6. Medications That Manage Your Cholesterol

You’re doing all the right things to improve your lipid profile. You’ve shed some extra pounds. You’re eating a heart-healthy diet. You’re exercising every day. Nevertheless, your doctor says your cholesterol still isn’t quite where it should be, and your odds of suffering a heart attack or stroke are still increased.

You need a medication to reduce your risk.

Fortunately, from the blockbuster statin drugs to newer, more potent injectable medications, you have a range of prescription medications (and a few non-prescription options) that can help you get your cholesterol under control.

In order to optimize the benefits of these medications, you have to take them and use them to complement the important lifestyle changes you need to make. But, many Americans aren’t doing all they can to manage their cholesterol, suggest data published in 2015 in the U.S. Centers for Disease Control and Prevention’s (CDC) Morbidity and Mortality Weekly Report.

Between 2005 and 2012, nearly 37 percent of U.S. adults age 21 or older (about 78.1 million people) qualified for cholesterol-lowering therapy, according to American College of Cardiology/American Heart Association criteria. Yet, only 55 percent were taking cholesterol-lowering medications, only 47 percent reported making healthful lifestyle changes, and only 37 percent were doing both—while about 35 percent were doing neither. The lower numbers were especially significant among African-American and Mexican-American patients, and men were less likely than women to be taking cholesterol-lowering drugs, the researchers noted.

Talk with your physician about your cardiovascular risk and how you can reduce it through lifestyle changes. Then, if you still need medical therapy, have a discussion with your doctor about all your treatment options. Here’s a look at them.

Statins

They’re known scientifically as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors. Most people know them as statins.

These drugs are the prime medical therapy used to reduce low-density lipoprotein (LDL, “bad”) cholesterol. They’re also among the most widely prescribed medications in the world—they’re so universally used that some people have joked that they should be added to the water supply.

Statins can effectively lower LDL and total cholesterol, and they have some triglyceride-lowering and anti-inflammatory effects. They also may modestly raise levels of high-density lipoprotein (HDL, “good”) cholesterol. Yet, statins have important side effects that you need to know about.

What Statins Do

Statins work by blocking the action of an enzyme (HMG-CoA) responsible for cholesterol production in the liver.

Members of the statin drug class include atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin (Mevacor®), pitavastatin (Livalo®), pravastatin (Pravachol®), rosuvastatin (Crestor®), and simvastatin (Zocor®). Most of the drugs are available in generic forms.

Although they belong to the same drug class, not all statins are equal in terms of their potency and the degree to which they reduce LDL—atorvastatin and rosuvastatin are among the most potent statins, while fluvastatin and pravastatin are among the least potent. Experts recognize three intensities of statin therapy, using varying doses to achieve different results:

• High-intensity statin therapy achieves a 50 percent or greater reduction in LDL using daily atorvastatin (40 to 80 mg) or rosuvastatin (20 to 40 mg).
• Moderate-intensity statin therapy achieves a 30 to 40 percent reduction in LDL using daily atorvastatin (10 to 20 mg), fluvastatin (40 mg twice a day or 80 mg [once-daily fluvastatin XL]), lovastatin (40 mg), pitavastatin (2 to 4 mg), pravastatin (40 to 80 mg), simvastatin (20 to 40 mg), or rosuvastatin (10 to 20 mg).
• Low-intensity statin therapy achieves an LDL reduction of less than 30 percent using daily fluvastatin (20 to 40 mg), lovastatin (20 mg), pitavastatin (1 mg), pravastatin (10 to 20 mg), or simvastatin (10 mg).

Other Statin Benefits

Statins may have a number of pleiotropic effects, or beneficial effects that are independent of the drugs’ intended action: LDL reduction. For instance, studies have found that statins might help stabilize arterial plaques and improve endothelial function.

Effects on Atherosclerosis

Not only can statin drugs reduce LDL cholesterol, but some research suggests that high-intensity statin therapy also can slow—and potentially reverse—the progression of atherosclerotic plaque.

