Etiopathogenesis and pharmacotherapy of hyperlipidemias a. the pathophysiology of selected disease states and the rationale for drug therapy; b. the therapeutic approach to management of these diseases; c. the controversies in drug therapy; d. the importance of preparation of individualised therapeutic plans based on diagnosis; e. needs to identify the patient-specific parameters relevant in initiating drug therapy, and monitoring therapy (including alternatives, time-course of clinical and laboratory indices of therapeutic response and adverse effects); f. describe the pathophysiology of selected disease states and explain the rationale for drug therapy; g. summarise the therapeutic approach to management of these diseases including reference to the latest available evidence; h. discuss the controversies in drug therapy; i. discuss the preparation of individualised therapeutic plans based on diagnosis; and j. identify the patient-specific parameters relevant in initiating drug therapy, and monitoring therapy (including alternatives, time-course of clinical and laboratory indices of therapeutic response and adverse effects).

1. DOCTOR OF PHARMACY
II YEAR
Hyperlipidemia
170101
CHAPTER-1
Cardiovascular system
Dr. V. Chanukya (Pharm D)

2. Back ground
Lipoprotein metabolism and transport
• The clinically important lipids in the blood (unesterified and esterified
cholesterol and triglycerides) are not readily soluble in serum and are
rendered miscible by incorporation into lipoproteins.
• There are six main classes of lipoproteins: chylomicrons, chylomicron
remnants, very low-density lipoproteins (VLDL-C), intermediate-
density lipoproteins (IDL-C), lowdensity lipoproteins (LDL-C) and
high-density lipoproteins (HDL-C).

3. Composition of Lipoprotein Isolated from Normal Subjects

4. • The protein components of lipoproteins are known as apoproteins
(apo), of which apoproteins A-I, E, C and B are perhaps the most
important.
• Apoprotein B exists in two forms: B-48, which is present in
chylomicrons and associated with the transport of ingested lipids, and
B-100, which is found in endogenously secreted VLDL-C and
associated with the transport of lipids from the liver

5. Characteristics and functions of apolipoproteins

7. Exogenous pathway
• When dietary cholesterol and triglycerides are absorbed from the
intestine they are transported in the intestinal lymphatics as
chylomicrons.
• These are the largest of the lipoprotein particles of which triglycerides
normally constitute approximately 80% of the lipid core.
• The chylomicrons pass through blood capillaries in adipose tissue and
skeletal muscle where the enzyme lipoprotein lipase is located, bound
to the endothelium.
• Lipoprotein lipase is activated by apoprotein C-II on the surface of the
chylomicron.

8. • The lipoprotein lipase catalyses the breakdown of the triglyceride in
the chylomicron to free fatty acid and glycerol, which then enter
adipose tissue and muscle.
• The cholesterol-rich chylomicron remnant is taken up by receptors on
hepatocyte membranes, and in this way dietary cholesterol is
delivered to the liver and cleared from the circulation.
• Dietary cholesterol and fat are transported in the exogenous
pathway.
• Cholesterol produced in the liver is transported in the endogenous
pathway.

10. • VLDL-C is formed in the liver and transports triglycerides, which
again make up approximately 80% of its lipid core, to the periphery.
• The triglyceride content of VLDL-C is removed by lipoprotein lipase
in a similar manner to that described for chylomicrons above, and
forms IDL-C particles.
• The core of IDL-C particles is roughly 50% triglyceride and 50%
cholesterol esters, acquired from HDL-C under the influence of the
enzyme lecithin-cholesterol acyltransferase (LCAT).
• Approximately 50% of the body's IDL particles are cleared from
serum by the liver.
Endogenous pathway

11. • The other 50% of IDL-C are further hydrolysed and modified to lose
triglyceride and apoprotein E1 and become LDL-C particles.
• LDL-C is the major cholesterol-carrying particle in serum.
• LDL-C provides cholesterol, an essential component of cell
membranes, bile acid and a precursor of steroid hormones to those
cells that require it.
• LDL-C is also the main lipoprotein involved in atherogenesis,
although it only appears to take on this role after it has been modified
by oxidation.

12. • For reasons that are not totally clear, the arterial endothelium becomes
permeable to the lipoprotein.
• Monocytes migrate through the permeable endothelium and engulf the
lipoprotein, resulting in the formation of lipid-laden macrophages that
have a key role in the subsequent development of atherosclerosis.
• The aim of treatment in dyslipidaemia is normally to reduce
concentrations of LDL-C and thus reduce TC at the same time.
• While VLDL-C and LDL-C are considered the ‘bad’ lipoproteins,
HDL-C is often considered to be the ‘good’ antiatherogenic
lipoprotein. In general, about 65% of TC is carried in LDL-C and
about 25% in HDL.

13. High-density lipoprotein
• HDL-C is formed from the unesterified cholesterol and phospholipid
removed from peripheral tissues and the surface of triglyceride-rich
proteins.
• The major structural protein is apoA-I.
• HDL-C mediates the return of lipoprotein and cholesterol from
peripheral tissues to the liver for excretion in a process known as
reverse cholesterol transport.

14. Lipoprotein metabolism and transport

15. Reverse cholesterol transport pathway
• The reverse cholesterol transport pathway controls the formation,
conversion, transformation and degradation of HDL-C and is the
target site for a number of new, novel drugs and has recently been
described.
• The reverse cholesterol transport system involves lipoprotein
mediated transport of cholesterol from peripheral, extra-hepatic
tissues and arterial tissue (potentially including cholesterol loaded
foam cell macrophages of the atherosclerotic plaque) to the liver for
excretion, either in the form of biliary cholesterol or bile acids.

