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98
CHAPTER 7 Lipid-Modifying Therapy
these fi ndings with basic science experiments detailing the complex functional-
ity of HDL particles. Mendelian randomization evidence might mean that the
complexity of HDL particles is not adequately captured by HDL-C levels alone
but also opens the debate regarding the causality of HDL in ASCVD.
Triglycerides
The effect of triglycerides and triglyceride-rich lipoproteins on atherosclerosis
has been a source of debate for many years. Observational studies dating back
decades implicate elevated triglyceride levels in ASCVD and clinical practice
guidelines recognize the potential ASCVD risk captured in triglyceride levels,
particularly non-fasting levels.
4,7
Recently, a pooled analysis of the Treating
to New Targets (TNT) and the Incremental Decrease in Endpoints through
Aggressive Lipid Lowering (IDEAL) studies, adjusted for age, gender, and study,
found increased cardiovascular risk with higher levels of triglycerides.
26
In
TNT and IDEAL, LDL-C levels were tightly controlled, often below 70 mg/dL.
Indeed, Mendelian randomization evidence is compatible with a causal associa-
tion between triglyceride-mediated pathways and CHD.
27
Events (% per annum)
<2 mmol/L
≥2 to <2.5 mmol/L
≥2 to <3.0 mmol/L
≥3 to <3.5 mmol/L
≥3.5 mmol/L
<2 mmol/L
≥2.5 to <2.5 mmol/L
≥2 to <3.0 mmol/L
≥3 to <3.5 mmol/L
≥3.5 mmol/L
<2 mmol/L
≥2 to <2.5 mmol/L
≥2.5 to <3.0 mmol/L
≥3 to <3.5 mmol/L
99% or
95% Cl
0.45 0.75 1 1.3
Control/less betterStatin/more better
≥3.5 mmol/L
More vs less statin
RR (CI) per 1 mmol/L reduction in LDL-C Trend
test
Statin vs control
All trials combined
Total
Total
704 (4.6%)
1189 (4.2%)
1065 (4.5%)
517 (4.5%)
303 (5.7%)
206 (2.9%)
339 (2.4%)
801 (2.5%)
1490 (2.9%
4205 (2.9%)
910 (4.1%)
1528 (3.6%)
1866 (3.3%)
2007 (3.2%)
4508 (3.0%)
3837 (4.5%)
7136 (2.8%)
10973 (3.2%)Total
Statin/more Control/less
795 (5.2%)
1317 (4.8%)
1203 (5.0%)
633 (5.8%)
398 (7.8%)
217 (3.2%)
412 (2.9%)
1022 (3.2%)
1821 (3.6%)
5338 (3.7%)
1012 (4.6%)
1729 (4.2%)
2225 (4.0%)
2454 (4.0%)
5736 (3.9%)
4416 (5.3%)
8946 (3.6%)
13350 (4.0%)
0.71 (0.52–0.98)
χ
2
1
=2.04
(p=0.2)
χ
2
1
=0.80
(p=0.4)
χ
2
1
=1.08
(p=0.3)
0.77 (0.64–0.94)
0.81 (0.67–0.97)
0.61 (0.46–0.81)
0.64 (0.47–0.86)
0.87 (0.60–1.28)
0.77 (0.62–0.97)
0.76 (0.67–0.86)
0.77 (0.71–0.84)
0.80 (0.77–0.84)
0.78 (0.61–0.99)
0.77 (0.67–0.89)
0.77 (0.70–0.85)
0.76 (0.70–0.82)
0.80 (0.76–0.83)
0.72 (0.66–0.78)
0.79 (0.77–0.81)
0.78 (0.76–0.80)
Figure 7.3 Effects on Major Vascular Events per 39 mg/dL (1.0 mmol/L) Reduction in
LDL-C, by Baseline LDL-C Cholesterol Concentration on the Less Intensive or Control
Regimen. Rate ratios (RRs) are plotted for each comparison of fi rst event rates between
treatment groups, and are weighted per 39 mg/dL (1.0 mmol/L) LDL-C difference at
1 year. Analyses were done with trial-specifi c and subgroup specifi c LDL-C weights for
each baseline LDL-C category. Missing data are not plotted. RRs are shown with hori-
zontal lines denoting 99% CIs or with open diamonds showing 95% CIs. (Source: From
Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C et al. Effi cacy and safety
of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000
participants in 26 randomised trials. Lancet 2010;376:1676, with permission.)
