Prescribing Lower Cholesterol
In This Chapter
� Describing the different types of cholesterol-lowering medicines
� Evaluating the risks and benefits of prescription products
� Deciding who should take an anti-cholesterol drug
� Remembering other ways to control cholesterol
Okay, so you’ve changed your diet to conform to the guidelines in Chapters 4 and 5, you’ve stepped up your exercise (see Chapter 8), and you’ve
lost a couple of pounds — maybe even more than a couple of pounds. But — can it be? — your cholesterol levels are still higher than your doctor considers healthy. What to do?
You may be a candidate for cholesterol-lowering drugs. This chapter, with eight tables and one very detailed drawing of your innards, compares the effectiveness of different kinds of drugs, explains the unfamiliar words used to name these drugs, lists potential side effects, and generally gives you the facts you need to make an informed decision as to whether you’re a candidate for cholesterol-busting meds. So read it.
Introducing Cholesterol-Lowering Medicines
Modern medicine has reduced the number of deaths from heart attacks, but, until recently, it hadn’t substantially lowered the number of heart attacks or cases of heart disease. One possible way to accomplish this is to eliminate the cause of many heart attacks — that is, to lower the amount of cholesterol swimming around in the blood.
Doctors currently use one (or more) of four different kinds of meds to lower cholesterol, which I list here:
� Statin drugs
� Cholesterol blockers
� Bile acid sequestrants
� Triglyceride inhibitors (including the B vitamin niacin)
To explain the particulars about these meds, I have created a separate section for each starting right after the nifty picture of your insides in Figure 12-1, which shows where in your body the cholesterol-lowering drugs do their good work.
Patients with high cholesterol (particularly those who’ve already had a heart attack) may also be given anticoagulants (blood thinners) such as aspirin and clopidogrel (Plavix). Anticoagulants don’t lower cholesterol, but they do reduce the risk of blood clots, thus reducing the risk that a blood clot gets stuck in a cholesterol-clogged artery.
Cutting cholesterol off at the source: Statins
Atorvastatin (Lipitor), fluvastatin (Lescol), pravastatin (Pravachol), simvastatin (Zocor), and rosuvastatin (Crestor) are medicines known collectively as “statins.” The statins reduce the body’s synthesis of cholesterol, which means they are definitely heart-healthy. In fact, the usual dozens of studies cited in cases like this show that taking a statin drug can do all these good things:
� Lower your LDLs
� Raise your HDLs
� Reduce your plaque (the technical term for gunk sticking to your artery walls that may break off and form clots, which can block the flow of blood and cause a heart attack)
� Protect the lining of your arteries
All arteries are lined with tissue called endothelium. When the endothelium doesn’t function properly, the artery starts to build up plaque. Statins, as well as some other drugs, keep the endothelium healthy — another way these drugs lower your risk of heart attack or stroke.
� Lower your C-reactive protein, another risk factor for heart attack that you can check out in Chapter 3
� Reduce your risk of a first heart attack
� Reduce your risk of a second heart attack if you’ve already had one
� Reduce your risk of stroke
Statins are sold as single ingredient pills or combo pills that add a second heart-healthy drug such as one that lowers blood pressure. Table 12-1 lists the various statin products currently on your drugstore shelf or behind the counter.
Statin side effects
Because you’re reading this book, I know that you’re an informed medical consumer. Because you’re an informed medical consumer, you know that even beneficial medicines may pose problems for some patients.
When statins first came on the market, manufacturers included a notice in the small print of their product information about muscle cramps, aches, pain, and weakness, but it sure looked insignificant. Yet from their introduction in the late 1980s, it was clear that statins may trigger rhabdomyolysis, an excessive breakdown of muscle tissue creating a flood of waste cells that tumble through the bloodstream and into the kidneys where they may clog small passages and — theoretically — cause kidney failure.
