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Editors

TimoStrandberg
HannuVanhanen

Treatment of Dyslipidaemias

Essentials

  • The aim of treatment is to:
  • Lifestyle modification is of primary importance in all patients.
  • Secondary hypercholesterolaemia (associated with hypothyroidism, for instance) must be excluded before starting medication.
  • The general goal of treatment is to lower plasma LDL cholesterol levels to:
    • below 3.0 mmol/l in low risk patients
    • below 2.6 mmol/l in moderate risk patients
    • below 1.8 mmol/l in high risk patients
    • below 1.4 mmol/l, as far as possible, in very high risk patients.
  • In hypertriglyceridaemia, triglyceride levels must be below (5-)10 mmol/l to reduce the risk of pancreatitis.

Treatment of various patient groups

  • The treatment and its goal depend on the magnitude of the risk. The most important target groups are high risk and very high risk patients (table T1).
  • In patients with acute coronary syndrome, high-dose therapy with most effective statins (atorvastatin 40-80 mg/day, rosuvastatin 20-40 mg/day) is indicated regardless of lipid levels.
  • Lifestyle guidance for all patients (particularly healthy diet, increasing exercise and smoking cessation)
  • Lipid-lowering medication should not be started without assessing the total risk of arterial disease.

The target LDL cholesterol level depends on the total risk of arterial disease.

Risk of arterial diseaseRisk factorsTreatment goal for LDL cholesterol
Very high
  • Arterial disease
    • Coronary artery disease (myocardial infarction, revascularization, arterial disease confirmed by imaging)
    • Cerebral infarction, TIA or cerebral or carotid artery disease confirmed by imaging
    • Other atherosclerotic disease (aorta, peripheral arteries)
  • Diabetes plus additional factor
    • Target organ damage or type 1 diabetes > 20 years
  • GFR < 30 ml/min/1.73 m2
  • SCORE HASH(0x2fcaf98) 10% or equivalent risk assessed by a calculator designed for local population
<1.4 mmol/l or as close as possible to this
High
  • Diabetes >10 years or diabetes plus a significant risk factor
    • E.g. smoking, hypertension, significant obesity (BMI > 30-35), insufficient exercise
  • GFR 30-59 ml/min/1.73 m2
  • Familial hypercholesterolaemia (FH)
  • SCORE 5-9.9% or equivalent risk assessed by a calculator designed for local population
< 1.8 mmol/l
Moderate
  • SCORE 1.0-4.9% or equivalent risk assessed by a calculator designed for local population
< 2.6 mmol/l
Low
  • SCORE < 1% or equivalent risk assessed by a calculator designed for local population
< 3.0 mmol/l

Very high risk

  • In patients with arterial disease, the risk of myocardial infarction or cardiac death increases very greatly with increasing plasma cholesterol levels.
  • The benefit of treatment has been clearly shown. The aim is to lower LDL cholesterol levels to below 1.4 mmol/l (or by at least 50% from the baseline level).
  • Intensified dietary management, lifestyle modification, review of efficacy of treatment in 1-2 months
  • Reduction of other risk factors
  • Medication is necessary in practically every case.

High risk Lipid Lowering Therapies in Renal Disease

  • See table T1
  • Lifestyle modification and medication if LDL > 1.8 mmol/l (the further the LDL level is from the target, the greater the need to start medication alongside the lifestyle modification)
  • The aim of the treatment is to lower LDL cholesterol levels to below 1.8 mmol/l.

Moderate risk

  • See table T1
  • Treatment by lifestyle modification
  • Medication should be considered if the LDL target (< 2.6 mmol/l) cannot be reached within 6 months. Monitoring alone will not lower LDL cholesterol levels.

Low risk

  • See table T1
  • The general aim is to lower plasma cholesterol levels to below 5.0 mmol/l (LDL cholesterol below 3.0 mmol/l).
  • When considering any measures, the total risk should be taken into account (age, gender, smoking, blood pressure); see Definition and Diagnosis of Dyslipidaemias. Family history and HDL and triglyceride levels also reflect the risk (working age people being the most significant group).
  • If the LDL level is < 2.5 mmol/l, treatment of lipid levels is not necessary.
  • If the LDL level is 2.5-4.9 mmol/l, lifestyle modification
  • Medication must be considered if the LDL level is > 4.9 mmol/l despite lifestyle modification.

