Dr. Laurence Berarducci, MD, FACC presents on "New Cholesterol Management Guidelines" at the March 4 -6, 2016 Cardiac and Thoracic Surgery Associates, Cardiovascular Summit at The Westin Riverfront Resort and Spa.

1. LAURENCE BERARDUCCI, MD, FACC
PUEBLO CARDIOLOGY ASSOCIATES
PUEBLO, COLORADO
Update in Cardiovascular Risk
Reduction

2. Educational Objectives
Review Current Guidelines
Review New Therapies
Real-world Perspective of a Clinical
Cardiologist

3. Current Treatment Guidelines
Clinical ASCVD
High intensity statin unless >
75 years old or intolerant
LDL > 190 mg/dL
High intensity statin unless
intolerant
DM 1 or 2 and age 40-75
High intensity statin unless 10
year ASCVD < 7.5 %
ASCVD 10 y risk > 7.5 % and
age 40-75
Moderate to high intensity
statin

4. 2013 ACC/AHA Guidelines for Cardiovascular
Risk Reduction
 High intensity statins and the importance of the LDLC percent
reduction
 The role of non-statin therapies and their failure to add incremental
reduction in MACE, in patient’s treated with optimal doses of statins
 Lifestyle, Lifestyle, Lifestyle….
 The cornerstone of risk reduction, but oh so difficult to achieve in Southern
Colorado

5. High Intensity Statin Therapy
% LDLC reduction is paramount
 Highly variable in individual patients with respect to LDLC,
apolipoprotein B, and non-HDLC reduction
 30-50% LDLC reduction = 39% RRR CV events
 > 50% LDLC reduction = 59% RRR CV events
Guideline recommendations
 Rosuvastatin 40 mg daily OR Atorvastatin 40 or 80 mg daily

6. Non-Statin Therapies
BAS
Niacin
Fibrates
Ezetinibe
CTEP Inhibitors
• Lack of data to support
meaningful risk reduction in
patients on optimal statin
therapy (IMPROVE-IT ?)
• Early trials have minor signals
of clinical benefit in ASCVD
patients not on statins
• CTEP Inhibitors – ¾ Phase III
clinical trials showed NO
BENEFIT or INCREASED
MORTALITY.

7. PCSK 9 Inhibitors
(Proprotein Convertase Subtillisin/kexin type 9)
PCSK9 Inhibitors
 Alivocumab (Praluent) and Evolocumab (Repatha)
 Development
 Mechanism of Action
 Efficacy
 Clinical Trial Data to Date
 Questions that remain

9. PCSK9 is a Regulator of LDL Metabolism

10. PCSK9 Binds to the LDL Receptor and Targets
the LDL Receptor for Degradation

11. Familial Hypercholesterolemia (FH)

12. PCSK9 Mutations Associated with Reduced
Levels of LDL-C

13. Genetic Variants Establish PCSK9 as a Modulator
of LDL-C

14. Phase 3 Program to Support LDL-C
Reduction in Targeted Populations
High CV Risk Patients
 Patients not at LDL-C goal with currently available LLT (even
high doses of potent statins) = >persistent risk
Familial Hypercholesterolemia
LDL-C levels often far from goal, even with potent statins and
combination Tx
Life-long exposure to high LDL-C; considered high risk even w/o
additional risk factors
Statin Intolerant Patients
LDL-C levels often far from goal, due to intolerance
Definition: unable to tolerate at least 2 statins, including one at
the lowest dose

15. Overview of ODYSSEY Phase 3 clinical trial program
ODYSSEYALTERNATIVE(CL1119) N=250
Patients with defined statin intolerance
LDL- ORLDL-
6 months
ODYSSEYOPTIONSI (CL1110) N=350
Patients not at goal on moderate dose atorvastatin
LDL- -
6 months
ODYSSEYFHII (CL1112) N=250
LDL- -
18 months
ODYSSEYHIGHFH(EFC12732) N=105
LDL-
18 months
12 global phase 3 trials
Including more than 23,500 patients across more than 2,000 study centers
HeFH population HC in high CV risk population Additional populations
ODYSSEYFHI (EFC12492) N=471
LDL- -
18 months
ODYSSEYLONGTERM (LTS11717) N=2,100
LDL-
18 months
ODYSSEYCOMBOI (EFC11568) N=306
LDL- -
12 months
ODYSSEYMONO(EFC11716) N=100
Patients on no background LMTs
LDL-
6 months
ODYSSEYOPTIONSII (CL1118) N=300
Patients not at goal on moderate dose rosuvastatin
LDL- -
6 months
ODYSSEYOUTCOMES(EFC11570) N=18,000
LDL-
Add-onto maxtoleratedstatin
(± other LMT)
Add-on tomaxtoleratedstatin
(± other LMT)
*ODYSSEYCOMBOII (EFC11569) N=660
LDL- -
24 months
HC = hypercholesterolemia; LMT = lipid-modifying therapy *For the ODYSSEY COMBO II other LMT not allowed at entry
ODYSSEYCHOICEI (CL1308) N=700
LDL- -
12 months

