Management of Diabetic Dyslipidemia: Recent Advances in Combination Therapy

1
Management of Diabetic Dyslipidemia Recent
Advances in Combination Therapy
Eliot A. Brinton, M.D. Director, Metabolism
Section Cardiovascular Genetics Associate
Professor University of Utah School of
Medicine eliot.brinton_at_utah.edu
2
Prevalence of Vascular Disease Risk Factors Among
Adults Aged gt20 Years
Overlap of Diabetes and Hypertension 70 of
Diabetes 22 of Hypertension
Dyslipidemia (35.6)
Hypertension (27.6)
None (53.2)
Diabetes Mellitus (8.7)
NHANES III The Third National Health and
Nutrition Examination Survey. Estimates based
on application of age- and sex-specific
prevalence estimates for each condition from the
NHANES III data to the Kaiser Permanente
membership to simulate full ascertainment. Selby
JV et al. Am J Manag Care. 200410163170.
3
Mechanisms of Dyslipidemia in the Metabolic
Syndrome
FFA free fatty acids TG triglycerides LPL
lipoprotein lipase HDL high density
lipoprotein CETP cholesterol ester transfer
protein CE cholesterol ester VLDL very low
density lipoprotein

• Proteolysis of Apo B-100

• ? Clearance LPL, APO CIII

Kolovo GD. Postgrad Med J. 200581358-366.
4
The Atherogenic Dyslipidemia of DM-2 (Insulin
Resistance and HTG)
Fat Cells
Liver
?CE on TGRL
?FFA
?HDL
CE
?VLDL
HDL
(CETP)
? TG ? Apo B ? VLDL
Hepatic lipase (removes PLTG)
TG
X
IR
(CETP)
Lipid-poor Apo A-1
TG
CE
Kidney
LDL
SDLDL
Insulin
Hepatic lipase or lipoprotein lipase (remove
PLTG)
?SD LDL
CETPcholesterol ester transfer protein.
Ginsberg HN. J Clin Invest. 2000106(4)453-457.
5
Atherogenic Dyslipidemia (Dyslipidemia of
Diabetes Mellitus/ Insulin Resistance)

• Hypertriglyceridemia (HTG)
• Low HDL-C
• Small, dense LDL
• (Increased VLDL-C)
• (NonHDL-C)

6
Increased Insulin Concentration Is Associated
With an Increase in CHD Mortality
Number of CHD Deaths Out of Total Population (N
970)
?237 238-337 338-437 438-669 gt669
AUC Fasting Plasma Insulin Quintiles, pmol/L/h
Insulin Sensitive Insulin Resistant
Pyörälä M, et al. Diabetes Care.
2000231097-1102.
7
Elevated Triglycerides Increase the Risk of CHD
at All Levels of LDL-C
Incidence of CHD Events According to Serum LDL-C
and TG Concentrationa
Baseline TG lt200 mg/dL
Baseline TG 200 mg/dL
aLipids from 4849 middle-aged men who were
followed up for 8 years to record incidence of
CHD study demonstrated that fasting levels of
TGs were an independent risk factor for CHD
events, irrespective of serum levels of LDL-C
Assmann G, et al. Eur Heart J. 199819(suppl
M)M8-M14.
8
CHD Risk Prediction byHDL-C vs. LDL-C
Patient 2 LDL-C 100 mg/dL HDL-C 25 mg/dL
Patient 1 LDL-C 220 mg/dL HDL-C 45 mg/dL
RR of CHDAfter 4 yr
HDL-C (mg/dL)
LDL-C (mg/dL)
Data in men age 5070 yr from the Framingham
Study.
Adapted from and reprinted with permission from
Castelli WP. Can J Cardiol. 19884(suppl A)5A.
9
Elevated Triglycerides Increase the Risk of CHD
at All Levels of HDL-C
Triglycerides, HDL-C Levels, and Associated Risk
for Premature Coronary Artery Diseasea
aLipids analyzed from 653 patients with premature
familial CHD and 1029 control subjects
Hopkins PN, et al. J Am Coll Cardiol.
2005451003-1012.
10
NCEP Guidelines Identify TG and NonHDL-C as
Important Parameters for Lipid Management
Treatment Objectives for Elevated Triglycerides

• Primary Objective TG reduction
• Secondary ObjectiveLDL-C and nonHDL-C reduction

Very High TG 500

• Primary Objective LDL-C goal
• Secondary Objective nonHDL-Creduction (VLDL-Ca
  and LDL-C)

