17 Statins

LALE TOKGÖZOĞLU, CARL ORRINGER, AND JOSEPH J. SASEEN

MECHANISM OF ACTION, 154 Older Adults, 156 Statin Effects on Liver, 159
Women, 157 Hemorrhagic Stroke, 159
PHARMACOKINETICS, 154
Adults With Chronic Kidney Disease, 157 Renal Effects of Statins, 159
DRUG–DRUG INTERACTIONS, 154 Ethnic Groups, 157
GENERAL REFERENCES, 159
LIPID-­ALTERING EFFICACY, 155 STATIN ADHERENCE, INTOLERANCE, AND
KEY REFERENCES, 160
SAFETY, 157
CARDIOVASCULAR EFFECTS, 155
Statin-­Associated Muscle Symptoms, 158 COMPLETE REFERENCES, 160.e1
SPECIAL POPULATIONS, 156 Statin-­Associated New-­Onset Type 2
Adults With Diabetes, 156 Diabetes, 159

MECHANISM OF ACTION metabolism can vary among different patient populations.

Statin medications are competitive inhibitors of
3-­hydroxy-­3methylglutaryl coenzyme A (HMG-CoA) reduc-
tase, which is the rate-­limiting step of hepatic cholesterol
production. Hence, statins reduce cholesterol biosynthesis
and subsequently hepatic cholesterol. Decreased hepatic
cholesterol production triggers an increased expression of
hepatic low-­density lipoprotein (LDL) receptors that trans-
fer LDL particles into the hepatocyte and reduce LDL cho-
lesterol (LDL-­C) in the blood. To a limited extent, statins
decrease apolipoprotein B-­100 (apoB-­100)–containing lipo-
protein production resulting in additional cholesterol and
triglyceride reduction. Reductions in LDL-­C and triglycerides
are directly proportionate to the intensity of statin used.
PHARMACOKINETICS
Table 17.1 summarizes the profile of different statins.
Absorption varies among different statins but is relatively
consistent making these variances mostly irrelevant, with
the exception of lovastatin, for which administration with
food enhances bioavailability. Atorvastatin, pitavastatin,
and rosuvastatin have long half-­lives and can be admin-
istered any time of the day. The other statins should be
administered in the evening to maximize efficacy because
HMG-CoA reductase has a diurnal rate of expression.
Statin medications are either lipophilic or hydrophilic
based on their log P value. The log P value is the partition
coefficient of a drug between an aqueous and lipophilic
phase. Values <1 indicate a medication is hydrophilic and
values >1 indicate a lipophilic medication. The log P value
may have some utility in clinical practice, as it is possible to
exchange a statin for one that is more hydrophilic (a lower
log P value) as a strategy to manage statin-­associated mus-
cle symptoms (SAMS). However, this is not an evidence-­
based management strategy.
Most statins require metabolism through hepatic
enzymes, with a small component of each drug elimi-
nated unchanged in the urine (renal elimination). Hepatic
Statins are subject to the influence of transporters and
other enzymes that contribute to drug absorption, distri-
bution, metabolism, and elimination. These transporters
include organic anion transporting polypeptides (OATPs),
organic anion transporters (OATs), breast cancer resistance
protein (BCRP), multidrug resistance protein (MDRP), the
sodium–taurocholate cotransporting polypeptide (NTCP),
and P-­glycoprotein (P-­gp) (Fig. 17.1).
DRUG–DRUG INTERACTIONS
Various transporters and metabolic pathways determine
the drug–drug interaction (DDI) potential of a statin. The
DDI profiles of simvastatin and lovastatin are nearly iden-
tical, but other statins have unique and different DDI pro-
files. Statins can be substrates or inhibitors of transporters
of drug metabolism and other transporters. The clinical
significance of a DDI can vary significantly. Some DDIs may
have a minor impact that requires monitoring for drug tox-
icity (e.g., muscle symptoms), while others require a pro-
active risk mitigation strategy. Risk mitigation strategies
include changing the statin medication to a different statin
without the DDI, using a lower dose of the interacting sta-
tin, or changing the perpetrating nonstatin drug. There are
several common statin DDIs.1,2 However, clinicians should
always consult a reliable drug information resource and/or
drug-­specific product labeling for specific guidance on DDI
management.
Underlying mechanisms of statin DDIs are multifaceted.
Inhibition of hepatic metabolism through the cytochrome
P450 (CYP; 3A4 or 2C9) pathway can increase systemic
statin exposure and increase risk of toxicity. Conversely,
induction of CYP enzymes can result in loss of efficacy.
The OATP transporters can simultaneously inhibit and
induce CYP enzymes and other transporters. Isolation of
specific OATP actions is difficult to predict, and interaction
through one transporter can increase risk of drug toxicity.
For example, gemfibrozil inhibits OATP1B1 and OATP2B1.
All statins utilize OATP transporters, so coadministration

154
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 155
TABLE 17.1 Pharmacokinetic Properties of Statins
ABSORPTION DISTRIBUTION METABOLISM ELIMINATION
17
Bioavailability CYP Hepatic Renal Excretion Transporters and

