Treating Dyslipidemia: An Evolving Paradigm

Om P. Ganda MDDirector, Lipid ClinicJoslin Diabetes Center

CVD Outcomes in DM vs non- DM102 Prospective studies; 698, 782 people, 8.5 million person-yr of follow-up

The Emerging Risk Factors Collaboration, Lancet 2010; 375: 2215-22Multivariate adjusted

Inflammation in Coronary Artery in Patients With Sudden Coronary Death

Type 1=16, Type 2=50, NDM = 66 matched for age, gender, race

Hyperlipidemia = Total-C >200 mg/dL or TC/HDL-C ratio >5

Burke et al. ATVB. 2004:24;1266-1271.

Macrophage infiltrate Necrotic core size

Log

CD

68 (%

)

Log

Plaq

ue (%

)

Normal Cholesterol

Hyperlipidemia

1.81.61.41.21.00.80.60.40.2

0

P=.04

P=.002

0.5

0

1

1.5

2

2.5P=.04

P=.001P=.003

P=.03

Normal Cholesterol

Hyperlipidemia

Non-DM DM

Supremacy of Statins in CVD Risk Reduction

Lipid Levelsat Entry

Simvastatin(10,269)

Placebo (10,267)

LDL cholesterol (mg/dl)

< 100 282 (16.4%) 358 (21.0%)

100 < 130 668 (18.9%) 871 (24.7%)

130 1083 (21.6%) 1356 (26.9%)

ALL PATIENTS 2033 (19.8%)2585

(25.2%)

HPS: Major Vascular Events by LDL Cholesterol

Risk ratio and 95% CI

STATINBetter

PLACEBOBetter

24% SE 3reduction(2P<0.00001)

0.6 0.8 1.0 1.2 1.40.4

HPS Collaborative Group. Lancet 2002; 360: 7-22.

Major Vascular Events with or without Diabetes: Effect per 40-mg/dL Reduction in LDL-C14 RCTs18,686 with DM71,370 without DM

CTT Collaborators et al. Lancet. 2008;371:117-125.

No differences by presence or absence of vascular disease, other risk factors, or baseline lipid levels

LDL-C : Less is More

3.7

2.9

2.2

1.7

1.3

1.0

40 70 100 130 160 190

Relative Risk for Coronary

Heart Disease (Log Scale)

LDL-Cholesterol (mg/dL)Grundy, S. et al., Circulation 2004;110:227-39.

CTT: Meta-analysis of 26 Statin Trials

CTT Trialists. Lancet 2010; 376: 167-181

n= 129, 526

n= 39612

Is there a point of No-Return?

23 % had diabetes: same outcome

~ 10-15 % of patients have significant myalgia with statins, most with dose escalation

Underlying Mechanism(s)?

FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for simvastatin to reduce the risk of muscle injury

06-08-2011

Audience Response Question 1

Recent meta-analysis of clinical trials have shown an increased risk of diabetes. How high is the approximate risk?

A. 5%B. 10%C. 15 %D. 20%

Statins and Incident diabetes

Significant correlation with age (p=0.02), not with BMI or LDL reduction

Sattar, N et al Lancet 2010; 375: 735-742

To put it in Perspective:

Incidence of Diabetes with statin therapy:

~1 new case per 200 persons treated over 5 years

Incidence of Major Cardiovascular Event~ 5 new events prevented per 200 persons treated over 5 years

JUPITER: Diabetes and CVD IncidenceRisk Factors for DM: Met Synd, BMI ≥ 30, IFG or A1c > 6.0%

Ridker, PM et alLancet 2012

HR 0.99

HR 1.28

HR 0.48

HR 0.61

LDL-C-Lowering Drugs

Drugs reducing cholesterol synthesis • HMG CoA reductase inhibitors: statins (preferred)

– LDL-C reduction up to 60% – Latest addition: pitavastatin

Drugs reducing cholesterol absorption• Bile acid sequestrants (BAS)

– Colesevelam, cholestyramine, colestipol Bind to bile acids > increase excretion of cholesterol

LDL-C reduction 15-25%; TG may rise– Cholesterol transport inhibitor

Ezetimibe; binds to intestinal cholesterol transporterLDL-C reduction ~15-20%

Potential LDL Lowering Agents

Anti-sense apoB synthesis inhibitor: Mipomersen

~ 30% reduction in LDL-C in patients with FH

(Baseline LDL-C: >300 mg/dl)

MTP-1 Inhibitors: Lomitapide

Inhibits assembly of all Apo-B lipoporoteins

PCSK-9 Inhibitors: REGN 727

Prevent degradation of LDL receptors

PCSK 9 : A Novel Target for LDL

From Dobbs, H, 2006

Effect of PCSK9 antibody (AMG-145), add-on to statin +/- Eze on LDL-C

Baseline LDL-C ~ 125 mg/dl

Gugliano, RP et al lancet 2012; 380: 2007-2017

How to deal with the Residual Risk of CVD after achieving

LDL-C Goal?

Patients with Diabetes Have High Residual CVD Risk After Statin Treatment

Event Rate (No Diabetes) Event Rate (Diabetes)

On Statin On Placebo On Statin On Placebo

HPS* (CHD patients) 19.8% 25.7% 33.4% 37.8%

CARE† 19.4% 24.6% 28.7% 36.8%LIPID‡ 11.7% 15.2% 19.2% 22.8%PROSPER§ 13.1% 16.0% 23.1% 18.4%ASCOT-LLA‡ 4.9% 8.7% 9.6% 11.4%TNT║ 7.8% 9.7% 13.8% 17.9%

* CHD death, nonfatal MI, stroke, revascularizations† CHD death, nonfatal MI, CABG, PTCA‡ CHD death and nonfatal MI

HPS Collaborative Group. Lancet. 2003;361:2005-2016. Sacks FM et al. N Engl J Med. 1996;335:1001-1009. LIPID Study Group. N Engl J Med. 1998;339:1349-1357.

