	Points if Treated
< 120 120-129 130-139 140-159 ≥ 160	0 1 2 3 4	0 3 4 5 6

WOMEN
Point Total	10-Year Risk %
< 9	< 1
9	1
10	1
11	1
12	1
13	2
14	2
15	3
16	4
17	5
18	6
19	8
20	11
21	14
22	17
23	22
24	27
≥ 25	≥ 30

	_____% Ten-Year risk

¹Reproduced, with permission, from Executive Summary of the third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486. http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm

There are new guidelines that have just come out last week, so let’s see what comes out of our lecture.

Tx consists of instituting dietary restrictions and changes (Dmod) with or without drug therapy and is based on lipid levels and risk factors for heart disease.

With risk factors: Dmod, decrease risk factors, repeat lipid measurements in 1-5 years

With risk factors: Dmod, reduce risk factors, consider drug Tx, repeat lipid measurements prn

No risk factors: Dmod, institute drug Tx if LDL exceeds 190, repeat lipid measurements prn

With risk factors: Dmod, reduce risk factors, institute drug Tx, repeat lipid measurements prn

4. Describe general principles of dietary and lifestyle modification in a patient with hyperlipidemia.

Studies of nonhospitalized adults have reported only modest cholesterol-lowering benefits of dietary therapy, typically in the range of a 5-10% decrease in LDL cholesterol, with even less in the long term. The effect of diet therapy, however, varies considerably among individuals, as some patients will have striking reductions in LDL cholesterol—up to a 25-30% decrease—while others will have clinically important increases. Thus, the results of diet therapy should be assessed about 4 weeks after initiation.

Cholesterol-lowering diets may also have a variable effect on lipid fractions. Diets very low in total fat or in saturated fat may lower HDL cholesterol as much as LDL cholesterol. It is not known how these diet-induced changes affect coronary risk.

Several nutritional approaches to diet therapy are available. Most Americans currently eat over 35% of calories as fat, of which 15% is saturated fat. Dietary cholesterol intake averages 400 mg/d. A cholesterol-lowering diet recommends reducing total fat to 25-30% and saturated fat to less than 7% of calories. Dietary cholesterol should be limited to less than 200 mg/d. These diets replace fat, particularly saturated fat, with carbohydrate. In most instances, this approach will also result in fewer total calories consumed and will facilitate weight loss in overweight patients. Other diet plans, including the Dean Ornish Diet, the Pritikin Diet, and most vegetarian diets, restrict fat even further. Low-fat, high-carbohydrate diets may, however, result in reductions in HDL cholesterol.

An alternative strategy is the "Mediterranean diet," which maintains total fat at approximately 35-40% of total calories but replaces saturated fat with monounsaturated fat such as that found in canola oil and in olives, peanuts, avocados, and their oils. This diet is equally effective at lowering LDL cholesterol but is less likely to lead to reductions in HDL cholesterol. This diet is less likely to lead to weight loss. Thus, a traditional low-fat approach is still preferred for patients with lipid disorders who are overweight.

Other dietary changes may also result in beneficial changes in blood lipids. Soluble fiber, such as that found in oat bran or psyllium, may reduce LDL cholesterol by 5-10%. Garlic, soy protein, vitamin C, pecans, and plant sterols may also result in reduction of LDL cholesterol. Because oxidation of LDL cholesterol is a potential initiating event in atherogenesis, diets rich in antioxidant vitamins, found primarily in fruits and vegetables, may be helpful (see Chapter 29).

Dietary modifications are the cornerstone of treatment for hyperlipidemia and may be effective by themselves in pts with mildly elevated cholesterol or triglyceride levels.

Even more severe restrictions may be considered in pts with multiple risk factors or angiographic evidence of CAD.

… supplementing the diet with fish oils that contain omega-3 fatty acids may be useful in lowering triglyceride levels.

