Hypercholesterolemia: Drug Therapy

Therapeutic target

The therapeutic goal is to reduce the risk of atherosclerosis and resultant cardiovascular disease. Notes

  • In familial hypercholesterolemia (FH), statin therapy should be started in early childhood and adolescence (>8 years of age). This may prevent the progression of atherosclerosis (arteriosclerosis, hardening of the arteries) in the carotid artery

Therapy recommendations

The treatment modality for hyperlipoproteinemia depends on the level of LDL measured and the individual risk factors that the affected person brings to the table:

Primary prevention

Intervention strategy according to overall cardiovascular risk and LDL cholesterol levels.

Total cardiovascular risk LDL level
<70 mg/dL< 1.8 mmol/dL 70 to < 100 mg/dL1.8 to < 2.5 mmol/dL 100 to < 155 mg/dL2.5 to < 4.0 mmol/dL 155 to 190 mg/dL4.0 to 4.9 mmol/dL > 190 mg/dL> 4.9 mmol/dL
<1% (low risk) No lipid lowering No lipid lowering Lifestyle intervention Lifestyle Intervention Lifestyle intervention;if uncontrolled, consider medication
Evidence class/level I/C I/C I/C I/C IIa/C
≥ 1 to < 5% (or moderate risk). Lifestyle intervention Lifestyle Intervention Lifestyle intervention;if uncontrolled, consider medication Lifestyle intervention;if uncontrolled, consider medication Lifestyle intervention;if uncontrolled, consider medication
Evidence class/level I/C I/C IIa/A IIa/A I/A
≥ 5 to < 10 % (or high) Lifestyle intervention,consider medications* Lifestyle intervention,consider medication* Lifestyle modification and immediate drug intervention. Lifestyle modification and immediate drug intervention Lifestyle modification and immediate drug intervention
Evidence class/level IIa/A IIa/A IIa/A I/A I/A
≥ 10 % (or very high risk) Lifestyle intervention,consider medications* Lifestyle modification and immediate drug intervention. Lifestyle modification and immediate drug intervention Lifestyle modification and immediate drug intervention Lifestyle modification and immediate drug intervention
Evidence class/level IIa/A I/A I/A I/A

* In patients with myocardial infarction (heart attack), statin therapy should be considered regardless of LDL cholesterol level. The current European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines on dyslipidemia recommend even lower low-density lipoprotein cholesterol (LDL-C) target levels [guidelines: see below 2019 ESC/EAS Guidelines]:

Total cardiovascular risk Target LDL cholesterol Comments
<1% (low risk) <3 mmol/l < 116 mg/dl
≥ 1 to < 5% (or moderate risk). < 2.6 mmol/l < 100 mg/dl
≥ 5 to < 10 % (or high) < 1.8 mmol/l < 70 mg/dl Or at least 50% LDL-C reduction; this group includes, among others, patients with familial hypercholesterolemia and diabetics
≥ 10% (or very high risk). < 1.4 mmol/l < 55 mg/dl Or at least 50% reduction in LDL-C.

No current statin use: this likely requires high-intensity LDL-lowering therapy. Current LDL-lowering treatment: increased treatment intensity is required.

<1.0 mmol/l < 40 mg/dl High-risk patients who have had a 2nd vascular event within 2 years despite maximal lipid-lowering therapy

Other treatment targets

  • Non-HDL-C: Non-HDL-C secondary targets are <2.2, 2.6, and 3.4 mmol/l (<85, 100, and 130 mg/dl) for individuals at very high, high, and intermediate risk, respectively.
  • ApoB: ApoB secondary targets are < 65, 80, and 100 mg/dl for individuals at very high, high, and intermediate risk, respectively.
  • Triglycerides: no target, but < 1.7 mmol/l.
  • Diabetes HbA1c: < 7%

Determination of total cardiovascular risk by priority:

Very high risk
  • Cardiovascular disease/cardiovascular disease (CVD).
  • Type 2 diabetes or type 1 diabetes with target organ damage.
  • Score ≥ 10
High risk
  • Pronounced individual risk factors such as:
    • Familial dyslipidemia (lipid metabolism disorder).
    • Severe hypertension (high blood pressure)
  • Score ≥ 5 and < 10
Moderate risk
  • Family history: coronary heart disease (CHD) – before age 55 (men) or 65 (women).
  • Abdominal obesity (waist circumference).
    • Women: ≥ 88 cm
    • Men: ≥ 102 cm
  • Lack of physical activity (lack of exercise).
  • Elevated triglycerides and hs-CRP
  • Score ≥ 1 to < 5
Low risk
  • Score <1

See also under: HeartScore or Euro Score

Note: Risk may be higher than that calculated by the SCORE risk estimation system: The following factors contribute to the increase in risk:

