agents to reduce ldl (and future developments) · pdf fileagents to reduce ldl (and future...
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Raul D. Santos MD, PhD Heart Institute-InCor
University of Sao Paulo Brazil
Agents to reduce LDL (and future developments)
Disclosure
• Honoraria for consulting and speaker activities on the last 2 years from
– Amgen, Aegerion, Astra Zeneca
– Biolab, BMS, Boehringer Ingelheim
– Genzyme, Merck, Praxis
– Pfizer, Eli Lilly, Novartis, Nestlé, Unilever
– Sanofi/Regeneron
2
• Epidemiology • Current options
– Statins – Ezetimibe – Resins – Niacin
• Recently approved and future treatments – Lomitapide – Mipomersen – CETP inhibitors – PCSK9 inhibitors
Agents do reduce LDL
3
Epidemiology
4
Cholesterol and CHD Mortality
Lancet 2007; 370: 1829–39
N=900,000
N=302.430
Non-HDL-cholesterol, CHD and Ischemic Stroke
CAD Stroke
N=173.312
JAMA 2009;302:1993-2000
Statins
Statins: Mechanism of Action
Statins inhibit HMG-CoA reductase
Intrahepatic cholesteorl pool reduction
Reduction of VLDL production
Less VLDL particles available to become LDL Incrementof LDL catabolsim
Increment on LDL receptor expression
Reduction of : LDL-C, TC, non-HDL-C and TG
HMG-CoA redutase
*P<0.002 vs ATV 10 mg; PRA 10 mg, 20 mg, 40 mg; SIN 10 mg, 20 mg, 40 mg. **P<0.002 vs ATV 20 mg, 40 mg; PRA 20 mg, 40 mg; SIN20 mg, 40 mg, 80 mg.
análise de 10-40 mg .
Jones PH et al. AJC. 2003;93:152-160.
RSV ATV SIN PRA
10 20 40 10 20 40 10 10 20 40
* -51
-55
-46
** ***
20 40 80 80
-46
-37
-43
-48
-28
-35
-20 -24
-30
-39
-60
-50
-40
-30
-20
-10
0
-52
Effects of Statins on LDL-C: STELLAR (% Changes vs. Baseline)
%
Impact of 1mmol/L reduction on LDL-C upon major
cardiovascular events and mortality
CTT 2010
Relative Risk (95% CI)
All cause mortality 0.90 (0.87-0.93), p<0.0001**
CHD mortality 0.80 (0.74—0.87); p<0.0001**
Other cardiac deaths 0.89 (0.81—0.98); p=0.002**
Stroke deaths 0.96 (0.84—1.09); p=0.5
Major vascular events 0.78 (0·76—0·80); p<0.0001
Non-fatal MI 0.73 (0.70 − 0.77); p<0.0001
Myocardial revascularization 0.75 (0.72 − 0.78); p<0.0001
Ischemic stroke 0.79 (0.74 − 0.85); p<0.0001
Cancer incidence 1.00 (0.96 − 1.04); p=0.9
Hemorrhagic stroke 1.12 (0.93 − 1.35); p=0.2
Adapted from The Lancet 2010.; 376:1670-81 **- CI 99%
Non-Lipid Lowering Effects of Statins
Jain MK, Ridker PM. Nature Rev Drug Discov, 2005
Statins: Side Effects
• Muscle
• Liver (??)
• Diabetes
• Hemorrhagic stroke (???)
• Cognitive functions ???????????
