Master Class Lipid Innovations
Prague, Czech Republic
May 27-28, 2011
Presentation topic
Vascular function as an early sign of
trouble: How can the inhibition of
cholesterol absorption reduce the
atherogenic load of intestinal lipoproteins?
Slide lecture prepared and held by:
Prof Frank Visseren, MD
Academic Medical Centre Utrecht
The Netherlands
Overview of Cholesterol Transport
Cholesterol transporter
Altman SW et al. Science 2004;303:1201-1204
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)
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
Nordestgaard B, et al. JAMA 2007;298:299-308.
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)
Bansal S, et al. JAMA 2007;298:309-316.
Tirglycerides (mmol/l)
Triglyceride concentrations after an oral
fatload in obese patients with metabolic
syndrome
3,5
2,5
1,5
0,5
0
1
2
3
4
5
6
7
8
hours post fatload
Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150
Drop in HDL-c after an oral fatload
N=19
Hajer et al. Clin Endocrinol 2008;69:870-877
Increase in Cholesterol Ester Transfer (CET) after an oral
fatload
N=19
Hajer et al. Clin Endocrinol 2008;69:870-877
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
Randomized, placebo controlled trial
Cerivastatin 0.4mg vs. gemfibrozil 900mg
15 healthy volunteers
Wilmink H et al. Cardiovasc Res 2001;50:577-582
Ezetimibe improves postprandial hyperlipemia and its
induced endothelial dysfunction
N=19
Yunoki K et al. Atherosclerosis 2011;epub
Ezetimibe improves postprandial hyperlipemia
and its induced endothelial dysfunction
N=19
Yunoki K et al. Atherosclerosis 2011;epub
Low-dose statin and ezetimibe compared to
high-dose simvastatin on postprandial lipids in
patients with the metabolic syndrome
6 weeks
4 weeks
Simva 80mg
washout
6 weeks
Simva/eze 10/10
FMD
Simva/eze 10/10
FMD
washout
Oral fatload
Simva 80mg
Oral fatload
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
Oral fatloading test
Tirglycerides (mmol/l)
3.5
2.5
No treatment
Simva 80mg
Simva/Eze 10/10mg
1.5
0.5
0
1
2
3
4
5
6
7
8
hours post fatload
Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150
Low-dose statin and ezetimibe compared to highdose simvastatin on postprandial lipids in patients
with the metabolic syndrome
p<0.001
FMD after ischemia (%)
10
8
6
pre fatload
4 hrs post fatload
4
2
0
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
6
5
5000
IL-6 (pg/ml)
Adiponectin (mg/l)
5500
4500
4000
4
No treatment
N
3
Simva 80mg
S
Simva/Eze 10/10mg
S
2
3500
1
3000
6
0
0
IL-6 (pg/ml)
5
4
3
2
1
1
2
3
4
5
6
7
0
8
1
2
3
4
5
6
7
8
hours post fatload
hours post fatload
No treatment
Simva 80mg
Simva/Eze 10/10mg
Olijhoek et al. J Cardiovasc Pharmacol 2008;52:145-150
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
Parallel study
A
B
Cross-over study
A
A
B
B
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 lipidlowering 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