novel approaches in lipid management
TRANSCRIPT
Novel Approachesin Lipid Management
Shashikiran Umakanth MBBS MD
Professor & Head, Department of Internal Medicine
Dr. TMA Pai Hospital, Udupi
Melaka Manipal Medical College
Manipal University, India
BUT…
Elephant-in-the-room
LDL-c
LDL cholesterol molecules typically have only Apo-B100
This is unlike HDL cholesterol, which have many apolipoproteins
Wiviott SD et al. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005 Oct 18;46(8):1411-6
0.1 0.51.7
8.2
15.2
19.218
13.3
8.3
5.6
3.22.1
1.4
3.2
0
5
10
15
20
25
Pe
rce
nt
(%)
of
sub
ject
s
Achieved LDL (mg/dL)
Residual Risk
Espeland MA1, Bray GA, Neiberg R et al. Describing patterns of weight changes using principal components analysis: results from the Action for Health in Diabetes (Look AHEAD) research group. Ann Epidemiol. 2009 Oct;19(10):701-10
Serum LDLc level is inversely proportional to LDL receptor expression on hepatocytes.
McKenney JM et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012 Jun 19;59(25):2344-53
Proproteinconvertasesubtilisin/kexintype 9 (PCSK9), a glycoprotein produced by the liver, binds to LDL receptors on the hepatocyte surface and facilitates the degradation of LDL receptors
Monoclonal antibodies that inhibit PCSK9 will reduce LDL receptor degradation.
% Reduction from Baseline in LDL-c in the Evolocumabgroup as compared to placebo group
420mg, q4wk, SC
800 patients9 countries52 weeks
Blom DJ et al. A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia. N Engl J Med 2014; 370:1809-1819
Roth EM et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol. 2014 Sep;176(1):55-61
LDL-C levels (mg/dl) versus study time point (on-treatment analysis)
• 75-150mg SC q2wk
• 103 patients• 24 weeks
• No injection site reactions• Good compliance
• 22,500 patients with clinically evident cardiovascular disease at high risk for a recurrent event
• Background LDL-lowering with effective statin therapy
• Randomized to Evolocumab SC q2wk or q4wk vs. placebo
• Primary outcome: time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first
Thomas GS et al. Mipomersen, an Apolipoprotein B Synthesis Inhibitor, Reduces Atherogenic Lipoproteins in Patients With Severe Hypercholesterolemia at High Cardiovascular Risk : A Randomized, Double-Blind, Placebo-Controlled Trial. J Am Coll Cardiol. 2013 Dec 10;62(23):2178-84
Mechanism of Mipomersenaction
Thomas GS et al. J Am CollCardiol. 2013 Dec10;62(23):2178-84
Thomas GS et al. Mipomersen, an Apolipoprotein B Synthesis Inhibitor, Reduces Atherogenic Lipoproteins in Patients With Severe Hypercholesterolemia at High Cardiovascular Risk : A Randomized, Double-Blind, Placebo-Controlled Trial. J Am Coll Cardiol. 2013 Dec 10;62(23):2178-84
Treatment Period Changes in LDL-C, apoB, and Lp[a] over time.
Mipomersen 200mg SCqWk
*PET = primary efficacy timepoint or 2 weeks from end of treatment for completers
Thomas GS et al. Mipomersen, an Apolipoprotein B Synthesis Inhibitor, Reduces Atherogenic Lipoproteins in Patients With Severe Hypercholesterolemia at High Cardiovascular Risk : A Randomized, Double-Blind, Placebo-Controlled Trial. J Am Coll Cardiol. 2013 Dec 10;62(23):2178-84
Adverse effects• ALT elevations 2xULN• Flu like symptoms• Injection site reactions
High rate of discontinuation due to AEs
Gutstein DE et al. Anacetrapib, a novel CETP inhibitor: pursuing a new approach to cardiovascular risk reduction.Clin Pharmacol Ther. 2012 Jan;91(1):109-22
Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ. 2014 Jul 18;349:g4379.
HDL-C
Base-line
6 12 18 24 30 46 62 76
HD
L-C
(m
g/d
L) (
SE)
0
20
40
60
80
100
120
AnacetrapibPlacebo
LDL-C
Study weekBase-line
LDL-
C (
mg/
dL)
(SE
)
0
20
40
60
80
100
AnacetrapibPlacebo
-39.8% (p<0.001) +138.1% (p<0.001)
6 12 18 24 30 46 62 76
Study week
Cannon CP et al (DEFINE Study). Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010 Dec 16;363(25):2406-15
• 30,000 patients with occlusive arterial disease in North America, Europe and Asia
• Background LDL-lowering with atorvastatin
• Randomized to anacetrapib 100 mg vs. placebo
• Primary outcome: Coronary death, myocardial infarction or coronary revascularization
PCSK9 Inhibitors CETP Inhibitors
Subcutaneous Oral
Bi-weekly or Monthly Daily
LDL-c reduction LDL-c reduction & HDL-c elevation
Thank you