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Trial offers objective evidence of muscle related side effects with statins

The first major clinical trial to include a blinded, placebo-controlled “statin re-challenge” in patients with a history of muscle-related side effects sheds new light on statin-associated muscle symptoms, according to research presented at the American College of Cardiology’s 65th Annual Scientific Session. The trial also demonstrates that monthly self-injection of the relatively new non-statin cholesterol-lowering drug evolocumab reduces levels of low-density lipoprotein, or LDL, cholesterol to a greater extent than ezetimibe, a traditional drug used in statin-intolerant patients.

The study showed that 42.6 percent of 491 patients who had previously reported muscle pain with at least two different statins had a recurrence of symptoms during blinded administration of atorvastatin, but not while taking a placebo.

After a 24-week treatment period, patients with confirmed statin intolerance who were given evolocumab on average showed a 52.8 percent reduction in LDL cholesterol, one of the study’s co-primary endpoints, compared with a 16.7 percent reduction for patients taking ezetimibe. For the study’s other co-primary endpoint, the average change in LDL cholesterol for weeks 22 and 24, patients taking evolocumab showed a reduction of 54.5 percent and patients taking ezetimibe showed a reduction of 16.7 percent.

“These findings provide unique insights into the challenging clinical problem of muscle symptoms in statin treated patients,” said Steven Nissen, M.D., MACC, chairman of Cardiovascular Medicine at Cleveland Clinic and the lead author of the trial. “Evolocumab substantially lowered LDL cholesterol with few patients experiencing muscle symptoms. The study has important implications for both guidelines and regulatory policy, because it provides strong evidence that muscle-related statin intolerance is a real and reproducible phenomenon.”

The patients in the GAUSS-3 trial had very high levels of LDL cholesterol, averaging more than 210 mg/dL. Untreated high LDL cholesterol increases the risk of heart disease, and statins are the most effective drugs available, yet some patients report that that they are unable to tolerate statins, mostly due to muscle pain or weakness.

There has been considerable controversy about the prevalence of muscle-related statin intolerance because large randomized trials have reported low rates of muscle symptoms, while observational studies have suggested that 5 to 20 percent of patients experience muscle symptoms when taking statins.

“Statin intolerance has been one of the most vexing problems faced by cardiologists,” Nissen said. “Patients with high levels of LDL cholesterol and a high risk of cardiovascular events are often reluctant or completely unwilling to take statins, the only cholesterol lowering drugs approved to reduce their risk of a cardiovascular event. This situation is extremely frustrating for both patients and physicians because there have not been good alternatives for treatment.”