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