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99
CHAPTER 7 Lipid-Modifying Therapy
When the triglyceride concentration is between 200 and 499 mg/dL, non-
HDL-C is a secondary target for ASCVD prevention in worldwide dyslipidemia
treatment guidelines. Non-HDL-C is total cholesterol minus HDL-C, which is
the sum of VLDL-C, IDL-C, and LDL-C, and refl ects total atherogenic choles-
terol burden. Non-HDL-C will likely become a more widely recognized and
commonly used clinical metric over time, even in patients with triglycerides
below 200 mg/dL. The usual conservative target of therapy is below 130 mg/dL
and a more aggressive target is below 100 mg/dL, though a level below 90 mg/
dL is probably ideal.
Lipid-modifying therapies
Tables 7.1 and 7.2 show recent European recommendations for the pharma-
cologic treatment of hypercholesterolemia and hypertriglyceridemia, respec-
tively. Pharmacotherapies to lower LDL-C include statins, ezetimibe, bile acid
sequestrants, and niacin. Niacin in particular has concurrent HDL-C-raising and
triglyceride-lowering properties. Fish oils (omega-3 fatty acids) and fi brates
have potent effects in lowering triglycerides. Nevertheless, the foundation of
lipid-modifying therapy is lifestyle modifi cation.
Lifestyle modifi cation
Adopting a healthier lifestyle can globally improve the lipid profi le, lead to cor-
onary lesion regression, and reduce the future risk of ASCVD.
28
Improvements
on the lipid profi le may include LDL-C and triglyceride lowering as well as an
increase in HDL-C. The randomized Lifestyle Heart Trial,
29
conducted between
1986 and 1992, examined intensive lifestyle changes in patients with angio-
graphically proven moderate to severe CHD. The intervention group partici-
pated in a program that included a 10 percent fat, vegetarian diet; moderate
Table 7.1 Recommendations for the Pharmacologic Treatment
of Hypercholesterolemia
Recommendations Class
a
Level
b
Prescribe statin up to the highest recommended
dose, or highest tolerable does to reach the target
level.
IA
In the case of statin intolerance, bile acid
sequestrants or nicotinic acid should be considered.
IIa B
A cholesterol absorption inhibitor, alone or in
combination with bile acid sequestrants or nicotinic
acid, may also be considered in the case of statin
intolerance.
IIb C
If target level is not reached, statin combination
with a cholesterol absorption inhibitor or bile acid
sequestrant or nicotinic acid may be considered.
IIb C
a
Class of recommendation,
b
Level of evidence.
From Reiner Z, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force
for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the
European Atherosclerosis Society (EAS). Eur Heart J 2011; 32 :1793, with permission.
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100
CHAPTER 7 Lipid-Modifying Therapy
aerobic exercise; stress management training; smoking cessation; and group
psychosocial support. LDL-C levels were 40 percent lower after 1 year and
20 percent lower at 5 years. In the intervention group, 82 percent of patients
had an average change toward CHD regression by quantitative coronary angi-
ography, and experimental-group patients were approximately two times less
likely to undergo a coronary intervention, bypass surgery, or cardiac-related
hospitalization.
27
Beyond LDL-C lowering, changes in diet and exercise, weight loss, smoking
cessation, and alcohol intake are each associated with higher HDL-C levels and
decreased ASCVD risk. Studies have shown that HDL-C increases approximately
1.6 mg/dL for every 10 pounds of weight loss.
