Statins

Statins, also known as HMG-CoA reductase inhibitors or CSE inhibitors for short, are the most important lipid-lowering drugs with a proven improvement in prognosis. Statins are effective LDL cholesterol-lowering agents. Among other things, they reduce the risk of heart attack and overall mortality and are recommended for all diseases associated with atherosclerosis. In addition, statins for LDL-C lowering are widely used in primary prevention to reduce the risk of atherosclerosis and serious secondary diseases (CHD, PAD, carotid stenosis) (Cholesterol Treatment Trialists CTT 2005;2010;2012;2019).

Mechanism of action:

Statins are selective, competitive inhibitors of hydroxymethylglutaryl-CoA reductase(HMG-CoA reductase), a rate-determining key enzyme in cholesterol synthesis that converts HMG-CoA to mevalonate, a precursor of cholesterol. By reducing endogenous hepatic cholesterol synthesis, LDL receptors of the cell membrane in the liver are upregulated and the uptake of LDL cholesterol (LDL-C) from the blood into the liver cells is increased. This lowers the LDL-C content of the blood. Statins reduce the synthesis of apolipoprotein B100, so that in addition to a decrease in cholesterol, there is also a slight decrease in triglycerides.
Due to genetic factors (differences in genes of the ATP binding cassette G2, lipoprotein(a), apoE, RhoA, genes that code for Cyt P 450 and hepatic transport proteins OATP, P-gp and others).a), there may be significant inter-individual differences in the response to statins and their tolerability (risk and severity of side effects) (Welter N 2025). Very rarely, the occurrence of non-responders is also possible.

In addition, pleiotropic effects: anti-inflammatory (CRP reduced), antioxidant, improvement of endothelial function (increases eNOS, vasodilation), antithrombotic (reduces thromboxane A2 synthesis), immunomodulating, and plaque-stabilizing (Oesterle A et al 2017), in some cases even plaque reduction has been demonstrated (Awayaa T et al 2020).

LDL-C reduction depending on dose and substance, on average by 30-40 %, TG by 10-20 % and increase in HDL by 6-10 %. In combination with ezitimib, an LDL-C reduction of over 70 % is possible.

All statins have the same mode of action, but differ in their potency and important pharmacokinetic properties, which should be taken into account when choosing a therapy (see Phamacokinetics)!

Active strengths can be classified as follows:

• Statins of low potency, LDL-C reduction ≤ 30 %: fluvastatin 20 to 40 mg, lovastatin 20 mg, pitavastatin 1 mg, pravastatin ≤ 20 mg, simvastatin 10 mg
• Statins of medium potency , LDL-C reduction 30-50 %: atorvastatin 10 to 20 mg, fluvastatin 80 mg, lovastatin 40 mg, pitavastatin 2 to 4 mg, pravastatin 40 (up to 80 mg), rosuvastatin 5 to 10 mg, simvastatin 20 to 40 mg
• High potencystatins , LDL-C lowering ≥ 50 %: atorvastatin 40 to 80 mg, rosuvastatin 20 to 40 mg

Average statin equivalent dose for LDL-C reduction of approx. 36 %: rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 20 mg,
lovastatin 40 mg, pravastatin 40 mg and fluvastatin 80 mg

Doubling the dose of a statin only results in an additional reduction in LDL-C of approx. 6 % (' rule of6 ') but increases side effects, as these are dose-dependent !

Avoidmaximum doses ! (especially simvastatin 80 mg), early combination therapy with other lipid-lowering drugs (ezetimibe) is better. Do not combine statins with other statins!

Individual factors (genetic factors, age, gender, underlying diseases) also play a role in the effectiveness.

Children and adolescents generally respond very well to statins, even very low doses have a good effect! In FH very high cholesterol levels and risk of atherosclerosis at an early age with the consequence of serious events very high! Therefore, effective drug therapy with statins is required (≥ 50% baseline) Statins are the drug of first choice - according to the guideline - with a few exceptions where statins are not effective (e.g. sitosterolemia). Problematic limited long-term data. A study with 20-year follow-up of 214 children with FH shows effective risk reduction with pravastatin. (Luirink IK et al 2019). Treatment only by experienced specialists! Pravastatin is approved from the age of 8 (some other statins from the age of 10).

