Statins

Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins can lower LDL 20%–60% (depending on their intensity) and have benefits that are cholesterol-independent (e.g., reduced vascular inflammation and atherosclerotic plaque stabilization). Indications for prescribing statins include prevention of primary or secondary cardiovascular disease in patients with dyslipidemia. The main adverse effects are transaminitis and muscle toxicity.

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Chemistry and Pharmacodynamics

Definition

Statins are competitive inhibitors of the enzyme HMG-CoA reductase, which is the rate-limiting step in cholesterol biosynthesis in the liver.

Chemical structure

Statins are structural analogs of HMG-CoA.

  • Some statins are inactive prodrugs with a lactone ring → hydrolyzed in the body to the open, active form
  • Others statins are active, fluorine-containing molecules.
Chemical structure of statins

The similarities in chemical structure of statins to HMG-CoA:
Lovastatin and simvastatin contain an inactive lactone ring, which is hydrolyzed in the body to the active form.

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Mechanism of action

Normal physiology:

  • Most circulating cholesterol originates from internal manufacture, rather than diet.
  • HMG-CoA reductase converts HMG-CoA to mevalonate (a precursor to cholesterol) in the liver.
  • This is a rate-limiting step in cholesterol synthesis.

Statins:

  • Competitively inhibit the enzyme HMG-CoA reductase in hepatic cells
  • Occupy a portion of the binding site of HMG CoA → block access of this substrate to the active site on the enzyme
  • ↓ Synthesis of cholesterol and isoprenoid intermediates (lipid compounds with downstream inflammatory pathways)
  • ↓ Cholesterol levels in hepatocytes → up-regulation of LDL receptors→ ↑ uptake of LDL from the circulation
  • Note: The medication effect is mostly due to ↑ LDL receptor expression (not necessarily the reduction of internal cholesterol biosynthesis).
Cholesterol synthesis

The cholesterol synthesis pathway:
Statins competitively inhibit HMG-CoA reductase, which is a rate-limiting step in the pathway.
NADPH: nicotinamide adenine dinucleotide phosphate

Image by Lecturio.
Mechanism of action of statins

The mechanism of action of statins (HMG-CoA reductase inhibitors) in comparison to other lipid-lowering therapies:
Statins block intrahepatocyte synthesis of cholesterol, resulting in up-regulation of LDL receptors and a reduction in serum LDL.
CoA: coenzyme A

Image by Lecturio.

Physiologic effects

  • ↓↓ LDL by 20%–60%
  • ↓ VLDL production
  • ↓ Triglyceride levels: 
    • 15%–30% reduction 
    • Due to ↓ VLDL synthesis and clearance of VLDL remnant particles
  • ↑ HDL levels (modest)
  • Effects of ↓ isoprenoid generation:
    • ↓ Reactive oxygen species
    • Improve endothelial function by ↑ nitric oxide bioavailability 
    • ↓ Vascular inflammation 
    • ↓ Platelet aggregation (prevent clot formation)
    • Stabilize atherosclerotic plaques

Pharmacokinetics

Absorption

  • All statins are administered orally.
  • Absorption may be reduced when taken with food (exception: lovastatin).

Distribution

  • High plasma-protein–binding
  • Widely distributed through the body, including:
    • Blood–brain barrier
    • Placenta
    • Breast milk
  • Solubility:
    • Most are lipophilic, allowing passive entry into hepatocytes.
    • Hydrophilic statins do not pass easily through membranes:
      • More likely to remain in the plasma
      • Organic anion transporter proteins (OATPs) assist with entry into hepatocytes.

Metabolism

  • Undergo 1st-pass extraction by the liver
  • Most are metabolized by members of the cytochrome P450 superfamily of drug oxidizing enzymes:
    • CYP2C9
    • CYP3A4
  • Exception: pravastatin (metabolized by sulfation and conjugation)

Excretion

  • Bile (majority)
  • Urine (5%–20%)

Classification

Statins are classified on the basis of their percent reduction of LDL and dosing:

  • High-intensity statins (lower LDL by ≥ 50% from baseline):
    • Atorvastatin: 40–80 mg
    • Rosuvastatin: 20–40 mg
  • Moderate-intensity statins (lower LDL by 30%–40% from baseline): 
    • Atorvastatin: 10–20 mg
    • Rosuvastatin: 5–10 mg
    • Simvastatin: 20–40 mg
    • Pravastatin: 40–80 mg
    • Lovastatin: 40 mg
    • Fluvastatin: 40 mg twice daily
    • Pitavastatin: 2–4 mg
  • Low-intensity statins (lower LDL by ≤ 30% from baseline):
    • Simvastatin: 10 mg
    • Pravastatin: 10–20 mg
    • Fluvastatin: 20–40 mg
    • Pitavastatin: 1 mg

Indications

Major adverse cardiovascular events

Statins are indicated to treat dyslipidemias with the intent of reducing major adverse cardiovascular events:

  • Major adverse cardiovascular events are defined as 1 or a combination of the following: 
    • Nonfatal myocardial infarction
    • Nonfatal stroke
    • Revascularization procedures
    • Cardiac death
  • Primary prevention of major adverse cardiovascular events:
    • For a patient who has not previously experienced an atherosclerotic vascular event (cardiovascular disease):
      • LDL > 100 mg/dL
      • Based on calculated cardiac risk (includes diabetes, hypertension, tobacco use, and age)
    • Rationale is based on data documenting:
      • Continuous, positive, graded relationship between LDL concentration and cardiovascular events and mortality
      • Evidence that ↓ LDL in patients with a broad range of LDL levels ↓ the risk of cardiovascular disease (clinical benefit)
    • MI risk is the most ↓ of all cardiovascular events.
    • There is benefit for LDL lowering with statin therapy with virtually all levels of cardiovascular risk.
  • Secondary prevention of major adverse cardiovascular events:
    • For patients with preexisting cardiovascular disease with prior:
      • MI
      • Stroke
      • Stable or unstable angina
      • Aortic aneurysm
      • Other arterial ischemic disease in the presence of atherosclerosis
    • Statin therapy produces an estimated:
      • 60% ↓ in the number of cardiac events 
      • 17% ↓ in stroke
    • Greater benefit with high-intensity statins

Familial hypercholesterolemia (FH)

  • Genetic disorder that causes a loss of function of the LDL receptor
  • Manifests in ↑ LDL levels from birth
  • LDL levels are generally > 190 mg/dL.
  • Can result in premature atherosclerotic coronary heart disease and death
  • Note: Statins may be less effective, especially for those with homozygous FH.

