Download except subgroup TG > 200 mg/dL and HDL-C

An Update on Niacin
Ernst J. Schaefer, MD
Distinguished University Professor, Tufts University
School of Medicine, Director, Lipid Metabolism
Laboratory & Cardiovascular Research Clinic, Boston, MA
February 25th, 2013
Ernst J. Schaefer, MD
Consulting: Merck and Company, Inc.
Grant Support: Abbott Laboratories and DuPont
Honoraria: Arisaph Pharmaceuticals
Stocks, Stock Options, other ownership interest:
Boston Heart Laboratory
An Update on
Niacin
Ernst J. Schaefer, MD
Distinguished University Professor
Director, Lipid Metabolism Laboratory,
Human Nutrition Research Center on
Aging at Tufts University &Tufts University
School of Medicine, Boston, MA USA
Washington DC, February 25th, 2013
Rudolph Altschul (1901-1963): Niacin
Arch Biochem 1955;54:558-9.
Niacin


“Niacin is the only available
agent that significantly
increases HDL-C
concentrations”1.
“Among lipid-lowering
agents, niacin is the most
effective “HDL-raising drug”
and effectively modifies all
of the lipoprotein
abnormalities associated
with atherogenic
dyslipidemia”2.
1Genest
J, Frohlich J, Fodor G, McPherson R. CMAJ 2003;168(9):921-4, 2Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, NIH 2002.
Niacin
Niacin – Mechanisms of Action
 Niacin is an effective TG lowering agent,
especially in those with elevated TG levels
 Decreases FFA flux, decreases TG production
in the liver, and also enhances the clearance of
TRL apoB-48 and apoB-100.
 Increases ABCA1 and ABCG1 gene
expression in cell and animal studies, and
increases very large protective alpha-1 HDL in
animal and human studies.
 Increase adiponectin gene expression and
plasma levels.
Human Apolipoprotein (Apo) Metabolism
Synthetic
Sites
FFA
LPL, HL,
LCAT
Chylomicron
ApoB-48
other Apos
Lipids
4
Chylomicron
Remnant
ApoB-48, ApoE
Lipids
Catabolic
Sites
5 hours, +48%
Liver
6
1
8
Kidney
Intestine
HDL
ApoA-I
other Apos
Lipids
12 mg/kg/d
3
Liver
+24%
Scavenger
Cells
9
2
VLDL
ApoB-100
other Apos
Lipids
12 mg//kg/d
LPL, HL, 5
LCAT
4 hours
FFA
LDL
ApoB-100
Lipids
3.5 days
Peripheral
Cells
7
, +46%
Cohn JS et al J Clin Invest 1990: 85:804, Lamon-Fava S et al ATVB 2008; 28:1672-8.
Niaspan: Combined Data from Pivotal Placebo-Controlled Studies
30
HDL-C
20
Change from Baseline
10
0
-10
16%
21%
24%
10%
-3%
-5%
-8%
-12%
-14%
-20
-13%
-17%
-21%
-30
-16%
LDL-C
-25% Lp(a)
-32%
-40
-50
500 mg
1000 mg
1500 mg
2000 mg
TG
* p<0.01
Niacin and Cardiovascular Protection:
Secondary Prevention Studies
Study
Coronary Drug
Project (CDP)1,-4
Treatment(s)
Duration
(years)
Results
5
Non-fatal MI  27%
Stroke/TIA  24%
Nicotinic acid vs placebo
15
Stockholm
Ischemic Heart
Disease Study
(IHD)5
Nicotinic acid + clofibrate
HDL
Atherosclerosis
Treatment Study
(HATS)6
Nicotinic acid + simvastatin ±
antioxidants vitamins vs
placebo
5
3
Total mortality  11%
Total mortality  26%
CHD mortality  36%
CHD mortality, non-fatal MI or
revascularization procedure –
 60%-90%
1. CDP Research Group. JAMA. 1975;231:360 (n=1119 in the niacin group) , 2. Canner PL et all J Am Coll Cardiol.
1986;8:1245, 3. Canner PL et al Am J Cardiol 2005;95:254-257, 4.Canner PL et al Am J Cardiol 2006;97:477-479.,
5. Carlson LA, Rosenhamer G. Acta Med Scand. 1988;223:405 , 6. Brown BG et al. New Engl J Med. 2001;345:1583
(n=160 total, 80 got niacin plus simvastatin with or without antioxidants).
