Tools
Lipid-Lowering Drug Therapy
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
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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]
References
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18:139(25):e1082-e1143. doi: 10.1161/CIR.0000000000000625. Epub 2018 Nov 10 [PubMed PMID: 30586774]
Level 1 (high-level) evidenceSizar O, Nassereddin A, Talati R. Ezetimibe. StatPearls. 2023 Jan:(): [PubMed PMID: 30422474]
Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. The New England journal of medicine. 1999 Aug 5:341(6):410-8 [PubMed PMID: 10438259]
Level 1 (high-level) evidenceWang D, Liu B, Tao W, Hao Z, Liu M. Fibrates for secondary prevention of cardiovascular disease and stroke. The Cochrane database of systematic reviews. 2015 Oct 25:2015(10):CD009580. doi: 10.1002/14651858.CD009580.pub2. Epub 2015 Oct 25 [PubMed PMID: 26497361]
Level 1 (high-level) evidenceProbstfield JL, Hunninghake DB. Nicotinic acid as a lipoprotein-altering agent. Therapy directed by the primary physician. Archives of internal medicine. 1994 Jul 25:154(14):1557-9 [PubMed PMID: 8031204]
Grundy SM, Mok HY, Zech L, Berman M. Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man. Journal of lipid research. 1981 Jan:22(1):24-36 [PubMed PMID: 7217784]
Handelsman Y. Role of bile acid sequestrants in the treatment of type 2 diabetes. Diabetes care. 2011 May:34 Suppl 2(Suppl 2):S244-50. doi: 10.2337/dc11-s237. Epub [PubMed PMID: 21525463]
Yang Y, Hwang S, Kim M, Lim Y, Kim MH, Lee S, Lim DJ, Kang MI, Cha BY. Refractory Graves' Disease Successfully Cured by Adjunctive Cholestyramine and Subsequent Total Thyroidectomy. Endocrinology and metabolism (Seoul, Korea). 2015 Dec:30(4):620-5. doi: 10.3803/EnM.2015.30.4.620. Epub 2015 Sep 22 [PubMed PMID: 26394731]
Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. The New England journal of medicine. 1990 Nov 8:323(19):1289-98 [PubMed PMID: 2215615]
Level 1 (high-level) evidenceKnapp HH, Schrott H, Ma P, Knopp R, Chin B, Gaziano JM, Donovan JM, Burke SK, Davidson MH. Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia. The American journal of medicine. 2001 Apr 1:110(5):352-60 [PubMed PMID: 11286949]
Level 1 (high-level) evidence. Comparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemia. Pravastatin Multicenter Study Group II. Archives of internal medicine. 1993 Jun 14:153(11):1321-9 [PubMed PMID: 8507122]
Level 1 (high-level) evidenceIstvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science (New York, N.Y.). 2001 May 11:292(5519):1160-4 [PubMed PMID: 11349148]
Ness GC, Zhao Z, Lopez D. Inhibitors of cholesterol biosynthesis increase hepatic low-density lipoprotein receptor protein degradation. Archives of biochemistry and biophysics. 1996 Jan 15:325(2):242-8 [PubMed PMID: 8561503]
Level 3 (low-level) evidenceConde K,Vergara-Jimenez M,Krause BR,Newton RS,Fernandez ML, Hypocholesterolemic actions of atorvastatin are associated with alterations on hepatic cholesterol metabolism and lipoprotein composition in the guinea pig. Journal of lipid research. 1996 Nov; [PubMed PMID: 8978489]
Level 3 (low-level) evidenceLarsen ML, Illingworth DR. Drug treatment of dyslipoproteinemia. The Medical clinics of North America. 1994 Jan:78(1):225-45 [PubMed PMID: 8283933]
Levy RI, Troendle AJ, Fattu JM. A quarter century of drug treatment of dyslipoproteinemia, with a focus on the new HMG-CoA reductase inhibitor fluvastatin. Circulation. 1993 Apr:87(4 Suppl):III45-53 [PubMed PMID: 8462180]
Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW, STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). The American journal of cardiology. 2003 Jul 15:92(2):152-60 [PubMed PMID: 12860216]
