What The Experts Say About The Side Effects Of Statins. What Are They? What Causes Them? Who Is Most At Risk? How Are They Treated?

Muscle problems are the best known of statin drugs' adverse side effects.  But cognitive problems and peripheral neuropathy, or pain or numbness in the extremities like fingers and toes, are also widely reported.

Dr. Beatrice Golomb, MD, PhD, Director of the UC San Diego Statin Study Group, Dr. Marcella A. Evans,  UCSD School of Medicine
Am J Cardiovasc Drug 2008;8(6):373-418

Because statin-related myopathy will probably become more common with greater numbers of persons starting high-dose statin therapy and the increasing stringency of low-density lipoprotein cholesterol level targets, research to better identify patients at risk for statin myopathy and to evaluate management strategies for statin-related myopathy is warranted.

Dr. Tisha R. Joy, MD, and Dr. Robert A. Hegele, MD, Robarts Research Institute and Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada
Ann Intern Med 2009 June 16;150(12)858-868

In the group that took red yeast rice, the average drop in LDL cholesterol was 43 points in 12 weeks.  We may actually have found a product that may be useful for patients and clinicians to deal with this problem of 'statin-caused muscle pain'.  There is a real potential here, but 'there are still a number of concerns' because the sources of red yeast rice 'are not very' reliable.

Dr. Ram Y. Gordon, MD, Dr. David J. Becker, Chestnut Hill Hospital, University of Pennsylvania School of Medicine, and Jefferson-Myrna Brind Center for Integrative Medicine, Philadelphia, Pennsylvania.
Ann Intern Med 2009 June 16(12):830-839

Those of us who care for patients who cannot tolerate lipid-lowering therapy are often confronted by anecdotes that contradict the findings of well-designed trials.  We still do not know whether statins directly induce muscle atrophy or whether lowering lipid levels by any means in patients with vulnerable muscles causes myotoxicity.

Dr. Paul S. Phillips, MD, Scripps Mercy Hospital, San Diego, CA
Ann Intern Med 2009 Jun 16;150(12):885-6

There's no doubt about it.  Statins provide a tremendous benefit by lowering cholesterol and inflammation and decreasing the incidence of cardiovascular disease.

But...our bodies are all different.  Even the statins, drugs hailed to have a high safety profile, also have the potential for causing adverse effects in some of us--dependent on the dosage, drug interactions, co-existing medical conditions, age, genetics, activity level, gender and other factors.

If you've had questions about the side effects of statins, these four recent articles will definitely give you a better understanding of who experiences statin problems, what might cause the problems, and how to deal with them.

Many of these side effects could be easily dismissed or assumed to be related to something else.  Better to be forewarned.  According to Dr. Beatrice Golomb, the expert on adverse effects,  "physician awareness for adverse effects is reportedly low, even for those most widely reported by patients." 

What Are Drs. Beatrice Golomb, Marcella Evans, David Becker, Ram Gordon, Paul Phillips, Tisha Joy & Robert Hegele Saying About Statin Side Effects? 

 

Golomb and Evans' "Statin Adverse Effects.  A Review of the Literature and Evidence for a Mitochondrial Mechanism"

• Golomb is one of the top experts on the adverse effects of statins.  She has previously conducted a "randomized controlled trial" of persons living in San Diego, examining effects of low dose statins on thinking, mood, behavior, and quality of life.  Additionally, she runs one of the largest observational studies on adverse effects of statins--providing a database for people all over the world to self-report any side effect to statins that they have experienced.  Read more about her work at UCSD here.
  
• Her paper is the first comprehensive review of the subject, covering almost 900 studies on the adverse effects of statins.  It's an exhaustive analysis of the research, including the most highly regarded of studies, the randomized controlled trial.

1.  Top statin complaint:  Muscle pain, fatigue & weakness.  These also include rhabdomyolysis (rare but life-threatening), new difficulty walking, exercise limitations, muscle inflammation, shoulder stiffness and more.

2.  Second most common statin complaint:  Cognitive problems: memory, thinking & concentration,  problems finding the right word, experiencing "holes in one's memory".  Since most people are older when starting on statins, this is often difficult to distinguish from age-related memory loss, but Golomb says many have reported that their thinking & memory improves when they stop statins, or lower the dose.  Read "Do Statins Make You Stupid? Asks Wall Street Journal and the New York Times" for more on Golomb's research.

3. Less common statin complaints: Depression and irritability, non-muscular pain, cancer, liver problems, hemorrhagic stroke, blood glucose impairments, reduction in sleep quality, peripheral neuropathy, sexual dysfunction, male endocrine disorders, aggression, renal problems, neuro-degenerative disorders like Parkinson Disease & ALS and more.