Until the summer of 2001, the word theoretically was very, very important. In clinical trials of more than 50,000 patients, researchers hadn’t linked a single death to statin-triggered kidney failure. But cerivastatin (Baycol), a new statin introduced by Bayer A.G. in 1997, was different. The incidence of rhabdomyoly- sis among Baycol users was about ten times higher than among people taking other statin drugs, and the reaction was more likely to be really serious — read: fatal.
Name games
When the words on this page move from unfa- miliar to incomprehensible, you know you’re into the serious stuff. That’s the case with HMG- CoA reductase inhibitors, the scientifically- correct name for statins.
The easy way to define HMG-CoA reductase inhibitors is to work backwards, starting with the last word in the name. Inhibitor is plain English for something that keeps something else from doing something.
Now, move back one word to reductase. Note the ending -ase, which is the scientific short- hand for enzyme. Now you know an HMG-CoA reductase inhibitor is a drug that interferes with (inhibits) the action of an enzyme. Hey, that’s not bad for a non-scientist!
Next step: CoA. The initials stand for coenzyme A. But if you look that term up in Stedman’s Medical Dictionary, the one most science writers use, it directs you to HMG-CoA, the abbreviation for — take a deep breath — beta-hydroxy-beta- methyl-glutaryl-CoA.
What in the world is beta-hy. . . . No, no, not again. I’m going to stick to the abbreviation. HMG-CoA is an important player in converting fats to lipoproteins and cholesterol.
Put it all together, filter out the science speak (well, most of it), and you get the plain-language definition of an HMG-CoA reductase inhibitor: A drug that reduces the activity of an enzyme needed to turn fats into lipoproteins and cho- lesterol, especially the nasty little LDLs.
Wait. Don’t leave. I’m not done.
The generic names for all HMG-CoA reductase inhibitors end in –statin because, as the International Union of Pure and Applied Chemistry and the International Union of Biochemistry and Molecular Biology so care- fully note, the suffix –statin stands for “factors inhibiting the release (and perhaps the synthe- sis) of pituitary hormones.”
Now we’re done. Whew.
By August 7, 2001, when Bayer took Baycol off the market, at least 31 deaths had been linked to the medication in the United States, and the Food and Drug Administration (FDA) had reports of nine more deaths abroad. The total number of deaths linked to Baycol has never been finalized, but the esti- mated number of cases of rhabdomyolysis eventually rose into the thousands, and according to the Kaiser Daily Health Policy Report of November 23, 2004, Bayer has settled nearly 3,000 lawsuits about Baycol-related injuries.
Today, the package inserts and advertising for all statin drugs include a warning about muscle pain, usually like this in bold black type. Forewarned, after all, is forearmed. The following list details the currently recognized side effects of statin drugs:
� Common side effects: Abnormal results on tests for liver enzymes (temporary), allergic rash, fatigue, headache and dizziness, low blood pressure, upset stomach (nausea, gas, diarrhea, or constipation)
� Less common/potentially serious side effects: Persistent abnormal results on liver function test, accompanied by hepatitis, abnormally low platelets (particles that enable blood to clot), emotional depression, memory loss, muscle pain and tenderness, muscle loss (rhabdomyolysis), protein in the urine
Naturally, because you are, as noted above, an informed medical consumer, you tell your doctor right away if you experience any of the more serious side effects. Right away. No waiting. Really.
Statin interactions with other drugs
If you take a statin along with a drug that blocks the action of liver enzymes required to eliminate statins from your body, the level of statins floating about your organs and tissues may rise high enough to cause serious muscle damage — and maybe even kidney failure — which isn’t a good thing. Among the drugs known to hit those liver enzymes and trigger this reaction are the antibiotics clarithromycin (Biaxin) and erythromycin; oral fungus fighters, such as keto- conazole and other meds whose names end in –azole; and protease inhibitors (HIV/AIDS drugs).
Taking two or more meds at once is a balancing act, so always tell your doctor exactly what you’re taking when she prescribes a new medicine, including a statin.
Nature’s cholesterol busters: Not
Hate doctors? Don’t want to spend all your money on prescription drugs? Think you can find an inexpensive over-the-counter cholesterol buster? Fuggeddabboudit.