Dietary modifications are the cornerstone for hyperlipidemia treatment and may be effective by themselves in pt with mildly elevated cholesterol or triglycerides levels. Diet should be low in cholesterol, saturated fats and calories. Cholesterol should be <200 mg /day and calories from fat limited to 20-25% of total calories with saturated fat limited to less than 8% of total calories. Pts with multiple risk factors or angiographic evidence of CAD should have more severe restrictions. In some pts it has been shown that supplementing the diet with fish oils high in omega 3 fatty acids may be useful in lowering triglycerides levels.

Diet of patients with hypercholesterolemia should be low in cholesterol, saturated fat, and calories.

Cholesterol intake should be limited to under 200 mg a day, and calories from fat should be limited to 20-25% of total calories, with saturated fat limited to less than 8% of total calories. Even more restrictions may be considered in patients with multiple risk factors or angiographic evidence of CAD.

In some patients with hypertriglyceridemia, supplementing the diet with fish oils that contain omega-3 fatty acids may be useful in lowering the triglyceride levels.

1. Low cholesterol diet with recommended intake of less than 200 mg a day. Cholesterol in the diet directly increases LDL cholesterol contributing to atherosclerosis

2. Low saturated fat diet with saturated fat in the diet only contributing 8% of total calories. Saturated fats directly increase LDL cholesterol contributing to atherosclerosis

3. Restrict total calories to help the patient achieve ideal body weight to reduce risk factor of obesity

4. Supplimentation with fish oils (omega-3 fatty acids) may lower LDL cholesterol

5. Describe the role of each of the following agents in treating hyperlidemia, and identify their most common or important adverse effects and drug interactions:

All patients whose risk from CHD is considered high enough to warrant pharmacologic therapy of an elevated LDL cholesterol should be given aspirin prophylaxis at a dose of 81-325 mg/d unless there are contraindications such as aspirin sensitivity, bleeding diatheses, or active peptic ulcer disease. The benefit of aspirin in reducing the risk of CHD is equivalent to that of cholesterol lowering. Other CHD risk factors, such as hypertension and smoking, should also be controlled.

If the decision to treat a patient with an LDL-lowering drug is made, a goal for treatment is set. For patients with CHD or CHD risk equivalents, the goal is LDL < 100 mg/dL. For patients with two or more risk factors the goal is LDL < 130 mg/dL. For those with zero or one risk factor the goal is LDL < 160 mg/dL. In each instance, the therapeutic goal is approached slowly, watching for side effects and encouraging continued adherence to nonpharmacologic therapies. Combinations of drugs may be necessary. Once the goal is reached, the lipid profile should be monitored periodically (every 6-12 months), with consideration given to periodic reductions in drug dose. With the exception of niacin (available generically for a few dollars per month), lipid-lowering agents are expensive and may need to be given for decades. Thus, their cost-effectiveness is generally low, especially in primary prevention.

Niacin was the first lipid-lowering agent that was associated with a reduction in total mortality. Long-term follow-up of a secondary prevention trial of middle-aged men with previous myocardial infarction disclosed that about half of those who had been previously treated with niacin had died, compared with nearly 60% of the placebo group. This favorable effect on mortality was not seen during the trial itself, though there was a reduction in the incidence of recurrent coronary events.

Niacin reduces the production of VLDL particles, with secondary reduction in LDL and increases in HDL cholesterol levels. The average effect of full-dose niacin therapy, 3-4.5 g/d, is a 15-25% reduction in LDL cholesterol and a 25-35% increase in HDL cholesterol. Full doses are required to obtain the LDL effect, but the HDL effect is observed at lower doses, eg, 1 g/d. Niacin will also reduce triglycerides by half and will lower lipoprotein(a) (Lp[a]) levels and will increase plasma homocysteine levels. Thus, its effect on blood lipids and CHD risk is nearly optimal. Intolerance to niacin is common; only 50-60% of patients can take full doses. Niacin causes a prostaglandin-mediated flushing that patients may describe as "hot flashes" or pruritus and can be decreased by pretreatment with aspirin (81-325 mg/d) or other nonsteroidal anti-inflammatory agents. Flushing may also be decreased by initiating niacin therapy with a very small dose, eg, 100 mg with the evening meal. The dose can be doubled each week until 1.5 g/d is tolerated. After rechecking blood lipids, the dose is divided and increased until the goal of 3-4.5 g/d is reached. Extended-release niacin is also available and may be better tolerated by some patients. It is not known whether routine monitoring of liver enzymes results in early detection and thus reduced severity of this side effect. Niacin can also exacerbate gout and peptic ulcer disease. Although niacin may increase blood sugar in some patients, clinical trials have shown that niacin can be safely used in diabetics.

