Editor's Note: Dr. Brinton is Director of the Metabolism Section of Cardiovascular Genetics, and Associate Professor at the University of Utah School of Medicine, Salt Lake City, Utah. He is board certified in internal medicine and endocrinology.
Dr. Brinton's areas of clinical interest include the management of dyslipidemia and prevention of atherosclerosis and the treatment of diabetes mellitus and metabolic syndrome. He also has research interests in lipoprotein metabolism and HDL-cholesterol metabolism in vivo and in vitro, including the effects of estrogen and other agents.
The author of numerous original scientific studies, Dr. Brinton has received many peer-reviewed research grants, and has held numerous leadership and advisory positions in scientific and governmental organizations, and in the pharmaceutical industry. He is a founding board member of the National Lipid Association. Dr. Brinton was interviewed for Medscape by Linda Brookes, MSc.
Medscape: Why is the safety of statins such a widely discussed issue at the moment?
Dr. Brinton: The safety of statins is of great interest to the public, as well as to clinicians and policy makers, in part because of the problems with the safety of cerivastatin (
Baycol, Bayer), which ultimately led to its withdrawal from the market. With the recent advent of a new statin, rosuvastatin (
Crestor, AstraZeneca), these concerns have resurfaced. Medication safety is always an issue, but especially so with the statins, for several reasons. First, and perhaps most importantly, they are prescribed frequently. Statins are the single most prescribed category of agents, in dollar value, in the United States today. Second, they are prescribed for long periods of time. Over the many years that a typical patient takes a statin, there are many chances for adverse events, including unforeseen changes in the patient's health status. A third and very important factor is that statins are most commonly used in middle-aged or elderly patients, who tend to be taking many other medications for other problems. This heightens safety concerns, both because the polypharmacy typical of these age groups greatly increases the overall risk of drug-drug interactions and because many of the diseases common in older patients contribute to drug safety concerns, and finally, because advanced age itself, even with excellent health, probably increases the risk of drug toxicity.
Medscape: There has been much discussion about myopathy in relation to statins. What is the difference between myopathy, myalgia, and rhabdomyolysis?
Dr. Brinton: There are 4 interrelated terms for muscle problems that can occur with statins. Unfortunately, they are often confused even by healthcare professionals.
Myopathy is a general term for disease of the muscles, and it is usually characterized by weakness. In the setting of statin treatment, myopathy is used to describe any muscle problem, whether or not it is actually related to the statin use.
Myalgia refers specifically to pain in the muscles. Muscle pain is often seen with statin-based myopathy; however, painless myopathy from statin therapy is also quite common and may be rather dangerous because it is often ignored. If the healthcare provider has not instructed the patient to look for this, the patient may not report it or, if the patient reports weakness without pain, the healthcare provider may not recognize it as constituting a true myopathy.
Myositis is inflammation of the muscle confirmed by histologic findings of muscle biopsy. We rarely know whether the patient has myositis because we rarely perform muscle biopsies. These are very accurate and, in many ways, they are the gold standard for diagnosing a statin-induced myopathy; however, the pain, inconvenience, and cost of biopsies make them impractical for most clinical and research settings. Since the word myositis is probably best reserved for biopsy-proven myopathy, it is not of much use. A recent study
[1] showed that patients without an elevation of their serum creatine phosphokinase (CPK) level can nevertheless have myositis on biopsy. Thus, we need to have a fairly high index of suspicion for myopathy, realizing that it may be more common than we think, especially if we are looking only for myalgia or only for an elevated CPK.
Finally,
rhabdomyolysis is the extreme type of myopathy, in which the muscle tissue is so inflamed that it breaks down in large quantities. It brings large amounts of myoglobin, the predominant muscle protein, to the circulation from which it then has to be removed by the kidney. Since the kidney is not well equipped to handle large amounts of myoglobin, it can become overwhelmed and damaged. Although the kidney usually recovers over time, rhabdomyolysis may be fatal due to acute renal failure and sequelae to other organs. Thankfully, most cases of rhabdomyolysis do not result in death, although they usually require hospitalization. Due to its seriousness, rhabdomyolysis is better prevented than treated, so we must do our best to see that myopathy does not progress to rhabdomyolysis.
