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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. "These drugs 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% and 30%. 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 new first-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 Association annual meeting on the coadministered ezetimibe/simvastatin tablet showed a reduction in LDL-C levels of 52% and in nonHDL-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 dosedependent 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 the impact 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 were not 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 development of 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, and ABCA1 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 negative impact 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 reduce LDL-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 GISSIPrevenzione study was actually not for this indication, and it needs to be made clear that the outcome 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 acids have 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 nonHDL-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 nonHDL-C targets for this population."

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