Statins
STATIN (%) Log Pa Enzyme (%) Half-­Life (hours) Enzymes
Atorvastatin 14 4.1 3A4 <2 14 BCRP, OAT1B1,
OAT2B1, P-­gp
Fluvastatin 24 3.2 2C9 (2C8, 3A4 5 3 BCRP, OATP1B1,
minor) OAT1B3,
OAT2B1
Lovastatin <5 4.3 3A4 10 2–3 BCRP, MDRP,
OAT1B1, P-­gp
Pitavastatin 43–51 1.5 2C9 (2C8 minor) 15 12 BCRP, MDRP,
OAT1B1,
OAT1B3,
OATP2B1
Pravastatin 17 −0.2 None 20 1.8 BCRP, OAT1B1,
OAT1B3,
OAT2B1
Rosuvastatin 20 −0.3 2C9 10 19 BCRP, NTCP,
OAT1B1,
OAT1B3,
OAT2B1
Simvastatin <5 4.7 3A4 13 2 BCRP, MDRP,
OAT1B1, P-­gp
a
<1 indicates hydrophilic, >1 indicates lipophilic.
BCRP, Breast cancer resistance protein; CYP, cytochrome P450; MDRP, multidrug resistance protein; NTCP, sodium–taurocholate cotransporting polypeptide; OAT, organic anion
transporter; OATP, organic anion transporting polypeptide; P-­gp, P-­glycoprotein.
Data from Web Supplement to the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management
of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
http://jaccjacc.acc.org/Clinical_Document/Cholesterol_GL_Web_Supplement.pdf; Kellick KA, Bottorff M, Toth PP, The National Lipid Associations Safety Task Force. A clinician’s
guide to statin drug-­drug interactions. J Clin Lipidol. 2014;8(3 Suppl):S30–S46.

FIG. 17.1 Transporters and enzymes in statin metabolism. BCRP, Breast cancer resistance protein; MDRP, multidrug resistance protein; OATP, organic anion
transporting proteins; P-­gp, P-­glycoprotein. (From Kellick KA, Bottorff M, Toth PP. The National Lipid Association’s Safety Task Force. A clinician’s guide to statin drug-­drug
interactions. J Clin Lipidol. 2014;8[3 Suppl]:S30–S46.) Adapted from M. Niemi, M.K. Pasanen, P.J. Neuvonen. Organic anion transporting polypeptide 1B1: a genetically polymor-
phic transporter of major importance for hepatic drug uptake. Pharmacol Rev, 63 (2011), pp. 157-181

of gemfibrozil with a statin alters intestinal drug absorp- (Table 17.2).5 Statin medications can also produce a dose-­
tion, decreases metabolism and/or reduction of hepatic dependent triglyceride reduction of 7%–30%, a non–HDL-­C
statin uptake, and ultimately increases toxicity risk.3 reduction of 15%–51%, and an HDL-­C increase of 5%–15%.4

LIPID-­ALTERING EFFICACY CARDIOVASCULAR EFFECTS

The primary lipid-­altering effect of statins is an LDL-­C reduc- Statins are the cornerstone of pharmacological cardio-
tion of 18%–55%.1,4 Further delineation of LDL-­C lowering vascular preventive therapy to reduce atherosclerotic
per dose is provided in the statin-­intensity categorization cardiovascular disease (ASCVD) risk. Three early, large

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 156
TABLE 17.2 Statin Intensity According to Daily Dose Used
III MODERATE INTENSITY (30%–49% LDL-­C
HIGH INTENSITY (≥50% LDL-­C LOWERING) LOWERING) LOW INTENSITY (<30% LDL-­C LOWERING)
THERAPY

Atorvastatin 40–80 mg Atorvastatin 10–20 mg Fluvastatin 20–40 mg

Rosuvastatin 20–40 mg Lovastatin 40–80 mg Lovastatin 20 mg
Fluvastatin XL 80 mg Pravastatin 10–20 mg
Pitavastatin 1–4 mg Simvastatin 10 mg
Pravastatin 40–80 mg
Rosuvastatin 5–10 mg
Simvastatin 20–40 mg
LDL-­C, Low-­density lipoprotein cholesterol.
Data from Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood
cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–e1143.