  • Socially disadvantaged
  • Sedentary patients and those with central obesity.
  • Patients with diabetes mellitus
  • Patients with low HDL cholesterol or apolipoprotein A1, apolipoprotein B as well as elevated triglycerides, fibrinogen, homocysteine, Lp(a) levels, hs-CRP; familial hypercholesterolemia; impaired glucose tolerance (inadequate regulation of blood glucose after oral glucose intake).
  • Asymptomatic subjects with preclinical evidence of atherosclerosis (arteriosclerosis; hardening of the arteries), for example, presence of plaques or increased intima-media thickness of the common carotid artery.
  • Patients with impaired renal function
  • Patients with a family history of premature coronary artery disease (CAD; coronary artery disease).
  • Patients with obesity and physical inactivity

In contrast, risk may be lower in those with very high HDL cholesterol or a family history of longevity. Targets defined according to SCORE risk categories:

Very high risk < 1.8 mmol/L (= 70 mg/dL) and/or an LDL reduction of at least 50% if the baseline value is in the range between 70 mg/dl and 135 mg/dl (1.8 mmol/L and 3.5 mmol/L) (class 1/B instead of previously 1/A recommendation)
High risk <2.5 mmol/L (= 100 mg/dL), alternatively lower LDL cholesterol by at least 50% if baseline is in the range of 100 mg/dl to 200 mg/dl (2.6 – 5.1 mmol/L) (1/B recommendation)
Moderate risk <3.0 mmol/L (= 115 mg/dL)

Secondary prevention

Disease Target [mg/dl] [mmmol/]
Stable coronary artery disease (CAD; coronary artery disease); diabetes mellitus without event. < 100 mg/dloptimal: < 70 mg/dl

Alternatively, LDL-C reduction of at least 50% from baseline should be achieved

< 2.6 mmol/loptimal: < 1.8 mmol/l
Acute coronary syndrome (AKS resp. ACS, acute coronary syndrome; spectrum of cardiovascular disease ranging from unstable angina pectoris (iAP; UA; “chest tightness”; sudden onset of pain in the region of the heart with inconstant symptoms) to the two main forms of myocardial infarction (heart attack), non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI)), coronary artery disease (CAD) with diabetes mellitus < 70 mg/dl

Or at least a 50% reduction if baseline had been between 1.8 mmol/L and 3.5 mmol/L (each class 1-B)

<1.8 mmol/L

For all other patients receiving lipid-lowering therapy, a target value of < 3 mmol/L ( should be aimed for (class IIa). Lipid target values in diabetes mellitus (ESC recommendations).(Off)

Risk Definition LDL cholesterol target Non-HDL cholesterol target value
Very high risk of atherosclerosis Patients with established atherosclerosis disease or additional risk factors or end-organ damage <70 mg/dl (1.8 mmol/l) < 100 mg/dl (2.6 mmol/l)
High risk of atherosclerosis Patients with diabetes mellitus without the above criteria <100 mg/dl (<2.6 mmol/l < 130 mg/dl ( <3.4 mmol/l)

Lipid target values and lipid-lowering therapy in patients with diabetes mellitus.

All patients with diabetes mellitus (DM) and atherosclerosis. LDL < 70 mg/dl (< 1.8 mmol/l)
<50% decrease in LDL-C from baseline.
High-dose statin; with ezetimibe and PCSK9 inhibitor if necessary.
All patients with DM and additional risk factors. LDL
>50% decrease in LDL-C from baseline.
High-dose statin; with ezetimibe and PCSK9 inhibitor, if necessary.
All patients with DM without additional risk factors. LDL-C
≥ 40 years: statin therapy
< 40 years: individual decision

Therapy of “hypercholesterolemia” for secondary and primary prevention.

An indication for statin therapy (first-line agent) exists (according to American College of Cardiology and American Heart Association guidelines; November 2013) for:

  • Patients with cardiovascular disease regardless of LDL levels.
  • Individuals with LDL levels from ≥ 4.9 mmol/l (≥ 190) mg/dl
  • Diabetics aged 40-75 years
  • Patients with a 10-year cardiovascular risk of 7.5% or more and an LDL level of 170 mg/dl or more