§ CHD death, nonfatal MI, stroke║ CHD death, nonfatal MI, resuscitated cardiac arrest, stroke (80 mg vs 10 mg atorvastatin)

Shepherd J et al. Lancet. 2002;360:1623-1630. Sever PS et al. Lancet. 2003;361:1149-1158.Shepherd J et al. Diabetes Care. 2006;:29:1220-1226.

Mechanisms Relating Insulin Resistance and Dyslipidemia

Fat Cells Liver

KidneyInsulin

IR X

(CETP)

CE

VLDL-TG Apo B Apo C-III

(CETP)

VLDL HDL

(lipoprotein or hepatic lipase)

SDLDLLDL

TGApo A-I

TGCE

FFA

ATPIII: Recommendations for Non-HDL-C

Grundy, SM et al Circulation 2004; 110:227-239

If Triglyceride 200 ‐499 mg/dL:

Non‐HDL‐C (total C  minus HDL) is a  secondary target of therapy with a goal of 30 mg/dL higher than the LDL goal.

ADA/ACC Consensus Statement

TREATMENT GOALS LDL‐C (mg/dL)

Non–HDL‐C (mg/dL)

ApoB (mg/dL)

Highest‐risk patientsIncluding those with 1) Known CVD or 2) Diabetes plus one or more additional CVD risk factor*

< 70 < 100 < 80

High‐risk patientsIncluding those with 1) No diabetes or known clinical CVD but 2 or more additional major CVD risk factors or 2) Diabetes but no other CVD risk factors

< 100 < 130 < 90

“…In patients with Cardio-metabolic Risk, we recommend guiding therapy with apo-B measurements, and treatment to apo-B goals, in addition to LDL-C and non-HDL-C assessment.”

*Smoking, HBP, f/h premature CHD Brunzell JD et al. Diabetes Care. 2008;31:811-822.

Discordance between non‐HDL‐C, and Apo‐B

n Apo‐B < 90mg/dl

Apo‐B ≥ mg/dl

Discordance

non‐HDL‐C  < 130 mg/dl 734 607   127 + 17.3 %

non‐HDL‐C ≥ 130 mg/dl 696 95 601 ‐ 13.6 %

Ganda, OP et al,  Diab Res  Clin Pract 2012 ; 97: 51‐56

n Apo‐B < 80mg/dl

Apo‐B ≥ mg/dl

Discordance

non‐HDL‐C  < 100 mg/dl 131 123     8 + 6.1 %

non‐HDL‐C ≥ 100 mg/dl 1299 232 1067 ‐ 17.8 %

Effect of Lowering Triglycerides (with Fibrates) in Reducing Residual Risk?

ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.

n=5518Mean f/u: 4.7 yrAdherence ~80%No Rhabdo.CK > 10x: 0.4 vs 0.3%ALT > 3x: 1.9 vs 1.5%

ACCORD: Lipid Results

ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.

ACCORD Lipid: Primary Outcome in Pre-specified Subgroups

NHANES

Circ 2011; 123: 2292-2333

TG > 200 mg/dl:~35% Prevalence in Adults with DiabetesNHANES, 1999-2002

Recommendation…Up to 50% reduction in TG levels by intensive lifestyle measures, including reduction in sucrose and fructose.

Effect of Raising HDL-C in Reducing Residual Risk?

Audience Response Question 2

Is HDL-C an important determinant of CVD events in patients with LDL-C < 70 mg/dL

A. YesB. NoC. Maybe

AIM-HIGH: Baseline Data n= 3,414, 85% men, 92% White Mean age, 64 9 Diabetes, 34%; Metabolic Syndrome, 81% CHD 92%, PAD, 11%, Cerebro-vascular 12% Prior MI 54% Prior statin Rx: 94%

Mean LDL-C : 71 mg/dl (Non-HDL: 107mg/dl)Mean TG : 161 mg/dlMean HDL-C: 34.9 mg/dl

Simvastatin 40 mg + Niaspan 1500-2000 mg, vs Simva 40 + Placebo

LDL-C Goal 40-80 mg/dl

AHJ, 2011

AIM-HIGH: Primary Endpoints

Boden,W et al NEJM 2011; Nov 15:on- line

25,673 high-risk patients with occlusive arterial disease from China, Scandinavia and UK

Randomized comparison: ER niacin/laropiprant (ERN/LRPT) 2g daily versus placebo

Primary end point: Major vascular events after median follow-up of 4 years

Pre-specified safety analyses: Median follow-up of 3.4 years (to January 2012)

Background LDL-lowering therapy with: Simvastatin 40mg (+/- ezetimibe 10mg) daily

ACC, 2013

Potential HDL Therapies Saga

Cholesterol ester transfer protein (CETP) inhibitors (Torcetrapib; Dalcetrapib) Anacetrapib

APO A-1 mimetic agents PPAR /- dual agonists

(Muraglitazar, Tesaglitazar); Aleglitazar

MK-0524A: ER Niacin + DP-1 receptor antagonist (Laropiprant)- available in EU (Tredaptive)