Hilton Parsippany

1
2008
Symposia Series 2

• Hilton Parsippany
• Parsippany, New Jersey
• June 7, 2008

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1
2
DyslipidemiaWhen Statins Alone Fail

• Joyce L. Ross, MSN, ANP, CRNP, CS
• Clinical Specialist
• Cardiovascular Risk Intervention Program
• University of Pennsylvania
• Philadelphia, Pennsylvania

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Faculty Disclosure

• Ms Ross consultant Kaneka America LLC speakers
  bureau Abbott Laboratories, AstraZeneca
  International, Pfizer Inc

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What percentage of your patients with
dyslipidemia who are receiving statin therapy
alone achieve their LDL-C goal?

1. 25
2. 26-50
3. 51-75
4. 76-100

Use your keypad to vote now!
LDL-C low-density lipoprotein cholesterol.
5
For what percentage of your patients do you use
nonHDL-C to guide management of dyslipidemia?

1. 25
2. 26-50
3. 51-75
4. 76-100

Use your keypad to vote now!
HDL-C high-density lipoprotein cholesterol.
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Learning Objectives

• Identify patients who would benefit from
  combination therapy for dyslipidemia based on
  results of recent clinical trials
• Develop optimal treatment strategies for lowering
  LDL-C and raising HDL-C levels in patients with
  mixed dyslipidemia
• Educate patients on the benefits and long-term
  safety data associated with combination drug
  therapy for dyslipidemia

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Case Study
8
History and Physical Findings

• 68-year-old white woman
• History
• Type 2 diabetes mellitus (10 years)
• Hypertension (12 years)
• Stage 3 renal insufficiency (3 years)
• Physical findings
• Height 1.6 m (5 ft 3 in) weight 83.9 kg (185
  lb) waist circumference 99.1 cm (39 in) BMI
  32.8 kg/m2
• BP 126/72 mm Hg
• ABI 0.84

ABI ankle-brachial index BMI body mass
index BP blood pressure.
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Current Medications

• Lisinopril/hydrochlorothiazide (20/12.5 mg once
  daily)
• Pravastatin (80 mg once daily)
• Glimepiride (2 mg once daily)
• Metformin (850 mg twice daily)
• Acetylsalicylic acid (aspirin) 81 mg (once daily)

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Laboratory Results

• Lipid profile
• TC 178 mg/dL
• LDL-C 72 mg/dL
• NonHDL-C 134 mg/dL
• HDL-C 44 mg/dL
• TG 240 mg/dL
• Glucose metabolism
• FPG level 114 mg/dL
• A1C 6.9

• Renal function
• Creatinine 1.3 mg/dL
• Estimated GFR 54 mL/min
• Microalbumin 34 mg/L

FPG fasting plasma glucose GFR glomerular
filtration rate TC total cholesterol TG
triglyceride.
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What is this patients CHD risk category?

1. Very high
2. High
3. Moderately high
4. Moderate
5. Low

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CHD coronary heart disease.
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12
Type 2 Diabetes and CHD 7-Year Incidence of
Fatal/Nonfatal MI (East West Study)
Patients without diabetes Patients with
diabetes (n 1373) (n 1059)
MI myocardial infarction. At baseline. Haffner
SM, et al. N Engl J Med. 1998339229-234.
13
NCEP ATP III 2004 Update Risk Categories
Risk Category Criteria
Very high (New) CVD multiple risk factors (especially diabetes), severe/poorly controlled risk factors, metabolic syndrome, or acute coronary syndromes
High CHD or CHD risk equivalents 10-year risk gt20
Moderately high 2 risk factors 10-year risk 10-20
Moderate 2 risk factors 10-year risk lt10
Low 0-1 risk factor
CVD cardiovascular disease NCEP ATP III
National Cholesterol Education Program Adult
Treatment Panel III. Adapted from Grundy SM, et
al. Circulation. 2004110227-239.
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NCEP ATP III 2004 Update LDL-C Goals and
Cutpoints
Risk Category LDL-C Level (mg/dL) LDL-C Level (mg/dL) LDL-C Level (mg/dL)
Risk Category Goal Initiate TLC Consider Drug Therapy
Very high (New) lt100 (optional lt70) 100 100
High lt100 100 100
Moderately high lt130 (optional lt100) 130 130
Moderate ?130 130 160
Low ?160 160 190
In patients with moderate or higher risk, use
therapy sufficient to achieve at least a 30-40
reduction in LDL-C levels.
TLC therapeutic lifestyle changes.
Adapted from Grundy SM, et al. Circulation.
2004110227-239.
15
What would be your next step in treating this
patient?