4.  What's causing the problems?   According to Golomb, statin-induced injury to the body's "energy-producing cells"--the mitochondria, is the root cause of many of statin's adverse effects.  When the mitochondria are impaired the body produces less energy and we end up with more damaging "free radicals".  Additionally, statins lower the body's production of co-enzyme Q10, a key component in the mitochondria that is necessary to produce energy & destroy "harmful free radicals".  To make matters even worse, there is a real Catch-22:  Statins not only lower our CoQ10 levels, but they also reduce our blood cholesterol which is the way CoQ10 and other fat-soluble antioxidants are transported throughout the body.   So, not only do we end up with low CoQ10, when our cholesterol is lowered, the CoQ10 has difficulty moving through the body.
**According to Golomb, there is evidence that this mitochondrial/CoQ10 connection relates to both muscle & brain pathology.

5. Age and adverse effects.  Now throw in the fact that as we age our mitochondria (the energy powerhouses) naturally weaken, and we produce less CoQ10--adding statins to the mix may not always be wise.  According to Golomb, "The risk of adverse effects goes up as age goes up, and this (the mitochondrial/CoQ10 connection) helps explain why statins' benefits have not been found to exceed their risks in those over 70 or 75 years old, even 'for' those with heart disease." 

High blood pressure and diabetes are also linked to higher rates of mitochondrial problems--which in turn ups the risk of statin complications for people with these conditions.

"Because statins may cause more mitochondrial problems over time--and as these energy powerhouses tend to weaken with age--new adverse effects can also develop the longer a patient takes statin drugs."  The risks go up as we age, as the dosage increases, and with certain genetic conditions that put one at a greater risk for developing side effects.

Joy & Hegele's "Narrative Review: Statin-Related Myopathy"

• This is the quintessential "cookbook" article on statin myopathy.  Believe me--this gets very complicated. The authors thoroughly explain what statin-caused muscle pain is.  Who is at risk.  What causes it.  What doses, which statins & circumstances increase the chances of risk.  And most importantly, how to make muscle pain go away.
• 10% of statin users experience muscle pain, but those numbers increase with excessive physical activity (which explains why most athletes avoid statins); when the statin dose increases; the older you get; in women; those with small body frames; with grapefruit juice consumption; in those with a family history of statin myopathy; in certain genetic profiles; with hypothyroidism; and in patients taking certain drugs--just to name a few.
• Muscle pain is usually in the thighs, calves or both, but 25% experience generalized muscle pain. The myopathy is described as heaviness, stiffness, or cramping, and is sometimes associated with weakness during exercise.  25% have tendon-associated pain.
• Professional athletes with familial high cholesterol rarely tolerate statin treatment because of muscular problems.  J Clin Pharmacol 2004;57:525-8
• Strategies to combat myopathy. Switch statins, particularly to fluvastatin (Lescol); try alternate-day use of certain statins like atorvastatin (Lipitor) or rosuvastatin (Crestor) because they are longer-acting; use of older generation non-statin drugs that work by inhibiting the absorption of cholesterol in the intestine, like ezetimibe and bile-acid-binding resins; and/or supplementing with CoEnzyme Q10.

Becker and Gordon's "Red Yeast Rice for Dyslipidemia in Statin-Intolerant Patients"

• This was a small study of 62 patients who had high cholesterol but couldn't tolerate statin therapy because of muscle pain.  Half the group were given three 600 mg of red yeast rice capsules twice a day; half took three placebos twice a day.  All 62 patients participated in a life-style change program of diet & exercise.
• During the 24 week study, LDL cholesterol decreased by 43 mg/dL in the red yeast rice group after 12 weeks--then dropped to 35 mg/dL at 24 weeks because of poorer compliance. The placebo group had a 15 mg/dL drop in LDL cholesterol.  Total cholesterol also improved in the red yeast rice group.
• Muscle pain scores, HDL cholesterol levels, weight loss, and muscle and liver enzymes levels remained the same for both groups--indicating that even though the red yeast rice lowered the subjects cholesterol, it did not cause muscle pain--the point of the study.
• Study limitations:  It was too small and short-term to indicate if the observed improvements would continue.  
• Red yeast rice is a dietary supplement and not regulated.  Potencies vary and when too potent they might cause muscle pain.  Lack of consistencies between manufacturers is a major problem with this therapy.