randomized controlled trials (RCTs) with approximately Absolute risk reduction benefit from statins depends
5 years of follow-­up, the Scandinavian Simvastatin Sur- on baseline LDL-­C levels, with the greatest benefit seen in
vival Study, the West of Scotland Coronary Prevention patients with the highest baseline LDL-­C levels.
Study, and the Heart Protection Study, demonstrated
a significant reduction in coronary events in high-­risk
patients treated with moderate-­ intensity statin ther- SPECIAL POPULATIONS
apy. All-­ cause mortality was significantly reduced in Adults With Diabetes
patients with established ASCVD. Subsequent large RCTs
The efficacy of statin therapy for ASCVD risk reduction in
further supported the ASCVD risk reduction benefit of
individuals with diabetes was examined in a 2008 CTTC
statins, providing the evidence base used by the Cho-
meta-­analysis of 14 statin trials. The study included 18,686
lesterol Treatment Trialists’ Collaboration (CTTC) in
individuals (1466 with type 1 and 17,220 with type 2 dia-
their meta-­analyses of individual patient data of large-­
betes) who were treated with moderate-­or low-­intensity
scale (≥2 years planned treatment duration with ≥1000
statins and followed for a mean of 4.3 years. Statin therapy
participants) statin RCTs. A 2010 CTTC meta-­ analysis
was associated with a 21% proportional reduction in major
of more-intensive versus less-intensive statin regimens
vascular events per 38.7-mg/dL (1-mmol/L) reduction in
(5 trials in 39,612 individuals; median follow-­up 5.1 years)
LDL-­C (RR 0.79, 99% CI 0.72–0.86, P < .0001) and a 9% pro-
and of statin versus control (21 trials in 129,526 individu-
portional reduction in all-­cause mortality per 38.7-mg/dL
als; median follow-­up 4.8 years) showed that when both
(1-mmol/L) reduction in LDL-­C (RR 0.91, 99% CI 0.82–1.01,
types of trials were combined, statin therapy resulted in
P = .02). These beneficial effects were similar to those
a 22% proportional reduction (rate ratio [RR] 0.78, 95%
achieved in patients without diabetes and were indepen-
confidence interval [CI] 0.76–0.80, P < .0001) in major
dent of the baseline LDL-­C or other lipid levels.8
ASCVD events for each 38.7-mg/dL (1-mmol/L) reduction
Moderate-­ intensity statin therapy is recommended
in LDL-­ C, regardless of baseline LDL-­ C concentration,
for primary prevention in most individuals with diabe-
even in individuals with LDL-­C levels <77 mg/dL on the
tes. However, because of the increased morbidity and
less-intensive or control regimen. Among the five RCTs
mortality associated with an initial ASCVD event in this
that compared high-intensity with moderate-­ intensity
population, the observed high residual risk among the
statins, high-­intensity statins significantly reduced the
statin-­treated groups in clinical trials, and the evidence of
incidence of major vascular events by 15% with no signif-
benefit from high-­intensity statin treatment in primary pre-
icant reduction in coronary deaths.6
vention in men >50 years of age and women >60 years of
A 2012 CTTC meta-­analysis examined 27 statin RCTs
age, the 2018 AHA/ACC/Multisociety cholesterol guideline
and separated participants into five categories of base-
recommended the use of high-­intensity statin therapy for
line 5-­year major vascular event risk on control therapy
patients with diabetes in these age groups, or those with
(no statin or low-­intensity statin) (<5%, ≥5% to <10%,
multiple ASCVD risk factors; a calculated 10-­year risk using
≥10% to <20%, ≥20% to <30%, ≥30%); in each category,
the pooled cohort equations of ≥20%; type 1 diabetes of
the RR per 38.7-mg/dL (1-mmol/L) LDL-­C reduction was
≥20 years in duration or type 2 diabetes of ≥10 years in
estimated. The proportional reduction in the incidence
duration; microalbuminuria, retinopathy, or neuropathy;
of major coronary events, coronary revascularization,
or an ankle-­brachial index <0.9.9
and both in the two lower-risk categories was compa-
rable with that in the higher-risk categories. The reduc-
tion in risk for stroke in participants with a 5-­year risk Older Adults
of major vascular events <10% was similar to that seen A 2019 CTTC meta-­ analysis of individual participant data
in the higher-risk groups. In participants with no history from 28 statin RCTs in 186,854 individuals, including data
of vascular disease, the proportional reductions in vas- from one trial (n = 12,705) of statin therapy versus con-
cular and all-­cause mortality were similar regardless of trol, plus data from five trials of more-intensive versus
baseline risk.7 less-intensive statin therapy (n = 39,612), identified 14,883

