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Evolocumab proven superior to ezetimibe
in lowering cholesterol
The first major clinical trial to
include a blinded, placebo-
controlled “statin rechallenge”
in patients with a history of
muscle-related side effects
has shed new light on statin-
associated muscle symptoms.
The trial also demonstrated
that monthly self-injection
of the nonstatin cholesterol-
lowering agent evolocumab
reduced levels of low density
lipoprotein (LDL) cholesterol
more than ezetimibe, a drug
used in statin-intolerant
patients. These findings were
reported at the ACC 2016.
S
teven Nissen, MD, MACC, of the
Cleveland Clinic, explained, “Statin
intolerance has been one of the most
vexing problems faced by cardiologists.
Patients with high levels of LDL cholesterol
and high risk of cardiovascular events are
often reluctant or unwilling to take statins.
This situation is extremely frustrating for both
patients and physicians because there have
not been good alternatives for treatment.”
The prevalence of muscle-related statin
intolerance is debated: large randomised trials
have reported low rates of muscle symptoms,
while observational studies have suggested
that 5 to 20% of patients experience muscle
symptoms.
The phase 3, randomised, double-blind Goal
Achievement after Utilizing an anti-PCSK9
antibody in Statin-intolerant Subjects
(GAUSS) 3 trial enrolled 511 patients at
53 centres. Their LDL cholesterol averaged
>210 mg/dL (5.44 mmol/L). Eighty two
percent had tried and failed to tolerate three
or more statins.
A total of 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 placebo.
More than a quarter, 26.5%, reported muscle
pain while taking placebo but not while
taking atorvastatin, suggesting that though
statin intolerance can be confirmed in a
substantial proportion of patients with self-
reported intolerance, a significant proportion
experience muscle pain that cannot be
attributed to statins.
After the initial phase, 218 patients with
confirmed statin intolerance were enrolled in
the second segment, with 145 randomised to
evolocumab and 73 to ezetimibe. Participants
in the second phase had an average baseline
LDL cholesterol of 220 mg/dL (5.7 mmol/L).
After 24 weeks of treatment with either
evolucumab or ezetimibe, patients with
confirmed statin intolerance who were
given evolocumab showed an average 52.8%
reduction in LDL cholesterol, a coprimary
endpoint, vs a 16.7% reduction in those
taking ezetimibe.
For the study’s other coprimary endpoint,
average change in LDL cholesterol for
weeks 22 and 24, patients taking evolocumab
showed a reduction of 54.5%, and those
taking ezetimibe, a 16.7% reduction.
After 24 weeks, those given evolocumab
exhibited an average LDL cholesterol level
of 104 mg/dL (2.69 mmol/L); 64.1% of
patients taking evolocumab finished the trial
with LDL cholesterol below 100 mg/dL (2.69
mmol/L), and 29.9% finished below 70 mg/
dL (2.69 mmol/L).
One patient receiving evolocumab and five
given ezetimibe discontinued due to muscle-
related adverse events.
Dr Nissen said, “The findings provide unique
insights into the challenging clinical problem
of muscle symptoms in statin treated patients.
Evolocumab lowered LDL cholesterol
substantially with few patients experiencing
muscle symptoms.”
He added, “The study carries 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 study was limited by modest size and short
duration, but Dr Nissen stated it was adequately
powered to address its primary endpoint.
The study carries important implications for both
guidelines and regulatory policy, because it provides
strong evidence that muscle-related statin intolerance
is a real and reproducible phenomenon.
PRACTICEUPDATE CARDIOLOGY
AMERICAN COLLEGE OF CARDIOLOGY SCIENTIFIC SESSIONS
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