Lipid-Lowering Drug Therapy

Minar Chhetry; Ishwarlal Jialal

Lipid-Lowering Drug Therapy

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Continuing Education Activity

Patients at an increased risk of cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina) benefit from lipid-lowering medications. It is essential to recognize that these drugs are useful in combination with lifestyle modification. These medications can be used for primary or secondary prevention of cardiovascular events. This activity covers lipid-lowering pharmaceutical interventions that members of the interprofessional team need to review the indications, contraindications, and adverse event profiles to optimally manage patients with abnormal lipid profiles and direct care to optimal outcomes.

Objectives:

Summarize the mechanisms of action of the most prominent lipid-lowering pharmaceutical agents.
Explain the indications for using the various agents in the lipid-lowering therapy family of medications.
Review the adverse effect profile of various individuals lipid-lowering therapy agents.
Describe interprofessional team strategies for improving care coordination and communication to properly use lipid-lowering medications to improve patient outcomes in the varied scenarios where lipid-lowering pharmaceutical therapy can be used.

Indications

Atherosclerosis is one of the major causes of coronary heart disease. According to the 2016 CDC data, heart disease is the leading cause of death in the United States. Dietary modifications, weight reduction, and exercise are the first line of defense. Patients at an increased risk of cardiovascular events (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina) benefit from lipid-lowering medications. It is essential to understand that these drugs are useful in combination with lifestyle modification. These medications can be used for primary or secondary prevention of cardiovascular events. Primary prevention includes patients without prior events but with risk factors such as diabetes mellitus and hypertension. Secondary prevention includes patients with a history of cardiovascular events. The 2018 ACC/AHA guideline emphasizes reducing the risk of ASCVD (atherosclerotic cardiovascular disease) through lipid management.[1] Lipoprotein modifying agents encompass several classes of drugs, including hydroxymethylglutaryl (HMG) CoA reductase inhibitors (statins), cholesterol absorbing inhibitors, fibric acid derivatives, bile acid sequestrants, PCSK9 inhibitors, and nicotinic acid.

Statins: They are the first line of lipid-lowering drugs, while others, discussed subsequently, are added to increase the efficiency of statins or in cases of statin intolerance or cases of severe hypertriglyceridemia. Statins can lower low-density lipoprotein (LDL) and triglyceride concentrations (at higher doses) while increasing high-density lipoprotein (HDL) concentrations.

Ezetimibe: Ezetimibe impairs cholesterol absorption and lowers LDL-C, apolipoprotein B (apo B), and non-HDL in patients with primary hyperlipidemia, mixed hyperlipidemia, and familial hypercholesterolemia (FH).[2]

Fibrates: Fibrates are known to decrease triglycerides by as much as 50 percent and also raise HDL by 5 to 20 percent.[3] Fibrates, despite their effects on lipids, have less favorable effects on clinical outcomes.[4] They are primarily used to lower triglycerides to avert the risk of pancreatitis.

Nicotinic Acid: Nicotinic acid (niacin) raises high-density lipoprotein cholesterol (HDL-C) significantly, but this has not been shown to improve patient outcomes in patients on statins.[5][6] Niacin use can help lower LDL in combination with statins plus ezetimibe in patients at extremely high cardiovascular risk, such as homozygous or heterozygous familial hypercholesterolemia, but not in secondary prevention.

Bile Acid Sequestrants(BAS): Bile acid sequestrants include cholestyramine, colestipol, and colesevelam. Bile acids sequestrants are indicated for primary hypercholesterolemia, usually in combination with statins or nicotinic acid. Cholestyramine has been shown to decrease cardiovascular mortality and morbidity by 19% compared to placebo in patients and benefit patients with Type 2 DM by decreasing blood sugar levels.[7] Bile acid sequestrants can also rapidly reduce plasma thyroid hormones, thus making them useful for refractory thyrotoxicosis.[8] They can also raise HDL-C.[9][10][11] They can be used to manage pruritus in patients with cholestatic disease and incomplete biliary obstruction.

PCSK9 Inhibitors: Proprotein convertase subtilisin/kexin type 9(PCSK9) inhibitors are a new group of drugs approved to lower LDL and have been shown to lower LDL by as much as 60 percent in patients taking statins. FDA has approved alirocumab and evolocumab for adult patients with heterozygous familial hypercholesterolemia or clinical ASCVD who require further lowering of LDL-cholesterol in addition to diet modification and maximally tolerated statin therapy. FDA has also approved evolocumab for adult patients with homozygous familial hypercholesterolemia who require further lowering of LDL-C in addition to other LDL-lowering therapies like statins or ezetimibe.

