Active Low-Carber Forums - Beating down LDL

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- - Beating down LDL - new drug in the pipeline (http://forum.lowcarber.org/showthread.php?t=468101)

Beating down LDL - new drug in the pipeline

This is in the "you gotta be kidding" department.

http://healthaffairs.org/blog/2015/...-challenge-yet/

I read this quickly, but I saw no mention of the fact that LDL might actually have some health benefits. I recall reading somewhere that LDL is active in the immune system. What would the long-term side effects be -- aside from bankrupting the whole system? And all to shift some numbers in a lab test.

Yeah, I'm just waiting for my SO's doctor to push this on him as soon as they're available because I have finally gotten my boyfriend to question statins. His other health markers don't matter, gotta get that LDL below 70! /s

edit - why is this thread in its own little category? Never noticed anything like that before.

[QUOTE=Ilikemice

edit - why is this thread in its own little category? Never noticed anything like that before.[/QUOTE]

I'm not sure. Other than that I'm fairly new to this game, and I screwed up when I posted it. Maybe a moderator can put it where it belongs??? Thanks.

Ilikemice, I don't think this will be available for a few years yet. Do I remember 2018? Maybe that will give you time to prepare your defense. I like Dr. Eades's quote: "Cholesterol is a lab value, not a disease."

A WSJ article about this drug is in the cholesterol forum, focused on the FDA review process. Two drugs paid to jump the queue in the review process...maybe end July?

http://forum.lowcarber.org/showthread.php?t=468095

Dr Kendrick has written about these drugs before, though it might have been part of other articles on cholesterol lowering medications. The cost will be a big factor in their success, there have been other articles about push-back from the likes of CVS, but the studies on whether or not reducing LDL actually reduces CVD aren't due until end of 2018!

Knock down activity of PCSK9, increase ldl receptors. What could go wrong?

Here's one I have to wonder about;

Quote:

Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue.
Roubtsova A1, Munkonda MN, Awan Z, Marcinkiewicz J, Chamberland A, Lazure C, Cianflone K, Seidah NG, Prat A.
Author information
Abstract
OBJECTIVE:
Proprotein convertase subtilisin/kexin 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptor (LDLR), and its gene is the third locus implicated in familial hypercholesterolemia. Herein, we investigated the role of PCSK9 in adipose tissue metabolism.

METHODS AND RESULTS:
At 6 months of age, Pcsk9(-/-) mice accumulated ≈80% more visceral adipose tissue than wild-type mice. This was associated with adipocyte hypertrophy and increased in vivo fatty acid uptake and ex vivo triglyceride synthesis. Moreover, adipocyte hypertrophy was also observed in Pcsk9(-/-) Ldlr(-/-) mice, indicating that the LDLR is not implicated. Rather, we show here by immunohistochemistry that Pcsk9(-/-) males and females exhibit 4- and ≈ 40-fold higher cell surface levels of very-low-density lipoprotein receptor (VLDLR) in perigonadal depots, respectively. Expression of PCSK9 in the liver of Pcsk9(-/-) females reestablished both circulating PCSK9 and normal VLDLR levels. In contrast, specific inactivation of PCSK9 in the liver of wild-type females led to ≈ 50-fold higher levels of perigonadal VLDLR.

CONCLUSIONS:
In vivo, endogenous PCSK9 regulates VLDLR protein levels in adipose tissue. This regulation is achieved by circulating PCSK9 that originates entirely in the liver. PCSK9 is thus pivotal in fat metabolism: it maintains high circulating cholesterol levels via hepatic LDLR degradation, but it also limits visceral adipogenesis likely via adipose VLDLR regulation.

Knock out PCSK9, decrease circulating ldl cholesterol. From the abstract, it looks like visceral fat cells--the ones that increase risk of diabetes, insulin resistance etc.-- increase VLDL receptors. VLDL is the lipoprotein that the liver exports triglycerides in, so they're fat rich. It sounds like Pcsk9 inhibition-->increase in visceral fat--> insulin resistance is a possibility to look out for.

Quote:

Because human PCSK9 targets ex vivo human VLDLR15 and binds in vitro mouse VLDLR,16 PCSK9 may also target VLDLR in humans. Whether an increased visceral fat deposition also occurs in humans lacking functional PCSK9 remains to be elucidated. Perigonadal fat is part of what is called the visceral adipose tissue, which correlates directly with obesity-related metabolic disease and coronary heart disease. However, it was recently reported that in obese patients with similar levels of visceral adipose tissue, metabolic complications were more prevalent in those exhibiting higher intrahepatic triglycerides.29 In a clinical perspective, because Pcsk9−/− mice do not develop liver steatosis and are not prone to obesity, the administration of a PCSK9 inhibitor developed for hypercholesterolemia treatment should not result in adverse effects.

Another rabbit hole. liver fat vs. visceral. And it's assumed here that humans will be like the mice--maybe they'll get "wheat" bellies, but not liver fat. A lot of people won't like that anyways.

I wonder if they're checking for visceral fat in the human trials--or pointedly not checking for it.

Quote:

Originally Posted by teaser

I wonder if they're checking for visceral fat in the human trials--or pointedly not checking for it.

Teaser, I get the impression that a whole lot of things are deliberately not being checked for. The thing that keeps going through my mind is: Is LDL so very evil that it's important to go to such extremes to rid ourselves of it? I can't imagine that we've evolved/been created with the ability to produce a substance the only function of which is to kill us.

Quote:

Originally Posted by Kinura

I can't imagine that we've evolved/been created with the ability to produce a substance the only function of which is to kill us.

I'm amazed that we used to function as a species without high pharmaceutical profits.

Not that I am shocked, but an Advisory panel already recommended approval for use in FH. All over the evening news.

http://www.wsj.com/articles/fda-pan...erns-1433884972

Quote:

Originally Posted by WereBear

I'm amazed that we used to function as a species without high pharmaceutical profits.

Ha ha ha ha ha!
too true WB :D

Quote:

Originally Posted by JEY100

Not that I am shocked, but an Advisory panel already recommended approval for use in FH. All over the evening news.

http://www.wsj.com/articles/fda-pan...erns-1433884972

Sounds like they're REALLY jumping the gun with getting this thing on the market.

I linked another article in the other thread, but FDA funding follows the rule: "if you pay, you can play"

Quote:

Background
The bill, the FDA Safety Over Sequestration (FDA SOS) Act would specifically exempt FDA's user fees from the effects of future budget sequestration.

The user fees, which come from the pharmaceutical and medical device industries, are meant to help fund FDA's regulatory activities, and have been a key source of the agency's funding since they were first introduced in the Prescription Drug User Fee Act (PDUFA) of 1992.

The fees, which are charged for product applications, facility inspections and manufacturer registrations, are supposed to support FDA's hiring of new regulatory staff. In return, FDA has pledged to review (though not necessarily approve) products more quickly.

FDA has become increasingly dependent on user fees in recent years. Since 1992, when FDA only relied on user fee funding for new pharmaceutical product reviews, it has enacted new user fee programs for medical devices, animal drugs, generic pharmaceuticals, biosimilars, generic animal drugs and its tobacco programs.

If FDA's proposed 2015 budget is enacted, it would receive just shy of 42% of its total funding from user fees—$1.855 billion of its $4.44 billion proposed budget.

- See more at: http://www.raps.org/Regulatory-Focu...get-Cuts/#.dpuf