Patients over 75 years of age

  • Should be treated case by case, particularly those with arterial disease, considering their biological age and general prognosis.
  • The therapeutic principles are the same as for younger patients but due to the risk of malnutrition and sarcopenia any dietary instructions should be given with caution.
  • Advancing age, as such, does not justify stopping well suited medication.
  • However, any adverse effects of medication must be monitored carefully (particularly in patients with polypharmacy or age-related frailty syndrome).
  • A systematic review of subjects over 75 included in randomized studies showed that lower LDL cholesterol levels achieved with a statin, combination of a statin and ezetimibe or combination of a statin and PCSK9 reduced arterial disease events as effectively as in younger patients.
    • As most of the studies were secondary prevention studies, the benefit of starting treatment for primary prevention in people over 75 is uncertain as yet and must be evaluated case by case.

Treatment of dyslipidaemia by lifestyle modification

General principles

  • Smoking cessation
  • Weight loss, as necessary
  • Increasing physical activity
  • Polyunsaturated (rapeseed oil) and monounsaturated (vegetable) fats should be favoured, cutting down on saturated fats (animal fats, milk fats) and trans fats (if locally relevant).
    • Palm oil in various forms and coconut fat contain high levels of saturated fatty acids and cannot therefore be recommended even though they are of vegetable origin.
    • Different types of health symbols or logos in food may help in identifying good choices as regards the amount and quality of fat.
  • Cholesterol intake should be reduced.
  • The intake of dietary fibre should be increased; gel-forming oat or barley beta glucan at a daily dose of approx. 3 g lowers LDL cholesterol levels.
  • Plant stanols and sterols in various forms (margarine, yoghurt, drink) at daily doses of 2 g lower LDL cholesterol by approx. 10%. Margarine with (40-)60% fat is recommended to guarantee the intake of essential fatty acids.
  • If the target lipid levels cannot be achieved by dietary treatment, medication should be added to the regimen.

Dietary recommendations

  • The main principles of a ”heart-friendly” diet have remained the same for decades, and no essential new information has been added.
  • Share of fats in total energy < 30 E%
    • Saturated < 10 E%
    • Mono- or polyunsaturated 20 E%
  • Dietary cholesterol 250-300 mg/day
  • Products rich in soluble dietary fibre instead of white carbohydrates (pure sugar, purified flour)
    • > 20 g/1 000 kcal (wholegrain products, 500 g daily of vegetables and fruits)
  • Fish twice a week
  • Unfiltered coffee (brewed coffee, espresso, French press, some capsule coffees) should be avoided; raises plasma cholesterol levels by approx. 0.5 mmol/l..
  • Alcohol consumption should be restricted particularly in a patient with:
    • overweight
    • hypertension
    • hypertriglyceridaemia.
  • Salt intake should be restricted. The challenge here is that approx. 80% of salt comes with finished food products; it is therefore important to choose products with appropriate health symbols/logos.

Expected effectiveness of dietary modification Dietary Treatment for Familial Hypercholesterolaemia

  • The efficacy of dietary modification for prevention of arterial disease depends on its individual effect on plasma lipid levels.
  • In some patients, plasma cholesterol levels may decrease by 15% but the average effect is still only 3-6%.
  • In individual patients, levels may fall by as much as > 30%, particularly if there was a lot to correct in their diet.