High TG 200-499
aVLDL-C levels are influenced by triglyceride
levels Prescription Omega-3 is indicated for the
reduction of very high triglycerides, in addition
to diet, in adult patients with triglycerides
500 mg/dL
HDL-C high-density lipoprotein cholesterol
LDL-C low density lipoprotein cholesterol
NCEP National Cholesterol Education Program
TG triglyceride VLDL-C very low-density
lipoprotein cholesterol
Third Report of the NCEP Expert Panel on
Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (ATP III).
Circulation. 20021063143-3421.
11
Non-HDL Includes All Atherogenic Lipoprotein
Classes

• Very low-density lipoprotein
• Made in the liver
• TG gtgt CE
• Carries lipids from the liver to peripheral
  tissues

VLDL

• Intermediate-density lipoprotein
• Formed from VLDL due to loss of TG
• Also known as a VLDL remnant

IDL

• Low-density lipoprotein
• Formed from IDL due to loss of TG
• CEgtgtTG

LDL

• Lipoprotein (a)
• Formed from LDL w/ addition of apo (a)?
• Very atherogenic

Lp(a)

• High-density lipoprotein
• Removes cholesterol from peripheral tissues

HDL
12
NonHDL-C Is Superior to LDL-C in Predicting CHD
Risk
The Framingham Study

• 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.
13
NonHDL-C A Neglected CVD Risk Factor/Rx Goal

• Whenever TG gt 200 mg/dL
• NonHDL-C Total C HDL-C (all atherogenic
  lipids)
• NonHDL-C goal LDL-C goal 30

• LDL-C Goal
  NonHDL-C Goal
• Patient Category (mg/dL)
  (mg/dL)
• No CHD, 0-1 risk factors lt160
  lt190
• No CHD, 2 risk factors lt130
  lt160
• CHD/CHD risk equivalent lt100 lt130
  
• CVD DM/MS/smoker/ACS lt70
  lt100

• Rx to lower NonHDL-C
• TG gt500 fibrate, omega-3, nicotinic acid,
  statin, ezetimibe?
• TG 200-500 statin, ezetimibe, fibrate, omega-3,
  nicotinic acid,
• bile acid sequestrants

ACS acute coronary syndrome MS metabolic
syndrome HTG hypertriglyceridemia
Adapted from Expert Panel on Detection,
Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 20012852486-2497.
Grundy SM et al. Circulation. 2004110227-239.
14
Why Treat to NonHDL-C Goals?
Two patient cases with same total cholesterol.
Without calculating nonHDL-C, Case 2 might not
get treated and therefore may be at risk since
nonHDL-C goal should not exceed 30 mg/dL above
LDL-C
225
Case 1
Case 2
TC 209 mg/dL
200
VLDL
VLDL
150
NonHDL Cholesterol 177 mg/dL
Cholesterol (mg/dL)
LDL
100
LDL
50
HDL
HDL
TG 120 mg/dL 400 mg/dL VLDL-C 24 mg/dL 88
mg/dL LDL-C 145 mg/dL 89 mg/dL HDL-C 40
mg/dL 32 mg/dL NonHDL-C 169 mg/dL 177
mg/dL TG/HDL-C ratio 3.0
12.5 TC 209 mg/dL 209 mg/dL
NonHDL-C goal LDL-C goal 30
HDL-C high-density lipoprotein cholesterol
LDL-C low-density lipoprotein cholesterol TC
total cholesterol TG triglyceride VLDL
very low-density lipoprotein
15
LDL-C vs. Non-HDL-C

• Favoring LDL-C
• Focus of most research
• Focus of current guidelines
• Always reported in lipid profile

• Favoring Non-HDL-C
• Conceptually better (all pro-athero lipos)
• Stronger CVD factor
• Valid in HTG
• Valid non-fasting
• Always measured in lipid profile

Bottom line Non-HDL-C is much better (no unique
advantages of LDL-C) but we are stuck with LDL-C
for now!
16
Relative Risk Ratios of Fatal MI by Quartiles of
Apo B and Apo A-I AMORIS
Men lt70 years
Women lt70 years
Risk Ratio
Risk Ratio
180
172
139
129
110
106
90
Apo B, mg/dL
80
Apo B, mg/dL
Apo A-I, mg/dL
Apo A-I, mg/dL
Walldius G, et al. Lancet. 20013582026-2033.
17
Non-HDL-C vs. Apo B

• Favoring Non-HDL-C
• Cholesterol content conceptually better
• Free with lipid profile (no extra testing needed)
• Well standardized
• Already incorporated in guidelines

• Favoring Apo B
• Apo B may play causal athero role
• Stronger CVD factor?
• Complementary to non-HDL-C?

