treatment, mean LDL-C levels in patients randomly assigned to receive atorvastatin
80 mg and pravastatin 40 mg were 62 and 95 mg/dL, respectively. The composite
cardiovascular endpoint (death from any cause, MI, documented unstable angina
requiring rehospitalization, revascularization, and stroke) was significantly reduced
by 16% with high-intensity atorvastatin compared with moderate-intensity
77 Data from the National Registry of Myocardial Infarction 4
demonstrated that early initiation of statins in the acute setting (with the first 24 hours
of an acute MI) was associated with a significantly lower rate of early complications
78 Additionally, discontinuation of statin in patients who
present with an ACS is associated with increased event rates above those who are
PHARMACOKINETICS/PHARMACODYNAMICS
The currently available statins are atorvastatin, fluvastatin, lovastatin, pitavastatin,
pravastatin, rosuvastatin, and simvastatin. These agents possess different
pharmacokinetic properties that may play a role in their efficacy and safety.
Three statins are derived from fungi (simvastatin, pravastatin, and lovastatin),
while the others (atorvastatin, rosuvastatin, pitavastatin, and fluvastatin) are
84–87 Lovastatin and simvastatin are prodrugs and must be converted to their
active form to exert a pharmacologic effect. Rosuvastatin and atorvastatin have the
longest half-lives of 19 and 14 hours, respectively, which enables longer inhibition
of the HMG-CoA enzyme and greater LDL-C reductions compared to other
84,86 Both of these agents lower LDL-C by a mean of approximately 60% at
maximum doses (rosuvastatin 40 mg daily and atorvastatin 80 mg daily). The long
half-life also allows for administration at any time of day rather than at bedtime for
maximum effect, which is recommended for simvastatin, lovastatin, pravastatin, and
81–83,85 Although pitavastatin has a shorter half-life (12 hours) than
rosuvastatin and atorvastatin it may also be taken at any time of day.
administration of the shorter acting agents at bedtime is important because
cholesterol biosynthesis occurs at its highest rate in the evening hours, thus allowing
these agents to have the greatest effect on HMG-CoA reductase inhibition and on
lowering of LDL-C. However, with extended-release (ER) formulations of lovastatin
and fluvastatin, bedtime administration is less important.
The amount of statin that reaches the systemic circulation is relatively small.
Bioavailability ranges from less than 5% with lovastatin and simvastatin to 51% with
pitavastatin (oral solution). Pravastatin, fluvastatin, and rosuvastatin are hydrophilic
agents and may have less tissue distribution and result in less muscle toxicity.
However, this aspect is more theoretical than it is clinically valid. All statins are
eliminated primarily by the liver, with substantial biliary excretion. However,
several statins require dose adjustments in patients with significant renal
Statins are generally well tolerated. The most common adverse effects reported
include muscle pain and weakness (myalgias), headache, GI symptoms, including
dyspepsia, flatus, constipation, and abdominal pain, and skin rashes.
symptoms are usually mild and often dissipate with continued therapy. Less common
adverse effects include myopathy, elevated hepatic transaminases, and diabetes.
Cognitive dysfunction may be potentially associated with statin therapy but this has
not yet been demonstrated to be causally related to statin treatment.
Muscle-related adverse effects associated with statins are divided into three
different types based on symptoms and the presence or absence of creatine kinase
(CK) elevations. These include myalgias, myopathy, and rhabdomyolysis. Myalgias
are the most commonly reported muscle symptoms with an incidence of around
92 Myalgias are defined as muscle aches or weakness without CK elevations.
This adverse effect is the most common reason for patients to discontinue statin
Dosing of Statins in Patients with Renal Insufficiency
Atorvastatin Doses up to 80 mg may be
Fluvastatin Doses up to 80 mg may be
Lovastatin Doses up to 80 mg may be
Pitavastatin Doses up to 2 mg may be used Doses up to 2 mg may be used Doses up to 2 mg may be used
Pravastatin Doses up to 40 mg may be
Simvastatin Doses up to 80 mg may be
Rosuvastatin Doses up to 40 mg may be
Myopathy is defined as the presence of myalgias, including aches, soreness, or
weakness, and an increase in serum CK more than 10 times the upper lipid of normal
usual causes (i.e., trauma, increased physical activity). Rhabdomyolysis is defined as
a CK of at least 10 times the ULN with an elevated serum creatinine and symptoms
93 Rhabdomyolysis is the least common of the muscle-related
adverse effects, but can be life threatening with acute renal failure, cardiac arrest, or
arrhythmias due to severe electrolyte abnormalities. Most cases of rhabdomyolysis
have occurred with high doses of statins, in patients with impaired renal or hepatic
function, in older individuals, or when statins are used in combination with
interacting drugs. The most common areas affected are in the belly of larger muscles.
