ISCHEMIC STROKE / PREVENTION

Lipid-lowering therapy

David Goldemund M.D.
Updated on 15/08/2024, 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 and inclisiran
  • 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   The effect of statins depending on age   → 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
inclisiran ↓↓↓ 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
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 (CrCl< 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
  • atorvastatin can be even used in hemodialysis patients
    • < 2% of atorvastatin is excreted unchanged via the kidneys
    • atorvastatin and its metabolites are not significantly removed by hemodialysis due to high protein binding
  • 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 due to drug interaction [Birtcher, 2015]
    • hepatopathy (1%) – risk is low
      • the FDA removed the recommendation for routine regular monitoring of liver function for patients on statins in 2012
    • 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
      • atorvastatin can be used in hemodialysis patients
    • neuropathy (symmetric axonal sensory-motor), often regressing after statin discontinuation
    • increased risk of diabetes
      • statins can cause a small increase in blood sugar levels, which may mean that people who take statins and are already at high risk of diabetes may develop the condition sooner (CTT collaboration, 2024)
  • 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 and discussed  (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

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

→ inclisiran

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
  • 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)
  • laboratory tests:
    • liver enzymes
      • check baseline liver enzyme levels (e.g., ALT, AST) before initiating statin therapy
      • routine periodic monitoring of liver enzymes is not generally recommended unless clinically indicated (guidelines emphasize symptom-driven liver enzyme checks)
      • 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 <0.5 mL/s

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