1. Change pravastatin (80 mg once daily) to
   atorvastatin (80 mg once daily)
2. Add pioglitazone (15 mg once daily) to her
   pravastatin regimen
3. Add fenofibrate (145 mg/d) to her pravastatin
   regimen
4. Add omega-3 fatty acids to her pravastatin
   regimen
5. Add niacin to her pravastatin regimen and titrate
   slowly to effective dose

Use your keypad to vote now!
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Treatment Decision (Option 1)

• What would be your next step in treating this
  patient?
• Change pravastatin (80 mg once daily) to
  atorvastatin (80 mg once daily)
• Add pioglitazone (15 mg once daily) to her
  pravastatin regimen
• Add fenofibrate (145 mg/d) to her pravastatin
  regimen
• Add omega-3 fatty acids to her pravastatin
  regimen
• Add niacin to her pravastatin regimen and titrate
  slowly to effective dose

17
ADA Evidence Grading System for Clinical
Practice Recommendations
Level of Evidence Description
A Clear evidence from well-conducted, generalizable, randomized controlled trials that are adequately powered
B Supportive evidence from well-conducted cohort studies
C Supportive evidence from poorly controlled or uncontrolled studies
E Expert consensus or clinical experience
ADA American Diabetes Association. American
Diabetes Association. Diabetes Care. 2008
31(suppl 1)S12-S54.
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ADA Recommendations for Dyslipidemia Management
Recommendation Level of Evidence
Statin therapy should be added to TLC regardless of baseline lipid levels for patients with diabetes who
Have overt CVD A
Do not have CVD but are gt40 years of age and have 1 or more other CVD risk factors A
Combination therapy using statins and other lipid-lowering agents may be considered to achieve lipid targets for mixed dyslipidemia E
American Diabetes Association. Diabetes Care.
2008 31(suppl 1)S12-S54.
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ADA Recommendations for Dyslipidemia Management
(contd)
Recommended Lipid Goals Level of Evidence
LDL-C
For patients without overt CVD lt100 mg/dL A
For patients with overt CVD lt70 mg/dL E
TG lt150 mg/dL (desirable level) C
HDL-C (desirable levels) Men gt40 mg/dL Women gt50 mg/dL C
LDL-Ctargeted statin therapy is the preferred
strategy. American Diabetes Association. Diabetes
Care. 200831(suppl 1)S12-S54.
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Clinical Study Evaluation

• For each study ask the following questions
• What is the primary question of the study?
• What is the answer of the study?
• How does the answer apply to your patients?
• What changes if any should you make in your
  clinical practice?

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Residual CHD Risk in Major Statin Trials
CHD events occur in patients treated with statins
Placebo
Statin
28.0
Patients Experiencing Major CHD Events ()
19.4
15.9
13.2
11.8
12.3
10.2
10.9
7.9
8.7
6.8
5.5
4S1
LIPID2
CARE3
HPS4
WOSCOPS5
AFCAPS/ TexCAPS6
N
4444
4159
20,536
6595
6605
9014
? LDL
-35
-28
-29
-26
-25
-25
Secondary
High Risk
Primary
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
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.
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Residual CVD Risk in Patients Treated With
Intensive Statin Therapy
Statistically significant reductions, but
significant residual CVD risk remains
Moderate statin therapy
Intensive high-dose statin therapy
Patients Experiencing Major CVD Events ()
PROVE IT-TIMI 221
IDEAL2
TNT3
8888
10,001
4162
N
LDL-C (mg/dL)
104
81
101
77
95
62
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.
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Diminished Benefit of Lowering LDL-C
Substantially Below 100 mg/dL in High-Risk
Patients
LDL-C Level (mg/dL)
CV cardiovascular NNT number needed to
treat RRR relative risk reduction. Adapted
from Hayward RA, et al. Ann Intern Med.
2006145520-530.
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Diminished Benefit of Lowering LDL-C
Substantially Below 100 mg/dL in High-Risk
Patients
LDL-C Level (mg/dL)
Adapted from Hayward RA, et al. Ann Intern Med.
2006145520-530.
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Residual CVD Risk in Patients With Diabetes
Treated With Statins
CARDS2 N 2838
HPS1 n 5963
30
16
25.1
13.4
14
25
22 Risk Reduction
32 Risk Reduction
12
20.2
20
9.4
10
Major Vascular Event Rate ()
Acute CVD Event Rate ()
15
8
Residual CVD Risk
6
Residual CVD Risk
10
4
5
2
0
0
Placebo
Simvastatin
Placebo
Atorvastatin
Patients with diabetes. (HPS also enrolled
14,573 high-risk patients without diagnosed
diabetes.)
1. Collins R, et al. Lancet. 20033612005-2016
2. Colhoun HM, et al. Lancet. 2004364685-696.
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Patients With Diabetes Have Particularly High
Residual CVD Risk After Statin Treatment
Event Rate (No Diabetes) Event Rate (No Diabetes) Event Rate (Diabetes) Event Rate (Diabetes)
On Statin On Placebo On Statin On Placebo
HPS1 (CHD patients) 19.8 25.7 33.4 37.8
CARE2 19.4 24.6 28.7 36.8
LIPID3 11.7 15.2 19.2 22.8
PROSPER4 13.1 16.0 23.1 18.4
ASCOT-LLA5 4.9 8.7 9.6 11.4
TNT6 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 CHD death,
nonfatal MI, stroke CHD death, nonfatal MI,
resuscitated cardiac arrest, stroke (80-mg vs
10-mg atorvastatin)
MI myocardial infarction PTCA percutaneous
transluminal coronary angioplasty.
1. HPS Collaborative Group. Lancet.
20033612005-2016. 2. Sacks FM, et al. N Engl J
Med. 19963351001-1009. 3. LIPID Study Group. N
Engl J Med. 19983391349-1357.4. Shepherd J, et
al. Lancet. 20023601623-1630. 5. Sever PS, et
al. Lancet. 20033611149-1158. 6. Shepherd J, et
al. Diabetes Care. 2006291220-1226.
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Lipids in Patients With Premature CHD
Men
Women


