Re: glycine;. Thanks for posting this! Glycine is cheap and is an amazing sweetener for morning coffee, for instance. I also take about 3 grams before bed to help with sleep.
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More good glycine news, especially in this age of Covid:
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Interesting post - thanks.
Being on Glycine and collagen (in my morning coffee) the past month - started on November 22âŚ, might have helped me with my Covid infection. Was pretty short in duration â 3 days and severity â just a stuffy nose.
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Glycine is a wonder supplement IMHO. I take it twice daily about a tbsp each time mixed with either coffee or tea. I also take 5 g of collagen peptides in the morning which also has glycine. The ITP also showed it had statistical significance in increasing the longevity of mice, albeit small. Every bit helps especially if it is synergistic.
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A reevaluation of the Fourier data for a PCSK9 inhibitor shows that, while LDL levels are slashed, the the cardiovascular mortality went Up! Risk of heart attack and overall cardiac mortality increased.
This reminds me of the trials where we attempted to increase HDL, only to find that it also increased cardiovascular mortality rates.
We need to be very careful with extreme tinkering since we know not what we do.
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Hold your horses.
Responding to âReanalysisâ
In response to the study, Sabatine highlighted the different ways the TIMI study group collected and analyzed data compared with the RIAT researchers.
âAnytime there is a cardiovascular event, that triggers the collection of a dossier containing all the relevant and available source documents,â he said. âIf somebody had a heart attack, we need to see discharge summary, the lab data for the troponin values, the ECGs, the angiogramsâwe get all the source documents. If thereâs been a death, we get the autopsy reports.â
These dossiers are reviewed independently by two board-certified cliniciansâa cardiologist for the cardiovascular outcomes and a neurologist for the cerebrovascular outcomesâwho are blinded to treatment. The criteria for clinical outcomes, including the type of death, are based on standard FDA definitions, said Sabatine. At the end of a large cardiovascular outcomes trial, the FDA even audits the adjudication process and results, which they did in FOURIER. The agency, he said, found nothing of concern.
Clinical trials also require the CSR narrative, which is generated 24 hours after a patient has a serious adverse event, such as death. These narratives describe the event but may be incomplete, said Sabatine, noting they may be based solely on information in the death certificate. For this reason, itâs not surprising to have the initial cause of death listed in the CSR narrative by the local investigator differ from the CEC-adjudicated cause of death. The CEC has much more information on which to base their decision, said Sabatine.
âThat process will naturally result in reclassification,â said Sabatine. âThatâs the very purpose. Thereâs nothing nefarious that it doesnât perfectly agree with the investigators.â
Sabatine said that among the deaths initially deemed to be from unknown causes by local investigators, the CEC classified roughly half to be the result of cardiovascular disease, which makes sense given the ASCVD patient population. As for missed MIs as the cause of death, as the RIAT group alleges, Sabatine argued that the patient dossiers used by the CEC do not support such an attribution. He also pointed out that because of the lack information in the CSR, the RIAT researchers readjudicated numerous deaths from cardiovascular disease to undetermined causes. Because fewer deaths were shifted from cardiovascular to undetermined causes in the evolocumab arm, this resulted in the higher hazard ratio than reported in the NEJM paper (HR 1.05 vs 1.20).
âItâs highly selective reporting on their part,â said Sabatine.
Article vouched by Thomas Dayspring:
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Sabatini was part of the original trial and of course doesnât like that itâs being criticized for sloppy methodology.
Very biased.
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Either they committed research fraud or the group basing their analysis on less data is more accurate.
No. The lesson here is that, just because youâre from Harvard, it doesnât mean that you can be lazy in your methodology. Lazy and sloppy is different from fraud .
It does demonstrate, however, once again that the human body is finely tuned, and we must be very careful in either dropping, or increasing, to extremes.
We donât know enough and the results are usually detrimental.
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They werenât lazy and sloppy, to the contrary it was the reanalysis that was sloppy. Read what Sabatine said. A lot more data than death certificates (which may be the only information in CSR), was used and cause of death was determined by blinded clinicians. That CSR cause of death differs from CEC adjusted causes of death is not surprising.
In response to the study, Sabatine highlighted the different ways the TIMI study group collected and analyzed data compared with the RIAT researchers.
âAnytime there is a cardiovascular event, that triggers the collection of a dossier containing all the relevant and available source documents,â he said. âIf somebody had a heart attack, we need to see discharge summary, the lab data for the troponin values, the ECGs, the angiogramsâwe get all the source documents. If thereâs been a death, we get the autopsy reports.â
These dossiers are reviewed independently by two board-certified cliniciansâa cardiologist for the cardiovascular outcomes and a neurologist for the cerebrovascular outcomesâwho are blinded to treatment. The criteria for clinical outcomes, including the type of death, are based on standard FDA definitions, said Sabatine. At the end of a large cardiovascular outcomes trial, the FDA even audits the adjudication process and results, which they did in FOURIER. The agency, he said, found nothing of concern.