The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) compared the effects of 80 mg of atorvastatin versus 40 mg of rosuvastatin (the highest doses available) on plaque progression in 1,039 people with stable coronary artery disease. The participants underwent intravascular ultrasound imaging to measure plaque volume in their coronary arteries at the beginning of the study and after two years of treatment with either of the statin drugs.

As expected, both medications significantly reduced LDL cholesterol, to an average level of 62.6 mg/dl for rosuvastatin and 70.2 mg/dl for atorvastatin. And, patients on rosuvastatin achieved slightly higher HDL cholesterol levels compared to the atorvastatin group (average of 50.4 mg/dl versus 48.6 mg/dl).

But, most notably, 63.2 percent of people taking atorvastatin and 68.5 percent on rosuvastatin experienced a regression, or reversal, of their atherosclerosis. The researchers reported few adverse events, no serious side effects, and a low incidence of heart attack or stroke among the study participants (New England Journal of Medicine, Dec. 1, 2011).

Researchers continue to study whether aggressive statin therapy can significantly reverse plaque formation.

Effects on Inflammation

Statins also have anti-inflammatory effects. Some studies have shown that even if you have a normal LDL level, you still may be at increased risk of cardiovascular events if you have elevated levels of inflammatory markers such as C-reactive protein (CRP). In one trial—Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)—investigators reported that rosuvastatin reduced the risk of heart attack, stroke, and death by 44 percent in more than 17,000 people with normal LDL but elevated CRP levels.

Benefits for Hypertensive Patients

Statins aren’t thought of as antihypertensive medications, because they are designed to lower LDL cholesterol, not blood pressure. But recent research suggests that for many patients with high blood pressure, adding statins to their antihypertensive medication regimen may make a huge difference.

In the Heart Outcomes Prevention Evaluation-3 (HOPE-3) trials, researchers explored various combinations of antihypertensive and cholesterol-lowering drugs among individuals considered to be at intermediate risk of coronary heart disease.

One of the main findings was that the combination of statin therapy and antihypertensive therapy significantly lowered the risk of cardiovascular events, such as heart attack and stroke, among intermediate-risk patients with high blood pressure. However, the researchers found that the outcomes with the combination of rosuvastatin and antihypertensive therapy (candesartan plus hydrochlorothiazide) were not significantly better compared with those of rosuvastatin alone, emphasizing the importance of the statin drug (New England Journal of Medicine, May 26, 2016).

Managing Statin Side Effects

Most patients tolerate statins well, but like all medications, statins can cause side effects, which tend to be more severe as the statin dose and potency increase. Some of the more common statin side effects include headache and gastrointestinal symptoms. Other potential side effects include:

• Myopathy: An estimated 5 to 20 percent of statin users report muscle pain and stiffness, or myopathy. (Very rarely, statin users may experience rhabdomyolysis, a potentially life-threatening muscle breakdown.) But, the exact percentage of statin users who actually experience muscle pain is a widely debated subject. In fact, some studies suggest that certain patients with statin-related muscle pain experience a “nocebo” effect, which occurs when a person taking a placebo reports side effects and negative consequences that he or she attributes to a medication. In one study, researchers reported that among more than 10,000 patients, excessive rates of muscle-related side effects were reported only when patients and their physicians knew they were using statin therapy (The Lancet, May 2, 2017).



