Beyond Statins: The

Current Cholesterol
Controversy
Joseph Saseen, PharmD, BCPS, BCACP
Evan Sisson, PharmD, MHA, CDE
Vincent Willey, PharmD, BCACP

Supporter Disclosures
Joseph Saseen: declares no conflicts of interest, real or
Supported by independent educational grants from apparent, and no financial interests in any company,
AstraZeneca LP and Pfizer.
product, or service mentioned in this program, including
grants, employment, gifts, stock holdings, and honoraria

Evan Sisson: declares no conflicts of interest, real or

apparent, and no financial interests in any company,
product, or service mentioned in this program, including
grants, employment, gifts, stock holdings, and honoraria
The American Pharmacists Association is accredited by the Accreditation
Council for Pharmacy Education as a provider of continuing pharmacy
education.

3 4

Disclosures
Vincent Willey: declares no personal conflicts of interest, Target Audience: Pharmacists
real or apparent, and no financial interests in any company,
product, or service mentioned in this program, including ACPE#: 0202-0000-16-011-L01-P
grants, employment, gifts, stock holdings, and honoraria

Activity Type: Knowledge-based

His employer, HealthCore, does perform research studies
that are funded by multiple pharmaceutical companies

5 6

2016 by the American Pharmacists Association. All rights reserved.

 According to the National Lipid Association
Learning Objectives (NLA), which of following is the most
appropriate goal of therapy for a patient with
1. Describe current guideline recommendations regarding the use of stains
and ezetimibe to treat patients with high cholesterol. very high ASCVD risk?
2. Explain results from recent clinical trials investigating the risks and
benefits of combination therapy with statins and ezetimibe. A. LDL-C <130 mg/dL
3. Describe characteristics of PCSK9 inhibitors including mechanism of
action and role in therapy.
B. Non-HDL-C <100 mg/dL
4. Review data from clinical trials investigating the safety and efficacy of C. 30% LDL-C reduction from
PCSK9 Inhibitors baseline
5. Discuss potential issues surrounding the use of PCSK9 Inhibitors,
including patient selection, cost and delivery. D. 50% reduction in hs-CRP from
baseline

7 8

Which of the following is true regarding the Pro-

Which of the following is the approximate protein convertase subtilisin/kexintype 9
additional percent reduction in LDL-C when (PCSK9) inhibitors?
ezetimibe is added to a patient already treated
A. PCSK9 inhibitors work by blocking
with statin therapy? cholesterol absorption in the intestines
B. Alirocumab is dosed orally every 2
A. 5% weeks
C. Evolocumab is indicated for both
B. 20% heterozygous and homozygous
familial hypercholesterolemia
C. 40% D. PCSK9 inhibitors on average lower
LDL-C by same amount as titrating a
D. > 50% statin from the lowest dose to the
highest dose (i.e. atorvastatin 10mg
to 80mg)

9 10

In the IMPROVE-IT trial, which endpoint was Which of the following is most
significantly lower in patients treated with appropriate initial therapy for a
ezetimibe/simvastatin combination therapy
comparted to simvastatin alone? patient at very high ASCVD risk?

A. All-cause mortality A. Alirocumab

B. Stroke B. Rosuvastatin
C. CVD/MI/Stroke C. Ezetimibe
D. All of the above D. Lomitapide

11 12

2016 by the American Pharmacists Association. All rights reserved.

 2013 ACC/AHA Guidelines:
Four Statin Benefit Groups
Clinical ASCVD Moderate-intensity statin (Age >75 )
(MI, angina, stroke,
TIA, PAD) High-intensity statin (Age 75 )

EZETIMIBE + STATINS
LDL-C 190 mg/dL High-intensity statin
A GOOD MATCH?
10-y risk 7.5%
Moderate-to-high intensity statin
(Age 40-75)

Diabetes Moderate-intensity statin

(Age 40-75) High-intensity statin if 10-y risk 7.5%

ASCVD: atherosclerotic cardiovascular disease

Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline.
13 14

Recommended Statin Doses Statins Residual Risk

High-Intensity Moderate-Intensity Low-Intensity
LDL-C 50% LDL-C 30 - 50% LDL-C <30%
Control Statin

Atorvastatin 40-80mg Atorvastatin 10-20mg Simvastatin 10mg

Rosuvastatin 20-40mg Rosuvastatin 5-10mg Pravastatin 10-20mg
Simvastatin 20-40mg Lovastatin 20mg
Pravastatin 40-80mg Fluvastatin 20-40mg
Lovastatin 40mg Pitavastatin 1mg
Fluvastatin 80mg
Pitavastatin 2-4mg
Sampson Uk, et al. Curr Atheroscler Rep. 2012 Feb; 14(1): 110.

15 16
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline.

Ezetimibe Mechanism of Action ENHANCE Study Results

Gotto AM, et al. Nat Clin Pract Cardiovasc Med. 2006;3: 664672. Kastelein, JJP, et al. NEJM. 2008;358:1431-43.

17 18

2016 by the American Pharmacists Association. All rights reserved.

 ENHANCE Study Results Ezetimibe & 2013 ACC/AHA Guidelines

Nonstatin therapies do not provide acceptable ASCVD risk

reduction benefits compared to their potential for adverse
effects in the routine prevention of ASCVD.

Kastelein, JJP, et al. NEJM. 2008;358:1431-43. Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline.

19 20

Variability of Achieved LDL-C with High-

Intensity Statin Therapy

SHOULD WE RECOMMEND 1,500 Mean = 696,217

St. Dev. = 26.95
N=18,661
STATINS AND EZETIMIBE FOR
Meta-analysis of 8 RCT with statins
TREATMENT OF PATIENTS WITH 1,000

38,153 subjects
6,286 major CV events in 5,387 patients
Frequency

DYSLIPIDEMIA?
500 40% did not achieve
LDL-C <70 mg/dL on

Let the debate begin!!!!! Atorvastatin 80 or

Rosuvastatin 20 mg daily

0
0 50 100 150 200 250
LDL-C (mg/dL)

21 22 22
Boekholdt SM, et al. J Am Coll Cardiol. 2014;64:485-494.