200
177
180
Controls
160
CHD
141
139
138
140
120
Plasma Lipid Concentration (mg/dL)
100
80

60

45
35
40
20
0
LDL-C
TG
HDL-C
P lt.005 compared with controls. P lt.05 compared
with controls.
Genest JJ Jr, et al. Circulation.
1992852025-2033.
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Independent risk factors for CVD in patients
with diabetes and the metabolic syndrome include

1. Low TG levels and high LDL-C levels
2. Low TG levels and high HDL-C levels
3. High TG levels and low LDL-C levels
4. High TG levels and low HDL-C levels

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Atherogenic Dyslipidemia in Patients With
Diabetes and the Metabolic Syndrome

• High TG levels (independent CVD risk factor)
• TG-rich remnant lipoproteins (VLDL)
• Altered metabolism (lipolysis) of LDL and HDL
  particles
• Absolute levels of LDL-C are commonly not
  significantly increased, but other LDL parameters
  significantly change
• ? Number of LDL particles (? LDL-P and Apo B)
• Predominantly small, dense LDL-P
• Low levels of HDL-C (major independent CVD risk
  factor)
• May reduce reverse cholesterol transport

Apo B apolipoprotein B LDL-P LDL particle
VLDL very low-density lipoprotein. Garvey WT,
et al. Diabetes. 200352453-462 Haffner SM.
Diabetes Care. 200326 (suppl 1)S83-S86.
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TG Level Is Significant CVD Risk Factor Recent
Meta-Analysis of 29 Studies
Groups CHD Cases
N 262,525
Duration of follow-up
10 years 5902
lt10 years 4256
Sex
Male 7728
Female 1994
Fasting status
Fasting 7484
Nonfasting 2674
Adjusted for HDL
Yes 4469
No 5689
1.72 (1.56-1.90)
Individuals in top vs bottom third of usual
log-TG values adjusted for at least age, sex,
smoking status, and lipid concentrations also
adjusted for BP (in most studies).
2
1
CHD Risk Ratio (95 CI)
Sarwar N, et al. Circulation. 2007115450-458.
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Risk of CHD by TG LevelPROCAM Study
8-Year Follow-Up
N 4639 men with no history of MI or stroke

• Elevated TG levels significantly increase CHD
  risk
• Significant correlation remains between TG level
  and CHD risk after adjustment for LDL-C and HDL-C
  
• 6-fold increased CHD risk in patients with TG
  gt200 mg/dL and LDL-CHDL-C gt5

P .001
2.6
P .01
1.6
Comparator 1.0
Relative CHD Risk
Assmann G, et al. Am J Cardiol.
1996771179-1184.
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TG Level Remains CVD Risk Factor in Patients
Treated With Statins CARE and LIPID
N 13,173
Slope .018 P .02
Placebo
Pravastatin
CVD Event Rate ()
Slope .029 P lt.001
lt98
99-126
127-158
159-207
gt207
TG Level (mg/dL)
CHD death, nonfatal MI, CABG, PTCA.
Sacks FM, et al. Circulation. 20001021893-1900.
33
NCEP ATP III TG-Rich Remnant Lipoproteins Are
Atherogenic

• Elevated TG levels are a marker for elevated
  levels of atherogenic remnant lipoproteins
• VLDL-C is the most readily available measure of
  atherogenic remnant lipoproteins for clinical
  practice
• When TG levels are elevated, nonHDL-C (TC -
  HDL-C) better represents the concentrations of
  all atherogenic lipoproteins than LDL-C alone
• NonHDL-C should be a secondary target of therapy
  when TG levels are 200 mg/dL

VLDL-C very low-density lipoprotein
cholesterol. NCEP ATP III. Circulation.
20021063143-3421.
34
NonHDL-C in Predicting CHD Risk

• Within nonHDL-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
190
160-189
lt160
lt130
130-159
160
NonHDL-C (mg/dL)
LDL-C (mg/dL)
Liu J, et al. Am J Cardiol. 2006981363-1368.
35
NCEP ATP III HDL-C Is an Independent Risk Factor
for CHD