This is how much they differed:
Instead of 251 and 240 cardiovascular deaths in the evolocumab and placebo arms, they counted 150 and 125, respectively. These cardiovascular deaths were readjudicated to be from noncardiovascular or unknown causes.
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They stopped the original trial early because they believed, due to faulty data, that the increase of 5% in cardiovascular mortality was insignificant. But now that we know that the increase in mortality was actually 20%, this would almost certainly have hit clinical significance if the trial had lasted the planned 56 months.
As the authors of the BMJ stated, clinicians need to be very careful using the drug.
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And of course, coroners commonly list heart disease, cardiac arrest, or other conditions related to the heart as a cause of death when no suspicious or obvious cause of death can be identified and no autopsy is performed. Which is often the case.
Does this skew almost all statistics related to CVD and death?
âCoronary heart disease may be overrepresented as a cause of death on death certificates. National mortality statistics, which are based on death certificate data, may overestimate the frequency of coronary heart disease by 7.9% to 24.3% overall and by as much as two-fold in older persons.â
âComparing CHD deaths as defined by the death certificate with validated CHD deaths indicated that the death certificate overestimated CHD mortality by approximately 20% in the ARIC communities. Within subgroups, death certificate overestimation was reduced with advancing age (up to age 74), was consistent over time, was not dependent on gender, and exhibited considerable variation among communities.â
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Thatâs a good point.
If youâre going to draw conclusions about the efficacy and safety of a drug, especially a cardiovascular drug, then you really need to carefully do the work and establish the cause of death. No laziness or guessing.
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Yes. It looks to me the FOURIER trial used a proper methodology for counting deaths vetted by the FDA.
Also, Amgenâs stock price hasnât tanked since the paper became public, which suggests that the market believes itâs noise no signal.
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Interesting how it doesnât concern you that a drug that slashed LDL by 59% actually not only failed to reduce total and cardiovascular mortality, but in fact Increased it.
It never made sense that a drug could reduce myocardial infarction rates while increasing mortality.
The study was seriously flawed.
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Because I donât believe their incomplete reanalysis for the reasons Iâve listed.
They counted completely differently, with 150 and 125 deaths in the active and placebo arm. While the original trial had 251 and 240.
Why are you so sure they are counting more accurately?
I think Sabatineâs explanation why the results differ so much is credible. Because they use discharge summaries, lab data, ECGS, angiograms, autopsies as well. And cause of death based on this extra data is decided by blinded clinicans meaning they donât know if theyâre investigating a placebo or drug case. The FDA auditing the entire process in this case makes it more credible to me unless you do not trust the FDA. Even if precisely this adjudication process came to be because of harmful drugs.
If you want bias fill a room with some rogue doctors looking at incomplete data unblinded going against Big Pharma. The stock price hasnât moved, so it seems unlikely to me they found something.
I also donât really care about this drug specifically - there are other PCSK9 inhibitors, unless you believe their FDA audited adjudication process is bad as well. If thatâs the case I donât know which drug you can trust as this started in 2008 after a bad diabetes drug.
IMO: The weight of the evidence still falls on the side of lower LDL levels being more healthy. There are a tremendous amount of studies verifying this.
While some studies have suggested that LDL-lowering medications may increase cardiovascular mortality, but they have not been conclusive.
It boggles my mind that after so many decades of research that says lower LDL is beneficial, that now a few studies that maybe that is not so, are now being taken as gospel.
The study you cite is for Evolocumab which is a PCSK9 inhibitor and one of a new class of drugs" and not a statin and may be the cause of increased cardiovascular disease, not the LDL lowering qualities of the drug.
Show me a study where giving statin LDL-lowering medications increased cardiovascular disease.
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Niacin lowers triglycerides and raises HDl. No effect on mortality.
PCSK9 inhibition slashed LDL. Increased mortality.
Statins in primary prevention show less than 1% absolute reduction in total mortality rates.
Drugs designed to raise HDL. Increased cardiovascular mortality.
The drugs have a role . They have their place for sure, but I doubt that it applies to > 95% of rapamycin users.
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Absence of evidence does not mean evidence of absence.
It is probably 20 times higher or more if we consider the genetic data, depending on the incidence rate of ASCVD mortality, Iâm basing it on 30% global rate, and a 80% reduction in ASCVD as per mendelian randomization. Longer lifespans with rapamycin or higher incidence rate mean even higher absolute risk reduction.
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This is really interesting - an interview today at the JPM conference in San Francisco with the founder of Verve Therapeutics - the PCSK9 gene editing company - which the MIT Technology Review identified as one of the breakthrough technologies for this year:
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