Medscape: How often does myopathy occur?
Dr. Brinton: In most clinical trials involving statins, less than 1% of subjects are reported to develop myopathy. In clinical practice, however, far more than 1% of patients will experience at least 1 symptom of myopathy. The much lower rate reported in clinical trials may be because eligibility criteria usually exclude patients with significant potential for drug-drug interactions or concurrent health problems, whereas healthcare providers cannot usually exclude those patients in clinical practice. Some studies have suggested that a quarter or even upwards of a third of patients who take statins will sooner or later develop a clinically significant myopathy.
Medscape: What are the risk factors for myopathy?
Dr. Brinton: The main risk factors for myopathy are: female gender, advanced age (> 60 years) dehydration, underlying renal or liver disease, and concomitant medications. There is a fairly long list of medications that increase the risk of myopathy. Some of these are relatively specific for one statin vs another, but most of them appear to apply to all statins.
Medscape: How do you monitor patients for myopathy?
Dr. Brinton: The first and best step is to ask about symptoms, but we have to be careful to ask about the right ones. We must ask not only about muscle pain, but about weakness and stiffness. Sometimes there can be stiffness without identifiable weakness or pain. When I start patients on a statin, I mention that they may experience any 1 or a combination of these 3 symptoms. I always make it a point to ask my patients about those 3 symptoms as I follow them in the clinic.
I measure CPK prior to starting statin treatment, and then, rather than measuring follow-up CPK levels routinely, I do so only when a patient presents with symptoms suggestive of myopathy. The reason for this is that CPK levels vary tremendously from day to day, and one may see a spurious elevation of CPK that has nothing to do with statin-based myopathy. If a patient has convincing myopathic symptoms but a normal CPK, I will defer to the patient and treat it as a true case of myopathy. If, in contrast, the CPK is clearly elevated but the muscle symptoms are somewhat equivocal, then the CPK elevation can be helpful to determine whether or not the patient has a true myopathy. Also, the degree of CPK elevation can be useful in estimating the severity of a myopathy.
Some physicians and lipidologists do not measure CPK at all, because the correlation is fairly poor between CPK levels and symptoms, but I find it useful for the above reasons. In any case, however, one should not rely on the CPK level to diagnose myopathy, because even a relatively severe case of myopathy may have normal or minimally elevated CPK.
Medscape: Can CPK be used to exclude patients from starting a statin?
Dr. Brinton: A patient with a very high CPK elevation initially should not be started on a statin. This is another reason to measure CPK at baseline. The upper threshold for a clinically significant CPK is quite high, 10 times the upper limit of normal, because CPK levels are so variable. If a patient develops a CPK over 10 times the upper limit of normal on statin use, you should stop statin therapy, at least temporarily, and consider either lowering the dose or switching to a different statin. In rare cases, for example, in a patient with a history of rhabdomyolysis, one may need to abandon the statin class altogether, even perhaps without trying other available statins.
Medscape: Are there other signs that would exclude a patient from treatment with a statin?
Dr. Brinton: Individuals with chronic active hepatitis are not good candidates for statin therapy. But one subset of patients with hepatitis -- those with nonalcoholic steatohepatitis (NASH), where the hepatitis is due to fatty infiltration of the liver -- may actually improve with a statin or other lipid-lowering agent.
Medscape: If CPK levels become elevated once a patient has started on a statin, do you always stop the drug?
Dr. Brinton: There are several different levels of action one can take if one suspects myopathy. If the myopathy appears to be mild or equivocal, the best action may simply be to continue the statin and monitor the patient without reducing the dose.
A second option, for slightly more severe but still relatively mild cases, is to stop the statin temporarily and allow the symptoms to resolve. This also will allow a CPK elevation, if present, to normalize. Later one can rechallenge the patient at the same dose of the same drug. This approach can be useful in cases where the statin may not have been responsible for the myopathy.
