PCSK9: The canine that escalates Your LDL

Yes. PCSK9 is a factor in escalating LDL cholesterol levels. The point was brought home as I rode the escalator up from the first to the top pcsk9floor of the San Diego Convention Center at this year’s American College of Cardiology meetings. I suspsect if I had taken an elevator I would have seen a sign proclaming that PCSK9 is a factor in elevating cholesterol levels.
And PCSK9 signage is everywhere in this meeting.

 

 

Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme that appears to degrade LDL receptors.

If you are born with a mutation that produces less active PCSK9 you have more LDL receptors and consequently more LDL is taken out of circulation leading to lower LDL levels.

Mutations leading to gain of PCSK9 function result in lower LDL receptors, higher LDL levels and substantial clinical evidence for premature atherosclerosis.

Amgen has produced all the PCSK9 signs that abound at the ACC meetings because they have produced a fully humanized monoclonal antibody (utilizing Chinese hamster ovaries) that inhibits PCSK9 and does a great job of lowering LDL without significant adverse effects.

At a late-breaking clinical trial session, results of longer term follow up of the company’s Osler randomized trials were presented and simultaneously published here.

The results were remarkably good. Not only did evolocumab drop LDL by 61% (from 120 down to 48) it showed significant improvement in cardiovascular outcomes.

“The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003).”

According to the biotech website fiercebiotech:

“The antibody is expected to win FDA approval by Aug. 27, trailing Sanofi ($SNY) and Regeneron’s ($REGN) alirocumab, which, thanks to some regulatory opportunism, is likely to hit the market a month or so before. Pfizer ($PFE) is in third place, working through Phase III with its bococizumab. Analysts say each treatment could bring in more than $3 billion a year at its peak…”

More study is needed of these drugs before approval in my opinion for a number of reasons. There is evidence of a small, but significant increase in neurocognitive side effects for one.

Although with evolocumab these were not related to the level of LDL achieved, there are concerns that extremely low LDL levels may interfere with neural development and such effects may not manifest for years.

The study authors did a good job of pointing out other limitations including small number of events, open-label design and patients selected who were free of adverse events. Hopefully, the FOURIER study will resolve these issues.

This post was also posted at SERMO, the physician social network. I would encourage physicians to join in the robust discussions on medicine and other topics at this site.

Skeptically Yours,

ACP

13 thoughts on “PCSK9: The canine that escalates Your LDL”

    1. I had not seen that. It looks like ETC-1002 drug is a long way from being approved.By the time i completes the process of proving safety and efficacy, the PCSK9 inhibitors may make it irrelevant.

  1. Please share more about the conference. Are PCSK9 “INHIBITORS” the appropriate lingo? Positive outcome data available after only one short year… no wonder the industry has jumped on this. Lets not throw caution to the wind.

  2. Some of the cardiology profession must live in an alternate reality. The American College of Cardiology, the American Heart Association, and the National Heart, Lung, and Blood Institute gave no recommendations in 2013 for lowering LDL. The reason given was that there was simply no scientific evidence that lowering LDL prevented either primary or secondary cardiovascular disease. Now we have come up with this new super drug to help us lower LDL levels further than ever. Why are we continuing to link LDL levels to health? The link has never been established. But wait you say. Studies show that our new PCSK9 inhibitors can reduce heart attacks by 1.2 percent. Are you kidding me? I think we’ve lost our collective minds.

    1. The 2013 ACC/AHA guidelines did not say that there was no evidence that lowering LDL prevented cardiovascular disease. The major shift in thinking was to assess global cardiovascular risk using the ASCVD calculator and base cholesterol lowering therapy on patients with a high risk , using predominantly statins which are believed to predominantly work by lowering LDL and not worry about “target LDL” levels.
      The link is pretty strong between LDL levels achieved in drug studies and lower rates of cardiovascular disease and CV mortality.
      The jury is still out on PCSK9 inhibitors, we need more outcomes data over longer periods of time

      1. All studies showing ‘strong’ links between lowering LDL levels and heart disease are relative risk studies .If it is not an absolute risk study its not worth the paper its printed on

  3. I quote from the ACC,AHA, and AHLBI guidelines, ‘There is simply no evidence from randomized ,controlled clinical trials to support treatment to a specific target. As a result the new guidelines make no recommendations for specific LDL- cholesterol or non HDL targets for the primary and secondary prevention of atherosclerotic cardio vascular disease .’
    Why do we continue to cling to a sinking ship that is cholesterol ? We have been handing out statin drugs like candy for decades ,yet heart disease is on the rise . Fifty percent of all those who die of coronary heart disease have normal cholesterol levels . How can these things be if cholesterol was the cause ? We need to quit chasing symptoms and start addressing underlying causes .

    1. “Fifty percent of all those who die of coronary heart disease have normal cholesterol levels”

      True with regard to TC BUT you must check the HDL and LDL.

      A study you might be interested in

      http://www.ahjonline.com/article/S0002-8703(08)00717-5/fulltext
      Lipid levels in patients hospitalized with coronary artery disease: An analysis of 136,905 hospitalizations in Get With The Guidelines

      “Ideal lipid levels (LDL <70 mg/dL with HDL ≥60 mg/dL) are seen in only 1.4% of patients hospitalized with CAD."

  4. The principal investigators at the UCLA School of Medicine on the study you mentioned are quoted as saying “Almost 75% of heart attack patients fell within recommended targets for LDL cholesterol.”

    Irregardless, if one is looking at elevated cholesterol (although HDL and LDL are not cholesterol but lipoproteins) are they seeing cause or effect? If one drives by a fire and sees fireman they may associate firemen with fires. Ergo, get rid of firemen and we will have no more fires. Is that what we’re doing with cholesterol? What do LDLs do? They try and promote repair. But what is causing injury to the epithelium in the first place? It’s not LDL. Quit chasing symptoms.

    1. Scientists don’t have the complete story on what causes atherosclerosis.
      But it’s clear that statin drugs reduce the progression of atherosclerosis and the complications.
      Statins lower LDL as does Ezetimibe which has also recently shown reduce cardiac events.
      It’s reasonable from these studies and other lines of information to presume that LDL plays a role in atherogenesis.

    2. If the endothelium is injured wouldn’t high levels of LDL-P provide more opportunity for oxidation to occur?

      High LDL-C = high LDL-P

  5. In Amgen’s own study,http://www.nejm.org/doi/pdf/10.1056/NEJMoa1500858, cardiovascular events were reduced from 2.18% in the standard-therapy group to .95% in the Evolocumab group. That’s a “whopping” 1.2% decrease. And that’s not even a standardized study. Of course with magic pharmaceutical math that was reported as a 50% reduction.

    1.2%, really? This is what we as physicians are chasing? Never mind the studies that show lowering LDL causes major increases in cancer, brain damage, and all cause mortality.

    Yes, as a matter of fact, we have a very good idea of what causes most cardiovascular disease. Insulin resistance (Dr. Antolio Cruz) homocysteine (Dr. Kilmer McCully), nutritional deficiencies (B Vitamins), toxic compounds (such as smoking), infections, disruptions of the endocrine and autonomic nervous system (from stress) and not the least of these, inflammation. These are the issues that must be addressed. Until they are, heart disease will remain the #1 killer, no matter how much one lowers LDL.

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