In the late 1980s, health food stores did a nifty business selling a “natural” cholesterol buster called Cholestin. The active ingredient in Cholestin was red yeast rice (or red rice yeast) produced by fermenting a particular strain of rice with — what else? — yeast, a process that created a form of lovastatin, the statin drug sold under the brand name Mevacor.
Because red yeast rice was introduced as a dietary supplement, not a drug, it didn’t have to go through the rigorous tests for safety and effectiveness required of lovastatin. Was it safe? Probably as safe as lovastatin. Did that mean perfectly harmless? Clearly not, as you can see for yourself by reading the side effects listed for lovastatin earlier in this chapter.
In 2000, the 10th U.S. Circuit Court of Appeals ruled that red yeast rice was a drug and therefore subject to regulation by the Food and Drug Administration (FDA). After that, the FDA went all out after any company selling red yeast rice, demanding to see proof — real scientific studies, please — demonstrating the safety and effectiveness of any product containing red yeast rice.
As an inevitable result, while products listing red yeast rice as an ingredient are still available on health food and drugstore shelves, the rice is made differ- ently and no longer contains any statin. Other “natural” cholesterol-lowering products may contain various herbs, vitamins, dietary fiber, and plant compounds such as stanols and sterols (the anti-cholesterol ingredients in some margarines described in Chapter 6). You don’t need a prescription for these products and the packages sure are pretty, but none of them will lower cholesterol as effectively as statin drugs.
Trading bile for cholesterol: Bile acid sequestrants
Right off the bat, here are a couple of those unfamiliar words I mentioned at the start of this chapter. Don’t panic. Just take ’em one at a time. Bile acids are digestive aids stored in your gallbladder. (If your gallbladder has been removed, your body still makes bile acids but releases them into the digestive tract instead of storing them.)
Bile acids enable you to metabolize fats so that your body can absorb fatty acids (no, ice cream doesn’t go straight from your lips to your hips) and convert them to useful products such as — you got it — cholesterol. Bile acid sequestrants are compounds that grab up bile acids in your intestines and eliminate them via your feces before the bile acids can do their job on fats.
You take bile acid sequestrants right before you eat so they’re readily available when the gallbladder begins to release bile acids for digestion. As the bile acid sequestrants grab up so much bile acid that you can’t efficiently digest fats, your body says, “Whoa there! I need some more of this stuff.” As a result, you begin to convert some of the cholesterol in your body to bile acids to replace the ones you’ve mopped up and eliminated, and the amount of cholesterol and triglycerides in your blood goes down.
The different bile acid sequestrants
The most commonly used bile acid sequestrants, listed in alphabetical order by their generic names, are
� Cholestyramine: Available either as a powder to mix with a clear liquid, such as water or juice, or as a chewable bar. The brand names for cholestyramine are Prevalite and Questran.
� Colesevelam: Available in tablet form — a unique selling point. The brand name for colesevelam is Welchol.
� Colestipol: Available as coated tablets, flavored granules, a liquid, or in packets of powder (to be dissolved in water). The brand names for colestipol are Colestid and Lestid.
Taking low doses of bile sequestrants (8 gram/day) may knock cholesterol levels down by 10 to 15 percent. Tripling the dose may lower LDL levels by 25 percent.
Taking bile sequestrants with a second drug improves their performance. For example, in one drug trial, taking colesevelam alone cut total cholesterol by about 10 percent and LDLs by about 18 percent. Taking colesevelam plus a statin drug cut total cholesterol up to 21 percent and LDLs up to 32 percent.
The side effects of bile acid sequestrants
Bile acid sequestrants have been in use for so long that their overall long-term safety is well established. But there are some drawbacks:
� Common side effects: Constipation, loss of appetite, gastric upset (indigestion, gas, nausea, vomiting, diarrhea), headache and dizziness, muscle and joint pain, discolored teeth
� Less common, more serious side effects: Reduced absorption of calcium, leading to increased side effects; risk of osteoporosis (loss of bone density); vitamin deficiencies due to reduced absorption of vitamins A, D, E, and K, as well as the B vitamins folic acid and niacin; decreased effectiveness of painkillers, diuretics, some diabetes drugs, some antibiotics, and some antifungal drugs
To reduce the side effects of bile acid sequestrants, the FDA suggests that you
� Start with small doses.