It is important to distinguish between this and joint pain that may be associated with
Simvastatin at a dose of 80 mg daily is associated with the highest incidence of
rhabdomyolysis among the statins agents. However, this dose is no longer
recommended by the US Food and Drug Administration (FDA) and the ACC/AHA
Management of statin-associated muscle adverse effects can be challenging.
Routine monitoring of CK levels in asymptomatic patients is unnecessary. However,
unexplained symptoms of muscle aches, weakness, or soreness should prompt
evaluation of CK and other potential underlying etiologies. Myopathy is more likely
to occur with high systemic concentrations of statin and when there are underlying
risk factors (e.g., age > 80 years, severe CKD, hypothyroidism, trauma, interacting
medications, or flu-like syndromes). If a patient develops signs and symptoms
consistent with myopathy, statin therapy should be withdrawn until CK levels return
to normal. If rhabdomyolysis is diagnosed, statin therapy should be discontinued
immediately and etiology determined. Re-challenge of a statin may be considered if
the cause was secondary to an interacting medication or other underlying cause that
can be identified and corrected. Occasionally, symptoms of myalgia are bothersome
or intolerable to the patient, even when the CK level is normal or elevated less than
10 times the ULN. In these cases, the statin should be discontinued. Once symptoms
subside, statin therapy can be restarted at the same or reduced dose, or with a
different statin. Alternate day and even once-weekly dosing of statins have been used
in patients who have statin intolerance caused by myopathy.
alternative regimens have not been evaluated in cardiovascular outcome trials.
Statins may also cause an elevation in transaminase enzyme levels of more than 3
times the ULN in 1% to 1.5% of patients in a dose-dependent manner. The
transaminase level will often return to normal spontaneously in 70% of cases even
with continued statin therapy.
93 Elevations in transaminases will also return to normal
if the statin is discontinued. Rechallenge with the same or a different statin after
enzymes have returned to normal limits is acceptable. If the medication is tolerated
on rechallenge, it can be continued; recurrence of transaminase elevation warrants
further evaluation of other potential causes. It is recommended that prior to initiating
statin therapy patients should have baseline liver function tests performed. The report
of the NLA Statin Safety Task Force recommends that if ALT or AST is 1 to 3 times
the ULN during statin therapy, there is no need to discontinue the statin.
AST exceeds 3 times the ULN during statin therapy, monitor the patient and repeat
the transaminase measures. There is no need to discontinue the statin. If a patient’s
transaminase levels continue to rise or if there is further objective evidence (i.e.,
hepatomegaly, jaundice, elevated direct bilirubin, related symptoms) of liver injury,
the statin should be discontinued. The estimated incidence of statin-associated liver
failure is 1 per million person-years of use.
95 There is evidence that patients with
chronic liver disease, nonalcoholic fatty liver disease, or nonalcoholic
steatohepatitis may safely receive statin therapy.
In 2012, the FDA required an update to the statin prescribing labeling to include
information regarding a potential increased risk of reversible cognitive impairment,
to include memory loss. Some case reports have suggested that the statins may cause
cognitive impairment or memory loss.
97 However, data from randomized controlled
trials have failed to show an association and some data even suggest a beneficial
effect on the progression of Alzheimer disease.
74,98,99 Therefore, if a patient presents
with cognitive deficits, he should first undergo an evaluation to identify other
potential causes. If the statin is suspected, it is reasonable to consider discontinuing
therapy for up to 3 months and monitor for improvment.
then a speculation may be made that the statin was the cause. However, one must
carefully balance the decision to discontinue the statin due to the proven benefit of
these agents. Consideration should be given to perhaps reintroduce a different statin
or a different statin dose and monitor for recurrence of deficits. Additionally,
because improvement in cognitive function is subjective, an objective test such as a
Mini Mental State Exam (MMSE) should be considered prior to discontinuation and
repeated after discontinuation to assess for any changes.
history of type 2 diabetes and hypertension. Current medications include metformin, lisinopril, and
that she struggles with weight management (BMI 33.8 kg/m
) and has difficulty with exercise due to previous
knee injury and a torn rotator cuff. She has a strong family history of premature ASCVD, diabetes,
results demonstrate the following:
What are your initial recommendations for lipid management for M.T.?