Level 1 (high-level) evidenceBakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn JL, Weiss SR, Keilson LM, Brown WV, Miller VT, Shurzinske LJ, Black DM. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA. 1996 Jan 10:275(2):128-33 [PubMed PMID: 8531308]
Level 1 (high-level) evidenceAltmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science (New York, N.Y.). 2004 Feb 20:303(5661):1201-4 [PubMed PMID: 14976318]
Level 3 (low-level) evidenceTemel RE, Tang W, Ma Y, Rudel LL, Willingham MC, Ioannou YA, Davies JP, Nilsson LM, Yu L. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe. The Journal of clinical investigation. 2007 Jul:117(7):1968-78 [PubMed PMID: 17571164]
Level 3 (low-level) evidenceShepherd J, Packard CJ, Morgan HG, Third JL, Stewart JM, Lawrie TD. The effects of cholestyramine on high density lipoprotein metabolism. Atherosclerosis. 1979 Aug:33(4):433-44 [PubMed PMID: 228682]
Davidson MH, Dillon MA, Gordon B, Jones P, Samuels J, Weiss S, Isaacsohn J, Toth P, Burke SK. Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Archives of internal medicine. 1999 Sep 13:159(16):1893-900 [PubMed PMID: 10493319]
Level 1 (high-level) evidenceMullard A. Cholesterol-lowering blockbuster candidates speed into Phase III trials. Nature reviews. Drug discovery. 2012 Nov:11(11):817-9. doi: 10.1038/nrd3879. Epub [PubMed PMID: 23123928]
Miettinen TA. Diurnal variation of cholesterol precursors squalene and methyl sterols in human plasma lipoproteins. Journal of lipid research. 1982 Mar:23(3):466-73 [PubMed PMID: 7200504]
Backes JM, Venero CV, Gibson CA, Ruisinger JF, Howard PA, Thompson PD, Moriarty PM. Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance. The Annals of pharmacotherapy. 2008 Mar:42(3):341-6. doi: 10.1345/aph.1K604. Epub 2008 Feb 19 [PubMed PMID: 18285559]
Level 2 (mid-level) evidenceKayikçioğlu M, Ozerkan F, Soydan I. Effectiveness and safety of alternate-day simvastatin and fenofibrate on mixed hyperlipidemia. The American journal of cardiology. 1999 Apr 1:83(7):1135-7, A9 [PubMed PMID: 10190536]
Level 1 (high-level) evidenceRuisinger JF, Backes JM, Gibson CA, Moriarty PM. Once-a-week rosuvastatin (2.5 to 20 mg) in patients with a previous statin intolerance. The American journal of cardiology. 2009 Feb 1:103(3):393-4. doi: 10.1016/j.amjcard.2008.09.095. Epub 2008 Nov 19 [PubMed PMID: 19166695]
Rosenson RS,Baker SK,Jacobson TA,Kopecky SL,Parker BA,The National Lipid Association's Muscle Safety Expert Panel, An assessment by the Statin Muscle Safety Task Force: 2014 update. Journal of clinical lipidology. 2014 May-Jun; [PubMed PMID: 24793443]
Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgözoğlu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, März W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN, European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. European heart journal. 2015 May 1:36(17):1012-22. doi: 10.1093/eurheartj/ehv043. Epub 2015 Feb 18 [PubMed PMID: 25694464]
Level 3 (low-level) evidenceRosenson RS. Current overview of statin-induced myopathy. The American journal of medicine. 2004 Mar 15:116(6):408-16 [PubMed PMID: 15006590]
Level 3 (low-level) evidenceGanga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. American heart journal. 2014 Jul:168(1):6-15. doi: 10.1016/j.ahj.2014.03.019. Epub 2014 Apr 12 [PubMed PMID: 24952854]
Level 1 (high-level) evidenceJoy TR, Hegele RA. Narrative review: statin-related myopathy. Annals of internal medicine. 2009 Jun 16:150(12):858-68 [PubMed PMID: 19528564]
Level 3 (low-level) evidenceParker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S, Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal muscle function. Circulation. 2013 Jan 1:127(1):96-103. doi: 10.1161/CIRCULATIONAHA.112.136101. Epub 2012 Nov 26 [PubMed PMID: 23183941]
Level 1 (high-level) evidenceTobert JA. Efficacy and long-term adverse effect pattern of lovastatin. The American journal of cardiology. 1988 Nov 11:62(15):28J-34J [PubMed PMID: 3055921]