• Liver abnormalities: Statins can cause elevations in liver enzymes, suggesting potential liver damage. So, your doctor may recommend liver-function tests in certain situations, such as when you start statin therapy, change the dose or the type of statin, or if you begin taking other medications metabolized by the same pathway in the liver as statins.
• Blood-sugar elevations: Some studies have found an increase in blood sugar among statin users. These findings prompted the U.S. Food and Drug Administration (FDA) to add to the statin safety information an advisory that the medications may slightly raise blood sugar, enough to push some patients’ glucose levels across the threshold of diabetes. The action was based, in part, on findings from two large meta-analyses that found a 9 to 13 percent increased risk of diabetes associated with statin use.
• Cognitive problems: Although some research suggests that statins may slow the progression of dementia and improve memory, as a rare side effect, some patients may experience cognitive problems, such as forgetfulness and mental “fogginess,” while taking a statin. Consequently, the FDA has added to the statin safety information a notice about possible cognitive problems associated with statin use. These side effects typically subside after stopping the medication. Overall, whether statins actually cause cognitive problems is unclear.
• Cataracts: In a study involving nearly 7,000 patients, statin users were 9 percent more likely than non-users to develop cataracts (JAMA Ophthalmology, Sept. 19, 2013). Another study (Canadian Journal of Cardiology, December 2014) found an association between statin use and a greater likelihood of cataract requiring surgery. But, although these studies have identified an association between statins and cataracts, a causal relationship has not been established.

Overcoming Statin Intolerance

In some cases statins can cause muscle-related and other side effects significant enough to prompt some patients to stop taking the drugs—a situation known as statin intolerance. Still, many people who are statin-intolerant can find a cholesterol-lowering strategy that agrees with them.

In one study, researchers reviewed data on 1,605 patients with intolerance to two or more statins. The researchers gave the patients a statin once a week and then administered varying doses and dosing schedules to determine what they could tolerate.

Overall, more than 72 percent of the patients who were previously statin-intolerant were able to resume statin therapy, often with the help of dosing adjustments or switching to a different medication in the statin class. While most of the patients were able to return to a daily statin regimen, others could tolerate only intermittent therapy, taking the drugs every other day or as infrequently as once a week.

The patients who resumed daily statin therapy overall achieved greater LDL reductions than those on intermittent therapy, but both groups experienced greater LDL reductions and were more likely to achieve their LDL goals compared to those who discontinued statin use, the study found (American Heart Journal, September 2013).

The findings suggest that complete statin intolerance (an inability to take any statins) is relatively rare and that patients and their physicians just need to persevere in finding the right treatment regimen and rule out potential causes of statin side effects (see sidebar).

A Final Word on Statin Side Effects

Given the extensive literature supporting the effectiveness of statins in preventing cardiovascular events, most experts agree that the benefits of statin therapy outweigh the risks associated with the drugs. So, take your statin exactly as prescribed, and do not stop taking your medication or otherwise alter your statin regimen without first consulting with your physician.

If you’re on statin therapy, follow your physician’s recommendations for follow-up testing. Promptly report any muscle aches or other statin-related side effects to your doctor, and explore novel statin regimens that work for you.

Be patient. It may take time and several tries to find a cholesterol-lowering regimen that you can tolerate. If you absolutely cannot tolerate statins, or if you can tolerate only intermittent statin dosing, other cholesterol-lowering medications may be necessary to reduce your LDL level. Explore all your options to optimize your LDL and reduce your cardiovascular risk.

PCSK9 Inhibitors

Cholesterol-lowering statins are wonder drugs for reducing LDL and lowering cardiovascular risk. However, a significant number of patients cannot tolerate the medications or fail to reach target LDL levels despite being on maximum-dose statin therapy.

Enter a new class of drugs—proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors—which can reduce LDL to levels beyond what most statins can achieve. The first PCSK9 inhibitors—alirocumab (Praluent®) and evolocumab (Repatha®)—were approved by the U.S. Food and Drug Administration in 2015.

The PCSK9s are given by injection every two weeks or once a month, compared with daily oral statin therapy. The drugs are indicated as a complement to a heart-healthy diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or those with coronary heart disease who require additional reductions in LDL.

While statin drugs work by decreasing the amount of cholesterol the liver synthesizes (reducing LDL) from the blood, the newer medications are antibodies that block the action of a protein (PCSK9) that degrades the receptors on the liver’s surface that remove LDL. The result is a greater number of receptors left to pull the particles carrying LDL from the blood.

With this mechanism of action, the PCSK9s produce significant reductions in LDL in addition to statin therapy—an average of 36 to 59 percent for alirocumab and an average of 60 percent for evolocumab.