16. • The ATP-binding cassette transporters, ABCA1 and ABCG1, and the
scavenger receptor B1, are all implicated in cellular cholesterol efflux
mechanisms to specific apoA-1/ HDL acceptors.
• The progressive action of lecithin:cholesterol acyl transferase on free
cholesterol in lipid-poor, apolipoprotein A-I-containing nascent high-
density lipoproteins, including pre- b-HDL, gives rise to the formation
of a spectrum of mature, spherical high-density lipoproteins with a
neutral lipid core of cholesteryl ester and triglyceride.
• Mature high-density lipoproteins consist of two major subclasses,
large cholesteryl ester-rich HDL2 and small cholesteryl ester-poor,
protein-rich HDL3 particles; the latter represent the intravascular
precursors of HDL2.

17. • The reverse cholesterol transport system involves two key pathways:
(a) the direct pathway (blue lines), in which the cholesteryl ester
content (and potentially some free cholesterol) of mature high-density
lipoprotein particles is taken up primarily by a selective uptake
process involving the hepatic scavenger receptor B1 and
• (b) an indirect pathway (dotted blue lines) in which cholesteryl ester
originating in HDL is deviated to potentially atherogenic VLDL, IDL
and LDL particles by cholesteryl ester transfer protein.
• Both the cholesteryl ester and free cholesterol content of these
particles are taken up by the liver, predominantly via the LDL receptor
which binds their apoB100 component.

18. • This latter pathway may represent up to 70% of cholesteryl ester
delivered to the liver per day.
• The hepatic LDL receptor is also responsible for the direct uptake of
high-density lipoprotein particles containing apoE; apoE may be
present as a component of both HDL2 and HDL3 particles, and may
be derived either by transfer from triglyceride-rich lipoproteins, or
from tissue sources (principally liver and monocyte-macrophages).
• Whereas HDL uptake by the LDL receptor results primarily in
lysosomal-mediated degradation of both lipids and apolipoproteins,
interaction of HDL with scavenger receptor B1 regenerates lipid-poor
apoA-I and cholesterol-depleted HDL, both of which may re-enter the
HDL/apoA-I cycle.

20. Triglycerides
• The role of hypertriglyceridaemia as an independent risk factor for
coronary heart disease (CHD) is unclear because triglyceride levels
are confounded by an association with low HDL-C, hypertension,
diabetes and obesity, and a synergistic effect with LDL-C and/or low
HDL-C.
• An isolated elevation of triglyceride may be the consequence of a
primary disorder of lipid metabolism, it may be secondary to the use
of medicines or it may be a component of the metabolic syndrome or
type 2 diabetes mellitus.

21. Introduction
• Disorders of lipoprotein metabolism together with high fat diets,
obesity and physical inactivity have all contributed to the current
epidemic of atherosclerotic disease seen in developed countries.
• Disorders of lipoprotein metabolism that result in elevated serum
concentrations of total cholesterol (TC) and low-density lipoprotein
cholesterol (LDL-C) increase the risk of an individual developing
cardiovascular disease (CVD).
• In contrast, high-density lipoprotein cholesterol (HDL-C) confers
protection against CVD, with the risk reducing as HDL-C increases.

22. • It is, therefore, clear that the term hyperlipidaemia, which was
formerly used to describe disorders of lipoprotein metabolism, is
inappropriate.
• It is more appropriate to use the term dyslipidaemia, which
encompasses both abnormally high levels of specific lipoproteins, for
example, LDL-C, and abnormally low levels of other lipoproteins, for
example, HDL-C, as well as disorders in the composition of the
various lipoprotein particles.
• It is particularly appropriate when considering the individual at risk of
CVD with a normal or high TC and low HDL-C (total
cholesterol:HDL-C ratio).

23. Definition
Hyperlipidemia
• Dyslipidemia is defined as elevated total cholesterol, low-density
lipoprotein (LDL) cholesterol, or triglycerides; a low high-density
lipoprotein (HDL) cholesterol; or a combination of these
abnormalities.
• Hyperlipoproteinemia describes an increased concentration of the
lipoprotein macromolecules that transport lipids in the plasma.
• Abnormalities of plasma lipids can result in a predisposition to
coronary, cerebrovascular, and peripheral vascular arterial disease.

24. Epidemiology
• Lipid and lipoprotein concentrations vary among different
populations, with countries consuming a Western type of diet
generally having higher TC and LDL-C levels than those where
regular consumption of saturated fat is low.
• The ideal serum lipid profile is unknown and varies between different
populations, even across Europe, and also within a given population.
• For completeness, the values for triglycerides and HDL-C are also
presented, although the benefit of achieving the stated targets is less
clear.

25. • For practical purposes the values presented in table below represent
the target levels for TC and LDL-C in the UK for adults receiving
treatment for secondary prevention of CVD.

26. • Despite a 50% reduction in the death rate from CVD over the past 25
years, it remains the leading cause of premature death and morbidity
in the UK, and the higher the levels of TC in an individual the greater
the chance of developing CVD.
• The death rate from CVD is threefold higher in males than females,
but because women live longer and are at increased risk of stroke after
the age of 75 years their lifetime risk of disease is greater.
• TC levels tend to increase with age such that 80% of British men aged
45–64 years have a level that exceeds 5 mmol/L and the population
average is 5.6 mmol/L.
• In contrast, in rural China and Japan, the average is 4 mmol/L.

