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Researchers Debate Ezetimibe (Vytorin) ENHANCE Trial -Part 1

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I’m peggy peck medpage today in light of the controversy surrounding enhance including the unanticipated and according to some biologically implausible finding that ldl reduction had no effect on atherosclerosis it is not surprising that there was little agreement between study investigator dr. evan stein and enhanced critic dr. alan taylor in this series of

Interviews we examine three key areas of disagreement mechanism of action trial design and clinical implications part one mechanism of action the critics don’t question the ldl theory they question how the ldl lowering takes place well mr. b that is the that is questioning the ldl you know questioning the mechanism by which you low ldl questions ldl the the ldl

Theory so let’s deal with the ldl fairy and the mechanism so let’s start with ldl reduction it is i think total ignorance of lipid metabolism to indicate that the mechanism by which ldl is lowered with statins bile acid binding sequestrants the old drugs that were used to establish the foundation of ldl lowering and reduction in cardiovascular risk that was the

Basis for atp one guidelines and atp to god lines before there was any evidence from any statin trial and cholesterol absorption transport inhibitors where you can go even wider than that diet reduction removal of cholesterol or saturated fats from your diet why do i say the mechanisms are all the same because all of those mechanisms result in a depletion of hepatic

Intracellular cholesterol whether you block it by synthesis whether you block it by reabsorption whether you block it by eliminating it from your diet or whether you increase cholesterol utilization by conversion to bile acid binding to bile acids and bind those bile acids in the intestinal tract prevent recycle recycle ization what happens then is that the cell

Up-regulates the ldl receptor and pulls ldl cholesterol out of the bloodstream let’s see ldl receptor binds m.o.b which is the main cholesterol containing fraction so the mechanism by which you lower ldl with all three mechanisms that i’ve described is identical in its final pathway not so explains dr. taylor who contends that ezetimibe has a unique and possibly

Harmful mechanism and so you say well now what’s the mechanism action well they find that it blocks a couple of key receptors in the gut that absorb cholesterol once called the niemann-pick c 1 like 1 receptor and the other one is called the scavenger receptor b-1s are and which in the end they both participate in this process we don’t know what niemann-pick see one

Like one does in the liver we know it’s active in the gut to absorb cholesterol and that’s what one mechanism of action for reducing cholesterol absorption but srb one is a pivotal receptor srb one is in your liver srb one is on your macrophage srb one is a high affinity receptor for hdl to participate in reverse cholesterol transport a key regression mechanism

For atherosclerosis this drug blocks that it blocks it at the receptor level and it blocks at the gene level and that’s not an intended effect of this drug this drug is intended to bought cholesterol intestinal uptake which it does but it’s absorbed and that same disruption in transporter cholesterol is translated to the liver and the bloodstream the vessel wall

The macrophage and that’s off target and that’s why this drug is at best ineffective and at worse progresses disease if you are going to develop a drug you would develop a drug that promotes clearance of cholesterol through srb one not that blocks it this is the exact wrong direction for this drug to act this drug developed as an a cat inhibitor found to inhibit

Cholesterol uptake from the gut acting an off-target a receptor system is pivotal in the transport of cholesterol throughout your body not just in the gut is off target dr. stein this drug is said to block lipid transport and critics suggest that that may be the problem with the drug could there be harm associated with that well you know it to go into the history

It has the generic name is it a mind okay because it came out of an a cat inhibitory class however it is not an a cat inhibitor i think people who perhaps watch direct-to-consumer advertising and believe the two sources of cholesterol perhaps and don’t understand anything fundamental about lipid metabolism can only make that statement because it’s a statement out

Of total ignorance so the i don’t think my carotid arteries say to my hepatic liver cell how did you up regulate that ldl receptor oh i don’t like that mechanism ok i think that’s absolute nonsense but dr. taylor contends that the issue is the drug this is not about ldl this is about a drug the admin that the confusion of this issue that lower is better this is

Fine because the drug lowers ldl has nothing to do with what this drug does it lowers ldl and that’s a smokescreen for off-target mechanism which seems to play out an end to feel function and now in atherosclerosis the burden of proof is on this drug but is the problem really not ldl and not the drug but the trial itself was there a fatal flaw in the trial design

We investigate that issue in the next segment of this exclusive report i’m peggy peck medpage today oh

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Researchers Debate Ezetimibe (Vytorin) ENHANCE Trial -Part 1 By MedPage Today