Pedersen TR, Berg K, Cook TJ, Faergeman O, Haghfelt T, Kjekshus J, Miettinen T, Musliner TA, Olsson AG, Pyörälä K, Thorgeirsson G, Tobert JA, Wedel H, Wilhelmsen L. Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study. Archives of internal medicine. 1996 Oct 14:156(18):2085-92 [PubMed PMID: 8862101]
Level 1 (high-level) evidenceGadbut AP, Caruso AP, Galper JB. Differential sensitivity of C2-C12 striated muscle cells to lovastatin and pravastatin. Journal of molecular and cellular cardiology. 1995 Oct:27(10):2397-402 [PubMed PMID: 8576954]
Level 3 (low-level) evidenceZinman L, Sadeghi R, Gawel M, Patton D, Kiss A. Are statin medications safe in patients with ALS? Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. 2008 Aug:9(4):223-8. doi: 10.1080/17482960802031092. Epub [PubMed PMID: 18608105]
Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, Vladutiu GD, England JD, Scripps Mercy Clinical Research Center. Statin-associated myopathy with normal creatine kinase levels. Annals of internal medicine. 2002 Oct 1:137(7):581-5 [PubMed PMID: 12353945]
Level 3 (low-level) evidenceSmith CC, Bernstein LI, Davis RB, Rind DM, Shmerling RH. Screening for statin-related toxicity: the yield of transaminase and creatine kinase measurements in a primary care setting. Archives of internal medicine. 2003 Mar 24:163(6):688-92 [PubMed PMID: 12639201]
Level 2 (mid-level) evidenceWeismantel D, Danis P. Clinical inquiries. What laboratory monitoring is appropriate to detect adverse drug reactions in patients on cholesterol-lowering agents? The Journal of family practice. 2001 Nov:50(11):927-8 [PubMed PMID: 11711005]
Gotto AM Jr. Safety and statin therapy: reconsidering the risks and benefits. Archives of internal medicine. 2003 Mar 24:163(6):657-9 [PubMed PMID: 12639194]
Level 2 (mid-level) evidenceRosenson RS, Miller K, Bayliss M, Sanchez RJ, Baccara-Dinet MT, Chibedi-De-Roche D, Taylor B, Khan I, Manvelian G, White M, Jacobson TA. The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI): Revision for Clinical Use, Content Validation, and Inter-rater Reliability. Cardiovascular drugs and therapy. 2017 Apr:31(2):179-186. doi: 10.1007/s10557-017-6723-4. Epub [PubMed PMID: 28421332]
Level 1 (high-level) evidenceBanach M, Serban C, Sahebkar A, Ursoniu S, Rysz J, Muntner P, Toth PP, Jones SR, Rizzo M, Glasser SP, Lip GY, Dragan S, Mikhailidis DP, Lipid and Blood Pressure Meta-analysis Collaboration Group. Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clinic proceedings. 2015 Jan:90(1):24-34. doi: 10.1016/j.mayocp.2014.08.021. Epub 2014 Nov 14 [PubMed PMID: 25440725]
Level 1 (high-level) evidenceIllingworth DR, Stein EA, Mitchel YB, Dujovne CA, Frost PH, Knopp RH, Tun P, Zupkis RV, Greguski RA. Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial. Archives of internal medicine. 1994 Jul 25:154(14):1586-95 [PubMed PMID: 8031206]
Level 1 (high-level) evidenceGrundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse JB, Robertson DD, Sheehan JP, Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Archives of internal medicine. 2002 Jul 22:162(14):1568-76 [PubMed PMID: 12123399]
Level 1 (high-level) evidencePasternak RC, Kolman BS. Unstable myocardial ischemia after the initiation of niacin therapy. The American journal of cardiology. 1991 Apr 15:67(9):904-6 [PubMed PMID: 2011995]
Level 3 (low-level) evidenceGarg R, Malinow M, Pettinger M, Upson B, Hunninghake D. Niacin treatment increases plasma homocyst(e)ine levels. American heart journal. 1999 Dec:138(6 Pt 1):1082-7 [PubMed PMID: 10577438]
Level 1 (high-level) evidenceRobinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ, ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. The New England journal of medicine. 2015 Apr 16:372(16):1489-99. doi: 10.1056/NEJMoa1501031. Epub 2015 Mar 15 [PubMed PMID: 25773378]
