View the Comparison Table: Some Lipid-Lowering Drugs

The FDA has approved the oral adenosine triphosphate-citrate lyase (ACL) inhibitor bempedoic acid for use alone (Nexletol – Esperion) and in a fixed-dose combination with the cholesterol absorption inhibitor ezetimibe (Nexlizet) as an adjunct to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of LDL-cholesterol (LDL-C). Bempedoic acid is the first ACL inhibitor to be approved in the US.

View the Expanded Table: Statins

Cholesterol management guidelines from the American College of Cardiology/American Heart Association Task Force have recently been published. See Table 1 for a brief summary of their recommendations.

View the Expanded Table: Lipid-Lowering Drugs

The FDA has approved the HMG-CoA reductase inhibitor (statin) pitavastatin magnesium (Zypitamag – Zydus) for use in adults with primary hyperlipidemia or mixed dyslipidemia. The FDA considers pitavastatin magnesium bioequivalent to pitavastatin calcium (Livalo), which was approved in 2009.1

Statins remain the treatment of choice for most patients who require lipid-lowering therapy. Taken as an adjunct to diet modification, increased exercise, and smoking cessation, statins can reduce the risk of primary and secondary cardiovascular events and death in patients with or at high risk for atherosclerotic cardiovascular disease.2 Even in patients at low risk for cardiovascular disease, treatment with a statin can significantly reduce the incidence of cardiovascular events.3

Controlled trials in patients with cardiovascular disease have shown that high-intensity statin therapy (defined as reducing LDL-cholesterol [LDL-C] by ≥50% on average) reduces the incidence of cardiac events, stroke, and coronary death significantly more than less intensive regimens. In one meta-analysis, each additional 1 mmol/L (39 mg/dL) reduction in LDL-C was associated with a 20% reduction in major vascular events and a 10% reduction in all-cause mortality.4 In a randomized trial in 13,054 Japanese patients with stable coronary artery disease, over a median follow-up of 3.9 years, patients taking pitavastatin calcium 4 mg daily were significantly less likely than those taking 1 mg daily to have a cardiovascular event (4.3% vs 5.4%).5

Approval of pitavastatin magnesium was based on the results of trials with pitavastatin calcium; no new efficacy trials were required. The Medical Letter's review of pitavastatin calcium concluded that recommended doses of the drug had not been shown to decrease LDL-C more than other statins with longer safety records and there was no good reason to use it. That conclusion applies to pitavastatin magnesium as well.

1. Pitavastatin (Livalo) – the seventh statin. Med Lett Drugs Ther 2010; 52:57.
2. Lipid-lowering drugs. Med Lett Drugs Ther 2016; 58:133.
3. CTT Collaboration et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380:581.
4. CTT Collaboration et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376:1670.
5. I Taguchi et al. High-dose versus low-dose pitavastatin in Japanese patients with stable coronary artery disease (REAL-CAD): a randomized superiority trial. Circulation 2018; 137:1997.

Download complete U.S. English article

The results of a recently published study suggest that taking the oral direct thrombin inhibitor dabigatran etexilate (Pradaxa) with either simvastatin (Zocor, and others) or lovastatin (Altoprev, and others) increases the risk of major hemorrhage.

Lipid-lowering drugs should be taken indefinitely; when they are stopped, plasma lipoproteins return to pretreatment levels. HMG-CoA reductase inhibitors (statins) remain the drugs of choice for treatment of most patients who require lipid-lowering therapy.

The FDA has approved the subcutaneously injected PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor alirocumab (Praluent – Sanofi/Regeneron) as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-cholesterol (LDL-C). It was not approved for general use in statin-intolerant patients. Alirocumab is the first PCSK9 inhibitor to be approved in the US. Evolocumab (Repatha – Amgen), another PCSK9 inhibitor, was recently approved in Europe and has been recommended for approval for the same indications in the US by an FDA Advisory Committee.