Older patients ≥ 75 years: statin administration should be discussed with patients, taking into account the level of cardiovascular risk, morbidity and life expectancy. Benefit-risk no longer generally positive. If the cardiovascular risk is high, there may still be a benefit (specially tailored SCORE-OP for older patients for risk stratification).

According to the guidelines, drug therapy should always be based on and combined with the adjustment of appropriate lifestyle factors (dietary changes, exercise, weight reduction and smoking cessation). Important for improved efficacy and reduction of side effects!

Lovastatin (first statin) isolated from fermentation by Aspergillus terreus; simvastatin and pravastatin, closely related to lovastatin, and other active substances are produced fully synthetically. The following half-lives (HWZ) and LDL reductions result for the individual preparations:

• Simvastatin: half-life of 3 hours; max. possible LDL reduction dose-dependent: 40 to 45 %
• Lovastatin: HWL of 1.1 hours; max. possible LDL reduction dose-dependent: 40 to 45 %
• Pravastatin: HWL of 1.8 hours; max. possible LDL reduction dose-dependent: 30 to 40 %
• Fluvastatin: HWL of 3 hours; max. possible LDL reduction dose-dependent: 30 to 44 %
• Atorvastatin: HWL of 14 hours; max. possible LDL reduction dose-dependent: 50 to 55 %
• Rosuvastatin: HWL of 20 hours; max. possible LDL reduction dose-dependent: 56 to 60 %
• Pitavastatin: HWL: 5.7-8.9 hours; max. possible LDL reduction dose-dependent: 33 to 54 %

Lipophilic and hydrophilic substances differ in their pharmacokinetics and may be important as replacement medication in the event of adverse drug reactions (see below):
Absorption: Lipophilic substances such as atorvastatin, fluvastatin, pitavastatin and lovastatin are absorbed more quickly than hydrophilic substances such as rosuvastatin and pravastatin.

The bioavailability of atorvastatin is approx. 12%. Pitavastatin has the highest bioavailability with approx. 60 %, followed by rosuvastatin with approx. 20 % and simvastatin with approx. 5 %. Simvastatin and lovastatin are pro-drugs (lactones, cyclic esters), which are first converted into their active form by hydrolysis.

Distribution: All statins show high plasma protein binding. An exception is pravastatin with a plasma protein binding of approx. 50 %.

Lipophilic statins (atorvastatin, fluvastatin, pitavastatin, lovastatin) penetrate the cell membrane via free diffusion and act widely in various tissue cells; hydrophilic statins (pravastatin, rosuvastatin) attach to the polar surface of the cell membrane and can only be taken up via protein transporters to act in a cell and predominantly more selectively in the liver and in contrast to lipophilic statins cannot penetrate the blood-brain barrier (Climent E et al 2021).

Metabolization: Atorvastatin, lovastatin and simvastatin are mainly metabolized by CYP3A4, fluvastatin by CYP2C9, rosuvastatin by CYP2C9 and CYP2C19.
Atorvastatin, rosuvastatin, simvastatin, pitavastatin and pravastatin are eliminated by OATPB1 (organic anion-transporting polyprotein) (glucuronidation), rosuvastatin, fluvastatin, and pravastatin also by OATPB3 (glucuronidation). Atorvastatin and lovastatin are both substrates and inhibitors of P-gp (permeability glycoprotein).

Varying degrees of metabolization in the liver, only minor excretion unchanged via the kidneys. Also enterohepatic circulation and excretion via bile and intestine (e.g. pitavastatin). Exception: Rosuvastatin is predominantly excreted unchanged via kidney and intestine.

Metabolization via Cyt P450 enzyme complex and partial glucuronidation must be specifically considered for the respective substance, as multiple interactions with other drug groups are possible. This is particularly important in elderly, multimorbid and chronically ill patients (can strongly influence the occurrence and severity of myotoxic and other side effects).

Metabolization via cytochrome P450, for example: Inhibition of CYP3A4 by other drugs leads to a considerable increase in the concentration of atorvastatin, lovastin and simvastatin with an increased risk of myotoxic ADRs. Fluvastatin is metabolized via CYP2C9, paravastatin and rosuvastatin have no significant cytochrome P450 metabolism.

