Bridging the Gap in Treatment Options for Hypertriglyceridemia

1
Primary Care Education Consortium Presents
Bridging the Gap in Treatment Options for
Hypertriglyceridemia
2
Welcome, Introduction and Overview
Richard Hays, MD, FAAFP Private Practice,
Wellington, Florida
3
Agenda
Introduction and Overview
630 - 700 PM Registration and Dinner 700 -
715 PM Welcome, Introductions and
Overview Richard Hays, MD 715 - 745 PM The
Evidence for Hypertriglyceridemia as a Risk
Factor William S. Harris, PhD 745 - 815
PM Real World Answers to Managing
Hypertriglyceridemia Richard Hays,
MD 815 - 830 PM Questions and Answers
4
Learning Objectives
Introduction and Overview

• At the conclusion of this program, participants
  will be able to
• Increase the ability to identify patient types
  at risk for
• hypertriglyceridemia and, if present, to
  treat the condition to improve
• outcomes
• Recognize the complex etiology of
  hypertriglyceridemia and the link
• to cardiovascular disease
• Appreciate the need to measure triglyceride
  levels in patients at risk,
• even those that may have normal LDL-C levels
• Assess the efficacy and safety of current
  first-line and adjunct
• therapies for hypertriglyceridemia
• Formulate patient specific treatment regimens
  that may include
• combination regimens that will improve
  patients prognosis

5
Accreditation Statement

• ACCREDITATION STATEMENT
• This activity has been reviewed and is acceptable
  for up to 3.00 prescribed credit hours by the
  American Academy of Family Physicians. 1.50 of
  these credits conforms to the AAFP criteria for
  evidence-based CME clinical content. CME credit
  has been increased to reflect 2 for 1 credit for
  only the EB CME portion.
•  
• COMMERCIAL SUPPORT STATEMENT
• This CME symposium is supported through an
  educational grant provided by Reliant
  Pharmaceutical, Inc.

6
Faculty
Richard Hays, MD Private Practice Wellington,
Florida William S. Harris, PhD Director Nutrit
ion Metabolic Disease Research Center Sanford
Research / USD Professor of Medicine Sanford
School of Medicine, University of S.
Dakota Sioux Falls, South Dakota
7
Disclosure Statement
Faculty Financial Disclosure It is PCEC's goal
to ensure balance, independence, objectivity, and
scientific rigor in all its educational
activities. To meet this goal, both real and/or
potential conflicts of interest must be
considered during the development of a continuing
educational activity. All individuals having
control over the development of an activitys
content and all faculty participating in PCEC
programs are expected to disclose any
relationships they may have with commercial
companies whose products or services may be
mentioned. Potential learners will be informed of
all disclosed relationships. The following are
all disclosures for this CME program.
8
Faculty Disclosure
Dr. Hays has disclosed that he is a consultant to
Glaxo Smith Klein, participates on the speakers'
bureau for Novartis and has received honoraria or
research support from Macrogenics and
Novartis. Dr. Harris has indicated that he is a
consultant for Monsanto and Reliant
Pharmaceuticals, Inc.
9
AAFP
New this year, you may report your AAFP
Prescribed credits earned for this event online
at the CME reporting booth at the convention
center. No documentation is needed. The course
number for this event is 801.
10
The Evidence for Hypertriglyceridemia as a Risk
Factor

• William S. Harris, PhD
• October 3, 2007

11
Evidence for Hypertriglyceridemia as a CHD Risk
Factor

• What is Hypertriglyceridemia ?
• How common is it?
• Metabolic pathways
• Causes of Hypertriglyceridemia
• Inherited vs. Environmental
• Triglycerides and CHD
• Treatment of Hypertriglyceridemia, with a focus
  on omega-3 fatty acids

12
Patient Case - Ms. Jacobs

• Ms. Jacobs, a 41-year-old female, with medical
  history significant for hypertension.
• Family history father had a heart attack at age
  52 mother has high cholesterol and hypertension.
  
