Next year marks the 25th anniversary of statins, best known as the blockbuster drug that carries low-density lipoprotein (LDL), often called “bad cholesterol,” out of the blood to help millions of people reduce the risk of heart attack and stroke and slow the progression of coronary artery disease.  

But not everyone benefits from this therapy. As many as 20% of the estimated 20 million statin users develop adverse events such as muscle fatigue, weakness, decreased cognition and elevation of liver enzymes, according to Rockefeller University physician researchers Patricia Maningat and Jan L. Breslow.  

Writing in the Nov.15 issue of the New England Journal of Medicine, they maintain these statin-intolerant patients—who have tried every brand of these drugs, even at the lowest dosages—have been largely bypassed and need better treatment options.  

“In calling attention to this group, there needs to be a dialog along with special clinical trials, such as pragmatic trials, and a recognition by the pharmaceutical industry that they cannot pretend these patients don’t exist,” said Breslow, a professor and head of the Laboratory of Biochemical Genetics and Metabolism.  

He and Maningat maintain that while randomized clinical trials for gaining statin approvals showed only 5% of those tested had significant side effects, the nearly 20% figure comes from patients in clinical practice. The discrepancy, they write, is largely due to the under-enrollment in trials of two groups—older patients and women—as well as patients who consumed significant amounts of alcohol and took other medications. However, in the real world these groups are the most likely to take statins every day.  

The researchers also cited how a muscular condition side effect, called a statin-associated myopathy, lacks a standard definition, resulting in a discrepancy in reported adverse events while cognitive impairment, a very common neurologic problem linked with statin use, is often not measured in the clinic or is dismissed as a consequence of aging.  

What’s needed, they say, are pragmatic clinical trials—possibly at lipid clinics, which see many patients who can not tolerate statins prescribed by primary care physicians. Unlike rigidly controlled, blinded, randomized clinical trials, pragmatic trials are designed to evaluate the benefits of a drug therapy in everyday practice and where participants are representative of the wider population. They could be randomly assigned to one management approach or another, and the efficacy of the approaches could be compared. Physicians and patients also have the flexibility to adjust or discontinue treatment.  

In designing the variables for such a trial, study participants could be stratified according to cardiovascular risk. Another option is to include all statin-intolerant patients or just those with specific muscle or neurologic effects, the authors noted. Outcomes could include lowering of lipid levels, cardivoscaular outcomes, quality of life, adherence to assigned therapy and recurrence of old/appearance of new adverse effects.  

A key component of pragmatic studies would be the use of quality-of-life questionnaires followed by screening tools to determine patients’ perceptions of their symptoms, quantify the effects of statin intolerance on their daily activities and monitor changes in quality of life.  

That approach is similar to an ongoing pragmatic study at Duke University’s Center for Personalized Medicine, where two years ago researchers reported finding a genetic variant linked to mild statin-induced side effects. The current trial includes a questionnaire and a genetic test both to identify participants who have the genetic mutation and to estimate their risk of side effects from different brands of statins. The findings are presented to patients and their physicians to determine a new treatment plan that might include a different statin brand drug or an alternative drug to reduce adverse events. 

“People who are intolerant of statins are a difficult group to target and treat,” said Deepak Voora, M.D., a cardiologist and lead investigator for the study. “They often have other barriers to taking their medication which predisposes them to some side effects. In general, women more than men are likely to have statin-intolerance. So we are providing information to the trial participants to help them find the best medication with the fewest adverse events.”  

Dr. Voora acknowledges the Rockefeller University researchers are taking a broader view of pragmatic trials than Duke’s genetic testing and questionnaire approach.  

“We’re not claiming that a pragmatic trial for statin-intolerant patients would be easy,” said Breslow. “But colleagues of mine who run these lipid clinics at major medical centers tell me half of the patients they see have statin intolerance who come to them fishing around with doses, with some taking a pill twice a week and trying different brands like Lipitor, Crestor, Zocor, Pravacol and others, on a very ad hoc basis. There needs to be a dialog to help this underserved population.”  

Ronald Rosenberg