ISCHEMIC STROKE / PREVENTION

Lipid-lowering therapy

David Goldemund M.D.
Updated on 21/03/2024, published on 18/10/2023

2019 – ESC/EAS Guidelines for the Management of Dyslipidaemias

dyslipidemia is a major modifiable vascular risk factor
treatment with lipid-lowering drugs (hypolipidemics) reduces the incidence of ischemic stroke and other atherosclerotic cardiovascular events (ASCVD)
hypolipidemics (and their combinations) help to achieve target levels for total and low-density lipoprotein cholesterol (LDL-C). Some agents have beneficial effects on triglyceride (TAG) and high-density lipoprotein (HDL) levels
- patients who do not achieve (LDL-C targets despite treatment with the maximal tolerated dose of a potent statin, the addition of ezetimibe should be considered (data on the efficacy of ezetimibe alone are not available in stroke prevention)
- selected patients who fail to achieve LDL-C targets despite a statin+ezetimibe combination may be candidates for treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors
- adding icosapent ethyl or fibrate may reduce cardiovascular morbidity in patients who have achieved LDL-C targets but have persistently elevated TAG levels

Atherosclerotic cardiovascular disease (ASCVD)

ASCVD is caused by plaque buildup (accumulation of lipids, calcium, and other blood components) in arterial walls and include:

cerebrovascular disease – such as TIA, ischemic stroke, and pre-cerebral and cerebral artery stenosis
coronary artery disease (CAD) – such as myocardial infarction, angina, and coronary artery stenosis
peripheral artery disease (PAD) – claudications, limb ischemia
aortic atherosclerotic disease – such as abdominal aortic aneurysm and descending thoracic aneurysm

Lipid-lowering therapy in stroke prevention

statins (HMG-CoA Reductase Inhibitors) are effective for both primary (JUPITER trial) and secondary stroke prevention (SPARCL trial)
- the benefit of achieving a specific LDL target has not been tested by randomized trials with stroke patients. However, a meta-analysis of the AFCAPS-TexCAPS, 4S, LIPID, SPARCL, TNT, IDEAL, and JUPITER trials involving 38 000 patients found that very low LDL levels were associated with cardiovascular (CV) risk reduction [Boekholdt, 2014]
- LDL reduction by 1mmol/L leads to a 22% reduction in CV events
- LDL reduction to < 2 mmol/L was associated with a 28% reduction in stroke risk (HR 0.72) in the SPARCL trial; ≥ 50% reduction in LDL level led to a 35% reduction in the combined risk of fatal and nonfatal ischemic stroke
- Treat Stroke to Target (TST) trial is still ongoing
a significant effect has also been demonstrated with ezetimibe (when added to statins) in the IMPROVE-IT, SEAS, and SHARP trials, and especially with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors – FOURIER trial
fibrates (PPAR-α Agonists) or icosapent ethyl may be added in cases of significant triglyceridemia
the benefit of HDL-raising drugs (niacin, CETP inhibitors) has not been proven

Primary stroke prevention

cholesterol target levels depend on individual risk (as delineated in the table below); the risk is determined by the following factors:
- comorbidities (presence of conditions such as diabetes, hypertension, or coronary artery disease necessitate more stringent LDL-C targets)
- family and personal history (familial hypercholesterolemia or a personal history of vascular events may require more aggressive lipid-lowering approaches)
- findings on vascular imaging (presence of atherosclerotic plaques or significant stenosis advocates for more stringent LDL-C goals)

Secondary stroke prevention

in patients with stroke/TIA, a statin should be administered to achieve LDL-C reduction ≥ 50% compared to baseline levels (without statins) + LDL-C levels < 1.4 mmol/L (according to ESC 2019)
- for patients ≤ 75 years, initiate intensive therapy (rosuvastatin 20-40 mg, atorvastatin 80mg or 40 mg); use lower doses only if the recommended doses are not tolerated (AHA/ASA 2018 I/A)
  for patients >75 years, a risk-benefit analysis for intensive statin therapy is advised, although benefits are generally present → see here
- for those not meeting LDL-C goals, the addition of ezetimibe is a valid approach (several fixed combinations are available)
- statin benefits extend to patients with initially low LDL-C levels (via non-lipid effects) [Nakano, 2013]
discontinuation of existing statin therapy may worsen the outcome of acute stroke (AHA/ASA 2018 I/A)
starting statins during hospitalization is reasonable (AHA/ASA 2018 IIa/C-LD); however, the effect of initiating statin therapy acutely (within 24h) versus delayed (< 7 days after stroke) has not been demonstrated – ASSORT, FASTER [Yoshimura, 2018]