Special patient groups:
Restrictions of liver function: Basically no statins in case of active liver disease! A slight increase in serum transaminases (temporary, asymptomatic) may occur during therapy and does not require dose adjustment. In chronic liver disease, substances with low hepatic metabolism such as pravastatin and rosuvastatin should be preferred.
Due to its pronounced first pass effect, atorvastatin can concentrate up to eleven times its Cmax expected with sufficient liver function and achieve a 16-fold increase in exposure in cases of impaired liver function! It is therefore not suitable or only suitable in very low doses in cases of impaired liver function.
Substances with low metabolization in the liver can have a mortality benefit in cases of non-alcoholic or metabolic fatty liver disease (risk factor for cardiovascular disease). No statins for decompensated liver cirrhosis! No statins for high alcohol consumption!

In kidney disease: Statins with low renal clearance are recommended in the case of reduced GFR, with atorvastatin as the drug of choice in advanced CKD (stage 4-5), also fluvastatin in an appropriately adjusted dose.
Statins should not be started in the case of CKD requiring dialysis, but can be continued if statin therapy is already in progress. Atorvastatin or fluvastatin 20 mg + ezetimibe 10 mg can stop a drop in eGFR and proteinuria. For other statins, a dose adjustment is required in stage 4 CKD (GFR ≤ 30 ml / min).

Elderly patients ≥ 75 years: statin administration should be discussed with patients taking into account the level of cardiovascular risk, morbidity and life expectancy. There are different opinions on this, risk-benefit is no longer fundamentally positive. If the cardiovascular risk is high, there may still be a benefit (specially tailored SCORE surgery for older patients for risk stratification).

Children and adolescents generally respond very well to statins, even very low doses have a high effect! Very high cholesterol levels in FH and very high risk of atherosclerosis at an early age, resulting in serious events! Therefore, effective drug therapy with statins is required (≥ 50% baseline) Statins are the first choice according to the guideline, with a few exceptions where statins are not effective (e.g. sitosterolemia). Problematic limited long-term data. A study with 20 years of follow-up was recently published. Treatment only by experienced specialists! Privastatin is approved from the age of 8 (some other statins are also approved from the age of 10).

Multimorbid patients, especially chronically ill patients with polypharmacy: Individually adapted therapy with selection of the appropriate statin in an adapted dose and regular therapy monitoring are particularly important, the risk of interactions with other medications is particularly high! Can significantly impair benefit and adherence to therapy.

HIV patients: HIV patients have an increased risk of atherosclerosis and a particularly high risk of adverse drug reactions due to interactions with long-term antiviral medication. Only certain statins can be considered (e.g. pravastatin, pitavastatin).

Important: Potential interactions must be clarified in detail and taken into account when choosing the statin and for concomitant medication (Red List, specialist information)!

Drug of first choice for hypercholesterolemia or hyperlipidemia with predominant hypercholesterolemia. Drug therapy should always be based on and in combination with lifestyle measures (dietary changes, exercise, weight loss, smoking cessation if necessary)!

For secondary prevention: for known atherosclerosis (CHD, PAD, etc.) and after a serious event (MI, stroke, TIA) in accordance with the latest guidelines with a target value ≤ 55 mg/dl (1.4 mmol/l)

For primary prevention: risk assessment after SCORE2/SCORE2 surgery and determination of the individual target value according to guidelines. Indication for drug therapy to reduce the risk of atherosclerosis and secondary diseases with a 10-year risk ≥10% (positive benefit assessment by the G-BA reduced from 20% to 10% and reimbursable! (G-BA press release 19.12.2024)).

Children and adolescents with familial hypercholesterolemia (FH) according to guideline Satine 1st choice; cholestyramine 2nd choice or in case of intolerance. However, therapy should only be carried out by a specialist (special features regarding indication and therapy monitoring!)