Bottom line Apo B slightly better but harder.
Non-HDL-C good enough, but adding apo B may be
useful
18
ADA/ACC 2008 Consensus StatementTreatment Goals
in Patients With Cardiometabolic Risk and
Lipoprotein Abnormalities
In individuals on statin therapy who continue to
have low HDL-C or elevated nonHDL-C, especially
if Apo B levels remain elevated, combination
therapy is recommended. The preferred agent to
use in combination with a statin is nicotinic
acid
aMajor risk factors beyond dyslipidemia include
smoking, hypertension, and family history of
premature CHD
Brunzell JD, et al. Diabetes Care.
200831811-822.
19
LDL-C Doubly Underestimates CVD Risk in Cases of
Small, Dense LDL
Large LDL
Small, Dense LDL
LDL-C 130 mg/dL
Apo B
More Apo B
Cholesterol Ester
Fewer Particles Less Risk/Particle
More Particles More Risk/Particle
Lipid profile TC 210 mg/dL LDL-C 130
mg/dL TG 250 mg/dL HDL-C 30
mg/dL NonHDL-C 180 mg/dL
Lipid profile TC 198 mg/dL LDL-C 130
mg/dL TG 90 mg/dL HDL-C 50 mg/dL NonHDL-C 14
8 mg/dL
Otvos JD, et al. Am J Cardiol. 20029022i-29i.
20
Small, Dense LDL May Predict CAD Better than
LDL-C, Apo B, and TG
6.5plt0.001(N50)
5.9plt0.001(N58)
5.6plt0.001(N65)
4.0plt0.001(N35)
3.9plt0.001(N27)
Relative Risk of CAD
Small, dense LDL (lt255 Å)
3.3plt0.001(N20)
6.5p0.13(N15)
2.0p0.12(N14)
1.9p0.15(N11)
?39.6
1.0(N35)
1.0(N9)
1.0(N12)
lt39.6
lt147
gt147
lt116
gt116
lt142
gt142
LDL-C (mg/dL)
Apolipoprotein B (mg/dL)
Triglycerides(mg/dL)
CAD, coronary artery disease LDL, low-density
lipoprotein LDL-C, low-density lipoprotein
cholesterol.
St-Pierre AC, et al. Circulation.
20011042295-2299.
21
Low-Density Lipoprotein (LDL) Consists of
Multiple Distinct Subclasses Differing in Size
and Lipid Content
Association with Cardiovascular Disease Risk
1
Large
Less Atherogenic
2

• ? clearance by LDL-R
• ? arterial entry
• ? arterial retention
• ? oxidation

3
Small
More Atherogenic
4
Distribution of subclasses is independent of
LDL-C.
Berneis KK, Krauss RM. J Lipid Res.
2002431363-1379.
22
SAFARI Increased LDL Particle Size With
Combination Therapy
100
B (Small, Dense)
AB (Intermediate)
80
A (Larger, Buoyant)
60
Proportion of Total LDL-C,
Increased Particle Size
40
20
0
Week 12
Week 12
Baseline
Baseline
Simvastatin
Simvastatin Fenofibrate
N 618
Significantly different pattern between the 2
treatment groups (Plt.001)
Grundy SM, et al. Am J Cardiol. 200595462-468.
23
Effects of P-OM3 With Simvastatin on LDL
Particle Size
P-OM3 4 g/d simvastatin 40 mg/d
0.70
0.60
0.60
0.50
0.40
0.40
Plt.001
Median change in particle size from baseline (nm)
0.30
0.20
0.15
0.10
0.20
0
0.10
0.20
200-249 mg/dL
150-199 mg/dL
lt150 mg/dL
250 mg/dL
End-of-treatment TG
P value derived by analysis of variance with
end-of-treatment TG category as a factor. Maki
KC et al. FASEB J. 200721231.2.
24
Screen/Treat in All Patients With
Hypertriglyceridemia

• Diseases/States
• Diabetes
• Obesity/insulin resistance
• Sedentary lifestyle
• Hypercortisolism
• Arthritis/inflammation
• Hypothyroidism
• Nephrotic syndrome (macroproteinuria)
• Chronic kidney disease
• HIV
• Psychiatric disorders

• Drugs
• EtOH
• Marijuana
• Glucocorticoids (except nasal or topical)
• Oral estrogen (BCP ERT)
• Retinoic acid derivatives
• Thiazide diuretics (minor)
• Beta-blockers (minor)
• Bile-acid sequestrants (minor)
• Cyclosporine
• HAART (for HIV)
• Anti-psych meds

