Cholesterol management guidelines from the American College of Cardiology/American Heart Association Task Force were last published in 2019.

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.

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

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.

Combining a statin with another drug that lowers low-density lipoprotein cholesterol (LDL-C), such as colesevelam (Welchol), niacin (Niaspan, and others), or ezetimibe (Zetia), can reduce LDL-C levels more than a statin alone, but studies convincingly demonstrating that such combinations improve clinical outcomes have been lacking. The results of a long-term randomized, double-blind clinical trial (IMPROVE-IT) recently presented at the American Heart Association's Scientific Sessions 2014 indicate that addition of ezetimibe to simvastatin in high-risk patients reduces cardiovascular events.1

IMPROVE-IT compared the efficacy of simvastatin 40 mg plus placebo with that of simvastatin 40 mg plus ezetimibe 10 mg (Vytorin) in preventing the primary endpoint, a composite of cardiovascular events (cardiovascular death, MI, hospital admission for unstable angina, coronary revascularization, or stroke) in patients with acute coronary syndrome and normal LDL-C levels (≤125 mg/dL; mean 95 mg/dL). After one year, mean LDL-C was reduced further with the addition of ezetimibe (to 53.2 vs. 69.9 mg/dL with simvastatin alone). After 7 years, 2742 events had occurred among the 9077 patients taking simvastatin plus placebo and 2572 among the 9067 taking simvastatin plus ezetimibe (event rate: 34.7% vs. 32.7%; p = 0.016). There was no significant difference between the 2 groups in noncardiovascular adverse events, including gallbladder-related events, myopathy, or cancer.

1. C Cannon et al. IMProved Reduction of Outcomes: Vytorin Efficacy International Trial. Available at www.timi.org. Accessed November 21, 2014.

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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.

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).

An FDA advisory committee has voted in favor of approving ezetimibe/simvastatin (Vytorin – Merck) for prevention of major cardiovascular events in patients with chronic kidney disease who are not on dialysis. The FDA itself is expected to make a decision on this potential new indication in the first quarter of 2012.

The manufacturer’s application for this new indication was based on a double-blind, randomized trial (SHARP) that compared the combination of ezetimibe 10 mg and simvastatin 20 mg with placebo in 9270 patients with chronic kidney disease who did not have a history of myocardial infarction or coronary revascularization.1 About one-third of patients were already on hemodialysis at the start of the trial. Over a median of 4.9 years, a major atherosclerotic event (the primary endpoint) occurred in 526 patients (11.3%) taking the active drugs and in 619 (13.4%) taking placebo. Myopathy occurred in 9 patients (0.2%) randomized to ezetimibe/simvastatin and in 5 (0.1%) of those in the placebo group, not a significant difference.

Whether simvastatin alone, which would cost much less, would similarly improve outcomes in such patients remains to be determined. The FDA advisory committee did not recommend approval of Vytorin for patients who were on hemodialysis.2 Previous trials with a statin alone in patients with end-stage renal disease on hemodialysis failed to show significant benefits in clinical outcomes.3,4

1. C Baigent et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011; 377: 2181.

2. S Sutter. Merck’s bid for Vytorin CV benefit claim muddled by earlier statin failures in dialysis patients. The Pink Sheet, November 7, 2011.

3. C Wanner et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238.

4. BC Fellström et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.N Engl J Med 2009; 360:1395.

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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.

Readers have asked us to update our 2004 article on tablet splitting. Breaking drug tablets in half is a common practice, but the FDA recently advised consumers against it (FDA Consumer Health Information, July 2009).

In recent months, both the lay media and some medical experts have raised concerns about the effectiveness and safety of ezetimibe, a widely used drug that prevents absorption of cholesterol from the GI tract. Ezetimibe is available alone as Zetia and in combination with 10, 20, 40 and 80 mg of simvastatin (Zocor, and others) as Vytorin.

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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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%.

Health Canada, the Canadian equivalent of the FDA, recently issued a public advisory about postmarketing reports of myalgia, rhabdomyolysis, hepatitis, pancreatitis and thrombocytopenia associated with use of ezetimibe (Zetia in the US; Ezetrol in Canada). Ezetimibe is often added to a statin to increase LDL cholesterol lowering (Drugs for Lipids, Treat Guidel Med Lett 2005; 3:15). The advisory did not specify whether these patients were also taking a statin, but according to the Canadian manufacturer Merck Frosst/Schering (Merck/Schering-Plough in the US), some of the patients who developed rhabdomyolysis were taking ezetimibe without a statin. In the US, ezetimibe is also available in a combination with simvastatin (Vytorin - Med Lett Drugs Ther 2004; 46:73). Recently, a few patients already taking a statin developed myalgia when ezetimibe was added (R Fux et al, Ann Intern Med 2004; 140:671). The possibility that adding ezetimibe to a statin could increase the risk of rhabdomyolysis should be kept in mind.

Breaking drug tablets in half is a common practice. In some cases, a lower drug dose may be as effective as a higher one, with fewer adverse effects. Sometimes tablets are split to achieve an intermediate dose between marketed strengths. When 2 tablet sizes cost the same, as they often do, splitting the larger size saves money. Is this a reasonable practice?

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.