� Drink a lot of water to prevent constipation.
� Ask your doctor about the need for nutritional supplements and the possibility of drug interactions.
Finishing off another kind of fat: Triglyceride inhibitors
Triglyceride inhibitors are medicines that reduce your liver’s natural production of triglycerides, a fat that circulates in your blood. Lowering the level of triglycerides means you convert less dietary fat to lipoproteins. As a result, triglyceride inhibitors lower the production of LDLs, the “bad” cholesterol. No surprise there. But for some unknown reason, they also increase the levels of HDLs, the “good” cholesterol. Down with the bad, up with the good. Go figure.
The most commonly used triglyceride inhibitors are fibrates and the B vitamin niacin, which are covered in the following sections.
Fighting cholesterol with fibrates
Fibrates, also known as fibric acids, are a class of drugs that reduce blood levels of triglycerides and increase the levels of HDLs (“good” cholesterol). The fibrates include clofibrate (Atromid-S), fenofibrate (Tricor), and gemfi- brozil (Gemcor, Lopid). Because these drugs haven’t been shown to reduce the overall incidence of heart attack, they’re not considered first-line treatment.
The fibrates come in capsules to be taken twice a day — 30 minutes before breakfast and 30 minutes before dinner. What? You have to get up half an hour early to take a pill? Oh, well . . .
Because taking fibrates may raise blood sugar, these drugs are rarely prescribed for people with diabetes. Following are other possible side effects of fibrates:
� Common side effects: Allergic, itchy, skin rashes and hives; blurred vision; fatigue; gastric upset (diarrhea, gas, nausea, vomiting); headache and dizziness; muscle aches
� Less common, more serious side effects: Flu-like symptoms (chills, fever, sore throat); gallstones; kidney failure; lower blood levels of potassium; lower levels of white blood cells (the cells that protect against infection); muscle weakness or loss of muscle tissue; Raynaud’s syndrome (constriction of small blood vessels in hands and feet)
Nipping the numbers with niacin
The recommended dietary allowance (RDA) for niacin is 16 mg/day for a man, 14 mg/day for a woman. Taking much larger amounts of this familiar B vitamin appears to reduce triglycerides. For example, in various clinical trials, people taking doses of niacin up to 375 mg/day were able to cut their total cholesterol levels by up to 10 percent and their LDLs by up to 14 percent while raising their HDLs by as much as 25 percent.
In addition, niacin/nicotinic acid dilates blood vessels so that (theoretically) blood flows more easily through even clogged blood vessels. When niacin dilates blood vessels, it causes a feeling of warmth and flushing much like the “hot flashes” many women experience at menopause. To reduce this effect, doctors who prescribe niacin often opt for the sustained release or extended release form of the med. Instead of sending niacin zooming into your bloodstream as soon as — or pretty soon after — you take the pill, these babies release their niacin slowly, over several hours. In 2006 and 2007, several studies showed that combining niacin with a statin drug was an even more effective treatment.
Currently, niacin is available as a single ingredient drug either as a generic or under the brand names Niacor, Nicolar, Niaspan, and Slo-Niacin. Advicor is a sustained release combination drug containing niacin and lovastatin (Mevacor) in two doses: 500 mg niacin/20 mg lovastatin and 1,000 mg niacin/20 mg lovastatin.
Questioning a cholesterol buster
The scenario is familiar: You open your morning newspaper or turn on the evening news and read or hear that a prestigious pharmaceutical company has discovered a splendiferous new medicine that will solve one of your most pressing health problems like, oh, high cholesterol. The FDA has signed on, so you hotfoot it over to the doctor who prescibes the new med. And then what happens? Two weeks, two months, or two years down the road — “Oooops!” they say. “We think we missed something here.”