In a third scenario, where the symptoms are more severe and the case is more troubling biochemically and/or clinically, one may conclude that the particular dose of that particular statin is no longer tenable. If this occurs at a high statin dose, one can consider giving a lower dose of the same statin or switching to a different statin. There are few published data about switching statins in this way, and most of our experience is anecdotal, but I can say that switching to a different statin often resolves the symptoms.
Finally, as I mentioned earlier, there are cases of myopathy so severe that one does not dare go back to any dose of any statin.
Medscape: How often are the symptoms of myopathy simply due to negative expectations on the part of the patient?
Dr. Brinton: One very interesting aspect of statin therapy is that physicians are pretty much required to create an adverse expectation, or negative placebo effect, when initiating statin therapy. This is true primarily for myopathy but can occur with other safety questions as well. Most of our patients know already that statin safety is an issue, but whether they do or not, as we start a patient on a statin for the first time, we are obligated to point out its possible adverse symptoms and effects. We must describe the symptoms of myopathy and ask patients to watch out for them. We also need to inform the patient of the possibility of liver dysfunction and perhaps other potential adverse events. Such warnings give patients the expectation that they are going to have a problem, and probably make it more likely that they will have adverse symptoms.
Patients' heightened awareness of the risks of statin therapy is good in the sense that if something truly bad happens, they are more likely to notice it early and contact us promptly. But it also means that when a patient reports muscle symptoms, we do not always know if myopathy is really present. Everyone has aches and pains; and so their association with drug treatment is often open to question. So we are setting up our patients to find something that may not truly exist. The good news, however, is that we can turn the effects of our suggestions to our advantage when and if a patient reports symptoms of myopathy. We do this by explaining that the myopathy often resolves with whatever course of action we have chosen from the several options I mentioned earlier. Whether we have the patient continue, temporarily stop, reduce the dose, change drugs, or stop statins altogether, we suggest that his/her symptoms will improve soon. We thus create a positive placebo situation. When the patient hears from his trusted healthcare provider that his symptoms are likely to get better, it becomes much more likely to occur.
Obviously we will not ignore a true myopathy, but it is reasonable to try to reverse any negative anticipation on the part of the patient, which may worsen any symptoms otherwise present.
Medscape: How do the statins compare in their propensity for inducing myopathy?
Dr. Brinton: First, we have to acknowledge that despite the clinical importance of statin-induced myopathy, we understand very little about its causes, which makes it hard to develop good treatments or preventive strategies.
Statin-induced myopathy is strongly dose related, so low doses of a given statin are usually much less likely to cause myopathy than high doses. For this reason, and perhaps because muscle benefits from statin-free periods of recovery, every-other-day dosing of a statin can be helpful in reducing muscle symptoms. This dosing regimen may be especially attractive for a statin with a longer half-life, or for a sustained-release formulation, where the longer dosing interval may still provide relatively continuous suppression of hepatic cholesterol synthesis, and hence still provide effective cholesterol lowering.
There are differences among the statins in terms of their propensity to cause myopathy. The statins that carry a higher than average overall risk are among the more potent: lovastatin (
Mevacor, Merck;
Altocor, Andrx; and generic) and simvastatin (
Zocor, Merck). Myopathy risk is not, however, simply directly proportional to cholesterol-lowering efficacy, since it appears to be relatively low with atorvastatin (
Lipitor, Pfizer), and may not be elevated with rosuvastatin (
Crestor, AstraZeneca), which are the most effective for LDL cholesterol lowering. By contrast, the 2 statins that appear to have lower-than-average risk of myopathy are fluvastatin (
Lescol, Reliant) and pravastatin (
Pravachol, Bristol-Myers Squibb). These can be especially useful in patients with symptoms or risk of myopathy.