NLA Steps in ASCVD Risk Assessment NLA Criteria for ASCVD Risk Assessment
1) Identify
and Treatment Goals
patients with ASCVD Target Goals (mg/dL) Non- LDL ApoB
very high risk Diabetes with 2 other major ASCVD risk factors or end organ damage
HDL
conditions
Very High ASCVD <100 <70 <80
Risk Diabetes mellitus (type 1 or 2)
2) Identify Diabetes with 0-1 other major ASCVD risk factors >2 other major ASCVD risk factors(s) OR
patients with Chronic kidney disease Stage 3 or 4
high risk Evidence of end-organ damage
LDL-C 190 mg/dL
conditions High Risk >3 major ASCVD risk factors <130 <100 <90
Diabetes mellitus (type 1 or 2)
If 0-1 and no other indicators of higher risk, assign to low risk category. 0-1 other major ASCVD risk factors, AND
3) Count major Consider assigning to a higher risk category based on other risk factors, if known.
ASCVD risk No evidence of end-organ damage
If 2, risk scoring is recommended and additional testing may be useful for some pts
factors If 3 major ASCVD risk factors are present, assign to high risk category
Chronic kidney disease Stage 3 or 4
LDL-C >190 mg/dL
>10% 10-year heard CHD event risk
If <10% 10-year hard CHD risk, assign to moderate risk category.
Moderate 2 ASCVD risk factors <130 <100
If 10% 10-year hard CHD risk, assign to high risk category.
4) Risk scoring Risk Quantitative risk scoring recommended
Consider assigning to high or very high risk category, as appropriate, if other risk
indicators are present based on additional testing. Consider other risk indicators
Low Risk 0-1 major ASCVD risk factors <130 <100
Consider other risk indicators, if known
23 23 24
Jacobson TA et al. J Clin Lipid. 2014;8:473-488. Jacobson TA et al. J Clin Lipid. 2014;8:473-488.

2016 by the American Pharmacists Association. All rights reserved.

 Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction,
by baseline LDL-C No. of events (% pa) Relative risk (CI) per
PROVE-IT Substudy: Primary End Point* and
Statin/more Control/less mmol/L LDL-C reduction Achieved LDL-C Levels
More vs less statin
Hazard Ratio

Achieved LDL (mg/dL)

2.0 (<77 mg/dL) 704 (17.9%) 795 (20.2%) 0.71 (0.52 - 0.98)
2,<2.5 (<97 mg/dL) 1189 (18.4%) 1317 (20.8%) 0.77 (0.64 - 0.94)
2.5,<3.0 (<116 mg/dL) 1065 (20.1%) 1203 (22.2%) 0.81 (0.67 - 0.97) >80100 Referent
3,<3.5 (<135 mg/dL) 517 (20.4%) 633 (25.8%) 0.61 (0.46 - 0.81)
3.5 (>135 mg/dL) 303 (23.9%) 398 (31.2%) 0.64 (0.47 - 0.86)
Total 3837 (19.4%) 4416 (22.3%) 0.72 (0.66 - 0.78) >6080 0.80 (0.59, 1.07)
Statin vs control
2.0 (<77 mg/dL) 206 (9.0%) 217 (9.7%) 0.87 (0.60 - 1.28)
2,<2.5 339 (7.7%) 412 (9.1%) 0.77 (0.62 - 0.97) >4060 0.67 (0.50, 0.92)
2.5,<3.0 801 (8.2%) 1022 (10.5%) 0.76 (0.67 - 0.86)
3,<3.5 1490 (10.8%) 1821 (13.3%) 0.77 (0.71 - 0.84)
3.5 4205 (12.6%) 5338 (15.9%) 0.80 (0.77 - 0.84) 40 0.61 (0.40, 0.91)
Total 7136 (11.0%) 8934 (13.8%) 0.79 (0.77 - 0.81)
All trials
2.0 (<77 mg/dL) 910 (14.7%) 1012 (16.4%) 0.78 (0.61 - 0.99)
2,<2.5 1528 (14.0%) 1729 (15.9%) 0.77 (0.67 - 0.89)
0 1 2
2.5,<3.0 1866 (12.4%) 2225 (14.7%) 0.77 (0.70 - 0.85) Lower Better Higher Better
3,<3.5 2007 (12.3%) 2454 (15.2%) 0.76 (0.70 - 0.82)
3.5 4508 (13.0%) 5736 (16.5%) 0.80 (0.76 - 0.83)
*All-cause mortality, myocardial infarction, coronary revascularization, unstable angina, and stroke.
Total 10973 (13.0%) 13350 (15.8%) 0.78 (0.76 - 0.80) Adjusted for multiple baseline characteristics, including LDL-C level.
99% or 95% CI Significantly lower than the referent group.
0.5 0.75 1 1.25 1.5
Statin/more better Control/less better

25
25 26
26

Lancet. 2010;376:167081 Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-1416.

How low is too low? 55 yo with statin intolerance

In vitro fibroblasts
2.5 mg/dL of LDL cholesterol required to meet cellular needs 55 yo AAM with HTN (166/94 mmHg) on therapy with
Translates to 25 mg/dL plasma LDL cholesterol in vivo
history of CABG 2 months ago. He does not smoke, and
has no significant family history. He does not like the
Human newborns
grittiness of colestipol. He has been tried on numerous
LDL cholesterol of 40-50 mg/dL statins but had to stop them due to muscle aches. He
currently feels fine off all statins.
TC TG HDL LDL Non-HDL
Hypobetalipoproteinemia
LDL cholesterol of 10 mg/dL
205 130 33 146 172
Appear to be resistant to atherosclerosis with
a normal life expectancy Framingham Risk = 12%; ASCVD 19.6%
NLA goal Non-HDL<100
Statins reduce major vascular events by 22%
for each 1 mmol/L (~40 mg/dL) LDL reduction
LDL <70 mg/dL yielded definite benefits (p=0.004)

27
27 28
28

Cholesterol Treatment Trialists (CTT) Collaboration. Lancet. 2010; 376: 167081.

Statin Dose-Response Curves

Safety LDL Reduction from Baseline
Muscle and Rhabdomyolysis
Myalgia
Muscle pain or soreness, weakness,
and/or cramps without CK elevations
Myopathy
Muscle symptoms plus CK >10 times the ULN Creatinine
Myoglobin
Occurs in 5 patients per 100,000 person-years
Rhabdomyolysis
CK >10,000 U/L, or CK >10 times ULN
with worsening renal function
Occurs in 1.6 patients per 100,000 person-years Pitavastatin1 mg 2 mg 4 mg

CK levels rarely change clinical decisions but are Increasing risk of myositis
necessary for diagnosis of rhabdomyolysis

Average LDL cholesterol reduction in patients with primary hypercholesterolemia on

monotherapy based Food and Drug Administration product labeling for each compound.
29
29 30
30

McKenney JM et al. Am J Cardiol 2006; 97[suppl]:89C94C

2016 by the American Pharmacists Association. All rights reserved.