Adverse Effects and Contraindications

Adverse effects

  • Muscle effects:
    • Myalgia: 
      • Most common side effect
      • Muscle pain, soreness, and tenderness
      • Normal CK level
    • Myopathy:
      • Muscle weakness
      • No pain
      • CK may or may not be elevated.
    • Myositis:
      • Muscle inflammation
      • Muscle symptoms
      • ↑ CK
    • Myonecrosis and rhabdomyolysis (rare): 
      • Muscle symptoms
      • CK > 10 times the upper limit of normal
      • Myoglobinuria or acute renal failure
  • Transaminitis: 
    • No need to routinely monitor transaminase levels
    • Rise in levels is generally seen within the first 3 months of therapy.
    • Dose-dependent
    • Levels < 3 times the upper limit of normal are acceptable.
    • Severe liver injury is rare.
  • ↑ Risk of developing type 2 diabetes mellitus: 
    • Occurs in patients with risk factors
    • Benefits still generally outweigh the risks.

Drug–drug interactions

  • Medications that inhibit CYP3A4 → ↑ blood concentrations of statins
    • Grapefruit, grapefruit juice, and bitter oranges
    • Cyclosporine
    • Macrolide antibiotics (except azithromycin)
    • Nondihydropyridine calcium channel blockers
    • HIV protease inhibitors
    • Azole antifungals
    • Amiodarone
    • Nefazodone
    • Rifampin
  • OATP inhibitors → ↑ blood concentrations of statins
    • Cyclosporine
    • Direct-acting antivirals for hepatitis C virus
    • Rifampin
  • Associated with ↑ muscle toxicity:
    • Niacin
    • Fenofibrates
    • Colchicine
  • Other considerations:
    • Bile acid sequestrants: ↓ statin absorption 
    • Warfarin: Fluvastatin raises warfarin levels via CYP2C9 inhibition.
    • Dabigatran: ↑ risk of major hemorrhage

Contraindications

  • Active liver disease
  • Pregnancy
  • Breastfeeding

Comparison of Statin Medications

The following table compares and contrasts members of the statin drug class. The drugs are listed in descending order of potency.

Table: Members of the statin class in descending order of potency
StatinSolubilityMetabolismPlasma half-lifeOptimal dosing time
PitavastatinLipophilicCYP2C912 hoursAnytime
RosuvastatinHydrophilicCYP2C919 hoursAnytime
AtorvastatinLipophilicCYP3A414 hoursAnytime
LovastatinLipophilicCYP3A42‒3 hoursEvening
SimvastatinLipophilicCYP3A42‒3 hoursEvening
PravastatinHydrophilicSulfation1‒3 hoursAnytime
FluvastatinLipophilicCYP2C91‒3 hoursEvening

References

  1. Grundy SM, Stone NJ, Bailey AL, et al. (2019). 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 139:e1046–e1081. https://doi.org/10.1161/CIR.0000000000000624.
  2. Oesterle A, Laufs U, Liao JK. (2017). Pleiotropic effects of statins on the cardiovascular system. Circ Res 120:229–243. https://doi.org/10.1161/CIRCRESAHA.116.308537
  3. Sirtori CR. (2014). The pharmacology of statins. Pharmacol Res 88:3–11. https://doi.org/10.1016/j.phrs.2014.03.002
  4. Bellosta S, Corsini A. (2018). Statin drug interactions and related adverse reactions: an update. Expert Opin Drug Saf 17:25–37. https://doi.org/10.1080/14740338.2018.1394455
  5. Robinson JG. (2020). Disorders of lipid metabolism. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine, 26th ed. Philadelphia: Elsevier.
  6. Pignone M. (2021). Management of elevated low density lipoprotein-cholesterol (LDL-C) in primary prevention of cardiovascular disease. In Freeman, M. (Ed.), UpToDate. Retrieved May 9, 2021, from https://www.uptodate.com/contents/management-of-elevated-low-density-lipoprotein-cholesterol-ldl-c-in-primary-prevention-of-cardiovascular-disease
  7. Rosenson RS. (2021). Statins: Actions, side effects, and administration. In Givens, J. (Ed.), UpToDate. Retrieved May 13, 2021, from https://www.uptodate.com/contents/statins-actions-side-effects-and-administration
  8. Katzung BG, Masters SB, Trevor AJ. (2012). Basic & clinical pharmacology. New York: McGraw-Hill Medical.
  9. Young SG, Fong LG. (2012). Lowering plasma cholesterol by raising LDLD receptors—revisited. N Engl J Med 366:115–-1155. doi: 10.1056/NEJMe1202168
  10. Sizar O, Khare S, Jamil RT, Talati R. (2021). Statin medications. StatPearls. Retrieved May 13, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK430940/
  11. Cid-Conde L, Lopez-Castro J. (2020). Pharmacokinetics aspects of statins. Cardiovascular Risk Factors in Pathology. IntechOpen. DOI: 10.5772/intechopen.91910

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