Ronald M. Krauss, M.D., is Senior Scientist and Director of Atherosclerosis Research at Children’s Hospital Oakland Research Institute (CHORI), where he holds the Dolores Jordan Endowed Chair. He is also Professor of Medicine at the University of California, San Francisco, and Adjunct Professor of Nutritional Sciences at UC Berkeley, as well as a member of the Editorial Board of the UC Berkeley Wellness Letter and BerkeleyWellness.com, and coauthor of the Wellness Report Controlling Your Cholesterol. In his specialty clinical practice, Dr. Krauss treats many patients who have statin intolerance, which is the main focus of this interview.
How often do adverse effects occur with statins?
Statin intolerance includes a range of possible side effects. Among these, it’s clear that muscle-related symptoms—including muscle weakness and, in particular, muscle pain—are by far the most frequently encountered in clinical practice and in the scientific literature. The prevalence of this has been reported in anywhere from 5 to 20 percent (or possibly even more) of people taking statins, depending on the studies, which is higher than the range we previously reported. It’s hard to put an exact number on it because muscle symptoms are subjective.
These new numbers are based on large population studies, not clinical trials. If one looks at the evidence from controlled clinical trials, where people are randomly assigned either a statin or placebo and are studied carefully, the risk of muscle symptoms appears to be much lower: 5 percent or less. There has been a lot of debate as to why that should be. One of the concerns is that people who enter these clinical trials may not represent the general population and may initially be more tolerant of statins.
Keep in mind that statin-related muscle inflammation and damage occur on a continuum. Usually the problem is mild and manifests itself as muscle discomfort or weakness. More serious muscle damage, or myopathy, causes moderate to severe pain. The most serious muscle disorder caused by statins, called rhabdomyolysis, can damage the kidneys and lead to kidney failure, but is rare, occurring in perhaps 1 in 10,000 to 15,000 statin users.
When do muscle symptoms develop with statin use, and are there predisposing factors?
Muscle symptoms can occur at almost any phase of statin use. They often occur shortly after statins are started, but sometimes much later. I’ve had patients who took statins for years, and when I increased their dose because their cholesterol levels had gone up, that triggered muscle problems that were not apparent at the lower dose.
For the vast majority of patients, there is no way to predict who will develop muscle symptoms. A very small minority of patients may be at elevated risk due to a genetic predisposition to muscle disease. My research program is partly dedicated to identifying markers that could help us predict that risk.
Many factors can increase the risk of muscle damage and other side effects, notably being over 80, female, or underweight; high statin doses; any disease affecting kidney or liver function; drinking grapefruit juice; dehydration; excessive alcohol intake; a family history of statin intolerance; certain medical conditions such as hypothyroidism; and taking certain other drugs. Some statins are more likely to cause adverse effects than others.
Another potential factor is the “nocebo effect,” which is the flip side of the placebo effect. This occurs when people experience certain side effects due to negative expectations, perhaps because they read about possible risks.
What about the rise in blood sugar that some people experience with statin use?
Other than muscle symptoms, the only other relatively common statin-related adverse effect is an increase in blood sugar, which can lead to the development of type 2 diabetes. Estimates vary, but this may affect about 10 percent of people, with a considerably higher prevalence among women than men. That’s why blood glucose levels should be monitored periodically in people taking statins. Typically the rise in blood sugar occurs in people who are already at elevated risk for developing diabetes, such as those with prediabetes or a family history of the disease. Also at higher risk are older people or those taking higher doses of statins. Nevertheless, for most people, the cardiovascular benefits of statins outweigh this diabetes risk.
What are other common or well-studied side effects that you have encountered?
Statins have also been studied in terms of a wide range of potential adverse effects besides muscle problems and diabetes. The best studied of these include changes in cognitive function (including Alzheimer’s disease) and changes in liver function that could, in theory, predispose to liver damage. Researchers have also looked at the effects on kidney function and on the risk of hemorrhagic stroke.