The FDA has approved Viekira Pak (Abbvie), a fixed-dose combination of two new direct-acting antiviral agents (ombitasvir, paritaprevir) with the pharmacologic enhancer ritonavir in one tablet, co-packaged with a third new direct-acting antiviral agent (dasabuvir) in a second tablet, for oral treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Genotype 1 is responsible for 70-80% of HCV infections in the US.

The treatment of atrial fibrillation includes anticoagulation, rate control, and rhythm control. New US guidelines for the management of atrial fibrillation have recently been published.

HMG-CoA reductase inhibitors (statins) inhibit the enzyme that catalyzes the rate-limiting step in cholesterol synthesis. The subsequent reduction in hepatic cholesterol leads to increased expression of LDL receptors, which in turn increases uptake and clearance of LDL-C from the blood. Statins also lower very low-density lipoprotein cholesterol (VLDL-C) and triglycerides. Most statins increase high-density lipoprotein cholesterol (HDL-C), but only modestly.

Citing some recent reports, the FDA has announced changes in the safety labeling of all HMG-CoA reductase inhibitors (statins).

The FDA has announced changes in the labeling of simvastatin to reduce the risk of myopathy. These changes include limiting the use of the 80-mg maximum dose to patients who have been taking it for 12 months or more without evidence of myopathy and new recommendations for use of simvastatin with other drugs. Simvastatin is available alone (Zocor, and others) and in combination with ezetimibe (Vytorin) and with niacin (Simcor).

Drugs that lower low-density lipoprotein cholesterol (LDL-C) concentrations can prevent formation, slow progression and cause regression of atherosclerotic lesions. Lipid-regulating drugs must be taken indefinitely; when they are stopped, plasma lipoproteins return to pretreatment levels in 2-3 weeks.

The treatment of atrial fibrillation includes ventricular rate control, anticoagulation, conversion to normal sinus rhythm and maintenance of sinus rhythm. The choice of therapies that can achieve these goals is discussed in the text that follows. Some drugs are recommended here for indications that have not been approved by the FDA.

The FDA has approved the marketing of pitavastatin (Livalo – Kowa), an HMG-CoA reductase inhibitor (“statin”), for treatment of primary hyperlipidemia or mixed dyslipidemia. It has been available in Japan since 2003. All of the statins now available in the US are listed in the table on page 58.

Red yeast rice is a food product that has been used in Chinese cooking and medicine for centuries. It is available in the US in a capsule formulation and is often used by patients who want a "natural" product to lower cholesterol.

The National Cholesterol Education Program recommends that LDL-C be lowered to less than 100 mg/dL (2.6 mmol/L) and considers a value <70 mg/dL (1.8 mmol/L) a reasonable goal for patients at very high risk.

A recent letter to the editor of the Annals of Internal Medicine documented a single case of myopathy apparently due to an interaction between simvastatin (Zocor, and others) and green tea. Since it became available generically, simvastatin has surpassed atorvastatin (Lipitor) as the best selling statin. As such, it is probably the most common cause of statin-induced myopathy, which is often a result of drug interactions.

Advertisements for atorvastatin (Lipitor), the market leader facing generic competition, have been in the news recently in the US. Lovastatin, pravastatin and simvastatin are all available generically at a much lower retail price or lower co-pay than atorvastatin.

The FDA has approved the marketing of a second fixed-dose combination of extended-release niacin (Niaspan) with a generic statin. Niaspan/simvastatin (Simcor - Abbott) is approved for use in patients with hypercholesterolemia or mixed dyslipidemia (high LDL-cholesterol, low HDL-cholesterol and high serum triglycerides). Niaspan/lovastatin (Advicor) was marketed previously for the same indications.

The FDA recently advised health care professionals and consumers not to use a number of dietary supplements found to contain the phosphodiesterase-5 inhibitor sildenafil (Viagra) or an analog of the drug (www.fda.gov). Although the effects of sildenafil may be noticeable (in men), the presence of other, possibly more toxic adulterants in dietary supplements may be more difficult or impossible to detect.

