Continuing Education Activity

HMG-CoA reductase inhibitors (statins) are lipid-lowering medications used in the primary and secondary prevention of coronary heart disease. This activity reviews the indications, contraindications, and mechanism of action of statins for the management of coronary heart disease and familial dyslipidemias. This activity will cover the indications, contraindications, activity, adverse events, and other critical elements of statin therapy, and highlight the crucial role of the interprofessional team in the management of patients with clinically significant atherosclerotic cardiovascular disease or individuals with risk factors for heart disease who can benefit from statin therapy.

Objectives:

• Describe the indications for HMG-CoA reductase inhibitors (statins).
• Identify potential adverse events and contraindications to statin use.
• Outline the appropriate follow-up and monitoring of statins.
• Review interprofessional team strategies for improving care coordination and communication to enhance patient adherence to statin medications.

Indications

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[1]:

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.

• LDL-C greater than 190 mg/dL: Initiate high-intensity statin therapy with an aim towards achieving over 50% reduction in LDL-C concentration. If LDL-C is greater than or equal to 100 mg/dL; add ezetimibe +/- PCSK9 inhibitor 
• LDL-C 70 to 189 mg/dL:
  • With diabetes mellitus: Initiate moderate-intensity statin with an aim towards achieving a 30 to 49% reduction in LDL-C concentration. If multiple ASCVD risk factors, age 50 to 77 years, initiate high-intensity aim to achieve over 50% reduction in LDL-C concentration.
  • Without diabetes mellitus and 10-year ASCVD risk greater than 20% (high risk): Initiate high-intensity statin therapy with an aim towards achieving over 50% reduction in LDL-C concentration
  • Without diabetes mellitus and 10-year ASCVD risk greater than or equal to 7.5% to less than 20% (intermediate risk): With the evaluation of risk enhancers (e.g., family history, chronic kidney disease, metabolic syndrome, inflammatory disease, ethnicity factors, condition-specific to women, persistently elevated LDL-C greater than or equal to 60 mg/dL) and coronary artery calcium score if uncertain. Initiate moderate-intensity statin with an aim towards achieving a 30 to 49% reduction in LDL-C concentration.
  • Without diabetes mellitus and 10-year ASCVD risk 5 to less than 7.5% (borderline risk):  Initiate lifestyle, select moderate intensity with the presence of risk enhancers (risk discussion indicated)
  • Without diabetes mellitus and 10-year ASCVD risk less than 5% (low risk): Initiate lifestyle and risk discussion 

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 one 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).

• Very high-risk ASCVD: Initiate maximally tolerated statin. If LDL-C greater than or equal to 70 mg/dL add ezetimibe +/- PCSK9 inhibitor (with LDL-C greater than or equal to 70 mg/dL and non-HDL-C higher than 100 mg/dL)
• Stable ASCVD: Initiate high to moderate-intensity statin with the aim towards achieving LDL-C lowering as described above

Additionally, statins are useful in the management of the following dyslipidemias:

• Familial hypercholesterolemia (type II a hyperlipoproteinemia), characterized by LDL receptor deficiency 
• Familial combined hyperlipidemia (type II b hyperlipoproteinemia), characterized by decreased LDL receptor and increased apo B lipoprotein
• Familial dysbetalipoproteinemia (type III hyperlipoproteinemia), characterized by abnormal function of apo E receptor that is necessary for the clearance of chylomicron remnants
• Familial hypertriglyceridemia (type IV hyperlipoproteinemia), characterized by increased VLDL production 

Mechanism of Action

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 10,000 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 the diet.[2]

The reduced intracellular concentrations of cholesterol in hepatocytes secondary to statin use activate the proteases that cleave membrane-bound sterol regulatory element-binding proteins (SREBP), which further migrate to the nucleus and bind to 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 concentrations.[3]

Statins reduce the plasma concentrations of total cholesterol, LDL-C, VLDL-C, triglycerides, apo-B, and increase the plasma concentrations of HDL-C.