In early 2018, I was part of a consensus panel convened by the European Atherosclerosis Society to extensively evaluate all of the potential adverse effects of statins. Other than muscle problems and diabetes, the others have not been clearly documented or shown to cause clinically relevant disease. For example, there have been many studies on the effect of statins, harmful or beneficial, on cognitive function. We concluded that, overall, the evidence doesn’t support either a clinically significant risk or benefit for cognitive function. Of course, as with any drug, there can be wide individual variations in response and in risk of adverse effects. So just because there is no overall association with changes in cognitive function, some individuals might experience cognitive changes that could be related to statins. It’s very hard to prove that, however, in any individual case.
Similarly, for liver function, maybe 2 percent of people taking statins will develop transient increases in blood tests for liver function, such as ALT [alanine aminotransferase], which could be a marker for liver stress. But there rarely have been reports of clinically relevant serious liver problems with statin use. In fact, the FDA, which had initially mandated periodic liver tests in people taking statins, no longer requires this.
As for the effects on the kidneys, it has never been shown that statins have a clinically significant effect on their function. In fact, statins are particularly important for people with chronic kidney disease since they are at elevated risk for heart disease—and there’s no evidence that the drugs worsen renal problems.
How do you determine if symptoms are caused by the statin or something else?
If there’s a dose response, that points to the statins as a causative factor. That is, if someone goes from a lower to a higher dose and then has more symptoms, or from a higher to a lower dose and then reduced symptoms, this suggests statin intolerance. But one has to be careful about drawing conclusions from any single patient’s experience.
One way to judge whether statins are causing the problems is to stop the drug for six to eight weeks and then rechallenge with it. Most patients can be taken off statins for such a period without hazard. And then, as long as the symptoms were not debilitating, most patients can be reintroduced to statins to see if the symptoms occur again. There are lots of ways of doing this. The best way to see if the symptoms are statin-related is to rechallenge with the same dose. But there are situations when the physician may want to exercise caution by restarting a patient on a lower dose and then gradually increasing it. In either case, you want to get the patient up to a therapeutic level and see whether that precipitates the symptoms.
Another way to judge if statins are causing muscle problems is to do a blood test for an enzyme called creatine kinase (CK), which is derived from muscle tissue. Elevated CK can be a marker for statin-related muscle damage. But this test applies only to a subset of patients with muscle symptoms, since most of them do not have elevated CK or any other blood abnormality.
If you suspect statin-related myopathy, do you switch the patient to a different statin?
Yes. There are half a dozen statins on the market, and they may have different likelihoods of risk for muscle problems because of their chemical properties. For instance, some statin molecules are more likely to get into muscle tissue, where they really don’t belong. This depends on how the drugs are metabolized in the liver, where they block cholesterol production. If a statin escapes the liver and goes into the muscle tissues, that can increase problems.
For patients with muscle problems from statins, I often have them switch to one that has a better track record in terms of such problems. Pravastatin is an early statin that is less likely to enter muscle tissue even when someone has a genetic abnormality that causes high blood levels of statins. Another option is pitavastatin, a newer statin that also has a somewhat better track record when it comes to adverse effects. The reason why I don’t start with these statins is because they lower cholesterol less than other statins. Because of that, if the muscle symptoms do not recur with pravastatin, for example, I might add another cholesterol-lowering agent to compensate for its reduced potency.
Do you try to explain to patients that statins may not be the cause of their symptoms?
I don’t try to talk them out of their symptoms. If they are experiencing symptoms, these have to be taken seriously. Still, if older patients have recently tried to become more physically active, I would suggest to them their aches and pains could be related to arthritis or overuse injuries rather than their statins. Statin-related muscle weakness or soreness typically occur in the legs, and often patients have aches and pains that don’t correspond to such typical statin symptoms. I do try to counsel those patients, looking for other possible causes of their aches and pains. Patients generally understand that if they stop taking statins and their aches and pains don’t clear up within a couple of months, that means other causes are involved, so the drug should be restarted.
Some people claim that the dietary supplement coenzyme Q10 (CoQ10) can help treat statin-related muscle symptoms. Do you recommend it to patients?
