Académique Documents
Professionnel Documents
Culture Documents
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
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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
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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?
11 12
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)
15 16
Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline.
Gotto AM, et al. Nat Clin Pract Cardiovasc Med. 2006;3: 664672. Kastelein, JJP, et al. NEJM. 2008;358:1431-43.
17 18
Kastelein, JJP, et al. NEJM. 2008;358:1431-43. Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline.
19 20
DYSLIPIDEMIA?
500 40% did not achieve
LDL-C <70 mg/dL on
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.
25
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27 28
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CK levels rarely change clinical decisions but are Increasing risk of myositis
necessary for diagnosis of rhabdomyolysis
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 ENHANCE: Effects on Lipoproteins and CIMT
Statin Interacting protease Prescribing recommendation
inhibitor(s)
Atorvastatin Tipranavir + ritonavir Avoid atorvastatin
Telaprevir
Lopinavir + ritonavir Use caution and with the lowest dose
Darunavir + ritonavir Do not exceed 20 mg atorvastatin daily NS
Fosamprenavir
Fosamprenavir + ritonavir No significant change in
Saquinavir + ritonavir carotid intima-media
thickness (CIMT)
Nelfinavir Do not exceed 40 mg atorvastatin daily Simvastatin 0.0058mm
Fluvastatin No data available Simvastatin/Ezetimibe
P<0.01
0.0111mm
Pitavastatin Atazanavir ritonavir No dose limitations
Darunavir + ritonavir
Lopinavir + ritonavir P<0.01
Pravastatin Darunavir + ritonavir No dose limitations P<0.01
Lopinavir + ritonavir
Potential explanations: 1) short trial duration; 2) previous statin use in 80% of
Rosuvastatin Atazanavir ritonavir Limit dose to 10 mg once daily patients caused thinner baseline CIMT levels
Lopinavir + ritonavir
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)
35 35 36
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Baigent C, et al. Lancet. 2011 Jun 25;377(9784):2181-92 Baigent C, et al. Lancet. 2011 Jun 25;377(9784):2181-92
32.7% event rate in EZ/Simva group vs. 34.7% in Placebo/Simva group Stroke 4.2 4.8 0.86 0.052
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.
39
39 40
40
41 http://www.medscape.com/viewarticle/855958?nlid=93603_2562&src=wnl_ 42
edit_medp_card&uac=39775MJ&spon=2&impID=921002&faf=1
43 44
Am Heart J 2008;156:826832.
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.
47 48 48
N Engl J Med 1997;341:709-717 Cannon CP et al. N Engl J Med 2015;372:2387-97.
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.
120 12 30
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
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.
http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm 59 60
Zetia Product Insert. Merck & Co. Inc, Whitehouse Station, NJ (August 2013)
61 62
Ahn, CH, et al. Diabetes Metab J. 2015:39:87-94. Ahn, CH, et al. Diabetes Metab J. 2015:39:87-94.
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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
Praluent [package insert]. Bridgewater, NJ: Sanofi-Aventis and Tarrytown, NY: Regeneron; 2015.
65 66
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
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
http://www.supermanhomepage.com
71 72
73 74
J Am Coll Cardiol 2014;64:48594 JAMA. Published online August 10, 2015
120 120
LDL-C (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.
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.
0.02
0 12 24 36 52 64 78
Time (weeks)
83 http://www.medscape.com/viewarticle/804574_5 84
http://www.medscape.com/viewarticle/811660
85 86
Shaughnessy AF: STEPS drug updates [editorial]. Am Fam Physician 2003. 68 (12): 2213. 87 88
88
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
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.
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
http://www.biotechduediligence.com/mipomersen-liver-safety.html
95 96
Juxtapid Package Insert
95
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
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