Treatment with these agents reduces the incidence of coronary events in middle-aged men by about 20%, with no significant effect on total mortality. The resins work by binding bile acids in the intestine. The resultant reduction in the enterohepatic circulation causes the liver to increase its production of bile acids, using hepatic cholesterol to do so. Thus, hepatic LDL receptor activity increases, with a decline in plasma LDL levels. The triglyceride level tends to increase slightly in some patients treated with bile acid-binding resins; they should be used with caution in those with elevated triglycerides and probably not at all in patients who have triglyceride levels above 500 mg/dL. The clinician can anticipate a reduction of 15-25% in the LDL cholesterol level, with insignificant effects on the HDL level.

The usual dose of cholestyramine is 12-36 g of resin per day in divided doses with meals, mixed in water or, more palatably, juice. Doses of colestipol are 20% higher (the packets each contain 5 g of resin). The dose of colesevelam is 625 mg 6-7 tablets per day.

These agents often cause gastrointestinal symptoms, such as constipation and gas. They may interfere with the absorption of fat-soluble vitamins (thereby complicating the management of patients receiving warfarin) and may bind other drugs in the intestine. Concurrent use of psyllium may ameliorate the gastrointestinal side effects.

C. HMG-CoA Reductase Inhibitors (Lovastatin, Pravastatin, Simvastatin, Fluvastatin, Atorvastatin)

These agents work by inhibiting the rate-limiting enzyme in the formation of cholesterol. They reduce myocardial infarctions and total mortality in secondary prevention, as well as in middle-aged men free of CHD. A meta-analysis has demonstrated significant reduction in risk of stroke. Cholesterol synthesis in the liver is reduced, with a compensatory increase in hepatic LDL receptors (presumably so that the liver can take more of the cholesterol that it needs from the blood) and a reduction in the circulating LDL cholesterol level by up to 35%. There are also modest increases in HDL levels and decreases in triglyceride levels.

Doses are as follows: lovastatin, 10-80 mg/d; pravastatin, 10-40 mg/d; simvastatin, 5-40 mg/d; fluvastatin, 20-40 mg/d; and atorvastatin, 10-80 mg/d. These agents are usually given once a day in the evening (most cholesterol synthesis takes place overnight); at the high end of the dose ranges, twice-a-day dosing may be used. Side effects include myositis, whose incidence may be higher in patients concurrently taking fibrates or niacin. Manufacturers recommend monitoring liver and muscle enzymes. Several agents (notably erythromycin, cyclosporine, and azole antifungals) reduce the metabolism of these agents.

Gemfibrozil reduced CHD rates in hypercholesterolemic middle-aged men free of coronary disease in the Helsinki Heart Study. The effect was only observed among those who also had lower HDL cholesterol levels and high triglyceride levels. In a recent VA study, gemfibrozil was also shown to reduce cardiovascular events in men with existing CHD whose primary lipid abnormality was a low HDL cholesterol. There was no effect on all-cause mortality.

The fibrates reduce the synthesis and increase the breakdown of VLDL particles, with secondary effects on LDL and HDL levels. They reduce LDL levels by about 10-15% and triglyceride levels by about 40% and raise HDL levels by about 15-20%. The usual dose of gemfibrozil is 600 mg once or twice a day. Side effects include cholelithiasis, hepatitis, and myositis. The incidence of the latter two conditions may be higher among patients also taking other lipid-lowering agents. In the largest clinical trial that used clofibrate, there were significantly more deaths—especially due to cancer—in the treatment group; it should not be used.

