Continuing Education Activity

Statin medications are used in the management and treatment of hypercholesteremia. They are known to be inhibitors of the hydroxymethylglutaryl-CoA reductase enzyme and lower total cholesterol, low-density lipoprotein (LDL), and triglyceride concentrations while increasing high-density lipoprotein (HDL) concentrations. FDA-approved statins include atorvastatin, rosuvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, and pitavastatin.This activity describes the indications, actions, and contraindications for statins as a valuable agent in treating hypercholesteremia. This activity will highlight the mechanism of action, dosing, and monitoring pertinent for members of the interprofessional team in the management of patients with hypocholesteremia.

Objectives:

• Identify indications for initiating statin therapy.
• Review contraindications for statin therapy.
• Explain common and uncommon adverse effects associated with statin therapy.
• Outline the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from therapy with statin drugs.

Indications

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, lower total cholesterol, low-density lipoprotein (LDL), and triglyceride concentrations while increasing high-density lipoprotein (HDL) concentrations. FDA-approved statins include atorvastatin, rosuvastatin, simvastatin, pravastatin, fluvastatin, lovastatin and pitavastatin.[1] Clinicians have long used statin medications to treat hypercholesterolemia, hyperlipoproteinemia, and hypertriglyceridemia as an adjunct to diet and exercise. These agents are used mainly for primary and secondary prevention of coronary artery disease. The approved FDA indications vary slightly between the medications in this class.

The FDA-approved indications for statins are:

• Hyperlipidemia and mixed dyslipidemia[2]
• Primary dysbetalipoproteinemia (Type III hyperlipoproteinemia)[3]
• Hypertriglyceridemia[4]
• Atherosclerosis[5]
• Primary prevention of ASCVD (atherosclerotic cardiovascular disease)[6]
• Secondary prevention in patients with clinical ASCVD[7]
• Pediatric patients with familial hypercholesterolemia[8]
• Adult patients with homozygous familial hypercholesterolemia[9]

Mechanism of Action

Statins are a selective, competitive inhibitor of hydroxymethylglutaryl-CoA (HMG-CoA) reductase, the enzyme responsible for converting HMG-CoA to mevalonate in the cholesterol synthesis pathway. By reducing hepatic cholesterol synthesis, an upregulation of LDL receptors and increased hepatic uptake of LDL-cholesterol from the circulation occurs. Statin treatment reduces the hepatic production rate of apo B100 containing lipoproteins, leading to a decrease in both cholesterol and triglyceride concentrations. Drug responses may also differ according to genetic factors, such as the ATP binding cassette G2, lipoprotein(a), and apo E genes [32]. The RhoA gene may play an important role in statin's LDL-C response.[10]

HMG CoA reductase inhibitors have pleiotropic effects. Statins inhibit the synthesis of isoprenoid intermediates required for activating intracellular/signaling proteins(Ras, Rho, Rab, Rac, Ral, or Rap). Consequently, statins have anti-inflammatory, antioxidant, antiproliferative, and immunomodulatory effects. In addition, they promote plaque stability and prevent platelet aggregation. This pleiotropic effect is the class effect of statins and is demonstrated by all statins. The COSMOS (coronary atherosclerosis Study measuring the effects of rosuvastatin using intravascular ultrasound in Japanese subjects) trial results indicated that patients treated with rosuvastatin had a substantial decrease in plaque volume independent of LDL-C reduction.[11]

Pharmacokinetics

Absorption: Absorption is faster for lipophilic drugs like atorvastatin, simvastatin, fluvastatin, pitavastatin, and lovastatin than hydrophilic statins like rosuvastatin or pravastatin. Atorvastatin is completely absorbed after oral administration, but atorvastatin undergoes extensive first-pass metabolism; hence the bioavailability is about 12%. The bioavailability of pitavastatin is highest (>60%), followed by rosuvastatin(20%), while simvastatin has <5% bioavailability.[12] Simvastatin and lovastatin are prodrugs converted to an active form by hydrolysis.[13]