 Simvastatin Myalgia Simvastatin Dose Limitations
Previous Simvastatin Label New Simvastatin Label

No New Patients start on Simvastatin 80mg

SEARCH Trial* Simvastatin 80 mg Simvastatin 20 mg Avoid simvastatin with: Contraindicated with simvastatin:

Simvastatin is a pro-drug of lovastatin

(6031) (6033) Itraconazole, Ketoconazole Itraconazole, Ketoconazole
Posaconazole (New)
Myopathy 52 (0.9%) 1 (0.02%) Erythromycin, Clarithromycin, Erythromycin, Clarithromycin,
Rhabdomyolysis 11 (0.2%) 0 Telithromycin Telithromycin
HIV protease inhibitors HIV protease inhibitors
*MACE in patients with previous heart attack over 6.7 years Nefazadone Nefazadone
Gemfibrozil
Heart Protection Study 2 (HPS2) Cyclosporine
Interim HPS2 results 40 mg simvastatin plus 1 g/day niacin Danazol
Myopathy: higher incidence in patients of Chinese descent
Do not exceed 10 mg daily with: Do not exceed 10 mg daily with:
(0.43%) compared with patients not of Chinese descent (0.03%) Gemfibrozil Amiodarone
Not known if the increased risk for myopathy applies to other Cyclosporine Verapamil
patients of Asian descent Danazol Diltiazem
FDA revised label in March 2010 Do not exceed 20 mg daily with: Do not exceed 20 mg daily with:
Patients of Chinese descent should not receive simvastatin 80 mg Amiodarone Amlodipine (New)
with cholesterol-modifying doses of niacin-containing products. Verapamil Ranolazine (New)
Use caution with simvastatin 40 mg or less with niacin Do not exceed 40 mg daily with: Avoid large quantities of grapefruit juice
Diltiazem (>1 quart daily)

FDA Drug Safety Communication. Available at

www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandPr 31
31
FDA Drug Safety Communication. Available at 32
32

oviders/ucm204882.htm. Accessed November 10, 2010 www.fda.gov/Drugs/DrugSafety/ucm256581.htm. Accessed July 21, 2011

Statin Dose Limitations with HIV or Hep C Drugs
Statin Interacting protease
inhibitor(s)
Atorvastatin Tipranavir + ritonavir
Telaprevir
Lopinavir + ritonavir
Darunavir + ritonavir
Fosamprenavir
Fosamprenavir + ritonavir
Saquinavir + ritonavir
Nelfinavir
Fluvastatin
Pitavastatin Atazanavir ritonavir
Darunavir + ritonavir
Lopinavir + ritonavir
Pravastatin Darunavir + ritonavir
Lopinavir + ritonavir
Rosuvastatin Atazanavir ritonavir
Lopinavir + ritonavir
ENHANCE: Effects on Lipoproteins and CIMT
Prescribing recommendation
Avoid atorvastatin
Use caution and with the lowest dose
Do not exceed 20 mg atorvastatin daily NS
No significant change in
carotid intima-media
thickness (CIMT)
Do not exceed 40 mg atorvastatin daily Simvastatin 0.0058mm
No data available Simvastatin/Ezetimibe
P<0.01
0.0111mm
No dose limitations
P<0.01
No dose limitations P<0.01
Potential explanations: 1) short trial duration; 2) previous statin use in 80% of
Limit dose to 10 mg once daily patients caused thinner baseline CIMT levels

FDA Drug Safety Communication. Available at 33

33 34
34

www.fda.gov/Drugs/DrugSafety/ucm293877.htm. Accessed 3/25/2012 Kastelein JP et al. N Engl J Med. 2008;358(14):1431-1443.

SHARP: Effect of Simvastatin/Ezetimibe SHARP: Major Vascular Events

on Lipids and Apolipoproteins at 2.5 years Event Simv/Eze
(n=4650)
Placebo
(n=4620)
Riskratio&95%CI

Majorcoronaryevent 213 (4.6%) 230 (5.0%)

Biochemical Simv/Eze Placebo Percentage p Nonhaemorrhagicstroke 131 (2.8%) 174 (3.8%)
Anyrevascularisationprocedure 284 (6.1%) 352 (7.6%)
parameter (mg/dL) (mg/dL) difference
16.6%SE5.4
Total cholesterol 142 183 -23% <0.0001 MajorAtheroscleroticEvent 526 (11.3%) 619 (13.4%) reduction
(p=0.0021)
LDL cholesterol 70 102 -32% <0.0001
Othercardiacdeath 162 (3.5%) 182 (3.9%)
HDL cholesterol 44 44 2% 0.03 Haemorrhagicstroke 45 (1.0%) 37 (0.8%)

Non-HDL cholesterol 97 139 -30% <0.0001 OtherMajorVascularEvents 207 (4.5%) 218 (4.7%) 5.5%SE9.4
reduction
Triglycerides 163 188 -13% <0.0001 (p=0.56)
Apolipoprotein B 70 93 -24% <0.0001 MajorVascularEvent 701 (15.1%) 814 (17.6%) 15.4%SE4.7
reduction
Apolipoprotein A1 145 143 1% 0.003 (p=0.0012)

0.6 0.8 1.0 1.2 1.4

Simv/Ezebetter Placebobetter

35 35 36
36

Baigent C, et al. Lancet. 2011 Jun 25;377(9784):2181-92 Baigent C, et al. Lancet. 2011 Jun 25;377(9784):2181-92

2016 by the American Pharmacists Association. All rights reserved.

 IMPROVE-IT: Individual Cardiovascular Endpoints
IMPROVE-IT: Ezetimibe + Simvastatin vs. and CVD/MI/Stroke
*7-year event rates (%)
Simvastatin for Post-MI Patients EZ/Simva* Simva*
Risk ratio & 95% CI
HR p-value
All-cause death 15.4 15.3 0.99 0.782
18,144 patients stabilized post ACS <10 days
Randomized to ezetimibe + simvastatin or simvastatin alone Cardiovascular disease 6.9 6.8 1.00 0.997
Baseline LDL-C at time of ACS event was 95 mg/dL Coronary heart disease 5.7 5.8 0.96 0.499
Primary composite endpoint: CV death, MI, hospital admission for UA,
revascularization, or stroke. Myocardial Infarction 13.1 14.8 0.87 0.002

32.7% event rate in EZ/Simva group vs. 34.7% in Placebo/Simva group Stroke 4.2 4.8 0.86 0.052

Ischemic Stroke 3.4 4.1 0.79 0.008

Lipid Measurement Ezetimibe/Sim Placebo/Simv Change in
(1 Year Mean) va a mg/dL
Revascularization 21.8 23.4 0.95 0.107
HDL-C 48.7 mg/dL 48.1 mg/dL +0.6
Unstable angina 2.1 1.9 1.06 0.618
Triglycerides 120.4 mg/dL 137.1 mg/dL -16.7
CVD/MI/Stroke 20.4 22.2 0.90 0.003
LDL-C 53.2 mg/dL 69.9 mg/dL -16.7
0.6 1.0 1.4
hs-CRP 3.3 mg/dL 3.8 mg/dL -0.5
EZ/Simva better Simva better

37 37 38 38
IMPROVE-IT (TIMI 40) website. www.timi.org. Accessed 5/4/2015. IMPROVE-IT (TIMI 40) website. www.timi.org. Accessed 5/4/2015.