Ezetimibe is a new lipid-lowering drug that inhibits the intestinal absorption of dietary and biliary cholesterol by blocking passage across the intestinal wall. Ezetimibe reduces LDL cholesterol between 15% and 20% when used as monotherapy and can further reduce LDL in patients on statins who are not yet at therapeutic goal. The effects of ezetimide on CHD and its long-term safety are not yet known. The usual dose of ezetimibe is 10 mg/d.

…high degree of effectiveness in treatment of hypercholesterolemia and have a good safety record.

Adverse effects: relatively free of adverse effects, but may elevate serum levels of hepatic enzymes and cause hepatitis.

Less frequently cause myalgia and rhabdomyolisis = muscle cells destroyed, releasing myoglobin into the circulation…can accumulate in the kidneys and cause kidney failure.

Moderately effective for hypercholesterolemia and have an excellent safety record.

good for reduction of LDL cholesterol but not so effective for lowering triglycerides.

…primarily used for the treatment of hypertriglyceridemia and marked HDL deficiency.

…reduction in triglyceride levels produced is accompanied by an impressive increase in HDL.

Adverse effects: the fibrates may cause blood cell deficiencies, hypersensitivity reactions, and like reductase inhibitors, can cause myopathies.

…decreases serum LDL cholesterol and triglyceride levels and usually increases HDL cholesterol levels.

Adverse effects: the large doses of niacin required to lower serum lipid levels sometimes produce marked vasodilation and flushing od skin, accompanied by pruritis and a feeling of warmth and tingling.

…probably the most effective single drug that is currently available for treatment of mixed hyperlipidemia.

Reductase inhibitors –lovastatin— by competitively inhibiting HMG-CoA reductase, this drug reduces hepatic cholesterol biosynthesis. This Increases the number of LDL receptors and enables more LDL to be delivered to the liver. As a result, there is a reduction in the level of LDL cholesterol in the serum and a reduction in the amount of cholesterol available for the formation of VLDL. Reduces risk of coronary diseases, treat hypercholesterolemia, and decrease mortality rate by 30% in men with a history of MI.

Adverse effects—may elevate serum level of hepatic enzymes and cause hepatitis. Less frequently, they cause myalgia and rhabdomyolysis. Myoglobin may accumulate in the kidneys and cause acute renal failure.

Indications—treat hypercholestrolemia, and treat diarrhea caused by excessive acid. secretion. They are indicated for pts. Who can not tolerate other drugs.

Adverse effects—constipation, fecal impaction, and other GI effects. Occasionally, perianal irritation and skin rash. In the gut, the resins can bind to digoxin, thyroxin, warfarin, and other drugs. For this reason, it is best to take resins 2 hours before or after taking other medications.

Fibric acid derivatives—gemfibrozil--- indicated for the treatment of hypertriglyceridemia. For mixed hyperlipidemia and can be administered to increase HDL cholesterol in pts. with an isolated HDL deficiency.

A) Reductase Inhibitors (Lovastatin)- these are prodrugs activated by the first pass through the liver. Once in circulation they competitively bind to HMG-CoA reductase which is an enzyme that is the rate limiting step in the hepatic cholesterol biosynthesis. With the liver producing less cholesterol there are more LDL receptors in the liver for HDL to return cholesterol from the peripheral circulation to. This lowers the serum cholesterol level. Drug interactions include:

4. Drugs inhibiting cytochrome P450 enzymes may interfere (decrease Warfarin metabolism)

B) Bile Acid-binding Resins (Cholestyramine & Colestipol)- These drugs are large moleculare weight polymers that are not absorbed from the gut. They bind to bile acids in the gut lumen and prevent these bile acids from being reabsorbed. This prevents the enterohepatic recycling of bile acids and forces the liver to produce more bile acids from cholesterol. The liver increases its LDL binding capacity and removes more LDL from circulation to replentish these bile acids. Adverse effects and interactions include:

1. May cause constipation, fecal impaction, and other GI effects some of which can be prevented by taking the drugs with a large glass of water

2. These drugs may bind to digoxin, thyroxine, warfarin, and other drugs not enabling them to be absorbed so it is best to take this resin 2 hours before or after taking other medications.