• Ms. Jacobs smokes 1 pack of cigarettes a day, and
  she has "a couple of drinks" each night.
• With 3 risk factors her target LDL-C 100 mg/dL

13
Ms. Jacobs

• Physical exam
• BMI of 29 kg/m2
• Waist circumference of 35 inches.
• Blood pressure is 142/87 mmHg.
• The rest of her physical examination is
  unremarkable
• Current medications
• Oral contraceptive pill
• Daily multivitamin
• No antihypertensive

14
Ms. Jacobs

• Laboratory Exam

15
What is Hypertriglyceridemia?
Third Report of the National Cholesterol
Education Panel (NCEP) on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III) National Institutes
of Health. September 2002.
16
US Hypertriglyceridemia (HTG) Prevalence
US Adult Population
TG 500 mg/dL2.5 - 3
TG 200-499 mg/dL13

• Clinical Relevance
• Risk for pancreatitis
• Cardiovascular risk

Third Report of the National Cholesterol
Education Panel (NCEP) on Detection, Evaluation,
and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III) National
Institutes of Health. September 2002.
17
What are Triglycerides?
TG Rich LP
18
(No Transcript)
19
Causes of Hypertriglyceridemia
20
Familial High TG Syndromes

• Familial hypertriglyceridemia (/- high
  chylomicrons)
• Family history of high TG
• Type IV with high VLDL-C, normal LDL-C and apo-B
• TG typically 250 1,000 mg/dL
• Commonly associated with insulin resistance
• May lead to early CVD
• TG gt1000 mg/dL risk of pancreatitis
• Familial chylomicronemia
• TG 1,000-10,000 mg/dL from birth
• Lipoprotein lipase or apo C-II defect
• No increase in CAD risk

Dunbar and Rader. CCJM 200572661-680.
21
Secondary Causes of High TG

• Lifestyle
• Physical inactivity
• High CHO intake (gt60)
• Excessive alcohol
• Obesity
• Medications
• ERT/ OCP/Tamoxifen
• Steroids/Immunosuppressants
• Beta-blockers/Thiazides
• Retinoids
• Protease inhibitors (HIV)
• Atypical anti-psychotics

• Associated Diseases
• Metabolic syndrome
• Diabetes (Type 2)
• Nephrotic syndrome
• Chronic kidney disease
• Cushing syndrome
• Hypothyroidism
• Pregnancy

Dunbar and Rader. CCJM 200572661-680.
22
Triglycerides and CHD
23
Residual Cardiovascular Risk in Major Statin
Trials
75
75
73
69
62
62
Patients Experiencing Major Coronary Events ()
AFCAPS/TexCAPS
4S
LIPID
CARE
HPS
WOS
4SScandinavian Simvastatin Survival Study
LIPIDLong-Term Intervention with Pravastatin in
Ischaemic Disease CARECholesterol and Recurrent
Events HPSHeart Protection Study WOSWest of
Scotland Coronary Prevention Study
AFCAPS/TexCAPSAir Force/Texas Coronary
Atherosclerosis Prevention Study. 
Libby PJ et al. J Am Coll Cardiol.
200546(7)1225-1228.
24
TG Level Remains a CVD Risk Factor Among
Statin-Treated Patients
n13,173
Slope0.018 P0.02
Placebo
Pravastatin
CVD Event Rate ()a
Slope0.029 Plt0.001
lt98
9926
127-158
159-207
gt207
TG Level (mg/dL)
aCoronary heart disease death, nonfatal
myocardial infarction, coronary artery bypass
grafting, percutaneous transluminal coronary
angioplasty
CARECholesterol and Recurrent Events
LIPIDLong-Term Intervention with Pravastatin in
Ischaemic Disease
Sacks FM et al. Circulation. 2000102(16)1893-190
0.
25
TGs and CHD Risk Meta-Analysis of 29 Studies in
Western Populations
Sarwar N et al. Circulation. 2007115(4)450-458.
26
Age-Adjusted Risk for CHD Events per 89 mg/dL
Increase in Fasting TG
All differences were statistically significant
Nordestgaard BG et al. JAMA. 2007298(3)299-308.
27
Fasting vs. Non-Fasting TG and CHD Risk
Fasting Non-fasting
lt91 lt105
91-147 105-170
gt147 gt170
28
TG/HDL Ratio and LDL Phenotype
Phenotype A Preponderance of large, buoyant
LDL-C
Phenotype B Preponderance of small, dense
LDL-C
?
TG/HDL-C ratio of 3.8 divided the distribution of
LDL phenotypes with 79 (95 CI 74 to 83) of
phenotype B greater than and 81 (95 CI 77 to
85) of phenotype A less than the ratio of 3.8.
Hanak et al. Am J Cardiol. 200494219222.
29
Non-HDL-Cholesterol