All available guidelines for the management of dyslipidemia and diabetes
recommend lifestyle counseling as the foundation of therapy. M.T.’s BMI is
consistent with obesity and she has inadequately controlled diabetes and
hypertension. Nutrition counseling and weight management will be critical to
improve control of these important ASCVD risk factors. Tobacco cessation
counseling, referral to a cessation program, and possible pharmacotherapy and/or
nicotine replacement therapy are important in this very high-risk patient with a strong
family history of premature ASCVD. Given the patient’s ongoing knee and shoulder
pain, her ability to engage in significant aerobic activity may be limited until
successful weight loss is achieved.
According to ACC/AHA, NLA, and ADA recommendations for management of
dyslipidemia M.T. qualifies for statin therapy in a high-risk diabetic. Her 10-year
ASCVD risk by the ACC/AHA CV Risk Calculator is 27.2% and high-intensity statin
is indicated by the ACC/AHA treatment algorithm. Patients with diabetes and two or
more other major ASCVD risk factors are considered to be at very high risk by the
patients between the ages of 40 to 75 with type 1 or type 2 diabetes. The intensity of
statin therapy is based upon the patient’s 10-year ASCVD risk by the ACC/AHA CV
Risk Calculator. High-intensity statin is considered reasonable in patients with 10-
year risk ≥7.5%. Thus, the recommendation for high-intensity statin therapy for M.T.
is consistent across all three of these US guidelines.
approach the evaluation of possible statin-related muscle symptoms?
Statin-related muscle symptoms present a significant challenge to clinicians,
though the prevalence of true statin intolerance is likely quite low. A systematic
approach to possible statin intolerance is required to confirm the diagnosis,
particularly in a very high-risk patient like M.T. The ACC/AHA guideline and NLA
recommendations provide similar strategies for patient evaluation and management
and these recommendations have been incorporated into the ACC Statin Intolerance
app for all mobile devices as well as a web-based version.
It is important for clinicians to take a careful musculoskeletal history and review
of systems and document patient complaints prior to initiation of statin therapy. As
reported by M.T., patients may report baseline muscle and joint symptoms that have
varied in severity and frequency prior to lipid management. Following initiation of
statin therapy, patient’s muscle symptoms should be compared to those at baseline
evaluation to determine if complaints are new or merely coincidental exacerbations
of prior existing symptoms. True statin-related myalgias are typically symmetric and
are described as aching, soreness, stiffness, tenderness, weakness, or cramping of
large proximal muscle groups. Tingling, numbness, sharp or stabbing pain, twitching,
nocturnal cramps, arthralgias/arthritis, or unilateral symptoms are less likely to be
abuse, frailty, low BMI, female gender, multiple or serious comorbidities, renal
insufficiency, hepatic dysfunction, or drug interactions. Other potential primary
causes of muscle symptoms should be evaluated such as hypothyroidism, vitamin D
deficiency, trauma, previous or new primary muscle diseases, rheumatologic
disorders, metabolic disorders (adrenal insufficiency, hypoparathyroidism, Cushing
syndrome), or peripheral arterial disease.
The ACC/AHA and NLA recommend temporary discontinuation of statin when a
been rare case reports of persistent myopathy following discontinuation of statin
therapy. When symptoms have resolved and the patient is asymptomatic, treatment
with the same statin at original or lower dose is reinitiated to determine if the
symptoms are definitively related to statin. If muscle complaints recur, it is assumed
that symptoms may be related to drug therapy and statin should be discontinued. Most
algorithms for evaluation and management of possible statin intolerance recommend
a trial of at least two to three statins, with discontinuation and re-challenge if the
patient again reports muscle-related symptoms.
The seven currently available statins differ in metabolism, half-life, and
lipophilicity, and some providers recommend that the second (or third) statin
prescribed in a patient with possible statin intolerance be chosen based on
characteristics that differ from the initial agent. There is no trial evidence that this
strategy is effective. There have been a number of smaller trials evaluating the
If a patient has failed a systematic challenge/re-challenge approach with two to
three statins, guidelines suggest consideration of non-statin therapies such as
ezetimibe, BASs ,or PCKS9 inhibitors.
Statins have been associated with an increased risk of type 2 diabetes. A review of
13 trials involving 19,140 patients showed a 9% relative increased risk for the
incidence of diabetes in those taking statins compared to placebo. This equates to
approximately one new case of diabetes for every 255 patients treated over a 4-year
101 A meta-analysis of five trials comparing high-dose versus low-dose statins
showed a 12% increased relative risk for incident diabetes over a 2- to 5-year
follow-up in those patients who received higher doses of statins.
data, there appears to be an increased risk of developing diabetes, albeit small.