• A low HDL-C level is strongly and inversely
  associated with CHD risk
• Independent relationship holds after correction
  for other risk variables in multivariate
  analysis
• A low HDL-C level often correlates with
  elevations of serum TG and remnant lipoproteins
• HDL may be antiatherogenic
• Promotes reverse cholesterol transport
• Antioxidant and anti-inflammatory properties
  inhibit atherogenesis

NCEP ATP III. Circulation. 20021063143-3421.
36
Meta-Analysis Predictive Value of HDL-C

• Coronary Primary Prevention Trial (CPPT)
• Multiple Risk Factor Intervention Trial (MRFIT)
• Lipid Research Clinics Prevalence Mortality
  Follow-up Study (LRCS)
• Framingham Heart Study (FHS)

1 mg/dL Increase in HDL-C
CPPT
MRFIT
LRCS
LRCS
FHS
FHS
2 ? CHD Risk in Men
3 ? CHD Risk in Women
Gordon DJ, et al. Circulation. 1989798-15.
37
Low HDL-C Increases CVD Risk Even If LDL-C
Levels Are Well ControlledTNT Study
Patients with LDL-C lt70 mg/dL (n 2661)
Hazard Ratio (95 CI) versus Q1 Q2 0.85
(0.57-1.25) Q3 0.57 (0.36-0.88) Q4 0.55 (0.35
-0.86) Q5 0.61 (0.38-0.97)
10
9
8
7
6
5-Year Risk of Major CV Events ()
5
4
3
2
1
0
Q1(lt37)
Q2(37 to lt42)
Q3(42 to lt47)
Q4(47 to lt55)
Q5(?55)
Quintile of HDL-C (mg/dL)
No. of Events 57 50 34 34 35
No. of Patients 473 525 550 569 544
On-treatment level (3 months). Barter P, et al.
N Engl J Med. 20073571301-1310.
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CVD Risk Associated With Low HDL-C Level Remains
in Patients Treated With Statins
Low HDL-C statin
High HDL-C statin
CVD Event Rate ()
CVD Event Rate ()
Sacks FM, et al. Circulation. 20001021893-1900.
HPS Collaborative Group. Lancet. 20023607-22.
39
In patients with diabetes who receive statin
therapy to reduce LDL-C levels

1. Residual CVD risk remains high
2. Residual CVD risk is low
3. Residual CVD risk has no impact on event rates
4. Residual CVD risk from low HDL-C levels is not
   clinically significant

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40
Key Points

• Residual CVD risk remains after patients are
  treated with statins to reduce LDL-C and is
  particularly high in patients with diabetes who
  are treated with statins
• Atherogenic dyslipidemia contributes to residual
  risk for atherosclerosis and CVD risk
• Increased levels of TG and TG-rich remnant
  lipoproteins
• Increased levels of nonHDL-C
• Increased numbers of Apo Bcontaining particles,
  including small, dense LDL
• Decreased levels of HDL-C
• The combination of high TG with low HDL-C and/or
  high LDL-C synergistically increases CHD risk

41
Treatment Decision (Option 2)

• What would be your next step in treating
• this patient?
• Change pravastatin (80 mg once daily) to
  atorvastatin (80 mg once daily)
• Add pioglitazone (15 mg once daily) to her
  pravastatin regimen
• Add fenofibrate (145 mg/d) to her pravastatin
  regimen
• Add omega-3 fatty acids to her pravastatin
  regimen
• Add niacin to her pravastatin regimen and titrate
  slowly to effective dose

42
PROACTIVE Primary End Point
Placebo No. of events
572 Pioglitazone No. of events 514
25
20
N 5238
15
Proportion of Events ()
10
HR 0.90 (95 CI, 0.80-1.02) P .095
5
0
6
12
18
24
30
36
0
Time From Randomization (mo)
Death from any cause, nonfatal MI (including
silent MI), stroke, acute coronary syndrome, leg
amputation, coronary revascularization, or
revascularization of the leg. HR hazard
ratio. Dormandy JA, et al. Lancet.
20053661279-1289.
43
PROACTIVE Secondary End Point
Placebo No. of events
358 Pioglitazone No. of events 301
25
20
N 5238
15
Proportion of Events ()
10
HR 0.84 (95 CI, 0.72-0.98) P .027
5
0
6
12
18
24
30
36
0
Time From Randomization (mo)
Death from any cause, nonfatal MI (excluding
silent MI), or stroke. Dormandy JA, et al.
Lancet. 20053661279-1289.
44
Treatment Decision (Option 3)

• What would be your next step in treating
• this patient?
• Change pravastatin (80 mg once daily) to
  atorvastatin (80 mg once daily)
• Add pioglitazone (15 mg once daily) to her
  pravastatin regimen
• Add fenofibrate (145 mg/d) to her pravastatin
  regimen
• Add omega-3 fatty acids to her pravastatin
  regimen
• Add niacin to her pravastatin regimen and titrate
  slowly to effective dose

45
Treatment Decision (Option 3) 3-Month Follow-up

• Visit 1
• TLC (diet, exercise) reinforced
• Fenofibrate (145 mg/d) prescribed as add-on to
  her statin therapy
• Visit 2
• Improvements in lipid profile
• No musculoskeletal side effects no hepatic or
  renal laboratory abnormalities