Response to LIPTRUZET in Patients with

Primary Hyperlipidemia at 12 weeks 55 yo with statin intolerance
55 yo AAM with HTN (166/94 mmHg) on therapy with
0%
history of CABG 2 months ago. He does not smoke, and
Mean % Change from Untreated

-10% has no significant family history. He does not like the

-20% grittiness of colestipol. He has been tried on numerous
-30% statins but had to stop them due to muscle aches. He
Baseline

currently feels fine off all statins.

-40%
TC TG HDL LDL Non-HDL
-50%
205 130 33 146 172
-60%
Framingham Risk = 12%; ASCVD 19.6%
-70%
Liptruzet Liptruzet Liptruzet Liptruzet Atorva Atorva Atorva Atorva NLA goal Non-HDL<100
10/10 10/20 10/40 10/80 10 20 40 80
LDL-C -53% -54% -56% -61% -37% -42% -45% -54% Plan: Start pravastatin 20mg then consider
Non-HDL -49% -50% -52% -58% -34% -39% -41% -51% combination therapy with niacin or ezetimibe.
Apo B -43% -44% -45% -50% -28% -34% -37% -46%

39
39 40
40

Liptruzet Package Insert 2013.

Heartwire from Medscape

PRO Ezetimibe Summary Points
FDA Advisors: Reject Secondary-
Significant residual CVD risk remains Prevention Ezetimibe Indication
Statin response is variable Deborah Brauser
Residual risk is related to non-HDL-C levels above goal December 14, 2015
Statin intolerance amplifies the need for effective
combination therapy SILVER SPRING, MD ( UPDATED ) The Endocrinologic
and Metabolic Drugs Advisory Committee of the US Food
Ezetimibe consistently lowers LDL-C and non-HDL-C in
and Drug Administration (FDA) voted 10 to 5 against
combination with statins
recommending the expanded use of ezetimibe (Zetia, Merck)
Poor results of ENHANCE related to trial design by adding it to statin therapy for reduction of
IMPROVE-IT reinforces LDL Hypothesis and supports cardiovascular events in patients with
benefits of ezetimibe + statin coronary heart disease

41 http://www.medscape.com/viewarticle/855958?nlid=93603_2562&src=wnl_ 42
edit_medp_card&uac=39775MJ&spon=2&impID=921002&faf=1

2016 by the American Pharmacists Association. All rights reserved.

 Schizophrenic Life of Ezetimibe IMPROVE-IT: Study Design Changes
2002 Approval of ezetimibe Original Design:
2004 Approval of ezetimibe/simvastatin combination Hypothesis: ezetimibe/simvastatin would reduce the incidence of
the composite CV end point over at least 2.5 years of follow-up
2005 IMPROVE-IT study starts targeting 12,500 patients relative to simvastatin monotherapy
2006 ENHANCE published after 18 month delay Sample Size Calculation
2008 Excess cancer cases in the SEAS trial 10,000 based a 2 year event rate of 23.5% (simvastatin alone)
2008 IMPROVE-IT changes target enrollment to 18,000; Statistical power to detect a 10% relative risk reduction
completion delayed until 2012 Endpoint driven with 5,250 primary end points needed

2009 FDA investigation concludes cancer risk unlikely Enrollment changes

Increased to 12,500 in the second study amendment
2010 IMPROVE-IT completion delayed until 2013
Increased to 18,000 in the third study amendment to complete
2015 Release of IMPROVE-IT results the trial in as timely a fashion as possible

43 44
Am Heart J 2008;156:826832.

IMPROVE-IT: Primary Endpoint

IMPROVE-IT: Clinically relevant?
Results
Composite Primary Endpoint:
Primary endpoint events:
CV death, major coronary event (nonfatal MI, unstable angina, or
Rate at 7-years: coronary revascularization), or nonfatal stroke
34.7% vs. 32.7% (p=0.016) After 7 years, among 100 patients:
Simvastatin Alone Ezetimibe/Simvastatin
Simvastatin
40 mg daily Absolute Risk Reduction:

2.0%; NNT = 50
Primary

Endpoint
Ezetimibe/Simvastatin
10/40 mg daily
Relative Risk Reduction: No

Endpoint

5.8%

45 46
Cannon CP et al. N Engl J Med 2015;372:2387-97.

Randomized Aldactone Evaluation IMPROVE-IT: Other Endpoints

Study (RALES) *7-year event rates (%) Risk ratio & 95% CI
EZ/Simva* Simva* HR p-value
Randomized, double-blind study in 1663 patients with
heart failure for 2 years All-cause death 15.4 15.3 0.99 0.782
Death from CV disease 6.9 6.8 1.00 0.997
50
46
Absolute Risk Reduction: Death from CHD 5.7 5.8 0.96 0.499
All-cause Mortality (%)
Primary Endpoint:

40 Myocardial Infarction 13.1 14.8 0.87 0.002

35 11%; NNT = 9
Stroke 4.2 4.8 0.86 0.052
30
Ischemic Stroke 3.4 4.1 0.79 0.008
20 Relative Risk Reduction: Revascularization 21.8 23.4 0.95 0.107
24%
10
Unstable angina 2.1 1.9 1.06 0.618

CVD/MI/Stroke 20.4 22.2 0.90 0.003

0
0.6 1.0 1.4
Spironolactone Placebo EZ/Simva better Simva better

47 48 48
N Engl J Med 1997;341:709-717 Cannon CP et al. N Engl J Med 2015;372:2387-97.

2016 by the American Pharmacists Association. All rights reserved.

 IMPROVE-IT: Who are these
4S: Results of All End-points
patients??
Simvastatin Better Placebo Better Median time-weighted LDL-C values achieved
Total P=0.0003 Simvastatin 40 mg daily 69.5 mg/dL
mortality
Ezetimibe/Simvastatin 10/40 mg daily 53.7 mg/dL
CAD mortality P<0.00001
Major
coronary
events P<0.00001
Baseline Characteristics:
Mean age 63.6 years, 76% men, 84% white, mean BMI 28 kg/m2
PTCA/CABG
P<0.00001
Other CV risk factors:
27% diabetes
Event-free
survival P<0.00001 61% hypertension
0.2 0.4 0.6 0.8 1.0 1.2
33% current smokers
Relative risk (95% CI) 35% statin use

The Scandinavian Simvastatin Survival Study Group. Lancet. 49 50

1994;344:1383-1389. 49 Cannon CP et al. N Engl J Med 2015;372:2387-97.