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Ezetimibe
NPC1L1 Transports Intestinal Cholesterol and
Phytosterols: Inhibition of NPC1L1 by Ezetimibe for
Hypercholesterolemia and Sitosterolemia
Sitosterolemia
Cholesterol and
Plant Sterols
NPC1L1
Ezetimibe reduces cholesterol absorption in humans F
ra
ct
io
na
l C
ho
le
ste
ro
l A
bs
orp
tio
n
(%
)
0
20
40
60
80
0
20
40
60
80Mean = -54%
Range: 0 to -94%
LDL-C = - 20.4%
Sudhop et al. Circulation 106:1943, 2002
Mild Hypercholesterolemic Pure Vegetarians
Clarenbach JJ et al. J Lipid Res. 47:2820,2006
Mean = -58%
LDL-C = -17.3%
15
Farnier M et al. Atherosclerosis 2013; 229:415 - 422
Effects of ezetimibe, simvastatin and simvastatin/ezetimibe on pro-atherogenic lipids and
apoB
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CTT/SHARP: Effects on ischemic events in CKD
Mean difference of LDL-C among treated groups (mg/dL)
Rel
ativ
e ri
sk r
edu
ctio
n
of
isch
emic
eve
nts
(9
5%
HF)
0%
5%
10%
15%
20%
25%
30%
0 20 40 10 30
Statins vs. control
(21 studies)
Intensive hypolipidemia
treatment vs.
Conventional
(5 studies)
SHARP
17%
risk
reduction
SHARP
32mg/dL
Baigent et al. Lancet 2011; 377;2181–2192. 17
IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit
CTT Collaboration.
Lancet 2005; 366:1267-78;
Lancet 2010;376:1670-81.
IMPROVE-IT
Cannon C. AHA Presentation 2014
Ezetimibe: Side Effects
• Gastro intestinal
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Bile acid binding resins
Bile Acid Binding Resins
:Mechanism of Action
Gotto AM and Pownall HJ: Manual of Lipid Disorders. 1992
The first study showing that cholesterol
reduction prevents CVD was done with a
resin
JAMA 1984; 251:351
Bile Acid Resins: Side effects
• Gastro intestinal (much less with colesevelam)
• Increase in TG levels
• Binding to other medications
23
Niacin
24
Niacin: Mechanisms of Action
• Adipose tissue
– Hormone sensitive Lipase (GPR109A)
– FFA to the liver and TG and VLDL
– PPAR gamma – ABCA1
• Liver
– Production and Apo B degradation
– Apo A-I (?)
Digby JE ATVB 2012;32:582-8
Lamon-Fava S et al . ATVB 2008;28:2672-8
Extended release Niacin
Capuzzi DM et al. Am J Cardiol 1998;82:74U-81U Guyton JR et al. Am J Cardiol 1998;82:82U-84U
Changes vs. baseline (Mean %)
ER Niacin +
Statins
ER Niacin
320 Week 48 -12 -18 +26 -30 -16 -27
225 Week 96 -13 -20 +28 -40 -17 -28
723 V. Baseline – – – – – –
120 Week 48 -27 -36 +28 -36 -30 -33
122 Week 96 -27 –36 +27 -41 -30 -35
Treatment n Duration TC LDL-c HDL-c Lp(a) ApoB TG
All changes significant
Coronary Drug Project: Long term mortality reduction in post
AMI patients with niacin
Niacin
Placebo
P = 0,0012
100
90 80
70
60 50
40 30 20 10
0 2 4 6 8 10 12 14 16
Years of follow-up
Surv
ivia
l (%
)
Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255
HPS 2 THRIVE: Niacin/Laropiprant not effective in patients with well controlled LDL-C
The HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203-212.
Niacin-ER: side effects
• Flushing
• Glucose intolerance/Diabetes
• Skin infections
• Gout
• Peptic Ulcer
Recently Approved Drugs for Homozygous Familial Hypercholesterolemia
30
MTP inhibitors
Lomitapide
Lomitapide: Mode of Action
32 p0300 Lomitapide causes a higher rate of gastrointestinal sideeffects and aminotransferase elevations than does ezeti-mibe. However, all adverse events disappeared after drugdiscontinuation.