Low cholesterol levels and bleeding risk

LDL-C levels < 1.7 mmol/L are not associated with a significantly increased risk of hemorrhagic complications, according to the TST trial
similarly, a meta-analysis of trials targeting an LDL-C level < 55 mg/dL (1.42 mmol/L) did not show an increased risk of hemorrhagic stroke (OR 1.05) [Masson, 2019]
an increased risk of bleeding is especially likely in patients with secondary hypolipidemia (malnutrition, hepatopathy, cancer, and hyperthyroidism) or patients generally at higher risk for ICH (those with poorly corrected hypertension or those receiving anticoagulant therapy)

Target values (ESC 2019)

Secondary prevention / very-high risk FH

LDL-C reduction ≥ 50% from baseline + LDL-C goal < 1.4 mmol/L (< 55mg/dL)

For patients with ASCVD who experience a second vascular event within 2 years (not necessarily of the same type as the first event) while taking maximally tolerated statin therapy

consider LDL-C < 1.0 mmol/L (< 40mg/dl)

Primary prevention

very-high risk without FH – LDL-C reduction ≥ 50% from baseline + LDL-C <1.4 mmol/L (<55mg/dL)
high risk – LDL-C reduction of ≥ 50% from baseline and an LDL-C goal of <1.8 mmol/L (<70 mg/dL)
moderate risk – LDL-C goal <2.6 mmol/L (<100mg/dl)
low risk – LDL-C goal <3 mmol/L (<116 mg/dL)

TAG <1.7 mmol/L (<150 mg/dL) indicates lower risk, and higher levels indicate a need to look for other risk factors
ApoB secondary goals are <65, 80, and 100 mg/dL for very-high-, high-, and moderate-risk people, respectively

Very high-risk FH (familial hypercholesterolemia): FH + ASCVD or major risk factors
High-risk FH: FH without major risk factors

Values based on ESC guidelines 2019

ESC guidelines 2019

Very-high-risk

documented ASCVD (either clinical or clear on imaging)
- CAD
  - acute coronary syndrome (ACS) – MI or unstable angina
  - stable AP
  - coronary revascularization (PCI, CABG) or other arterial revascularization procedures
- stroke/TIA
- peripheral arterial disease (PAD)
- significant atherosclerosis on carotid ultrasound, coronary CTA, etc.
diabetes with organ damage (proteinuria, retinopathy, polyneuropathy) or ≥ 3 major risk factors and/or T1DM with long duration (> 20 years)
severe CKD (eGFR: <30 mL/min/1.73 m2 (0.5 mL/s)
a calculated SCORE ≥ 10% for a 10-year risk of fatal CVD
FH + ASCVD or with another major risk factor

High-risk (elevated single risk factors)

total cholesterol > 8 mmol/L (> 310 mg/dL)
LDL-C >4.9 mmol/L (>190 mg/dL)
BP ≥ 180/110 mmHg
patients with FH without other major risk factors
diabetes without organ damage with a duration ≥ 10 years or any other additional risk factor
moderate CKD – eGFR 30-59 mL/min/1.73 m2 ( 0.5-0.99 mL/s)
calculated SCORE ≥ 5% and <10% for a 10-year risk of fatal CVD

Moderate-risk

T1DM (age < 35y) or T2DM (age < 50y) with diabetes duration <10 years without other risk factors
calculated SCORE ≥ 1 % and <5% for a 10-year risk of fatal CVD

Low-risk

calculated SCORE <1% for a 10-year risk of fatal CVD

SCORE calculator

Lipid-lowering drugs overview

Hypolipidemic drug	Dominant effect
statins	↓ LDL + total cholesterol
ezetimibe	↓↓ LDL + total cholesterol
PCSK9 inhibitors	↓↓ LDL + total cholesterol
fibrates	↓↓ TG ↑ HDL
icosapent ethyl	↓↓ TG
niacin	↑ HDL ↓ TG

Statins

Mechanism of action

statins are competitive inhibitors of HMG-CoA reductase, that
- decrease LDL-C and total cholesterol plasma levels
- have non-lipid effects (anti-inflammatory, antithrombotic, and antioxidant properties)
statins are effective in preventing ischemic stroke and other cardiovascular diseases