25
Statin Therapy Reduces CVD Events in DM
Approximately to Un-Rxd Risk in Non-Diabetics
CTT Meta-Analysis of 14 Statin Trialsa
Control
CVD Risk Higher Than Patients With No Diabetes
on Placebo
Treatmentc
Major Vascular Event Rateb,
Diabetes
No Diabetes
a4.3-year mean follow-up of 18 686 patients with
diabetes n 71 370 patients with no
diabetes bNonfatal MI, CHD death, stroke, or
coronary revascularization cEvent rate per 1
mmol/L (39 mg/dL) reduction in LDL-C
CTT Collaborators. Lancet. 2008371117-125.
26
Adults With Diabetes Achieving Vascular Disease
Risk Factor Goals
NHANES III 19881994 (n1204)
60
NHANES 19992000 (n370)
48.2
50
44.3
37.0
40
35.8
33.9
29.0
30
Adults,
20
7.3
10
5.2
0
A1C Levellt7
Blood Pressure lt130/80 mmHg
Total Cholesterol lt200 mg/dL
Achieved All 3 Treatment Goals
Vascular Disease Risk Factors
Saydah SH et al. JAMA. 2004291335342.
27
Residual CVD Risk With Monotherapy Versus
Combination Therapy
Patients ExperiencingMajor CHD Events,
LIPID2
4S1
HPS3
VA-HIT6
CDP7
FATS8
HATS9
TNT5
WOS4
N
4444
20 536
9014
6605
10 001
2531
146
160
6595
5LaRosa JC, et al. N Engl J Med.
20053521425-1435. 6Rubins HB, et al. N Engl J
Med. 1999341410-418. 7CDP Research Group.
JAMA. 1975231360-381. 8Brown BG, et al. N Engl
J Med. 19903231289-1298. 9Brown BG, et al. N
Engl J Med. 20013451583-1592.
14S Group. Lancet. 19943441383-1389. 2LIPID
Study Group. N Engl J Med. 19983391349-1357.
3HPS Collaborative Group. Lancet.
20023607-22. 4Shepherd J, et al. N Engl J Med.
19953331301-1307.
28
Patients With CHD Risk Equivalentsa and Low HDL-C
or High TG Taking Niacin or Fibrates
Niacin
Fibrates
Niacin Fibrates
Patients,
Low HDL-C n 577
Elevated TGb n 158
a96 had diabetes bTG 200 mg/dL
Alsheikh-Ali AA, et al. Am J Cardiol.
2006981231-1233.
29
Helsinki Heart StudyIncidence of CHD Events
20
Gemfibrozil Placebo
15
Incidence of cardiac events (per 1,000
person-years)
10
5
0
mg/dL
TG ?200 TG ?200
TG ?200 TG ?200
HDL-C ?42
HDL-C ?42
Fibrates reduce CVD best in HTG/low HDL-C patients
Manninen V et al. Circulation. 1992853745
30
VA-HIT Results Gemfibrozil in 2o Prevention
HDL-C
LDL-C
TG
Relative risk reduction ()
Change From Baseline ()
Total death (NS)
CHD death (NS)
Nonfatal MI or CHD death (P.006)
Stroke (NS)
VA-HIT The Veterans Affairs High-Density
Lipoprotein Cholesterol Intervention Trial NS
nonsignificant. Rubins HB, et al. N Engl J Med.
1999341410-418.
31
VA-HIT Gemfibrozil Prevents CVD With Average to
Elevated Insulin Levels
Baseline Fasting Insulin Quartile ----1----
----2---- ----3---- ----4----
15 10 5 0 -5 -10 -15 -20 -25 -30 -35 -40
23 n 434
24-29
30-38
?39
Favors Gemfibrozil Favors Placebo
CVD Risk Reduction,
n 431
n 426
n 442
Fibrates reduce CVD best in Insulin Resistance
P.04 Versus Placebo
Rubins HB, et al. Arch Intern Med.
20021622597-2604.
32
VA-HIT CVD Risk Reduction with or w/o Diabetes
Combined End Point
Nonfatal MI
CHD Death
Stroke
0
3
5
P0.88
10
10
P0.67
DM
18
15
No DM
21
20
22
P0.07
Cumulative Event Rate Change ()
P0.17
25
P0.09
32
30
P0.004
35
40
41
40
P0.26
P0.046
P0.02
45
Rubins HB et al. Arch Intern Med.
20021622597-2604
33
DAIS Combined Clinical End Points With
Fenofibrate
Placebo
25
-23
Fenofibrate
20
15
Event Rate ()
10
Preliminary
5
50
38
0
DAIS Diabetes Atherosclerosis Intervention
Study Number of participants with at least one
clinical or interventional end point, including
death, stroke, MI, CABG, PTCA and hospitalization
for angina DAIS was not powered to examine
clinical events. Even though the results suggest
a trend, they were not statistically
significant. Diabetes Atherosclerosis
Intervention Study Investigators. Lancet.
2001357905-910.
34
FIELD Primary and Secondary End Points
11 Reduction P.035
Placebo
Fenofibrate
21 Reduction P.003
11 Reduction P.16
24 Reduction P.01
19 Increase P.22
CHD Events (Primary EP)
Nonfatal MI
Total CVD Events (Secondary EP)
Coronary Revascularization
CHD Death
Nonfatal MI and CHD death CHD events, stroke,
CVD death, revascularizations.
Keech A, et al. Lancet. 20053661849-1861.
35
FIELD Fenofibrate Reduces the Risk for Vascular
Complications of Diabetes
Macrovascular
Microvascular
CVD
Angina
Risk Reduction,
Nonfatal MI
Albuminuria
Amputations
Coronary Revasc.
Retinal Laser Therapy
Effective Add-on to Statin for Patients With
Diabetes?
P.01
P.035
P.003
P.011
P.0003
P.002
P.04
Keech A, et al. Lancet. 2005366(9500)1849-1861.
Keech A. Atherosclerosis Supplements.
20067342. Abstract.
36
Fibrates and Renal Function