National Lipid Association:

Familial Hypercholesterolemia
Limited Applicability FH Patients
Familial hypercholesterolemias (FH) are genetic defects Ezetimibe failed to demonstrate benefits in the ENHANCE,
resulting in severe cholesterol elevations and increased patients with familial hypercholesterolemia (FH)
risk of premature CHD Baseline LDL-C values of 318-319 mg/dL
Prevalence of FH is 1 in 300 to 500 No difference in primary endpoint of cIMT
Homozygous FH affects 1 in 1,000,000 No difference in CV events
12 with ezetimibe/simvastatin and 9 with simvastatin alone
Aggressive lipid lowering is necessary
Target LDL-C reduction of at least 50% IMPROVE-IT eliminated FH patients based on LDL-C
Greater LDL-C reductions may be necessary for FH patients with criteria for eligibility
other CHD risk factors Despite IMPROVE-IT results, ezetimibe is unproven in very
high CV risk patients with FH

51 Kastelein JP, et al. N Engl J Med. 2008;358:1431-1443. 52

Journal of Clinical Lipidology 2011;5:133140. Cannon CP et al. N Engl J Med 2015;372:2387-97.

ACC/AHA 2013 Blood Cholesterol Guideline:

The LDL-C Principle ASCVD
LDL-C lowering is the Class I Recommendations Level of
principal driver for Evidence
benefit, not ezetimibe High-Intensity statin therapy should be initiated or A
continued as first line therapy in men and women for
75 years of age, unless contraindicated
If high-Intensity statin therapy is contraindicated or A
when characteristics predisposing to statin-associated
adverse effects are present, Moderate-Intensity statin
therapy should be the second option if tolerated

53 54
Cannon CP et al. N Engl J Med 2015;372:2387-97 Stone NJ et al. Circulation. 2014; 129(25 suppl 2):S1-45.

2016 by the American Pharmacists Association. All rights reserved.

 TNT Trial: Results Atorvastatin 10 mg PROVE-IT: Results
Atorvastatin 80 mg

120 12 30

Patients with an Event (%)

Pravastatin 40 mg
100 10 25 (26.3%)

80 8 20

60 6 15
Atorvastatin 80 mg
Median LDL-C
40 4
10 (22.4%) values:
20 2 Atorvastatin 62 mg/dL
5
P=0.005 Pravastatin 95 mg/dL
0 0
0 (P<0.001)
Mean LDL-C Value Patients with Major 0 3 6 9 12 15 18 21 24 27 30
(mg/dL) CV Event (%)
P<0.001 P<0.001 Months of Follow-up

55 56
LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435. Cannon C, et al. N Engl J Med. 2004;350:1495-1504. 56

ALLHAT-Lipid Lowering Trial (LLT) IMPROVE-IT: Results

Randomized, blinded trial of 10,355 patients from Median time-weighted LDL-C values achieved
Simvastatin 40 mg daily 69.5 mg/dL
the ALLHAT trial for up to 8 years Ezetimibe/Simvastatin 10/40 mg daily 53.7 mg/dL
18
Primary Endpoint

16
14
Death (%)

12
10
8
6 Mean LDL-C values:
4 Pravastatin 104 mg/dL
2
Usual Care 121 mg/dL
0
Pravastatin Usual Care
40 mg daily
P=0.88

57 58
JAMA 2002;288:2998-3007. Cannon CP et al. N Engl J Med 2015;372:2387-97.

Additional Safety Monitoring Needed CON Ezetimibe Summary Points

Statin Product Labeling (revised February 28, 2012) IMPROVE-IT trial required multiple study design
Labels revised to remove the need for routine periodic monitoring modifications to demonstrate a benefit
of liver enzymes in patients taking statins

Proven benefits, but minimal with questionable clinical

Ezetimibe Product Labeling significance in patients requiring robust LDL-C lowering to
Persistent elevations in hepatic transaminase can occur when assure meaningful CV event reductions (i.e., FH)
ezetimibe is added to a statin; monitor hepatic transaminase levels
before and during treatment
Incidence of consecutive elevations (>3 X ULN) in hepatic Additional safety monitoring required when ezetimibe is
transaminase 1.3% in patients treated with ezetimibe/statin therapy added to statin therapy
and 0.4% for patients treated with statin therapy alone

http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm 59 60
Zetia Product Insert. Merck & Co. Inc, Whitehouse Station, NJ (August 2013)

2016 by the American Pharmacists Association. All rights reserved.

 WHAT ARE THESE NEW
CHOLESTEROL DRUGS
ALL ABOUT?
REBUTTALS PCSK9 Inhibitors

61 62

Role of LDL-C Receptors (LDLR) PCSK9 Inhibitor Mechanism of Action

Expressed on the surface of the liver

Function as the primary mechanism to reduce LDL-C from

the bloodstream

Pro-protein convertase subtilisin/kexintype 9 (PCSK9)

Enzyme that is responsible for degrading the LDLR
Inhibit PCSK9 LDLR LDL-C in the bloodstream

Ahn, CH, et al. Diabetes Metab J. 2015:39:87-94. Ahn, CH, et al. Diabetes Metab J. 2015:39:87-94.

63 64

Alirocumab
Indications
Adjunct to diet and maximally tolerated statin dose in patients who
require additional LDL-C lowering with
Heterozygous familial hypercholesterolemia
PCSK9 INHIBITORS Clinical ASCVD

AVAILABLE IN THE US Route of administration

Subcutaneous self administered
Alirocumab (Praluent)
Dosing
Evolocumab (Repatha) Starting dose = 75mg SC every 2 weeks
Maximum dose = 150 mg SC every 2 weeks

Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis and Tarrytown, NY: Regeneron; 2015.

65 66

2016 by the American Pharmacists Association. All rights reserved.

 Alirocumab Impact on LDL-C Evolocumab
Indications
Adjunct to diet and maximally tolerated statin dose in patients who
require additional LDL-C lowering with
Heterozygous familial hypercholesterolemia (HeFH)
Clinical ASCVD

Adjunct to diet and other LDL-C lowering therapies in patients who

require additional LDL-C lowering with
Homozygous familial hypercholesterolemia (HoFH)

Route of administration
Subcutaneous self administered

Robinson, JG, et al. NEJM. 2015:372:1489-99. RepathaTM [package insert]. Thousand Oaks, CA: Amgen; 2015.

67 68

Evolocumab - Dosing Evolocumab Impact on LDL-C

Difference between evolocumab and placebo in LDL-C
Clinical ASCVD and HeFH indications
140mg SC every 2 weeks
420 mg SC every month
Need to administer 3 140mg injections consecutively within
30 minutes

HoFH indication
420 mg SC every month
Need to administer 3 140mg injections consecutively within
30 minutes

RepathaTM [package insert]. Thousand Oaks, CA: Amgen; 2015. Blom, DJ, et al. NEJM. 2014:370:1809-19.

69 70

Who here likes statin therapy?

SHOULD WE RECOMMEND
PCSK9 INHIBITORS FOR
TREATMENT OF PATIENTS WITH
DYSLIPIDEMIA?

