Whenever I write any article about Cardiovascular Disease (CV), it is imperative that I remind people that CV disease is the #1 killer of men and women in the United States. The major risk factors for CV disease include smoking, age, high blood pressure, Type 2 Diabetes Mellitus, and high cholesterol. The most modifiable risk factor is high cholesterol. The most commonly used medicine to lower one’s cholesterol is a statin.
Many large randomized trials of statin therapy have demonstrated reductions in myocardial infarction (heart attack) and CV mortality. The following are representative studies:
The West of Scotland Coronary Prevention Study (WOSCOPS) showed that cholesterol lowering with pravastatin (40 mg daily) for five years reduced both the number of nonfatal myocardial infarctions and coronary heart disease (CHD) mortality in middle-aged men with a serum LDL-C concentration above 155 mg/dL. Extended follow-up of the trial examining outcomes 10, 15, and 20 years after the trial concluded found continued reductions in mortality in patients who had initially been assigned to receive pravastatin.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) found that lovastatin (20 to 40 mg daily), which reduced the serum LDL-C concentration by 25 percent, reduced the incidence of a first major coronary event (unstable angina pectoris, fatal and nonfatal heart attack, and sudden cardiac death) in low-risk men and women without clinical evidence of CV disease.
The JUPITER trial of rosuvastatin 20 mg daily in 17,802 healthy adult men and women with a C-reactive protein ≥2 mg/L and LDL-C levels below 130 mg/dL ) found a marked reduction in the primary end point of first major CV events and all-cause mortality. The trial was stopped early at the recommendation of its Independent Data and Safety Monitoring Board after a median follow up of 1.9 years because of a 44% reduction in all vascular events, 54% reduction in heart attacks, a 48% reduction in stroke, a 46% reduction in the need for arterial revascularization, and a 20% reduction in all cause mortality.
Multiple meta-analyses of clinical trials of LDL-C lowering therapy in patients with and without manifest CV disease have been performed and have all found strong evidence of reductions in CV events and deaths. So the bottom line is that statins are life saving!
I am asked most frequently by patients if statins are bad for your muscles. First, I want to give you some definitions. Myalgia is a non-specific common complaint of muscle ache and there are no abnormalities of the muscle enzyme called CPK on a blood test. Statin muscle pain typically occurs in the proximal muscle groups(closer to the trunk of the body) and also lower back. Historically, it is thought that some type of muscle aches can occur in up to 30% of patients on statins. Fortunately, many of these patients start a vigorous exercise program at the time they are diagnosed with high cholesterol and start their statin because they decide it is time to “get in shape”. Obviously, the most logical explanation of the cause of muscle aches right after starting exercise would be that it is not from a statin. There are many other causes of myalgias too. Myopathy has been used to refer to all muscle complaints or CPK elevations > 10 times the upper limits of normal with or without associated muscle symptoms. Finally, Myositis has been defined as muscle symptoms with increased CPK levels. This term implies muscle inflammation but this appears to be a secondary event associated with the healing process. Something called Rhabdomyolysis, by strict definition exists whenever there is evidence of muscle damage and a an elevated CPK level, but is used clinically to refer to severe muscle damage and is usually associated with kidney dysfunction.
The Muscle Expert Panel of the Statin Safety Task Force believes that due to all this confusion about terms, a new format should be made as follows. Myopathy should be used as a general term for all muscle problems. Symptomatic Myopathy should be used to refer to muscle pain (myalgias), weakness, and cramps. Asymptomatic Myopathy should be used to refer to CPK elevations without any symptoms. Finally, Rhabdomyolysis should be used to refer to any evidence of muscle cell destruction with resulting change of kidney function.
What does all this mean other than being confusing? First of all, muscle problems do occur with all statins. Muscle complaints have been documented to increase with increasing blood levels of the statin. There are 2 different classes of statins. Fat soluble and water soluble statins. The fat soluble statins include Lipitor (Atorvastatin) and Zocor (Simvastatin) and the water soluble include Pravachol (Pravastatin) and Crestor (Rosuvastatin). Since fat soluble statins can easily enter the inside of the muscle cells, theoretically, muscle damage should be increased with their use, as water soluble statins do not easily get into the muscle cells. This hypothesis has not been confirmed and cases of Rhabdomyolysis, and while extremely rare, occurring about 1 time for every 15 million prescriptions written, has occurred with all statins.