• Very low-density lipoprotein (VLDL)
• Made in the liver1
• TG-rich1
• Atherogenic2

• Intermediate-density lipoprotein (IDL)
• Formed from VLDL by TG lipolysis1
• Also known as a VLDL remnant particle1
• Atherogenic2

• Low-density lipoprotein (LDL)
• Formed from IDL due to further TG lipolysis1
• Taken up by the liver and other organs via the
  LDL receptor1
• Major atherogenic particle2
• sdLDL is a highly atherogenic form of LDL that
  may occur under high TG levels1

• High-density lipoprotein (HDL)
• Carries cholesterol away from artery wall (and
  other peripheral tissues) for metabolism or
  excretion1
• Other possible antiatherogenic effects include
  anti-inflammatory and antioxidant actions, and
  improvement in endothelial function1

Formed in the liver and cleared by LDL
receptor. Apoapolipoprotein sdLDLsmall, dense
low-density lipoprotein TGtriglyceride. 1.
Stone NJ, Blum CB. Management of Lipids in
Clinical Practice. 200524-27, 33, 34, 102. 2.
Garg R et al. Prev Cardiol. 20058173-177.
30
Ms. Jacobs

• Laboratory Exam

31
NonHDL-C and CVD Risk

• NonHDL-C calculation
• LDL-C VLDL-C
• TC HDL-C
• NonHDL-C goal
• Normal VLDL-C defined as value when
• TG lt150 mg/dL (30 mg/dL)
• NonHDL-C goal is 30 mg/dL above LDL-C goal

Bittner V. Curr Opin Lipidol. 200314(4)367-371.
Cui Y et al. Arch Intern Med. 2001161(11)1413-14
19. NCEP ATP III Final Report. Circulation.
2002106(25)3143-3421.
32
Significance of NonHDL-C

• Encompasses all known and potential atherogenic
  
• lipid particles
• Correlates closely with obesity, particularly
  visceral
• adiposity
• Has been shown to be a stronger predictor of CV
  risk
• than LDL-C
• Bittner-Prev Card 2005
• Cui, Blumenthal-Arch Int Med 2001
• Ridker JAMA 2005

33
Non-HDL-C Superior to LDL-C in Predicting CVD
Risk in Women
Womens Health Study 15,632 healthy women
followed 10 years for CVD endpoints
LDL-C Range (mg/dL)
lt97.7
97.7-115.4
115.5-132.1
132.2-153.9
gt153.9
lt123.2
123.2-144.9
145.0-165.5
165.6-191.0
gt191.0
Ridker PM, et al. JAMA. 2005294326-333.
34
Lipid Research Clinic Follow-Up Study
19-Year CVD Mortality
Men
Cui et al. Arch Int Med. 2001. 161(11)1413-9.
35
The NCEP Guidelines Identify TG as an Important
Parameter for Lipid Management

