Mixed Dyslipidemia Attenuating risk treatment beyond LDL'

1
Mixed Dyslipidemia Attenuating risk- treatment
beyond LDL.
Michael Davidson, MD Executive Medical
Director Radiant Research Director Preventive
Cardiology Center Professor of Medicine Rush
University Medical Center Chicago, IL.
Christie Ballantyne, MD Professor of
Atherosclerosis and Lipoprotein Research
Director Center for Cardiovascular Disease
Prevention Baylor College of Medicine and
Methodist DeBakey Heart Center, Houston, TX.
2
Residual Cardiovascular Risk in Major Statin
Trials
CHD events occur in patients treated with statins
28.0
19.4
Patients Experiencing Major CHD Events,
15.9
12.3
13.2
11.8
10.2
10.9
8.7
7.9
6.8
5.5
4S1
LIPID2
CARE3
HPS4
WOSCOPS5
AFCAPS/ TexCAPS6
N
4444
4159
20 536
6595
6605
9014
? LDL-C
-35
-28
-29
-26
-25
-25
Secondary
High Risk
Primary
4 HPS Collaborative Group. Lancet.
20023607-22. 5 Shepherd J, et al. N Engl J Med.
19953331301-1307 6 Downs JR, et al. JAMA.
19982791615-1622.
1 4S Group. Lancet. 19943441383-1389. 2 LIPID
Study Group. N Engl J Med. 19983391349-1357.
3 Sacks FM, et al. N Engl J Med.
19963351001-1009.
3
Low HDL-C Increases CVD Risk Even ifLDL-C Levels
Are Well-Controlled
Treating to New Targets (TNT) Study
Patients With LDL-C 80 mg/dL on Atorvastatin 80
mg
P lt 0.0001 for Inverse Relationship
Major CVD Events,
40
41-50
51-60
gt60
HDL-C (mg/dL)
n 4874 On-treatment level (3 months)
Barter P, et al. Poster ACC. 2006. Abstract
914-203.
4

• Pathophysiology
• Patients with high triglycerides
• Increase in VLDL remnants
• Increase in IDL
• Small, dense LDL
• Lp-PLA2 and Apo-CIII - pro-atherogenic
• Even on statins these patients have increased
  risk
• What is optimum TG level?
• Guidelines lt 150
• In patients with coronary disease, worsening
  disease, recurrent symptoms, lt100 may be optimal.
• TG/HDL Ratio 3.5

Lp-PLA2 lipoprotein-associated phospholipase
A2 APO-CIII Apolipoprotein CIII
5

• Beyond LDL as a Target
• Addressed in guidelines as concept of
  "non-HDL-cholesterol"
• Not a new concept Helsinki Heart Study of 1987
  entry criteria was high levels of non-HDL-C 1
• Target non-HDL lt 100 (but not routinely on lab
  request slip)
• ADA Expert Panel Patients with type 2 diabetes
  and other risk factors should also have non-HDL lt
  100 apoB goal lt 90 mg/dl, LDL particle number lt
  1000 2

1. Frick et al. N Engl J Med. 19873171237-1245.
2. Brunzell et al. Diabetes Care 31 811-822
6
NonHDL-C Superior to LDL-C in Predicting CHD
Risk
NonHDL-C, mg/dL

• Within non-HDL-C levels, no association was
  found between LDL-C and the risk for CHD.
• In contrast, a strong positive and graded
  association between nonHDL-C and risk for CHD
  occurred within every level of LDL-C
• NonHDL-C is a stronger predictor of CHD risk
  than LDL-C