Reductions in Cardiovascular Risk

Not only do the PCSK9s reduce LDL, but a seminal international trial showed that they can prevent cardiovascular events, as well.

In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial, 27,564 patients with cardiovascular disease treated with moderate- to high-intensity statin therapy received evolocumab (every two weeks or once a month) or a placebo and were followed every 12 weeks for an average of 2.2 years. Compared with placebo, evolocumab lowered LDL from a median of 92 mg/dl to 30 mg/dl, a 59 percent reduction, the study found.

The drug reduced the risk of the study’s primary endpoint—a composite of heart attack, stroke, cardiovascular death, hospitalization for cardiac chest pain (angina), or revascularization—by 15 percent. More specifically, the drug reduced the composite of heart attack, stroke, and cardiovascular death by 25 percent. The benefits were seen regardless of the dose of the drug, gender, age, differences in the type of cardiovascular disease, baseline LDL level, and the type of statin therapy the participants used (New England Journal of Medicine, May 4, 2017).

“With this trial, we now have definitive data that by adding evolocumab to a background of statin therapy, we can significantly improve cardiovascular outcomes and do so safely,” the study’s lead author, Marc S. Sabatine, MD, of Brigham and Women’s Hospital, said in a statement. “I think these results are very good news for patients with atherosclerotic disease, who remain at high risk for these events.”

Lingering Questions

Despite the benefits of the PCSK9s, some uncertainties regarding the drugs remain. For instance, the long-term side effect profile of the new medications hasn’t been fully elucidated. The drugs, for the most part, appear to spare patients the muscle aches and stiffness associated with statin use.

The most common side effects associated with the PCSK9s include mild cold- or flu-like symptoms, as well as itching, swelling, or other reactions at the injection site. In the FOURIER trial, aside from a higher rate of injection-site reactions, no significant differences in adverse events (including new cases of diabetes or cognitive problems) occurred between the two study groups, the researchers reported.

A major limitation to using the PCSK9s may be the price. By some estimates, the cost of the new medications can exceed $12,000 per year, and not all insurance providers will pay for them. The drug manufacturers do offer financial assistance programs.

Just remember that, like statins, the PCSK9 inhibitors should be considered as an adjunct to, not a replacement for, a heart-healthy diet and regular exercise. The drugs are intended to complement, not replace, statin therapy. If you can’t tolerate statins, discuss alternative statin regimens and other medications that can help you manage your cholesterol.

Other Options

Ezetimibe

Oftentimes, statin medications are enough to achieve sufficient cholesterol reductions, but some people may need extra help from a non-statin drug, like the cholesterol absorption inhibitor ezetimibe (Zetia®). Like statins, ezetimibe reduces LDL, but via a different mechanism. While statins reduce the amount of cholesterol your body produces, ezetimibe lowers the amount of cholesterol absorbed through your small intestine. Ezetimibe is widely used in a combination pill with simvastatin (Vytorin®).

Ezetimibe can lower LDL by an average of about 18 to 20 percent, compared to LDL reductions of up to 50 to 60 percent seen with high-potency statin therapy. The drug also may produce slight reductions in triglycerides and slight increases in HDL. Ezetimibe may cause some mild gastrointestinal side effects, but otherwise it is generally well tolerated.

One study suggests that, for people with established heart disease, achieving a low LDL level with statin therapy is good, but adding ezetimibe to reduce it further may be even better at preventing heart attacks, strokes, and other cardiovascular complications.

In the study, 18,144 high-risk patients, age 50 and older, were given simvastatin or an ezetimibe/simvastatin combination within 10 days of being admitted to a hospital because of chest pain (unstable angina) or heart attack. The patients’ average LDL cholesterol level was 95 mg/dl when the study began.

After one year, the dual therapy reduced LDL levels to an average of 54 mg/dl, while simvastatin therapy alone trimmed LDL to an average of 69 mg/dl. No increase in side effects was seen when ezetimibe was added to simvastatin, the researchers reported.