It has been theorized that the adverse muscle effects of statins occur because statins inhibit the body’s production of CoQ10, which is an antioxidant, and that this can be counteracted by taking the supplement. However, well-designed clinical studies have found that CoQ10 is no better than a placebo at relieving or preventing muscle symptoms. Still, as a physician, I’ve had some patients with muscle symptoms report benefits when they take CoQ10.
Do you use ezetimibe?
Ezetimibe [brand name Zetia] can be a useful adjunct to statins. It works completely differently than statins, by blocking cholesterol absorption in the intestine, and can complement and amplify their effect. It has been shown to be quite safe. Clinical trials clearly showed that it is able to reduce heart disease risk to the extent that it can lower cholesterol further when added to statins. Adding ezetimibe can be the equivalent of tripling the statin dose. It’s a very effective way of avoiding high-dose statins without increasing the risk of side effects. In my patients who have a genetic risk for heart disease and whose cholesterol levels have to come way down, a statin plus ezetimibe has been very effective.
How often do you use other cholesterol-lowering drugs?
In patients who are statin-intolerant, we sometimes use drugs called resins, which were among the first drugs that were approved for cholesterol lowering. Some have been around for 40 years. There are some recent additions to these resin drugs that are a little more potent and can be useful adjuncts to or sometimes substitutes for statins. But unlike statins, which are also anti-inflammatory and have other ways of reducing heart disease risk, these other drugs just lower cholesterol.
There’s also red rice yeast extract, which has been advocated by the supplement industry as a way to reduce cholesterol without taking statins. But that’s misleading because the active ingredients in red rice yeast are statins. My feeling is that if you are going to use a statin, you should take the standardized, FDA-regulated forms. But some patients claim they can tolerate red rice yeast better than other statins. I don’t insist that they stop taking it, but I certainly don’t advocate it, especially since the amount of statins in red yeast rice products can vary greatly.
Do you still prescribe extended-release niacin?
Yes, for some patients I prescribe Niaspan or recommend an over-the-counter brand called Slo-Niacin. But I rarely use niacin alone for cholesterol lowering. Many of my patients have high triglycerides and increased levels of small LDL particles [considered a heart disease risk factor]. Adding niacin to statins can have a complementary beneficial effect for such patients. For patients with high Lp(a) [another lipid particle linked with heart disease risk], niacin is one of the two available treatments (the other being PCSK9 inhibitors), though it hasn’t been proven that lowering Lp(a) is clinically beneficial.
What do you think of PCSK9 inhibitors?
They can lower cholesterol dramatically and can be even more effective than statins, without statins’ side effects. If PCSK9 inhibitors were not very expensive and insurers didn’t usually balk at covering them, there’s no question that we would be using them quite extensively. For patients who are statin-intolerant, there’s an extensive process that clinicians have to use to document that they’ve tried everything else. PCSK9 inhibitors can be extremely effective in some patients, who have been waiting for something like this for a long time. This is a tremendously attractive option for patients who have a strong family history of heart disease and have high cholesterol and high Lp(a), especially if they can’t tolerate statins or if statins haven’t lowered cholesterol enough.
How important is it for doctors to focus on patients’ other cardiovascular disease risk factors, such as smoking or obesity?
There’s no question that tobacco smoke is a cardiac toxin. I won’t even talk to patients about cholesterol lowering until I’m sure they have stopped smoking. Beyond that, there are many reasons to encourage weight loss when patients are overweight, along with a healthful diet and physical activity, which can all help counter high LDL levels and have other cardiovascular benefits. Some people will respond nicely to these lifestyle changes and may not need to start on a statin. But many won’t, especially if they are genetically programmed to have higher cholesterol that doesn’t respond enough to diet. If LDL isn’t coming down much or at all after six to eight weeks of cutting out red meat and high-fat dairy, for example, and the patient is at risk because of family history, one has to accept the fact that improving diet isn’t going to be the answer.
Also see Cholesterol Testing: What’s on the Horizon, another interview with Dr. Krauss.