Ezetimibe (Zetia) is the first prescription drug created specifically to lower LDLs (“bad” cholesterol) by reducing your body’s absorption of the cholesterol in food. The med was introduced in 2003 as a single ingredient product (Zetia) and in 2004 as the second ingredient (along with simvastatin) in the combo pill Vytorin. When the FDA approved ezetimibe in 2003, it did so on the basis of several small trials, none of which ran longer than three months — and which hinted at trouble ahead. The people in the trial took either ezetimibe or a look-alike pill without ezetimibe, and the people in the ezetimibe group were 11 times more likely to experience serious adverse effects, most commonly liver damage. (Other possible side effects in the ezetimibe group — allergic reactions, increased risk of gallstones, and potentially serious muscle and liver damage — were described as “rare.”)
In December 2007, this situation became more troublesome when non-government experts on drug safety, including researchers at the University of Washington, discovered that Merck and Schering-Plough, the companies
that jointly market ezetimibe, had not published the data from a 2-year, 760-person clinical trial called “Enhance” that ended in April 2006 and was originally scheduled to be made public in 2007. The FDA said the agency had seen the unpublished studies and considered ezetimibe safe, but in January 2008, when the study was finally published, ezetimibe’s rep took a tumble.
The Enhance study was designed specifically to show that ezetimibe not only lowers LDLs (“bad” cholesterol), but also — like statins — reduces the buildup of plaque inside blood ves- sels that can lead to heart attack and stroke. In fact, that did not happen. Patients in the trial took either simvastatin (Zocor) alone or a com- bination of simvastatin and ezetimibe (Vytorin). Simvastatin alone lowered LDLs by 41 percent on average; simvastatin plus ezetimibe, by 58 percent. But among patients given the combi- nation pill, the plaque accumulated twice as fast as among those taking simvastatin alone. In short, taking ezetimibe appeared to increase the risk of both heart attack and stroke.
Many experts called this development “shock- ing.” Others said the data required further investigation. Congress called for an inquiry into the delay in releasing the trial results. Merck and Schering-Plough announced that the results of a longer, larger study of ezetimibe would be released in a few years. Patients and doctors fumed.
As of this writing, both Zetia and Vytorin are still on the market, but stay tuned — and if you are taking either one, be sure to check with your doctor for the latest update.
The possible side effects of single-ingredient niacin are as follows:
� Reduced effectiveness of diabetes medicines
� Reduced effectiveness of drugs used to treat gout (a form of arthritis)
� Reduced effectiveness of painkillers and anti-inflammatory drugs such as ibuprofen (Advil), naproxen (Naprosyn), and naproxen sodium (Aleve and Anaprox)
� Liver damage (high doses)
� Dizziness
Check earlier in this chapter for the side effects of statin drugs.
The word niacin is used interchangeably for two different chemical compounds, nicotinic acid and nicotinamide (also known as niacinamide). Nicotinic acid reduces levels of triglycerides. Nicotinamide does not. Also, the niacin sold as a dietary supplement (vitamin) isn’t a substitute for prescription niacin, a product whose use must be monitored by your doctor.
Comparing the Benefits of Cholesterol-Buster Drugs
Assuming that you worked your way through all the paragraphs before this, you’re now definitely an expert on the virtues of the various drugs your doctor may prescribe to lower your cholesterol. What? You didn’t read every single word? Twice? Not to worry. Table 12-2 pretty much sums it all up as of Winter 2008.
The doses listed in Table 12-2 are the highest prescribed in one day. They are not the doses prescribed for every patient. In fact, your doctor may achieve satisfactory results — lower LDLs — with lower doses. Do not change your dose of any of these medicines without your doctor’s approval!
Picking the Perfect Pill Candidate
Should you be using a cholesterol-lowering medicine? Maybe. One way to decide is to review the recommendations of the experts at the National Heart, Lung, and Blood Institute’s Web site: www.nhlbi.nih.gov. The recommendations are contained in two reports:
� The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
� ATP III Update 2004: Implications of Recent Clinical Trials for the ATP III Guidelines
To save time, ink, and the lives of all the trees that would otherwise be cut down to make the paper for the extra pages required to print that entire title over and over again, I’ve made an important decision. From now on, I refer to these reports by their nicknames: ATP III and ATP III Update. If you’re absolutely committed to reading both reports in their mind-numbing entirety, feel free to visit www.nhlbi.nih.gov/guidelines/cholesterol/index.htm.
