How Should Clinicians Treat Patients Who Report Muscle-Related Statin Intolerance?

Summary and Comment |
April 7, 2016

How Should Clinicians Treat Patients Who Report Muscle-Related Statin Intolerance?

  1. Karol E. Watson, MD, PhD, FACC

A PCSK9 inhibitor lowered LDL-cholesterol levels more than ezetimibe, but statin intolerance was not confirmed in half of the enrolled patients, and PCSK9 inhibitors still lack long-term outcomes data.

  1. Karol E. Watson, MD, PhD, FACC

To learn whether a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor would be effective in patients reporting muscle effects while on a statin, investigators performed a manufacturer-funded, two-phase, randomized clinical trial.

The 491 patients had uncontrolled LDL-cholesterol levels and muscle-related intolerance with two or more statins. The first study phase used a crossover design to confirm statin intolerance and incorporated drug wash-outs before, during, and afterwards. The patients were randomized to atorvastatin 20 mg/day or placebo for 10 weeks and then received the alternate therapy. There were 209 patients who had symptoms only with atorvastatin (42.6%); 35.3% had symptoms on placebo, and 17.3% had no symptoms on either the statin or placebo. In the second phase, 199 of these patients, along with 19 other patients with muscle pain and elevated creatine kinase levels, were randomized in a 2:1 ratio to receive the PCSK9 inhibitor evolocumab subcutaneously (420 mg monthly) or ezetimibe orally (10 mg/day) for 24 weeks.

Mean percentage change in LDL-cholesterol at 24 weeks was significantly greater with evolocumab (−52.8% vs. −16.7% with ezetimibe). Fewer evolocumab recipients reported muscle symptoms (20.7% vs. 28.8%), but this was not statistically significant. Because of muscle symptoms, 6.8% of ezetimibe-treated patients and 0.7% of evolocumab-treated patients discontinued their medication.

Comment — Cardiology

This study of patients with confirmed muscle-related statin intolerance has three key findings:

  1. Evolocumab 420 mg monthly lowered LDL-cholesterol more than ezetimibe 10 mg daily.

  2. In phase one, the statin truly caused muscle symptoms in only a minority of patients.

  3. Evolocumab patients and ezetimibe recipients did not differ significantly in muscle symptoms.

That most patients had muscle symptoms on placebo highlights the possibility that many patients with reported statin intolerance could tolerate a statin or have symptoms related to something other than the statin. Overall, however, the dramatic LDL-cholesterol reduction achieved with the PCSK9 inhibitor makes us hopeful that these drugs will become valuable tools in our armamentarium. Still, as authors and editorialists note, we need to await long-term outcome studies to verify their safety, efficacy, and cardiovascular outcomes.

Comment — Neurology

  1. Michael Benatar, MD, MS, PhD

For the neurologist, it is important to remember that statins may very rarely trigger an autoimmune myopathy that is characterized by progressive muscle weakness, prominent necrosis of muscle fibers, elevated creatine kinase, and antibodies that recognize 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase. Although a statin-triggered autoimmune myopathy is typically progressive despite stopping statins, anecdotal evidence suggests that intravenous immunoglobulin may be particular effective in treating this disorder.

Editor Disclosures at Time of Publication

  • Disclosures for Karol E. Watson, MD, PhD, FACC at time of publication Consultant / Advisory board: Amgen; GlaxoSmithKline; Merck; Quest Editorial boards: Reviews in Cardiovascular Medicine; Circulation Quality Outcomes; Circulation


Reader Comments (2)

MOHAMMAD DAOUD Physician, Endocrinology

The Old and the New :

Apparently the PCSK9 inhibitors are very effective but also very costly alternative for a patient who is intolerant to statins.
The cost issue is unlikely to be solved soon

Though Ezetimibe and its modest effect is better than nothing and may help using smaller dose of a statin (moderate intensity dose) ,still it fell in between being endorsed by European side (EMA) and being denied such endorsment by the FDA.
I still do use it in selected cases,no doubt.

Not tolerating two statins should not mean the end of the story with statins; I have found that many patient who are intolerant to Atorvastatin or Simvastatin as an example do very well with Fluvastatin or Pravastatin (though they hardly fit in the moderate intensity group as per current ACC/AHA guidelines ) ; still this should be a reasonable alternative as long it does get us the minimum of >30%-40 % drop of LDL or non-HDL from baseline.

For the time being , using such costy big guns should be limited to difficult case where it is needed like FH.

Sanford Kimmel Physician, Family Medicine/General Practice, Indian Creek Family Medicine in Oxford, Ohio; Retired Professor of Family Medicine, University of Toledo

I saw a brief interview about this study with Dr. Steven Nissen on one of the national TV new programs. Having been in practice for over 30 years, I would like to make the following observations:
1. I noticed that about 10% of my patients could not tolerate statins due to severe myalgias although few had actual myopathy. This was when we were initially told that the incidence of these adverse effects was 2%
2. We were then told that although ezetimibe lowered LDL levels, it did not affect the coronary intima levels of atherosclerosis leading to the question, "Are LDL levels an appropriate surrogate for the endpoint of CAD and cardiac end points?" There was also the issue of whether ezetimibe had other undesireable effects.
3. We are now told that the PCSK9 inhibitors significantly lower LDL, although the cost is tremendously high, about $14,000 per year per Dr. Nissen.
4. Primary care physicians such as myself have to deal with medication cost issues on a daily basis. The availability of statins as generics greatly helped to ameliorate this although it did still not help with the issue of patients who are statin sensitive.
5. As a result, I have recommended that some patients take Co-enzyme Q10 to see if this relieves the side effects of statin myalgia. Some patients find this helpful. Is it a placebo effect? I don't know but the cost is surely less than a PCSK9 inhibitor. By the way, I recommend they take a reliable brand of Co-Q10 such as reported by (I have no financial interest in this organization).

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