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Epidemiology and Management of Hyperlipidemia
Samantha Karr, PharmD, FCCP, BCPS, BCACP, BC-ADM
Participating Faculty

Epidemiology and Management of Hyperlipidemia

Samantha Karr, PharmD, FCCP, BCPS, BCACP, BC-ADM
Management of Hyperlipidemia and FH
Statins reduce total cholesterol and LDL-C via inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Multiple studies have clearly shown that statins can lower LDL-C levels, thereby reducing the risk of developing CVD in patients with elevated LDL-C and reducing mortality and disease progression among patients with clinical ASCVD.3,22-29 Statins are the mainstay of treatment for hyperlipidemia, including use in FH.3,4

Seven statins are currently approved by the FDA for the treatment of hyperlipidemia in combination with a heart-healthy diet.30-37 A meta-analysis of 26 randomized trials involving 170,000 patients treated with various statins showed that a decrease in LDL-C of 39 mg/dL was associated with a 24% risk reduction in major vascular events.29 The trials included patients being treated for either primary or secondary prevention of cardiovascular disease, and the duration of treatment was at least 2 years. In general, statins can reduce LDL-C by approximately 20% to 65% with greater reductions seen with atorvastatin, rosuvastatin, and pitavastatin; moderate decreases with lovastatin and simvastatin; and the lowest decreases with fluvastatin and pravastatin.22,24-28,35 All but pitavastatin have indications for patients with FH.

While statins are generally well tolerated, they are associated with numerous adverse effects, including gastrointestinal events, musculoskeletal pain, respiratory infections, and headaches.30-34,36,37 Statins can also be associated with elevated blood glucose and glycated hemoglobin (A1C) levels.38-40 Increases in liver enzyme transaminases can occur infrequently, and statins are contraindicated in patients with active liver disease, as well as in patients with unexplained and chronic elevations in liver enzyme transaminases. Caution is advised regarding the concomitant use of most statins and anticoagulants; a reduction in the dose of the anticoagulant is recommended.30-32,34,36,37

Approximately 10% of patients receiving statins experience muscle-related symptoms, including bilateral muscle pain, weakness, and inflammation.41-43 Results from studies have indicated that simvastatin, atorvastatin, and lovastatin are associated with a higher incidence of muscle-related adverse events, and pravastatin, fluvastatin, and rosuvastatin have the lowest rates.41,43,44 Serious adverse events, including myopathy and rhabdomyolysis, are less common, with an incidence of approximately ≤5 of every 1000 patients receiving statins. Severe rhabdomyolysis is a serious form of statin-induced myopathy that is associated with high elevations in serum creatinine kinase, myoglobinuria, and acute kidney injury, and may be life threatening.45 Concomitant use of various drug classes, such as strong CYP3A4 inhibitors, including macrolide antibiotics, HIV and hepatitis C protease inhibitors, gemfibrozil, cyclosporine, danazol, as well as some antifungals, antihypertensives, and antiarrhythmic agents can increase the risk of developing rhabdomyolysis, as can use of higher statin doses.30-34,36,37 Combinations of statins with either niacin or fibrates can also increase the risk of serious adverse events.46,47 Several factors, including older age (≥65 years), renal impairment, and uncontrolled hypothyroidism, can also contribute to the risk of rhabdomyolysis.

Limitations of Statins
While statin monotherapy can lower LDL-C levels in most patients, some patients are nonadherent, intolerant, or resistant, resulting in poor outcomes.

Nonadherence to Statin Treatment
Nonadherence to statin treatment is a common issue, and has been shown to lead to an increased risk of ASCVD and mortality.10,48-50 Studies have found that 10% to 30% of patients never fill their first statin prescription, and adherence rates are roughly 25% to 50% among patients with acute coronary syndrome and those receiving statins for primary prevention of ASCVD.51-57 Further, within the first year, approximately 50% of patients discontinue statin therapy, and discontinuation rates at 2 years can be ≥75%.10,58 Nonadherence and nonpersistence are associated with an increase in both ASCVD risk and mortality.50 Factors contributing to nonadherence include comorbidities, AEs, regimen complexity, age, sex, co-payment, and income.10,57,59,60 Data from a meta-analysis of 22 cohort studies revealed that patients ≥70 years and <50 years of age were more likely to be nonadherent compared with those 50 to 69 years of age.57 In addition, nonadherence was greater among women and patients with lower incomes. Conversely, better adherence was noted among patients with a history of myocardial infarction or stroke, hypertension, or diabetes. Recommendations for addressing nonadherence include assessing the number of missed doses per month and discussing any barriers to adherence with the patient.61 Medication therapy management, pharmacy disease management programs, and other pharmacist-driven efforts can help to improve clinical outcomes, improve adherence, and minimize cost.62