46
Treatment Decision (Option 3) 3-Month
Follow-up (contd)

• After 3 months therapy with pravastatin plus
  fenofibrate

Lipid Profile Visit 1 Visit 2 (3-month follow-up)
TC (mg/dL) 178 142 (20 reduction)
LDL-C (mg/dL) 72 69 (4 reduction)
NonHDL-C (mg/dL) 134 94 (30 reduction)
HDL-C (mg/dL) 44 48 (9 increase)
TG (mg/dL) 240 140 (42 reduction)
Glucose Level Visit 1 Visit 2 (3-month follow-up)
FPG (mg/dL) 114 112 (unchanged)
47
Treating Beyond LDL-C Other Targets of
Lipid-Lowering Therapy

• Lipoproteins other than LDL are involved in
  atherogenesis (pro VLDL, IDL anti HDL)1
• NCEP ATP III concluded (on the basis of several
  types of data) that an elevated nonHDL-C in
  patients with hypertriglyceridemia will impart
  increased risk even after the goal of LDL-C has
  been reached1
• NCEP ATP III 2004 update For those high-risk
  patients who have elevated triglycerides or low
  HDL-C levels, addition of a fibrate or nicotinic
  acid to LDL-lowering therapy can be considered.2

IDL intermediate-density lipoprotein.
1. Grundy SM. Circulation. 20021062526-2529 2.
Grundy SM, et al. Circulation. 2004110227-239.
48
ADA Standards of Medical Care in
DiabetesDyslipidemia Management
First Priority Second Priority
LDL-C Lowering Goal lt100 mg/dL TLC Statins Niacin, ezetimibe, bile acid sequestrants, or fenofibrate
HDL-C Raising Goal gt40 mg/dL TLC Niacin or fibrates
TG Lowering Goal lt150 mg/dL TLC Glycemic control Fibrates (fenofibrate, gemfibrozil) Niacin Statins (if LDL-C is also high)
Combined Hyperlipidemia Glycemic control high-dose statin Glycemic control statin fibrate Glycemic control statin niacin
An LDL-C goal lt70 mg/dL is an option in patients
with overt CVD. An HDL-C goal gt50 mg/dL should
be considered for women. At high doses, niacin
may increase blood glucose levels.
American Diabetes Association. Diabetes Care.
200427S68-S71. American Diabetes Association.
Diabetes Care. 200730(suppl 1)S4-S41.
49
Lipid Management in Patients With Diabetes or
Metabolic Syndrome

• Therapeutic lifestyle changes (TLC)
• Glycemic control
• Statin therapy to achieve LDL-C lt100 mg/dL (lt70
  mg/dL with CHD)
• TG 500 mg/dL Fibrate Omega-3 fatty
  acids
• TG 150-500 mg/dL Fibrate (with slightly low or
  normal HDL-C) Niacin (with very low HDL-C)
• TG lt150 mg/dL and Niacin
• Low HDL-C
• Well-controlled diabetes A1C lt7.0. HDL-C lt40
  mg/dL in men or lt50 mg/dL in women.

Adapted from American Diabetes Association.
Diabetes Care. 200427S68-S71. Adapted from
American Diabetes Association. Diabetes Care.
200730(suppl 1)S4-S41. Adapted from Physicians
Desk Reference. 61st ed. Montvale, NJ Thomson
PDR 20072725-2727.
50
Outcomes in Fibrate Trials Patients With
Diabetes or Metabolic Syndrome
Major CVD Event Rate
P
Control
RRR
Drug
N
Trial
Primary Prevention
lt.005
13.0
71
3.9
292
HHS1
.004
19
8.9
10.8
7664
FIELD2
Secondary Prevention
.03
18.4
25
14.1
1470
BIP3
.004
29.4
32
21.2
769
VA-HIT4
Patients with TG gt204 mg/dL and an LDLHDL gt5
(may or may not have had diabetes or metabolic
syndrome). Patients with diabetes and no prior
CVD. Patients with metabolic syndrome. Patients
with diabetes.
1. Manninen V, et al. Circulation. 19928537-45
2. Keech A, et al. Lancet. 20053661849-1861 3.
Tenenbaum A, et al. Arch Intern Med.
20051651154-1160 4. Rubins HB, et al. Arch
Intern Med. 20021622597-2604.
51
VA-HIT CVD Risk Reduction in Diabetics Compared
With Nondiabetics
Combined End Point
Nonfatal MI
CHD Death
Stroke
0
5
3
P .88
10
10
15
P .67
Cumulative Event Rate Change ()
20
18
22
21
P .07
25
P .09
P .17
30
32
35
P .004
DM
40
No DM
40
41
P .26
45
P .046
P .02
DM diabetes mellitus. Rubins HB, et al. Arch
Intern Med. 20021622597-2604.
52
FIELD Primary and Secondary End Points
11 Reduction P .035
Placebo
Fenofibrate
21 Reduction P .003
11 Reduction P .16
24 Reduction P .01
Event Rate ()
19 Increase P .22
Total CVD Events (Secondary End Point)
CHD Death
Nonfatal MI
CHD Events (Primary End Point)
Coronary Revascularization
Nonfatal MI and CHD death. CHD events, stroke,
CVD death, revascularizations.
Keech A, et al. Lancet. 20053661849-1861.
53
FIELD End Points in Patients With No Prior CVD
(78 of Study Population)
CHD Events
Total CVD
(n 7664)
(n 7664)
0
-5
-10
Risk Reduction ()
-15
-20
-19
P .004
-25
Secondary End Point
-25
P .014
-30
Primary End Point
Keech A, et al. Lancet. 20053661849-1861.
54
Treatment Decision (Option 4)

