GAUSS-3 Compares Evolocumab PCSK9 Inhibitor to Ezetimibe and Studies Muscle-Related Side Effects of Statins

April 3, 2016—The GAUSS-3 study was presented by Lead Investigator Steven Nissen, MD, at ACC.16, the American College of Cardiology’s 65th Annual Scientific Session held April 2–4 in Chicago, Illinois. The study was simultaneously published online by Dr. Nissen et al in the Journal of the American Medical Association.

According to the ACC, GAUSS-3 is the first major clinical trial to include a blinded, placebo-controlled “statin rechallenge” in patients with a history of muscle-related side effects and sheds new light on statin-associated muscle symptoms. The trial also demonstrates that monthly self-injection of the nonstatin cholesterol-lowering drug evolocumab reduces levels of low-density lipoprotein (LDL) to a greater extent than ezetimibe, which is used in statin-intolerant patients. 

Evolocumab is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. Ezetimibe, used as a control in the trial, lowers blood cholesterol by decreasing the absorption of cholesterol in the small intestine. 

As summarized by the ACC, the study showed that 42.6% 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% reduction in LDL cholesterol, one of the study’s coprimary endpoints, compared with a 16.7% reduction for patients taking ezetimibe. For the study’s other coprimary endpoint—the average change in LDL cholesterol for weeks 22 and 24—patients taking evolocumab showed a reduction of 54.5% and those taking ezetimibe showed a reduction of 16.7%. 

The phase 3, randomized, double-blind GAUSS-3 trial enrolled 511 patients at 53 health care centers. The patients in the GAUSS-3 trial had very high levels of LDL cholesterol, averaging more than 210 mg/dL. Additionally, a vast majority of participants (82%) had tried and failed to tolerate three or more statins. Previous studies, including the trial’s predecessor, GAUSS-2, have shown that evolocumab reduces LDL cholesterol levels more effectively than ezetimibe. 

As noted by the ACC, because the trial was intended to evaluate evolocumab in statin-intolerant patients, it included an initial statin rechallenge procedure designed to confirm that patients had reproducible muscle symptoms when taking a statin. There were 19 enrolled patients who bypassed this initial segment because they were documented to have creatine kinase levels at least 10 times higher than the upper limit of "normal" when taking a statin. 

Patients who participated in the statin challenge were given 20 mg of atorvastatin or a placebo daily for 10 weeks, and then switched over to either a placebo or atorvastatin—whichever one they had not been given in the first phase—for 10 more weeks. 

Of the 491 participants, 209 (42.6%) reported muscle-related side effects while taking atorvastatin, but not while taking the placebo; 26.5% reported muscle pain while taking the placebo, but not while taking atorvastatin, suggesting that although statin intolerance can be confirmed in a substantial proportion of patients with self-reported intolerance, there is also a significant proportion who experience muscle pain that cannot be attributed to taking statins.

After the initial phase, 218 patients with confirmed statin intolerance were enrolled in the trial’s second segment, with 145 patients randomly assigned to receive evolocumab and 73 randomized to receive ezetimibe. Evolocumab was given through self-administered injections totaling 420 mg per month, and ezetimibe was administered through a 10-mg daily pill; therefore, those randomized to receive evolocumab were given injections of evolocumab and daily placebo pills, and those randomized to receive ezetimibe were given placebo injections and a daily ezetimibe pill. 

Participants in the study’s second phase had an average baseline LDL cholesterol of 220 mg/dL. After 24 weeks, those given evolocumab had an LDL cholesterol of 104 mg/dL on average; 64.1% of patients taking evolocumab finished the trial with an LDL cholesterol below 100 mg/dL, and 29.9% finished with an LDL cholesterol below 70 mg/dL.

The study’s limitations included its modest size and relatively short duration, but Dr. Nissen stated that it was adequately powered to address its primary endpoint. Longer-term results from another evolocumab trial showing health outcomes may be available by the end of 2016, reported the ACC.