Statin Intolerance
Statin intolerance is often associated with poor adherence. Results of a meta-analysis comparing high-intensity and moderate-intensity statins revealed an increased risk of adverse events and adverse event-related treatment discontinuation with higher intensity statins63; however, another more recent meta-analysis noted less risk with rosuvastatin.64 Patients drinking grapefruit juice, especially large quantities, should be reminded of the potential for an interaction with statins, metabolized by CYP3A4. In addition, drugs that affect the CYP3A4 pathway can alter the metabolism of statins that are major substrates of CYP3A4, such as simvastatin, atorvastatin, and lovastatin. This can result in muscle-related adverse events.65-68 Approximately 7% to 29% of patients receiving statins experience muscle-related adverse events, which can contribute to poor adherence and nonpersistence.41,69-71 Rhabdomyolysis is a severe and potentially fatal form of muscle-related adverse event  that occurs at a rate of 3.4 per 100,000 person-years.72 A systematic review noted higher incidences of rhabdomyolysis among patients receiving simvastatin or atorvastatin as compared with pravastatin or fluvastatin, and among patients receiving fibrates in combination with statins.64 As pravastatin, fluvastatin, and rosuvastatin are only minor substrates of CYP3A4, these statins have a lower incidence of drug–drug interactions and also may be a better option for patients at an increased risk of developing rhabdomyolysis.64,73 In cases where musculoskeletal events occur in patients receiving statins, it is important to first verify that statins are the cause of the events.

Recommendations for management of skeletal-related events in patients receiving statins from the NLA include decreasing the dose of a daily statin, incorporating a once-weekly dose of a long-acting statin, such as rosuvastatin or atorvastatin, as well as switching to either a different statin or a nonstatin, such as ezetimibe or bile acid sequestrants (BASs).46 The ACC recommends discontinuing the statin and rechallenging to verify that the statin is indeed the cause of the muscle-related symptoms.61 In patients with unexplained severe muscle pain, test for rhabdomyolysis by evaluating creatine kinase and creatinine levels and perform a urinalysis for myoglobin.3 For mild to moderate muscle symptoms, it is recommended to discontinue the statin and determine the cause of the symptoms. If no causal relationship between the muscle symptoms and the statin is found, and there are no contraindications, the original statin can be given to the patient at either the original dose or at a lower dose.3 Finally, if a causal relationship between statin use and muscle symptoms is found, it is recommended to use a low dose of a different statin, increasing the dose until the maximum tolerated dose is determined.3 ACC has developed the ACC Statin Intolerance app, which is available as a Web version or application that can be accessed by smartphones or tablets. This ACC resource is based on recommendations in the 2013 ACC/AHA guideline and helps to direct clinicians through a detailed algorithm to help determine if severe muscle-related pain during statin therapy meets criteria for rhabdomyolysis and provides follow-up steps that should be taken after investigation of muscle-related AEs.74

Data from studies indicate an increased risk of high glycemic effects with higher doses of statins, especially among patients already at an increased risk of developing diabetes.75-77 Among patients receiving statins, the increased risk of diabetes incidence was noted with simvastatin, atorvastatin, and rosuvastatin as compared with pravastatin.78 Additionally, no increased risk of developing diabetes was noted among patients receiving fluvastatin or lovastatin. Patients with diabetes are often at an increased risk of ASCVD, especially without statin use. Guidelines, including those from the ACC/AHA, recommend statin therapy for patients 40 to 75 years of age with diabetes and LDL-C 70 to 189 mg/dL.3 The  NLA Statin Safety Assessment Task Force notes that while there is a modest level of evidence correlating statin use with new-onset type 2 diabetes, there is a high level of evidence that the benefit of statins in reducing the risk of ASCVD outweigh the risk of developing diabetes.40 Rather than making specific recommendations for treating patients at an increased risk of diabetes, the NLA recommends that treatment decisions should be based on guidelines for the management of hyperlipidemia.40 It is important to discuss the benefits and risks of statin therapy with patients before initiating treatment.

Statin Resistance
Studies estimate that 30% of patients treated with statins, especially those with FH, did not reach LDL-C levels <100 mg/dL.79,80 Very high baseline levels, such as those seen in patients with FH, predispose patients to statin resistance.10 Data from studies indicate that statins can reduce LDL-C levels by 35% to 50% in patients with HeFH; however, in patients with HoFH, LDL-C levels are typically only reduced by 10% to 25%.81-86 A 25% to 50% reduction in LDL-C levels may not be adequate to achieve optimal LDL-C target levels in FH.82,86,87 For example, a study of rosuvastatin in children with FH demonstrated that although there was a 50% reduction in LDL-C among those receiving rosuvastatin 20 mg daily, only 40% of these patients achieved optimal LDL-C target levels.82 Thus, many patients with FH require additional therapies to attain optimal LDL-C levels to reduce the substantial ASCVD risk inherent to this condition.

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