• Modest ? in serum creatinine frequently seen with
  fibrate use
• No evident ? in GFR
• Mechanism unknown (? muscle production vs ? renal
  secretion vs ?)
• Clinical meaning unknown

37
Statin/Fibrate Combination Therapy
Pharmacokinetic Interactions

• Gemfibrozil Fenofibrate
• Atorvastatin Not available No effect
• Simvastatin ? in Cmax by 2-fold No effect
• Pravastatin ? in Cmax by 2-fold No effect
• Rosuvastatin ? in Cmax by 2-fold No effect
• Fluvastatin No effect No effect
• Lovastatin ? in Cmax by 2.8-fold No effect
• Cerivastatin ? in Cmax by 2-3fold No effect

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.
TriCor package insert. 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.
38
Rhabdomyolysis Rate in Statins Combo
Gemfibrozil gtgt Fenofibrate
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.
39
Synthesis of Eicosanoids FromOmega-6 and Omega-3
Fatty Acids
Omega-3 from flaxseed
Omega-6 Linoleic Acid
Omega-3 ?-Linolenic Acid
lt5 Conversion
Arachidonic acid
Eicosapentaenoic acid
Cyclo-oxygenase
Lipoxygenase
Anti-inflammatory - Antithrombotic
Proinflammatory - Pro-thrombotic
Din JN et al. BMJ. 200432830-35.
40
Prescription Omega-3, Highly Concentrated EPA
and DHA
1-gram capsule
Ethyl Esters
Docosahexaenoic acid (DHA)
Eicosapentaenoic acid (EPA)
3.36 g EPA/DHA in only 4 capsules
1. LOVAZA package insert. Liberty Corner, NJ
Reliant Pharmaceuticals, Inc. 2007. 2. Data on
file. Reliant Pharmaceuticals, Inc., Liberty
Corner, NJ.
41
Dose Range of P-OM3 Required to Reduce TG
Dose of P-OM3
Change TG (mg/dL) ()

• TG 177-442 mg/dL at baseline (after 8-week
  run-in) 8-week treatment
• Source Pronova, data on file

Bottom line use full-dose POm3 (4g/d)
42
TG Lowering Depends on Baseline TG (all with
POm3 4g/d)
Am J Cardiol. 1996 1 31-36 J Intern Med. 1995
237 249-259 J Cardiovasc Risk. 1997 4 385-391
43
POm3, A More Practical Source of EPA and DHA
Than Dietary Supplements
--Rx-- -------Dietary Supplements-------

• Benefits of higher-concentration omega-3 product
• Likely Improved Compliance
• 12 capsules fish oil 72 extra fat calories/day
  (non omega 3) 7 kg weight gain/year!

Pronova AB and product brand labels
44
Why Dietary Supplement Fish Oil is Not
Appropriate for Treating a Disease (HTG)
Structure, function and qualifying health
claims only.