During an average follow-up period of about seven years, 32.7 percent of patients on the ezetimibe/simvastatin combination experienced a heart attack, stroke or unstable angina, required a revascularization procedure to reopen blocked coronary arteries, or died from cardiovascular causes, compared with 34.7 percent of the simvastatin-only group. The difference was statistically significant (New England Journal of Medicine, June 18, 2015).

Based on the study findings, if you have heart disease and are already on statin therapy, you could safely gain extra benefits by adding ezetimibe to further lower your LDL. And, if you can’t tolerate a statin due to side effects or if a statin isn’t sufficiently lowering your LDL on its own, ask your doctor if ezetimibe may be reasonable to add for further reducing your LDL and, presumably, your cardiovascular risk.

Bile Acid Sequestrants

This older class of medications includes cholestyramine (Prevalite®), colestipol (Colestid®) and colesevelam (Welchol®). These drugs prompt the liver to convert more cholesterol into bile acids, subsequently lowering LDL levels by 10-15 percent with low doses and up to 25 percent with higher doses. Given the modest LDL reductions that bile acid sequestrants can produce, they’re usually prescribed only as an adjunct to statins or in people with statin intolerance.

Side effects include constipation, gas, bloating, heartburn, diarrhea, and nausea.

Fibrates

These drugs reduce fat production in the liver and are generally used to treat patients with high triglycerides. In the process, fibrates, such as fenofibric acid (Antara®, Tricor®) and gemfibrozil (Lopid®), may increase HDL and lower LDL somewhat. Side effects include nausea and stomach pain.

Niacin

Also known as vitamin B3 and nicotinic acid, niacin, like all B vitamins, is important for converting food into energy. But, in high doses, niacin can be used to treat dyslipidemia, often in conjunction with statin therapy. Prescription-strength doses (Niacor®, Niaspan®) can reduce LDL by about 20 percent, lower triglycerides, and give your HDL a boost.

But, research suggests that increasing HDL levels doesn’t necessarily translate into reduced cardiovascular risk. For example, in the AIM-HIGH trial, niacin therapy improved HDL and triglyceride levels but provided no additional clinical benefit among statin patients with established cardiovascular disease and LDL levels below 70 mg/dl (New England Journal of Medicine, Dec. 15, 2011).

Prescription-strength niacin causes facial and neck flushing in a large number of users—to reduce flushing, take a non-enteric-coated aspirin 30 to 40 minutes before taking niacin, and avoid spicy foods or stimulants, such as caffeine. Niacin may increase blood-sugar levels and cause stomach upset, dizziness, headache, and blurred vision.

Niacin also can increase uric acid levels and contribute to painful gout. At high, therapeutic doses, niacin may contribute to liver damage and stomach ulcers. Considering these side effects, it’s best not to self-medicate with over-the-counter niacin supplements, but rather to use niacin with care only under your doctor’s supervision

The HDL Paradox

Despite achieving treatment goals with LDL-lowering statins and other drugs, many patients remain at risk of heart attack and stroke. Seeking ways to further reduce this residual risk, researchers have looked to medications that increase HDL levels. Higher levels of HDL cholesterol are considered protective against cardiovascular disease because HDL transports harmful LDL cholesterol away from your arteries and back to the liver, where it’s removed from the body.

Unfortunately, the “good” cholesterol has gotten a bad rap from several studies that cast doubt on the value of increasing HDL to prevent cardiovascular events in people at high risk.

Raising HDL: Early Failures

As mentioned earlier, the AIM-HIGH trial found that niacin therapy increased HDL but provided no additional clinical benefit when added to optimal statin therapy.

The disappointing results don’t stop at niacin. In one clinical trial, more than 300 patients who had suffered a heart attack received 10 infusions of a synthetic HDL known as CER-001 or placebo. Researchers then used intravascular ultrasound to look at plaque in the coronary arteries. The researchers saw no changes in the vessels of those who had received the placebo or the experimental drug, either in the diseased portion of the artery where the heart attack occurred or anywhere else in the vessel (American College of Cardiology 2017 Scientific Sessions, March 18, 2017).

