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.

The Good and Bad About a Pain-Free Statin

By Pat Anson, Editor

New research has confirmed what a lot of us already know about statins: the cholesterol fighting drugs may lower your risk of heart disease, but they can also cause painful muscle cramps, memory loss and other side effects.

In the first major trial of its kind, researchers at the Cleveland Clinic gave atorvastatin (Lipitor) or a placebo to nearly 500 patients with very high cholesterol levels, many of whom had a history of muscle related statin intolerance. Over 42 percent of the patients reported muscle pain or weakness on atorvastatin.  

Those patients were then enrolled in another phase of the study and given a non-statin drug called evolocumab, which inhibits a protein in the liver (PCSK9) that helps produce cholesterol.  

The good news? Evolocumab was very effective in lowering cholesterol and rarely produced muscle problems.

The bad news? Evolocumab would cost about $14,000 a year and is self-administered monthly by injection only. Double ouch.

"Statin intolerance has been a very challenging clinical problem," said Steven Nissen, MD, chairman of Cardiovascular Medicine at Cleveland Clinic. "The study showed that PCSK9 inhibitors can significantly lower cholesterol in patients with documented statin intolerance, providing an effective treatment for these difficult to manage patients."

While the study findings, published in JAMA, were mainly meant to test the efficacy of evolocumab, it’s nice to see the medical community acknowledge that statins have painful side-effects and that drug makers are trying to find alternatives.

I started taking statins over a decade ago on the recommendation of a family physician, because of mildly elevated cholesterol and a scary family history of coronary artery disease. Right away I started having painful leg cramps at night, and during the day I felt lethargic and less alert.  My doctor was a bit skeptical and switched me from one statin to another (Lipitor, Vytorin and finally Crestor), but the cramps and brain “fogginess” continued. When I stopped taking statins, the symptoms disappeared.

I’m certainly not alone. Muscle pain is reported by an estimated 5% to 29% of statin users, but there are no blood or diagnostic tests to document muscle-related statin intolerance. It’s also hard to fight conventional thinking (and extensive advertising) that statins are good for you, so a lot of patients are encouraged to keep on taking them, even if they do cause pain.

Only in 2014 did the Food and Drug Administration require 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.   

The first statin, lovastatin, was approved by the FDA in 1987 – meaning it took the agency nearly three decades to start warning about these side effects. It’s only through patient complaints that the FDA even learned about them, a concept that the American College of Emergency Physicians (ACEP) should probably brush up on.

As Pain News Network has reported, ACEP wants Medicare to stop requiring hospitals to ask patients about the quality of their pain care. That's not a good idea. And the painful history of statins is proof of that.