Pravastatin has been considered by many as the only safe statin with regard to myopathy. Evidence in the scientific literature, however, is actually stronger for fluvastatin as having the lowest myopathy risk. There are few comparative data between fluvastatin and pravastatin, but in the Assessment of Lescol in Renal Transplantation (ALERT)
[2] study, fluvastatin passed perhaps the most severe test of myopathy risk. That trial included more than 2000 patients who had undergone renal transplantation and were taking cyclosporine. Half of these, or about 1000 patients, also took fluvastatin.
Surprisingly, over several years of follow-up, the patients receiving both cyclosporine and fluvastatin were at no higher risk for myopathy than those on placebo. This is impressive evidence for a low myopathy risk with fluvastatin. We are often looking to use statins in such high-risk patients, and so the ALERT data are very encouraging with regard to the use of full-dose fluvastatin for atheroprevention when the risk of drug-drug interaction is high.
Medscape: What about other drug interactions?
Dr. Brinton: Fluvastatin and pravastatin each appears to have fewer drug-drug interactions than other statins. Although some clinicians have felt that the safety of pravastatin was primarily due to its water solubility, the other water-soluble statin, rosuvastatin, has yet to be fully proven as safe. Moreover, fluvastatin, which is not water soluble, has excellent safety data, few potential adverse drug-drug interactions, and appears to be as safe as, or even safer in many contexts than pravastatin.
Mention has been made in the scientific literature about the risk of myopathy when the dosage of a statin is increased in patients concurrently receiving niacin. Interestingly, however, there is a Food and Drug Administration (FDA)-approved tablet (
Advicor, Kos) that combines extended-release niacin (
Niaspan, Kos) and generic lovastatin, and appears to carry no excess myopathy risk. Use of any combination therapy for lipid disorders should not be done in a cavalier manner, but the added risk of myopathy with niacin plus a statin appears to be at least as low as it is for fenofibrate.
Gemfibrozil is a very commonly used fibrate that is inexpensive and well proven to reduce coronary heart disease (CHD) events. However, it increases circulating statin levels and possibly CPK levels and muscle symptoms when administered with all the statins except fluvastatin. So fluvastatin is particularly useful in this situation. By contrast, the other fibrate available in the United States, fenofibrate, appears to be safe in combination with all statins. Unfortunately, it is more expensive and less widely available on managed care formularies. Also, its ability to reduce CHD events is not as well proven.
I should also mention that the bile acid sequestrants have a likely adverse interaction with statins in that if they are taken at the same time as the statin, they may reduce its absorption. This is also true of many other medications. Otherwise, however, there are no safety or toxicity issues surrounding the concurrent use of bile-acid sequestrants and statins. The intestinal cholesterol absorption inhibitor ezetimibe (
Zetia, Merck/Schering Plough) has no adverse interaction with statins. Specifically, the likelihood of statin myopathy is not increased by concurrent ezetimibe use and any effects on liver dysfunction are very small. If anything, ezetimibe may reduce myopathy risk by allowing a reduction in the statin dose needed for a given patient.
Medscape: How do you follow transaminases in patients on statins?
Dr. Brinton: We measure transaminases at baseline, either alanine aminotransferase or aspartate aminotransferase or both. If one reading is > 3 times the upper limit of normal, a statin should not be started except to treat NASH. Follow-up usually consists of another transaminase at the next visit, usually after 2 or 3 months. If a transaminase elevation occurs, it usually happens early in the course of the statin use, so a single measurement after starting the statin is usually sufficient. The one exception to this rule is a patient with underlying liver disease or a high risk of it, such as a binge drinker. In lower-risk patients, transaminases need be measured in follow-up primarily only if the statin dose is increased, if the patient is switched to another statin, or if another medication like niacin, a fibrate, or ezetimibe is added.
Medscape: Which patients are more likely to have elevations of transaminases while on statins?
Dr. Brinton: Risk factors for transaminase elevation are advanced age, female gender, alcohol use, and prior history of hepatitis.
Medscape: What do you do in a case of transaminase level elevation?