30
Additionally, diets with higher
intakes of marine-based omega-3 fatty acids correspond with higher HDL-C
levels without elevations in triglycerides. The Mediterranean diet incorporates
omega-3 fatty acids and is characterized by a high intake of monounsaturated fat,
plant proteins, whole grains, and fi sh with moderate intake of alcohol, and low
consumption of red meat, refi ned grains, and sweets. A recent meta-analysis
supports favorable infl uences of the Mediterranean diet on cardiovascular and
infl ammatory risk factors,
31
and the diet is linked to lower cardiovascular and
all-cause mortality. Exercise, especially intense aerobic exercise, may increase
HDL-C by an average of 5 to 10 percent, with a 10 to 20 percent increase in
HDL-C when at least 1,200 kcal are burned on a weekly basis.
20
Cigarette smoking, an established ASCVD risk factor, is associated with lower
HDL-C levels. This seems to occur through impairment of the lecithin-choles-
terol acyltransferase (LCAT) enzyme, which sequesters cholesterol into the HDL
core.
32
A recent randomized controlled trial demonstrated that cessation from
smoking for 1 year raised HDL-C by an average of 2.4 mg/dL compared to those
who continued to smoke in a study population where less than 5 percent of the
entire population was on medication to lower cholesterol.
33
Given that a 1 mg/dL
increase in HDL-C is associated with a 2 to 3 percent decrease in ASCVD, these
results imply that cessation of smoking for 1 year may reduce CVD events by 4 to
6 percent over 10 years on the basis of the lipid effects alone.
33
Table 7.2 Recommendations for the Pharmacologic Treatment of
Hypertriglyceridemia (HTG)
Recommendations Class
a
Level
b
In particular high-risk patients (see above), lowering
of HTG by using the following drugs:
Is recommended: fi brates I B
Should be considered: nicotinic acid IIa B
Nicotinic acid + laropiprant IIa C
Omega-3 fatty acids IIa B
Statin + nicotinic acid
c
IIa A
Statin + fi brate
c
IIa C
May be considered: combinations with omega-3 fatty acids
d
IIb B
a
Class of recommendation,
b
Level of evidence,
c
Evidence for additional lipid lowering, compared
with monotherapy,
d
The evidence for prevention of cardiovascular disease using combination
therapy is in general limited.
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101
CHAPTER 7 Lipid-Modifying Therapy
Alcohol inhibits hepatic lipase and is associated with a rise in HDL-C, par-
ticularly the smaller, dense form (HDL3-C). One ounce of alcohol consumed
daily is associated with a 15 percent increase in HDL-C. In the recent Veteran’s
Affairs Normative Aging Study (VA NAS), increases in HDL-C were associated
with maintaining an alcohol intake of at least two drinks daily, along with main-
taining a normal (less than 25 kg/m
2
) body mass index.
34
Aerobic exercise is a critical component of any healthy lifestyle program.
Given that it is associated with a roughly 20 percent reduction in serum trig-
lyceride levels and improved glycemic control, it is of particular importance in
patients with type 2 diabetes. Currently, the American Heart Association rec-
ommends moderately intense aerobic exercise for a minimum of 30 minutes,
5 to 7 days a week, or vigorous-intensity aerobic exercise for a minimum of
20 minutes, 3 days a week.
Statins
HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors,
otherwise known as statins, are the single hypercholesterolemia treatment with
a class IA indication (see Table 7.1) and are widely used for treatment of dys-
lipidemia. Standard statin therapy (e.g., 20 to 40 mg simvastatin daily) reduces
LDL-C by approximately 30 percent, while more intense therapy (e.g., 40 to
80 mg atorvastatin or 20 to 40 mg rosuvastatin) reduces LDL-C by approxi-
mately 50 percent. Statins also lower triglycerides and can increase HDL-C
levels. More potent statins can robustly lower triglycerides and are generally
considered fi rst-line therapy for patients with modest hypertriglyceridemia. For
example, atorvastatin and rosuvastatin can reduce triglyceride levels by 22 to
45 percent.
35
The combination of fenofi brate with fl uvastatin has been shown
to decrease serum triglyceride levels by approximately 15 to 30 percent with
the concurrent HDL-C raising of 5 to 20 percent, with greater benefi ts seen
among patients with type 2 diabetes.