Other drugs previously found in dietary supplements have included lovastatin (Mevacor, and others), estrogen, alprazolam (Xanax, and others), indomethacin (Indocin, and others) and warfarin (Coumadin, and others). Aristolochic acid in Chinese herbal weight loss products caused acute renal failure in about 100 women in Belgium; at least 70 of them required dialysis or transplantation, and at least 18 developed urothelial cancer (Med Lett Drugs Ther 2002; 44:84).

Dietary supplements do not require FDA approval before marketing. The agency does have the power to remove mislabeled or adulterated products from store shelves, but the burden of discovery and proof is entirely on the government.

Download U.S. English

Drugs that lower low-density lipoprotein cholesterol (LDL-C) concentrations can prevent formation, slow progression and cause regression of atherosclerotic lesions. They should not be used as a substitute for lifestyle changes; a combination of diet, exercise and lipid-lowering drugs is optimal for prevention of coronary disease. Lipid-regulating drugs must be taken indefinitely; when they are stopped, plasma lipoprotein levels return to pretreatment levels in 2-3 weeks.

The drugs of choice for treatment of some fungal infections are listed in the tables. Some of the indications and dosages recommended here have not been approved by the FDA. Other guidelines are available from the Infectious Diseases Society of America (www.idsociety.org).

The FDA recently approved the use of atorvastatin (Lipitor) to reduce the risk of heart attack and stroke in patients without heart disease who have type 2 diabetes plus other risk factors, with or without hypercholesterolemia. The agency also approved the drug's use to reduce the risk of stroke in high-risk nondiabetic patients without heart disease, whether or not they have hypercholesterolemia. Similar indications were previously approved for simvastatin (Zocor).

A highly concentrated omega-3 polyunsaturated fatty acid (PUFA) preparation (Omacor - Reliant) has been approved by the FDA as an adjunct to diet for treatment of very high plasma triglyceride concentrations (>=500 mg/dL). Omacor is a combination of the ethyl esters of icosapentaenoic (EPA) and docosahexaenoic (DHA) acids. It is the first drug derived from omega-3 PUFAs to be sold by prescription.

Tipranavir (Aptivus - Boehringer Ingelheim), a new protease inhibitor, has received accelerated approval from the FDA. It must be given with ritonavir (Norvir). The combination is indicated for use with other antiretrovirals to treat HIV infection in highly treatment-experienced adults who have ongoing viral replication or in those with HIV strains known to be resistant to multiple protease inhibitors.

Serious adverse interactions between drugs continue to be reported. Many of these are due to inhibition or induction of cytochrome P450 (CYP) enzymes, particularly CYP3A4. CYP3A is thought to be involved in the metabolism of more than 50 percent of currently prescribed drugs.2 CYP3A4, which is more abundantly expressed than CYP3A5, accounts for most CYP3A activity in vivo.

Drugs that lower low-density lipoprotein cholesterol (LDL-C) concentrations can prevent formation, slow progression and cause regression of atherosclerotic lesions. In controlled trials in patients with coronary disease, some of these drugs have reduced mortality by 20% to 30%.

The drugs of choice for treatment of some fungal infections are listed in the table that begins on page 8. Some of the indications and dosages recommended here have not been approved by the FDA.

New guidelines from The National Cholesterol Education Program recommend, as a therapeutic option, lowering treatment goals for LDL cholesterol (LDL-C) from <100 mg/dL to <70 mg/dL for patients at very high risk for coronary heart disease and from 130 mg/dL to <100 mg/dL for those at moderately high risk. A likely consequence of these recommendations is increased use of statins and use of higher doses with a concomitant increase in adverse effects.

Telithromycin (Ketek - Aventis) has been approved by the FDA for oral treatment of mild to moderate community-acquired pneumonia, acute exacerbations of chronic bronchitis and acute bacterial sinusitis in patients age 18 and older. The drug is the first in a new class of antibiotics, the ketolides, derived from the macrolide erythromycin. Telithromycin has been marketed in Europe since 2001.