Distribution: Protein binding affects drug distribution and the pharmacological efficacy of drugs because only the unbound or free drug can elicit targeted effects. All statins have high plasma protein binding(PPB) except pravastatin(PPB ~50%). Lipophilic statins can penetrate cells by passive diffusion and are widely distributed in different tissues. Hydrophilic statins pravastatin and to and rosuvastatin are attached to the polar surface of the cell membrane and require protein transporters to enter the cell to inhibit the HMG-CoA reductase.[14]

Metabolism: CYP3A4 plays a crucial role in the metabolism of atorvastatin, lovastatin, and simvastatin. Fluvastatin is metabolized by CYP2C9. Rosuvastatin is metabolized(to a lesser degree) by CYP2C9 and CYP2C19. OATPB1(organic anion-transporting polyprotein) plays a role in eliminating atorvastatin, rosuvastatin, simvastatin, pitavastatin, and pravastatin, while OATPB3 is involved in the elimination of rosuvastatin, fluvastatin, and pravastatin. Atorvastatin and lovastatin are both substrates and inhibitors of P-gp(permeability glycoprotein).[15]

Excretion: Statins are extensively metabolized, and the amount of statin excreted in its unchanged form through renal elimination is comparatively less. Rosuvastatin does not undergo extensive metabolism and is primarily excreted unchanged in urine and feces. Fluvastatin, lovastatin, pravastatin, and simvastatin have a rather short half-life. These drugs should be administered in the evening or as an extended-release formulation (for fluvastatin or lovastatin) to maximize their efficacy. In contrast, atorvastatin and rosuvastatin have longer half-lives and can be administered at any time of the day. HMG CoA reductase inhibitors are also excreted into bile and feces.[16]

Administration

Statin medications can be taken with or without food. Grapefruit juice should be avoided with some statins to minimize CYP3A4 interactions that could increase serum concentrations. Due to the diurnal variation in hepatic cholesterol synthesis, synthesis is highest in the early morning hours. An evening dose of some statins is the recommended dosing approach (e.g., fluvastatin, lovastatin, pravastatin, and simvastatin).[17] Atorvastatin, pitavastatin, and rosuvastatin dosing can be without regard to morning or evening administration, but their administration should be at the same time of day.

According to AHA/ACC guidelines, based on estimated LDL level reductions, statins can be classified into high-intensity, moderate-intensity, and low-intensity statins.[18]

• High-intensity statin(LDL-C lowering > 50%): rosuvastatin 20 mg, rosuvastatin 40 mg, atorvastatin 40 mg, atorvastatin 80 mg
• Moderate-intensity statin(LDL-C lowering 30% to 49%): atorvastatin 10 mg, atorvastatin 20 mg, pravastatin 40 mg, pravastatin 80 mg, lovastatin 40 mg, lovastatin 80 mg, fluvastatin XL 80 mg,  fluvastatin 40 mg BID, pitavastatin 1–4 mg
• Low-intensity statin(LDL-C lowering < 30%): simvastatin 10 mg,  pravastatin 20 mg, pravastatin 10 mg, lovastatin 20 mg, fluvastatin 20 mg, fluvastatin 40 mg.[19]

Patients with severe primary hypercholesterolemia (LDL-C ≥ 190 mg/dL) have a high risk of atherosclerotic cardiovascular disease (ASCVD); high-intensity statin therapy is recommended.[20]

For young adults between 20-39 years, consider statin therapy if only in high-risk patients (family history of premature CAD and very high LDL-C ≥160 mg/dL)

Patients between 40 to 75 years of age with diabetes are at intermediate or high risk of future ASCVD, and moderate-intensity statin is recommended.

Patients between 40 to 75 years of age with diabetes-specific risk factors(≥ 10 years for T2DM or ≥20 years for type 1 DM or albuminuria, retinopathy, neuropathy, eGFR<60 mL/min/1.73 m² or ankle-brachial index <0.9) high-intensity statin therapy is recommended.