However, due to the demonstrated clinical benefit of statin therapy, the benefit
clearly outweighs the risk of developing diabetes and statin therapy should not be
avoided due to the concern for this adverse effect.
Overall, the incidence of adverse effects with statins varies with myalgia being the
most common. When choosing a statin as well as a statin dose, one must consider the
various pharmacokinetic characteristics of that statin, the patients’ comorbid
conditions, and concomitant medications to minimize risk.
Statins are considered first-line pharmacologic therapy for prevention of ASCVD
events. They have demonstrated significant reductions in morbidity and mortality
across many patient populations.
68–72,103,104 Statin therapy should be initiated before or
simultaneously with therapeutic lifestyle modifications.
The initial dose of statin is determined by certain criteria that then place them into
any of the four statin benefit groups. The criteria are based on age, presence or
absence of ASCVD, presence or absence of diabetes, LDL-C level, and their
estimated risk based on the Pooled Cohort Equation.
5 High-intensity statin therapy is
recommended in the following patient populations: patients <75 years of age who
have clinical ASCVD; patients over 21 years of age and an LDL-C of >190 mg/dL;
or patients with diabetes (type 1 or 2) between the ages of 40 and 75 with an
estimated 10-year ASCVD risk of >7.5%. Moderate-intensity therapy is
age 40 to 75 years; or a 10-year ASCVD risk of >7.5% and age 40 to 75 years. The
later population may be initiated on high-intensity therapy if clinically indicated. The
intensity of doses of the various statins is outlined in Table 8-3.
with LDL-C > 190 mg/dL, combination therapy with a non-statin agent may be
needed to achieve additional LDL-C lowering if desired.
There are two patient populations for which there are limited data on the benefit of
statin therapy. These include patients with ASCVD and heart failure (New York
Heart Association Class II to IV) and patients on chronic hemodialysis. There are
currently no recommendations to initiate statin therapy in these patient populations.
In addition to their ability to lower LDL-C, statin also have many “pleiotropic”
effects that play a role in patients with ASCVD, independent of their ability to lower
LDL-C. These effects include improvement in endothelial function, plaque
stabilization, antithrombotic effects, anti-inflammatory, antioxidant effects, increased
nitric oxide bioavailability, and reduced plaque progression.
Although well demonstrated as beneficial in patients with established CHD, this
benefit in primary prevention is less well defined. In patients without CHD, statins
have not been shown to reduce mortality. They have demonstrated a lowering of
future vascular events over a time frame of 5 to 10 years, albeit small. As a result,
prescribing statins in patients without ASCVD but who are between the ages 40 to 75
years with an estimated ASCVD risk of ≥7.5% remains controversial.
Drug interactions with statins that result in higher blood levels of the statin or an
active metabolite can increase the risk of myositis. Statins that depend on the
cytochrome P-450 (CYP) 3A4 enzyme system to be metabolized are most vulnerable
to this interaction (i.e., lovastatin, simvastatin, and to a lesser extent atorvastatin).
Fluvastatin is primarily a substrate of the 2C9 isoenzyme and, to a lesser extent, 2C8
and 3A4 and, therefore, is more vulnerable to interactions with drugs that directly
inhibit CYP2C9 or act as competitive inhibitors (substrates) for this alternative
system. Pravastatin, pitavastatin, and rosuvastatin are not extensively metabolized by
85–87 Rosuvastatin is metabolized minimally (about 10%)
with CYP2C9 and CYP2C19 being the primary isoenzymes involved. Pitavastatin is
marginally metabolized by CYP2C9 and to a lesser extent by CYP2C8. The major
metabolite in human plasma is lactone, which is formed via glucuronidation by
uridine 5′-diphospho-glucuronosyltransferases UGTA3 and UGT2B7. Pravastatin
undergoes isomerization in the gut to a relatively inactive metabolite. Variability of
gastric metabolism has been shown to be associated with the LDL-C–lowering
106 Therefore, rosuvastatin and pravastatin have the lowest
potential for interaction with medications that inhibit the CYP metabolic pathways.