• http//www.fda.gov/cder/drugsatfda/glossary.htmpr
  escription_drug
• http//www.cfsan.fda.gov/dms/cos-218.html
• http//vm.cfsan.fda.gov/dms/ds-oview.html

45
Addition of Eicosapentaenoic Acid (EPA) to Statin
Therapy in Japanese Patients
JELIS Results
Major CHD Eventsa
Lipid Effects
19 Reduction P.011
Change From Baseline,
Event Rate,
Plt.001
HDL-C
LDL-C
TG
4.6-year mean follow-up aSudden cardiac death,
fatal and nonfatal MI, unstable angina
pectoris, angioplasty, stenting, or CABG
Yokoyama M, et al. Lancet. 20073691090-1098.
46
Lipid Efficacy POm3 vs. Fenofibrate
Rx EPADHA (Omega-3 Acid Ethyl Esters)
Fenofibrate
TGa
HDL-C
CHOL
VLDL-C
LDL-C
TGa
HDL-C
CHOL
VLDL-C
LDL-C
50
50
30
30
10
10
Change From Placebo,
Change From Placebo,
-10
-10
-30
-30
-50
-50
N 92 All Plt0.003
N 84 All Plt0.006
-70
-70
Harris WS, et al. J Cardiovasc Risk.
19974385-391. Pownall HJ, et al.
Atherosclerosis. 1999143285-297. Goldberg AC,
et al. Clin Ther. 19891169-73.
aBaseline TG500 mg/dL
47
Non-Lipid Atherosclerosis and Cardiac Effects of
Omega-3 Fatty Acids

• ?Malignant ventricular arrhythmias (via cardiac
  membrane enrichment)
• ?ICD triggering (malignant ventr. arrhythmias)
• ?Heart rate and ?Heart rate variability (via
  ?parasympathetic tone, altered cytokine levels?)
• Antithrombotic effects
• (?platelet reactivity, ?AA)
• ?Plasma viscosity
• ?Endothelial relaxation
• (via ?NO ?NO independent mech.)
• ?Blood pressure

• Anti-inflammatory effects
• ?Inflammatory cytokines (interleukins, TNF)
• ?Mitogens
• ?Cell-adhesion molecule expression
• Altered eicosanoid synthesis (?AA)
• ?PON (antioxidant on HDL)
• Anti-proliferative effect/?smooth-muscle cell
  proliferation
• Possible ?CHF
• ?Sudden death
• ?Total and CVD mortality

Only known adverse CV effect of POm3 After
Holub BJ. CMAJ. 2002166(5)608-615.
48
Atheroprotective Mechanismsof Fibrates
Fibrate (PPARa agonist)
?TGRLp ?Plasma TG
?LDL Particle Size
?HDL Synthesis
?Inflammation
?Reverse Cholesterol Transport
Stone NJ, Blum CB. Management of Lipids in
Clinical Practice. 5th ed. 2004. Barbier O, et
al. Arterioscler Thromb Vasc Biol.
200222717-726.
49
Fibrates Versus Omega-3 to Rx HTG and for
Atheroprevention

• Favoring Fibrates
• More conventional
• Often better ?HDL-C
• Often better ?LDL-C
• Other PPAR-a benefits?
• More convenient (fewer capsules)
• Better formulary coverage
• No fishy burping
• No ?glucose
• No ?ALT

• Favoring Omega-3
• More natural
• ?CVD and total mortality
• Greater range of mechanisms
• antiplatelet
• anti-inflammatory
• anti-arrhythmic, etc.
• No transaminase contraindic.
• No statin precaution/warning
• No nausea and vomiting
• No ?creatinine
• No warfarin interaction
• No DVT or PE

• Bottom line
• Both are good as first-line mono Rx
• Both often needed in combination!

50
Suggested Anti-Atherogenic Mechanisms of HDL

• Promotes reverse cholesterol transport
• Facilitates TG metabolism
• Antioxidant
• May be oxidized in place of apo B particles
• May reverse oxidation of apo B particles
• Pro-endothelial
• ?NO production
• ?Endothelial progenitor cells
• Anti-coagulant
• Anti-platelet
• Pro-fibrinolytic

• Prostacyclin stabilization/ ?production
• Anti-inflammatory
• ?Cell-adhesion molecules
• Scavenges acute-phase reactants
• ?Neutrophil degranulation
• Anti-complement?
• Anti-T-cell effect?
• Anti-apoptotic (prevents death of MF, EC, SMC)
• Blocks other adverse effects of apo B particles?

Griffin J, et al. J Clin Invest.
1999103219-227. Blackburn W, et al. J Lipid
Res. 1991321911-1918. Fleisher L, et al. J
Biol Chem. 19822576653-6655. Brewer H. Am J
Cardiol. 1999833F-12F.
Phillips M, et al. Atherosclerosis
1998137(suppl)13S-17S. Avarim M, et al.
Circulation. 20001012252-2257. Cockerill G, et
al. Arterioscler Thromb Vasc Biol.
1995151987-1994. Li X, et al. Int J Cardiol.
200073231-236.
51
Agents That Raise HDL-C

