The FDA has approved inclisiran (Leqvio – Novartis), a small interfering RNA (siRNA) directed to proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA, as an adjunct to diet and maximally tolerated statin therapy for subcutaneous (SC) treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of low-density lipoprotein cholesterol (LDL-C). Inclisiran is the first FDA-approved PCSK9-directed siRNA therapeutic agent.

The FDA has approved evinacumab-dgnb (Evkeeza – Regeneron), an angiopoietin-like 3 (ANGPTL3) inhibitor, for adjunctive IV treatment of homozygous familial hypercholesterolemia (HoFH) in patients ≥12 years old. Evinacumab is the first ANGPTL3 inhibitor to be approved in the US.

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.

In our recent article on Lipid-Lowering Drugs,1 we said that statins can reduce the risk of first cardiovascular events and death (primary prevention) in patients at high risk for atherosclerotic cardiovascular disease (CVD) and significantly reduce the incidence of cardiovascular events in patients at lower risk for CVD. Now the United States Preventive Services Task Force (USPSTF) has issued new recommendations on the appropriate use of statins for primary prevention of CVD.2

The USPSTF states that clinicians should periodically screen all persons 40-75 years old for cardiovascular risk factors and evaluate their 10-year risk of CVD using the ACC/AHA Pooled Cohort Equation.3 It recommends starting low- to moderate-intensity statin therapy (lowintensity statin therapy lowers LDL-cholesterol <30%; moderate-intensity statin therapy lowers it 30-<50%) in adults 40-75 years old without CVD who have one or more CVD risk factors (dyslipidemia, diabetes, hypertension, or smoking) and a calculated 10-year CVD event risk of >10%. For patients with the same characteristics but a 7.5-10% 10-year risk, the USPSTF recommends that clinicians "selectively offer" the same treatment.

The new recommendations do not apply to patients with familial hypercholesterolemia or LDL-cholesterol levels ≥190 mg/dL, who should take a statin regardless of calculated risk. The USPSTF found the evidence insufficient to recommend starting a statin for primary prevention in persons >75 years old.

1. Lipid-lowering drugs. Med Lett Drugs Ther 2016; 58:133.
2. US Preventive Services Task Force et al. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force Recommendation Statement. JAMA 2016; 316:1997.
3. American Heart Association and American College of Cardiology. ASCVD Risk Estimator. Available at: tools.acc.org. Accessed November 22, 2016.

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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 PCSK9 inhibitor evolocumab (Repatha – Amgen) is now available in a single-dose, hands-free device (Repatha Pushtronex) for once-monthly subcutaneous infusion. Evolocumab is FDA-approved as an adjunct to diet and maximally tolerated statin therapy for patients with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of low-density lipoprotein cholesterol (LDL-C), and as an adjunct to diet and other LDL-lowering therapies for patients with homozygous familial hypercholesterolemia (HoFH).

Evolocumab is also available in 140-mg single-use prefilled syringes and autoinjectors (Repatha Sureclick).1 Use of these formulations to administer the once-monthly dose (420 mg) requires patients to inject themselves three consecutive times within 30 minutes. Another PCSK9 inhibitor, alirocumab (Praluent), is injected every 2 weeks; it is available in single-dose prefilled syringes and pens.

The Repatha Pushtronex system consists of a single-use, battery-powered infusor and a prefilled cartridge containing a 420-mg dose of evolocumab. Once assembled, the patient adheres the device to the skin of the abdomen, thigh, or upper arm and presses a button to begin the subcutaneous injection; infusion of the dose takes about 9 minutes. One Repatha Pushtronex device costs $1175. Three 140-mg Repatha Sureclick autoinjectors or Repatha prefilled syringes cost $1627.2

1. Evolocumab (Repatha) – a second PCSK9 inhibitor to lower LDL-cholesterol. Med Lett Drugs Ther 2015; 57:140.
2. Approximate WAC for one 420-mg dose. WAC = wholesaler acquisition cost or manufacturer's published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. August 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.

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Evolocumab (Repatha – Amgen), a subcutaneously injected PCSK9 inhibitor, has been approved by the FDA 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 also approved as an adjunct to diet and other LDL-lowering therapies in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. Evolocumab is the second PCSK9 inhibitor to be approved in the US; alirocumab (Praluent) was approved earlier.