Interactions

interactions of statins with other drugs affect their metabolism and can be clinically serious → Statins and their interactions

Dosing

Intensity of statin therapy (AHA/ASA 2013)
High intensity avg LDL reduction LDL > 50%	Moderate intensity avg LDL reduction 30-50%	Low intensity LDL reduction < 30%
atorvastatin (40) 80mg	atorvastatin 10 (20) mg
rosuvastatin 20 (40) mg	rosuvastatin 5 (10) mg
	simvastatin 20-40 mg	simvastatin 10 mg
	pravastatin 40 (80mg)	pravastatin 10-20 mg
	lovastatin 40 mg	lovastatin 20 mg

Statin equivalent doses
Statin	Notes	Equivalent dose on LDL reduction
ROSUVASTATIN (10-40 mg) (Rosucard / Mertenil / Crestor / Rosumop)	caution is advised in individuals > 70 years of age titrate to a maximum dose of 40 mg only in patients with severe hypercholesterolemia at high and very-high CV risk who have not achieved the therapeutic goal with 20 mg (used for at least 4 weeks) – these patients should be monitored regularly rosuvastatin is contraindicated in ClCr< 0.5 mL/s a dose of 40 mg is contraindicated in patients predisposed to myopathy/rhabdomyolysis, e.g.: moderate renal impairment (creatinine clearance < 1 mL/s) with thyroid hypofunction a personal or family history of hereditary muscular disorders a previous history of muscular toxicity following administration of other HMG-CoA reductase inhibitors or fibrates excessive alcohol use concomitant use of fibrates in these cases, use an initial dose of 5 mg	5 mg
ATORVASTATIN (10-80 mg) (Atoris / Torvacard / Sortis / Lipitor/ Tulip)	no need for dose reduction in renal insufficiency or at older ages contraindicated in 3-fold elevation of transaminases, and if myopathy occurs	10 mg
SIMVASTATIN (10-40 mg) (Zocor / Simvax / Vasilip / Simvor)	initial dose of 10-20 mg per day, with a maximum dose of 40 mg per day a dose of 80 mg simvastatin is not recommended due to the high risk of rhabdomyolysis dose reduction: severe renal insufficiency (ClCr <30 mL/min); use max 10 mg do not use with fibrates (especially with gemfibrozil) max dose 20mg with concomitant use of moderate 3A4 inhibitors (amiodarone, amlodipine, verapamil, or diltiazem) contraindicated if strong CYP3A4 inhibitors are used (e.g., itraconazole, ketoconazole, erythromycin, clarithromycin, protease inhibitors)	40 mg
FLUVASTATIN (80 mg) (Lescol)		80 mg
LOVASTATIN (20-80 mg) (Medostatin / Mevacor / Altoprev)		80mg

Adverse events, intolerance

General contraindications to statins

hypersensitivity to the medicinal substance or any excipient
active liver disease or unexplained persistent elevation of AST/ALT > 3x ULN (Upper Limit of Normal)
pregnancy and lactation, or in women of childbearing age who are not using effective contraception
severe renal impairment with rosuvastatin (creatinine clearance < 0.30 mL/min)
myopathy or creatine kinase (CK) elevation > 10-fold
medications that may interact adversely (such as simvastatin + clarithromycin)

many side effects may not actually be attributable to statins; rechallenge is successful in up to 92% of cases [Zhang, 2013]
most common adverse effects (AEs):
- myopathy (3-5%, severe <1%) – more likely due to a combination of hypolipidemic drugs (with fibrates) or when statins interact with other drugs [Birtcher, 2015]
- hepatopathy (1%)
- nephropathy (causality unclear/questionable)
  - observed at higher doses [Dormuth, 2013]
  - some studies showed no association between nephropathy and statin use [Bangalore, 2014]
  - the SPARCL trial analysis even suggests better renal function in patients on statins compared to placebo [Amarenco, 2014]i
  - initiation of statin therapy is not recommended in patients undergoing hemodialysis (AHA/ASA 2019 Acute Stroke III/B-R)
- neuropathy (symmetric axonal sensory-motor), often regressing after statin discontinuation
evaluate the risk of concomitant medications (for instance, the combination of rosuvastatin and clarithromycin increases the risk of acute renal failure [Li, 2014]