36–38
Many randomized controlled trials have shown that statin therapy reduces
ASCVD events. In 1994, the Cholesterol Treatment Trialists (CTT) collabora-
tion was formed to perform periodic, prospective meta-analyses on statin trials
focused on the outcome of major ASCVD events, defi ned as coronary death,
nonfatal myocardial infarction, coronary revascularization, or stroke. A recent
meta-analysis from the CTT investigated 26 trials (n = 169,138) utilizing statin
therapy.
10
Of the 26 studies, 5 trials investigated more- versus less-intensive
statin therapy treatment and the others statin versus placebo.
Overall, the weighted average reduction in major cardiovascular events for
all 26 trials was 22 percent per 1.0 mmol/L (39 mg/dL) reduction in LDL-C.
Separately, the more- versus less-intense therapy analysis and the statin versus
control analysis demonstrated proportional reductions for major cardiovascu-
lar events of 28 and 21 percent per 39 mg/dL (1.0 mmol/L) reduction in LDL-C
levels, respectively. There was a signifi cant reduction in mortality due to CHD,
with a risk reduction of 20 percent. First major CHD events, fi rst coronary
revascularizations, and fi rst major vascular events were all signifi cantly reduced
in both analysis groups. Similar proportional reductions in ASCVD events were
found in all types of patients studied, including old and young, men and women,
and primary or secondary prevention patients.
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102
CHAPTER 7 Lipid-Modifying Therapy
In August 2012, the CTT collaborators published an additional meta-analysis
with the purpose of determining the effects of lowering LDL-C in the low-risk
population.
11
The meta-analysis demonstrated that for individuals with a 5-year
ASCVD risk of 10 percent or less, an LDL-C reduction of 39 mg/dL (1 mmol/L)
produced an absolute reduction in ASCVD events of approximately 11 per
1,000 over 5 years. Weighing the risk reduction against possible adverse effects
of statin therapy such as myopathy, hemorrhagic stroke, and new-onset diabe-
tes, it appeared that the risk reduction still outweighed any adverse effects of
statin use for most patients.
Statin side effects are related to the type and potency of the statin but are
independent of on-treatment LDL-C levels. Myopathy is commonly considered
in clinical practice; the vast majority of cases are myalgias or mild myositis, while
rhabdomyolysis occurs in only 1 per 10,000 patients, typically in the setting of
drug–drug interactions and certain comorbidities. Asymptomatic transaminitis
may be a statin class effect but is not strongly tied to an increased risk of liver
disease, and the U.S. Food & Drug Administration (FDA) no longer recom-
mends liver tests for routine surveillance. Statins seem to be linked to a modest
increase in the diagnosis of diabetes mellitus, on the order of one new case per
1,000 person-years of treatment.
Nevertheless, patients with insulin resistance, diabetes, and metabolic syn-
drome have derived net cardiovascular protection from statin therapy in clinical
trials. Despite some concerns, there is no convincing evidence to date demon-
strating an increase in the rate of malignancy or memory loss or hemorrhagic
stroke associated with statin use. Overall, many myocardial infarctions and
other ASCVD events are prevented with statin therapy for every side effect
that is incurred. As the National Lipid Association Statin Safety Task Force has
stated, “the person should fear the heart attack, not the statin.”
Nevertheless, some patients cannot tolerate statins or have persistent hyper-
lipidemia on maximally tolerated statin therapy. For such patients, a choles-
terol absorption inhibitor (ezetimibe), bile acid sequestrant, or niacin may be
considered based on IIa or IIb recommendations and a lower level of evidence
(Table 7.1). These agents have been shown to lower LDL-C by 15 to 20 percent.
This is the equivalent of tripling the dose of a statin. On the horizon, PCSK9
inhibitors are being evaluated in large cardiovascular outcome trials and appear
to offer large incremental reductions in LDL-C beyond that offered by statins.