Coronary Drug Project:
Effect of Niacin in Post-MI Patients
Cumulative Rate of Nonfatal MI in
Post-MI Patients Treated With Niacin or Placebo
Cumulative Event Rate (%)
15
Recurrent
nonfatal MI
Placebo
Niacin
10
27%
5
(P < 0.004)
0
12
34
36
48
60
Months of Follow-up
Patients receiving niacin (n=1119) vs patients receiving placebo (n=2789). Total mortality
was similar between the 2 groups at 5 years.
The Coronary Drug Project Research Group. JAMA. 1975;231:360-381.
ApoA-I-Containing HDL Subpopulation Profiles of a Control
and a CHD Patient (b) – Lack of Large HDL in CHD
pre
 pre
[nm]
17.0
9.51
8.16
7.10
4.66
Asztalos et al. Arterioscler Thromb Vasc Biol. 2003;23:847-852;
2004; 24:2181-2187, 2005; 25:2185-2191, HATS Trial, Framingham
Offspring Study, and the Veterans Affairs HDL Intervention Trial
Differences in HDL Particles in Male CHD Cases vs
Controls in the Framingham Offspring Study
Apo A-I Concentration
Controls (n=1277)
17 mg/dl
% Difference
Cases (n=169)
- 39%*
(16% of total)
40 mg/dl
- 9%
(37% of total)
38 mg/dl
+ 29%*
(36% of total)
12 mg/dl
+ 16%*
(11% of total)
“For each 1 mg/dl apoA-I increase in alpha 1 HDL - 26% reduction in CHD risk
Asztalos BF et al. Arterioscler Thromb Vasc Biol 2004; 24:2181-2187.
Effects of Simvastatin/Niacin on HDL Particles in CHD
Cases in HATS (n=123)
Apo A-I Concentration
Difference
9 mg/dl
%
+ 115%*
30 mg/dl
+ 27%
45 mg/dl
- 17%*
15 mg/dl
- 39%*
“The increase in apoA-I in large alpha 1 HDL was significantly related (p<0.01) to
lack of progression or regression of coronary artery stenosis.”
Asztalos BF, Batista M, Horvath KV, Cox CE, Dallal GE, Morse JS, Brown GB, Schaefer EJ. Arterioscler
Thromb Vasc Biol 2003;23:847-852.
AIM HIGH -1
(Atherothrombosis Intervention in Metabolic
Syndrome with Low HDL/ Hi TG and Impact on Global Health Outcomes)
> 3414 vascular disease patients on simvastatin or
simvastatin/ezetimibe received niacin (1718) or placebo (1696).
> The trial was stopped after a mean follow-up period of 3 years
owing to a lack of efficacy. At 2 years vs. baseline, niacin
therapy had significantly:
- increased HDL-C by 20% from 35 mg/dL to 42 mg/dl
- lowered TG levels by 26% from 164 mg/dL to 122 mg/dL
- lowered LDL-C by 16% from 74 mg/dL to 62 mg/dl.
> However the primary end point occurred in 282 patients in the
niacin group (16.4%) and in 274 patients in the placebo group
(16.2%) (hazard ratio, 1.02, P=0.79 by the log-rank test).
AIM HIGH -2
(Atherothrombosis Intervention in Metabolic
Syndrome with Low HDL/ Hi TG and Impact on Global Health Outcomes)
 Each placebo capsule contained 50 mg of niacin, so
subjects on placebo received up to 200 mg/day of
niacin.
 In order to control for LDL-C levels, 22% of subjects in
the placebo group and 10% in the niacin group were
on ezetimibe 10 mg/day.
 LDL-C and HDL-C were 68 and 38 mg/dl on trial in the
control group and 63 (-7%) and 42 (+9%) mg/dl in the
treatment group on trial.
 The study was powered to see a 25% risk reduction in
the primary endpoint.
Boden W et al N Engl J Med.2011;365:2255-67.
AIM HIGH – Why Did the Study Fail? All of the
Below May Have Contributed.
 The study was underpowered.
 The study was stopped too early.
 The placebo group got low dose niacin which may have had an
effect, and also had beneficial changes relative to baseline.
 Twice as many patients in the placebo group received ezetimibe
as compared to the treatment group.
 Mean LDL-C at 63 mg/dL was only 7% lower in the treatment
group than in the placebo group. Raising HDL-C when LDL-C is <
70 mg/dL may not be effective in CHD risk reduction.
 Mean HDL-C at 42 mg/dL was only 9% higher in the treatment
group than in the placebo group.