27. Pathophysiology
• The response-to-injury hypothesis states that risk factors such as
oxidized LDL, mechanical injury to the endothelium, excessive
homocysteine, immunologic attack, or infection-induced (e.g.,
Chlamydia, herpes simplex virus) changes in endothelial and
intimal function lead to endothelial dysfunction and a series of
cellular interactions that culminate in atherosclerosis.
• The eventual clinical outcomes may include angina, myocardial
infarction, arrhythmias, stroke, peripheral arterial disease,
abdominal aortic aneurysm, and sudden death.

28. • Atherosclerotic lesions are thought to arise from transport and
retention of plasma LDL through the endothelial cell layer into the
extracellular matrix of the subendothelial space.
• Once in the artery wall, LDL is chemically modified through
oxidation and nonenzymatic glycation.
• Mildly oxidized LDL then recruits monocytes into the artery wall.
• These monocytes then become transformed into macrophages that
accelerate LDL oxidation.
• Oxidized LDL provokes an inflammatory response mediated by a
number of chemo attractants and cytokines (e.g., monocyte colony-
stimulating factor, intercellular adhesion molecule, platelet-derived
growth factor, transforming growth factors, interleukin-1, interleukin-
6).

29. Pathophysiology -Atherosclerosis

30. • Repeated injury and repair within an atherosclerotic plaque eventually
lead to a fibrous cap protecting the underlying core of lipids, collagen,
calcium, and inflammatory cells such as T lymphocytes.
• Maintenance of the fibrous plaque is critical to prevent plaque rupture
and subsequent coronary thrombosis.
• Primary or genetic lipoprotein disorders are classified into six
categories for the phenotypic description of dyslipidemia.

31. Types of Hyperlipidaemias
• The types and corresponding lipoprotein elevations include the
following: I (chylomicrons), IIa (LDL), IIb (LDL + very low density
lipoprotein, or VLDL), III (intermediate-density lipoprotein), IV
(VLDL), and V (VLDL + chylomicrons).
• Secondary forms of hyperlipidemia also exist, and several drug
classes may elevate lipid levels (e.g., progestins, thiazide diuretics,
glucocorticoids, β-blockers, isotretinoin, protease inhibitors,
cyclosporine, mirtazapine, sirolimus).
• The primary defect in familial hypercholesterolemia is the inability to
bind LDL to the LDL receptor (LDL-R) or, rarely, a defect of
internalizing the LDL-R complex into the cell after normal binding.
• This leads to lack of LDL degradation by cells and unregulated
biosynthesis of cholesterol, with total cholesterol and LDL cholesterol
(LDL-C) being inversely proportional to the deficit in LDL-Rs.

32. Types of Hyperlipidaemias

33. Lipoprotein Disorders types

34. Aetiology, types clinical presentations
Primary dyslipidaemia
• Up to 60% of the variability in cholesterol fasting lipids may be
genetically determined, although expression is often influenced by
interaction with environmental factors.
• The common familial (genetic) disorders can be classified as:
1. The primary hypercholesterolaemias such as familial
hypercholesterolaemias in which LDL-C is raised
2. The primary mixed (combined) hyperlipidaemias in which both
LDL-C and triglycerides are raised
3. The primary hypertriglyceridaemias such as type III
hyperlipoproteinaemia, familial lipoprotein lipase deficiency and
familial apoc-ii deficiency.

35. Familial hypercholesterolaemia
• Heterozygous familial hypercholesterolaemia (often referred to as FH)
is an inherited metabolic disease.
• Familial hypercholesterolaemia is caused by a range of mutations,
which vary from family to family, in genes for the pathway that clear
LDL-C from the blood.
• The most common mutation affects the LDL receptor gene.
• Given the key role of LDL receptors in the catabolism of LDL-C,
patients with FH may have serum levels of LDL-C two to three times
higher than the general population.

36. • It is important to identify and treat these individuals from birth,
otherwise they will be exposed to high concentrations of LDL-C and
will suffer the consequences.
• Familial hypercholesterolaemia is transmitted as a dominant gene,
with siblings and children of a parent with FH having a 50% risk of
inheriting it.
• It is important to suspect FH in people that present with TC >7.5
mmol/L, particularly where there is evidence of premature CV disease
within the family.

37. • In patients with heterozygous FH, CVD presents about 20 years
earlier than in the general population, with some individuals,
particularly men, dying from atherosclerotic heart disease often before
the age of 40 years.
• The adult heterozygote typically exhibits the signs of cholesterol
deposition such as corneal arcus (crescentic deposition of lipids in the
cornea), tendon xanthoma and xanthelasma (yellow plaques or
nodules of lipids deposited on eyelids) in their third decade.

38. • In contrast to the heterozygous form, homozygous FH is extremely
rare (1 per million) and associated with an absence of LDL receptors
and almost absolute inability to clear LDL-C.
• In these individuals, involvement of the aorta is evident by puberty
and usually accompanied by cutaneous and tendon xanthomas.
• Myocardial infarction has been reported in homozygous children as
early as 1.5–3 years of age.
• Up to the 1980s, sudden death from acute coronary insufficiency
before the age of 20 years was normal

39. Familial combined hyperlipidaemia
• Familial combined hyperlipidaemia has an incidence of 1 in 200 and
is associated with excessive synthesis of VLDL-C.
• In addition to increases in triglyceride and LDL-C levels, patients also
typically have raised levels of apoB and elevated levels of small,
dense LDL particles.
• It is associated with an increased risk of atherosclerosis and occurs in
approximately 15% of patients who present with CHD before the age
of 60 years.