s0145 Phase 3 Studyp0305 Research has shown that HoFH patients given an average
dose of 40 mg/day of lomitapide had reductions in LDL-C,apoB, and TG concentrations of 50%, 49%, and 45%, respec-tively, after 26 weeksof treatment. Similarly, Lp(a) and HDL-C levels were reduced at week 26, but these levels returnedto baseline by week 78 (Table 38-7). Of 29 HoFH patientswho took lomitapide, 3 were able to discontinue LA, and3 others permanently increased the time interval betweenLA treatments.133
s0150 Safetyp0310 Phase 3 studies indicate that the most common side effects
(seen in 28%of patients) of lomitapide are diarrhea, nausea,vomiting, dyspepsia, and abdominal pain.133Approximatelyone third of study participants had an elevation in at least
one liver enzyme to greater than or equal to three timesthe upper limit of normal. Approximately 14% of studypatients had elevated liver enzymes at greater than or equalto five times the upper limit of normal. Dose reduction ortemporary drug discontinuation resulted in normalizationof liver enzymes. No clinically significant changes in biliru-bin, prothrombin time, or alkaline phosphatase occurred.As expected, because of lomitapide's mechanism ofaction,130mean hepatic fat content increased approximately7.6%on average (range 0%–30%) by week 26, but no furtherincreases were reported at week 78. Longer term hepaticsafety studies of lomitapide still need to be conducted.
p0315Because individuals taking lomitapide must consume alow-fat diet, and because lomitapide causes fat malabsorp-tion, patientsshould concomitantly be given vitamin E, lino-leic acid, alpha-linolenic acid, eicosapentaenoic acid, anddocosahexaenoic acid supplementation.134 As with mipo-mersen, because lomitapide can cause adverse events suchas liver toxicity, it is available in the United States onlythrough a risk evaluation and mitigation strategy program.
Comp. by: GAsokpandian Stage: Revises1 Chapter No.: 38 Title Name: BallantyneDate:22/8/14 Time:14:40:34 Page Number: 11
TABLE 38-7t0040 Effects of Lomitapide 5 to 60 mg (Average Dose 40 mg/day) on Plasma Lipids, Apolipoprotein B, andLipoprotein(a)
PATIENT POPULATION(BASELINE: N =29)
% CHANGE INLDL-C
% CHANGE INAPOB
% CHANGE INTRIGLYCERIDES
% CHANGE INLP(A)
% CHANGE INHDL-C
Week 26 (n¼26) –50* –49* –45* –15* –12*
Week 56 (n¼26) –44* –45* –29* –19* 1
Week 78 (n¼26) –38* –43* –31* –1 –5
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
Baseline lipid levels (n¼29): LDL-C¼336 mg/dL; apoB¼259 mg/dL; triglycerides¼92 mg/dL; HDL-C¼43 mg/dL; Lp(a)¼67 mg/dL.*Significant change versus baseline.
Data from reference 133
Lower VLDL, LDL,chylomicrons, and
chylomicron remnants
Blood vessel
Intestinal epithelial cell
Cytoplasm
ER
Luman
ApoB48degraded
MTP
TG
Liver cell
Cytoplasm
ER
Luman
ApoBdegraded
MTP
FIGURE 38-9f0050Au1 Effects of microsomal triglyceride transport protein (MTP) inhibit ion by lomitapide. ApoB, apolipoprotein B; LDL, low-density lipoprotein; TG, triglyceride;VLDL, very-low-density lipoprotein. (Modified from references 130,132,134,135.)
B978-0-323-28786-9.00038-4, 00038
Ballantyne, 978-0-323-28786-9
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Moriarty & Santos In Clinical Lipidology: A companion to Braunwald’s Heart DIsease 2015
Phase 3 Study in Patients with HoFH: LDL-C Reduction (Mean % Change) From Baseline to Week
78
3
3
352mg/dL 336mg/dL
Baseline Week 26 Week 56
50.2% reduction
40.1% reduction
Week 78
44.0% reduction 38.4% reduction
(CA) 0mg (ITT)
44.6mg 38.4mg 40.2mg 40.7mg 0mg
Adapted from Cuchel M et al. Lancet 2013; 381:40-46
Adverse Event Category
n of subjects (%)
weeks 0-26
N=29
n of subjects (%)
weeks 26-78
N=23
Any adverse event 27 (93.1) 21 (91.3)
GI Disorders 27 (93.1) 17 (73.9)
Diarrhea 23 (79) 8 (35)
Nausea 18 (62) 7 (30)
Lab abnormalities 15 (51.7) 10 (43.5)
ALT elevation >5 x ULN 4 (13.8) 1 (4.3)
HoFH Phase 3 Study
Treatment Emergent Adverse Events
Adapted from Cuchel M et al. Lancet 2013; 381:40-46
Figure 2
Lomitapide: Hepatic Safety
Cuchel M et al. Lancet 2013; 381:40-46
Antisense Oligonucleotides
Mipomersen
Antisense Therapy1-3
mRNA = messenger RNA.