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(8%) individuals older than 75 years of age at randomization,
with a median follow-­up of 4.9 years. Overall, statin or more-in-
tensive therapy yielded a 24% (RR 0.76, 95% CI 0.73–0.79) pro-
portional reduction in major coronary events per 38.7-mg/
dL (1-mmol/L) reduction in LDL-­C, and with increasing age,
a trend toward smaller proportional risk reductions in major
coronary events.10 These results were amplified by another
study in older adults that included 24 trials from the CTTC
meta-­analysis plus five individual trials, in which 11,750 par-
ticipants were from statin trials. With a median follow-­up of
2.2–6.0 years, LDL-­C reduction significantly lowered the risk
of major vascular events (n = 3519) in older patients by 26%
per 38.7-mg/dL reduction in LDL-­C (RR 0.74, 95% CI 0.61–0.89,
P = .0019). There was no significant difference in risk reduc-
tion observed between individuals 75 years of age or older
versus those younger than 75 years of age.11
Thus, for adults >75 years of age, it is reasonable to
initiate moderate-intensity or, in selected patients, high-­
intensity statins and to continue high-­intensity statins in
those already taking them. Consideration may be given
to discontinuation of statins when physical or cognitive
decline, multimorbidity, frailty, or reduced life expectancy
limits the potential benefits. When there is uncertainty
about initiation of a statin in such patients, a coronary
calcium score of zero, and possibly <10 Agatston units, is
associated with a low short-­and intermediate-­term risk
of ASCVD events and may be used as a factor supporting
avoidance of such therapy.9,12
Women
A 2015 CTTC meta-­analysis of data from 22 trials of statin
therapy versus control (n = 134,537) and 5 trials of more
intensive versus less intensive statin therapy (n = 39,612)
showed that proportional reductions in major vascu-
lar events per 38.7-mg/dL reduction in LDL-­ C were simi-
lar overall for women (RR 0.84, 99% CI 0.78–0.91) and men
(RR 0.78, 99% CI 0.75–0.81; adjusted P value for heterogeneity
by sex = .33) and also for women and men with <10% pre-
dicted 5-­year absolute cardiovascular risk (adjusted hetero-
geneity P = .11).13 The 2018 AHA/ACC/Multisociety guideline
makes similar recommendations for statin therapy in men
and women but identifies menopause at <40 years of age
and a history of pregnancy-­ associated disorders (hyper-
tension, preeclampsia, gestational diabetes mellitus, small-­
for-­gestational-­age infants, preterm deliveries) as factors to
include in shared decision making when discussing lifestyle
intervention and the potential for benefit of statin therapy.
The guideline reinforces the importance of reliable contra-
ception in women of childbearing age who are sexually active
and are being treated with statin therapy and advises discon-
tinuation of statins 1–2 months prior to planned conception,
during pregnancy, and while breastfeeding. Female sex is des-
ignated as a predisposing factor to statin-­associated myalgias
with normal creatine kinase (CK) levels.9
Adults With Chronic Kidney Disease
An estimated glomerular filtration rate (eFGR) of <60 mL/
min/1.73 m2 is associated with increased ASCVD risk, and
albuminuria further increases this risk. A CTTC meta-­analysis
of data from 28 trials (N = 183,419) subdivided into catego-
ries of eGFR at baseline examined the effect of statin-­based
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157
therapy on major vascular events (major coronary event
[nonfatal myocardial infarction or coronary death], stroke, 17
or coronary revascularization) and mortality. As compared
Statins
with eGFR ≥60 ml/min/1.73 m2, smaller relative effects on
major vascular events were observed as eGFR declined, no
benefit was seen in individuals on hemodialysis, and there
was no impact on total mortality.14 Guideline-­directed medi-
cal therapy advocates the use of moderate-­intensity statins
with or without ezetimibe in adults 40–75 years of age with
a 10-­year risk of ≥7.5% not on hemodialysis. Shared decision
making about continuation of statins in those already t­ aking
statins is warranted. Initiation of statin therapy in individ-
uals on maintenance hemodialysis is not recommended
based on lack of benefit compared with placebo.9
Ethnic Groups
Higher statin blood levels are observed in individuals of
Japanese, Chinese, and Malay ethnicity than in other ethnic
groups, and consequently, starting doses of statins should
be employed, with upward titration in accordance with the
patient’s absolute risk.9 Adults of South Asian ethnicity have
an increased risk of clinical ASCVD. While data on the impact
of statins for both primary and secondary prevention in this
group are limited, one statin safety and efficacy study in
486 North American patients of South Asian ethnicity who
were identified as being at high coronary heart disease risk
showed that therapy with both rosuvastatin and atorvasta-
tin was well tolerated and was associated with LDL-­C reduc-
tion similar to that in other populations.15
STATIN ADHERENCE, INTOLERANCE, AND
SAFETY
Although statins have been proven to decrease cardiovas-
cular events substantially, adherence to statins is subopti-
mal (Fig. 17.2). The benefits of therapy seen in randomized
clinical statin trials will only be replicated in real life if the
patients adhere to statins. After experiencing a cardio-
vascular event, nearly one-­half of patients are nonadher-