C) Fibric Acid Derivatives (Gemfibrozil)- These medications activate lipoprotein lipase and promote the delivery of triglycerides to adipose tissue. They also interfere with the liver producing VLDL thus reducing the amount of VLDL that can be converted into LDL. These medications also have remarkable effects on HDL production increasing the HDL dramatically. Adverse effects and interactions include:

3. No interactions, can be given comcommitently with bile acid binding resins but must be separated in dosing by at least 2 hours.

D) Niacin (Nicotinic Acid)- this is a vitamin that when ingested in normal diet has no real effect on lipid levels. When administered at higher doses of several grams a day it has more effect. This vitamin when administered at high doses acts like Gemfibrozil in that it reduces hepatic VLDL secretion and activates lipoprotein lipase which enhances the displacement of cholesterol into adipose tissue. Niacin also has been shown to be effective at increasing HDL levels. Adverse effects and interactions include:

1. Potent vasodilation causing flushing accompanied by pruritis and a feeling of warmth and tingling. This can be reduced by a taking and aspirin 1 hour prior to niacin dose.

E) Ezetimibe- this medication is administered orally as a prodrug that is activated in the small intestine and liver. This drug selectively inhibits intestinal absorption of dietary and biliary cholesterol at the brush border of the small intestine. Adverse effects and interactions include:

1. May cause transaminase elevations and should be avoided in patients with moderate to severe hepatic insufficiency

2. Ezetimibe and fibrates both increase cholesterol in bile, which would predispose to gall bladder disease

3. Cholextyramine and colestipol interfere with absorption of ezetimibe so if they are taken concurrently they should be taken at least 2 hours before or 4 hours after the acid sequestriant.

At present there are no absolute guidelines for selection of available lipid-modifying medications in particular patients. Nonetheless, clinical trials provide guidance (Table 28-4). For most patients who require a lipid-modifying medication, an HMG-CoA reductase inhibitor is preferred. Although niacin will also have beneficial effects on lipids in both men and women with CHD, there is less evidence demonstrating the desired effects on CHD and all-cause mortality. Resins are the only lipid-modifying medication considered safe in pregnancy.

Combinations of lipid-modifying medications may be more cost-effective than high doses of a single medication (usually an HMG-CoA reductase inhibitor) and may have beneficial effects on lipids. Low-dose niacin (0.5-1 g/d), for example, will substantially increase the HDL cholesterol when added to an HMG-CoA reductase inhibitor. Combinations, however, may increase the risk of severe complications of drug therapy. The combination of gemfibrozil and HMG-CoA reductase inhibitors increases the risk of myopathy more than either drug alone.

Multi drug therapy works for some that don’t respond to monotherapy. The safest combos of multi drugs are those consisting of a bile-acid binding resin and either an HMG-CoA reductase inhibitor, niacin, or gemfibrozil. Some drug combos should be avoided or only used with great caution. The combo of gemfibrozil plus an HMG-CoA reductase inhibitor has a greater tendency to cause myopathy than does the use of either drug alone. Fot the same reason, lovastatin should not be used in combo with niacin, but other HMG-CoA reductase inhibitors appear to be safer with niacin.

Safest combos are those with bile acid-binding resin and either an HMG-CoA Reductase inhibitor, niacin or gemfibrozil. Effective treatment may require the use of niacin and either gemfibrozil or an HMG-Co A Reductase inhibitor, and the most severe case may need a three-drug regimen.

Avoid the combo of gemfibrozil + HMG-Co A Reductase inhibitor, together they ↑ risk of myopathies, and the same with lovastatin + Niacin combo.

Drugs may be used in combination to treat hyperlipidemia in patients who do not respond to a single drug. The safest combinations are those consisting of a bile acid-binding resin and either an HMG-CoA reductase inhibitor, niacin, or gemfibrozil. The effective Tx of primary hyperlipoproteinemias may require the use of niacin and either gemfibrozil or an HMG-CoA reductase inhibitor, and the most severe cases of hyperlipidemia may require the use of the three-drug regimen.