Some of the most commonly encountered medications that interact with statins by
inhibiting the CYP3A4 enzyme system are azole antifungals (itraconazole,
ketoconazole, and miconazole), certain calcium-channel blockers (diltiazem and
verapamil), macrolide antibiotics (clarithromycin and erythromycin), protease
inhibitors (e.g., ritonavir), grapefruit juice (>1 quart), cyclosporine, and
antidepressants (nefazodone). Drugs that are substrates for the CYP3A4 system
estradiol, felodipine, loratadine, quinidine, and terfenadine. When these substrate
drugs are used together with simvastatin or lovastatin (and to a lesser extent
atorvastatin), systemic blood levels of the statin may be increased because of
competitive inhibition of the CYP3A4 enzymes, and this may increase the risk for
Added caution should also be exercised when adding gemfibrozil with a statin to
treat patients who also have elevated triglyceride levels. Gemfibrozil interferes with
the glucuronidation of statins, thereby interfering with their renal clearance. This
impact may be minimal or up to a three- to fourfold increase in statin levels
depending upon the specific agent.
107–116 Due to the significance of this interaction,
fenofibrate is the preferred fibric acid derivative to use in combination with statins.
However, gemfibrozil may be used in combination with certain statins if clinically
86,109–114,117,118 A list of select statin drug interactions is presented in Table
QUESTION 1: J.G. is a 63-year-old white woman who implemented lifestyle modifications for her
mg/dL, TG 98 mg/dL, and TC 185 mg/dL.
What is her 10-year ASCVD risk based on the calculator?
The components of the risk calculator that impact J.G. include her age, gender,
total cholesterol, HDL cholesterol, and diabetes. She does not have hypertension and
smoking does not count as a risk factor due to the fact that she is not a current smoker.
Therefore, her 10-year ASCVD risk is 7.1%.
CASE 8-4, QUESTION 2: Based on her risk, what is the most appropriate next step for J.G.?
Select Drug Interactions with Statins
Medications Medications with Dose Limits
Atorvastatin Tipranavir plus ritonavir
Cyclosporine/tacrolimus/everolimus/sirolimus
Pitavastatin Rifampin Do not exceed 2 mg
Cyclosporine/tacrolimus/everolimus/sirolimus
Rosuvastatin Cyclosporine/tacrolimus/everolimus/sirolimus
J.G. falls into the statin benefit group of a diabetic with a 10-year risk of <7.5%.
The guidelines recommend that she be initiated on moderate-intensity statin therapy.
Therefore, any statin dose within this category that would lower LDL-C by 30% to
<50% would be appropriate. At this time she is not a candidate for a high-intensity
statin, despite having diabetes. The decision is made to initiate simvastatin 40 mg
medication regimen at this time?
The addition of amiodarone to her medication regimen necessitates a reduction in
her dose of simvastatin to 20 mg daily. This dose is still within moderate-intensity
range and is acceptable. The other option would be to switch her to different statin
that is either not metabolized by CYP3A4 or metabolized to a lesser extent than
simvastatin. Reasonable choices of statins would be pravastatin 40 to 80 mg daily,
fluvastatin 40 mg BID or XL 80 mg daily, atorvastatin 10 to 80 mg daily, pitavastatin
2 to 4 mg daily, lovastatin 40 mg daily, and rosuvastatin 5 to 40 mg daily.
Approximately 50% of patients discontinue statin therapy within 6 months of
initiation and only one-third are still adherent after
a year. Therefore, it is important to minimize adverse effects and be able to identify
if the statin may be the cause. The incidence of statin intolerance is estimated to be
5% to 10% among statin-treated patients. However, in light of the new AHA/ACC
cholesterol guidelines, 13 million more individuals have become eligible for statin
therapy and the overall prevalence of statin intolerance in the United States is likely
to increase. Diagnosing statin intolerance is challenging as no universal definition
exists. The NLA has several definitions of statin intolerance, but the one most
clinically useful is the inability to tolerate at least two statins. The two statins should
be one that was prescribed and taken at the lowest starting dose and another one that
was taken at any dose. In addition to the two statins challenge, patients need to have
either objectionable symptoms, or abnormal laboratory values, which are temporally
related to statin therapy and reverse upon statin discontinuation and recur upon
reinitiation. The ACC has also developed an application called “ACC Statin
Intolerance App” designed to assist providers in making the diagnosis of true statin
intolerance. The application provides the clinician with a systematic strategy for
evaluation of symptoms, management recommendations, as well as information
regarding statin characteristics and drug interactions. This application is available on
the web at http://tools.acc.org/StatinIntolerance, via Itunes at
https://itunes.apple.com/us/app/statin-intolerance/id985805274?mt=8 or via
Google Play at https://play.google.com/store/apps/details?
id=org.acc.StatinIntolerance&hl=en.
