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