Here is the problem. Myalgia has rarely been examined in clinical trials until now. At the European Society of Cardiology Congress, according to a large meta-analysis which was presented, concluded that muscle aches and pains (myalgias) attributed to regular statin use is most often something other than drug-related discomfort. The study was also published in The Lancet. For this meta-analysis, randomized trials of statin therapy with at least 1,000 patients with a scheduled treatment duration of at least 2 years. They analyzed individual patient data from 19 double-blind trials of statin versus placebo (123,940 patients) and four double-blind trials of a more intensive versus a less intensive statin regimen (30,724 patients).
The authors noted “After 1 year, there was no significant excess in first reports of muscle pain or weakness….for most people taking a statin, any muscle-related symptoms they experience are not likely to be caused by the drug." Furthermore, "the known protective effects of statins against cardiovascular disease greatly exceed the slightly increased risk of muscle symptoms.”
For every 1,000 people taking a moderate-intensity statin, the treatment would cause 11 generally mild episodes of muscle pain or weakness in the first year, with no significant excess in subsequent years. Over a 5-year period, statins typically prevent 50 major vascular events in those with pre-existing vascular disease, and 25 major vascular events in those with no pre-existing vascular disease, with longer treatment yielding larger benefits.
The results of another study were published Nov. 15, 2020, in The New England Journal of Medicine. In this study, researchers recruited 60 people, average age 66, who had previously stopped statins after two weeks because of side effects. Some recruits had muscle aches. For one month each, they took 20 milligrams of Atorvastatin , a placebo, or no pill. They then continued this monthly rotation for a year without knowing which pill was which. The participants recorded their daily symptoms. Symptom scores ranged from zero (no symptoms) to 100 (extremely severe). People whose symptoms became too intense could discontinue the pill for that month. After a year, the researchers found that 90% of the symptoms people recorded when taking statins were also present when they took the placebo. The authors concluded that people who are worried about statins because of possible side effects may experience what's called the "nocebo effect" when they try taking the drugs. This is the opposite of the placebo effect; with the nocebo effect, people who have negative expectations about medicine or a treatment experience harmful symptoms they otherwise wouldn't have. Once the group was shown these results and saw their nocebo response, half felt confident to restart statins and were able to tolerate them. This suggests that many people who have stopped taking a statin due to side effects might have been experiencing the "nocebo effect" and be able to resume statin treatment.
Now I will discuss my personal experience in nearly 3000 patients. It is the rare patient who cannot tolerate a statin. Often, it takes some creativity to do so. The problem exists, however, that frequent inquires may prompt symptoms in suggestible patients. Patients need to be reassured statin-related muscle aches resolve when stopping the medicine. There is insufficient evidence to conclude whether myalgias that persists after stopping the statin is that caused by the medication. All patients who are symptomatic on statin therapy should have thyroid function tests done as hypothyroidism can exacerbate symptoms. Also, other medications or nutraceuticals that slow down statin metabolism should be identified such as Red Yeast Rice( which may contain a statin marketed with a different name and can produce myopathy). In addition, grapefruit juice consumption impedes the breakdown of fat soluble statins and can cause high statin levels in the blood. Any patient who enjoys drinking grapefruit juice should not be on a fat soluble statin. If the pain is severe, the statin should be stopped until all the symptoms resolve. Once this occurs, the same statin could be started at the same dose to see if symptoms recur or started at a lower dose. Alternatively, a different statin can be tried. There is no direct comparison of tolerability among statins and; therefore, no definitive evidence to recommend a given statin. In my practice; however, I will change a patient from a fat soluble statin to a water soluble statin if myalgias start. This has been successful for me in reducing muscle problems. As I said earlier; however, there is no direct evidence that water soluble statins produce less muscle pain as compared to fat soluble statins. If the muscle pains are tolerable with or without a CPK elevation < 10 times the upper limit of normal, The Muscle Expert Panel of the Statin Safety Task Force recommends that statin therapy be continued at the same dose or a reduced dose. Most muscle aches do go away or become tolerable to the patients if the statin is continued. Many physicians are too quick to stop statins with any muscle aches. The risks vs benefits of statins need to be weighed. One must remember that statins have reduced CV morbidity and mortality by approximately 50%. While there is no definitive clinical evidence of any strategies that can be used to prevent or reduce muscle injury, there is some evidence that Coenzyme Q10 may cause a significant reduction in statin-induced pain. Since the response has been variable, the use of Coenzyme Q 10 cannot be recommended with any degree of confidence.
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