Additionally, scientists have developed a class of medications known as cholesteryl ester transfer protein (CETP) inhibitors, which block the ability of an enzyme (CETP) to transfer cholesterol particles from HDL to LDL.

Unfortunately, development of the first of these drugs, torcetrapib, was halted in late 2006 after studies linked it to a greater risk of adverse outcomes. The second drug, dalcetrapib, increased HDL levels by 31 to 40 percent among nearly 16,000 patients, but that HDL boost did not translate into a lower risk of death, heart attack, stroke, or hospitalization for chest pain (New England Journal of Medicine, Nov. 29, 2012).

As a result, work on this drug was suspended. Development of a third CETP inhibitor, evacetrapib, was stopped after a study involving more than 12,000 high-risk patients showed that the drug failed to reduce cardiovascular events despite more than doubling HDL levels and reducing LDL cholesterol by nearly a third (New England Journal of Medicine, May 18, 2017).

Lipid-Lowering Supplements

Red Yeast Rice

The medicinal properties of Chinese red yeast rice have been documented for about 1,200 years. But, in more recent years, this herbal supplement has been the subject of controversy, despite evidence that it can reduce cholesterol.

That’s because red yeast rice contains substances known as monacolins, including monacolin K, which is identical to the active ingredient in the drug lovastatin (Mevacor®). The U.S. Food and Drug Administration has labeled red yeast rice products containing more than trace amounts of monacolin K as “unapproved new drugs,” meaning they can’t be sold as dietary supplements.

Like any drug or supplement that can produce a therapeutic effect, red yeast rice may cause the same types of side effects and drug interactions as lovastatin.

Also, the National Center for Complementary and Integrative Health notes that some red yeast rice products contain a substance known as citrinin, which can cause kidney damage.

Inform your doctor if you use red yeast rice, and report any side effects. Better yet, if you need to reduce your cholesterol, ask your physician about other, more proven cholesterol-lowering therapies, such as statins.

Get Fishy and Lower Your Triglycerides

Diets containing the omega-3s eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are heart-healthy, but like many people, you may not consume enough fatty fish or other dietary sources of these potent omega-3s. So, you’re thinking about getting omega-3s from fish oil supplements to lower your cardiovascular risk.

EPA and DHA are polyunsaturated fats found prominently in fatty fish such as wild salmon, mackerel, tuna and herring.

Studies have found that diets rich in EPA and DHA can benefit heart health in several ways, such as lowering triglycerides, slightly reducing blood pressure, and reducing the risk of abnormal heart rhythms. But, studies examining the effects of fish oil supplements on various health conditions have produced mixed results.

After reviewing the scientific literature, the American Heart Association (AHA) in March 2017 released a scientific advisory concluding that omega-3 fish oil supplements may benefit people who have had a heart attack or have documented cardiovascular disease or heart failure.

The organization noted, though, that evidence is lacking to support using the supplements to prevent cardiovascular disease in the general population.

However, another patient population who can benefit significantly from fish oil supplements are people with high triglycerides. For those with hypertriglyceridemia, EPA/DHA supplements of two to four grams a day may be used to reduce triglycerides, but first consult your physician. Several prescription omega-3 supplements are available, as are myriad over-the-counter products.

Caveat Emptor

Any manufacturer who extracts oil from a fish can place the words “fish oil” on a product label, but that doesn’t mean you’ll get what you need from the supplement. In fact, it may be rich in fish blubber and little else.

So, as with any dietary supplement, you need to check the label of your fish oil supplement to make sure it contains adequate amounts of EPA and DHA.

A 2015 survey by the U.S. Department of Agriculture found that most omega-3 supplements contained, on average, 180 mg of EPA and 120 mg of DHA per serving. To reduce the number of pills needed to meet recommended omega-3 levels, choose products that contain a total of 600 to 700 mg of EPA and DHA (combined) per capsule.

Also, look for products with the U.S. Pharmacopeia seal, which shows the supplements have been independently reviewed for quality, content and purity.

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