Apart from lowering lipid concentrations, statins also have cardiovascular protective effects (pleiotropic effects), which are primarily because of the inhibition of the production of prenylated proteins (mainly farnesyl pyrophosphate and geranylgeranyl pyrophosphate) in the cholesterol biosynthetic pathway. Statins prevent cardiovascular disease progression via the following mechanisms[4][5]:

• Plaque stabilization: Coronary artery plaque rupture predisposes to acute coronary syndrome. Statins maintain the integrity of the fibrous cap of atherosclerotic plaque, inhibit the proliferation of macrophages, and decrease the expression of matrix metalloproteinases (MMP).
• Reduces inflammation: Inflammation plays an essential role in atherosclerotic plaque rupture. Statins reduce the level of pro-inflammatory cytokines (TNF-a, IL-6, IL-8) and decrease the concentration of CRP.
• Improve endothelial function: Statins increase eNOS activity within the endothelial cells resulting in vasodilation and thus improving myocardial blood flow.
• Decreased thrombogenicity: Statins decrease the activity of platelets and reduce thromboxane A2 synthesis.

Administration

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[6]. Dosing with statins with a longer half-life such as atorvastatin, rosuvastatin, or pitavastatin can be in the 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 increases with food.

Statins are classified based on their intensity as follows[7]:

• Low-intensity statins: These include 20 to 40 mg fluvastatin, 20 mg lovastatin, 1 mg pitavastatin, 10 to 20 mg pravastatin, or 10 mg simvastatin. Low-intensity statins reduce LDL-C by less than 30%.
• Moderate-intensity statins: These include 10 to 20 mg atorvastatin, 80 mg fluvastatin, 40 mg lovastatin, 2 to 4 mg pitavastatin, 40 to 80 mg pravastatin, 5 to 10 mg rosuvastatin, or 20 to 40 mg simvastatin. Moderate-intensity statins reduce LDL-C by 30 to 50%.
• High-intensity statins: These include 40 to 80 mg atorvastatin or 20 to 40 mg rosuvastatin. High-intensity statins reduce LDL-C by greater than 50%.

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 older than 75 years of age, who have a clinically significant ASCV, the recommendation is to start them on moderate-intensity statins rather than high-intensity statins; this is because of increased side effects associated with 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. When initiating statins in patients with liver disease, patients must abstain from alcohol. The statins mentioned above should initiate at a low dose and liver enzymes, and LDL-C should get 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.

Drug Interactions

Increase in plasma concentration of statins result from the following:

CYP3A4 inhibition: Statins that are metabolized by CYP450 3A4 isozyme include lovastatin, simvastatin, and atorvastatin.[8] If patients use these statins in combination with CYP3A4 inhibitors, it causes an increase in the plasma concentrations 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 CYP3A4 activity. Medications that increase the plasma concentrations of statins are:

• Macrolide antimicrobials: clarithromycin and azithromycin
• Immunosuppressants: immunosuppressive agents, including cyclosporine, or tacrolimus, are CYP3A4 inhibitors, and they also inhibit OATP1B1. All the statins are substrates of OATP1B1 transporter, and thus, using them along with immunosuppressive agents increases the plasma concentration of statins. Among the statins, pravastatin or fluvastatin are the recommended agents for use in combination with immunosuppressive agents.
• Protease inhibitors: protease inhibitors interact with statins metabolized by CYP3A4 and increase the risk of muscle toxicity. Fluvastatin or pravastatin is the statin of choice in patients taking protease inhibitors
• Grapefruit juice
• Azole antifungals: itraconazole, ketoconazole

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:

1. CYP3A4 induction: When the statins that are metabolized by CYP3A4 are co-administered with CYP3A4 inducers (efavirenz, rifampin, phenytoin), it results in a decrease in plasma concentrations of statins and decreases their effectiveness. 
2. Bile acid sequestrants: The plasma concentration of statins decrease when used in combination with bile acid sequestrants such as colestipol
3. Antacids: The plasma concentration of statins decrease when combined with antacids 

Adverse Effects

Adverse effects of statins include the following[9][10]: 