Further notes

  • In familial hypercholesterolemia (FH), statin therapy should be started in early childhood and adolescence (>8 years of age). This may prevent progression of atherosclerosis at the carotid artery.Treatment of patients with familial hypercholesterolemia from infancy to forty years of age, protects even if target LDL cholesterol levels have rarely been reached. After a mean of 31.7 years, the mean LDL cholesterol level is 160.7 mg/dl (one-third lower than before initiation of therapy in childhood/237, 3 mg/dl); 20% (37 patients had the recommended value of < 100 mg/dl ranges. The increase in carotid intima-media thickness was 0.0056 mm per year versus 0.0057 mm per year in siblings unaffected by familial hypercholesterolemia. The data are particularly encouraging with respect to a cardiovascular event: only one patient aged 28.6 years had to undergo percutaneous coronary intervention for angina. Patients of the parent with the same genetic defect had already suffered a cardiovascular event at the same age in 26% of cases (41 patients); most of these were myocardial infarction (27 patients) or angina (7 patients).
  • Statins can also prevent myocardial infarctions (heart attacks) and apoplectic strokes (strokes) in people older than 75 years, but statins did not have a positive effect in patients with heart failure (heart weakness) and renal failure (kidney weakness); Statins reduced the risk of vascular (vessel-related) events by about one-fifth per 1 mmol/L (39 mg/dl) reduction in LDL cholesterol; they reduced serious coronary (coronary vessel-related) events overall by about one-fourth per 1 mmol/L LDL reduction.
  • In patients 75 years and older, lipid lowering was as effective in reducing cardiovascular events as in patients younger than 75 years. These findings should strengthen guideline recommendations for the use of lipid-lowering therapies, including statin-free treatment, in elderly patients.
  • See also “Other Therapy.

Therapy algorithm to achieve the LDL target value.

Steps Actions
1st step Definition of LDL cholesterol target value(estimation of absolute risk).
2nd step Lifestyle modification + statin If goal not achieved then next step in each case
3rd step Increase of statin dose
4th step Combination with ezetimibe
5. step Additional administration of a PCSK9 inhibitor.
6th step Regular apheresis therapy

Active ingredients (main indications)

Effect of different lipid-lowering agents on lipid fractions:

LDL HDL TG
HMG-CoA reductase inhibitors (statins). Up to 40 %↓ Up to 10 % ↑ Up to 20 % ↓
Nicotinic acid derivative Up to 30 % ↓ Up to 20 % ↑ Up to 40 % ↓
Ezetimibe (cholesterol absorption inhibitor). approx. 20 slightly No data
Ezetimibe (dual lipid lowering with statin). Up to 25% ↓ No data No data
Fibrate (fenofibrate) Up to 20 % ↓ Up to 20 % ↑ Up to 40 % ↓
Exchange resins Up to 20 % ↓ Up to 8 % ↑ –
  • * The combination of fibrates with omega-3 fatty acids (DHA, EPA) is suitable to treat refractory hypertriglyceridemia.
  • Note: Nicotinic acid preparations had their marketing authorization withdrawn by the European Medicines Agency (EMA) in 2013.
  • Lipoprotein apheresis is available as an ultima ratio therapy.

The following groups of agents (agents) are used to lower LDL cholesterol:

  • HMG-CoA reductase inhibitors (statins), first-line agents.
  • If the LDL target is not reached with the highest statin dose that can still be tolerated, lipid-lowering combinations should be considered.
  • Anion exchange resins (eg, colestyramine).
  • Cholesterol absorption inhibitors: ezetimibe: combination with statins advisable (additive effect); e.g., combination of 20 mg atorvastatin and 10 mg ezetimibe brings an additional LDL reduction of 31%.
  • Monoclonal antibodies: evolocumab and alirocumab can significantly reduce cholesterol serum concentrations in patients with familial hypercholesterolemia.
  • Ezetimibe-statin combination therapy was shown to reduce the risk of cardiovascular events compared with statin monotherapy. However, combination therapy did not reduce cardiovascular mortality or all-cause mortality. Side effects did not differ relevantly between combination therapy and monotherapy.
  • Patients in the “very high risk” cardiovascular risk group who continue to have persistently high LDL levels despite having exhausted therapy with a statin in combination with ezetimibe (IIb/C recommendation).The FOURRIER endpoint study confirms this: Evolocumab significantly reduced the risk of the primary composite endpoint of cardiovascular death, myocardial infarction (heart attack), apoplexy (stroke), hospitalization for unstable angina (unstable angina is when symptoms have increased in intensity or duration compared with previous angina attacks), or coronary revascularization.

Monoclonal antibodies (in this case, PCSK9 inhibitors).