Let the debate begin!!!!!

http://www.supermanhomepage.com

71 72

2016 by the American Pharmacists Association. All rights reserved.

 Very Low LDL-C Linked to Reduced CV Events

Meta-analysis of 8 randomized controlled trials (n=38,153)

More than 40% of patients randomized to high-dose statin
therapy did not achieve an LDL-C <70 mg/dL
Results:
Risk for major CV Events by achieved on-trial LDL-C (mg/dL)
<50 50-74 75-99 100-124 125-149 150-174 175
n 194 1,184 1,664 1,480 557 184 123 William H. Shrank, MD, MSHS
Adjusted
HR 0.44 0.51 0.56 0.58 0.64 0.71 1.00
Jane F. Barlow, MD, MPH
(95% CI) (0.35-0.55) (0.42-0.62) (0.46-0.67) (0.48-0.69) (0.53-0.79) (0.56-0.89) (Ref)
Troyen A. Brennan, MD, JD

-- CVS Health; Woonsoket, Rhode Island

73 74
J Am Coll Cardiol 2014;64:48594 JAMA. Published online August 10, 2015

Drugs Affecting Lipoprotein Metabolism PCSK9 Inhibitors: Role in Therapy

LDL-C HDL-C TG Aliroculmab and Evolocumab FDA approval:
Statins 18-55% 5-15% 7-30% Adjunct to diet and maximally tolerated statin therapy
for the treatment of adults with heterozygous familial
Bile acid sequestrants 15-30% 3-5% 0-10%
hypercholesterolemia (FH) or clinical atherosclerotic
Nicotinic acid 5-25% 15-35% 20-50% cardiovascular disease, who require additional
Fibric Acids 5-20% 10-20% 20-50% lowering of LDL-C
Ezetimibe 13-20% 3-5% 5-11% Evolocumab also approved for homozygous FH
Omega-3 fatty acids 6-25% 5-7% 19-44% Dosing
Alirocumab 75 150 mg sq every 2 weeks
PCSK9 inhibitors 40-72% 0-10% 0-17%
(Praluent)
For LDL-C lowering Evolocumab 140 sq every 2 weeks or
Primarily for hypertriglyceridemia
(Repatha) 420 mg once monthly in homozygous FH patients

Jacobson TA et al. J Clin Lipidol. 2014; 8:473-88. 75 . 76

Shimada YJ and Cannon CP. European Heart Journal doi:10.1093/eurheartj/ehv174

Evolocumab (OSLER-1 and OSLER-2): Alirocumab (ODYSSEY LONGTERM)

LDL-C Levels Over Time Calculated LDL-C Levels Over Time
Standard of Care
140
Least-Squares Mean Calculated

140 Placebo + maximum tolerated statin dose +/- LLT

120 120
LDL-C (mg/dL)

LDL-C Level (mg/dL)

100
100
80
80
60
60
40 -56.3%* -54.0%* -58.4%*
-60.9%* -58.8%* -52.4%*
20 40 -61.0%*
Evolocumab + Standard of Care Alirocumab + maximum tolerated statin dose +/- LLT
0 20
Baseline 4 12 24 36 48
Time (weeks) 0
0 4 8 12 16 24 36 52 64 78
* All < 0.001 * All P < 0.001
Time (weeks) LLT = lipid-lowering therapy

77 78
Sabatine MS, et al. N Engl J Med. 2015;372(16):1500-1509. Robinson JG, et al. N Engl J Med. 2015;372(16):1489-1499.

2016 by the American Pharmacists Association. All rights reserved.

 Alirocumab (ODYSSEY LONGTERM)
Safety Analysis Outcomes Studies with PCSK9s
Alirocumab Placebo
P Value
Several pending large-scale outcome trials
Summary of Adverse Events (n = 1,550) (n = 788)
Serious Adverse Events 290 (18.7%) 154 (19.5%) 0.66
Preliminary Findings
AE leading to discontinuation 111 (7.2%) 46 (5.8%) 0.26
Meta-analysis of 24 clinical trials (n=10,159)
AE leading to death 8 (0.5%) 10 (1.3%) 0.08 Reduced MI OR 0.49 (0.26-0.93)
General allergic reaction events 156 (0.1%) 75 (9.5%) 0.71 Reduced all cause mortality OR 0.45 (0.23-0.86)
Local injection site reactions 91 (5.9%) 33 (4.2%) 0.10 No increase in serious adverse events
Neurologic events 65 (4.2%) 35 (4.4%) 0.83

Neurocognitive events 18 (1.2%) 4 (0.5%) 0.17

Among patients who received alirocumab, 575 (37.1%) had a calculated LDL-C level of < 25 mg/dL
at 2 consecutive measurements. Rates of AEs were similar to those in the overall alirocumab group.

79 80
Robinson JG, et al. N Engl J Med. 2015;372(16):1489-1499. Ann Intern Med. 2015;163:40-51.

Post-Hoc Analysis of Adjudicated

Evolocumab and CV Events from
Major CV Events* from ODYSSEY
OSLER-1 and OSLER-2
LONG TERM Open-label trials: 1489 placebo, 2976 evolocumab
0.06
Cox model analysis Placebo + statin therapy at
Cumulative Probability of

HR = 0.52 (95% CI 0.310.90) maximum tolerated dose +/-

CumulativeIncidence

Nominal P value 0.01 lipid lowering therapy

(n=788)
0.04
ofCVevents
Event (%)

0.02

Alirocumab + statin therapy at

maximum tolerated dose +/-
lipid lowering therapy
0.00 (n=1550)

0 12 24 36 52 64 78
Time (weeks)

*same primary endpoint as ongoing ODYSSEY OUTCOMES trial

81 82
Robinson JG, et al. N Engl J Med. 2015;372(16):1489-1499. N Engl J Med 2015;372:1500-9

Targeted Populations for PCSK9 Options for FH patients after Statin

Inhibitors Therapy
Traditional nonstatins (ezetimibe, bile acid resins, niacin)
Clinical Familial
ASCVD Hypercholesterolemia Homozygous FH only drugs: Mipomersen and Lomitapide
(FH) REMS program required
Significant adverse events limit use
$176,000 to >250,000 annually!
Residual CV risk as CV events seen despite aggressive
LDL-lowering therapy in many patients, especially in FH
Other options do not provide robust LDL-C reductions LDL Apheresis
$2500/treatment, repeated every 1 to 2 weeks
Some other options are inconvenient, not well tolerated Each treatment takes 2 to 3 hours
and more costly than PCSK9 inhibitors

83 http://www.medscape.com/viewarticle/804574_5 84
http://www.medscape.com/viewarticle/811660

2016 by the American Pharmacists Association. All rights reserved.