1. Musculoskeletal: Myalgia is the most common side effect of statins, and 1 to 10% of individuals using statins have myalgias. Myositis is less common and characteristically presents by an increase in creatine kinase (CK). Rhabdomyolysis rarely occurs (0.1% individuals) but is the most serious side effect of statins and is associated with marked elevation in CK (10 times the upper limit of normal), acute renal failure secondary to myoglobinuria, electrolyte disturbances, and hemodynamic instability. Statins cause musculoskeletal toxicity because they decrease the concentration of coenzyme Q10 (ubiquinone) and end products of the mevalonate pathway (farnesyl pyrophosphate, geranylgeranyl pyrophosphate), which are essential for skeletal muscle energy production. The symptoms usually occur within weeks to months of therapy initiation. Individuals experience relief, and serum CK normalizes within days to weeks of medication discontinuation. Amongst the statins, pravastatin and fluvastatin have the least muscle-related adverse effects. In patients who develop myopathy on statins other than pravastatin or fluvastatin, the recommendation is to switch to one of these two statins once symptoms have resolved. In patients who develop muscle side effects on pravastatin or fluvastatin, decrease the dose of statins. 
2. Hepatic dysfunction: Statins can cause an increase in the concentrations of serum transaminases. If an individual develops serum transaminases three times the upper limit of normal, then reduce the dose of statin or change to a different statin (preferably pravastatin) or switch to a different class of lipid-lowering drugs. 
3. Renal dysfunction: High-intensity statins can cause proteinuria and hematuria. Also, rhabdomyolysis secondary to statin use can lead to renal failure. Rosuvastatin and simvastatin are the statins that cause kidney injury. Atorvastatin, fluvastatin, or pravastatin are the indicated choices in patients with renal impairment.
4. Diabetes mellitus: Individuals taking high-intensity statins have a slightly increased risk of developing diabetes mellitus. The proposed mechanism is that statins inhibit the biosynthesis of cholesterol, which is essential for the production of GLUT-1, which mediates glucose uptake into the cell.[11] This mechanism results in increased plasma concetrations of glucose.

Other side effects reported with statins in various case reports/case series include:

• Respiratory: shortness of breath, interstitial lung disease
• Gastrointestinal: statin-induced pancreatitis
• Neurological: peripheral neuropathy, insomnia, dizziness, reversible cognitive impairment
• Reproductive: sexual dysfunction, gynecomastia, oligospermia
• Psychiatric: irritability, aggression, or behavioral changes
• Autoimmune: lupus-like syndrome, myasthenia gravis
• Ophthalmic: cataract
• Urinary tract: urinary tract infection, hematuria, albuminuria

Contraindications

The contraindications of statins include the following:

• Hypersensitivity to medication
• Pregnancy: Statins are contraindicated in pregnancy (category X under the prior FDA pregnancy classification system). Cholesterol and its substrates are imperative for fetal development. Since statins inhibit cholesterol synthesis, it causes damage to the fetus. Reports exist of congenital anomalies including anal atresia, tracheoesophageal fistula (VATER association) in women taking statins. If a patient becomes pregnant while taking statins, they should discontinue the medication immediately, and the patient should have counseling regarding the potential hazards.
• Lactation: Statin contraindications also include breastfeeding mothers
• Acute liver failure or decompensated cirrhosis

Monitoring

Monitor lipid profile, liver function tests, creatine kinase (CK), and thyroid function tests in individuals who start statin treatment:

• Lipid profile: Perform a lipid profile at baseline before initiating statins. The lipid panel should be repeated two months after starting the therapy. If the concentration of LDL-C reduction is less than expected in an individual adherent to medication, then increase the dose of statin or change to another potent statin medication and repeat lipid profile after two months. If the concentration of LDL-C is within the expected range, repeat the lipid profile every 6 to 12 months.
• Liver function tests: Perform liver function tests at baseline before initiating statins. Routine monitoring of LFTs is not a recommendation. LFTs require rechecking when the patient develops symptoms of liver disease.
• Creatine kinase (CK): CK levels are optionally obtainable at baseline before initiating statins. Routine monitoring of CK is not a recommendation.
• Thyroid function tests: Hypothyroidism can cause abnormal lipid profile and myopathy. Recommendations are to obtain thyroid hormone levels before starting statin therapy.

Toxicity

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.

Enhancing Healthcare Team Outcomes

Statins play an essential role in lowering the plasma concentrations of atherogenic lipids and in the prevention of clinical ASCVD. It is vital for healthcare professionals 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.

Clinicians (MDs, DOs, NPs, PAs) will prescribe these drugs and decide both which agent as well as the dose based on the patient's lipid status. Nurses will often offer initial counseling to the patient as they start statin therapy, and can be the first line on monitoring treatment success, medication adherence, and the presence of adverse medication effects.  Pharmacist involvement comes in the form of verifying the agent selected, checking the dose, and performing medication reconciliation, as well as counseling on optimal administration and monitoring for adverse events. In both cases, nurses and pharmacists should report any concerns they encounter to the rest of the healthcare team.

The medical personnel, including the physicians, specialists, nurse practitioners, specialty-trained nurses, and pharmacists, should all work collaboratively as an interprofessional team when administering statin therapy. All parties must be aware of the drug interactions and take a proper medication history before initiating statins. [Level V]