1. Safest Combination- Bile acid binding resins & HMG-CoA Reductase Inhibitor, Niacin or Gemfibrozil

2. Most Dangerous- Gemfibrozil & HMG-CoA Reductase Inhibitor have greater chance to cause

Table 28-1. Secondary causes of lipid abnormalities.
Cause	Associated Lipid Abnormality
Obesity	Increased triglycerides, decreased HDL cholesterol
Sedentary lifestyle	Decreased HDL cholesterol
Diabetes mellitus	Increased triglycerides, increased total cholesterol
Alcohol use	Increased triglycerides, increased HDL cholesterol
Hypothyroidism	Increased total cholesterol
Hyperthyroidism	Decreased total cholesterol
Nephrotic syndrome	Increased total cholesterol
Chronic renal insufficiency	Increased total cholesterol, increased triglycerides
Hepatic disease (cirrhosis)	Decreased total cholesterol
Obstructive liver disease	Increased total cholesterol
Malignancy	Decreased total cholesterol
Cushing's disease (or steroid use)	Increased total cholesterol
Oral contraceptives	Increased triglycerides, increased total cholesterol
Diuretics¹	Increased total cholesterol, increased triglycerides
Beta-blockers^1,2	Increased total cholesterol, decreased HDL
¹Short-term effects only.
²Beta-blockers with intrinsic sympathomimetic activity, such as pindolol and acebutolol, do not affect lipid levels.

Table 28-3. LDL goals and treatment cutpoints: recommendations of the NCEP Adult Treatment Panet III Report.¹
Risk Category	LDL Goal (mg/dL)	LDL at Which to Initiate Lifestyle Changes (mg/dL)	LDL Level at Which to Consider Drug Changes (mg/dL)
CHD or CHD risk equivalents	< 100	≥ 100	≥ 130
≥ 2 risk factors	< 130	≥ 130	10-year risk 10-20%: ≥ 130 10-year risk <10%: ≥ 160
0-1 risk factors	< 160	≥ 160	≥ 190
¹Reproduced, with permission, from Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of HIgh Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486. http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm

Cholesterol	Total (mg/dL)	LDL (mg/dL)	Presence of other risk factors	Management
Desirable levels	< 200	< 130	No	Repeat lipid measurement in 5 years
Desirable levels	< 200	< 100	Yes	Recommend dietary modifications; review other methods to reduce risk factors; and repeat lipid measurements in 1-5 years.
Borderline to High Cholesterol concentrations	200 – 239	130 – 159	No	Recommend dietary modifications and repeat lipid measurements annually
Borderline to High Cholesterol concentrations	200 – 239	130 – 159	Yes	Recommend dietary modifications; review other methods to reduce risk factors; consider drug therapy; repeat lipid levels prn.
High Cholesterol concentrations	>/= 240	>/= 160	No	Recommend dietary modifications; institute drug therapy if LDL exceeds 190mg/dL; repeat lipid measurements prn
High Cholesterol concentrations	>/= 240	>/= 160	Yes	Recommend dietary mod.; institute drug therapy; repeat lipid measurements prn.

Category	Total Cholesterol Concentration (mg/dL)	LDL Cholesterol Concentration (mg/dL)	Presence of Other Risk Factors	Management
Desirable Cholesterol Concentrations	<200	<130	No	Repeat Lipid measurements in 5 years.
Desirable Cholesterol Concentrations	<200	<100	Yes	Recommend dietary modifications; Review other methods to reduce risk factors; Repeat lipid Measurement in 1-5 years
Borderline to High Cholesterol Concentrations	200-239	130-159	No	Recommend dietary modifications and repeat lipid measurements annually
Borderline to High Cholesterol Concentrations	200-239	130-159	Yes	Recommend dietary modifications; Review other methods to reduce other risk factors; Consider drug therapy; Repeat lipid measurements as needed
High Cholesterol COncentrations	³240	³160	No	Recommend dietary modifications; Institutedrug therapy if the LDL cholesterol concentration exceeds 190 mg/dL; Repeat lipid measurements as needed
High Cholesterol COncentrations	³240	³160	Yes	Recommend dietary modifications; Review other methods to reduce risk factors; Institute drug therapy; Repeat lipid measurements as needed