• Treatment Objectives for Elevated TGs
• Primary objective TG reduction
• Secondary objective LDL-C reduction and
  non-HDL-C reduction
• Primary objective LDL-C reduction
• Secondary objective non HDL-C reduction (VLDL
  and LDL)

TG 500 mg/dL
TG 200-499 mg/dL
Third Report of the National Cholesterol
Education Panel (NCEP) on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III) National Institutes
of Health. September 2002.
36
Management of HTG
aPrimary aim of therapy is to get to LDL-C
goal. bPrimary aim of therapy is to reduce risk
for pancreatitis through TG lowering first, then
focus on LDL-C. cTo achieve nonHDL-C goal (set
at 30 mg/dL higher than LDL-C goal), intensify
therapy with LDL-Clowering drug, or add
nicotinic acid or fibrate.
NCEP ATP III Final Report. Circulation.
2002106(25)3143-3421. Capell WH, Eckel RH. Curr
Diabetes Reports. 20066(3)230-240.
37
Essential Fatty Acid Families
?-3 family
?-6 family
C183 ?-3

• ?-Linolenic
• Flaxseed Oil
• Canola Oil
• Soybean Oil

C182 ?-6
Linoleic

• Corn Oil
• Safflower Oil
• Sunflower Oil

H3C
COOH
H3C
C205 ?-3
Eicosapentaenoic (EPA)
COOH
C204 ?-6
Arachidonic
H3C
COOH
C226 ?-3
Docosahexaenoic (DHA)
Less thrombotic and inflammatory metabolites
More thrombotic and inflammatory metabolites

• Oily Fish
• Fish Oil Capsules

38
Omega-3 Acid Ethyl Esters
Omega-3 fatty acid derived prescription
pharmaceutical product
DHA
90 Omega-3
EPA
39
Potential Triglyceride-Lowering Mechanisms of
Omega-3 FA
NEFA
Hormone-Sensitive Lipase
Glucose Uptake

Adipose TG
FA Uptake
Cell membrane
Acetyl-CoA carboxylase FA synthase

Acyl-CoA synthase
?-oxidation
Acyl-CoA
FA
Acetyl CoA
MitochondriaCPT-I, -II Acyl-CoAdehydrogenase
Lipogenesis


?-oxidation
DAG
TG
VLDL
DGAT

PA
Glycerol-3-P
Lyso PA
PAP



Apo B-100
Phospholipids
Peroxisome Acyl-CoA oxidase (rodents only?)

Degradation
Harris WS Curr Opin Lipidol 2006 17387-393.
40
Omega-3 Acid Ethyl Esters Lipid Effects in
Patients with TGgt500 mg/dL
Omega-3 (4 g/d) for 4 months(n42)
Placebo
Omega-3 acid ethyl esters
Change from Baseline ()
Plt0.00001
Plt0.001
Plt0.0001
P0.014
P0.0014
TG
TC
VLDL-C
HDL-C
LDL-C
Placebo-controlled studyTG gt500 mg/dL average
baseline TG 816 mg/dL LDL, 89 mg/dL
Harris WS et al. J Cardiovasc Risk.
19974(5/6)385-391.
41
Omega-3 Index A New CHD Risk Factor?
A measure of the amount of EPADHA in red blood
cell membranes expressed as the percent of total
fatty acids
There are 64 fatty acids in this model membrane,
3 of which are EPA or DHA 3/64 4.6 Omega-3
Index 4.6
Harris WS and von Schacky. Prev Med
200439212-220.
42
RBC Omega-3 Fatty Acids and Acute Coronary
Syndromes (768 case-control pairs)
Block RC, Harris WS et al. Atherosclerosis 2007
(in press)
43
Risk for Primary Cardiac Arrest and Red Blood
Cell EPADHA Level
90reductionin risk
plt0.05 vs Q1
Odds Ratio
Midrange RBC EPADHA by Quartile
Adapted from Siscovick DS et al. JAMA
19952741363-1367.
44
Relative Risk of Sudden Cardiac Death and Blood
Omega-3 Levels - Physicians' Health Study
90reductionin risk
p for trend 0.001
Relative Risk
3.9
5.1
6.0
7.3
Blood Omega-3 FA () by Quartile
Albert CM et al. N Engl J Med 20023461113-1118.
45
Summary