Consider treatment with a high-intensity statin for patients between 40 to 75 years of age with ASCVD > 20%(high risk)over ten years.

Consider treatment with a moderate-intensity statin for patients between 40 to 75 years of age with ASCVD ≥ 7.5 to < 20%(moderate risk) over ten years.

Consider treatment with a moderate-intensity statin for patients between 40 to 75 years of age with ASCVD 5% to <7 .5%(high risk) over ten years if risk enhancers are present. Risk enhancers are a family history of premature ASCVD, persistently elevated LDL-C>160 mg/dl, metabolic syndrome, chronic kidney disease, chronic inflammatory conditions(psoriasis, RA, or HIV), history of premature menopause (before age 40 years), preeclampsia, high-risk race/ethnicity (e.g., south Asian ancestry), lipids/biomarkers(persistently elevated primary hypertriglyceridemia (≥ 175 mg/dL),hs-CRP (≥ 2.0 mg/L), Lp(a)≥5 0 mg/dL, apoB (≥130 mg/dL), ankle branchial index<0.9.[21]

 In adults with intermediate risk (≥ 7.5% to < 20%) or adults at borderline risk (5% to < 7.5%), measure coronary artery calcium (CAC) levels if:

• If CAC is 0 Agatston units, no statin is required unless there is a history of diabetes mellitus, a family history of premature CHD, or cigarette smoking is present. 
• If CAC is 1 to 99 Agatston units, consider statin therapy, especially after the age of 55 years.
• If CAC is greater than 100 Agatston units, initiate statin therapy.[22]

For young adults(20-39) years, consider statin therapy, if only in patients with a family history of premature CAD and very high LDL-C (≥160 mg/dL).

Secondary ASCVD prevention: According to AHA/ACC, the very high-risk category has been defined as a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions. Major ASCVD events are recent acute coronary syndrome(ACS) within the past 12 months, MI other than the ACS, ischemic stroke, and symptomatic peripheral arterial disease (ABI <0.85 or amputation or previous revascularization). High-risk conditions are age ≥65 years, prior PCI/CABG, heterozygous familial hypercholesterolemia, diabetes mellitus, hypertension, chronic kidney disease, current smoking, history of heart failure, and LDL-C ≥100 mg/dL.

• In patients ≤75 years of age with clinical ASCVD, high-intensity statin therapy should be started or continued with the goal of ≥50% reduction in LDL-C.
• For patients in the very high-risk category, if LDL-C is ≥70 mg/dL on a maximally tolerated statin therapy, clinicians should consider adding ezetimibe to statin therapy. If LDL-C is still ≥70 mg/dL or if non–HDL-C ≥100 mg/dL, clinicians should consider adding a PCSK9 inhibitor.

Homozygous familial hypercholesterolemia(HoFH): Statin therapy is recommended in combination with lipoprotein apheresis, PCSK9 inhibitors, and microsomal triglyceride transfer protein (MTP) inhibitor(lomitapide).[23]

Pediatric Considerations: For patients with familial hypercholesterolemia, moderate to high-intensity statin therapy is recommended.[24] 

Geriatric Considerations: For patients >75 years of age, the clinician and patient should discuss the potential benefits of preventative therapies in the context of comorbidities and life expectancy.

Patients with Hepatic Impairment: All statins are contraindicated in active liver disease. Statins have been associated with mild-to-moderate serum aminotransferase elevations during therapy that is typically temporary, asymptomatic, and usually resolve even with continuation without dose adjustment. Statins with minimal hepatic metabolism, such as pravastatin and rosuvastatin, are preferred in chronic liver disease.[25] NAFLD(nonalcoholic fatty liver disease) is a known risk factor for cardiovascular disease. According to American gastroenterological association guidelines, statins benefit patients with NAFLD.[26]

