Cholesterol

The Importance of Identifying Muscle Events in Statin Users

Author:
Robert S. Rosenson, MD
Icahn School of Medicine at Mount Sinai, New York

Citation:
Rosenson RS. The importance of identifying muscle events in statin users [published online April 3, 2019]. Cardiology Consultant.

 

Many patients who take statins report muscle symptoms. These muscle symptoms may range from myalgia to myopathy; there can be tenderness to the touch due to inflammation (myositis), and sometimes myonecrosis (muscle breakdown). The concern regarding muscle-related symptoms is that severe elevations in creatine kinase may increase the risk of acute renal failure.

If your patient is not taking a statin after a myocardial infarction (MI), he or she has a higher risk for a recurrent cardiovascular event that includes a higher likelihood of having a second MI, a higher risk for being hospitalized in the next year for a cardiovascular (CV) event.

 

What Does the Research Say?

There has been debate regarding the number of patients reporting statin-associated muscle symptoms; the frequency differs markedly—from 5% to 20%—with each randomized clinical trial. While the adverse muscle events reported in clinical trials are reported infrequently, it is important to understand the definition used by some of the clinical trialists.

For example, in the Heart Protection Study,1 myopathy was reported when participants had characteristic muscle symptoms and a creatine kinase level greater than 10 times the upper limit of normal. The extremes of the spectrum of statin-associated muscle symptoms was reported. Recently, the investigators have discounted the importance of statin-associated muscle symptoms that are reported more commonly in our patients.

In turn, my research team and I sought to determine the risk for a CV event in patients with coronary disease who are unable to tolerate a statin. Using a validated tool developed by Colantonio and colleagues,2 we identified 2.3% of participants from a Medicare population who had had an MI and had then down-titrated or discontinued their statin due to muscle events. We evaluated the event rates in these individuals with statin down-titration and discontinuation.

We found that in the year following MI, participants who had had previously tolerated high-intensity statins often discontinued or down-titrated. In the year following the event, those participants who down-titrated or discontinued had a 50% higher risk of a recurrent MI and a 51% higher risk of hospitalization for coronary heart disease events. So, the inability to tolerate a statin—at least at a dose that is needed or recommended based on guidelines—due to complete muscle intolerance has consequences with regard to more CV events and more hospitalizations.

 

A Spectrum of Statin Muscle Symptoms >>

A Spectrum of Statin Muscle Symptoms

We then asked, “How can we better understand the spectrum of statin muscle symptoms.”

First, it is important that we have precise definitions. To better understand whether patient reports of muscle adverse symptoms are truly related to the statin or not, my team identified patterns of statin muscle-associated symptoms that were reproduced upon double-blind re-challenge in the Effect of Statins on Skeletal Muscle Function (STOMP) trial.3 Doing this provided a weighted score based on the likelihood that the muscle symptoms were strongly associated with statins on repeat challenge or were unlikely, and of course there were individuals who were in the intermediate zone.

Following that proposed muscle index, known as the Clinical Myalgia Index, we had the opportunity to validate that tool in another randomized, double-blind, placebo-controlled crossover trial.4 The results demonstrated that participants with a low score were 91% likely to not have a true statin muscle intolerance. In other words, the negative predictive value of our tool was 91%.

Understanding the spectrum of muscle symptoms using a convenient clinical tool is an important step, but how do we reduce the risk of individuals who have hypercholesterolemia and CV disease?

Number one, statins differ markedly with regard to tissue solubility, bioavailability, drug interactions, and pharmacogenomic factors. The inability to tolerate a statin at a high dose does not preclude the ability to tolerate the same statin at a lower dose or a different statin with different pharmacogenomic characteristics. Our approach suggested we try more than one statin. The standard protocol is to try 2 additional statins and then switch to a different agent—often at a lower dose—to see if the patient can tolerate that medication.

It is my hope that these findings help practitioners better understand the symptoms their patients are reporting and provide solutions to reduce patients’ CV risk.

Robert S. Rosenson, MD, is Professor of Medicine at the Icahn School of Medicine at Mount Sinai - New York, where he serves as Director of Cardiometabolic Disorders. He is a Fellow of the American Heart Association Council on Epidemiology and Prevention; Fellow of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Fellow of the National Lipid Association; and a past Fellow of the American College of Chest Physicians (inactive).

 

References:

  1. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial [published online July 6, 2002]. Lancet. https://doi.org/10.1016/S0140-6736(02)09327-3.
  2. Serban MC, Colantonio LD, Manthripragada AD, et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J Am Coll Cardiol. 2017;69(11):1386-1395. https://doi.org/10.1016/j.jacc.2016.12.036.
  3. Parker BA, Capizzi JA, Grimaldi AD, et al. Effect of statins on skeletal muscle function. Circulation. 2012;127(1):96-103. https://doi.org/10.1161/CIRCULATIONAHA.112.136101.
  4. Parker BA, Gregory SM, Lorson L, Polk D, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with statin myopathy: rationale and study design. J Clin Lipidol. 2013;7(3):187-193. https://doi.org/10.1016/j.jacl.2013.02.002.