• Agent HDL-C ? Primary Use
• Nicotinic acid 15-35 ? HDL
• Fibrates 5-20 ? TG
• Statins 5-15 ? LDL
• Rx omega-3a 5-10 ? TG
• Bile-acid resinsa 2-5 ? LDL
• Ezetimibea 1-3 ? LDL
• Pioglitazonea 5-20 ? Glucose
• Estrogensa 10-25 ? Hot flashes
• ?-blockersa 10-20 ? BPH
• Alcohol 5-10 Social

aWithout FDA-approved indication for HDL-raising
After Belalcazar LM, et al. Prog Cardiovasc Dis.
199841151-174. Insull W, et al. Mayo Clin
Proc. 200176971-982. McKenney JM, et al.
Pharmacotherapy. 200727715-728.
52
Coronary Drug Project Decreased Macrovascular
Outcomesa w/ Niacin MonoRx
15 Reduction Plt.05
Placebo (n 2789)
Niacin (n 1119)
26 Reduction Plt.05
24 Reduction Plt.05
Event Rate,
47 Reduction Plt.05
CHD Death/ Nonfatal MI
Nonfatal MI
Stroke/TIA
CV Surgeryb
aTotal follow-up experience (mean, 6.2
yrs) b5-year incidence TIA, transient ischemic
attack
CDP Research Group. JAMA. 1975231360-381.
53
Effect of Niacin ER on Lipids and Glycemic
Control in Patients With Diabetes Mellitus
ADVENT Trial
aMedian values
Grundy S, et al. Arch Int Med. 20021621568-76.
54
CDP Reduction in Recurrence of MIa by Baseline
Fasting Plasma Glucose
Placebo (n 2787)
Niacin 3000 mg (n 1119)
Interactive P-value NS
57 Reduction
30 Reduction
25 Reduction
24 Reduction
Nonfatal MI Event Rate,
lt95
95-104
105-125
126b
Baseline Fasting Plasma Glucose, mg/dL
a6-year follow-up bADA definition of diabetes
Canner PL, et al. Am J Cardiol. 200595254-257.
55
CDP Reduction in Recurrence of MI By Change in
Fasting Plasma Glucose At 1 Year
Placebo
Niacin
Interactive P-value NS
45 Reduction
32 Reduction
38 Reduction
Nonfatal MI Event Rate,
lt0
0-9
10
Change From Baseline Fasting Plasma Glucose, mg/dL
6-year follow-up
Canner PL, et al. Am J Cardiol. 200595254-257.
56
Linear Dose-Response of Lipid Effects of ER
Niacin
30
HDL-C
29
30
26
20
22
15
10
10
0
-3
-9
-14
Change From Baseline,
-10
-11
-17
-5
-21
-22
-20
-12
LDL-C
-20
Lp(a)
-24
-30
-26
-30
-28
-40
-35
TG
-39
-44
-50
500
1000
1500
2000
2500a
3000a
Dose of ER-Niacin, mg
Lp(a) lipoprotein (a) aGreater-than-recommended
daily doses
Goldberg AC. Am J Cardiol. 19988235U-38U.
57
Liver Safety of ER Niacin Versus
Dietary-Supplement IR and SR Niacin
Dietary-Supplement Niacin
100
100
80
80
Sustained Release (SR)
60
60
Mean, U/L
Mean, U/L
Extended Release (ER Niacin)
40
40
20
20
Immediate Release (IR)
0
0
0.0
0.5
1.0
1.5
2.0
3.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Dosage (g)
Dosage (g)
McKenney J, et. al. JAMA. 1994271672-677.
58
Niacin Therapy Choices

AHA says dont use dietary-supplement niacin!
OTC over-the-counter FDA Food and Drug
Administration.

• Dietary Supplement Health and Education Act of
  1994. Available at http//www.fda.gov/opacom/laws/
  dshea.html.
• Accessed on 01/05/05 2. Available at
  http//www.fda.gov/cder/ob/. Accessed on 01/05/05.

59
Niacin Flushing by Formulation and Duration
Flushing Episodes/Patient/Month
IR Niacin
ER Niacin
49-72
13-24
73-96
25-48
0-12
Weeks
4-Month Studya
Long-Term Studya
aThe dropout rate due to flushing in both
controlled and long-term trials was lt6 Note
Flushing was reported one month after stable dose
of 1500 mg of IR and ER Niacin
Knopp RH, et al. Metabolism. 1998471097-1104.
60
Effect of Reformulated ER Niacin and Aspirin on
Flushing Severity
100
Plt.001
80
Reformulation 39 flush severity
60
Severity (VAS) ()
?
40
ASA extra 42 severity
?
20
0
Reformulated ER niacin
Reformulated ER niacin ASA
ER niacin
70 fewer flushes with ER vs IR niacin. Mean
severity of first flush by visual analog scale
(VAS) 0none, 100intolerable.89 of subjects
had flushing in these studies with an initial 2-g
dose of ER niacin. Knopp RH et al. Metabolism.
1998471097-1104 Cefali EA et al. Int J Clin
Pharmacol Ther. 200644633-640 Cefali EA et
al. Int J Clin Pharmacol Ther. 20074578-88.
61
Laropiprant (Investigational Agent) for Reducing
Niacin Flushing