 Monoclonal Antibodies are not new.. PRO PCSK9 Summary Points
TNF-alpha blockers Robust reductions in LDL-C have best potential to
Entered the market in the late 90s significantly lower CV events, on top of statin
Novel mechanism of action therapy
Highly effective Every 2 to 4 week dosing that is well tolerated
Slowly increased in use Preliminary outcomes data has positive trends and
Long term data demonstrated significant benefits early benefit, with complete data available in the
Now have revolutionized treatment of rheumatoid arthritis, future
Crohns disease, psoriasis
Best option after statin therapy for patients with FH
Could this happen with PCSK9 inhibitors?

85 86

Quantitative Effects on Lipid Profile

STEPS to Drug Selection Agents Lower Raise Lower
LDL-C HDL-C VLDL-C
HMG-CoA Reductase 18-55% 5-15% 7-30%
Inhibitors (statins)
PCSK9 Inhibitors 58% NR NR
Ezetimibe 18% 1% 7-9%
Bile acid sequestrants 15-30% 3-5% or
Niacin 5-25% 15-35% 20-50%
Safety Mipomersen 25% NR 18%
Tolerability Lomitapide 40% NR 45%
Effectiveness Fibric acid derivatives 5-20% 10-20% 20-50%
Price Omega 3 Fatty Acids or 45% 9% 42%
Simplicity (fish oil)

Shaughnessy AF: STEPS drug updates [editorial]. Am Fam Physician 2003. 68 (12): 2213. 87 88
88

Adapted from NCEP ATP-III Guidelines and product information.

Meta-analysis of PCSK9-Inihibtor
PCSK9 Inhibitor Clinical Outcomes Outcomes
Randomized, double-blind, placebo-controlled Meta-analysis 24 phase II and III of 10,159 patients
Alirocumab ODYSSEY LONG-TERM LDL-C reduction 50% vs. placebo (36% vs. ezetimibe)
Evolocumab OSLER long-term extension Limitations small sample size and short duration of
50% reduction in major cardiovascular events follow-up
Treatment duration of 11-18 months
Parameter PCSK9-inhibitor Placebo Odds Ratio
Limitations of post-hoc analyses (95% CI)
Underpowered observations All-cause mortality 0.31% 0.53% 0.45 (0.23-0.86)
Cardiovascular mortality 0.19% 0.33% 0.50 (0.23-1.10)
Myocardial infarction 0.58% 1.0% 0.49 (0.26-0.93)
Adverse events 9.26% 7.73% 1.01 (0.87-1.18)

Shantha GP et al. Clin Pharmacol Ther. 2015 Oct 22. doi: 10.1002/cpt.281. 89 90
[Epub ahead of print] PMID: 26492546 Navarese EP, et al. Ann Intern Med. 2015;163:40-51

2016 by the American Pharmacists Association. All rights reserved.

 Ongoing PCSK9 Outcomes Trials PCSK9 Cost Effectiveness
ODYSSEY FOURIER SPIRE I SPIRE 2
OUTCOMES Annual Cost
Number of 18,000 27,500 17,000 9,000 Alirocumab $14,600
patients
Evolocumab $14,100
Patient <1 yr post ACS Prior MI, PVD, High CV risk High CV risk
characteristics or CVD Assumptions
Baseline >70 mg/L >70 mg/L 70-100 mg/dL >100 mg/dL 100% reduction in cardiovascular events
LDL-C 3% absolute risk reduction
Background Max tolerated Statins NR NR $20,000 cost savings per event
therapy atorvastatin or
rosuvastatin Annual cost savings = $600
Regimen Alirocumab Evolocumab Bococizumab Bococizumab
75mg every 2 140mg every 2 150mg every 2 150mg every 2
weeks (150mg weeks or weeks weeks
for LDL-C >50 420mg every 4
mg/dL) weeks

Shantha GP et al. Clin Pharmacol Ther. 2015 Oct 22. doi: 10.1002/cpt.281. 91 92
[Epub ahead of print] PMID: 26492546 Schulman KA, et al. NEJM 2015;373(17):1591-1592.

Lomitapide (Juxtapid) Approved Dec 2012

Effect on Insurance Premiums MOA: Microsomal triglyceride transfer protein (MTP) Inhibitor

Assumptions
25% negotiated discount for drug acquisition
$600 annual cost savings
27% of US adults 40-64 years old with elevated LDL-C
5% eligible for treatment with PCSK9 inhibitors
Annual insurance premium increase
$124 per person in the insurance pool

http://www.pace-cme.org/d/443/mtp-inhibitors

93 94
Schulman KA, et al. NEJM 2015;373(17):1591-1592.

Lomitapide (Juxtapid)
Indication: Homozygous Familial Mipomersen (Kynamro) Approved Jan 2013
Hypercholesterolemia MOA: antisense therapy that prevents formation of Apo B
FDA required REMS Program
Dosing: 5mg by mouth once daily
Titrate every 2 weeks to a maximum dose of 60mg once daily
Metabolized via CYP3A4

LDL-C TG apo B Black Box

Warning!
Transaminase
40% 45% 39% Elevations
Steatohepatitis

http://www.biotechduediligence.com/mipomersen-liver-safety.html

95 96
Juxtapid Package Insert
95

2016 by the American Pharmacists Association. All rights reserved.

 Mipomersen (Kynamro)
Indication: Homozygous Familial
Niacin Product Comparison
Hypercholesterolemia LDL
Max Risk of Risk of
FDA required REMS Program Reduction
Dose Flushing Hepatoxocity
(1.5 g/day)
Dosing: 200mg once weekly (SQ injection) Niacin IR (OTC) 13% 6 g/day +++ +
Not metabolized by the liver Niacin SR (OTC) 2 g/day + +++
Slo-Niacin (OTC) 12% 2 g/day ++ +
Niaspan (RX) 13% 2 g/day ++ +

Black Box USE Immediate Release Niacin

LDL-C TG apo B Squibb (or other pharmaceutical manufactures who abide by good
Warning! manufacturing practices)
Transaminase Twin Labs (crystalline niacin from health food stores)

25% 18% 27% Elevations USE with caution Slo-Niacin

Steatohepatitis Upsher-Smith Laboratories, Inc.
AVOID Sustained Release Niacin
Associated with increased hepatotoxicity risk
Guyton JR et al. Am J Cardiol 2007;99:22C-31C. McKenney JM. Am J
Health-System Pharm. 2003;60:995-1005.
97 98
98
Knopp RH et al. J Clin Lipidol 2009;3(3):167-178.
Kynamro Package Insert