Ezetimibe
Ezetimibe is a selective cholesterol inhibitor that binds to the Niemann-Pick
C1-like 1 (NPC1L1) protein found at the brush border of enterocytes within
the intestinal lumen. Ezetimibe blocks the activity of NPC1L1, thereby inhibiting
the uptake and cellular transport of cholesterol and non-cholesterol sterols.
Ezetimibe 10 mg daily in combination with simvastatin 10 mg daily reduced
LDL-C by 44 percent, similar to simvastatin 80 mg daily.
39
Recently, ezetimibe has come under some scrutiny with the results of
smaller studies in which it failed to meet the study’s primary end point.
The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances
Atherosclerosis Regression (ENHANCE) study and the Arterial Biology for
the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL
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CHAPTER 7 Lipid-Modifying Therapy
and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) trial
both showed that the addition of ezetimibe did not improve carotid intima–
medial thickness (CIMT).
However, the validity of CIMT as a surrogate end point is uncertain. Animal
models have shown atherosclerotic regression with ezetimibe. Moreover, the
Study of Heart and Renal Protection (SHARP) trial found an improvement
in ASCVD outcomes with use of ezetimibe in combination with simvastatin.
Currently, the Improved Reduction of Outcomes: Vytorin Effi cacy International
Trial (IMPROVE-IT) is under way and expected to be completed in 2014.
IMPROVE-IT compares ezetimibe/simvastatin with simvastatin alone on cardio-
vascular end points in approximately 18,000 patients with recent acute coro-
nary syndromes who had a baseline LDL-C of less than 125 mg/dL.
Bile acid sequestrants
Bile acid sequestrants decrease LDL-C by 5 to 30 percent by enhancing conver-
sion to bile acid and increasing expression of LDL receptors (LDL-R), thereby
promoting the increased uptake of circulating LDL-C. The Lipid Research Clinics
Coronary Primary Prevention Trial demonstrated a 19 percent reduction in the
composite end point of nonfatal myocardial infarction and death with the use of
cholestyramine. Bile acid sequestrants should probably be avoided in patients
with elevated triglyceride levels. Bile acid sequestrants activate phosphatidic
acid phosphatase, which promotes hepatic triglyceride synthesis, inducing
secretion of triglyceride-rich, very-low-density-lipoprotein (VLDL) particles,
and consequently can increase triglyceride levels.
One obstacle that many clinicians face with bile acid sequestrants is adher-
ence due to gastrointestinal disturbances, especially constipation. Remaining
in the gut without systemic absorption, colesevelam and cholestyramine have
respective incidences of constipation of 10 and 26 percent. While administra-
tion as a large pill multiple times a day also presents a challenge to adherence,
the introduction of a once-daily colesevelam suspension may facilitate patient
adherence to therapy.
Niacin
Nicotinic acid, or niacin, is a B vitamin that seems to inhibit adenylate cyclase
and lead to both a reduction in HDL catabolism as well as an increase in HDL
production by blocking hepatic apolipoprotein A-I removal. Niacin also appears
to inhibit the adipose hormone-sensitive lipase, thereby reducing free fatty acid
fl ux to hepatocytes, causing a decrease in VLDL and triglyceride production. In
daily doses of 1,500 to 3,000 mg, niacin reduces total cholesterol and LDL-C
levels by about 10 to 25 percent, increases HDL-C levels by 15 to 30 percent,
and reduces triglyceride levels by up to 20 to 50 percent.
40
Niacin can also
lower lipoprotein (a) by 20 percent at doses of 2 grams per day.
40
In the Coronary Drug Project (CDP), immediate-release niacin (3 grams daily)
yielded an 11 percent total mortality benefi t along with a reduction in nonfatal
myocardial infarction. The series of Arterial Biology for the Investigation of
the Treatment Effects of Reducing Cholesterol (ARBITER) trials demonstrated
CIMT regression when extended-release niacin was combined with statin ther-
apy. This was also supported by the HDL Atherosclerosis Treatment (HATS)
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104
CHAPTER 7 Lipid-Modifying Therapy
study, in which there was angiographic evidence of decreased atherosclerosis
with the combination of niacin and statin therapy.