The recent "PROVE IT" trial in patients with coronary heart disease showed clinical benefits associated with reducing LDL cholesterol concentrations lower than the 100 mg/dL (2.59 mmol/L) or less that had been considered optimal.

The ability of grapefruit juice to increase serum concentrations of drugs was first discovered during a study of the effect of ethanol on felodipine (Plendil) pharmacokinetics. Double-strength grapefruit juice used to disguise the taste of ethanol resulted in higher than expected serum concentrations of felodipine (DG Bailey et al, Clin Invest Med 1989; 12:357).

Rosuvastatin (Crestor - AstraZeneca), an HMG-CoA reductase inhibitor (or "statin"), was recently approved by the FDA for lowering serum cholesterol and triglyceride concentrations and raising HDL cholesterol levels. Rosuvastatin, like other statins, inhibits the enzyme that catalyzes the rate-limiting step in cholesterol synthesis, but it is claimed to be more potent than the others. All of these drugs must be taken indefinitely; if they are discontinued, lipid levels return to baseline.

Drugs that lower low-density lipoprotein (LDL) cholesterol concentrations can prevent formation, slow progression and cause regression of atherosclerotic lesions, and also improve vasodilatation. In controlled trials in patients with coronary disease, they have reduced mortality by 30% to 40%. Lipid-regulating drugs must be taken indefinitely; when they are stopped, plasma lipid levels return to pretreatment levels in 2-3 weeks.

Changes caused by one drug in the absorption, distribution, metabolism or excretion of another may lead to a pharmacokinetic adverse drug interaction (DN Juurlink et al, JAMA 2003; 289:1652). Additive drug interactions, such as vasodilation caused by both sildenafil (Viagra) and nitrates, can also have adverse effects.

The FDA recently approved three new drugs for treatment of hyperlipidemia. Ezetimibe (ez et' i mibe; Zetia) is the first in a new class of drugs that inhibit intestinal absorption of cholesterol. Extended-release lovastatin (Altocor) is a new formulation of lovastatin (Mevacor, and others). Extended-release niacin plus (immediate-release) lovastatin (Advicor) is the first fixed-dose combination of lipid-lowering drugs.

Because of a last minute change in an FDA ruling, generic lovastatin will not be available until after December 15, contrary to the statement in the September 17 Medical Letter article on Substituing for Cerivastatin (vol. 23, page 79)

Full-page newspaper advertisements are urging patients with high cholesterol levels who are stopping Baycol (cerivastatin) to ask their doctors about Pravachol (pravastatin), Lipitor (atorvastatin), Zocor (simvastatin) or Lescol (fluvastatin). Some advertisements come with a coupon for free medication. Lovastatin, which is available generically, has not appeared in similar advertisements. Cerivastatin was withdrawn from the market on August 8 because of post-marketing reports of 31 cases of fatal rhabdomyolysis.

New recommendations for drug treatment of hypercholesterolemia, if widely followed, will lead to a marked increase in the number of people taking lipid-regulating drugs.

Colesevelam hydrochloride (Welchol - Sankyo Pharma), a nonabsorbed hydrophilic polymer that binds bile acids, has been approved by the FDA for reduction of plasma LDL cholesterol in patients with primary hypercholesterolemia.

Reports of adverse interactions between drugs continue to accumulate. Recently, the FDA has expanded the recommendations on drug interactions found in the package inserts of new drugs.

Drugs that lower-density-lipoprotein (LDL) cholesterol concentrations can prevent formation, slow progression and cause regression of atherosclerotic lesions, improve coronary vasodilatation, and decrease mortality from coronary heart disease. All of these drugs must be continued indefinitely; when they are stopped, plasma cholesterol concentrations generally return to pretreatment levels. Elevated serum triglyceride concentrations appear to be an independent risk factor for cardiovascular disease in both women and men, but direct evidence of clinical benefit from triglyceride reduction is lacking.

Cerivastatin (Baycol - Bayer), a new HMG-CoA reductase inhibitor (or "statin"), has been approved by the FDA for treatment of hypercholesterolemia. Cerivastatin is the sodium salt of a synthetic fluorophenyl pyridinyl-substituted heptanoic acid.