40. Familial type III hyperlipoproteinaemia
• Familial type III hyperlipoproteinaemia has an incidence of 1 in 5000.
• It is characterised by the accumulation of chylomicron and VLDL
remnants that fail to get cleared at a normal rate by hepatic receptors
due to the presence of less active polymorphic forms of apoE.
• Triglycerides and TC are both elevated and accompanied by corneal
arcus, xanthelasma, tuberoeruptive xanthomas (groups of flat or
yellowish raised nodules on the skin over joints, especially the elbows
and knees) and palmar striae (yellow raised streaks across the palms
of the hand).
• The disorder predisposes to premature atherosclerosis.

41. Familial lipoprotein lipase deficiency
• Familial lipoprotein lipase deficiency is characterised by marked
hypertriglyceridaemia and chylomicronaemia, and usually presents in
childhood.
• It has an incidence of 1 per million and is due to a deficiency of the
extrahepatic enzyme lipoprotein lipase, which results in a failure of
lipolysis and the accumulation of chylomicrons in plasma.
• The affected patient presents with recurrent episodes of abdominal
pain, eruptive xanthomas, lipaemia retinalis (retinal deposition of
lipid) and enlarged spleen.
• This disorder is not associated with an increased susceptibility to
atherosclerosis; the major complication is acute pancreatitis.

42. Familial apolipoprotein C-II deficiency
• In the heterozygous state, familial apoC-II deficiency is associated
with reduced levels of apoC-II, the activator of lipoprotein lipase.
• Typically, levels of apoC-II are 50–80% of normal.
• This level of activity can maintain normal lipid levels.
• In the rare homozygous state, there is an absence of apolipoprotein C-
II and despite normal levels of lipoprotein lipase, it cannot be
activated.
• Consequently, homozygotes have triglyceride levels from 15 to above
100 mmol/L (normal range <1.7 mmol/L) and may develop acute
pancreatitis.
• Premature atherosclerosis is unusual but has been described.

43. Lipoprotein(a)
• There are many other familial disorders of lipid metabolism in
addition to those mentioned above but most are very rare.
• However, a raised level of lipoprotein(a), otherwise known as Lp(a),
appears to be a genetically inherited determinant of CVD.
• Lp(a) is a low-density lipoprotein-like particle synthesised by the liver
and first described more than 40 years ago.
• It is found in the serum of virtually everyone in a wide concentration
range (0.01–2 g/L) with up to 70% of the variation in concentration
being genetically determined.

44. • The concentration of Lp(a) is not normally distributed and the
contribution of inheritance to circulating Lp(a) levels is more
pronounced than for any other lipoprotein or apoprotein.
• A parental history of early-onset CVD is associated with raised
concentrations of Lp(a), and these appear to play a role in both
atherogenesis and thrombosis.
• An important component of Lp(a) is apo(a), which is structurally and
functionally similar to plasminogen and may competitively bind to
fibrin and impair fibrinolysis.

45. • Concentrations of Lp(a) above 0.3 g/L occur in about 20% of
caucasians and increase the risk of coronary atherosclerosis and
stroke.
• Under a wide range of circumstances, there are continuous,
independent, and modest associations of Lp(a) concentration with the
risk of CHD and stroke.

46. Secondary dyslipidaemia
• Dyslipidaemias that occur secondary to a number of disorders, dietary
indiscretion or as a side effect of drug therapy account for up to 40%
of all dyslipidaemias.
• Fortunately, the lipid abnormalities in secondary dyslipidaemia can
often be corrected if the underlying disorder is treated, effective
dietary advice implemented or the offending drug withdrawn.
• On occasion, a disorder may be associated with dyslipidaemia but not
the cause of it.
• For example, hyperuricaemia (gout) and hypertriglyceridaemia co-
exist in approximately 50% of men.

47. • In this particular example, neither is the cause Some of the more
common disorders that cause secondary dyslipidaemias include the
following.
• Diabetes mellitus
• Hypothyroidism
• Chronic renal failure
• Nephrotic syndrome
• Obesity
• Alcohol

49. Diagnosis
• A fasting lipoprotein profile including total cholesterol, LDL, HDL,
and triglycerides should be measured in all adults 20 years of age or
older at least once every 5 years.
• Measurement of plasma cholesterol (which is about 3% lower than
serum determinations), triglyceride, and HDL levels after a 12-hour or
longer fast is important, because triglycerides may be elevated in
nonfasted individuals; total cholesterol is only modestly affected by
fasting.
• Two determinations, 1 to 8 weeks apart, with the patient on a stable
diet and weight, and in the absence of acute illness, are recommended
to minimize variability and to obtain a reliable baseline.
• If the total cholesterol is >200 mg/dL, a second determination is
recommended, and if the values are more than 30 mg/dL apart, the
average of three values should be used.