HPS2-Thrive: ER Niacin + Laropiprant

Nicotinic Acid: Niacin for Vascular Risk Reduction
25,673 patients with Prior history of: myocardial infarction; ischaemic stroke or
Niacin Study Event risk reduction TIA; peripheral arterial disease; or diabetes with other CHD
IR Niacin (crystalline) Coronary 27% non-fatal MI (5 years) Randomized to ER niacin 2g + laropiprant 40mg daily, or placebo
Drug Project 11% mortality (15 years) Background simvastatin 40mg or ezetimibe/simvastatin 10/40mg therapy
IR Niacin + Colestipol FATS 78% composite Primary endpoint: time to first major vascular event composite of CHD
death, nonfatal MI, stroke, or arterial revascularization
Slo-Niacin or IR + Simvastatin HATS 61% composite
ER Niacin 282 (16.4%) vs. 274 (16.25%)
Preferred second agent (added to statin therapy ) Trial was stopped after a mean follow-up period of 3.9 years due to
Mechanism not fully understood significant adverse events, principally myopathy with niacin
Inhibit FA release from adipose tissue
Reducing hepatic synthesis of triglycerides and secretion of VLDL
Inhibit conversion of VLDL to LDL Lipid Particle Baseline Mean Mean at 4-years
Side effects:
Flushing (common), alleviated by aspirin or food HDL 44 mg/dL 50 mg/dL
Diabetes impairs glucose tolerance (doses >1500 mg/day) Triglycerides 125 mg/dL 94 mg/dL
PUD prostaglandin mediated vasodilation
Gout increased uric acid levels LDL 63 mg/dL 56 mg/dL
Liver enzyme elevations (uncommon)

Brunzell JD, et al. Diabetes Care. 2008;31:811-822. Guyton JR et al. Am J Cardiol HPS2-Thrive Collaborative Group. Eur heart J. 2013. doi:10.1093/eurheart/eht055.
2007;99:22C-31C. McKenney JM. Am J Health-Syst Pharm. 2003;60:995-1005. Brown 99 100
100

BG et al. NEJM 2001;345:1583-1592. Taylor AJ et al. Circulation 2004;110:3512-3517.

HPS2-Thrive: Major Vascular Event by age, sex, region and therapy

Randomized allocation Risk ratio & 95% CI Hetortrend Summary of Recent Trials
ERN/LRPT Placebo (uncorrected p value)
Age(years) (12,838) (12,835)
Study Achieved
< 65 740(11.4%) 786(12.2%) 0.00
65<70 392(13.9%) 367(13.1%) (p=0.98) (Intervention) LDL-C
70 564(15.9%) 605(17.0%) Snow tires Background treatment
in summer? AIM-HIGH 62 mg/dL
Sex
Was lack of overall (Niacin ER vs. Placebo)
Male 1397(13.2%) 1485(14.0%) 3.21
Female
benefit due to niacin,
299(13.4%) 273(12.3%) (p=0.07) simvastatin 40-80 mg
laropiprant or ethnicity? plus ezetimibe 10 mg as needed
Region
Europe 832(11.3%) 913(12.4%) 3.61 HPS2-Thrive 56 mg/dL
China 864(15.8%) 845(15.5%) (p=0.06) (Niacin ER + laropiprant)
simvastatin 40mg
Statinbasedtherapy or ezetimibe/simvastatin 10/40mg
Simvastatin 40mg 945(14.0%) 949(14.0%) 1.28
Ezetimibe/simvastatin 751(12.4%) 809(13.3%) (p=0.26) ACCORD-Lipid 81 mg/dL
(Fenofibrate vs. Placebo)
All 1696(13.2%) 1758(13.7%) 3.5%SE3.3 simvastatin
reduction

0.8 1.0 1.2

ERN/LRPT better Placebo better HPS2-Thrive website.
101
www.thrivestudy.org/docs_prof.htm. Accessed
101 102
102
5/1/2013.

2016 by the American Pharmacists Association. All rights reserved.

 Comparison of LDL-C Lowering, NNT
CON PCSK9 Summary Points
and CVD Prevention Costs
Study Therapy Time
(yrs)
Relative
Risk
Absolute
Risk
NNT 2016
Cost
Annual Cost
per Event
PCSK9 inhibitors effectively lower LDL-C but their true
Difference ($) Prevented impact on CV events is uncertain
($)
WOSCOPS Pravstatin 4.8 0.69 2.4% 42 50 2,083
Post hoc analyses and meta-analyses of phase II and
(1 prevention) vs. Placebo phase III trials are promising
TNT
(2 Prevention)
Hi
Atorvastatin
5.0 0.78 2.2% 45 50 2,273 Four clinical outcomes trials are ongoing
vs. Lo High annual acquisition cost is problematic
Atorvastatin
$600 annual cost savings
IMPROVE-IT Statin + 7.0 0.94 2.0% 50 1000 50,000
(High Risk) ezetimibe Potential increase in insurance premiums for entire pool
vs. Statin Cost effectiveness studies comparing options are needed
ODYSSEY
(HeFH)
Statin +
alirocumab
1.5 0.52 1.6% 63 12,000 756,000
Combination drug therapy with niacin or ezetimibe should
vs. Statin be considered before PCSK9 inhibitors
OSLER Statin + 1.0 0.47 1.2% 81 12,000 972,000
(HeFH) evolocumab
103 104
Wilson, PW. Presented at National Lipid Association Meeting, Pittsburgh, PA. 9/18/2015

According to the National Lipid Association

(NLA), which of following is the most
appropriate goal of therapy for a patient with
very high ASCVD risk?

A. LDL-C <130 mg/dL

B. Non-HDL-C <100 mg/dL
C. 30% LDL-C reduction from
baseline
D. 50% reduction in hs-CRP from
REBUTTALS baseline

105 106

Which of the following is true regarding the Pro-

Which of the following is the approximate protein convertase subtilisin/kexintype 9
additional percent reduction in LDL-C when (PCSK9) inhibitors?
ezetimibe is added to a patient already treated
A. PCSK9 inhibitors work by blocking
with statin therapy? cholesterol absorption in the intestines
B. Alirocumab is dosed orally every 2
A. 5% weeks
C. Evolocumab is indicated for both
B. 20% heterozygous and homozygous
familial hypercholesterolemia
C. 40% D. PCSK9 inhibitors on average lower
LDL-C by same amount as titrating a
D. > 50% statin from the lowest dose to the
highest dose (i.e. atorvastatin 10mg
to 80mg)

107 108

2016 by the American Pharmacists Association. All rights reserved.

 In the IMPROVE-IT trial, which endpoint was Which of the following is most
significantly lower in patients treated with appropriate initial therapy for a
ezetimibe/simvastatin combination therapy
comparted to simvastatin alone? patient at very high ASCVD risk?

A. All-cause mortality A. Alirocumab

B. Stroke B. Rosuvastatin
C. CVD/MI/Stroke C. Ezetimibe
D. All of the above D. Lomitapide

109 110

2016 by the American Pharmacists Association. All rights reserved.