Effects of the CETP Inhibitor Evacetrapib Administered as

Robert K Huff
PharmD. Candidate
May 2012
 The study was designed to examine 3 main aspects
 Biochemical effects
 Safety
 Tolerability
 Evacetrapib was used as monotherapy and in
combination with statins
 Used in patients with dylipidemia
 The study was a randomized controlled trial
conducted among 398 patients with elevated LDL or
elevated low HDL (HDL-c) levels
 Multicenter, randomized, double-blind, placebo
controlled trial
 Conducted from April 2010 to January 2011
 Studies conducted in The United States and Europe
 Patients had to be at least 18 years old and must have
had low HDL-C or high LDL-C in the presence of Tg
levels >400mg/dl.
 This after a dietary lead in period
 Low HDL-c critera had an HDL-c level of <45mg/dL for
men and <50mg/dL for women
Needed an LDL-C level that met NCEP ATP III panel goals.
 LDL-c criteria
 LDL-c level b/w 100-190mg/dl in the presence of (0 or 1
risk factors)
 b/w 100-160mg/dl in the presence of (at least 2 risk
factors) and a 10-year coronary risk of < 10%
 b/w 100-130mg/dl with at least 2 risk factors and a 10 –
year coronary risk of 10 to 20%.
 Exclusion Criteria
 Clinical manifestation of atherosclerotic disease
 Hypertension (systolic > 140 mm Hg or diastolic >90
mm HG )
 Documented hyperaldosteronism
 Uncontrolled diabetes (A1C >8%)
 Liver, kidney, cardiac or neuromuscular disease
Design Cont
 Patients entered a 2 to 8 week washout period
 Used to evaluate the effect of NCEP Therapeutic
Lifestyle Changes
 Also used as a washout for any previous lipid therapy
 Study evaluated the effects of 12 weeks of tx with
evacetrapib as monotherapy and in combination with
 Monotherapy evaluation
 Patients received
Evacetrapib 30mg/d, 100mg/d, 500mg/d
 Combination treatment
 Patients received
Evacetrapib 100 mg/d in combination with the 3 most
prescribed statins used in clinical practice
 simvastatin 40mg/d
 rosuvastatin 10mg/d
 atorvastatin 20mg/d
 Randomization to statin groups
 Performed by an interactive voice response system and
was stratified according to geographic region and
baseline levels of HDL-C and Tg’s.
 Clinic Visits
 Examine during scheduled visits at 2, 4, 8 and 12 weeks
during the treatment phase
 Follow-up visit of 4 to 6 weeks after cessation of the
study drug
Lipid Measurements
 A central laboratory (Covance) performed all biochemical
 Enzymatic assay was performed for
 LDL-c
 HDL-c
 Triglycerides
 Immunonephelometry was performed for
 High Sensitivity C-Reactive Protein
 Enzyme linked immunosorbent assay used to measure
 All reported CV events and rashes were evaluated and
adjudicated by a blinded clinical end-point committee
 Samples of 35 patients per group was calculated to
provide 87% power to simultaneously detect a 40%
increase in HDL-C and a 10% decrease in LDL-C
compared with statin alone for each or in combined
therapy groups.
 Gives (0.1 type 1 error rate for a 2 sided-test)
 Reflects an increase in HDL-c greater than observed in
Niacin therapy
 Incremental reduction in LDL-c of at least 10% in
addition to statin therapy
 Participants
 April 15 2010 through January 14 2011 – 1154 patients were
screened in the study at 70 sites
 Baseline characterisitics
Similar for all treatment groups
 Mean age 58.3
 56% of patients were women
 Baseline lipid profiles
 LDL-c mean 144.3
 HDL-c mean 55.1
 TG – median 121.3
 Used to measure level of significance
 Usually <.05 or <.1
 When the p-value is less than the significance level we
can reject the null hypothesis (no difference)
 In this study a p value <.05 is statistically significant
Results – lipoprotein effects
 Evacetrapib monotherapy
 Dose dependent increases in HDL-c ranging from 30.0 t
66.0 mg/dl (53.6% to 128.8%; P<.001 vs placebo)
 Decrease in LDL-c 0f -20.5 to -51.4 mg/dl (-13.6% to 35.9%; P<.001 vs. placebo)
 Triglyceride levels decreased by 26.7 mg/dl (10.8%) with
500mg/d dosage (P <0.006)
Dose-dependent reductions in non HDL-c by -23.2 to -45.8
mg/dl (-12.9 to -26.4% ; P<.001 vs. placebo)
Dose-dependent reductions in Apolipoprotein B by -13.8 to 29.7 mg/dl (-12.4 to -26.6%; P<.001 vs. placebo)
 evacetrapib in combination with statin
 100mg/d increased HDL-c levels by 42.1 to 50.5 mg/dl
(78.5% to 88.5%; P<.001 vs. statin alone)
 Resulted in greater reductions in LDL-c (P<.001) and
non-HDL-c (P<.05) * for atorvastatin and rosuvastatin
When compared with effects observed with statin mono.