ent with their prescribed regimen for over 2 years, and in
primary prevention adherence is even lower.16 Multiple
potential barriers exist to adherence at the healthcare pro-
vider, patient, and system levels. Patient-­related factors
include low health literacy, cost, psychosocial factors, atti-
tudes concerning the effectiveness of the treatment, and
previous negative experience with drugs.17 There are also
physician-­ related factors like prescribing complex drug
regimens and not spending enough time with the patient
to explain risks and benefits of treatment to reach a shared
decision. Telephone and calendar reminders, integrated
multidisciplinary educational activities, simplification of
the drug regimen to once-­daily dosing, and pharmacist-­
led interventions are evidence-­ based ways to improve
adherence.18
A major barrier to the efficacious use of statin therapy
is statin intolerance, which contributes to treatment nonad-
herence. Statin intolerance can be described as the inability
to tolerate at least two statins—one at the lowest dose—
because of symptoms or biomarker changes not attributable
to predisposing conditions.19 In true intolerance, symptoms
usually resolve or decrease on discontinuation of statins.
 158
III
100%
THERAPY
Common barriers
• Understanding
benefits of therapy
• Denial
• Financial
• Health literacy
Medication
prescription process
in the Prescriber’s
office
FIG. 17.2 Statin adherence over time. (From Cohen JD, Aspry KE, Brown AS, et al. Use of health information technology (HIT) to improve statin adherence and low-density
lipoprotein cholesterol goal attainment in high-risk patients: proceedings from a workshop. J Clin Lipidol. 2013;7:573–609; and National Lipid Association Toolkit.)
Diagnosis and management of statin intolerance is difficult
because of the heterogeneity of symptoms and the lack of
agreed-upon clinical, biomarker, or diagnostic criteria.
Statin-­Associated Muscle Symptoms
The principal side effects reported on statin therapy
are muscle symptoms (SAMS). Patients usually com-
plain about symmetrical pain and weakness in large
proximal muscle groups typically occurring within 4 to
6 weeks after starting statin therapy.20 Symptoms usu-
ally regress within a few weeks on cessation of the statin
and reappear with a rechallenge. In most cases, SAMS
are not accompanied by marked CK elevations. Based on
21 randomized clinical trials providing 180,000 person-­
years of follow-­up on statin therapy or placebo, more
serious SAMS like myopathy (muscle symptoms plus an
increase in CK of >10 times upper limit of normal [ULN])
occurred in only 5 patients per 100,000 person-­years,
and rhabdomyolysis in 1.6 patients per 100,000 person-­
years.21 The risk varies among different statin regimens
and increases with the dose of statin and predisposing
factors such as age >80 years, female sex, low body
mass index, Asian descent, history of muscle disorders,
concurrent conditions like acute infection, impaired
renal or hepatic function hypothyroidism, vitamin D
deficiency, or concomitant interacting medications.20
In addition, the SLCO1B1 rs4149056 polymorphism is
associated with increased statin blood levels and may
increase the risk of SAMS with simvastatin.22 In clinical
practice, patients on statins frequently complain about
muscle symptoms, whereas randomized statin trials
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Not filled
–12%
Not started
88% –12%
76% Not finished
–29%
47%
Common barriers Common barriers
• Perceived side effects • Forgetfulness
• Not understanding • Side effects
benefits and risks • Financial
• Polypharmacy • Polypharmacy
• Denial • Ongoing reinforcement
Medication
Medication
taking process
dispensing process
in the Patient’s
in the Pharmacy
home
do not report more frequent muscular symptoms with
statin compared with placebo. Therefore, estimating the
prevalence of true statin muscle-­related intolerance is
difficult. Two observational studies report the incidence
of SAMS to be around 10%.23,24 Some of these symptoms
may be due to the nocebo effect. The Anglo-Scandi-
navian Cardiac Outcomes Trial–Lipid Lowering Arm
(ASCOT-­LLA) showed that the reporting rate of muscle
adverse events was higher among statin users than non-
users in the nonblinded phase but did not differ between
atorvastatin and placebo groups in the blinded phase.25
The Self-Assessment Method for Statin Side-effects Or
Nocebo (SAMSON) study demonstrated that symp-
tom intensity was similar during placebo or statin use,
and both were significantly higher than during the no-­
treatment period.26
If a patient complains of SAMS, sufficient time should
be spent to discuss the risk/benefit ratio with the patient,
and CK should be measured. The majority of these patients
have normal or mildly/moderately elevated CK levels (4×
ULN). The statin can be stopped for 3– 4 weeks to see if
symptoms resolve. If symptoms/CK abnormalities resolve
after discontinuation of statin, either treatment with the
same statin at a lower dose or switching to an alternative
statin or the use of less than a daily dose (lower than the
recommended daily dose or alternate-day dosing) of a
long-­acting statin in combination with a nonstatin that low-
ers LDL-­C should be considered (Fig. 17.3). Most patients
tolerate a statin when rechallenged. Once the highest toler-
able dose is established, if the patient is not at goal and is
at high risk, combination therapy can be considered.