Patients with Renal Impairment: According to KDIGO(kidney disease improving global outcomes)guidelines, statin therapy is recommended for adults>50 years with CKD stages 1 and 2. For stage 3 to stage 5 CKD(not on HD), a statin+ezetemibe combination is recommended. Statin therapy is recommended for patients between 18 to 49 years(stage 1 to 5) of age with one risk factor (known coronary artery disease, diabetes mellitus, prior ischemic stroke, the estimated 10-year incidence of coronary death, or non-fatal MI >10%). In adult patients with dialysis-dependent CKD, statins should NOT be initiated; however, statins can be continued if the patient is already being administered statins at the time of dialysis initiation.[27] A network meta-analysis demonstrated that high dose atorvastatin and fluvastatin 20 mg/ezetimibe 10 mg significantly prevented eGFR decline and proteinuria. Dose adjustment is required with other statins in patients with stage 4 CKD(creatinine clearance< 30 mL/min).[28]

Pregnancy Considerations: Statins are typically contraindicated in pregnancy. In 2021, the FDA advised removing the contraindications of statin use during pregnancy for high-risk patients. Clinicians can consider the use of statins in pregnant patients at very high risk of cardiovascular events during pregnancy(patients with homozygous familial hypercholesterolemia and established cardiovascular disease).[29]

Breastfeeding Considerations: The consensus is that statins should not be used during breastfeeding due to disruption in the infant's lipid metabolism. Other agents, such as cholestyramine, colesevelam, and colestipol, may be safe during breastfeeding.[30][31][32]

Adverse Effects

Statins are usually well-tolerated, with myopathy, rhabdomyolysis, hepatotoxicity, and diabetes mellitus being the most common adverse reactions. The incidence of myopathy is dose-dependent and may present as diffuse myalgias or otherwise unexplainable muscle tenderness or weakness with reversal upon medication discontinuation. Rhabdomyolysis is the most serious complication of statin use, but its occurrence is rare. Rarely elevated hepatic transaminases can occur. This elevation is usually a transient effect and resolves with continued therapy or after a brief therapy interruption. Patients with statin-induced hepatotoxicity have hepatocellular rather than cholestatic or mixed liver injury. Cholestatic/mixed hepatic injury appeared to be more predominant in patients taking atorvastatin.[33] The FDA no longer supports liver function tests for monitoring the use of these medications without symptoms of hepatotoxicity, such as unusual weakness or fatigue, jaundice, or dark-colored urine.[34][35][36]

Statin-associated cognitive dysfunction is a rare adverse drug reaction; changing lipophilic to hydrophilic statins may resolve cognitive impairment.[37] Statin therapy is also associated with an increased risk of developing new-onset diabetes mellitus.[38] There have been concerns regarding hemorrhagic stroke with statins; however, a large cohort study found no evidence that HMG-Co-A-reductase inhibitors increase the risk of intracerebral hemorrhage in individuals with a history of stroke.[39]  Statin-associated immune-mediated necrotizing myopathy(IMNM) is due to the development of antibodies against the HMG-CoA reductase enzyme. Symmetrical, proximal muscle weakness with significantly increased CPK that persists for months after discontinuation of statins is common in IMNM.[40]

Drug-Drug Interactions

Gemfibrozil-simvastatin: Reduced metabolism of simvastatin leads to increased concentration and increased risk of myopathy. Avoid combination.[16] 

Gemfibrozil-pravastatin: Reduced metabolism of pravastatin leads to increased concentrations and increased risk of myopathy. Avoid combination.[16] 

Coadministration of a statin with a fibrate may be required to treat complex dyslipidemias or hypertriglyceridemia; fenofibrate is preferred due to the reduced incidence of drug interactions compared with statin-gemfibrozil therapy. (The rate of gemfibrozil-associated rhabdomyolysis is approximately ten times higher than fenofibrate).[41]

Amiodarone-lovastatin: Limit the dose of lovastatin to 40 mg daily.

Amiodarone-simvastatin: Limit the dose of simvastatin to 20 mg daily.

Conivaptan-simvastatin: Reduced metabolism of simvastatin leads to increased concentrations and increased risk of myopathy.

Cyclosporine/tacrolimus/everolimus/sirolimus with lovastatin/pitavastatin - Avoid combination.

Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CPYP3A4. Therefore, closely monitor when administered with CYP3A4 inhibitors such as amiodarone, amlodipine, ciprofloxacin, clarithromycin, telithromycin, diltiazem, erythromycin, fluconazole, fluoxetine, sertraline, TCAs,  isoniazid, itraconazole, ketoconazole, midazolam, nefazodone, posaconazole, protease inhibitors, ranolazine, tacrolimus, ticagrelor, verapamil, and voriconazole. 

Fluvastatin, and rosuvastatin is primarily metabolized by CYP2C9. Monitor for drug interactions when administered with amiodarone, etravirine, fluconazole, fluvoxamine, fluvastatin,ketoconazole, metronidazole, miconazole, sulfamethoxazole/trimethoprim, voriconazole, zafirlukast.

Atorvastatin, lovastatin, pitavastatin, and simvastatin are substrates if P-gp: Monitor for drug interactions when given with P-gp inhibitors like amiodarone, azithromycin, captopril, carvedilol, cimetidine, clarithromycin, colchicine, conivaptan, cyclosporine, diltiazem, dipyridamole, dronedarone, erythromycin, felodipine, grapefruit juice, itraconazole, ketoconazole, mefloquine, nicardipine, omeprazole, protease inhibitors, quinidine, ranolazine, sertraline, tacrolimus, verapamil. It is important to recognize that atorvastatin, pitavastatin, lovastatin, and simvastatin are both P-gp substrates and P-gp inhibitors.

OATP1B1 is involved in statin uptake and metabolism of atorvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Therefore, monitor drug interactions when these drugs are given with carbamazepine, clarithromycin, erythromycin, gemfibrozil, protease inhibitors, rifampin, sildenafil, sacubitril, and telithromycin.

OATP1B3 is involved in statin uptake and metabolism of fluvastatin, pravastatin, and rosuvastatin: Monitor for drug interactions when given clarithromycin, cyclosporine, erythromycin, rifampin, roxithromycin, rifampin, sacubitril, telithromycin. OATP inhibitors may increase concentrations of statins, consequently increasing the rate of adverse drug reactions, including myopathy.[16]

Diltiazem is frequently prescribed with statins. Rhabdomyolysis has been reported in a patient taking atorvastatin after diltiazem.[42] Avoid concurrent administration of verapamil and diltiazem with simvastatin and lovastatin as AUC increases by 3- to 8-folds.[43][44]

Contraindications

Coadministration of CYP3A4 substrate statins (atorvastatin, lovastatin, and simvastatin) with medications that are potent 3A4 inhibitors (diltiazem, erythromycin, -azoles) may result in increased serum concentrations with an increased risk of side effects. A reduced dose may be appropriate, or a selection of an alternative statin that does not undergo metabolism via the 3A4 pathway. Administration with other drugs associated with myopathy requires caution. Simvastatin and gemfibrozil coadministration is contraindicated because of the risk of rhabdomyolysis. Dose restrictions are recommended with the coadministration of gemfibrozil or other fibrates with statins, and using more than one statin is not recommended.[45][46][47]

Statins are contraindicated for use by patients with active hepatic disease or unexplained persistent elevations in aminotransferase levels. Statins are now relatively contraindicated during pregnancy.[29] Statins are also contraindicated while breastfeeding because of the effects on the cholesterol pathway, as cholesterol is essential for fetal and infant synthesis of steroids and cell membrane development.[30][31]

Monitoring

Liver function tests should be assessed before therapy initiation, as statins are contraindicated in patients with active hepatic disease. It is unnecessary to schedule regular follow-ups of the patient's liver function unless clinical symptoms of the hepatic disease become apparent. Moderate-intensity therapy should result in an LDL reduction of 30% to 50% from baseline, and a high-intensity regimen should result in a reduction of more than 50% from baseline. Other than atorvastatin, statin medications have renal dosing guidelines that require an assessment of serum creatinine and creatinine clearance.[48][49][50] 