  • Mode of action: Drug class of PCSK9 inhibitors; indirectly promotes the uptake of LDL cholesterol into the liver by blocking the enzyme PCSK9 (for proprotein convertase subtilisin/keckin type 9). PCSK9 promotes the degradation of LDL receptors in the liver. As a result, the liver‘s ability to. LDL cholesterol to absorb from the blood (LDL cholesterol: 50-60% ↓).
  • The American Heart Association (AHA) and the American College of Cardiology (ACC) recommend the use of PCSK9 inhibitors; for rationale, see.
  • Indications Evolocumab:
    • Adults with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia (in combination with a statin or a statin plus other lipid-lowering therapies)
      • In whom target LDL levels are not achieved with the maximum tolerated dose of a statin, the agent may be used in combination with a statin, with or without other lipid-lowering therapies.
      • Who are statin-intolerant or in whom a statin is contraindicated.
    • Adults and adolescents (12 years and older) with homozygous familial hypercholesterolemia (HoFH) in combination with other lipid-lowering therapies.
    • Patients in the “very high risk” cardiovascular group who continue to have persistently high LDL levels despite having exhausted therapy with a statin in combination with ezetimibe (IIb/C recommendation).The FOURRIER endpoint study confirms this: Evolocumab significantly reduced the risk of the primary composite endpoint of cardiovascular death, myocardial infarction, apoplexy, hospitalization for unstable angina, or coronary revascularization.
    • Evolocumab was able to significantly reduce cholesterol serum concentrations in patients with familial hypercholesterolemia.IQwiG pronounced no added benefit for evolocumab, dated Dec. 11, 2015. They stated, “In the absence of suitable data, no such additional benefit can be derived from the dossier for either indication.”
  • Indications Alirocumab: adults with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia (in combination with a statin or a statin plus other lipid-lowering therapies).
    • In whom target LDL levels are not achieved with the maximum tolerated dose of a statin, the agent may be used in combination with a statin, with or without other lipid-lowering therapies.
    • Who are statin-intolerant or in whom a statin is contraindicated.
    • Reduction of cardiovascular risk in adults with existing atherosclerotic cardiovascular disease by lowering low-density lipoprotein cholesterol (LDL-C) levels as an adjunct to correction of other risk factors (approval based on data from ODYSSEY OUTCOMES trial)
  • Side effects: Nasopharyngitis; due tocurrent approval, the data on side effects are certainly still incomplete.
  • Alirocumab may protect patients who have elevated LDL cholesterol levels (>70 mg/dl) after an acute coronary syndrome (STEMI, NSTEMI, or unstable angina) from further cardiovascular events (death from coronary artery disease or myocardial infarction, unstable angina, or stroke) despite high-dose statin therapy: Alirocumab group in 903 patients (9.5%) on versus 1,052 patients (11.1%) in the placebo group.
  • In two-thirds of all cases, this therapy spared previously required regular LDL apheresis.
  • Withdrawn from the market in Germany for patent reasons, according to a notification dated July 18, 2019.
  • New lipid-lowering agent: Inclisiran, which also specifically targets the enzyme PCSK9 (proprotein convertase subtilisin / kexin type 9).
    • Dosage: 300 mgs.c., twice a year.
    • Inclisiran results in a mean LDL reduction of approximately 50% relative to baseline.Conclusion:Statins and ezetimibe (cholesterol resorption inhibitors: see above) are the first-line therapeutic agents for elevated LDL levels, but includeisiran could become an interesting additional option for patients who miss their target levels with them.
  • Bempedoic acid (ATP citrate lyase (ACL) inhibitor):reduction of LDL-C levels by about 18% additive to other lipid-lowering therapy; bempedoic acid/ezetimibe combination alone or additive to statins: LDL-C reduction by more than 35%.
    • Indication: treatment of adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) or with a mixed form of dyslipidemia
      • In combination with a statin or a statin together with other lipid-lowering therapies in patients who are unable to achieve their target LDL-C level despite maximum tolerated dose of a statin; or
      • As monotherapy or combination therapy with other lipid-lowering drugs in patients who are statin intolerant or in whom a statin is contraindicated.

Supplements (dietary supplements; vital substances) in statin intolerance

Suitable dietary supplements should contain the following vital substances:

  • Red mold rice: 1,200 to 4,800 mg/d; monacolin K chemically identical to lovastatin; class 1A recommendation; effect on LDL-C levels: -15 to -25%; side effects: probably identical to statins.
  • Omega-3 fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)): 1-4 g/d; class IIa/B recommendation; effect on LDL-C levels: -3 to -7%; indications:
    • Statin-intolerant patients with obesity, diabetes (insulin resistance), or metabolic syndrome.
    • Patients who have elevated triglyceride levels in addition to high LDL-C levels.
  • Phytosterols: 800-2,400 mg/d; class IIa/C recommendation; effect on LDL-C levels: -7 to -10%; indications:
    • Patients at >high risk who do not achieve their target LDL-C levels on statin therapy or who are statin intolerant.
  • Bergamot (citrus): 500-1,500 mg/d.
  • Soy: 25-100 g per day/d

See also under “Other therapy”.