Myalgia on a Statin
Check for preexisting condition and drug interaction
Nocebo effect?
Other cause of myalgia?
Educate patient
Shared Decision Making
Continue statin
FIG. 17.3 Approach to patient complaining of myalgia while using statins. CK, Creatine kinase; CV, cardiovascular; SAMS, statin-­associated muscle
symptoms.
Statin-­Associated New-­Onset Type 2 Diabetes
Statin therapy has been shown to be associated with a
small increase in fasting blood glucose levels. In a meta-­
analysis including 91,140 subjects without diabetes at
baseline, statin treatment increased incident diabetes mel-
litus by 9%, equating to about 1 new case per 1000 patients
per year of exposure, whereas 5 new cardiovascular events
were prevented.27 This risk is higher with more-intensive
statin therapy, in individuals with features of the metabolic
syndrome at the initiation of therapy, and in the elderly.
However, in high-­risk patients who develop new-­onset dia-
betes mellitus, the risk of ASCVD events is lower on statin
therapy, demonstrating that the potential adverse effects
of hyperglycemia do not negate the benefits of LDL-­ C dysfunction for some statin regimens. Atorvastatin and flu-
reduction.
Statin Effects on Liver
Mild elevation in liver transaminases occurs in 0.5%–2.0% of
patients usually within 3 months of initiation of therapy, is
dose related, and is not clinically relevant.28 Clinically appar-
ent idiosyncratic liver injury with statin therapy is very
rare but can be severe. Liver enzymes should be measured
if a patient develops symptoms suggestive of hepatotoxic-
ity, and statins should not be prescribed in patients with
active hepatitis. In patients with mild alanine aminotrans-
ferase (ALT) elevation due to steatosis or nonalcoholic fatty
liver disease, statin therapy does not worsen liver disease.
Routine periodic monitoring of liver enzymes is not recom-
mended unless symptoms of hepatotoxicity appear.
Hemorrhagic Stroke
There is substantial evidence showing that statins decrease
ischemic stroke. The meta-­analysis by the CTTC in 170,000
individuals documented a risk reduction in first stroke of 16%
per 39-mg/dL LDL-­C reduction; when the occurrence of isch-
emic strokes only was specifically considered, the results
showed a 21% risk reduction.29 However, in the Stroke Preven-
tion by Aggressive Reduction in Cholesterol Levels (SPARCL)
trial in patients with a prior stroke or transient ischemic
attack, a numerically higher number of hemorrhagic strokes
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159
17
Statins
SAMS
Measure CK
Myalgia with or Rhabdomyolysis
Myositis (very rare):
without CK (very rare):
Immune treatment
elevation Treatment
Statin washout
Statin washout 6 weeks
2–6 weeks if high CV risk
Same/alternative statin
Smaller dose statin + ezetimibe
Bempedoic acid
PCSK9 inhibitors
were seen on statin therapy, whereas ischemic stroke was
reduced.30 This has raised concern that low LDL-­C levels may
increase risk for hemorrhagic stroke; however, other RCTs,
cohort studies, and proprotein convertase subtilisin/kexin
type 9 (PCSK9) inhibitor trials in which very low LDL-­C levels
were attained did not confirm this finding.31
Renal Effects of Statins
Statin treatment is not associated with clinically signifi-
cant deterioration of renal function. Mild proteinuria, often
transient, is rarely seen with high-­ dose statin treatment
but is not associated with impaired renal function.28 Dose
reduction may be necessary in patients with severe kidney
vastatin are less dependent on the kidney for elimination.
Chronic kidney disease patients are at high risk for cardio-
vascular events, and statins reduce ASCVD events by 20% in
these patients but are not beneficial in patients on dialysis.32
Although protective effect of statins on the kidney has been
suggested by some studies, this has not been confirmed by
others.
GENERAL REFERENCES
4. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations
for patient-­centered management of dyslipidemia: part 1—executive summary. J
Clin Lipidol. 2014;8(5):473–488.
5. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/
ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood choles-
terol: a report of the American College of Cardiology/American Heart Association
Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–e1143.
6. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L,
et al. Efficacy 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(9753):1670–1681.
7. Cholesterol Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J,
Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in
people at low risk of vascular disease: meta-­analysis of individual data from 27
randomised trials. Lancet. 2012;380(9841):581–590.
8. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Col-
lins R, et al. Efficacy of cholesterol-­lowering therapy in 18,686 people with diabetes
in 14 randomised trials of statins: a meta-­analysis. Lancet. 2008;371(9607):117–125.
11. Gencer B, Marston NA, Im K, et al. Efficacy and safety of lowering LDL cholesterol
in older patients: a systematic review and meta-­analysis of randomised controlled
trials. Lancet. 2020;396(10263):1637–1643.
19. Banach M, Rizzo M, Toth PP, et al. Statin intolerance—an attempt at a unified
definition. Position paper from an International Lipid Expert Panel. Arch Med Sci.
2015;11:1–23.
 160
