Scientists May Finally Know Why Statins Cause Muscle Pain

By Pat Anson

Many people stop taking cholesterol-lowering statins because they experience painful muscle cramps, weakness, and fatigue. I know, because I was one of them.

I started taking statins in my 40’s on the advice of our family physician, because of mildly elevated cholesterol and a family history of coronary artery disease. Soon I was having stinging cramps in my legs overnight, which were painful enough to wake me up. 

My doctor was skeptical that statins were the cause, but switched me from Lipitor to Vytorin and finally to Crestor. The muscle cramps continued. Only when I stopped taking statins did the symptoms disappear.

“I’ve had patients who’ve been prescribed statins, and they refused to take them because of the side effects. It’s the most common reason patients quit statins, and it’s a very real problem that needs a solution,” says Andrew Marks, MD, Professor and Chair of the Department of Physiology and Cellular Biophysics at Columbia University.

To find a solution, first you need to identify the cause, and Marks and his colleagues have finally discovered why about 10% of people on statins experience those muscular side effects.

Their research, recently published in The Journal of Clinical Investigation, found that a widely-used statin called simvastatin (Zocor) binds to a protein in muscle cells, which causes a leak of calcium ions inside the cells.

Using an electron microscope, researchers watched simvastatin molecules bind to two locations in a muscle protein called the ryanodine receptor, which opened a channel in the receptor that allowed calcium to flow through. 

Marks says the calcium leak could be weakening the muscle directly or by activating enzymes that degrade muscle tissue.

“It is unlikely that this explanation applies to everyone who experiences muscular side effects with statins, but even if it explains a small subset, that’s a lot of people we could help if we can resolve the issue,” Marks said in a press release.

The electron images suggest that statins could be redesigned so they don’t bind to the ryanodine receptor, but retain their cholesterol-lowering ability. 

Marks is now collaborating with chemists to create such a statin. He owns stock in RyCarma Therapeutics, a company developing compounds that target the ryanodine receptor.

Plugging the calcium leak could be another option: Statin-induced calcium leaks in laboratory mice can be closed with an experimental drug developed by Marks for other muscle conditions involving calcium leaks.

“These drugs are currently being tested in people with rare muscle diseases. If it shows efficacy in those patients, we can test it in statin-induced myopathies,” Marks says.

The first statin was approved by the FDA in 1987, but it took the agency nearly three decades to listen to patients like me and update warning labels on statins in 2014, cautioning that statins can cause myopathy. In rare instances, the FDA says statins can also cause liver injury, diabetes and memory loss.   

Study Finds Low Risk of Muscle Pain From Statins

By Pat Anson, PNN Editor

Have you experienced muscle pain, memory loss or other side effects from statins? If so, you’re not alone. A many as one in two patients stop taking the cholesterol-lowering drugs because they don’t like the side-effects.

But the authors of a large new study say statin intolerance is over-estimated and over-diagnosed, resulting in too many patients raising their risk of heart disease because they refuse to take the drugs.

An international team of researchers conducted a meta-analysis of 176 clinical studies involving over 4 million statin users and found that only about 9 percent have statin intolerance. Their findings are published in the journal European Heart Journal.

“I believe the size of our study, which is the largest in the world to investigate this question, means we are able to finally and effectively answer the question about the true prevalence of statin intolerance,” said lead author Maciej Banach, MD, a cardiologist and professor at Medical University of Lodz and the University of Zielona Góra in Poland.

“Patients need to know that statins may prolong their life, and in cases where side effects appear, we have enough knowledge to manage these effectively. The most important message to patients as a result of this study is that they should keep on taking statins according to the prescribed dose, and discuss any side effects with their doctor, rather than discontinuing the medication.”

The research team found that patients who are older, female, obese, diabetic, or suffering from an under-active thyroid or chronic liver or kidney failure were more likely to be statin intolerant.