50. • After a lipid abnormality is confirmed, major components of the
evaluation are the history (including age, gender, and, if female,
menstrual and estrogen replacement status), physical examination, and
laboratory investigations.
• A complete history and physical examination should assess
• (1) presence or absence of cardiovascular risk factors or definite
cardiovascular disease in the individual;
• (2) family history of premature cardiovascular disease or lipid
disorders;
• (3) presence or absence of secondary causes of hyperlipidemia,
including concurrent medications; and
• (4) presence or absence of xanthomas, abdominal pain, or history of
pancreatitis, renal or liver disease, peripheral vascular disease,
abdominal aortic aneurysm, or cerebral vascular disease (carotid
bruits, stroke, or transient ischemic attack).

51. • Diabetes mellitus is regarded as a CHD risk equivalent.
• That is, the presence of diabetes in patients without known CHD is
associated with the same level of risk as patients without diabetes but
having confirmed CHD.
• If the physical examination and history are insufficient to diagnose a
familial disorder, then agarose-gel lipoprotein electrophoresis is useful
to determine which class of lipoproteins is affected.
• If the triglyceride levels are <400 mg/dL and neither type III
hyperlipidemia nor chylomicrons are detected by electrophoresis, then
one can calculate VLDL and LDL concentrations:
• VLDL = triglycerides ÷ 5; LDL = total cholesterol – (VLDL + HDL).

52. • Initial testing uses total cholesterol for case finding, but subsequent
management decisions should be based on LDL.
• Because total cholesterol is composed of cholesterol derived from
LDL, VLDL, and HDL, determination of HDL is useful when total
plasma cholesterol is elevated. HDL may be elevated by moderate
alcohol ingestion (fewer than two drinks per day), physical exercise,
smoking cessation, weight loss, oral contraceptives, phenytoin, and
terbutaline.
• HDL may be lowered by smoking, obesity, a sedentary lifestyle, and
drugs such as β-blockers.
• Diagnosis of lipoprotein lipase deficiency is based on low or absent
enzyme activity with normal human plasma or apolipoprotein C-II, a
cofactor of the enzyme.

53. Risk factors
• When using the Joint British Societies (JBS2) risk prediction charts a
number of factors need to be taken into account at screening and
include:
1. Age: in individuals under 40 years of age the charts overestimate
risk; over the age of 70 years risk is underestimated by the charts and
most have a 10-year risk >20%.
2. Gender: there are separate charts for men and women.
3. Ethnicity: the risk prediction charts have only been validated in
white caucasians and underestimate risk in individuals from the
Indian subcontinent by a factor of 1.5.

54. 4. Smoking history: individuals who have stopped smoking within 5
years of assessment should be considered as current smokers.
5. Family history: risk increases by a factor of 1.5 when CHD has
occurred in a first-degree relative male <55 years or female <65
years, when a number of family members have developed CHD risk
increases by a factor of 2.
6. BMI and waist circumference: the charts do not adjust for either
BMI or waist circumference; these factors need to be taken into
account in the clinical decision-making process.
7. Non-fasting blood glucose: if non-fasting glucose >6.1 mmol/L, the
individual should be assessed for impaired glucose regulation or
diabetes.

55. Treatment
General approach
• The National Cholesterol Education Program Adult Treatment Panel
III (NCEP ATP III) recommends that a fasting lipoprotein profile and
risk factor assessment be used in the initial classification of adults.
• If the total cholesterol is <200 mg/dL, then the patient has a desirable
• blood cholesterol level.
• If the HDL is also >40 mg/dL, no further follow-up is recommended
for patients without known CHD and who have fewer than two risk
factors.

57. • In patients with borderline-high blood cholesterol (200 to 239 mg/dL),
assessment of risk factors is needed to more clearly define disease
risk.
• Decisions regarding classification and management are based on the
LDL cholesterol levels listed in Table 9-3.
• There are four categories of risk that modify the goals and modalities
of LDL-lowering therapy. The highest risk category is having known
CHD or CHD risk equivalents; the risk for major coronary events is
equal to or greater than that for established CHD (i.e., >20% per 10
years, or 2% per year).

59. • The next category is moderately high risk, consisting of patients with
two or more risk factors in which 10-year risk for CHD is 10% to
20%.
• Moderate risk is defined as two or more risk factors and a 10-year risk
of ≥ 10%.
• The lowest risk category is persons with zero to one risk factor, which
is usually associated with a 10-year CHD risk of <10%.
• ATP III recognizes the metabolic syndrome as a secondary target of
risk reduction after LDL-C has been addressed.

60. • This syndrome is characterized by abdominal obesity, atherogenic
dyslipidemia (elevated triglycerides, small LDL particles, low HDL
cholesterol), increased blood pressure, insulin resistance (with or
without glucose intolerance), and prothrombotic and proinflammatory
states.
• If the metabolic syndrome is present, the patient is considered to have
a CHD risk equivalent.
• Other targets include non-HDL goals for patients with triglycerides
>200 mg/dL.
• Non-HDL cholesterol is calculated by subtracting HDL from total
cholesterol, and the targets are 30 mg/dL greater than for LDL at each
risk stratum.

61. Nonpharmacologic therapy
• Therapeutic lifestyle changes are begun on the first visit and include
dietary therapy, weight reduction, and increased physical activity.
• Inducing a weight loss of 10% should be discussed with patients who
are overweight.
• In general, physical activity of moderate intensity 30 minutes a day
for most days of the week should be encouraged.
• All patients should be counseled to stop smoking and to meet the
Seventh Joint National Committee on the Detection, Evaluation, and
Treatment of High Blood Pressure guidelines for control of
hypertension.