When colchicine is used along with statins, close monitoring of CPK should be done. Patients on high-intensity atorvastatin may be at increased risk of digoxin toxicity, and monitoring for digoxin toxicity is suggested. [16] The response of LDL-C should be monitored to adjust the dose and intensity of statin therapy. According to AHA, fasting lipid panel monitoring should be measured at baseline and 4 to 12 weeks after statin initiation or dose adjustment. Follow-up monitoring should be done every 3 to 12 months.[16]

Toxicity

Statins are now well-established drugs with proven effectiveness in reducing adverse cardiovascular and cerebrovascular events. There is no antidote to reverse the myopathy or rhabdomyolysis caused by statins. The general treatment is supportive and comprises immediate discontinuation of the offending drug. Aggressive fluid management is the cornerstone of therapy.[51]The urine output requires monitoring, and a foley catheter insertion may be necessary. Other supportive measures include correcting any electrolyte disturbances and monitoring the patient with continuous EKG monitoring if hyperkalemia is present. Insulin-dextrose treatment (IDT) is a first-line treatment for moderate (K+ 6 to 7 mmol/L) to severe hyperkalemia (K+ > 7 mmol/L).[52]

All patients need continual follow-ups to monitor for hyperkalemia and acute kidney injury. The patient may receive a discharge once electrolytes return to normal and there is no renal dysfunction. The decision to restart a statin requires good clinical judgment. Only the lowest dose of another statin should be used, and one should avoid the concomitant use of fibrates. The patient should be monitored for muscle pain and routine urine and blood tests to ensure muscle breakdown is not recurring. The statin-associated autoimmune myopathy will require aggressive immunosuppression with steroids, methotrexate, and intravenous immunoglobulin (IVIG) or rituximab.[40]

Enhancing Healthcare Team Outcomes

Statins have been around for over two decades and have proven effective at lowering cholesterol. Statin therapy requires an interprofessional healthcare team that includes clinicians (MDs, DOs, NPs, and PAs), nurses, and pharmacists. When the patient has been prescribed a statin, the nurse and pharmacist should educate the patient on the dose and side effects of the drugs. The pharmacist must regularly check the patient's list of medications to ensure safety and prevent polypharmacy interactions. Nursing staff should verify medication compliance, ask about any new symptoms that may have links to statin use, counsel the patient on administration, and inform the prescriber if there are any concerns. Further, clinicians should monitor liver function because these statins cause transaminase elevations. These monitoring practices should occur within an interprofessional team environment so that all team members have access to the same information and can make decisions and recommendations based on the latest data for the patient, leading to improved therapeutic outcomes. [Level 5]

Statin therapy correlates with an increased risk of diabetes, with the first notable JUPITER trial published in 2008.[53] A meta-analysis study involving 91140 patients published in 2014 showed a 9% increase in the likelihood of developing diabetes mellitus.[54] Studies have found that pitavastatin should be the drug of choice in pre-diabetic patients to reduce the risk of developing diabetes. The REAL-CAD trial published in 2018 found that a higher dose of pitavastatin significantly reduced cardiovascular events in Japanese patients with coronary artery disease compared to a lower dose of pitavastatin.[55] A recent updated meta-analysis showed that Coenzyme Q10 supplementation reduced statin-associated muscle symptoms.[56] Practitioners should consider coq10 supplementation before discontinuing statin medication. 

Outcomes

Clinical trials have shown that statins effectively lower cholesterol and the risk of adverse cardiac events. The ALLHAT-LLT trial found no benefit in primary prevention in older adults above 75 years of age with statin therapy and hyperlipidemia.[50] Statin therapy should still resume in elderly patients with a history of coronary artery disease, stroke, and diabetes mellitus. [Level 5] A systemic review of 35 studies (925,171 patients) demonstrated that pharmacist-led medication reconciliation, patient education, and interprofessional team-based intensification between pharmacists, primary care clinicians, and cardiologist improves patient compliance with lipid-lowering medications, including statins.[57] [Level 1]