 Evacetrapib in combo with statins resulted in greater
reductions in LDL-c but showed no greater increase in
 Increase in HDL-c with evacetrapib produced dose
dependent increases in
 apolipoprotein A1 ranging from 35.7 to 72.6 mg/dl (22.7
to 49.6% ; P<.001 vs. placebo)
 Apolipoprotein A-2 by 4.8 to 7.4 mg/dl (12.7 to 19.7%;
P<.001 vs. placebo )
 Apolipoprotein E by 5.7 to 9.2mg/dl (15.8 to 83.7% ;
P<.001 for the 2 highest doses compared to placebo)
 Dose dependent decrease in CETP activity
 From -11.5 to -20.8 pmol/mL per minute (-49.5 to 89.1%;
P<.001 vs. placebo in evacetrapib monotherapy
 C-reactive protein levels remained unchanged through
the 12 week administration period. There were no
changes in as monotherapy or in combination with
 Differences b/w evacetrapib monotherapy and
 Greater percentage increases in HDL-c among patients
who were younger, had lower baseline HDL-c and had
higher baseline triglycerides
 Also greater percentage decreases in LDL-c among
patients who were younger and had lower baseline LDLc levels.
 Evacetrapib as monotherapy was not associated with an
increase in blood pressure compared with placebo
Increases in blood pressure were observed when
evacetrapib 100mg/d was administered in combination
with simvastatin 40mg/d vs. simvastatin monotherapy.
No other differences were observed in diastolic or systolic
blood pressure changes.
2 significant rashes were observed and one patient
developed angioedema
One patient also had a morbilliform reaction post cessation
 Evacetrapib administered as monotherapy or in
combination with statin therapy was not associated
with significant laboratory abnormalities related to
liver, kidney or muscle toxicity. No adjudicated
cardiovascular events were observed during the study.
 No new classes of antiatherosclerotic therapies with
clinically proven benefits have emerged since the
introduction of statins in the 1980’s.
 Drugs that inhibit CETP produce the largest increases
in HDL-c
 This study demonstrated that evacetrapib produced
marked alterations in important lipoproteins,
including large increases in HDL-c level and decreases
in LDL-c levels.
 HDL changes were significantly greater in patients with
lower levels of HDL and higher TG’s at baseline
 Underpowerd to rule out uncommon adverse effects
 Evacetrapib use in combo with statins showed potentially
useful effects as HDL increased and LDL decreased at
percentages to be considered clinically significant.
 Previous CETP inhibitor
 Torcetrapib
 Increase in HDL
 Did not slow disease progression and lead to increased mortality
 Some researches think this showed the detrimental effect of CETP
inhibition on HDL functionality.
 Additional studies found that torcetrapib had off target effects
that more than likely contributed to the observed adverse
cardiovascular outcomes.
 Low rate of treatment related adverse effects
 No increase in blood pressure
 No mineralocorticoird or glucocorticoid activity were
 Some rashes occurred
 *full safety assessment of evacetrapib will require
exposure to a much larger group of patients
 Inability of torcetrapib to slow disease progression in
humans raised concerns and questions about HDL
 No studies have yet demonstrated that any CETP
inhibitor reduces disease progression or promotes
plaque regression.
 There is a need for prospective, randomized, clinical
outcome trials.
 This study provides the foundation needed for a larger
phase 3 clinical trial to further assess the safety and
efficacy of evacetrapib.
 Funded by Eli Lilly
Level of Evidence

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