Despite niacin’s clinical outcomes benefi t in the pre-statin era and ben-
efi t on surrogate markers of ASCVD, there is still debate whether adding
niacin can improve clinical outcomes on a background of statin therapy. The
Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High
Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial inves-
tigated the addition of niacin in patients with well-controlled LDL-C (less than
70 mg/dL) through combinations of statin and ezetimibe therapy. In this context,
no additional ASCVD benefi t was conferred by niacin over a mean follow-up
of 3 years. The results of this trial reinforce the benefi ts of tight LDL-C control.
The Heart Protection Study 2—Treatment of HDL to Reduce the Incidence of
Vascular Events (HPS2-THRIVE) investigated the combination of nicotinic acid/
laropiprant (a fl ushing inhibitor) and statin therapy versus statin therapy alone
and also found no overall benefi t in individuals with tightly controlled LDL-C
(baseline 63 mg/dL).
Niacin-induced fl ushing (prostaglandin-mediated) may be prevented or mini-
mized by giving aspirin 30 minutes prior to niacin. Avoidance of alcohol, mono-
sodium glutamate, hot beverages, and spicy foods can also help. Once-daily
sustained-release formulations may improve adherence. Other side effects
from high-dose niacin include a small increase in the serum glucose level, a
moderate increase in the serum uric acid level, and a small reduction in the
serum phosphorus level.
Fibrates
Fibrates seem to activate nuclear transcription of peroxisome proliferator-acti-
vated receptor α (PPAR α ), decreasing apoC-III concentration, increasing lipo-
protein lipase activity, and ultimately increasing VLDL clearance and reducing
triglyceride concentrations. Fibrates may also act by increasing fatty oxidation
in the liver and muscle, thus reducing hepatic secretion of VLDL triglycerides.
The effects of fi brates are greatest on triglyceride concentrations, where stud-
ies have shown a 30 to 50 percent decrease in plasma triglyceride concentra-
tions.
41
Fibrates generally increase HDL-C levels by 10 to 25 percent.
42
The
effects on LDL-C are more modest (0 to 10 percent reduction).
43
Therefore,
they are predominantly considered for triglyceride lowering.
In a recent meta-analysis of 18 fi brate trials with a total of 45,058 participants,
fi brates had statistically signifi cant relative risk reductions on major cardiovas-
cular events (10 percent) and on coronary events (13 percent).
44
However,
there was no signifi cant reduction in all-cause or cardiovascular mortality or
on sudden death.
44
Multiple studies in this meta-analysis included the use of
clofi brate, which was removed from the market more than 25 years ago due to
increases in cholangiocarcinoma and other gastrointestinal cancers. Therefore,
this analysis may not be entirely applicable to current times.
Two notable trials testing fi brates are the Veterans Affairs High-Density
Lipoprotein Intervention Trial (VA-HIT)
45
and the Action to Control
Cardiovascular Risk in Diabetes (ACCORD)
46
trials. In the VA-HIT, among
2,531 men with ASCVD and HDL-C below 40 mg/dL, LDL-C below 140 mg/dL,
and triglycerides below 300 mg/dL, ASCVD events were reduced by 11 percent
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105
CHAPTER 7 Lipid-Modifying Therapy
with gemfi brozil for every 5-mg/dL increase in HDL-C. Additionally, there was
a 22 percent risk reduction in nonfatal myocardial infarction or death due to
ASCVD. In those patients with diabetes mellitus, there was a 32 percent reduc-
tion in the combined end point of death due to CHD or stroke.
45
More recently, the ACCORD trial
46
investigated the benefi t of fenofi brate
therapy on top of simvastatin therapy in 10,251 patients with type 2 diabetes
mellitus. Although the trial was neutral with respect to the primary outcomes
(fatal ASCVD events, nonfatal myocardial infarction, or nonfatal stroke), the
subgroup with triglyceride levels of 204 mg/dL or more and HDL-C levels of
34 mg/dL or less showed a strong trend for clinical benefi t.