Phillips' Editorial, "Balancing Randomized Trials With Anecdote"

• Phillips is just the right physician to comment on both the Becker/Gordon red yeast rice article and the Joy/Hegele statin-myopathy "cookbook" review.  He runs a statin myopathy clinic, which now exceeds 600 patients, at the Scripps Mercy Hospital in San Diego, CA.  He knows statin-myopathy well--what works--what doesn't.
• According to Phillips, treating statin-myopathy is more of an art--and the clinical trials don't always tell the whole story, or provide clinicians with the best therapies.   "Those of us who care for patients who cannot tolerate lipid-lowering therapy are often confronted by anecdotes that contradict the findings of well-designed trials." 
• Outside of the clinical trials, Phillips' clinic has discovered that vitamin D deficiency explains many mild cases of statin-induced aching. 
• He's also discovered that absorbable forms of CoEnzyme Q10, which may be depleted by statins, seem to help some patients with muscle pain---but most formulations sold over the counter may be inactive. I'm wondering which formulation he would recommend.
  
• Although clinical trials have convinced many physicians to switch patients with muscle pain over to ezetimibe (bile-acid-binding resins), there are many individual reports that suggest that ezetimbe might not be safe for patients who can't tolerate statins. The reason for this--many of these patients have an abnormal lipid metabolism--rendering both drugs unacceptable.
• In spite of the positive results of the Becker/Gordon study, Phillips' experience makes him reluctant to use red yeast rice to lower cholesterol & prevent muscle pain.  Why? Red yeast rice is not regulated or dose-standardized and since it contains the natural form of a lovastatin, it could have the potential for causing serious side effects.  In his clinic he "sees many patients in whom red yeast rice use has repeatedly caused recurrence of muscle toxicity symptoms, occasionally with increased creatine kinase (CPK) levels."
• The red yeast rice study only measured muscle pain.  Phillips wants to know--what about the malaise, fatigue, and weakness that he sees in his patients who use red yeast rice? 
• The FDA continues to warn against inconsistent and possibly toxic formulations of red yeast rice.  Phillips advises physicians not to prescribe it until it has been standardized and tested further.

Two other articles to check out:

Siddiqi, SA, Thompson, PD.  How do you treat patients with myalgia who take statins?  Curr Atheroscler Rep.  2009;11:9-14.

Jacobson, TA. Toward "pain-free" statin prescribing: clinical algorithm for diagnosis and management of myalgia.  Mayo Clin Proc.  2008;83:687-700.

From Becker/Gordon. Ann Intern Med 2009 June 16;150(12)858-868

Approach to Patients With a History of Statin-Associated Myalgias  (based on the Siddiqui & Jacobson articles--see full Becker/Gordon article to follow up on the references below)

1. Initiate or intensify therapeutic lifestyle changes (National Cholesterol Education Program Adult Treatment Panel III Guidelines) (18)
2. Decrease statin dose
3. Discontinue statin and rechallenge at a later date
4. Reduce dose of statin and add ezetimibe (19)
5. Use a different statin or statin-like supplement
    a. Fluvastatin, 80 mg/d (20)
    b. Rosuvastatin at a low dosage (5 or 10 mg/d) (21)
    c. Rosuvastatin once weekly (22), twice weekly (23), or every other day (24)
    d. Atorvastatin, 10–40 mg, 3 times weekly (25)
    e. Red yeast rice, 1800 mg, twice daily
6. Pulse statin therapy (16)
7. Switch class of lipid-lowering agent
    a. Use ezetimibe alone (19)
    b. Combine ezetimibe and colesevelam (26)
8. Check vitamin D levels and replenish if low (27)
9. Low-density lipoprotein cholesterol apheresis in qualified patients (16)
10. Add coenzyme Q10 (ubiquinone), 200 mg/d, to statin therapy (28)

I've never been prescribed, nor taken statins.  I know many who take them without a problem.  I know others who have experienced side effects that they never considered to be statin-related, but found they went away when they stopped taking statins.  I would always recommend discussing this with one's physician, and sharing any of these articles with them, as well.  You won't know what questions to ask, if you don't do the research.

Remember, there's always Option 2: Switch to a plant-based diet, and don't worry about side effects.

Click here and here for information on a non-drug approach to treating heart disease, cholesterol & inflammation.

Comments

[Rachel]

So many people seem to use cholesterol-lowering drugs as a license to continuing abusing their bodies through poor diet, obesity, and a sedentary lifestyle. These drugs should be used as a last resort when natural methods don't work at lowering cholesterol.

[Rebecca Cody]

I understand that in Japan, when a doctor prescribes a statin, they prescribe CoQ10 to be taken as well. Statins don't just cause muscle pain. They can cause irreversible muscle destruction.

There is also research showing that statin users still die at the same rates as those who don't take them, but they die more frequently of cancer and violence and less from heart attacks. It isn't a trade-off I'd be willing to make.