Dr. Brinton: The approach is much the same as it is for myopathy. One has several options. If the elevation is minor, one can continue the statin and check the transaminase levels again. If the elevation is more significant, one can stop the drug and then consider rechallenging the patient at the same dose. If it is more severe, one can lower the dose of the same statin since transaminase elevations are usually dose-related. Finally, one can switch to a different statin. Of course, one can always try to reduce or eliminate the adverse effects of other hepatically adverse factors, such as other hepatotoxic drugs. There does not appear to be any large difference among statins in terms of risk of transaminase elevations.
Medscape: What are the properties of statins that affect their safety profile?
Dr. Brinton: The statins that are metabolized through the cytochrome P450 3A4 systems are more prone to drug-drug interactions because so many medications use the same pathway. Other cytochrome P450 pathways are much less problematic. Two statins are available in extended-release formulation: fluvastatin (
Lescol XL, Reliant) and lovastatin (
Altocor, Andrx). Both probably reduce the tendency for systemic complications of the drug, such as myopathy and possibly other drug-drug interactions. This is especially important when choosing a statin for a patient who may be at elevated risk of 1 or more drug-drug interactions, due to polypharmacy, frailty, or advanced age.
Both fluvastatin and rosuvastatin are metabolized primarily by the cytochrome P450 2C9 pathway, yet they appear to have different safety profiles. We do not know why this might be. We have much safety evidence for fluvastatin, but little so far for rosuvastatin. Recent concerns about an apparent excess of myopathy induced by high-dose rosuvastatin have prompted the European Union (EU) to make its label for rosuvastatin more conservative regarding the recommended starting doses. Although this only brings the EU label closer to the existing US label for this agent, the FDA has felt the need to alert healthcare practitioners to carefully follow US label instructions to reduce myopathy risk.
Medscape: Are there other safety concerns with the statins?
Dr. Brinton: Just about any drug can cause headache, skin rash, fatigue, and malaise, but statins do not cause these any more than placebo. One or two earlier studies suggested that statins increase the risk of cancer, but more recent reviews show no increase in any cancer with any statin.
[3]
Medscape: What is the rationale for combination therapy in treating dyslipidemia?
Dr. Brinton: Combination therapy is, I believe, the wave of the future for the management of dyslipidemia. First, we are learning more and more about the benefits of LDL-cholesterol lowering. We have long known that LDL-cholesterol levels strongly predict CHD risk, but we are continually seeing new data suggesting that the lower the level of LDL-cholesterol, the better. Which is not to say that we should treat every patient to lower his or her LDL-cholesterol to, say, 40 or 50 mg/dL, but in patients at unacceptably high risk, more aggressive LDL-cholesterol lowering can be useful.
Even with more effective statins, cost, safety, and logistical concerns often make it impossible to attain the desired level of LDL cholesterol with statin monotherapy. The problem is that doubling the dose of any statin gives only about an additional 6% LDL-cholesterol-lowering effect, while that same doubling may bring a significant increase in cost, and a geometric rise in potential toxicity. An exception to these rules about uptitration is fluvastatin in the extended-release formulation (
Lescol XL) at the 80-mg dose, which is the dose and formulation of this agent most often used. In this one case, you actually pay less to uptitrate a statin. Second, there is no increase in safety concerns with this dose and formulation compared to lower doses of fluvastatin or other statins. It may, in fact, be the safest statin of all. Third, as an extended-release formulation, it has more LDL-cholesterol-lowering efficacy than the immediate-release form.
Medscape: Are there benefits of statin combination therapy beyond greater LDL-cholesterol lowering?
Dr. Brinton: There are other, independent benefits of combination therapy in terms of atheroprevention. For example, we know that niacin lowers lipoprotein (a) and that statins do not. So adding niacin to a statin will give that added dimension that you cannot get from a statin. In addition, niacin would be much more effective in raising HDL cholesterol than any statin. For triglyceride lowering, a fibrate is more effective than a statin. Even though niacin is comparable with statins in terms of its triglyceride lowering, adding niacin to a statin will give more triglyceride lowering than a statin alone. Ezetimibe, which is a not a very potent HDL-cholesterol-raising or triglyceride-lowering drug, will add to the HDL-cholesterol-raising effect and the triglyceride-lowering effect of statins, just as it adds to the LDL-cholesterol lowering.
