Lipid Lowering Drug Therapy


Article Author:
Minar Chhetry


Article Editor:
Ishwarlal Jialal


Editors In Chief:
Michael Firstenberg
Lawrence Greiten


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
4/10/2019 9:12:54 PM

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 having a cardiovascular event (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 shown to improve patient outcomes in patients on statins.[5][6] Niacin is usually used to 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 also benefit patients with Type 2 DM by decreasing blood sugar levels.[7] Bile acid sequestrants can also lead to a rapid reduction in plasma thyroid hormones thus making it 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 has 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, which is a rate-limiting critical step in cholesterol biosynthesis.[12] This leads to an increase in low-density lipoprotein (LDL) clearance from the serum by 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 250mg/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 also 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 resulting in interruption of the reabsorption of bile acids. The ensuing reduction in the cholesterol pool lowers intrahepatic cholesterol, which promotes the upregulation of LDL receptors, causing a further reduction 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 it is recommended 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 100mg three times a day and gradually increased as tolerated to 2.0g/d.[5] LDL-C lowering occurs at doses greater than 1.5g/day.

Bile acid sequestrants are available as granules or tablets. Cholestyramine should ideally be taken with breakfast when it is 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 major limiting factors for PCSK9 inhibitors.

Adverse Effects

Statins are one of 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 placebo.[33] Clinically significant myonecrosis, defined as a serum CK elevation over 10 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]

It has been 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 has been shown 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 have also been shown to produce fatigue, vertigo, pancytopenia and elevation of serum transaminases.

Nicotinic acid is poorly tolerated with flushing occurring in 80 percent of patients, and also pruritus, paresthesia, 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[45], hyperuricemia, liver dysfunction, hypotension in patients taking vasodilators[46], 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.[47]

Bile Acid sequestrants cause gastrointestinal side effect 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 been found in patients after administering PCSK9 antibodies.[48][49][50]

Contraindications

Hypersensitivity reaction, such as anaphylaxis and angioedema, is an absolute contraindication, universal to all the 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 during breastfeeding as cholesterol is an essential component for fetal and infant synthesis of steroids and cell membrane development. Statins have an increased risk of developing diabetes mellitus thus caution should be exercised in 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, and HIV/HCV protease inhibitors, gemfibrozil, diltiazem, verapamil, amiodarone, colchicine, and also grapefruit juice.[51][52]

Ezetimibe is contraindicated in patients who are 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 ulcer 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 followup 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 a recommendation as the risk of severe liver injury is uncommon.[53]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.[54] The 2014 taskforce on statin therapy concluded that the ‘‘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. It is recommended to discontinue use of ezetimibe if ALT elevations are greater than three times the upper limit of normal persist.[55]

Fibrate use requires monitoring with liver function tests, renal function tests, and also CBC due to 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 correction of any electrolyte disturbances especially hyperkalemia which can cause life-threatening arrhythmias.  

Ezetimibe, when used with a statin, 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.[56]

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 absorption of medications such as statins, ezetimibe, warfarin, NSAIDs, and propranolol; thus; it is advised to administer these medications 1 hour before or 4 hours after taking cholestyramine.[57]

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 can be offered, which has been shown 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 be used to prevent pancreatitis in the hospital.[58]

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.[59]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.[60] Some studies have also found that adding ezetimibe to atorvastatin 80 mg can further lower the LDC by 9 percent as compared to statin alone.[61]

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 also 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.[62]

Fish oil (omega-3 fatty acids) is a common supplement used for prevention of cardiovascular events, but a recent large randomized controlled study showed no benefit of omega-3 fatty acids in the incidence of major cardiovascular events.[63]


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Lipid Lowering Drug Therapy - References

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