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CHICAGO -- Among patients with very high LDL levels and confirmed muscle-related statin intolerance, evolocumab (Repatha) appears to achieve greater reductions in LDL cholesterol levels than ezetimibe (Zetia), the phase III GAUSS-3 trial showed.

Averaged across the co-primary endpoints at 22 and 24 weeks, reduction in LDL levels came out at a mean 54.5% with the PCSK9 inhibitor versus 16.7% with ezetimibe (absolute -106.8 versus -31.0 mg/dL, P<0.001), , of the Cleveland Clinic, reported here at the American College of Cardiology meeting and online in the Journal of the American Medical Association.

But neither evolocumab nor ezetimibe treatment achieved optimal LDL levels, nor were muscle symptoms eliminated with these statin alternatives: persistent muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P=0.17).

"This result is not surprising," , of San Francisco General Hospital, and colleagues agreed in an editorial accompanying the paper, adding that "similar results have been reported with evolocumab or alirocumab in statin-intolerant patients in three previous trials, although in this trial Nissen et al followed a precise protocol that identified patients who were truly statin intolerant."

That rigorous protocol for defining statin intolerance was a key difference from the prior phase III GAUSS-2 trial in statin intolerance, defined by "intolerable muscle-related side effects" with any dose of at least two statins or inability to increase their dose above the smallest tablet strength due to such symptoms.

"To our knowledge, the GAUSS-3 trial represents the largest and most comprehensive study using a blinded rechallenge procedure to assess the ability of patients with a history of muscle-related adverse effects to tolerate statins," the researchers pointed out.

Nissen acknowledged at the late-breaking clinical trial session that absence of an objective biomarker for statin intolerance has subjected the entire field to controversy. “All we have is a good medical history.”

Discussant Jennifer Robinson, MD, MPH, of the University of Iowa in Iowa City, called GAUSS-3 “another trial of expectations” but one that’s informative for the clinical approach to statin intolerance.

“The fact that 60% could be rechallenged with a good dose of a statin tells us that we need to talk to all of our statin intolerant patients and … try it again. Statins are the evidence-based therapy. They’re generic. Let’s not give up statin prematurely.”

Nissen agreed that “this nocebo effect we saw in a substantial number of these patient. But we can’t forget that in this study 43% of patients had reproducible symptoms on statins -- a strong history. This is a real disorder and we need to develop alternative approaches to treating these patients.”

Still "the results are illuminating, but many unanswered questions remain," the editorialists cautioned. Chief among them are the lack of hard clinical outcomes data from the pending trials that might support such further expansion of the indication.

Another argument against using PCSK9 inhibitors -- which appear thus far to be fairly interchangeable in efficacy and safety -- in statin intolerance is persistence of muscle complaints, they wrote.

In GAUSS-3, 20.7% of evolocumab recipients reported muscle symptoms, similar to the 28.8% among ezetimibe-treated patients (log-rank P=0.17). Among the 199 patients who entered the second phase of the study, 6.8% of the ezetimibe-treated patients and 0.7% of those on evolocumab stopped treatment for muscle symptoms.

The high price tag of the anti-PCSK9 monoclonal antibody is also a barrier to use in statin intolerance, Waters' group suggested.

"However, a patient at very high risk for a cardiovascular event with intolerable muscle symptoms while taking even a low statin dose should be considered as a candidate for this treatment," they concluded. "Less than 1% of all 'statin-intolerant' patients might belong in this group at present. For other patients with statin intolerance, the appropriateness of the use of these agents is less clear."

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