• Not all TG are created equal, think atherogenic
  particles, not just overall TG levels
• TG-associated CHD risk can be assessed by looking
  at the standard lipid profile
• Non-HDL-C should be lt 30LDL goal
• TG/HDL ratio should be lt 3.8
• Omega-3 acid ethyl esters at doses of 4 g/d are
  effective TG-lowering agents
• Increased RBC Omega-3 fatty acid levels are
  associated with reduced risk for CHD events,
  especially sudden cardiac death

46
Real World Answers to Managing Hypertriglyceridemi
a

• Richard Hays, MD
• October 3, 2007

47
Ms. Jacobs-Treatment Plan

• A nicotine patch, buproprion prescription, and
  smoking quit date (her upcoming birthday) will
  assist her in smoking cessation.
• She will rejoin Weight Watchers and see a
  nutritionist for more education on eating a
  heart-healthy diet.
• She agrees to limit her alcohol use to 1 drink on
  the weekends.
• She also commits to taking a brisk 30-minute walk
  in the evenings around her neighborhood most days
  of the week.

48
NCEP ATP III Triglyceridemia Treatment
Recommendations

• After achievement of LDL goal
• 150-199 mg/dL emphasize weight reduction and
  physical activity
• 200-499 mg/dL Non-HDL-C secondary target and
  pharmacologic tx for those with h/o MI or at high
  risk
• gt500 mg/dL prevention of pancreatitis with
  non-pharmacologic and pharmacologic therapy

NCEP ATP III. Circulation. 2002 1063143-3421.
49
Real World Answers to Managing Hypertriglyceridemi
a

• Lifestyle Modification
• Increase exercise
• Reduce alcohol intake
• Reduce weight
• Dietary Management
• Reduce simple carbohydrates
• Reduce caloric intake
• Pharmacological Management
• Statins
• Fibrates
• Niacin
• Omega-3

50
Therapeutic Lifestyle Changes in LDL-Lowering
Therapy Major Features

• Reduce
• Saturated fats lt7 of total calories
• Dietary cholesterol lt200 mg per day
• Add
• Plant stanols/sterols (2 g per day)
• fruit, vegetables, legumes, cereals
• Viscous (soluble) fiber (1025 g per day)
• oats, barley, soybeans, peas
• Improve
• Weight reduction
• Amount of physical activity

NCEP ATP III. Circulation. 2002 1063143-3421.
51
Are we Meeting our EPA DHA Needs?
AHA Recommended Intakes
Kris Etherton PM. AM J Clin Nut.
2000711795-1885 Kris - Etherton PM.
Circulation. 2002 1062747-2757
52
Did We Meet our EPA-DHA Needs with Tonight's
Dinner?
4 oz Salmon
53
Approximate Omega-3 Fatty Acid Contents (as EPA
DHA) of Selected Fish/Seafood


Kris-Etherton PM, Circulation 20021062747-2757
54
(No Transcript)
55
Approximate Omega-3 Fatty Acid Contents (as EPA
DHA) of Fish Oil Supplements
Kris-Etherton PM, Circulation 20021062747-2757
56
Benefits of Fish Oil

• Diet and Reinfarction Trial (DART)
• 2033 men with CHD, lt70 yo, non-diabetic
• Increased intake of fish 200-400 g twice a week
  or use of 2-3 fish oil caps/day
• Reduced CHD mortality 29 over 2 years

57
Fish Tale or Fact?

• Tale
• Fish Odor, Dyspepsia
• Vitamin A D Toxicity
• Increased Bleeding Time
• Mercury Toxicity

• Fact
• Take at Bedtime
• Only with Cod Liver Oil
• Theoretical, not Clinically Relevant
• Not with Commercial Supplements

58
Ms. Jacobs-3 Months Later

• Ms. Jacobs happily reports that she has lost 10
  pounds, and she is walking 30 minutes most days
  of the week. She is still smoking, but she has
  cut back to 1 pack a week.
• Her blood pressure is 134/78 mmHg.
• Dr. Wright applauds Ms. Jacobs for her weight
  loss and exercise efforts and encourages her to
  continue, but he recommends that she initiate
  drug therapy to get her lipids under better
  control and to reduce her cardiovascular risk.