→ Statin intolerance

→ Statins and their interactions

Statin intolerance

statin intolerance refers to the inability to tolerate statin therapy due to the occurrence of adverse effects (usually musculoskeletal symptoms or elevated muscle or liver enzymes)
intolerance leads to either the discontinuation of therapy or dose reduction
intolerance is confirmed by:
- the reversal of clinical symptoms and/or normalization of creatine kinase levels upon discontinuation of statin therapy
- recurrence of myalgia or a minimum 4-fold elevation of CK levels after reinitiation of therapy
at least two different statins should be tested for a comprehensive assessment

Monitoring of therapy

see below

Statins in women of childbearing age

statins should not be used:
- during pregnancy and breastfeeding
- in women who are not using effective contraception
discontinue 1-2 months before planned conception; discontinue immediately if an unplanned pregnancy is detected
according to a recent study, statin use during pregnancy is associated with lower birth weight (< 2500g) and preterm birth but does not cause birth defects (Chang, 2021)
- statin therapy may be considered in patients at very high cardiovascular risk – risk-benefit must be assessed (Chang, 2021)

Ezetimibe

ezetimibe is a selective inhibitor of intestinal cholesterol absorption
- due to a reduced supply of dietary cholesterol, endogenous cholesterol synthesis increases, which should be inhibited by a concomitant statin therapy (combination with statin at any dose is essential)
lowers total and, especially, LDL-C levels
- in monotherapy, LDL is reduced by 20%; in combination with a statin, this reduction can be up to 2-fold
has a positive effect on endothelial dysfunction and the intensity of the inflammatory response, as well as on insulin resistance
improves the course of Non-Alcoholic Fatty Liver Disease (NAFLD), a common finding in patients with metabolic syndrome or type 2 diabetes mellitus (DM2T)
the IMPROVE-IT trial demonstrated a reduced risk of stroke
- reduction in primary endpoint (vascular death, MI, nonfatal stroke, and hospitalization for unstable AP or coronary revascularization) – 32.7% vs. 34.7% over 7 years
- significantly greater effect in high-risk populations (e.g., with diabetes, hypertension, renal disease) – risk reduction was up to 19%
generally well tolerated with minimal AEs
- most commonly GI intolerance (dyspepsia, abdominal pain, diarrhea, or flatulence)
- less frequently myalgia, hepatopathy, or fatigue

used as add-on therapy in patients at increased risk of stroke who do not achieve target total and LDL cholesterol levels at the maximum tolerated statin dose

EZETIMIBE

(Ezetrol / Zetia) 10mg/tablet

dosing: 10 mg once daily
- with or without food
contraindications
- moderate and severe hepatic insufficiency (Child-Pugh score > 7)
- pregnancy and breastfeeding
- concomitant administration of active CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, erythromycin, clarithromycin, etc.)
adjustments are generally not required for renal or hepatic impairment (including patients with calculated GFR< 30 mL/min/1.73 m2) or in the elderly
co-administration with a statin or fenofibrate is possible for enhanced lipid-lowering effects

Fixed combinations are available under various brand names
ezetimibe / rosuvastatin	Rozetin / Arosuva / Zenon / Ezeros 10 mg / 10-40 mg
ezetimibe / atorvastatin	Zetovar / Ezeato / Ezator 10mg / 10-80 mg
ezetimibe / simvastatin	Inegy / Ezesim 10 mg / 10-80 mg

Antibodies against PCSK9 (proprotein convertase subtilisin/kexin type 9)

monoclonal antibodies against PCSK9 receptors bind to circulating PCSK9 proteins in the bloodstream and prevent PCSK9 from binding to LDL receptors on the surface of liver cells
this allows the LDL receptors to remain on the surface of liver cells and continue to remove LDL cholesterol from the bloodstream more effectively
as a result, levels of LDL cholesterol in the bloodstream decrease (by ~ 50-60%), leading to reduced risk of cardiovascular events
- FOURIER trial (phase 3) compared statin vs. statin + evolocumab 140mg administered every 14 days
  - combination of evolocumab+statins resulted in a significant reduction in cardiovascular events and LDL levels
  - the relative reduction in combined endpoint (MI, stroke, CV death, coronary revascularization, and unstable angina) was 15% over 22 months – 9.8% vs. 11.3%
indications
- hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia
  - in combination with a statin (and possibly other hypolipidemics) for patients in whom target LDL-C levels are not achieved with the maximum tolerated dose of statin or
  - in monotherapy or with other hypolipidemic agents in patients who are statin-intolerant or for whom statins are contraindicated
- homozygous familial hypercholesterolemia (FH) – in adults and adolescents > 12 years, in combination with other hypolipidemics
- proven atherosclerotic cardiovascular disease (myocardial infarction, stroke, or PAD)
  - in combination with the maximum tolerated dose of statin or other hypolipidemics
  - in monotherapy or in combination with other hypolipidemics in patients who are intolerant to statin or statin is contraindicated