1. Crooke RM, Graham MJ. Clin Lipidol. 2011;6,675-692.
2. Koller E, et al. Trends Pharmacol Sci. 2000;21:142-148.
3. Visser ME, et al. Eur Heart J. 2012;33:1451-1458.
• Antisense molecules are short, single-stranded, synthetic analogues of natural nucleic acids that are complementary to, and thus bind with, a specific mRNA to prevent disease-related protein synthesis
+
mRNA
mRNA
Protein synthesis Proteins
Antisense Protein synthesis inhibited
Fewer proteins
Raal FJ, Santos RD et al. Lancet. 2010;375:998-1006
39
Pooled Population Homozygous FH
Santos RD et al ATVB 2015 e pub
Incidence of injection site reactions (ISRs) and flu-like symptom (FLS)
events occurring at least once over time.
Santos R D et al. Eur Heart J 2013;eurheartj.eht549
All Subjects
Completers
ISR = 1 in 10 FLS= 1 in 52
Change from baseline in ALT levels and liver fat fraction over time.
Santos R D et al. Eur Heart J 2013;eurheartj.eht549
ALT
Liver Fat
Antibodies against PCSK9
Effect of PCSK9 antibodies in increasing the expression of the LDLR
Percent Reduction from Baseline in Low-Density Lipoprotein (LDL) Cholesterol Levels in the Evolocumab Group, as Compared with the Placebo Group, at
Weeks 12 and 52, According to Background Lipid-Lowering Therapy.
Blom DJ et al. N Engl J Med 2014;370:1809-1819.
N=901
45
Evolocumab Reduces Lp(a) in Heterozygous FH
-35
-30
-25
-20
-15
-10
-5
0
350 mg 420 mg
Lp(a)
46 Raal F et al. Circulation 2012;126:2408-2417
% C
han
ge F
rom
Bas
elin
e
CETP Inhibitors
47
CETP inhibition
Forrester J et al. Circulation. 2005;111:1847-1854
Changes in Cholesterol and Blood Pressure : Anacetrapib
Cannon CP et al. N Engl J Med 2010;363:2406-2415
Ongoing Phase III Trials Anacetrapib Evacetrapib
Name (ID) REVEAL (NCT01252953) ACCELERATE (NCT01687998)
Company Merck (Oxford trial Sponsor) Eli Lilly
Dose 100mg daily 130mg daily
Sample size 30,000 11,000
Inclusion 1) Age ≥50yrs 2) Hx of MI 3) Stroke or cerebr. revasc 4) PAD repair/revasc 5) DM with symptomatic CAD
1) Age ≥18yrs 2) Hx of ACS (30 to 365 days) 3) Cerebrovascular 4) PAD 5) DM with documented CAD
PEP Coronary death, MI, or Coronary Revascularization
CV death, MI, Stroke, Coronary Revascularization, or Hospitalization for UA
Study duration 1) Median ~4 yrs 2) ≥1900 Primary endpoints
1) Median ~2yrs 2) ≥1136 Primary endpoints
• LDL-C is an independent risk factor for atherosclerosis
• There are many proven therapies that reduce LDL-C and prevent CVD
• Statins are the cornerstone of LDL-C lowering
• Other drugs should be added to control LDL-C adequately
Conclusions
51