• What would be your next step in treating this
  patient?
• Change pravastatin (80 mg once daily) to
  atorvastatin (80 mg once daily)
• Add pioglitazone (15 mg once daily) to her
  pravastatin regimen
• Add fenofibrate (145 mg/d) to her pravastatin
  regimen
• Add omega-3 fatty acids to her pravastatin
  regimen
• Add niacin to her pravastatin regimen and
  titrate slowly to effective dose

55
Treatment Decision (Option 4)

• Data suggest omega-3 fatty acid supplementation
  is a useful treatment option for patients with
  severe hypertriglyceridemia
• This patients TG level (on statin monotherapy)
  is 240 mg/dL
• Interesting data available for omega-3 fatty
  acids include
• JELIS trial1
• GISSI-P trial2

1. Yokoyama M, et al. Lancet 20073691090-1098
2. GISSI-P Investigators. Lancet.
1999354447-455.
56
JELIS Omega-3 Fatty Acids Plus Statins in
Patients With Hypercholesterolemia

• All patients had TC levels gt6.5 mmol/L (gt251
  mg/dL)
• Randomized to treatment with a statin or a statin
  plus 1800 mg/d EPA

Outcome (mean follow-up, 4.6 y) Statin Alone (n 9319), Statin EPA (n 9326), HR (95 CI)
Major coronary events 3.5 2.8 0.81 (0.69-0.95)
Sudden cardiac death 0.2 0.2 1.06 (0.55-2.07)
Fatal MI 0.2 0.1 0.79 (0.36-1.74)
Nonfatal MI 0.9 0.7 0.75 (0.54-1.04)
Unstable angina 2.1 1.6 0.76 (0.62-0.95)
CABG or PTCA 2.4 2.1 0.86 (0.71-1.05)
P .011
CABG coronary artery bypass graft EPA
eicosapentaenoic acid. Yokoyama M, et al. Lancet
20073691090-1098.
57
Dietary Supplementation With Omega-3 Fatty Acids
After MI
GISSI-P Results
Placebo (n 2828)
Omega-3 fatty acids 1 g (n 2836)
15 Reduction P .023
20 Reduction P .008
Event Rate ()
Death/ Nonfatal MI/ Nonfatal Stroke
CVD Death/ Nonfatal MI/ Nonfatal Stroke
GISSI-P Investigators. Lancet. 1999354447-455.
58
Efficacy of Omega-3 Fatty Acids for Patients
With Severe Hypertriglyceridemia
Placebo

Omega-3 fatty acids 4 g

Change From Baseline ()


TG level 500-2000 mg/dL, N 42. P lt.02 vs
placebo.
Harris WS, et al. J Cardiovasc Risk.
19974385-391.
59
Omega-3 Fatty Acids/Statin Combination Therapy in
Insulin-Resistant Obese Men
Atorvastatin 40 mg

Omega-3 fatty acids 4 g
Combination
Change From Baseline ()







LDL-C
NonHDL-C
HDL-C
TG
Insulin Resistance (HOMA Score)
N 48 P lt.05 vs placebo. HOMA homeostasis
model assessment.
Chan DC, et al. Diabetes. 2002512377-2386.
60
Treatment Decision (Option 5)

• What would be your next step in treating this
  patient?
• Change pravastatin (80 mg once daily) to
  atorvastatin (80 mg once daily)
• Add pioglitazone (15 mg once daily) to her
  pravastatin regimen
• Add fenofibrate (145 mg/d) to her pravastatin
  regimen
• Add omega-3 fatty acids to her pravastatin
  regimen
• Add niacin to her pravastatin regimen and titrate
  slowly to effective dose

61
Treatment Decision (Option 5)3-Month
Follow-up

• Visit 1
• TLC (diet, exercise) reinforced
• Long-acting niacin prescribed as add-on to statin
  therapy, at 500 mg/d and increased to 1000 mg/d
  after 4 weeks
• Visit 2
• Lipid profile improved
• No worsening of diabetes control noted
• Normal liver function studies