EVOLOCUMAB

(Repatha) 140mg/1mL or 420 mg/3.5 mL

dosing: SC injection 140 mg every 14 days or 420 mg once a month
PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody used as an adjunct to LDL cholesterol-reducing therapies, aiding in the prevention of cardiovascular events and cardiovascular revascularization procedures

ALIROCUMAB

(Praluent) 75 or 150mg/1mL and 300 mg/2mL

the usual initial dose is 75 mg CS every 2 weeks
4 to 8 weeks after initiation of treatment or dose adjustment, check lipids and adjust the dose if required
dose may be increased to 300 mg every 4 weeks or to a maximum dose of 150 mg every 2 weeks
to administer the 300 mg dose, either one 300 mg injection or two 150 mg injections should be administered at two different injection sites

BOCOCIZUMAB

phase 3 SPIRE trial was terminated prematurely; the benefit of bococizumab was demonstrated only in high-risk patients
sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies [Ridker, 2017]

PCSK9 synthesis inhibitors

inclisiran (LEQVIO)
- the first subcutaneous application is followed by a second after 3 months and then every 6 months
inclisiran is a siRNA (small interfering RNA) representative that inhibits PCSK9 synthesis in the liver and helps increase the number of LDL cholesterol receptors on the surface of liver cells (resulting in more efficient removal of LDL cholesterol from the bloodstream)
reduces mainly LDL cholesterol (as anti-PCSK9 monoclonal antibodies)
treatment with inclisiran is accompanied by a long-term ~50% reduction in LDL cholesterol and is very well tolerated
results of the ORION4 trial (testing effect of inclisiran on vascular events rate) are awaited

Bempedoic acid

used for the treatment of primary hypercholesterolemia or mixed dyslipidemia
- combination with statins when target LDL is not achieved
  - when concomitant statin use is used, the occurrence of myopathy should be monitored (bempedoic acid increases plasma statin levels)
  - reduce the dose of simvastatin to 20-40mg, no dose adjustment is necessary for other statins
  - reduce statin dose if myopathic symptoms occur, discontinue both drugs if CK > 10x ULN
- in patients who are intolerant to statins or contraindicated
daily dose: 180 mg
dose reduction is not necessary for milder nephropathy and hepatopathy; insufficient data for more severe disorders
women of childbearing age must use contraception (same as for statins)

BEMPEDOIC ACID

NUSTENDI (bempedoic acid 180 mg)
NILEMDO (bempedoic acid 180 mg + ezetimibe 10 mg)

Fibrates

a class of lipid-lowering drugs used for the management of hypertriglyceridemia and mixed dyslipidemia (may also moderately increase HDL levels)
they act by activating peroxisome proliferator-activated receptors (PPARs), leading to increased lipolysis and reduced triglyceride-rich particles
caution is advised when co-administered with statins due to increased risk of myopathy

FENOFIBRATE

(Fenofix / Suprelip / Lipanthyl / Fenomax / Tricor)

dosing: 48 – 200 mg daily, administered typically once daily, with or without food
dose adjustment based on renal function and triglyceride levels may be required

GEMFIBROZIL

(Gemfibrozil / Lopid) 300 or 600 mg/tablet

dosing: 600mg twice daily, 30 minutes before the morning and evening meals
renal function should be considered for dosing adjustments
monitoring of lipid profiles and liver function is recommended during therapy

