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Title: Gaylord National Resort


1
2008
Symposia Series 1
  • Gaylord National Resort Convention Center
  • National Harbor, Maryland
  • April 12, 2008

1
1
2
DyslipidemiaWhen Statins Alone Fail
  • Roy C. Blank, MD
  • Southern Piedmont Primary Care
  • Monroe, North Carolina

3
What percentage of your patients with
dyslipidemia who are receiving statin therapy
alone achieve their LDL-C goal?
  • 25
  • 26-50
  • 51-75
  • 76-100

Use your keypad to vote now!
LDL-C low-density lipoprotein cholesterol.
4
For what percentage of your patients do you use
nonHDL-C to guide management of dyslipidemia?
  • 25
  • 26-50
  • 51-75
  • 76-100

Use your keypad to vote now!
LDL-C low-density lipoprotein cholesterol.
5
Faculty Disclosure
  • Dr Blank speakers bureau Merck Co., Inc.,
    Pfizer Inc, Takeda Pharmaceuticals, Inc

6
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

7
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.
9
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)

10
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.
11
What is this patients CHD risk category?
  • Very high
  • High
  • Moderately high
  • Moderate
  • Low

Use your keypad to vote now!
CHD coronary heart disease.
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
CVD cardiovascular disease NCEP ATP III
National Cholesterol Education Program Adult
Treatment Panel III. Adapted from Grundy SM, et
al. Circulation. 2004110227-239.
14
NCEP ATP III 2004 Update LDL-C Goals and
Cutpoints
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?
  • Increase atorvastatin dose to40 mg once daily
  • Add a glucose-lowering agent and a fibrate to her
    current atorvastatin regimen (20 mg once daily)
  • Add omega-3 fatty acids(3-4 g/d) to her current
    atorvastatin regimen (20 mg once daily)
  • Add extended-release niacin (1000 mg/d) to her
    current atorvastatin regimen (20 mg once daily)

Use your keypad to vote now!
16
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

Use your keypad to vote now!
17
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

18
ADA Evidence Grading System for Clinical
Practice Recommendations
ADA American Diabetes Association. American
Diabetes Association. Diabetes Care. 2008
31(suppl 1)S12-S54.
19
ADA Recommendations for Dyslipidemia Management
American Diabetes Association. Diabetes Care.
2008 31(suppl 1)S12-S54.
20
ADA Recommendations for Dyslipidemia Management
(contd)
LDL-Ctargeted statin therapy is the preferred
strategy. American Diabetes Association. Diabetes
Care. 200831(suppl 1)S12-S54.
21
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?

22
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.
23
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.
24
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.
25
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.
26
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.
27
Patients With Diabetes Have Particularly High
Residual CVD Risk After Statin Treatment
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.
28
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.
29
Independent risk factors for CVD in patients
with diabetes and the metabolic syndrome include
  • Low TG levels and high LDL-C levels
  • Low TG levels and high HDL-C levels
  • High TG levels and low LDL-C levels
  • High TG levels and low HDL-C levels

Use your keypad to vote now!
30
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.
31
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.
32
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.
33
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.
34
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.
35
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.
36
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.
37
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.
38
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)
On-treatment level (3 months). Barter P, et al.
N Engl J Med. 20073571301-1310.
39
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.
40
In patients with diabetes who receive statin
therapy to reduce LDL-C levels
  • Residual CVD risk remains high
  • Residual CVD risk is low
  • Residual CVD risk has no impact on event rates
  • Residual CVD risk from low HDL-C levels is not
    clinically significant

Use your keypad to vote now!
41
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

42
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

43
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.
44
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.
45
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

46
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

47
Treatment Decision (Option 3) 3-Month
Follow-up (contd)
  • After 3 months therapy with pravastatin plus
    fenofibrate

48
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.
49
ADA Standards of Medical Care in
DiabetesDyslipidemia Management
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.
50
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.
51
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.
52
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.
53
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.
54
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.
55
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

56
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.
57
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

P .011
CABG coronary artery bypass graft EPA
eicosapentaenoic acid. Yokoyama M, et al. Lancet
20073691090-1098.
58
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.
59
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.
60
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.
61
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

62
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

63
Treatment Decision (Option 5)3-Month Follow-up
(contd)
  • After 3 months therapy with pravastatin plus
    niacin

64
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.
65
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.
66
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.
67
Fibrate/statin combination therapy has the
potential to increase the risk of
  • Arrhythmia
  • Myopathy
  • Osteoporosis
  • Thrombosis

Use your keypad to vote now!
68
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.
69
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.
70
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.
71
Potential Cautions With Intensive Lipid Therapy
CHF congestive heart failure LV left
ventricular.
72
Ongoing Trials With Fibrate/Statin or
Niacin/Statin Combination Therapy
CIMT carotid artery intima media thickening.
73
Q A
74
PCE Takeaways
75
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.
76
Based on the clinical data presented on residual
CVD risk, what percentage of your patients with
dyslipidemia would benefit from statin
combination therapy?
  • 25
  • 26-50
  • 51-75
  • 76-100

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77
Based on the clinical data presented, for
whatpercentage of your patients will you use
nonHDL-C to guide management of dyslipidemia?
  • 25
  • 26-50
  • 51-75
  • 76-100

Use your keypad to vote now!
78
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

79
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

80
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

81
BreakClinical Application Workshops
82
2008
Symposia Series 1
  • Gaylord National Resort Convention Center
  • National Harbor, Maryland
  • April 12, 2008

82
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