62. • The objectives of dietary therapy are to progressively decrease the
intake of total fat, saturated fat, and cholesterol and to achieve a
desirable body weight.

63. Lifestyle changes
• Do not smoke
• Maintain ideal body weight (BMI 20–25 kg/m2)
• Avoid central obesity
• Reduce total dietary intake of fat to ≤30% of total energy intake
• Reduce intake of saturated fats to ≤10% of total fat intake
• Reduce intake of dietary cholesterol to <300 mg/day
• Replace saturated fats by an increased intake of monounsaturated fats

64. • Increase intake of fresh fruit and vegetables to at least five portions
per day
• Regularly eat fish and other sources of omega-3 fatty acids (at least
two portions of fish each week)
• Limit alcohol intake to <21 units/week for men and <14 units/ week
for women
• Restrict intake of salt to <100 mmol day (<6 g of sodium chloride or
<2.4 g sodium/day)
• Undertake regular aerobic exercise of at least 30 min/day, most days
of the week
• Avoid excess intake of coffee or other caffeine-rich containing
products

65. • Excessive dietary intake of cholesterol and saturated fatty acids leads
to decreased hepatic clearance of LDL and deposition of LDL and
oxidized LDL in peripheral tissues.
• Increased intake of soluble fiber in the form of oat bran, pectins,
certain gums, and psyllium products can result in useful
adjunctive reductions in total and LDL cholesterol (5% to 20%),
but these dietary alterations or supplements should not be substituted
for more active forms of treatment.
• They have little or no effect on HDL-C or triglyceride concentrations.
• These products may also be useful in managing constipation
associated with the bile acid resins (BARs).

66. • Ingestion of 2 to 3 g/day of plant sterols and stanols will reduce LDL by 6% to
15%. They are usually available in commercial margarines.
• In epidemiologic studies, ingestion of large amounts of cold-water oily fish was
associated with a reduction in CHD risk.
• Fish oil supplementation has a fairly large effect in reducing triglycerides and VLDL
cholesterol, but it either has no effect on total and LDL cholesterol or may cause
elevations in these fractions.
• Other actions of fish oil may account for any cardioprotective effects.
• If all recommended dietary changes from the NCEP were instituted, the estimated
average reduction in LDL would range from 20% to 30%.

67. Pharmacologic therapy
Lipid-lowering therapy
There are five main classes of lipid-lowering agents available:
• Statins
• Fibrates
• Bile acid binding agents
• Cholesterol absorption inhibitors
• Nicotinic acid and derivatives.
• Agents such as soluble fibre and fish oils have also been used to
reduce lipid levels.
• A number of new agents are also under investigation for their novel
effect on different parts of the cholesterol biosynthesis pathway

68. The effect of drug therapy on lipids and
lipoproteins is shown as

69. Mechanism of lipid-lowering agents under
investigation

70. • Recommended drugs of choice for each lipoprotein phenotype are
given as

71. 1. Bile Acid Resins (Cholestyramine, Colestipol, Colesevelam)
• The primary action of BARs is to bind bile acids in the intestinal
lumen, with a concurrent interruption of enterohepatic circulation of
bile acids, which decreases the bile acid pool size and stimulates
hepatic synthesis of bile acids from cholesterol.
• Depletion of the hepatic pool of cholesterol results in an increase in
cholesterol biosynthesis and an increase in the number of LDL-Rs on
the hepatocyte membrane, which stimulates an enhanced rate of
catabolism from plasma and lowers LDL levels.

72. • The increase in hepatic cholesterol biosynthesis may be paralleled by
increased hepatic VLDL production, and, consequently, BARs may
aggravate hypertriglyceridemia in patients with combined
hyperlipidemia.
• BARs are useful in treating primary hypercholesterolemia (familial
hypercholesterolemia, familial combined hyperlipidemia, type IIa
hyperlipoproteinemia).
• GI complaints of constipation, bloating, epigastric fullness, nausea,
and flatulence are most commonly reported.
• These adverse effects can be managed by increasing fluid intake,
modifying the diet to increase bulk, and using stool softeners.

73. • The gritty texture and bulk may be minimized by mixing the powder
with orange drink or juice.
• Colestipol may have better palatability than cholestyramine because it
is odorless and tasteless.
• Tablet forms should help improve adherence with this form of therapy.
• Other potential adverse effects include impaired absorption of fat-
soluble vitamins A, D, E, and K; hypernatremia and hyperchloremia;
GI obstruction; and reduced bioavailability of acidic drugs such as
warfarin, nicotinic acid, thyroxine, acetaminophen, hydrocortisone,
hydrochlorothiazide, loperamide, and possibly iron.
• Drug interactions may be avoided by alternating administration times
with an interval of 6 hours or greater between the BAR and other
drugs.

74. Comparison of Drugs Used in the Treatment of
Hyperlipidemia

76. 2. Niacin
• Niacin (nicotinic acid) reduces the hepatic synthesis of VLDL, which
in turn leads to a reduction in the synthesis of LDL. Niacin also
increases HDL by reducing its catabolism.
• The principal use of niacin is for mixed hyperlipidemia or as a
second-line agent in combination therapy for hypercholesterolemia.
• It is a first-line agent or alternative for the treatment of
hypertriglyceridemia and diabetic dyslipidemia.
• Niacin has many common adverse drug reactions; most of the
symptoms and biochemical abnormalities seen do not require
discontinuation of therapy.