Mechanism of Action

Statins are competitive inhibitors of hydroxymethylglutaryl (HMG) CoA reductase, an enzyme that participates in a crucial rate-limiting step in cholesterol biosynthesis.[12] This enzymatic inhibition increases low-density lipoprotein (LDL) clearance from the serum by the upregulation of LDL receptors on the liver.[13] Statins can also reduce very-low-density lipoprotein (VLDL) by an effect hepatic apolipoprotein B secretion.[14] Statins have a modest effect on increasing high-density lipoprotein (HDL) and can also reduce triglycerides levels depending upon the statin and the dose used. Statins can lower LDL cholesterol by up to 63%.[15][16] Rosuvastatin and atorvastatin are high-intensity statins, with rosuvastatin being slightly more potent than atorvastatin.[17] Statins can also lower triglycerides (TG), especially if the TG level is greater than 250 mg/dl.[18]

Ezetimibe impedes dietary and biliary cholesterol absorption at the brush border of the intestine without increasing bile acid excretion or inhibiting cholesterol synthesis in the liver. It inhibits Nieman-Pick C1 like 1(NPC1L1) protein, which is present in both the intestine and the liver.[19][20] This leads to a decrease in the delivery of cholesterol to the liver, an increase in cholesterol clearance from the blood, and a reduction in hepatic cholesterol stores.

Fibrates are agonists for the nuclear transcription factor peroxisome proliferator-activated receptor alpha (PPAR-alpha). This receptor downregulates apoprotein C-III (an inhibitor of lipoprotein lipase) while upregulating the synthesis of apolipoprotein A-I, lipoprotein lipase, and fatty acid transport protein, resulting in an increase in VLDL catabolism and elimination of triglyceride-rich particles; this results in lowering of total plasma triglycerides by 30% to 60%; also a modest increase in HDL has been observed.

The mechanism by which nicotinic acid affects plasma lipoproteins is not fully known. It may involve several mechanisms, including partial inhibition of free fatty acid release from adipose tissue and increased lipoprotein lipase action, which may increase the rate of triglyceride removal from plasma.

Bile acid sequestrants bind with bile acids in the intestines, thus interrupting the reabsorption of bile acids. The ensuing reduction in the cholesterol pool lowers intrahepatic cholesterol, promoting the upregulation of LDL receptors, causing a further decrease in blood cholesterol. The bile acid sequestrants also induce a minimal elevation in high-density lipoprotein cholesterol (HDL-C).[21] BAS can reduce LDL starting at 15 percent and up by 24 percent at the maximal recommended dose.[22] They can raise triglyceride levels and should not be used if TG is greater than 400 mg/dl.

PCSK9 binds to the low-density lipoprotein receptor (LDL-R) on the surface of hepatocytes leading to the targeted degradation of LDL-R by lysosomes and, ultimately, an increase in plasma LDL-cholesterol (LDL-C) levels. Antibodies to PCSK9 interfere with its binding of the LDL-R, leading to higher hepatic LDL-R expression and lower plasma LDL-C levels.[23]

Administration

Most cholesterol synthesis occurs at night, reflecting the fasting state. Thus, prompting the statins to be administered at evening or bedtime.[24] Some studies have suggested every other day regimen of statin to reduce cost and improve the tolerability of statins while major outcome trials of statins base their results on daily statin therapy; thus, every other day is not a common practice except in patients unable to tolerate statins.[25][26][27]

Ezetimibe may be taken with meals and can be safely administered along with a statin or a fibrate. It may be taken at the same time as fenofibrate or HMG-CoA reductase inhibitors, but the recommendation is to take it at least 1 hour before or 4 hours after taking bile acid sequestrants.

Fibrates dosing is usually 30 minutes before meals.

Nicotinic acid is given orally with a meal and usually started at 100 mg three times a day and gradually increased as tolerated to 2.0g/dL.[5] LDL-C lowering occurs at doses greater than 1.5 g/day.

Bile acid sequestrants are available as granules or tablets. Cholestyramine should ideally be taken with breakfast when given to treat pruritus associated with cholestasis. Symptoms of pruritus are less frequent in the morning as the belief is that the pruritogenic factors concentrate in the gallbladder during overnight fasting.

PCSK9 inhibitors are administered by subcutaneous injections, with enzyme inactivation occurring within four to eight hours. Cost is the primary limiting factor for PCSK9 inhibitors.

Adverse Effects

Statins are among the safest medications to lower lipids, with muscle injury being the most common injury.[28][29] Other adverse effects include new-onset diabetes mellitus and hepatotoxicity.

