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The concept of Diabetes & CV risk:A lifetime risk challenge
Vascular function as an early sign of trouble: How can the inhibition of cholesterol absorption reduce the
atherogenic load of intestinal lipoproteins?
Prof Frank Visseren, MDAcademic Medical Centre UtrechtThe Netherlands
Master Class Lipid InnovationsPrague, Czech RepublicMay 27-28, 2011
Slide lecture prepared and held by:
Presentation topic
Overview of Cholesterol Transport
Altman SW et al. Science 2004;303:1201-1204
Cholesterol transporter
Postprandial lipidemia
Postprandial lipids (triglyceride-rich lipoprotein or lipoprotein-remnant particles) are associated with:
– Endothelial dysfunction
– Elevated small LDL particles
– Elevated Factor VII
– Elevated plasminogen activator inhibitor-1 (PAI-1)
– Elevated C-reactive protein (CRP)
Nordestgaard B, et al. JAMA 2007;298:299-308.
Copenhagen City Heart Study
Nordestgaard B, et al. JAMA 2007;298:299-308.
Triglyceride levels and levels of remnant lipoprotein cholesterol since last meal
Nordestgaard B, et al. JAMA 2007;298:299-308.
Levels of Remnant Lipoprotein Cholesterol as a function of levels of nonfasting Triglycerides
Nordestgaard B, et al. JAMA 2007;298:299-308.
Non-fasting triglycerides and risk for MI, IHD and death in Women
Nordestgaard B, et al. JAMA 2007;298:299-308.
Non-fasting triglycerides and risk for MI, IHD and death in Men
Bansal S, et al. JAMA 2007;298:309-316.
Women’s Health Study (WHS)
Bansal S, et al. JAMA 2007;298:309-316.
Association of triglyceride levels with incident CVD according to fasting status
Bansal S, et al. JAMA 2007;298:309-316.
Womens Health Study (WHS)
Triglyceride concentrations after an oral fatload in obese patients with metabolic syndrome
0,5
1,5
2,5
3,5
0 1 2 3 4 5 6 7 8
hours post fatload
Tirg
lyce
rides
(mm
ol/l)
Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150
Drop in HDL-c after an oral fatload
Hajer et al. Clin Endocrinol 2008;69:870-877
N=19
Increase in Cholesterol Ester Transfer (CET) after an oral fatload
Hajer et al. Clin Endocrinol 2008;69:870-877
N=19
Oral Triglyceride Tolerance Test!??
Standardized Oral Triglyceride Tolerance Test (OTTT):
• 1g dairy cream/kg body weight• 50g fat plus 50 g carbohydrate• Mixed meal
But:
No evidence for CVD risk stratification
No evidence for clinical benefit of treatment of postprandial lipids
Effect of statin versus fibrate on postprandial endothelial dysfunction: role of remnant-like particles
Wilmink H et al. Cardiovasc Res 2001;50:577-582
Randomized, placebo controlled trial Cerivastatin 0.4mg vs. gemfibrozil 900mg 15 healthy volunteers
Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction
Yunoki K et al. Atherosclerosis 2011;epub
N=19
Ezetimibe improves postprandial hyperlipemia and its induced endothelial dysfunction
Yunoki K et al. Atherosclerosis 2011;epub
N=19
washout
Simva 80mg
Simva 80mgSimva/eze 10/10
washout
Oral fatload Oral fatload
6 weeks 4 weeks 6 weeks
FMD FMD
Simva/eze 10/10
Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150
Low-dose statin and ezetimibe compared to high-dose simvastatin on postprandial lipids in patients with the metabolic syndrome
0.5
1.5
2.5
3.5
0 1 2 3 4 5 6 7 8
hours post fatload
Tirg
lyce
ride
s (m
mol
/l)
No treatment
Simva 80mg
Simva/Eze 10/10mg
Oral fatloading test
Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150
Low-dose statin and ezetimibe compared to high-dose simvastatin on postprandial lipids in patients with the metabolic syndrome
0
2
4
6
8
10
Simva 80mg Simva/eze 10/10mg
FMD
afte
r is
chem
ia (%
)
pre fatload
4 hrs post fatload
p<0.001
Low-dose statin and ezetimibe compared to high-dose simvastatin on postprandial lipids in patients with the metabolic syndrome
Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150
3000
3500
4000
4500
5000
5500
0 1 2 3 4 5 6 7 8
hours post fatload
Adipo
necti
n (mg
/l)
No treatment
Simva 80mg
Simva/Eze 10/10mg
0
1
2
3
4
5
6
0 1 2 3 4 5 6 7 8
hours post fatloadIL-
6 (pg
/ml)
No treatment
Simva 80mg
Simva/Eze 10/10mg
0
1
2
3
4
5
6
0 1 2 3 4 5 6 7 8
hours post fatload
IL-6 (pg
/ml)
No treatment
Simva 80mg
Simva/Eze 10/10mg
Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150
Low-dose statin and ezetimibe compared to high-dose simvastatin on postprandial lipids in patients with the metabolic syndrome
Conclusions
HDL-c drops after an oral fatload
Statins, fibrates, statin/ezetimibe lower post-fatload hyperlipidemia (triglycerides, LDL-c, remnant particles)
Statin monotherapy and Ezetimibe monotherapy preserve post-fatload endothelial function
Combination of low-dose statine with ezetimibe preserve post-fatload endothelial function
But: small studies
The PostprAndial eNdothelial function After Combination of Ezetimibe and
simvAstatin (PANACEA) Study
The PostprAndial eNdothelial function After Combination of Ezetimibe and simvAstatin (PANACEA) Study
Primary objective:
To evaluate the effect of simvastatin/ezetimibe or high-dose simvastatin alone on fasting and postprandial endothelial function as measured with FMD and EndoPat in obese patients with metabolic syndrome.
The PostprAndial eNdothelial function After Combination of Ezetimibe and simvAstatin (PANACEA) Study
Study design:
Randomized, double blind
2 period cross-over
100 patients
5 centers in The Netherlands and Spain
6 weeks simvastatin 80mg
6 weeks simvastatin/ezetimibe 10/10mg
PANACEA trial design
A
B B
A
A
B
Parallel study
Cross-over study
Conclusions Non-fasting triglycerde plasma levels are associated with
increased CVD risk
In the postprandial phase HDL-c plasma levels drop
Postprandial hyperlipidemia can be reduced with lipid-lowering therapy
Postprandial endothelial dysfunction can be diminished by lipid-lowering therapy
Although an appealing pathophysiological concept, the clinical usefulness of postprandial hyperlipidemia remains to be determined
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