Diet therapy in practice

  • Individual dietary counselling should be based on a detailed dietary history, preferably a food diary.
  • The intake of hard animal and milk fat should be reduced.
    • Skimmed milk or skimmed sour milk should be chosen.
    • Other dairy products with low fat content should be preferred; of cheeses, for instance, those with HASH(0x2fcb3a0) 17% fat.
    • A soft margarine, low-fat spread, plant stanol or plant sterol margarine should be used on bread. Spreads with a combination of butter and vegetable oil are not recommended. In addition to spreads, equivalent yoghurt products can be used particularly if the amount of spread used is small.
    • Lean meat products, fish, skinned poultry and low-fat cold cuts (poultry, pork) should be favoured and processed meat, such as sausages, avoided.
  • Foods high in cholesterol should be avoided.
    • Fatty meat products and milk fat
    • Offal
    • Egg yolk
  • Hidden fat is often saturated.
    • Pizza
    • Fast food
    • Danish and other sweet pastries
  • Overweight should be reduced by following a low-calorie diet (supported by a very-low-energy diet, as necessary) and by physical exercise Conservative (Non-Surgical) Treatment of Obesity.
  • Dietary fibre should be increased, favouring:
    • vegetables, root vegetables and legumes
    • berries and fruit
    • wholegrain products.
  • Food should be prepared by boiling, simmering or in the oven, using no added fat or using vegetable oils or vegetable margarines. Suitable oils include rapeseed (best fatty acid composition), camelina, olive, sunflower, soybean and corn oil but not palm oil or coconut fat.
  • Prefer filtered or instant coffee, avoiding brewed coffee, espresso, French press and other unfiltered types of coffee. Some capsule coffees, too, contain harmful diterpenes increasing cholesterol levels.
  • As the share of fats as a source of energy is reduced, they need to be replaced by carbohydrates high in fibre: wholegrain products, brown rice, wholegrain pasta, potatoes, vegetables, root vegetables, fruit and berries.

Effect of plant stanol and plant sterol margarines on cholesterol levels

  • Regular use of approx. 2-3 g/day of plant stanols or sterols in addition to a diet conforming to the recommendations will reduce plasma LDL cholesterol levels by 10%. HDL cholesterol or triglyceride levels will not be affected.
  • Plant stanol or plant sterol margarine may be suitable as the sole treatment of mild hypercholesterolaemia combined with other dietary treatment. If cholesterol levels do not fall sufficiently, a sitostanol or sitosterol can be combined with a statin, with ezetimibe (which, like sitostanol and sitosterol, prevents the absorption of cholesterol, but by a different mechanism) or with PCKS9 inhibitors.
  • Plant stanol or plant sterol margarine may lessen the need for hypolipidaemic drug treatment and lower the required statin dose in patients with familial or even other types of hypercholesterolaemia.
  • Low-fat products with plant stanols or plant sterols are recommended for overweight people.
  • Check the treatment response and weigh the patient.

Principles of drug therapy , Statins for the Primary Prevention of Cardiovascular Disease, Efficacy and Safety of Cholesterol Lowering by Statins, Fixed-Dose Combination Therapy for the Prevention of Atherosclerotic Cardiovascular Diseases

  • Make sure that the most effective possible dietary treatment is being used but do not delay the beginning of necessary drug therapy.
  • Drug therapy is indicated at least if the total risk is high or very high and lifestyle modification is not sufficient to reach the treatment goals within 3-6 months.
  • Patients with arterial disease or diabetes are an important target group.
  • Before starting drug therapy, perform plasma cholesterol, plasma triglycerides, plasma HDL cholesterol, plasma LDL cholesterol and ALT tests.
  • Exclude secondary hypercholesterolaemia Definition and Diagnosis of Dyslipidaemias. If the cause of secondary hypercholesterolaemia cannot be treated, treat the patient as if the hypercholesterolaemia were primary.
  • Identify familial hypercholesterolaemia Definition and Diagnosis of Dyslipidaemias (plasma cholesterol usually exceeding 8 mmol/l [but may be lower], xanthomas, family history); this is important both for finding relatives and, depending on local policies, for the reimbursability of medication.
  • Of the most common drugs, statins and cholestyramine, as well as fibrates and ezetimibe or PCSK9 inhibitors combined with statins have been tested in long-term randomized therapeutic trials based on significant clinical end points.
  • Statins are the first-line drugs for dyslipidaemia. If the main abnormality is hypertriglyceridaemia, a fibrate may be considered.
  • The efficacy of statins can be improved by combining them with ezetimibe, which may in some cases also be used alone. However, its efficacy in monotherapy is usually modest.
  • Resins (cholestyramine, colesevelam) and guar gum can be used as monotherapy only exceptionally.
  • PCSK9 inhibitors(antibodies evolocumab and alirocumab as well as synthesis inhibitor inclisiran) are a new effective (but expensive) group of drugs. Their use can be considered and reimbursement obtained, under special conditions and depending on local policies, for patients with very high risk and patients with FH
    • who cannot use statins due to their adverse effects or
    • whose LDL cholesterol levels do not fall into the target range despite use of the highest tolerated statin dose combined with ezetimibe.
    • Find out about local policies and patient groups concerning the reimbursement of PCSK9 inhibitors.