Lipophilic statins (simvastatin, lovastatin, atorvastatin, and fluvastatin) may be associated with more adverse events than the more hydrophilic statins (pravastatin and rosuvastatin).[30]

Muscle Injury

Statin-induced muscle injury can vary from myalgias to rarely myonecrosis or rhabdomyolysis.[29] A meta-analysis of 42 randomized trials of statins found little or no excess risk of myalgias, CK elevations, rhabdomyolysis, or discontinuation of therapy versus placebo; however, in clinical practice, muscle side effects are relatively common, and the explanation for this difference is uncertain.[31][32] A higher incidence of myalgia was seen in patients treated with atorvastatin 80 mg daily than with a placebo.[33] Clinically significant myonecrosis, defined as a serum CK elevation over ten times normal, occurred in less than 0.5 percent of patients in large clinical trials.[34][35] Statin-induced myopathy was noted to be worse with higher doses of statins and the sensitivity of statins on striated muscles. Simvastatin and lovastatin have the highest risk of myopathy, while fluvastatin and pravastatin have the lowest risk.[36] Patients with pre-existing neuromuscular disease make them prone to muscle injuries such as myasthenia gravis, mitochondrial myopathy, McArdle disease, acid maltase deficiency, and amyotrophic lateral sclerosis (ALS).[37][38]

Research has shown that vigorous exercise in those on statins may increase the risk of muscle injury. Creatine kinase (CK) is the measure for the diagnosis of severe myositis and myonecrosis. However, many patients will not have an elevation in CK. Thus, routine monitoring of CK is usually not recommended; however, it is useful to get a baseline CK level before initiation of treatment.[39][40][41]

Management of Muscle Injury

Strategies include assessing drug interaction, vitamin D deficiency, and hypothyroidism, switching between statins, or a trial of an alternate-day regimen.[42] Coenzyme Q10 appears to benefit patients with muscle events, but there is minimal published evidence showing the benefit of CoQ10.[43] Further, large-scale studies are necessary to assess the beneficial effects of CoQ10.

Ezetimibe can cause fatigue, diarrhea, headache, runny nose, body aches, back pain, chest pain, diarrhea, joint pain, sore throat, and elevation of serum transaminases.

Fibrate commonly causes dyspepsia and has also been shown to produce fatigue, vertigo, pancytopenia, and elevation of serum transaminases.

Nicotinic acid is often poorly tolerated, with flushing occurring in 80 percent of patients, along with pruritus, paresthesia, and nausea in about 20 percent of patients.[44] These symptoms can last from 10 to 20 minutes, and pretreatment with aspirin or ibuprofen 60 minutes prior can minimize flushing and other prostaglandin-mediated side effects. Other concerns are hyperglycemia with an increased risk of diabetes mellitus, hyperuricemia, liver dysfunction, hypotension in patients taking vasodilators, increased chances of infection, and bleeding as they decrease platelet function and increase prothrombin time. Nicotinic acid has also been shown to increase the levels of homocysteine levels.[45][46][45][47]

Bile Acid sequestrants cause gastrointestinal side effects, including nausea, bloating, cramping, and an increase in liver enzymes. Dyspepsia and bloating can be decreased if cholestyramine is completely suspended in liquid several hours before ingestion.

PCSK9 inhibitors can cause Local injection site reactions such as erythema, pain, and bruising. Neither muscle toxicity nor creatine kinase elevations have appeared in patients after administering PCSK9 antibodies.[48][49][50]

Contraindications

Hypersensitivity reaction, such as anaphylaxis and angioedema, is an absolute contraindication, universal to all lipid-lowering drugs.

Contraindications to statins include use by patients with active hepatic disease or unexplained persistent elevations in aminotransferase levels. Statins are contraindicated in pregnancy and breastfeeding as cholesterol is essential for fetal and infant synthesis of steroids and cell membrane development, although some recent studies question this.[51] Statins demonstrate an increased risk of developing diabetes mellitus; thus, caution is necessary for patients with already increased blood glucose levels or increased Hba1c levels. Drugs that inhibit cytochrome P450 3A4(CYP3A4) can increase the risk of statin-induced myopathy. These include cyclosporine, macrolide antibiotics, system-azole antifungals, HIV/HCV protease inhibitors, gemfibrozil, diltiazem, verapamil, amiodarone, colchicine, and also grapefruit juice.[52][53]

Ezetimibe is contraindicated in patients using an HMG-CoA reductase inhibitor (statin) in patients with active liver disease or otherwise unexplained elevated serum transaminase values. Ezetimibe alone is not contraindicated in patients with mild to moderate hepatic impairment. Contraindications to ezetimibe include patients who are pregnant and breastfeeding when used in patients already on statins.

Fibrates are contraindicated in those patients with active liver disease, including primary biliary cirrhosis and unexplained, persistent liver function abnormality; severe renal impairment, and/or end-stage renal disease (ESRD), including patients receiving dialysis; preexisting gallbladder disease; and breastfeeding.

Nicotinic acid is contraindicated in active hepatic disease or significant persistent elevations of hepatic transaminases. These effects will be amplified when used with statins, fibrates, etc. They are also contraindicated in patients with active peptic ulcers and arterial hemorrhage.