59
Pharmacological Options
60
Statin Mechanism of Action and Clinical Rationale

• Competitive inhibitors of HMG CoA reductase,
  rate-limiting step in cholesterol biosynthesis
• Reduction in TG due to decreased VLDL synthesis
  and clearance of VLDL remnants by apo B/E (LDL)
  receptors
• Reduction in oxidized and small dense LDL
  subfractions and reduce remnant lipoprotein
  cholesterol levels (reduction of CE transfer from
  LDL to VLDL)

61
Statin Side Effects

• Generally tolerable and safe
• Myopathy
• Myalgias (2-11), myositis(0.5), rhabdomyolysis
  (lt0.1)
• Few weeks-4 months onset
• Hepatic
• 0.5 to 3 persistent elevations in LFTs in first
  3 months and dose-dependent
• Several randomized trials have found no
  difference compared with placebo

62
Evolving Treatment Paradigm

• Statin monotherapy reduces risk, but significant
  residual risk remains
• Future of therapy is aggressive management of
• LDL-C, Non-HDL-C, TG, and HDL-C
• Combination therapy increasingly important
• Addresses multiple risk contributors
• Effective through multiple mechanisms

63
Fibrates Mechanism of Action and Clinical
Rationale

• Fibrates activate the nuclear transcription
  factor peroxisome proliferator-activated
  receptor-alpha (PPARa) and
• Upregulate genes for apolipoprotein A-I, fatty
  acid transport protein, fatty acid oxidation, and
  possibly lipoprotein lipase
• Downregulate the apolipoprotein C-III gene
• Reduce VLDL-C TG formation
• Serum TG lowering and increased synthesis of
  apolipoproteins raise HDL-C
• Extra-atherogenic, small, dense LDL-C converted
  to normal-sized LDL-C

National Cholesterol Education Program.
Circulation. 20021063143-3421.
64
VA-HIT Effect of Gemfibrozil
Placebo
Placebo
Plt0.001
Gemfibrozil
Plt0.001
Gemfibrozil
Change From Baseline
22 RR reduction(95 CI, 735)P0.006
6.3
3.8
5
0.9

0.9
0.0
25
-5
20
NS
15
-15
10
-25
5
-28.6
-35
0
Primary Endpoint Occurrencea
LDL-C
TG
HDL-C
65
Fibrates Side Effects

• Fibrates are generally well tolerated1
• GI side effects are the most common complaints
• Adverse drug interaction
• Gemfibrozil- inhibits glucuronidation of
  lipophilic statins and increases levels thus
  increased risk of myopathy.

Backes JM, Pharmacotherapy 200727412-424
66
Number of Cases of Rhabdomyolysis with
Combination Fibrate Plus Statin
Cases Reported per Million Prescriptions
15-Fold Increase
Excludes cases involving cerivastatin. Jones PH
et al. Am J Cardiol. 200595120-122.
67
Ms. Jacobs - 3 months Later

• Ms. Jacobs reports that she is tolerating the
  gemfibrozil well. Her liver function tests are
  within the normal range.
• Although her TG level has improved, Dr. Wright
  recommends adding another agent to optimize her
  levels.