16. 99
HeFH
Phase 3
(N = 300)5
Combo-
therapy
Phase 3
(N = 1,700)5
HoFH
Phase 3
(N = 125)5
Mono-
therapy
Phase 3
(N = 600)5
Phase 3
(N = 22,500)5
Secondary
Prevention
Phase 3
(N = 950)5Athero
PROFICIO
Program to Reduce LDL-C and Cardiovascular Outcomes
Following Inhibition of PCSK9 In Different Populations
1. Giugliano RP, et al. Lancet. 2012;380:2007-2017. 2. Koren MJ, et al. Lancet. 2012;380:1995-2006. 3. Sullivan D, et al. JAMA. 2012;308:2497-2506.
4. Raal F, et al. Circulation. 2012;126:2408-2417. 5. Clinical Trials.gov. Available at: http://www.clinicaltrials.gov. Accessed Oct. 2, 2013.
6. Data on file, Amgen; [AMG 145 Protocol 20120332].
Open-label
Extension
Phase 3
(N ~ 3,515)5
Non-Commercial Class D Materials for Investigator Communications. Not for Reproduction or Distribution
Phase 3
(N = 300)5
Statin-
intolerant
Long-term
safety and
efficacy
Phase 3
(N = 905)5
*Subjects completed a qualifying Phase 2 study. Subjects completed a qualifying Phase 3 study.

17. 10
SPIREPhase 3 Bococizumab Clinical Development Program:
DesignedtoAddressUnmet Needsinthe Management of CVDin
HighRiskPatients
SPIRE(Studiesof PCSK9 Inhibition and
the Reduction of Vascular Events) N=~30,000
SPIREHR(n=300)
On statin
High risk of CV event
LDL-
SPIRELDL(n=1,932)
On statin
High risk of CV event
LDL-
SPIREFH(n=300)
HeFH (genetic diagnosis or
Simon Broome Criteria),
LDL >70 mg/dL
SPIRELipidLoweringStudies SPIRECVOutcome Studies
SPIRELL(n=690)
On statin
High / very high risk of
CV event
LDL-
SPIRESI (n=150)
Statin intolerant
LDL-
SPIRE-1 (n=17,000)
High Risk Primary and
Secondary Prevention
LDL-
on statins (or statin
intolerant)
SPIRE-2 (n=9,000)
High Risk Primary and
Secondary Prevention
LDL-
statins (or statin intolerant)
NCT#: https://clinicaltrials.gov
SPIRE HR: NCT01968954
SPIRE LDL: NCT01968967
SPIRE HF: NCT01968980
SPIRE-LL: NCT02100514
SPIRE-SI: NCT02135029
SPIRE-1: NCT01975376
SPIRE-2: NCT01975389
Studieson PCSK9Inhibition and the
Reduction of Vascular Events

18. Recommended Use of PCSK9I’s
Based on current guidelines, available evidence, and
economic considerations:
 Patients with FH or ASCVD and statin resistance (on max
dose) for additional LDL lowering is a reasonable strategy.
 Discuss with patient costs vs uncertain clinical benefit
 In FH patients to avoid apheresis
 Consider in statin intolerant patients

19. Case Studies
51 y/o female with MI age 39, stents, IDCM (EF 30%)
and RA. Intolerant to Atorvastatin, Rosuvastatin and
Simvastatin. LDL-C 203 mg/dl Lp(a) 450.
Counseled and stared on Alirocumab

20. Case Studies
69 y//o female with MVCAD/LMCAD with CABG x 3,
& RCA stent. Intolerant to all statins except
pravastatin 40 mg. Intolerant to Niacin and Zetia.
LDL-C currently 85 mg/dl and Lp(a) 290.
Counseled and started on Praluent

21. Non-Medical Issues
Cost ~ $1,000/month
Requires insurance preauthorization
Both pharmaceutical companies (Sanofi and Amgen)
have robust bridge programs and patient support.