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Artificially Reduced LDL Cholesterol Levels Far Lower than those of Healthy, Young Individuals Appear to be Beneficial

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Posted 14 September 2017 - 02:06 AM

Therapies such as statins, that aim to reduce circulating levels of low-density lipoprotein (LDL) cholesterol, are perhaps the most prevalent medical approach to cardiovascular disease. Indeed, when measured against the low bar set for past attempts to treat age-related conditions, they are one of the most successful forms of treatment to date. A sizable fraction of the reduction in cardiovascular mortality over the past few decades is attributed to the widespread use of statins and similar treatments. Still, this is only a delaying action, it is not a fix for the underlying problems.

How do reductions in LDL cholesterol slow the consequences of cardiovascular aging? The processes of interest involve damaged cholesterol molecules and cellular reactions to their presence. As the various causes of aging progress, there is ever greater inflammation and oxidative stress to produce damaged, oxidized cholesterols that find their way into the bloodstream. Once there, this mix of damaged molecules irritates blood vessel walls. In most cases unwanted metabolic waste of this sort is promptly cleaned up, consumed by the immune cells called macrophages, and disposed of. In some cases, however, there is an overreaction, or macrophages become overwhelmed by the damaged forms of cholesterol. A feedback loop is created in which the blood vessel wall becomes inflammatory, drawing in ever more macrophages that become dysfunction and die to add their mass to the creation of the characteristic fatty lesions of atherosclerosis. These masses narrow blood vessels and disrupt the structure of the blood vessel wall. They reduce critical blood flow, and eventually, as blood pressure rises due to other age-related issues, these fatty plaques rupture to kill or seriously injure the individual.

All of this can be slowed by interfering in any of the critical steps, even without preventing the underlying causes. It can't be reversed without forms of repair, however. So researchers could aim to make macrophages more resilient, could reduce the flux of damaged cholesterol by reducing the overall level of cholesterol, could dampen inflammation by attempting to adjust the regulation of the immune system, and so forth. All of these will slow down atherosclerosis to the degree that any particular implementation can produce change. But to turn it back, themedical community would need means of safely breaking down the problem compounds that irritate blood vessels and kill macrophages. Researchers associated with the SENS Research Foundation have investigated this class of treatment over the years, as their budget has permitted, and made some progress in targeting the problem compound of 7-ketocholesterol via adaptation of baterial enzymes.

Just how low can LDL cholesterol go, however? If less is consistently better, because it slows down atherosclerosis, does less ever stop being better? At some point, one has to presume that running out of LDL cholesterol has to be a bad thing, or else we wouldn't evolved to have it to begin with. With the advent of new and far more effective approaches such as PCSK9 inhibitors, a considerably more powerful intervention than statins, it is possible to reduce cholesterol levels to a fraction of what they would otherwise be. Normal healthy adults have LDL cholesterol measures somewhere below 100 mg/dL. The most severely impacted older people can be nearing or passing 200 mg/dL. The latest therapies can push LDL cholesterol in older people down below 10 mg/dL, far beneath that of normal, young, healthy individuals. The evidence suggests that this is beneficial, and for exactly the same reasons that smaller reductions are beneficial: it reduces the pace at which atherosclerosis progresses. This leads to a number of questions that researchers seem generally unwilling to state in print at this point in time, such as whether or not all adults should be lowering cholesterol throughout their lives, or whether to focus on gene therapies that can achieve this effect across the entire life span without the need for drugs.

How Low Should LDL Cholesterol Go?

A newer class of cholesterol lowering drugs known as PCSK9 inhibitors has emerged as an effective treatment for drastically lowering LDL cholesterol beyond current treatment targets. In a new analysis, researchers sought to explore whether there was "floor effect" in the lowering of LDL cholesterol - essentially, is there a threshold below which there would be no added clinical benefit? Additionally, researchers explored whether ultra-low LDL cholesterol levels would have any negative impact.

Using data from the FOURIER trial (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk), which found that patients treated with the PCSK9 inhibitor evolocumab and statin therapy had a 20 percent reduction in the risk of cardiovascular death, myocardial infarction, or stroke, researchers examined the efficacy and safety of very low levels of LDL cholesterol among 25,982 patients per the degree of LDL-C reduction following one month of treatment. Researchers found that the risk for cardiovascular events (including cardiovascular death, heart attack, and stroke) over 2.2 years progressively declined as LDL cholesterol levels decreased to below 20 mg/dL (0.5 mmol/L), and participants who achieved an LDL-C of less than 10 mg/dL (0.26 mmol/L) had a more than 40 percent lower risk of cardiovascular events than those with an LDL cholesterol equal to or greater than 100 mg/dL (2.6 mmol/L).

"Our findings demonstrate that there is essentially no floor effect, and that lower levels translated to a greater reduction in risk. Among high-risk patients, achieving a LDL cholesterol level far below the most common treatment target of 70 mg/dL (1.8 mmol/L) can further reduce the risk for an adverse cardiovascular event, with no major safety concerns."

Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial

27,564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25,982 patients (94% of those randomly assigned) 13,013 were assigned evolocumab and 12,969 were assigned placebo. 2,669 (10%) of 25,982 patients achieved LDL-cholesterol concentrations of less than 0.5 mmol/L, 8,003 (31%) patients achieved concentrations between 0.5 and less than 1.3 mmol/L, 3,444 (13%) patients achieved concentrations between 1.3 and less than 1.8 mmol/L, 7471 (29%) patients achieved concentrations between 1.8 to less than 2.6 mmol/L, and 4,395 (17%) patients achieved concentrations of 2.6 mmol/L or higher.

There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0.2 mmol/L). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations.

View the full article at FightAging


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Posted 14 September 2017 - 07:26 AM

So using a PCSK9 inhibitor would be a good idea if you can afford it?

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