Fibrates and stroke prevention

In the VA-HIT trial, gemfibrozil administration was associated with a significant 31% reduction in the risk of ischemic stroke compared to placebo in patients with CAD+low HDL and LDL levels
in the FIELD trial, which evaluated the effect of fenofibrate on the incidence of cardiovascular complications in patients with type 2 diabetes; fenofibrate administration was not associated with a significant reduction in the risk of all strokes or a subset of ischemic strokes (10% and 9% risk reduction, respectively). The FIELD trial had several methodological limitations, and the results should be interpreted with these limitations in mind. In the subpopulation meeting criteria for metabolic syndrome, including the presence of typical diabetic dyslipidemia, treatment with fenofibrate resulted in a significant 26% reduction in the risk of macrovascular events (p = 0.014)

Ethyl eicosapentaenoic acid

an ethyl ester form of the omega-3 fatty acid eicosapentaenoic acid (EPA)
improves the lipoprotein profile by suppressing cholesterol, fatty acid, and triacylglycerol (TAG) synthesizing enzymes; the mechanism of action also includes anti-inflammatory and antithrombotic effects
indications:
- primarily used for treating hypertriglyceridemia in adults with high triglyceride levels (>500 mg/dL)
- also approved for cardiovascular risk reduction in specific high-risk patient populations (together with statins)

ICOSAPENT-ETHYL

(Vazkepa / Vascepa) 998 mg/capsule

dosing: 4 g/day, administered as two 1-gram capsules twice daily with meals
monitoring of triglyceride levels and liver function is advised during treatment

Other lipid-lowering agents

Cholesteryl ester transfer protein (CETP) inhibitors – trapibs

torcetrapib and dalcetrapib were ineffective or burdened with AEs
- e.g., negative dal-OUTCOMES trial with dalcetrapib [O´Riordan, 2012]
safety of anacetrapib and its good effect on ↓LDL and ↑HDL were demonstrated by the DEFINE and REVEAL trials
the negative results and early termination of the evacetrapib Phase 3 ACCELERATE trial meant a major disappointment [Stiles, 2015]
- evacetrapib had favorable effects on established lipid biomarkers, but treatment did not result in a lower rate of cardiovascular events than placebo in patients with high-risk vascular disease

Niacin

raises HDL and lowers TAG levels
in 2013, the niacin/laropiprant combination was recommended for withdrawal
- the randomized HPS-2 THRIVE trial did not show an additive effect with statins + showed a higher incidence of AEs

Monitoring of lipid-lowering therapy

Monitoring of therapy effectiveness

check lipid profile 3 months (4-12 weeks) after starting hypolipidemic therapy and after any dose adjustment
conduct periodic evaluations at 6-12 month intervals if blood lipids are stable and good compliance is assumed
re-evaluate cardiovascular risk regularly and adjust target lipid levels

Notes on blood collection

lifestyle should remain stable before testing (diet, weight change); alcohol should be avoided two days before testing (as it increases triglycerides).
it is recommended that non-fasting blood samples be routinely used to assess plasma lipid profiles (EAS guidelines 2016 and 2019) [Nordestgaard, 2016]
- non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease; only slight changes were observed for triglycerides [Mora, 2016]
- fasting sampling may be considered when non-fasting triglycerides are >5 mmol/L (440 mg/dL)
- non-fasting tests accurately predict cardiovascular risk

do not perform lipid sampling:
- in decompensated diabetes
  - secondary hyperlipidemia occurs; perform testing after 2-3 weeks of adequate diabetes compensation
- in pregnant women and women < 6 months postpartum
- with concurrent acute or subacute illness
  - < 3 weeks after common diseases (tonsillitis, virosis, etc)
  - < 3 months after serious condition (surgery, myocardial infarction, etc.)

Monitoring of adverse events

clinical examination
- check regularly for muscle pain or weakness, which may indicate side effects, especially during the first 12 months
- check for drug interactions (always ask about new medications)
periodic laboratory tests:
- liver enzymes
  - before starting statin therapy and then after 3 months
  - with stable dosage, check every 6-12 months
  - re-check after 3 months if the dose is increased
  - reduce/discontinue statins if AST/ALT increases ≥ 3 times
- creatine kinase (CK)
  - before starting statin therapy and then after 3 months
  - follow-up every 6-12 months at a stable dose
  - discontinue therapy if :
    - CK rises 5 times in patients with myopathic symptoms
    - CK rises 10 times in asymptomatic patients
- renal function (urea, creatinine, glomerular filtration rate)
  - every 12 months at a stable dose
  - reduce dose of rosuvastatin if ClCr<1mL/s); recommended initial dose is 5 mg/d
  - avoid rosuvastatin if ClCr <0.5mL/s