20. Stroes ES, Thompson PD, Corsini A, et al. Statin-­associated muscle symptoms:
impact on statin therapy—European Atherosclerosis Society Consensus Panel
III Statement on Assessment, aetiology and Management. Eur Heart J. 2015;36:
1012–1022.
THERAPY
27. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collabo-
rative meta-­analysis of randomized statin trials. Lancet. 2010;375:735–742.
28. Mach F, Ray KK,Wiklund O, et al.Adverse effects of statin therapy: perception vs. the
evidence—focus on glucose homeostasis, cognitive, renal and hepatic function,
haemorrhagic stroke, and cataract. Eur Heart J. 2018;39:2526–2539.
KEY REFERENCES
2. Kellick KA, Bottorff M, Toth PP. A clinician’s guide to statin drug-­drug interactions. J
Clin Lipidol. 2014;8(suppl 3):S30–S46.
4. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations
for patient-­centered management of dyslipidemia: part 1—executive summary. J
Clin Lipidol. 2014;8(5):473–488.
5. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/
ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of
blood cholesterol: a report of the American College of Cardiology/Ameri-
can Heart Association Task Force on Clinical Practice Guidelines. Circulation.
2019;139(25):e1082–e1143.
6. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L,
et al. Efficacy 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(9753):1670–1681.
7. Cholesterol Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J,
Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in
people at low risk of vascular disease: meta-­analysis of individual data from 27
randomised trials. Lancet. 2012;380(9841):581–590.
8. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Col-
lins R, et al. Efficacy of cholesterol-­lowering therapy in 18,686 people with diabetes
in 14 randomised trials of statins: a meta-­analysis. Lancet. 2008;371(9607):117–125.
10. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of statin therapy
in older people: a meta-­analysis of individual participant data from 28 randomised
controlled trials. Lancet. 2019;393(10170):407–415.
13. Cholesterol Treatment Trialists’ (CTT) Collaboration, Fulcher J, O’Connell R, Voy-
sey M, et al. Efficacy and safety of LDL-­lowering therapy among men and women:
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de ClinicalKey.es por Elsevier en marzo 15, 2024. Para
uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.
meta-­analysis of individual data from 174,000 participants in 27 randomised trials.
Lancet. 2015;385(9976):1397–1405.
14. Cholesterol Treatment Trialists’ (CTT) Collaboration, Herrington W, Emberson J,
Mihaylova B, et al. Impact of renal function on the effects of LDL cholesterol lower-
ing with statin-­based regimens: a meta-­analysis of individual participant data from
28 randomised trials. Lancet Diabetes Endocrinol. 2016;4(10):829–839.
18. van Driel ML, Morledge MD, Ulep R, et al. Interventions to improve adherence to
lipid-­lowering medication. Cochrane Database Syst Rev. 2016;12:CD004371.
19. Banach M, Rizzo M, Toth PP, et al. Statin intolerance—an attempt at a unified
definition. Position paper from an International Lipid Expert Panel. Arch Med Sci.
2015;11:1–23.
20. Stroes ES,Thompson PD, Corsini A, et al. Statin-­associated muscle symptoms: impact
on statin therapy—European Atherosclerosis Society Consensus Panel Statement
on Assessment, aetiology and Management. Eur Heart J. 2015;36:1012–1022.
21. Law M, Rudnicka AR. Statin safety: a systemic review. Am J Cardiol.
2006;97(suppl):52C–60C.
26. Wood FA, Howard JP, Finegold JA, et al. N-­of-­1 trial of a statin, placebo, or no treat-
ment to assess side effects. N Engl J Med. 2020;383:2182–2184.
27. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collabo-
rative meta-­analysis of randomized statin trials. Lancet. 2010;375:735–742.
28. Mach F, Ray KK,Wiklund O, et al.Adverse effects of statin therapy: perception vs. the
evidence—focus on glucose homeostasis, cognitive, renal and hepatic function,
haemorrhagic stroke, and cataract. Eur Heart J. 2018;39:2526–2539.
29. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Ember-
son J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a
meta-­analysis of data from 170,000 participants in 26 randomised trials. Lancet.
2010;376:1670–1678.
30. Amarenco P, Bogousslavsky J, Callahan A, et al. High-­dose atorvastatin after stroke
or transient ischemic attack. N Engl J Med. 2006;355:549–559.
31. Hackam DG, Woodward M, Newby LK, et al. Statins and intracerebral hemorrhage:
collaborative systematic review and meta-­analysis. Circulation. 2011;124:2233–2242.
32. Cholesterol Treatment Trialists’ (CTT) Collaboration, Herrington WG, Emberson J,
Mihaylova B, et al. Impact of renal function on the effects of LDL cholesterol lower-
ing with statin-­based regimens: a meta-­analysis of individual participant data from
28 randomised trials. Lancet Diabetes Endocrinol. 2016;4:829–839.
NOTE: Access the complete reference list online at Expert-
Consult.com.
COMPLETE REFERENCES 15. Deedwania PC, Gupta M, Stein M, et al. Comparison of rosuvastatin versus atorvas-
tatin in South-­Asian patients at risk of coronary heart disease (from the IRIS Trial).
1. Web Supplement to the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/
Am J Cardiol. 2007;99(11):1538–1543.
ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of
16. Naderi SH, Bestwick JP, Wald DS. Adherence to drugs that prevent cardiovascular