62
Treatment Decision (Option 5)3-Month Follow-up
(contd)

• After 3 months therapy with pravastatin plus
  niacin

Lipid Profile Visit 1 Visit 2 (3-month follow-up)
TC (mg/dL) 178 167 (6 reduction)
LDL-C (mg/dL) 72 65 (10 reduction)
NonHDL-C (mg/dL) 134 115 (14 reduction)
HDL-C (mg/dL) 44 52 (18 increase)
TG (mg/dL) 240 168 (30 reduction)
Glucose Level Visit 1 Visit 2 (3-month follow-up)
FPG (mg/dL) 114 118 (unchanged)
63
Lipid Effects of Adding Niacin ER to Baseline
Statin Therapy
Statin niacin ER 1 g (n 66)
Statin niacin ER 2 g (n 29)
Change From Baseline Statin Therapy ()
TG
TC
LDL-C
HDL-C
niacin ER niacin extended-release. Wolfe ML, et
al. Am J Cardiol. 200187476-479.
64
HATS Lipid-Altering/Antioxidant Therapy in
Patients With CAD and Low HDL-C

• S-N group mean LDL-C ? (-46), mean HDL-C ?
  (26)
• Placebo and AVit groups mean LDL-C and HDL-C
  levels unaltered
• Antioxidants ? HDL2 (protective component of HDL)
  levels and attenuated protective ? seen with S-N

Mean Change in Proximal Stenosis ()
Composite CV Event Rate ()
Composite of death from CV causes, nonfatal
infarction, or revascularization procedure. AVit
antioxidant vitamins CAD coronary artery
disease S-N simvastatin plus niacin. Brown BG,
et al. N Engl J Med. 20013451583-1592.
65
COMPELL Lipid Effects of Niacin ER/Statin
Combination Therapy
Atorvastatin 40 mg niacin ER 2 g
Simvastatin 40 mg ezetimibe 10 mg
Rosuvastatin 40 mg
Rosuvastatin 20 mg niacin ER 1 g




Change From Baseline ()


TG
LDL-C
HDL-C
Lp(a)
N 292 12 weeks. P lt.05 vs atorvastatin
niacin ER.
Lp(a) lipoprotein (a). McKenney JM, et al.
Atherosclerosis. 2007192432-437.
66
Fibrate/statin combination therapy has the
potential to increase the risk of

1. Arrhythmia
2. Myopathy
3. Osteoporosis
4. Thrombosis

Use your keypad to vote now!
66
67
Safety of Fibrate/Statin Combination Therapy

• Fibrates improve all components of atherogenic
  dyslipidemia and appear to reduce the risk for
  CVD their use in combination with statins is
  particularly attractive1
• Both statins and fibrates have the potential to
  produce myopathy, and the risk for myopathy is
  enhanced when they are used together1
• Clinical and preclinical studies indicate that
  gemfibrozil interferes with catabolism of statins
  in the liver (ie, inhibits glucuronidation),
  which can raise statin blood levels, thereby
  predisposing to myopathy1-3
• Fenofibrate does not interact adversely with
  statin catabolism and thus may be safer to use in
  combination therapy with statins1-3

1. Grundy SM, et al. Circulation.
2004109551-556 2. Davidson MH. Expert Opin
Drug Saf. 20065145-156 3. Davidson MH. Am J
Cardiol. 20029050K-60K.
68
Number of Cases of Rhabdomyolysis in Combination
Therapy With Statins
10
8.6
9
8
7
6
No. Cases Reported per Million Prescriptions
5
15-Fold Increase
4
3
2
0.58
1
0
Fenofibrate
Gemfibrozil
Excludes cases involving cerivastatin.
Jones PH, et al. Am J Cardiol. 200595120-122.
69
Safety of Lovastatin/Niacin ER and Niacin ER vs
Statin Monotherapy (FDA-AERS)

P lt.05 versus L/N

Serious AERs Per Million Prescriptions
L/N
N
L
A
S
P

Liver AERs Per Million Prescriptions
Rhabdomyolysis AERs Per Million Prescriptions
L/N
N
L
A
S
P
L/N
N
L
A
S
P
A atorvastatin AERs adverse event reports
FDA-AERS US Food and Drug Administration
Adverse Event Reporting System L lovastatin N
niacin ER P pravastatin S simvastatin.
Alsheikh-Ali AA, et al. Am J Cardiol.
200799379-381.
70
Potential Cautions With Intensive Lipid Therapy
Option Caveat
Intensify statin regimen Little data on use of high doses in patients with diabetes mellitus
Add pioglitazone May cause weight gain, fluid retention may cause or worsen CHF requires knowledge of LV function
Add fenofibrate No outcome data for combination therapy may cause a functional increase in creatinine level
Add omega-3 fatty acids No outcome data in patients with diabetes mellitus
Add extended-release niacin Can increase glucose level in patients with diabetes be sure diabetes is well controlled, prescribe low dosage, and ask patients to monitor their glucose levels closely
CHF congestive heart failure LV left
ventricular.
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Ongoing Trials With Fibrate/Statin or
Niacin/Statin Combination Therapy
Trial Therapy End Point N Patients Dates
ACCORD Simvastatin Fenofibrate CVD 10,000 1st and 2nd prevention All have DM 03-09 (6 y)
AIM-HIGH Simvastatin Niacin ER CVD 3300 2nd prevention ?HDL and ?TG 06-10 (4 y)
HPS2-THRIVE Simvastatin MK524A/niacin CVD 20,000 2nd prevention 7000 DM 07-11 (4 y)
72
When Traditional Treatment Strategies Are Just
Not Enough, Is There Nothing I Can Do?
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What Is LDL Apheresis?