Contraindicated during pregnancy. Adequate contraception is necessary! Cholesterol and other intermediate products of cholesterol biosynthesis are essential in embryonic and fetal development and necessary for the synthesis of steroids and cell membranes! The potential risk for the development of the child outweighs the benefit even if the mother is at high cardiovascular risk and justifies a break in therapy for the duration of the pregnancy and breastfeeding period. The importance and necessity of lifestyle factors (diet, exercise, weight management, smoking cessation) as part and basis of the basic therapy and simultaneous benefits during pregnancy should be particularly emphasized and advised!

Discontinue statins in the event of unexpected pregnancy during therapy! For risks of unwanted exposure see also: Embryotox Charité

Contraindicated during breastfeeding (statins pass into breast milk in animal experiments).

For further details, see the technical information for the respective preparation!

1 tablet of the corresponding dosage orally.

Preferably in the evening, as better efficacy especially for substances with a short half-life, due to circadian cholesterol biosynthesis with maximum cholesterol synthesis at night and in the early morning hours;

independent of food;

Important: the daily intake time should always be kept the same!

NW are strongly dose-dependent , therefore avoid high doses, if necessary change statins or start combination therapy early!

Headaches, dizziness, gastrointestinal complaints are common.

Slight increase in transaminases (0.5-2%) (frequent, reversible); discontinue therapy if >3 times the norm. Nausea, jaundice, brown coloration of the urine.

CK increase: still tolerable up to 4 times the norm; discontinue above this level! (especially with a feeling of sickness and fever).

Myopathic complaints or severe myopathy with rhabdomyolysis (very rare); also immune-mediated necrotizing myopathy (IMNM), toxic liver damage and deterioration of blood glucose control or first manifestation of diabetes (increased risk in predisposition: prediabetes, metabolic syndrome, obesity; important: compliance with accompanying lifestyle measures, accompanying control, therapy if necessary). Muscle pain: reversible after discontinuation of the medication within 2-4 days (CK determination, exclude other causes, nocebo effect, change statin if necessary). SAMS (intolerance despite therapy break, dose reduction and statin change) (procedure see Stürzebecher et al 2022).

Serious drug-induced skin reactions (eosinophilia with systemic reaction (DRESS), Stevens-Johnson syndrome (SJS)) have also been reported sporadically with rosuvastatin.

Statins and skin:

Urticaria and urticarial exanthema, itching

There is evidence of increased sensitivity to light exposure (UV light).

Pseudoangioedema: A statin-associated immune-mediated necrotizing myopathy with facial swelling and heliotropic pattern has been described (Ortiz C et al. 2022). The clinical aspect may resemble dermatomyositis.

DRESS: Serious drug-induced skin reactions (eosinophilia with systemic reaction(DRESS), Stevens-Johnson syndrome (SJS)) have also been reported sporadically with rosuvastatin.

WW for enzymes/carrier systems for corresponding statins and selection of substances with interaction potential (inhibition) with risk of concentration increase and NW (taken from Lipp HP 2020)

CYP2C9

• fluvastatin
• (rosuvastatin)
  • Amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvoxamine, ketoconazole,
  • metronidazole, oxandrolone, voriconazole

CYP3A4

• Atorvastatin
• lovastatin
• simastatin
  • Amiodarone, amlodipine (CYP3A5), aprepitant, cilostazol, cimetidine, clarithromycin, conivaptan,
  • Ciclosporin, cobicistat, diltiazem, erythromycin, fluconazole (higher doses), fluvoxamine,
  • Grapefruit, idelalisib, imatinib, isavuconazole, itraconazole, netupitant, posaconazole, ritonavir,
  • voriconazole

P-gp (ABCB1)

• Atorvastatin
• lovastatin
• Pitavastatin
• simvastatin
  • Amiodarone, azithromycin, captopril, carvedilol, quinidine, cimetidine, clarithromycin, colchicine,
  • Conivaptan, ciclosporin, diltiazem, dronedarone (potent), erythromycin, itraconazole, nicardipine,
  • protease inhibitors (HIV), ranolazine, ticagrelor, verapamil

OATP1B1

• Atorvastatin
• pitavastatin
• pravastatin
• rosuvastatin
• simvastatin
  • Carbamazepine, clarithromycin, ciclosporin, erythromycin,
  • gemfibrozil, protease inhibitors (HIV), roxithromycin, sacubitril

OATP1B3

• fluvastatin
• pravastatin
• rosuvastatin
  • Clarithromycin, Ciclosporin, Erythromycin, Roxithromycin, Sacubitril

This list is only a selection! There may be a wide range of drug interactions. Drug interactions must therefore be clarified in each individual case! For further information, see also the technical information of the respective preparation or databases on drug interactions.