Relative CHD Risk
LDL-C, mg/dL
Liu J, et al. Am J Cardiol. 2006981363-1368.
7
Residual CVD Risk in Patients Treated With
Intensive Statin Therapy
Standard statin therapy
Intensive high-dose statin therapy
26.3
22.4
Patients Experiencing Major CVD Events,
13.7
12.0
10.9
8.7
LDL-C, mg/dL
95
62
104
81
101
77
PROVE IT-TIMI 221
IDEAL2
TNT3
N
4162
8888
10 001
Mean or median LDL-C after treatment
1 Cannon CP, et al. N Engl J Med.
20043501495-1504. 2 Pedersen TR, et al. JAMA.
20052942437-2445. 3 LaRosa JC, et al. N Engl J
Med. 20053521425-1435.
8
Statin/ Fibrate Combination Therapy
Pharmacokinetic Interactions
Backman JT, et al. Clin Pharmacol Ther.
200272685-691. Abbott Laboratories. Data on
file 2005. Davidson MH. Am J Cardiol.
200290(suppl)50K-60K. Prueksaritanont T, et al.
Drug Metab Dispos. 2002301280-1287. Martin PD,
et al. Clin Ther. 200325459-471. Bergman AJ, et
al. J Clin Pharmacol. 2004441054-1062.
Backman JT, et al. Clin Pharmacol Ther.
200578154-67. TriCor PI. Abbott
Laboratories2004. Kyrklund C, et al. Clin
Pharmacol Ther. 200169340-345. Pan W-J, et al.
J Clin Pharmacol. 200040316-323. Backman JT, et
al. Clin Pharmacol Ther. 200068122-129.
9

• New agent ABT-335 is being studies in
  combination with simvastatin and with
  atorvastatin. Study results at ACC 08 - good
  efficacy and safety in lowering TG and raising
  HDL
• Good safety data for extended-release niacin plus
  statins but some adherence/dose titration issues
• In patients with high/very high TG, and poorly
  controlled diabetes, fenofibrate or fenofibrate
  plus omega-3 fatty acids may be better choice
• Other benefits of fenofibrate on small vessels
  disease
• SEACOAST data niacin raises HDL independent of
  TG level
• Fenofibrate requires TG to be high to raise HDL
• Generally, men tolerate niacin better than women

10

• AIM HIGH Atherothrombosis Intervention in
  Metabolic Syndrome with Low HDL/High
  Triglycerides and Impact on Global Health
  Outcomes 1
• ER niacin plus simvastatin vs simvastatin alone
  at comparable levels of on-treatment LDL-C
• n 3,300
• Completion Q3, 2010
• HPS2-THRIVE A Randomized Trial of the Long-Term
  Clinical Effects of Raising HDL Cholesterol With
  Extended Release Niacin/Laropiprant 2
• Participants have established CVD and receive
  LDL lowering therapy (40 mg of simvastatin or
  10/40 mg ezetimibe/simvastatin)
• Laropiprant - selective prostaglandin D2
  receptor-1 (DP1) antagonist -reduces frequency
  and intensity of niacin-induced flushing
• n 20,000
• Completion Q4, 2011

1. http//clinicaltrials.gov/ct/show/NCT00120289 2
. http//www.controlled-trials.com/ISRCTN29503772
11

• ACCORD Action to Control Cardiovascular Risk in
  Diabetes
• Clinical benefit of adding fenofibrate to
  patients receiving simvastatin therapy
• n 5,900 Completion Q3, 2009
• FIRST The effects of Fenofibrate on cIMT in
  patients with Residual risk on Statin Therapy 1
• Safety and efficacy study of ABT-335 in
  combination with atorvastatin
• Uses carotid intima media thickness as surrogate
  end point
• Recruiting
• ARBITER-2 Arterial Biology for the Investigation
  of the Treatment Effects of Reducing Cholesterol
  2
• ER niacin added to lipid-lowering therapy in
  patients with known CHD and low HDL-C levels
• Mean CIMT increased significantly in those not
  treated with niacin, while no significant
  increase in CIMT was found in the niacin-treated
  patients.

1. http//clinicaltrials.gov/ct2/show/NCT00616772
2. Taylor et al. Circulation 110 (2004), pp.
35123517
12
Summary

• Residual risk remains when LDL is low, but TG
  remains high, HDL is low
• Diet and exercise are foundation to therapy
• Aspirin therapy, blood pressure and diabetes
  control
• Need to correct metabolic "derangement" to
  improve patient outcomes - less progression of
  disease, fewer CV events
• Combination therapy control all abnormal lipids
  to achieve LDL lt 70 TG lt 150 and HDL gt 40 -
  dont see events