77. • Cutaneous flushing and itching appear to be prostaglandin mediated
and can be reduced by taking aspirin 325 mg shortly before niacin
ingestion.
• Taking the niacin dose with meals and slowly titrating the dose
upward may minimize these effects.
• Concomitant alcohol and hot drinks may magnify the flushing and
pruritus from niacin, and they should be avoided at the time of
ingestion. GI intolerance is also a common problem.
• Potentially important laboratory abnormalities occurring with niacin
therapy include elevated liver function tests, hyperuricemia, and
hyperglycemia.

78. • Niacin-associated hepatitis is more common with sustained-release
preparations, and their use should be restricted to patients intolerant of
regular-release products.
• Niacin is contraindicated in patients with active liver disease, and it
may exacerbate preexisting gout and diabetes.
• Nicotinamide should not be used in the treatment of hyperlipidemia
because it does not effectively lower cholesterol or triglyceride levels.

79. 3. HMG-CoA Reductase Inhibitors (Atorvastatin, Fluvastatin,
Lovastatin, Pravastatin, Rosuvastatin, Simvastatin)
• Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase, interrupting the conversion of HMG-CoA to mevalonate,
the rate-limiting step in de novo cholesterol biosynthesis.
• Reduced synthesis of LDL and enhanced catabolism of LDL mediated
through LDL-Rs appear to be the principal mechanisms for lipid-
lowering effects.
• When used as monotherapy, statins are the most potent total and LDL
cholesterol-lowering agents and among the best tolerated.
• .

80. • Total and LDL cholesterol are reduced in a dose-related fashion by
30% or more when added to dietary therapy.
• Combination therapy with a statin and BAR is rational because
numbers of LDL-Rs are increased, leading to greater degradation of
LDL cholesterol; intracellular synthesis of cholesterol is inhibited; and
enterohepatic recycling of bile acids is interrupted.
• Combination therapy with a statin and ezetimibe is also rational
because ezetimibe inhibits cholesterol absorption across the gut border
and adds 12% to 20% further reduction when combined with a statin
or other drugs.

81. • Constipation occurs in fewer than 10% of patients taking statins.
• Other adverse effects include elevated serum aminotransferase levels
(primarily alanine aminotransferase), elevated creatine kinase levels,
myopathy, and rarely rhabdomyolysis.

82. 4. Fibric Acids (Gemfibrozil, Fenofibrate, Clofibrate)
• Fibrate monotherapy is effective in reducing VLDL, but a reciprocal
rise in LDL may occur and total cholesterol values may remain
relatively unchanged.
• Plasma HDL concentrations may rise 10% to 15% or more with
fibrates.
• Gemfibrozil reduces the synthesis of VLDL and, to a lesser extent,
apolipoprotein B with a concurrent increase in the rate of removal of
triglyceride-rich lipoproteins from plasma.

83. • Clofibrate is less effective than gemfibrozil or niacin in reducing
VLDL production.
• GI complaints occur in 3% to 5% of patients, rash in 2%, dizziness in
2.4%, and transient elevations in transaminase levels and alkaline
phosphatase in 4.5% and 1.3%, respectively.
• Clofibrate and, less commonly, gemfibrozil may enhance the
formation of gallstones.
• A myositis syndrome of myalgia, weakness, stiffness, malaise, and
elevations in creatine kinase and aspartate aminotransferase may
occur and seems to be more common in patients with renal
insufficiency.

84. 5. Ezetimibe
• Ezetimibe interferes with the absorption of cholesterol from the brush
border of the intestine, a novel mechanism that makes it a good choice
for adjunctive therapy.
• It is approved as both monotherapy and for use with a statin.
• The dose is 10 mg once daily, given with or without food.
• When used alone, it results in an approximate 18% reduction in LDL
cholesterol.
• When added to a statin, ezetimibe lowers LDL by about an additional
12% to 20%.

85. • A combination product (Vytorin) containing ezetimibe 10 mg and
simvastatin 10, 20, 40, or 80 mg is available.
• Ezetimibe is well tolerated; approximately 4% of patients experience
GI upset.
• Because cardiovascular outcomes with ezetimibe have not been
evaluated, it should be reserved for patients unable to tolerate statin
therapy or those who do not achieve satisfactory lipid lowering with a
statin alone.

86. 6. Fish Oil Supplementation
• Diets high in omega-3 polyunsaturated fatty acids (from fish oil), most
commonly eicosapentaenoic acid (EPA), reduce cholesterol,
triglycerides, LDL, and VLDL and may elevate HDL cholesterol.
• Fish oil supplementation may be most useful in patients with
hypertriglyceridemia, but its role in treatment is not well defined.
• Lovaza (omega-3-acid ethyl esters) is a prescription form of
concentrated fish oil EPA 465 mg and docosahexaenoic acid 375 mg.
• The daily dose is 4 g/day, which can be taken as four 1-g capsules
once daily or two 1-g capsules twice daily.

87. • This product lowers triglycerides by 14% to 30% and raises HDL by
about 10%.
• Complications of fish oil supplementation such as thrombocytopenia
and bleeding disorders have been noted, especially with high doses
(EPA, 15 to 30 g/day).

