Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, also known as "statins," are used adjunctively to diet and exercise to treat hypercholesterolemia by lowering total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) concentrations while increasing high-density lipoprotein cholesterol (HDL-C) concentrations. The approved FDA indications vary slightly between each statin but generally are indicated for the treatment and/or prevention of primary and secondary prevention clinical atherosclerotic cardiovascular disease (ASCVD) (e.g., myocardial infarction or stroke). The choice of agent should have its basis on patient-specific characteristics, the pharmacokinetic profiles of each medication, and the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol:
Primary prevention (age 40 to 75 years): In patients without clinically significant cardiovascular disease, statins in addition to heart-healthy lifestyle measures are indicated in the following conditions to reduce the risk of developing myocardial infarction, stroke or undergoing revascularization procedures.
Secondary prevention (age over 18 years): History of multiple major ASCVD events (recent acute coronary syndrome within the past 12 months, history of MI, history of ischemic stroke, symptomatic peripheral artery disease) or 1 major ASCVD event with multiple high-risk conditions (age greater than or equal to 65 years, heterozygous familial hypercholesterolemia, diabetes mellitus, hypertension, chronic kidney disease, current smoking, history of heart failure, history of PCI or CABG, persistently elevated LDL-C greater than or equal to 60 mg/dL).
Additionally, statins are useful in the management of the following dyslipidemias:
Conversion of 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA) to mevalonate by HMG-CoA reductase in the hepatocytes is the first and rate-limiting step in cholesterol biosynthesis. Statins competitively inhibit HMG-CoA reductase enzyme. Statins bind to the active site of the enzyme and induce a conformational change in its structure, thus reducing its activity. Also, the binding affinity of statins for HMG-CoA reductase is 10000 times higher than the substrate (HMG-CoA), thus preventing the action of the enzyme and reducing the intracellular synthesis of cholesterol. Statins have a significant impact on lowering cholesterol since most of the circulating plasma cholesterol comes from the internal synthesis in hepatocytes rather than diet.
The reduced level of cholesterol in hepatocytes secondary to statin use activates the proteases that cleave membrane-bound sterol regulatory element binding proteins (SREBP), which further migrate to the nucleus and binds sterol response elements. This binding results in increased transcription of the LDL receptor, which translocates to the liver cell membrane. The LDL and VLDL particles in plasma bind to the LDL receptors and endocytose in hepatocytes, where their cholesterol component gets processed into bile salts which are then excreted or recycled. This process increases the catabolism of LDL and VLDL cholesterol and results in further reduction of plasma cholesterol levels.
Statins reduce the level of total cholesterol, LDL-C, VLDL-C, triglycerides, apo-B, and increase the level of HDL-C.
Apart from lowering lipid concentrations, statins also have cardiovascular protective effects (pleiotropic effects) which are primarily because of the inhibition of production of prenylated proteins (mainly farnesyl pyrophosphate and geranylgeranyl pyrophosphate) in the cholesterol biosynthetic pathway. Statins prevent cardiovascular disease progression via the following mechanisms:
Since a majority of the cholesterol synthesis occurs at night in a fasting state, the recommendation is that statins with a shorter half-life (i.e., simvastatin, pravastatin, or fluvastatin) should be taken orally before bedtime to maximize its action. Dosing with statins with a longer half-life such as atorvastatin, rosuvastatin, or pitavastatin can be in morning or evening, but individuals should take the medication around the same time every day. Lovastatin should be taken with morning or evening meals since its absorption is increased with food.
Statins are classified based on their intensity as follows:
Rosuvastatin is the most potent statin followed by atorvastatin. Statins also classify as lipophilic or hydrophilic. Lipophilic statins include simvastatin, lovastatin, and atorvastatin. Hydrophilic statins include pravastatin, fluvastatin, and rosuvastatin. Simvastatin 80 mg should not be a therapeutic choice in most patients.
Statins administration in specific patient population groups:
Elderly patients: In individuals greater than 75 years, who have a clinically significant ASCV, it is recommended to start them on moderate-intensity statins rather than high-intensity statins; this is because of greater side effects associated high-intensity statins, and reduction in the efficacy of metabolic pathways in elderly individuals.
Renal impairment: atorvastatin, fluvastatin, pravastatin, or simvastatin are indicated in patients with chronic kidney disease since they do not undergo renal elimination, and hence, no dose adjustment is required.
Liver impairment: pravastatin and rosuvastatin can be used in patients with compensated liver disease since they are metabolized to a lesser extent by the liver in comparison to other statins. While initiating statins in patients with liver disease, it is crucial for patients to abstain from alcohol. The statins mentioned above should initiate at a low dose and liver enzymes, and LDL-C should be monitored within 1 to 3 months. If no significant change occurs in the level of aminotransferase, therapy does not achieve the LDL-C target, increase the dose of statins. Statins are contraindicated in patients with acute liver failure or decompensated cirrhosis.
Increase in plasma concentration of statins result from the following:
CYP 3A4 inhibition: Statins that are metabolized by CYP450 3A4 include lovastatin, simvastatin, and atorvastatin. If these statins are used in combination with CYP 3A4 inhibitors, it causes an increase in plasma level of statins and increases the risk of dose-related adverse effects (including myopathy). Pravastatin, fluvastatin, rosuvastatin, and pitavastatin are the drugs of choice when patients are concurrently using drugs that interfere with CYP 3A4. Medications which increase the plasma levels of statins are:
Using statins in combination with gemfibrozil increases the risk of muscle toxicity, including rhabdomyolysis. Fenofibrate is preferred if there is a need to start statin-fibrate combination therapy. However, if gemfibrozil is the only available fibrate or fenofibrate is not tolerated, then gemfibrozil should be used in combination with low-dose atorvastatin, pitavastatin or rosuvastatin.
Calcium channel blockers: Using amlodipine, diltiazem or verapamil in combination with simvastatin and lovastatin, increases the risk of toxicity due to statins
A decrease in plasma concentration of statins result from the following:
Other side effects reported with statins in various case reports/case series include:
The contraindications of statins include the following:
Monitor lipid profile, liver function tests, creatine kinase (CK) and thyroid function tests in individuals who start statin treatment:
The most common presentation of statin overdose is muscle toxicity. In case of severe muscle symptoms or rhabdomyolysis, statins therapy should stop immediately, and patients require symptomatic care. This care includes adequate fluid resuscitation, monitoring urine output, and correcting electrolyte imbalances, especially hyperkalemia. There is no antidote available for statin overdose. After the recovery from an overdose, patients should restart on low-dose statins.
Statins play an important role in lowering the level of lipids and in the prevention of clinical ASCVD. It is vital for healthcare personnel to educate patients about the benefits of statins and the importance of medication adherence. Additionally, patients need education about the side effects of statins to help improve their adherence to medication. The medical personnel, including the physicians, specialists, nurse practitioner, specialty-trained nurses, and pharmacist, should all work collaboratively as an interprofessional team when administering stains therapy. [Level V] All parties must be aware of the drug interactions and take a proper medication history before initiating statins.
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