• Treatment to remove LDL-C from the blood while
  keeping the HDL-C
• Extracorporeal procedure
• Blood taken outside of the body and returned to
  the patient without need for albumin or other
  blood products
• FDA-approved for patients1
• With homozygous familial hypercholesterolemia
  and an LDL-C level gt500 mg/dL
• With CAD and an LDL-C level 200 mg/dL or
• Without CAD but an LDL-C level 300 mg/dL

1. Gordon BR, et al. J Clin Apher.
199611128-131.
73
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Lipid Reductions With LDL Apheresis

• Lipid/Lipoprotein Acute Reduction ()
• TC 61-71
• LDL-C 73-83
• HDL-C 3-14
• Lp(a) 53-76
• TGs 47-68

Bambauer R, et al. Ther Apher. 19971242-248.
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75
Q A
76
PCE Takeaways
77
PCE Takeaways

• Lipid abnormalities beyond LDL-C (ie, nonHDL-C,
  TG, HDL-C) should be intensively treated to
  reduce residual CVD risk
• Fibrate monotherapy is particularly beneficial in
  reducing CVD risk in patients with metabolic
  syndrome or diabetes
• Niacin is effective therapy for reducing CVD
  risk adding niacin to statin therapy slows
  atherosclerosis progression in patients with CHD
  and reduces CVD risk
• Fibrate/statin and niacin/statin combination
  therapy correct atherogenic lipid abnormalities
  and appear to be safe

Indication not approved by FDA.
78
Based on the clinical data presented on residual
CVD risk, what percentage of your patients with
dyslipidemia would benefit from statin
combination therapy?

1. 25
2. 26-50
3. 51-75
4. 76-100

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78
79
Based on the clinical data presented, for
whatpercentage of your patients will you use
nonHDL-C to guide management of dyslipidemia?

1. 25
2. 26-50
3. 51-75
4. 76-100

Use your keypad to vote now!
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Glossary of Study Acronyms

• 4S Scandinavian Simvastatin Survival Study
• ACCORD Action to Control Cardiovascular Risk in
  Diabetes
• AFCAPS/TexCAPS Air Force/Texas Coronary
  Atherosclerosis Prevention Study
• AIM-HIGH Niacin Plus Statin to Prevent Vascular
  Events
• ASCOT-LLA Anglo-Scandinavian Cardiac Outcomes
  TrialLipid Lowering Arm
• BIP Bezafibrate Infarction Prevention
• CARDS Collaborative Atorvastatin Diabetes Study
• CARE Cholesterol and Recurrent Events
• COMPELL COMParative Effects on Lipid Levels of
  Niaspan and a Statin versus Other
  Lipid-Modifying Therapies

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Glossary of Study Acronyms (contd)

• CPPT Coronary Primary Prevention Trial
• FHS Framingham Heart Study
• FIELD Fenofibrate Intervention and Event
  Lowering in Diabetes
• GISSI-P Gruppo Italiano per lo Studio della
  Sopravvivenza nellInfarto miocardicoPrevenzione
• HATS HDL-Atherosclerosis Treatment Study
• HHS Helsinki Heart Study
• HPS Heart Protection Study
• HPS2-THRIVE Heart Protection Study 2Treatment
  of HDL to Reduce the Incidence of Vascular
  Events
• IDEAL Incremental Decrease in End Points
  Through Aggressive Lipid Lowering
• JELIS Japan EPA Lipid Intervention Study

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Glossary of Study Acronyms (contd)

• LIPID Long-Term Intervention with Pravastatin
  in Ischaemic Disease
• LRCS Lipid Research Clinics Prevalence
  Mortality Follow-up Study
• MRFIT Multiple Risk Factor Intervention Trial
• PROACTIVE PROspective pioglitAzone Clinical
  Trial In macroVascular Events
• PROCAM Prospective Cardiovascular Münster
• PROSPER PROspective Study of Pravastatin in the
  Elderly at Risk
• PROVE ITTIMI 22 Pravastatin or Atorvastatin
  Evaluation and Infection TherapyThrombolysis in
  Myocardial Infarction 22
• TNT Treating to New Targets
• VA-HIT Veterans Affairs High-Density
  Lipoprotein Intervention Trial
• WOSCOPS West of Scotland Coronary Prevention
  Study

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BreakClinical Application Workshops
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84
2008
Symposia Series 2

• Hilton Parsippany
• Parsippany, New Jersey
• June 7, 2008

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