Choice of medication based on type of dyslipidaemia

  • See table T2

Choice of medication based on type of dyslipidaemia

(Pheno)type of dyslipidaemiaMedication
Hypercholesterolaemia alone
  • A statin or a combination of a statin and ezetimibe
    • For patients with very high risk, combination of a statin and a PCSK9 inhibitor (or a PCSK9 inhibitor alone) if a statin + ezetimibe is insufficient or statins are unsuitable
    • Resins in special cases, only
Both plasma cholesterol and plasma triglycerides elevated
  • Plasma triglycerides HASH(0x2fcb3a0) 4.5 mmol/l: a statin
  • Plasma triglycerides > 4.5 mmol/l: a statin
Pure hypertriglyceridaemia
  • Weight loss and restriction of alcohol consumption are essential before drug treatment; in people with diabetes, glycaemic control should be optimized
  • Fenofibrate or bezafibrate (or fish oil product*)
* Primarily in specialized care; the efficacy of various products and dosages differs.
Statins Statin Treatment for Cardiovascular Events in Patients with Coronary Heart Disease and Abnormal Liver Tests, Statin Administration in the Morning or in the Evening
  • The most important and most commonly used medication in practice

Mechanism of action

  • The action of statins is based on the inhibition of HMG-CoA reductase, preventing the synthesis of cholesterol in hepatocytes. The number of LDL receptors in hepatocytes increases and the elimination of LDL from the circulation is accelerated. Statins also act through VLDL. There may be other mechanisms, as well.

Efficacy Statins for Improving Renal Outcomes, Lipid-Lowering Efficacy of Rosuvastatin, Lipid Lowering Efficacy of Atorvastatin, Fluvastatin for Lowering Lipids

  • LDL cholesterol levels decrease by 30-40%.
  • HDL cholesterol levels increase by 5-15%.
  • Triglyceride levels decrease by 10-30% or even more.
  • Concomitant use of ezetimibe or a resin will intensify the effects.

DosageIntensive Versus Moderate Statin Therapy, Lipid Lowering Efficacy of Atorvastatin, Lipid-Lowering Efficacy of Rosuvastatin, Fluvastatin for Lowering Lipids