It should also be noted that statins can alter the effect of concomitant medication and this can also result in additional incompatibilities!

• Hypersensitivity to the respective substance or ingredients
• active liver disease or unclear increase in transaminases
• muscle diseases
• Pregnancy, breastfeeding
• Combination with Ciclosporin! Fibrates etc.

For further information, see individual substances and relevant specialist information!

Atorvastatin (^Sortis®, generics) 10mg, 20mg, 40mg, 80mg

Simvastatin (^Zocor®, generics) 5mg, 10mg, 20mg, 40mg

Pravastatin (generics) 10mg, 20mg, 40mg

Rosuvastatin (^Crestor®, generics) 5mg, 10mg, 20mg, 40mg

Lovastatin (generics) 10mg, 20mg, 40mg, 80mg

Fluvastatin (generics) 20mg, 40mg, 80mg (retard)

Pitavastatin (^Livazo®) 1mg, 2mg, 4mg

Note: All products are also available as generics. Prolonged-release preparations are also available for individual substances. In addition, there are numerous combination products (ezetimibe) in different concentrations as generics.

Approval for children and adolescents: Pitavastatin, Rosuvastatin from 6 years; Pravastatin from 8 years; Fluvastatin (heterozygous FH) from 9 years; some other statins from 10 years.

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2. Cholesterol Treatment Trialists' (CTT) Collaboration (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Lancet 366;9493:1267-78. doi 10.1016/S0140-6736(05)67394-1
3. Cholesterol Treatment Trialists' (CTT) Collaboration (2010) Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet. (2010) 376;9753:1670-81. doi 10.1016/S0140-6736(10)61350-5.
4. Cholesterol Treatment Trialists' (CTT) Collaborators (2012) The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomized trials. Lancet 380;9841:581-90. doi 10.1016/S0140-6736(12)60367-5.
5. Cholesterol Treatment Trialists' Collaboration (2019) Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomized controlled trials. Lancet 393;10170:407-15. doi 10.1016/S0140-6736(18)31942-1.
6. Climent E et al (2021) Hydrophilic or lipophilic statins? Front Cardiovasc Med 8:687585. doi 10.3389/fcvm.2021.687585.
7. Federal Joint Committee G-BA (2024). Extension of the prescription option for lipid-lowering drugs. G-BA press release from 19.12.2024
8. Lee JI et al (2021). Effects of statin use on the development and progression of nonalcoholic fatty liver disease: a nationwide nested case-control study. Am J Gastroenterol;116(1):116-24
9. Lipp H-P (2020) Selection of statins against the background of newly drafted lipid guidelines. Status of generic rosuvastatin. Drug Therapy 38:117-124. https://www.arzneimitteltherapie.de/heftarchiv/2020/04/auswahl-von-statinen-vor-dem-hintergrund-neu-verfasster-lipidleitlinien-stellenwert-von-generischem-rosuvastatin.html.
10. Luirink IK et al (2019) 20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia. N Engl J Med 381:1547-1556 doi 10.1056/NEJMoa1816454.
11. Mach F et al (2020). 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) European Heart Journal 41;1:111-188 https://doi.org/10.1093/eurheartj/ehz455
12. Oesterle A et al (2017). Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res. 2017;6;120(1):229-243, doi: 10.1161/CIRCRES-AHA.116.308537. Erratum in: Circ Res. 2018;28;123(8):e20; DOI: 10.1161/RES.0000000000000228.
13. Ortiz C et al. (2022) Statin-naïve anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibody-positive necrotizing myopathy with heliotropic pseudoangioedema. JAAD Case Rep 21:198-200.
14. SCORE2/SCORE2OP (2021) https://www.escardio.org/Education/Practice-Tools/CVD-prevention-toolbox/SCORE-Risk-Charts
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    therapeutic effects. Bulletin on drug safety. Information from BfArM and PEI. Issue 1/2025.