Meanwhile, I dance through the highlights:
� In the context of ATP III and ATP III Update, a major risk factor is diabetes, high blood pressure, high levels of LDLs, high levels of triglycerides, smoking, being older than 45 (men) or 55 (women), or having a family history of early heart disease (before 55 for your dad, before 55 for your mom).
� To estimate your risk of suffering a heart attack in the next ten years, click the interactive National Cholesterol Education Project (NCEP) Risk Assessment Tool for Estimating Your 10-Year Risk of Having a Heart Attack at http://hp2010.nhlbihin.net/atpiii/calculator.asp.
No computer handy? Zip over to the library computer, or check with your doctor.
Categorizing risk
ATP III divided Americans into four large categories based on their risk of heart disease. The categories are
� High risk: Known coronary artery disease and/or blocked arteries in the legs or brain, plus multiple major risk factors
� Intermediate risk: No known vascular disease, at least two major risk factors, and 10 to 20 percent risk of heart attack in the next ten years
� Moderate risk: No known vascular disease, at least two major risk factors
� Low risk: One or no major risk factors, less than 10 percent risk of heart attack in the next ten years
The ATP III Update revised the risk categories as follows
� Very high risk: Previous heart attack or stroke, plus several major risk factors
� High risk: Known coronary artery disease and/or blocked arteries in the legs or brain, plus multiple major risk factors
� Moderately high risk: No known vascular disease, at least two major risk factors
� Moderate risk: No known vascular disease, at least two major risk factors
� Low risk: One or no major risk factors, less than 10 percent risk of heart attack in the next ten years
As a result of this update, several million more Americans were now classified as being at high risk or very high risk, necessitating — you guessed it — more meds.
Recommending treatment
The treatment recommendations in both ATP III and ATP III Update are both based on the proposition that lowering a person’s level of LDLs lowers her risk of heart attack. The difference lies in the decision about who needs to be treated and how low she needs to go.
ATP III’s treatment recommendations were simple:
� The first line of defense in ATP III is diet. The report recommends that a whopping 65 million Americans change what they eat in order to lower their cholesterol.
� If changing the diet doesn’t do the trick, the NHLBI recommends that an almost-equally-whopping 35 million Americans with a more than 20-percent risk of heart attack in the next ten years and/or an LDL level higher than 130 mg/dL begin drug treatment to push their LDLs down to 100 mg/dL.
The treatment recommendations in the ATP III Update are dramatically different:
� For people in the very high risk and high risk categories, the recommended level of LDLs was lowered to 70 mg/dL, a level virtually impossible to reach without drugs.
� If a very high-risk or high-risk person has high levels of triglycerides, a fibrate or nicotinic acid should be given along with a cholesterol- lowering med.
� The best option for moderately high-risk people is to aim for LDL levels less than 100 mg/dL. Any moderately high-risk person with LDL levels of more than 130 mg/dL plus major risk factors is a candidate for cholesterol- lowering drugs.
� Low-risk people don’t have to take cholesterol-lowering drugs.
Seems like practically everyone you know is a candidate for cholesterol-buster meds. Not surprisingly, that conclusion hasn’t been universally applauded.
Many critics note (correctly) that the ATP III Update pretty much ignores the benefits of lifestyle changes such as diet and exercise, while passing over studies showing virtually no benefits in giving cholesterol-lowering meds to older people. Others are distressed by the makeup of the ATP III Update panel: Eight of the nine panel members had financial ties to companies producing cholesterol-lowering drugs. Ooops.
As the debate simmers, will the ATP III Update recommendations become the norm? Maybe. Should you check with your own doctor before diving into drugs? You bet. Case closed.
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