AIM HIGH – Subgroup Analysis
 Post-hoc subgroup analysis of AIM-HIGH
 CHD subjects with TG > 200 mg/dL and HDL-C <
32 mg/dL
 This group had the highest risk of recurrent CHD
events in the placebo group (statin alone or statin
plus ezetimibe)
 Moreover in this subgroup those who received
niacin had a relative risk of 0.63 (p=0.017) versus
placebo group.
Guyton J et al AHA November 7th, 2012
Fibrates
Fibrates – Subgroup Analysis
 In ACCORD Lipid – overall event rate was 11.3%
in the simvastatin monotherapy group and 10.5%
in the simvastatin/ fenofibrate group (p=0.32).
 In the subgroup with TG > 200 mg/dL and HDLC < 35 mg/dL event rate was 17.3% (+53%) in the
simvastatin monotherapy group and 12.4% (-28%)
in the simvastatin/ fenofibrate group (p=0.03).
 Similar observations in BIP and FIELD
Ginsberg HN et al New Engl J Med 2010;362:1563-9
HPS2-THRIVE: Heart Protection Study 2: Treatment of
HDL to Reduce the Incidence of Vascular Events
 Presented by Prof. Jane Armitage, Oxford, PI, ESC/ 9/2012
 25,673 high-risk patients with occlusive arterial disease from
China, Scandinavia and UK randomized into study
 Randomized blinded comparison: ER niacin/ laropiprant
(ERN/LRPT) 2g daily versus placebo
 Primary end point: Major vascular events after median
follow-up of 4 years
 Pre-specified safety analyses: Median follow-up of 3.4 years
(to January 2012)
 Background LDL-lowering therapy with: Simvastatin 40mg
(+/- ezetimibe 10mg) daily
HPS2-THRIVE
Lipid levels by Region: Effect of 8 Weeks
ERN/LRPT during Pre-randomization Run-in
LDL-C (mg/dL)
n
Baseline Change % Change
China
10932
59
-12.4
Europe
14741
68
-14.0
All
25673
64
-13.2
-20%*
HDL-C (mg/dL)
China
Europe
10932
14741
41.2
46.2
+5.8
+7.8
All
25673
44.3
+7.0
+17%*
HPS2-THRIVE
Summary HPS2-THRIVE
• Largest ever randomized trial of effects of ER niacin on safety and CV events
in diverse high-risk patients – no significant benefit reported in press 2012.
• Among those tolerating ERN/LRPT for 8 weeks, 76% remained compliant
with active treatment after 3 years vs 85% on placebo
• ERN/LRPT increases risk of myopathy among patients on statin therapy,
particularly in the Chinese
• No clear adverse effects of ERN/LRPT on liver, but known niacin side-effects
on skin & GI confirmed
• Effects of 4 years of ERN/LRPT on vascular events in HPS2-THRIVE - full data
to be presented at ACC 3/9/13
Potential Adverse Effects of Laropiprant
 The effects of niacin on lipids are independent of GPR109A, but not the
flushing effects, which are due to cyclooxygenase (COX)-1 mediated
production of prostaglandin (PG) D2, followed by the COX-2 mediated
production of PGE2 (1).
 PGD2 acts by binding to the prostanoid receptors DP1 and DP2. Laropiprant
decreases the flushing induced by niacin by inhibiting the DP1 receptor.
 DP1 depletion in mice leads to increased atherosclerosis, thrombosis,
aneurysm formation, and hypertensive response to angiotensinogen II (2).
 Niacin inhibits atherosclerosis in mice via GPR109A by inducing ABCG1
dependent macrophage cholesterol efflux, and by inhibiting MIP-1 dependent
macrophage recruitment (1).
 Laropiprant, like COX-2 inhibitors, may cause increased CVD risk. Low dose
aspirin might be a far better alternative to lower flushing (2).
(1) Lukasova M et al J Clin Invest 2010;121:1163-73.
(2) Song WL et al. J Clin Invest 2012;122:1459-68.
Niacin Score Card
 Coronary Drug Project +
 Stockholm Ischemic Heart Disease
Study +
 HATS, Other Angiographic Studies +
 AIM HIGH – except subgroup TG > 200
mg/dL and HDL-C < 32 mg/dL -37% RR
 HPS2-THRIVE – subgroup analysis?
 More data from Dr. Armitage at ACC
3/9/13 Late Breaking Trials
Niacin
Thank you for your attention