88. Treatment recommendations
• Treatment of type I hyperlipoproteinemia is directed toward reduction
of chylomicrons derived from dietary fat with the subsequent
reduction in plasma triglycerides.
• Total daily fat intake should be no more than 10 to 25 g/day, or
approximately 15% of total calories.
• Secondary causes of hypertriglyceridemia should be excluded, and, if
present, the underlying disorder should be treated appropriately.

89. • Primary hypercholesterolemia (familial hypercholesterolemia, familial
combined hyperlipidemia, type IIa hyperlipoproteinemia) is treated
with BARs, statins, niacin, or ezetimibe.
• Combined hyperlipoproteinemia (type IIb) may be treated with
statins, niacin, or gemfibrozil to lower LDL-C without elevating
VLDL and triglycerides.
• Niacin is the most effective agent and may be combined with a BAR.
• A BAR alone in this disorder may elevate VLDL and triglycerides,
and their use as single agents for treating combined
hyperlipoproteinemia should be avoided.

90. • Type III hyperlipoproteinemia may be treated with fibrates or niacin.
• Although fibrates have been suggested as the drugs of choice, niacin
is a reasonable alternative because of the lack of data supporting a
cardiovascular mortality benefit from fibrates and because of their
potentially serious adverse effects.
• Fish oil supplementation may be an alternative therapy.
• Type V hyperlipoproteinemia requires stringent restriction of dietary
fat intake.
• Drug therapy with fibrates or niacin is indicated if the response to diet
alone is inadequate.
• Medium-chain triglycerides, which are absorbed without chylomicron
formation, may be used as a dietary supplement for caloric intake if
needed for both types I and V.

91. Combination Drug Therapy
• Combination therapy may be considered after adequate trials of
monotherapy and for patients documented to be adherent to the
prescribed regimen.
• Two or three lipoprotein profiles at 6-week intervals should confirm
lack of response prior to initiation of combination therapy.
• Contraindications to and drug interactions with combined therapy
should be screened carefully, and the extra cost of drug product and
monitoring should be considered.
• In general, a statin plus a BAR or niacin plus a BAR provide the
greatest reduction in total and LDL cholesterol.

92. • Regimens intended to increase HDL levels should include either
gemfibrozil or niacin, bearing in mind that statins combined with
either of these drugs may result in a greater incidence of
hepatotoxicity or myositis.
• Familial combined hyperlipidemia may respond better to a fibrate and
a statin than to a fibrate and a BAR.

93. Treatment of Hypertriglyceridemia
• Lipoprotein pattern types I, III, IV, and V are associated with
hypertriglyceridemia, and these primary lipoprotein disorders should
be excluded prior to implementing therapy.
• A family history positive for CHD is important in identifying patients
at risk for premature atherosclerosis.
• If a patient with CHD has elevated triglycerides, the associated
abnormality is probably a contributing factor to CHD and should be
treated.

94. • High serum triglycerides should be treated by achieving desirable
body weight, consumption of a low saturated fat and cholesterol diet,
regular exercise, smoking cessation, and restriction of alcohol (in
selected patients).
• ATP III identifies the sum of LDL and VLDL (termed non-HDL
[total cholesterol – HDL]) as a secondary therapeutic target in
persons with high triglycerides (≥200 mg/dL).
• The goal for non-HDL with high serum triglycerides is set at 30
mg/dL higher than that for LDL on the premise that a VLDL level of
30 mg/dL or less is normal.

95. • Drug therapy with niacin should be considered in patients with
borderline- high triglycerides but with accompanying risk factors of
established CHD, family history of premature CHD, concomitant LDL
elevation or low HDL, and genetic forms of hypertriglyceridemia
associated with CHD.
• Niacin may be used cautiously in persons with diabetes because a
clinical trial found only a slight increase in glucose and no change in
hemoglobin A1C.
• Alternative therapies include gemfibrozil, statins, and fish oil.

96. • The goal of therapy is to lower triglycerides and VLDL particles that
may be atherogenic, increase HDL, and reduce LDL.
• Very high triglycerides are associated with pancreatitis and other
adverse consequences.
• Management includes dietary fat restriction (10% to 20% of calories
as fat), weight loss, alcohol restriction, and treatment of coexisting
disorders (e.g., diabetes). Drug therapy includes gemfibrozil, niacin,
and higher-potency statins (atorvastatin, rosuvastatin, and
simvastatin).

97. Treatment of low high-density lipoprotein cholesterol
• Low HDL cholesterol is a strong independent risk predictor of CHD.
• ATP III redefined low HDL cholesterol as <40 mg/dL but specified no
goal for
• HDL cholesterol raising.
• In low HDL, the primary target remains LDL, but treatment emphasis
shifts to weight reduction, increased physical activity, smoking
cessation, and to fibrates and niacin if drug therapy is required.

98. Treatment of diabetic dyslipidemia
• Diabetic dyslipidemia is characterized by hypertriglyceridemia, low
HDL, and minimally elevated LDL.
• Small, dense LDL (pattern B) in diabetes is more atherogenic than
larger, more buoyant forms of LDL (pattern A).
• ATP III considers diabetes to be a CHD risk equivalent, and the
primary target is to lower the LDL to <100 mg/dL. When LDL is >130
mg/dL, most patients require simultaneous therapeutic lifestyle
changes and drug therapy.
• When LDL is between 100 and 129 mg/dL, intensifying glycemic
control, adding drugs for atherogenic dyslipidemia (fibrates, niacin),
and intensifying LDL-lowering therapy are options.
• Statins are considered by many to be the drugs of choice because the
primary target is LDL.