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 a fixed-dose combination of the cholesterol absorption inhibitor ezetimibe and the HMG-CoA reductase inhibitor (statin) atorvastatin as Liptruzet (Merck) for treatment of hyperlipidemia. Ezetimibe is also available in a fixed-dose combination with simvastatin (Vytorin).

Fibrates, niacin and fish oil are promoted for treatment of hypertriglyceridemia. HMG-CoA reductase inhibitors (statins) can lower elevated serum concentrations of triglycerides, but less so than fibrates, niacins or fish oil. Lifestyle changes such as weight reduction, exercise and decreasing alcohol intake can also lower serum triglyceride levels and should be tried first.

The FDA has approved 2 products containing omega-3 polyunsaturated fatty acids (PUFAs) for treatment of patients with severe hypertriglyceridemia (>500 mg/dL). Lovaza (formerly Omacor) is available by prescription. The second FDA-approved omega-3 product, Vascepa, which contains only EPA, will not be available until 2013. Many other brands of fish oil capsules are sold over the counter (OTC) as dietary supplements; the US Pharmacopeia has verified that some of these contain their labeled content, are soluble in the body, and contain neither heavy metals nor contaminants.

The results of the AIM-HIGH trial conducted by the US National Heart, Lung and Blood Institute (NHLBI) were recently published. The goal of the trial was to test whether addition of niacin to intensive statin therapy would further reduce the risk of cardiovascular disease. The trial was stopped prematurely after an average follow-up of 3 years because niacin therapy had not shown any clinical benefit.

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 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.

The FDA has approved the marketing of fenofibric acid (Trilipix - Abbott) to reduce triglycerides and increase HDL-C in patients with mixed dyslipidemia on optimal doses of a HMG-CoA reductase inhibitor (statin) who have, or have risk factors for, coronary heart disease. It is the first fibrate approved by the FDA specifically for combined use with a statin. Trilipix is also approved as monotherapy for hypertriglyceridemia, hypercholesterolemia and low HDL-C. The patent for Tricor, Abbott's older formulation of fenofibrate, will expire in 2011.

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.

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.

An unpublished 2-year randomized study (ENHANCE) on the effect of adding ezetimibe 10 mg to simvastatin 80 mg in 720 patients with heterozygous familial hypercholesterolemia has been in the news recently. About 80% of these patients had previously been treated with statins. The primary endpoint was the change in the intima-media thickness (IMT) of the carotid artery (baseline 0.68 and 0.69 mm); the IMT increased by 0.0111 mm with ezetimibe plus simvastatin and 0.0058 mm with simvastatin 80 mg alone (p=0.29). The ezetimibe- simvastatin combination lowered LDL-C by 58% compared to 41% lowering with simvastatin alone (p<0.01). The study was not powered to assess cardiovascular events; cardiovascular deaths occurred in 2 patients treated with both drugs and 1 on simvastatin alone.

Ezetimibe, an inhibitor of cholesterol absorption, is available both alone (Zetia) and in combination with 10, 20, 40 and 80 mg of simvastatin (Vytorin). No data have been published on the effect of ezetimibe on cardiovascular events with or without simvastatin. Whether addition of ezetimibe to a statin is as effective as raising the dose of the statin in decreasing the number of cardiovascular events remains to be determined in larger studies that are underway.

Neither Zetia or Vytorin is recommended for initial treatment of hypercholesterolemia.

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Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential human nutrients. The main dietary source of PUFAs is fatty fish such as salmon, but small amounts may be converted from α-linolenic acid in nuts, seeds, and plant oils such as canola or flaxseed oil. An increased intake of these fatty acids has been shown to modify membrane function, inhibit thrombus formation, decrease inflammation, lower plasma triglycerides, and alter the electrical activity of the myocardium.

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).

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%.

Vytorin, a fixed-dose combination of the cholesterol absorption inhibitor ezetimibe (Zetia - Merck/Schering Plough) and the HMG-CoA reductase inhibitor ("statin") simvastatin (Zocor - Merck), has been approved by the FDA for treatment of hypercholesterolemia. It is available as tablets containing 10 mg of ezetimibe combined with 10, 20, 40 or 80 mg of simvastatin.

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.

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.

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.