Level 1 (high-level) evidenceSabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA, Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. The New England journal of medicine. 2015 Apr 16:372(16):1500-9. doi: 10.1056/NEJMoa1500858. Epub 2015 Mar 15 [PubMed PMID: 25773607]
Level 1 (high-level) evidenceZhang XL, Zhu QQ, Zhu L, Chen JZ, Chen QH, Li GN, Xie J, Kang LN, Xu B. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC medicine. 2015 Jun 23:13():123. doi: 10.1186/s12916-015-0358-8. Epub 2015 Jun 23 [PubMed PMID: 26099511]
Level 1 (high-level) evidenceVahedian-Azimi A, Makvandi S, Banach M, Reiner Ž, Sahebkar A. Fetal toxicity associated with statins: A systematic review and meta-analysis. Atherosclerosis. 2021 Jun:327():59-67. doi: 10.1016/j.atherosclerosis.2021.05.006. Epub 2021 May 16 [PubMed PMID: 34044205]
Level 1 (high-level) evidenceLees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. The New England journal of medicine. 1995 Sep 7:333(10):664-5 [PubMed PMID: 7637734]
Level 3 (low-level) evidenceFichtenbaum CJ, Gerber JG, Rosenkranz SL, Segal Y, Aberg JA, Blaschke T, Alston B, Fang F, Kosel B, Aweeka F, NIAID AIDS Clinical Trials Group. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS (London, England). 2002 Mar 8:16(4):569-77 [PubMed PMID: 11873000]
Level 1 (high-level) evidenceMcKenney JM, Davidson MH, Jacobson TA, Guyton JR, National Lipid Association Statin Safety Assessment Task Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. The American journal of cardiology. 2006 Apr 17:97(8A):89C-94C [PubMed PMID: 16581336]
Jacobson TA. NLA Task Force on Statin Safety--2014 update. Journal of clinical lipidology. 2014 May-Jun:8(3 Suppl):S1-4. doi: 10.1016/j.jacl.2014.03.003. Epub [PubMed PMID: 24793438]
Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF, American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24:129(25 Suppl 2):S1-45. doi: 10.1161/01.cir.0000437738.63853.7a. Epub 2013 Nov 12 [PubMed PMID: 24222016]
Level 1 (high-level) evidencePatel J, Sheehan V, Gurk-Turner C. Ezetimibe (Zetia): a new type of lipid-lowering agent. Proceedings (Baylor University. Medical Center). 2003 Jul:16(3):354-8 [PubMed PMID: 16278712]
Jacobson TA, Armani A, McKenney JM, Guyton JR. Safety considerations with gastrointestinally active lipid-lowering drugs. The American journal of cardiology. 2007 Mar 19:99(6A):47C-55C [PubMed PMID: 17368279]
Jialal I, Amess W, Kaur M. Management of hypertriglyceridemia in the diabetic patient. Current diabetes reports. 2010 Aug:10(4):316-20. doi: 10.1007/s11892-010-0124-4. Epub [PubMed PMID: 20532703]
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England journal of medicine. 2017 May 4:376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17 [PubMed PMID: 28304224]
Level 2 (mid-level) evidenceCannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM, IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. The New England journal of medicine. 2015 Jun 18:372(25):2387-97. doi: 10.1056/NEJMoa1410489. Epub 2015 Jun 3 [PubMed PMID: 26039521]
Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, Sun S, LeBeaut AP, Sager PT, Veltri EP, Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003 May 20:107(19):2409-15 [PubMed PMID: 12719279]
Level 1 (high-level) evidenceBhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM, REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. The New England journal of medicine. 2019 Jan 3:380(1):11-22. doi: 10.1056/NEJMoa1812792. Epub 2018 Nov 10 [PubMed PMID: 30415628]
Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, D'Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE, VITAL Research Group. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. The New England journal of medicine. 2019 Jan 3:380(1):23-32. doi: 10.1056/NEJMoa1811403. Epub 2018 Nov 10 [PubMed PMID: 30415637]