• Significantly fewer ERN/Laropiprant vs ERN
  patients experienced
• Moderate or greater flushing(31 vs 56)
• Severe or greater flushing(14 vs 33)
• 69 of patients on ERN/Laropiprant had no/mild
  flushing during week 1

None/mild (GFSS 0-3)
Severe (GFSS 7-9)
Extreme (GFSS 10)
Moderate (GFSS 4-6)
0.4
4
100
6
8
10
80
17
25
60
94
Patients ()
23
40
69
44
20
0
Placebo(n262)
ERN 1 g(n529)
ERN 1 g/Laropiprant 20 mg(n781)
GFSSGlobal Flushing Severity Score. Maccubbin D
et al. Presented at AHA Scientific Sessions
2007 November 3-7, 2007 Orlando, FL. Abstract
191.
62
Instructions to Reduce Niacin-Induced Flushing
and Improve Patient Adherence

• Use ER-niacin instead of IR-niacin , dont cut or
  crush tablet
• Take niacin at bedtime (alternates supper or
  morning)
• Start at 0.5g and uptitrate at 14 wk intervals
  to max dose 2g hs
• Take with
• ASA 325mg
• Naproxen 250-500 mg (not ibuprofen, which may
  raise CVD risk)
• Fish oil 1g/d Rx or 12g/d diet-supplement?
• Diphenhydramine?
• Avoid interrupting niacin Rx whenever possible
• Avoid spicy foods, hot beverages, alcohol and
  external heat near time of niacin dose
• Remind patient
• Flushing is not harmful and shows niacin is
  working
• Niacin is a vitamin
• Dont take with high-dose antioxidant supplements
• Consistent, long-term use may prevent CVD and
  save lives

After McKenney J. Arch Intern Med.
2004164697-705. Rubenfire M. Am J Cardiol.
200494306-311. Flushing indicates best lipid
and athero effects, see Taylor AJ and Staneck EJ,
J Clin Lipidology 20082285-288
63
Niacin vs Fibratesfor Diabetic Dyslipidemia

• Favoring Niacin
• Better HDL-C raising
• Reasonable ?LDL-C and TG
• Better ?Lp(a) (esp vs. gemfib)
• ?CHD events (mono combo)
• ?Total mortality
• Statin combo compatibility (better than gemfib
  only)
• Statin combo tablet (ERNL)
• Some tolerability advantages
• Fewer GI Sx (N V)
• No?creatinine
• No?gallstones

• Favoring Fibrates
• Better TG lowering
• Reasonable ?LDL-C and ?HDL-C
• Good ?Lp(a) (feno only)
• Ezetimibe combo data
• Some ?CHD events (mono)
• ? Microvasc. dis. (feno)
• Better overall tolerability
• No flushing
• No?glucose levels
• No?gout/uric acid
• No?PUD
• Less ?Hcy

64
HDL- Clinical Summary
Levels--Basal vs. Intervention 1. HDL is
protective, but 2. Lowering it may not be bad
(e.g. good diet), and 3. Raising it may not be
good (data not definitive) 4. LDL/HDL ratio
estimates risk but confuses Rx Treatment (goal
gt40 mg/dl in men gt50 in women) 1. Not Diet (bad
diet is bad, high mono unproven) 2. Not Ethanol
(adverse events, bene. unproven) 3. Lifestyle wt
loss, exercise, smoking cessation 4. Meds niacin
(?effective but ?Sx), fibrates, or statins
(?effective but ?Sx) Med Rx to ?HDL in 2o and
high-risk 1o prev
65
Optimal Atheroprevention in Insulin Resistance

• Aggressive ?LDL-C (non-HDL-C) goal/Rx
• Aggressive ?HDL-C goal/Rx
• Aggressive ?TG goal/Rx
• If SD-LDL Rx to ?LDL particle size (pio, fibr,
  NA), and/or further LDL-C lowering
• Lp(a) lowering (NA, feno, HRT) vs. further LDL-C
  lowering
• ?IR/Prevent DM TLC, TZD, metformin, AGI, ACEI,
  HRT
• Other non-lipid RxTLC, ?BP (ACEI/ARB),
  anti-platelet (ASA, fish oil, clopidogrel), pio