Despite the widespread use of
statins, patients continue to experience major side effects such us
gastrointestinal disturbances, rhabdomyolysis, acute pancreatitis, headaches,
dizziness, irregular sleep cycles, and possible heart failure. Statins work by inhibiting
the rate-limiting step in hepatic cholesterol synthesis. They decrease
intracellular cholesterol, resulting in increased expression of hepatic
low-density lipoprotein (LDL) receptors and increased hepatic clearance of
circulating LDL. Less recognized is that statins increase the expression of
proprotein convertase subtilisin kexin 9 (PCSK9). PCSK9 acts by
reducing the amount of LDL receptors in hepatocytes. Circulating PCSK9 binds to
the LDL receptor on the cell surface and is subsequently co-internalized
together with the LDL receptor. This promotes the degradation of the receptor
in the lysosome, thereby reducing LDL receptor density and clearance of LDL
particles.
The number of low-density lipoprotein receptors on
the surface of hepatic cells determines how quickly cholesterol is removed from
the bloodstream. Thus, inhibiting the role of PCSK9 leads to an increase in the number of low-density
lipoprotein receptors on the surface of liver cells. The extra receptors can
remove low-density lipoproteins from the blood more quickly than usual, which
decreases the amount of cholesterol circulating in the bloodstream. Since excess
cholesterol circulating through the bloodstream can be deposited abnormally in
tissues such as the skin, tendons, and arteries that supply blood to the heart, a buildup of cholesterol in the walls of coronary arteries greatly increases a
person's risk of having a heart attack.
In a
Phase 2 trial PCSK9 inhibitor, AMG145, showed in can reduce LDL levels as much
as 55% when combined with statin with patients genetically predisposed to high
cholesterol. Patients treated with a placebo saw a 1% increase in LDL
cholesterol. A second Phase 2 trial of AMG145 found that it reduced LDL by 51%
in patients who are unable to tolerate statins. This drug was administered
every 2-4 weeks through injections, and so far, the main side effects reported
have been minor reactions at the injection site, diarrhea, and headaches. A
Phase 3 trial is underway to see whether AMG145 can lower the risk of heart
problems, though the researches stress that this phase could take as long as 5
years. Still all this is exciting because PCSK9 inhibitors appear to be very
effective, well-tolerated, and have no allergic reactions or major safety
issues associated with its use.
References:
http://www.jlr.org/content/early/2012/07/17/jlr.R026658.full.pdf
This new PCSK9 inhibitor drug seems promising, and the fact that it doesn't show major side effects is a positive. We will still need to see how the drug reacts when is used over a extended length of time. This seems to be a big problem in the development of new drugs, there just enough time or money to conduct large longitudinal studies. Researchers also can't predict every single side effect that could occur when the drug is released into the public, this is something the public should keep in mind. I guess we will have to wait and see how AMG145 turns out.
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