COMPLETE REFERENCES
blood cholesterol: a report of the American College of Cardiology/Amer-
disease: metaanalysis on 376,162 patients. Am J Med. 2012;125:882–887.
ican Heart Association Task Force on Clinical Practice Guidelines. http://
17. Maningat P, Gordon BR, Breslow JL. How do we improve patient compliance and
jaccjacc.acc.org/Clinical_Document/Cholesterol_GL_Web_Supplement.pdf.
adherence to long-­term statin therapy? Curr Atheroscler Rep. 2013;15(1):291.
2. Kellick KA, Bottorff M, Toth PP. The National Lipid Association’s Safety Task
18. van Driel ML, Morledge MD, Ulep R, et al. Interventions to improve adherence to
Force. A clinician’s guide to statin drug-­ drug interactions. J Clin Lipidol.
lipid-­lowering medication. Cochrane Database Syst Rev. 2016;12:CD004371.
2014;8(suppl 3):S30–S46.
19. Banach M, Rizzo M, Toth PP, et al. Statin intolerance—an attempt at a unified
3. Shitara Y, Hirano M, Sato H, Sugiyama Y. Gemfibrozil and its glucuronide inhibit the
definition. Position paper from an International Lipid Expert Panel. Arch Med Sci.
organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-­mediated
2015;11:1–23.
hepatic uptake and CYP2C8-­mediated metabolism of cerivastatin: analysis of the
20. Stroes ES,Thompson PD, Corsini A, et al. Statin-­associated muscle symptoms: impact
mechanism of the clinically relevant drug-­drug interaction between cerivastatin
on statin therapy—European Atherosclerosis Society Consensus Panel Statement
and gemfibrozil. J Pharmacol Exp Ther. 2004;311(1):228–236.
on Assessment, Aetiology and Management. Eur Heart J. 2015;36:1012–1022.
4. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations
21. Law M, Rudnicka AR. Statin safety: a systemic review. Am J Cardiol.
for patient-­centered management of dyslipidemia: part 1—executive summary. J
2006;97(suppl):52C–60C.
Clin Lipidol. 2014;8(5):473–488.
22. Hopewell JC, Offer A, Haynes R, et al. Independent risk factors for simvastatin-­
5. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/
related myopathy and relevance to different types of muscle symptom. Eur Heart J.
ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood choles-
2020;41:3336–3342.
terol: a report of the American College of Cardiology/American Heart Association
23. Casula M, Gazzotti M, Bonaiti F, et al. Reported muscle symptoms during statin treat-
Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–e1143.
ment among Italian dyslipidemic patients in the real-­life setting: the PROSISA Study.
6. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L,
J Intern Med. 2021;290(1):116–128.
et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-­
24. Bruckert E, Hayem G, Dejager S,Yau C, Bégaud B. Mild to moderate muscular symp-
analysis of data from 170,000 participants in 26 randomised trials. Lancet.
toms with high-­dosage statin therapy in hyperlipidemic patients—the PRIMO study.
2010;376(9753):1670–1681.
Cardiovasc Drugs Ther. 2005;19(6):403–414.
7. Cholesterol Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J,
25. Gupta A, Thompson D, Whitehouse A, et al. Adverse events associated with
Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in
unblinded, but not with blinded, statin therapy in the Anglo‐Scandinavian Cardiac
people at low risk of vascular disease: meta-­analysis of individual data from 27
Outcomes Trial‐Lipid‐Lowering Arm (ASCOT‐LLA): a randomised double‐blind
randomised trials. Lancet. 2012;380(9841):581–590.
placebo‐controlled trial and its non‐randomised non‐blind extension phase.
8. Cholesterol Treatment Trialists’ (CTT) Collaborators, Kearney PM, Blackwell L, Col-
Lancet. 2017;389:2473–2481.
lins R, et al. Efficacy of cholesterol-­lowering therapy in 18,686 people with diabetes
26. Wood FA, Howard JP, Finegold JA, et al. N-­of-­1 trial of a statin, placebo, or no treat-
in 14 randomised trials of statins: a meta-­analysis. Lancet. 2008;371(9607):117–125.
ment to assess side effects. N Engl J Med. 2020;383:2182–2184.
9. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/
27. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collabo-
ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood choles-
rative meta-­analysis of randomized statin trials. Lancet. 2010;375:735–742.
terol: a report of the American College of Cardiology/American Heart Association
28. Mach F, Ray KK,Wiklund O, et al.Adverse effects of statin therapy: perception vs. the
Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–e1143.
evidence—focus on glucose homeostasis, cognitive, renal and hepatic function,
10. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of statin therapy
haemorrhagic stroke, and cataract. Eur Heart J. 2018;39:2526–2539.
in older people: a meta-­analysis of individual participant data from 28 randomised
29. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Ember-
controlled trials. Lancet. 2019;393(10170):407–415.
son J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a
11. Gencer B, Marston NA, Im K, et al. Efficacy and safety of lowering LDL cholesterol
meta-­analysis of data from 170,000 participants in 26 randomised trials. Lancet.
in older patients: a systematic review and meta-­analysis of randomised controlled
2010;376:1670–1678.
trials. Lancet. 2020;396(10263):1637–1643.
30. Amarenco P, Bogousslavsky J, Callahan A, et al. High-­dose atorvastatin after stroke
12. Mortensen MB, Fuster V, Muntendam P, et al. Negative risk markers for cardiovascu-
or transient ischemic attack. N Engl J Med. 2006;355:549–559.
lar events in the elderly. J Am Coll Cardiol. 2019;74(1):1–11.
31. Hackam DG, Woodward M, Newby LK, et al. Statins and intracerebral hemorrhage:
13. Cholesterol Treatment Trialists’ (CTT) Collaboration, Fulcher J, O’Connell R, Voy-
collaborative systematic review and meta-­analysis. Circulation. 2011;124:2233–2242.
sey M, et al. Efficacy and safety of LDL-­lowering therapy among men and women:
32. Cholesterol Treatment Trialists’ (CTT) Collaboration, Herrington WG, Emberson J,
meta-­analysis of individual data from 174,000 participants in 27 randomised trials.
Mihaylova B, et al. Impact of renal function on the effects of LDL cholesterol lower-
Lancet. 2015;385(9976):1397–1405.
ing with statin-­based regimens: a meta-­analysis of individual participant data from
14. Cholesterol Treatment Trialists’ (CTT) Collaboration, Herrington W, Emberson J,
28 randomised trials. Lancet Diabetes Endocrinol. 2016;4:829–839.
Mihaylova B, et al. Impact of renal function on the effects of LDL cholesterol lower-
ing with statin-­based regimens: a meta-­analysis of individual participant data from
28 randomised trials. Lancet Diabetes Endocrinol. 2016;4(10):829–839.

160.e1
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de ClinicalKey.es por Elsevier en marzo 15, 2024. Para
uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos reservados.