Drug	Adverse effects	Interactions	Contradictions
*Hypercholesterolemia treatments:*
HMG-CoA Reductase-inhibitors (lovastatin: the only drug of its class that crosses blood brain barrier)	↑ serums levels of: hepatic enzymes; hepatitis; myalgia, rhabdomyolysis & other myopathies	Slight ↑ in serum warfin. ↑ risk of myopathies when taken w/erythromycin, gemfibrozil or niacin	Hepatic disease and hypersensitivity
Bile acid-binding resins (cholestyramine and colestipol: powders that must be mixed w/H20 and administered @meals and hs)	Constipation, fecal impaction and rash	↓ Absorption of digoxin, thyroxin warfin & other drugs	Hypersensitivity
*Hypercholesterolemia & hyperlipidemia treatments:*
Fibric acid derivatives (gemfibrozil: primarily for hyperlipidemia, mixed& HDL deficiency)	Allergic rxn, blood cell deficiencies, myalgia, rhabdomyolysis & other myopathies	↑ risk of myopathies when taken w/ HMG-CoA Reductase inhibitors or niacin	Biliary or gallbladder dz; hypersensitivity; severe hepatic dz or severe renal dz
Niacin (nicotinic acid : vtm, most useful for mixed, dietary supply not adequate, must take ↑ supplements)	GI irritation; glucose intolerance; myalgia, rhabdomyolysis & other myopathies and vasodilation, flushing, and pruritus, (pretreatment w/ ASA ↓ these effects)	↑ risk of myopathies when taken w/ HMG-CoA Reductase inhibitors or niacin*	Diabetes mellitus; hepatic dz, hypersensitivity, and peptic ulcers
If niacin must be used in combo w/HMG-CoA, the safest combo is niacin+ fluastatin and the worst combo (↑risk) is niacin + lovastatin.

Table 28-4. Effects of selected lipid-modifying drugs.
	Liqid-Modifying Effects
Drug	LDL	HDL	Triglyceride	Initial Daily Dose	Maximum Daily Dose	Cost for 30 Days' Treatment With Dose Listed¹
Atorvastatin (Lipitor)	-25 to -40%	+5 to -10%	↓↓	10 mg once	80 mg once	$109.31 (20 mg once)
Cholestyramine (Questran, others)	-15 to -25%	+5%	±	4 g bid	24 g divided	$126.68 (8 g divided)
Colestipol (Colestid)	-15 to -25%	+5%	±	5 g bid	30 g divided	$106.45 (10 g divided)
Fluvastatin (Lescol)	-20 to -30%	+5 to -10%	↓	20 mg once	40 mg once	$53.42 (20 mg once)
Gemfibrozil (Lopid)	-10 to -15%	+15 to -20%	↓↓	600 mg once	1200 mg divided	$74.75 (600 mg bid)
Lovastatin (Mevacor)	-25 to -40%	+5 to -10%	↓	10 mg once	80 mg divided	$71.10 (20 mg once)
Niacin	-15 to -25%	+25 to -35%	↓↓	100 mg once	3-4.5 g divided	$7.20 (1.5 g bid)
Pravastatin (Pravachol)	-25 to -40%	+5 to -10%	↓	20 mg once	40 mg once	$92.41 (20 mg once)
Simvastatin (Zocor)	-25 to -40%	+5 to -10%	↓↓	5 mg once	80 mg once	$78.85 (10 mg once)
¹Cost to pharmacist (average wholesale price, generic when possible) for quantity listed. Source: Drug Topics Red Book, May 2003; Vol. 22, No. 5.
± = variable, if any.