Treatment Lipid

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Treatment

Dr. Feldman then turned the discussion to treatment in terms of mechanisms of action and

efficacy.

Statins

"We don't need to remind you of the important role of statins," remarked Dr. Feldman. "Thesedrugs principally reduce LDL-C levels by reducing the rate-limiting step in cholesterol synthesis.

As a result, there is up-regulation of LDL receptors, more LDL is taken from the circulation, and

less LDL is available to be incorporated into the atherosclerotic plaque."

Slide 17. Statins: Mechanism of Action

In regard to efficacy, Dr. Feldman stated that statins lower LDL-C levels on average between

20% and 50% and increase HDL-C levels by 3% to 9%.[30]

"We have very little idea why statins

increase HDL-C levels, and they also appear to decrease triglyceride levels between 5% and30%. What is interesting is that the greater the elevation of baseline triglyceride levels, the

greater the reduction in triglyceride levels by statin drugs."



Ezetimibe

Ezetimibe is another treatment option; this cholesterol-absorption inhibitor is a relatively newfirst-in-class agent. "Ezetimibe essentially creates a pharmacologic ileal bypass, blocking about

55% of cholesterol absorption in the gut and reducing the return of cholesterol from the gut to

the liver," explained Dr. Feldman. Data presented at the 2005 American Diabetes Associationannual meeting on the coadministered ezetimibe/simvastatin tablet showed a reduction in LDL-C

levels of 52% and in non – HDL-C levels of approximately 48%.[31]

Ezetimibe is certainly a new

and novel way of impacting not only LDL-C but HDL-C levels as well.

Slide 18. Ezetimibe: Mechanism of Action



Niacin

Niacin is an extremely physiologic lipid-lowering agent, noted Dr. Feldman. "It has a dose-dependent effect on LDL-C levels, decreases triglyceride levels by 15% to 50%, and increases

HDL-C levels by 15% to 30%. It reduces the mobilization of free fatty acids in hepatocytes,

reduces triglyceride synthesis, and reduces VLDL secretion, and decreasing the hepatic production of VLDL in Apo B has this impact on all of the lipid parameters."[32, 33]

Slide 19. Niacin: Mechanism of Action

One of the concerns in diabetic patients with metabolic syndrome, explained Dr. Feldman, is theimpact of niacin on glycemic control. "Studies have shown that about one third of patients with

diabetes treated with niacin require an alteration in their diabetic medication. There is an increase

on average of about 2.9% in hemoglobin A1C levels, but in a baseline group of patients who werenot receiving niacin, about 16% needed adjustment of their hyperglycemic medication.

[34] I

would encourage you to consider niacin as a reasonable agent in some diabetic patients, but there

are certainly some patients in whom niacin probably should not be used." The main limiting

factor with niacin is flushing. "This is quite significant, and there has been a lot of developmentof new drugs that have the potential to be no-flush niacin. The no-flush niacin available over the

counter is principally a no-flush because there's not a whole lot of niacin in those tablets."



Fibrates

"Fibrates increase a variety of expression of proteins," stated Dr. Feldman. "Apo AI, AII, andABCA1 have the effect of increasing HDL, the reduction in Apo CIII impacts VLDL synthesis,

and through the conversion of VLDL by lipoprotein lipase (LPL), they either reduce LDL-C

levels or increase HDL-C levels. There are a lot of other proteins that may have some negativeimpact on overall well-being. This new class of PPAR-alpha and PPAR-gamma drugs, of which

about a dozen have been in development, appears to be associated with adverse effects that may

prevent most of these drugs from ever getting to market." Fibrates have been shown to reduceLDL-C levels by 5% to 20%, increase HDL-C levels by 10% to 29%, and decrease triglyceride

levels by 20% to 50%.[30]

Slide 20. Fibrates: Mechanisms of Action on Lipids



Omega-3 Fatty Acids

"The mechanism of action of omega-3 fatty acids is not completely understood," remarked Dr.Feldman. The prescription omega-3 fatty acid preparation is approved by the FDA as an

adjunctive [to] diet for the treatment of plasma triglyceride levels >500 mg/dL. "The GISSI-

Prevenzione study was actually not for this indication, and it needs to be made clear that theoutcome study with omega-3 fatty acids is not based on its present indication. One of the main

problems with dietary supplement omega-3 fatty acids in general is dyspepsia or taste perversion,

but this seems to be less of a problem with this [prescription]." Prescription omega-3 fatty acidshave been shown to decrease triglyceride levels by 45%, decrease VLDL levels by 42%, increase

HDL-C levels by 9%, and increase LDL-C levels by 45%.[35]

"The increase in LDL-C levels is

obviously a potential negative, but there appears to be some phase shifting from small dense

LDL to the larger buoyant LDL as a result of this reduction in triglyceride levels."

Slide 21. Omega-3

Dr. Feldman summarized his presentation by stating that patients with diabetes and metabolic

syndrome have significantly elevated levels of triglycerides, increased levels of non – HDL-C,reduced levels of HDL-C, increased numbers of small dense atherogenic LDL particles, and, as a

result, an increased risk of atherosclerosis and cardiovascular events. "Combination therapy may be better to lower both LDL-C and non – HDL-C targets for this population."



Slide 22. Summary: Dyslipidemia in Diabetes and the Metabolic Syndrome

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