Patients taking drugs used to control an irregular heartbeat or calcium channel blockers for chest pain and high blood pressure were also more likely to have side effects, as did those with high alcohol consumption.

“It is critically important to know about these risk factors so that we can predict effectively that a particular patient is at higher risk of statin intolerance. Then we can consider upfront other ways to treat them in order to reduce the risk and improve adherence to treatment. This could include lower statin doses, combination therapy and use of innovative new drugs,” said Banach. 

“Most cases of statin intolerance observed in clinical practice are associated with effects caused by patients’ misconceptions about the side effects of statins or may be due to other reasons. Therefore, we should carefully evaluate symptoms, assessing in detail patients’ medical histories, when the symptoms appeared, specific details of pain, other medications the patients are taking, and other conditions and risk factors. Then we will see that statins can be used safely in most patients.”

Previous research on side effects from statins have had mixed results. A 2017 study found that only about 2 percent of patients on Lipitor (atorvastatin) had muscle pain. That finding is in marked contrast to a Cleveland Clinic study, which found that 42% of patients taking Lipitor reported muscle pain and weakness.

In 2014, the Food and Drug Administration required warning labels on statins, cautioning that statins can cause a muscle injury called myopathy, which is characterized by muscle pain or weakness. In rare instances, the FDA says statins can also cause liver injury, diabetes and memory loss.

Study Finds ‘Nocebo Effect’ of Statins Cause Pain

By Pat Anson, Editor

An industry funded study is adding more fuel to a sometimes heated debate over statins – and whether the cholesterol-lowering drugs cause muscle pain and weakness.

Research involving nearly 10,000 patients published in The Lancet medical journal suggests that people taking Lipitor – the brand name for the statin atorvastatin -- are more likely to report muscle aches and other side effects, but only if they knew there were taking the drug.

This is what is called the “nocebo effect” – the opposite of the placebo effect – where people complain of side effects because they expect to have them.

"Just as the placebo effect can be very strong, so too can the nocebo effect. This is not a case of people making up symptoms, or that the symptoms are 'all in their heads'. Patients can experience very real pain as a result of the nocebo effect and the expectation that drugs will cause harm,” said lead author Peter Sever of the National Heart and Lung Institute at Imperial College London.

“What our study shows is that it's precisely the expectation of harm that is likely causing the increase in muscle pain and weakness, rather than the drugs themselves causing them."

Sever said complaints about the side effects overstate how common the problems are and discourage people from taking statins, resulting in "thousands of fatal and disabling heart attacks and strokes, which would otherwise have been avoided."

“These results will help assure both physicians and patients that most AEs (adverse effects) associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects,” he said.

The study was funded by Servier Research Group, Leo Laboratories and Pfizer – the maker of Lipitor. Five of the eight co-authors reported potential conflicts of interest, including payments from Pfizer and other drug makers that manufacture statins.  

Only about 2 percent of the patients taking Lipitor in The Lancet study reported having muscle pain, a finding that is substantially at odds with previous research.

For example, in a study at the Cleveland Clinic last year, 42 percent of patients taking Lipitor reported muscle pain and weakness. Other studies have found muscle pain in 5% to 29% of statin users.

The Food and Drug Administration considered the problem serious enough that in 2014 it required warning labels on statins, cautioning that some statins can cause a muscle injury called myopathy, which is characterized by muscle pain or weakness. In rare instances, the FDA says statins can also cause liver injury, diabetes and memory loss.

Another study this week, published in JAMA Internal Medicine, linked statin use to back pain conditions such as spondylosis and intervertebral disc disorders. The study involved over 13,000 military veterans and their families.

“To our knowledge, this study is the first to report greater odds of back disorders among statin users compared with the odds of nonusers in a population with equal access to and the same cost of health care,” said Una Makris, MD,  of the VA North Texas Health Care System in Dallas. “Our results provide additional motivation to further investigate the overall influence of statin therapy on musculoskeletal health, specifically if prescribed for primary prevention in physically active individuals.”