Adverse effects

  • Statins are usually well tolerated by elderly patients, as well.
  • Plasma aminotransferase levels may increase in less than 2% of patients but the clinical significance of the phenomenon is uncertain and routine monitoring of liver enzymes is not necessary.
    • Slight elevation does not prevent treatment (levels exceeding 3 times the upper limit of the reference range represent significant elevation).
    • If the levels return to normal after withdrawal of the statin, treatment can be started at a lower dose or with another statin and/or the statin can first be taken at longer intervals than once daily.
  • Statins cause muscle pain in about 5(-10)% of patients. The incidence of significant muscular adverse effects is less than 0.1%.
    • In studies, muscle pain has occurred more frequently when subjects have known they are taking a statin, which suggests a nocebo effect (e.g. in the follow-up of the ASCOT study).
  • Muscle symptoms are not necessarily due to the statin, as they are also otherwise common in the treated age groups.
  • Routine plasma creatine kinase (CK) tests are not necessary.
  • The following appear to be predisposing factors for myopathy:
    • other concomitant factors raising statin levels (such as treatment with ciclosporine, fibrates, macrolides or azoles)
    • hereditary susceptibility associated with, for example, polymorphism of the SLCO1B1 gene regulating drug metabolism; a genetic test can be taken to investigate this
    • very advanced age
    • multiple concomitant diseases
    • surgery
    • hypothyroidism
    • vitamin D deficiency.
  • If a statin causes muscle pain:
    • try a lower dose or less frequent dosage of an effective statin, starting with a lower dose
    • switch to a statin with a metabolic pathway other than cytochrome 3A4, such as fluvastatin, pravastatin or rosuvastatin
    • switch to combination treatment (e.g. statin + ezetimibe) to enable lowering the statin dose
    • consider using another group of drugs (in patients with a very high risk, reimbursement may also be available for a PCSK9 inhibitor).
  • The risk of diabetes is slightly increased during statin therapy, particularly in those already otherwise at risk (metabolic syndrome, elevated fasting glucose values). Statins prevent macrovascular complications also in people with diabetes.
  • Single adverse effects (such as polyneuropathy) have been described in association with statin treatment but no true association with the treatment has been confirmed. There is no evidence of increased risk of pancreatitis, cognitive adverse effects or cataracts.

Ezetimibe Ezetimibe for the Prevention of Cardiovascular Disease

  • Adding ezetimibe to the regimen is usually considered if the efficacy of a statin alone is insufficient. Combined with a statin, ezetimibe has been shown to reduce end points.
  • The effect of ezetimibe monotherapy is usually modest, and its effect on end points has not been studied.

Mechanism of action

  • Ezetimibe acts by preventing the absorption of cholesterol from the small intestine.
  • The effect is additive to that of statins which prevent cholesterol synthesis.

Efficacy

  • Ezetimibe alone lowers LDL cholesterol levels by 19%.
  • The combination of a low statin dose + ezetimibe lowers cholesterol levels as much as a high statin dose alone.
  • The combination of an effective statin dose and ezetimibe can lower LDL cholesterol levels by more than 50%.

Dosage

  • 10 mg daily

Adverse effects

  • There are few adverse effects.

Resins (cholestyramine and cholesevelam)

Mechanism of action

  • Resins bind bile acids in the intestine, preventing their reabsorption and increasing their excretion in faeces.
  • Resins do not increase the secretion of neutral steroids or cause fat malabsorption.
  • Increased bile acid secretion accelerates the metabolism of cholesterol to bile acids in the liver, and the resulting lack of cholesterol in turn leads to an increased number of LDL receptors and increased uptake of LDL cholesterol in hepatocytes.
  • Being nonabsorbable, resins are safe and can be used in pregnant women and children, for instance.

Efficacy

  • Resins reduce total and LDL cholesterol levels by 15-30%.
  • Triglyceride levels may increase.

Dosage

  • Cholestyramine powder, 4 g, 16-32 g/day (doses below 20 g are better tolerated)
  • Colesevelam tablets, 625 mg, 4-6 tablets/day

Adverse effects

  • Intestinal symptoms: constipation, flatulence, nausea, epigastric pain
  • Fat-soluble vitamin and folic acid deficiency, as their absorption is impaired

Interactions

  • The absorption of the following drugs may be impaired (these should be taken at least one hour before or 4 hours after the resin):
    • digoxin
    • thyroxine
    • warfarin
    • thiazide diuretics.