Fibrates are generally well tolerated. However, one major caution that
should be noted with respect to fi brate therapy is that gemfi brozil in combina-
tion with statins is more likely to cause myositis than fenofi brate.
47
This has
been attributed to gemfi brozil’s inhibition of hepatic glucuronidation of statins
that is necessary for renal statin excretion.
48
Moreover, fi brates have important
interactions with other drugs. An interaction with warfarin leads to an increase
in warfarin levels and the International Normalized Ratio. Fibrates require dose
adjustment in the setting of chronic kidney disease. Gastrointestinal side effects
are also seen, particularly when therapy is started.
Fish oil (omega-3 fatty acids)
Fish oil (containing omega-3 fatty acids or “omega-3s”) are potent agents for
hypertriglyceridemia that can be considered to lower serum triglyceride con-
centrations. While found in the Mediterranean diet, omega-3 fatty acids can
also be concentrated into over-the-counter and prescription-strength fi sh oil
capsules. The key active components appear to be eicosapentaenoic acid (EPA)
and docosahexaenoic acid (DHA). The mechanism of action is poorly under-
stood but may relate to PPARs.
Clinical trial evidence does not justify widespread use of fi sh oil. Fish oil
may be especially considered as an adjunct to dietary modifi cation in patients
where the goal is to decrease triglyceride levels to below 500 mg/dL to prevent
pancreatitis.
49,50
The FDA has approved omega-3 fatty acids for this indication.
The standard dosing is 2 to 4 grams daily. Regarding side effects, fi sh oils seem
to have antithrombotic effects and may increase bleeding, especially when
given in addition to antiplatelet agents. Otherwise, theys appear to be very safe
and well tolerated. An ongoing trial, REDUCE-IT, is attempting to determine
whether omega-3 fatty acids on top of statin therapy reduce cardiovascular
events in patients at risk.
On the horizon: Adult Treatment Panel IV guidelines
This chapter emphasizes recommendations for lipid-modifying therapy based
on the recent European guidelines
7
(Tables 7.1 and 7.2). In the United States,
the National Heart, Lung, and Blood Institute’s National Cholesterol Education
Program Adult Treatment Panel last published guidelines for lipid-modifying
therapy in 2001,
4
with a white paper update in 2004.
5
At this time, the Adult
Treatment Panel IV guideline is under review but not yet publicly released. Like
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106
CHAPTER 7 Lipid-Modifying Therapy
the European guidelines,
7
the Adult Treatment Panel III report focuses on treat-
ing to targets of low LDL-C levels. Indeed, such an approach is rated as class IA
in the European guidelines
7
(and Canadian guidelines
8
) and is consistent with a
vast body of evidence, from basic science, to animal studies, to genetic work, to
numerous randomized control trials of lipid-modifying therapies.
While there is a consensus in the need to treat the right patients with the
right treatments and the right dose of treatments, there is some emerging con-
troversy about the role of lipid targets to help guide therapy. Recently, some
experts have proposed abandoning lipid targets altogether, submitting that the
most robust evidence is for employing the highest tolerated dose of a statin.
51
Maximizing statin therapy is a laudable goal. Moreover, randomized clinical tri-
als were drug-centric, randomizing to drug or no drug, or drug or more drug,
and therefore were not designed to directly test lipid targets. Nevertheless, as
deeply engrained in clinical practice, and recognized in guidelines around the
globe, lipid targets represent a synthesis of prevailing evidence and can help
personalize ongoing therapy.
The biggest downside to lipid targets may be when they lead to treatment
withholding due to relatively low LDL-C levels despite elevated absolute risk.
52
Such an approach runs contrary to clinical trial evidence (see Fig. 7.3). At base-
line, integrating the lipid profi le with other cardiovascular risk information to
most accurately determine absolute risk may help best allocate lipid-modifying
therapies.
52
We look forward to seeing how the Adult Treatment Panel IV
report integrates these concepts in an updated guideline for the management
of patients with dyslipidemia.
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2. Davidson M, Toth P . Low-density lipoprotein cholesterol: role in atheroscle-
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