68
Niacin Mechanism of Action and Clinical Rationale

• Niacin appears to modify lipids by
• Inhibiting mobilization of free fatty acids and
  lipoprotein synthesis
• Decreasing HDL-C catabolism and VLDL-C
  production
• Shifting LDL-C from small, denser LDL-C particles
  to larger, more buoyant LDL-C particles

Adapted from National Cholesterol Education
Program. Circulation. 20021063143-3421.
69
HATS Patients Free of Events
Simvastatin-niacin
100
97
90
Patients Free of Events ()
All placebos
80
76
RR 0.10 P 0.03
70
0
2
3
0
1
Years
HATS HDL-Atherosclerosis Treatment
Study. Adapted from Brown BG et al. N Engl J Med.
20013451583-1592.
70
Niacin Side Effects

• Flushing (less common with controlled release)
• Nausea, paresthesias, pruritis
• Elevation of hepatocellular enzymes and possible
  hepatotoxicity, jaundice and fulminant hepatitis
• Insulin resistance and worsening hyperglycemia
• Hyperuricemia
• Hypotension in combination with other
  vasodilators
• (can increase unstable angina)

71
Using Niacin

• Tolerability can be enhanced by
• Initiating therapy with small doses taken with
  meals and slowly titrating upward
• Taking aspirin or other NSAID prior to the
  morning dose
• Avoiding taking niacin with alcohol, spicy foods,
  or hot beverages
• Avoiding interruptions in niacin therapy
• Using newer formulation/extended-release niacin
  instead of immediate-release niacin
• Educating patients about the possibility of side
  effects

McKenney J. Arch Intern Med. 2004164697-705.
72
Prescription Omega-3 (P-OM3) Fatty Acids
Mechanism of Action and Clinical Rationale

• Reduce hepatic secretion and increase plasma
  clearance of TG-rich lipoproteins at indicated
  doses (4 g/day)1
• Available as 1 g capsules daily dose is 4 g per
  day2

1. National Cholesterol Education Program.
Circulation. 20021063143-3421. 2. Davidson MH
et al. Clin Therapeutics. 200729(7)1354-1367.
73
COMBOS P-OM3 and Simvastatin in Patients With
High TGsa on Simvastatin
Omega-3 4 g/d simvastatin 40 mg qd
Placebo simvastatin 40 mg qd
TG
VLDL-C
LDL-C
HDL-C
NonHDL-C
3.4
0.7
-1.2
-2.2
-2.8
-6.3
-7.2
-9.0
Change from Baseline
Plt0.05 vs placebo for all
-27.5
-29.5
74
P-OM3 Non-lipid Effects GISSI-Prevenzione Trial

• Secondary Prevention RCT factorial design
• 11,324 patients assigned to one of four groups
• 1. 1 g P-OM3 3. Both P-OM3
  Vitamin E
• 2. 300 mg Vitamin E 4. Double placebo
• 3.5 years follow-up
• All patients on standard post MI therapy

GISSI-Prevenzione Investigators. Lancet
1999354447-55
75
GISSI-Prevenzione Time Course of Clinical Events
Total mortality reduced by 28 (p0.027)
n-3 PUFA Control
Probability
0.59 (0.360.97)p0.037
0.72 (0.540.96)p0.027
Days
Sudden deathreduced by 47 (p0.0136)
n-3 PUFA Control
Probability
0.47 (0.220.99)p0.048
0.53 (0.320.88)p0.0136
Days
Marchioli R et al. Circulation 20021051897-1903.
76
Using Omega-3 Fatty Acids

• Prescription omega-3 fatty acids are indicated
  for use as an adjunct to diet for reducing very
  high levels of TG (500 mg/dL) in adult patients
• AHA recommends patients taking gt3 g of omega-3
  fatty acids and should do so under a physicians
  care

Pejic RN, et al. J Am Board Fam Med.
200619310-316. Kris-Etherton PM, et al.
Arterioscler Thromb Vasc Biol. 200323151-152.
77
Summary

• Consider combination therapy
• Combination therapy may further reduce CHD risk
• Patients accept therapy with P-OM3 as a natural
  remedy