Routine monitoring of liver function tests is no longer recommended during statin
treatment. However, patients should be made aware of symptoms that may indicate
potential hepatic disease such as flu-like symptoms, fatigue, sluggishness, anorexia,
weight loss, right upper quadrant pain, yellowing of eyes, or jaundice.
All patients should have a fasting lipid panel prior to statin initiation. The
ACC/AHA guidelines for monitoring of statin therapy recommend a follow-up lipid
panel in 4 to 12 weeks following statin initiation to assess patient adherence and
response to therapy and then every 3 to 12 months as clinically indicated.
Coenzyme Q10 is an isoprenoid that plays a unique role in cellular electron
transport and energy synthesis. It is essential for the normal functioning of muscles.
Statins have been shown to reduce blood levels of coenzyme Q10 but muscle tissue
concentrations are unaffected. Evidence of the value of supplementing coenzyme Q10
in patients experiencing statin-induced myopathy has been mainly anecdotal.
However, the risk of taking CQ10 is relatively small and may be considered in
patients complaining of muscle aches in the absence of symptoms that are concerning
for more serious muscle-related disease.
Cholesterol Absorption Inhibitor (Ezetimibe)
Cholesterol that is ingested in the diet and circulated through the bile from the liver is
actively reabsorbed in the intestines. Once transported across the intestinal lumen
into the enterocyte, it is combined with TG and apo B-48 to form chylomicron
particles that transport the lipids through the lymphatic system to the hepatocyte. The
TG and cholesterol can then be packaged into VLDL particles and secreted into the
systemic circulation (Fig. 8-12).
In the small intestine the Niemann–Pick C1L1 (NPC1L1) transporter is responsible
for the uptake of dietary and biliary cholesterol into the small intestine. Ezetimibe
interferes with the active absorption of cholesterol and plant sterols from the
intestinal lumen into the enterocyte by binding to and inhibiting this transporter. By
interfering with the absorption of cholesterol, about 50% less cholesterol is
transported from the intestines to the liver by the chylomicrons. This causes an
upregulation of hepatic LDL receptors and increased clearance of circulating VLDL
and LDL particles. There is also an upregulation in hepatic cholesterol synthesis,
which is diverted to the intestines via the bile to replenish the cholesterol available
for intestinal absorption processes. The net effect of the inhibition of the NPC1L1
transporter is an approximate 70% increase in GI sterol excretion, a 50% reduction
in hepatic cholesterol concentration, a 90% increase in hepatic cholesterol synthesis,
and an approximate 20% increase in LDL-C clearance from the systemic circulation
via upregulated LDL receptors.
Ezetimibe also inhibits the absorption of sitosterol and other plant sterols from the
gut, resulting in about a 40% reduction in blood sitosterol levels. The occurrence of
sitosterolemia is rare, but is associated with a high CHD risk. Ezetimibe provides
one of the first effective treatments for this rare disorder.
The ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances
simvastatin 80 mg alone administered once daily in 720 patients with HeFH.
primary outcome was the change in mean carotid intima media thickness (CIMT)
after 24 months of treatment. This trial was not statistically powered to determine
differences in vascular disease event rates between treatments because of the short
study duration and the small number of patients. Mean baseline LDL-C (319 vs. 318
mg/dL, respectively) and CIMT (0.69 vs. 0.70 mm, respectively) were similar
between the treatment groups. The percent change in LDL-C was significantly (p
<0.01) greater in the simvastatin–ezetimibe group (−55.6%) compared with the
simvastatin–placebo group (−39.1%). However, there was no regression in CIMT in
either treatment group, and the mean changes in the CIMT were similar between the
treatment groups (p = 0.29) after 24 months of treatment. Why was there not a greater
change in CIMT in patients randomly assigned to the simvastatin–ezetimibe group
compared with the simvastatin–placebo group given that these patients had a greater
reduction in LDL-C? Before randomization, approximately 80% of the patients in
both treatment groups were receiving statin therapy. Moreover, these patients had
thinner or near-normal CIMT at baseline when compared with patients with HeFH
studied in previously published statin trials
that did demonstrate reduced CIMT
with high-dose statin therapy. Collectively, this suggests that the patients studied in
the ENHANCE trial were aggressively managed for their cholesterol for many years,
resulting in the depletion of vascular wall lipids. Therefore, additional aggressive
treatment would unlikely result in further regression of an already lipid-depleted
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