PCSK9 inhibitors Pcsk9 Inhibitors for Prevention of Cardiovascular Disease

  • The number of LDL receptors increases because their degradation slows down increasing their number on the cell surface.
  • The use of PCSK9 inhibitors should be considered in very high risk patients and patients with FH:
    • who cannot use statins due to their adverse effects or
    • whose LDL cholesterol levels do not fall into the target range despite use of the highest tolerated statin dose combined with ezetimibe.
  • In the above cases, for example, PCSK9 inhibitors may be reimbursable. Find out about local policies.
  • Regardless of statin therapy, PCSK9 inhibitors lower LDL cholesterol levels by an average of 50-60%.
  • In various studies, PCSK9 inhibitors have lowered the relative risk of cardiovascular events in patients with arterial disease by approximately 15-20%, and the absolute risk by 1.5-2%.
  • Alirocumab and evolocumab are injected subcutaneously once or twice a month. Inclisiran is injected subcutaneously as one injection in the beginning of the treatment, the second dose is administered after 3 months and after that every six months.
  • PCSK9 inhibitors are well tolerated.

Fibrates Fibrates for Primary Prevention of Cardiovascular Disease

Mechanism of action

  • Fibrates act through the PPAR (perixosome proliferator activated receptors) system; the activity of lipoprotein lipase in fat and muscle tissue and the elimination of lipoproteins containing triglyceride increase.

Efficacy

  • Triglyceride levels fall by 20-70%.
  • HDL cholesterol levels increase by 10-25%.
  • LDL cholesterol levels decrease if the initial levels were high.

Contraindications

  • Severe kidney or liver failure and gall bladder diseases

Dosage

Adverse effects

  • Mild gastrointestinal irritation
  • Muscle pain and elevated plasma CK levels
  • Possibly gallstone formation
  • Elevated liver enzyme values
  • Water retention, breast growth and potency disorders occur rarely.

Interactions

  • Drugs bound to protein are displaced and their concentrations increase (warfarin, sulphonylureas).
  • Of fibrates, fenofibrate or bezafibrate are preferable for use with statins.
    • The decision on combination with statins should be made in specialized care.

Omega 3 fatty acids

  • High doses may increase the bleeding tendency.
  • Icosapent ethyl (a drug preparation containing purified eicosapentaenoic acid [EPA]) is intended for patients on statin therapy who have elevated triglyceride concentration and very high risk of arterial disease. Find out about local reimbursement policies.

Thyroxine replacement in patients with hypothyroidism

Monitoring of drug treatment

  • Lipid levels should first be checked after 1-2 months, then at 3-6 months, as necessary, and subsequently according to individual need.
  • If the goal of treatment cannot be reached, switch to combination therapy.
  • Even though the goal cannot be reached in all patients, the aim is to get as close to the goal as possible, while considering the overall situation.

Safety tests

Statins

  • ALT should be tested, as considered appropriate, about 1-2 months after the beginning of medication, when controlling the lipid levels. Routine follow-up of liver enzyme values is not necessary.
    • Values exceeding the upper limit of normal by more than threefold warrant withdrawing the medication and investigations mainly to exclude other causes.
    • Other causes of elevated liver enzyme levels (e.g. obesity, heavy alcohol use, several drugs) lower the threshold of controlling ALT in association with statin therapy.
    • In the context of fatty liver associated with metabolic syndrome, a mild increase in ALT (less than 3 times the upper limit of normal) may also be an indication for statin therapy, and in such a case ALT usually decreases during therapy 9.
  • If unexplained muscle pain occurs, test CK.

Fibrates

  • Test ALT first every 1-2 months, subsequently every 6-12 months. If fibrates are combined with statins, ALT should be tested every 3-4 months (if combined with fibrates, half the normal dose of statins should be used).
  • If muscle pain occurs, always test CK.

Possible indications for specialist consultation

  • In case of unconfirmed suspicion of FH (definite or probable FH based on assessment by a calculator, see e.g. http://www.mdcalc.com/dutch-criteria-familial-hypercholesterolemia-fh) to confirm the diagnosis, and new cases of FH (counselling, family screening)
  • High or very high risk patients whose treatment goals cannot be achieved with a combination of statin and ezetimibe
  • Planning the combination of a statin and fibrate
  • Triglyceride levels primarily above 10 mmol/l or remaining above 5 mmol/l despite treatment
  • High-risk patients planning to become pregnant (FH, arterial disease)
  • HDL cholesterol level below 0.5 mmol/l, where the use of anabolic steroids has been excluded

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