The drugs of choice for treatment of deep fungal infections are listed in the table below. Some of the indications and dosages recommended here have not been approved by the FDA.

Atorvastatin (Lipitor - Parke-Davis), an HMG-CoA reductase inhibitor (or 'statin'), was recently approved by the US Food and Drug Administration for treatment of primary hypercholesterolemia and mixed dyslipidemia. A single stereoisomer of a pyrrole derivative, the new drug is chemically different from other statins.

Drugs that lower elevated plasma cholesterol concentrations can prevent formation, slow progression and cause regression of atherosclerotic lesions, and may also improve coronary vasodilatation (JW Jukema et al, circulation, 91:2528, 1995: CB Treasure er al, N Engl J Med, 332:481, 1995; TJ Anderson et al, N Engl J Med, 332:488, 1995). All these drugs must be continued indefinitely; when htey are stopped, plasma cholesterol concentrations generally return to pretreatment levels.

The drugs of choice for treatment of deep fungal infections are listed in the table on page 101. Some of the indications and dosages recommended here have not been approved by the US Food and Drug Administration. More detailed guidelines are available from the Infectious Diseases Society of America (J Sobel et al, Clin Infect Dis, volume 30, April 2000).

Itraconazole (Sporanox - Janssen), an oral antifungal triazole that has been available in the USA since 1992 for treatment of deep fungal infections (Medical Letter, 35:7, 1993), is now being marketed for treatment of dermatophyte infections of the toenails, with or without fingernail involvement.

Fluvastatin (Lescol - Sandoz), an HMG-CoA reductase inhibitor, was recently marketed in the USA for treatment of hypercholesterolemia. A synthetic mevalonolactone derivative, it is chemically distinct from previously available drugs in this class.

Lowering elevated serum cholesterol concentrations can slow progression and sometimes cause regression of atherosclerotic lesions. Most authorities advise patients with high cholesterol concentrations to eat less fat and less cholesterol and, when appropriate, to lose weight. If these measures do not lower serum lipids sufficiently, drugs are frequently added to the regimen. When drugs are discontinued, serum cholesterol concentrations generally return to pretreatment levels.

Pravastatin - Bristol-Myers Squibb) and simvastatin (Zocor -Merck), two new inhibitors of cholesterol synthesis similar to lovastatin (Mevacor - Merck), have now been marketed in the USA for treatment of hypercholesterolemia. Lovastatin (Medical Letter, 29:99, 1987) is the most frequently prescribed of all cholesterol-lowering drugs in the USA. Pravastatin and simvastatin were previously reviewed in The Medical Letter when they became available in Canada (volume 33, page 18, 1991).

Pravastatin (Pravachol - Bristol-Myers Squibb) and simvastatin (Zocor - Merck), two new inhibitors of cholesterol synthesis similar to lovastatin (Mevacor - Merck), have been marketed in Canada and several European countries and may soon be available in the USA for treatment of high plasma cholesterol concentrations. Drugs already marketed here for this indication were recently reviewed in The Medical Letter (Volume 33, page 1, January 11, 1991).

Recent reports indicate that lowering elevated serum cholesterol concentrations not only decreases mortality from coronary artery disease, but may cause regression of atherosclerotic lesions (JP Kane et al, JAMA, 264:3007, Dec 19, 1990). Most authorities advise patients with high cholesterol concentrations to eat less saturated and total fat and lose weight. If these measures do not lower serum lipids, drugs are frequently added to the regimen. When drugs are discontinued, serum cholesterol concentrations generally return to pretreatment levels.

The recent surge of interest in lowering serum cholesterol concentrations has led to vigorous promotion of various hypocholesterolemic drugs in the USA. Since the risk of coronary heart disease is increased in patients with high serum cholesterol concentrations, most authorities advise such patients to eat less fat and try to lose weight (The Expert Panel, Arch Intern Med, 148:36, 1988). When these measures fail, cholesterol-lowering drugs are frequently recommended.