Another advantage for combination treatment is in atheroprevention. Most statins reduce cardiovascular events by 20% to 35%. Studies of combination therapy have generally shown an event reduction of 70% to 90%, and even though we cannot extrapolate directly from this, clinical data strongly suggest that combination therapy is much more efficacious in reducing cardiovascular events, which is not surprising given that the lipid-lowering effect is much greater. Thus, almost without exception, adding an agent to a statin will give at least additive lipid benefit, and in some cases an additional benefit that a statin cannot give. As we learn more and more about atheroprevention and have more targets for therapy and more aggressive goals with those targets, combination therapy will become more and more appealing, not only in terms of efficacy with regard to lipids and atheroprevention, but also from a safety standpoint.
Combination therapy has not been widely used in the past, but it is increasing and I anticipate that it will continue to increase. Only 1 combination tablet is currently available in the United States, lovastatin plus extended-release niacin (
Advicor, Kos), which produces more LDL-cholesterol lowering and a greater increase in HDL-cholesterol than either agent alone. There is indirect evidence that it may be effective in terms of event reduction. Another combination tablet that will be available soon in the United States, simvastatin plus ezetimibe (
Vytorin, Merck/Schering Plough), is very promising.
Not every patient who needs to be treated for dyslipidemia should get 2 or more drugs, but in general we are undertreating our patients. Combination therapy is often a much better way to increase treatment benefit than uptitration of statin monotherapy.
Medscape: With safety in mind, what is your opinion about the possibility of statins being made available over the counter (OTC)?
Dr. Brinton: The FDA is currently considering whether statins should be made available without a prescription in the United States. OTC status would make statins more widely accessible and more widely used, which would address one of the biggest single problems with statins in this country, which is that they tend to be underutilized.
Despite that major advantage, however, there are a number of serious objections to making them available over the counter, the first of which is the safety issue. Although statins are quite safe, the safety issues are best addressed by a physician or other licensed healthcare provider. Even though I am confident that the vast majority of patients would have no safety problems with OTC statins, I believe that many significant and even severe safety problems would arise that could not be handled by laypersons. Another disadvantage is that statin use is always based on baseline lipid levels and the availability of OTC lipid testing is somewhat limited and problematic. I am certain that cholesterol testing performed by regular laboratories in a controlled setting with proper standards and controls is far superior to the type of testing that a patient could do at home.
Other issues that would arise with OTC status are related to coordination of treatment of dyslipidemia with other atheropreventive measures. I believe that there is much benefit in having healthcare professionals involved in issues such as diet and exercise, smoking cessation, treatment of obesity, insulin resistance, diabetes, and hypertension, and in the screening for progression of disease. Other serious concerns would be that statins might be used inappropriately, such as by someone who does not need them, or there could be overtreatment or inappropriate choice of a statin. This currently happens only rarely.
And so there are many reasons why the movement to make statins available over the counter is a bad idea. I am very much in favor of patient empowerment and involvement, but I believe that because of the complexities of atheroprevention in general and lipid treatment in particular, we are ill-advised to make these very powerful medications available to the general public without proper supervision by a physician.
Conclusion
As a class, the statins are remarkably safe and their use in patients who need LDL lowering for atheroprevention has a very high benefit/risk ratio. But because they are most commonly used in older patients with complicated health histories, and because of heightened public concerns, we must always remember to address several safety issues when prescribing statins. Although there is increasing impetus toward more and more aggressive lipid-lowering therapy, we need to keep the following always in mind:
- Safety, cost, and efficacy considerations often point to:
- Use of lower doses of a given statin and/or
- Use of safer statins such as fluvastatin and pravastatin; and
- Use of other agents (ezetimibe, niacin, fibrates, and/or sequestrants) in combination with statins for greater LDL-lowering and/or other lipid benefits
- When starting statins, patients must always be informed of potential safety risks, and any symptoms or signs of adverse effects must be taken seriously and handled properly.
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