Bile acid sequestrants are contraindicated in cases of severe hypertriglyceridemia and complete biliary obstruction. Bile acid sequestrants do not get absorbed into the bloodstream, making them safe for use by patients who are unable to use other lipid-lowering medications because of liver problems.

PCSK9 inhibitors do not cause muscle toxicity or an elevation in hepatic enzymes.

Monitoring

Practitioners should check the patient's lipid profile within 4 to 8 weeks of starting treatment with follow-up checks every 6 to 12 months to monitor the effectiveness of therapy.

In 2006, The National Lipid Association's Statin Task Force stated that routine monitoring of liver enzymes in asymptomatic patients is not recommended as the risk of severe liver injury is uncommon.[54] This ruling was revised in 2012 by the US Food and Drug Administration (FDA) with new labeling rules for statins, recommending instead performing liver enzyme tests before initiating statin therapy and as clinically indicated thereafter.[55] The 2014 task force on statin therapy concluded that "the decision on statin intolerance is the patient's decision, based on subjective feelings, preferences, and judgment," but best when guided "by evaluation and effective communication from the clinician."

Moderate-intensity therapy is expected to result in an LDL reduction of 30% to 50% from baseline, while a high-intensity regimen can result in a reduction of more than 50% from baseline.

When combining ezetimibe with statins or fenofibrate, monitor LFTs and signs of cholelithiasis. The recommendation is to discontinue the use of ezetimibe if ALT elevations are greater than three times the upper limit of normal persist.[56]

Fibrate use requires monitoring with liver function tests, renal function tests, and CBC due to the risk for pancytopenia.

Nicotinic acid needs monitoring of blood sugar, coagulation profile, and liver function.

Toxicity

Rhabdomyolysis is a severe and potentially fatal complication with statins. The general treatment is supportive and comprises immediate discontinuation of the offending drug. Other supportive measures include correcting any electrolyte disturbances, especially hyperkalemia, which can cause life-threatening arrhythmias.

When used with a statin, ezetimibe can increase the risk of muscle toxicity, especially in advanced age over 65 years old, renal impairment, or hypothyroidism. Patients taking ezetimibe with cyclosporine are at an increased risk of ezetimibe toxicity as it can result in a 2.3- to 12-fold increase in ezetimibe concentration.[57]

Bile acid sequestrants can inhibit the absorption of fat-soluble vitamins such as vitamin K, which can cause derangements in clotting factors. They can also interfere with the absorption of medications such as statins, ezetimibe, warfarin, NSAIDs, and propranolol; thus, the advice is to administer these medications 1 hour before or 4 hours after taking cholestyramine.[58]

Enhancing Healthcare Team Outcomes

The success of lipid-lowering medications to prevent cardiovascular events depends on the patient's medication adherence. It is common for patients to stop taking statins when they start to experience muscle aches. It is critical to reiterate the need for patients to continue statins in these situations. Alternatives such as switching to a different statin, adding coenzyme Q10, or an alternate day dosing is an option, which has demonstrated to help to a certain extent.

Lipid-lowering therapy is best delivered by an interprofessional team consisting of physicians (both primary care and cardiologist), pharmacist, and cardiovascular specialty trained nursing staff to guide and monitor the therapeutic course and ensure the best possible patient outcomes. [Level V]

In patients with severe HTG, particularly triglyceride levels greater than 1000 mg/dL, fibrate therapy and/or niacin and fish oil can be useful to lower triglycerides to under 500 mg/dL and to help reduce the risk of pancreatitis. Intravenous insulin can help to prevent pancreatitis in the hospital.[59]

FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study showed no mortality benefit but lowered the risk of myocardial infarction or stroke.[60] The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with alirocumab) was able to show a 2% absolute risk reduction in major adverse cardiovascular events with alirocumab therapy.[48]

IMPROVE-IT found in a follow-up of 6 years that patients with an acute coronary syndrome randomized to ezetimibe/simvastatin had a lower rate of cardiovascular events than those randomized to simvastatin alone.[61] Some studies have also found that adding ezetimibe to atorvastatin 80 mg can further lower the LDC by 9 percent compared to statin alone.[62]

A recent 2018 Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) trial used 2 g of icosapent ethyl twice daily (4 g daily). The patients in the study had established atherosclerotic heart disease or other risk factors such as diabetes and were already on pre-existing statin therapy with residual hypertriglyceridemia (triglyceride level 135 to 499 mg/dL). The intervention group was associated with an absolute 4.8% reduction in cardiovascular events and a 0.9% absolute reduction in cardiovascular death at 4.9 years.[63]

Fish oil (omega-3 fatty acids) is a common supplement used to prevent cardiovascular events, but a recent large randomized controlled study showed no benefit of omega-3 fatty acids in the incidence of major cardiovascular events.[64]

Details

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