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Good News on the Coronavirus-Angiotensin Connection

Let’s use some news this morning as an example of how things go in clinical research. You’ll remember that earlier in the epidemic there was a sudden scare about angiotensin-targeting medications (ACE inhibitors and angiotensin receptor blockers, two very common modes of hypertension therapy). This came from the realization that the coronavirus uses ACE2 as an entry point to infect cells, and the worry was that such drugs might upregulate ACE2 protein levels and give the virus an even bigger head start on infecting you.

Since then there’s been a small study from Wuhan that did not show evidence of this effect – in fact, it had a trend towards the opposite effect: patient with hypertension, they found, were at greater risk from the virus (a finding in line with what’s been seen elsewhere), but the ones taking ACE inhibitors or ARBs actually fared better than the ones who weren’t. Today we have a larger study (open access) that seems to confirm that. It’s a retrospective look from the Wuhan area at 1128 coronavirus patients, 188 of them who were taking drugs in those two classes and 940 of them who were not, median age 64, 53% men.

The unadjusted mortality rate between the two groups was certainly different: 9.8% death in the larger group versus 3.7% in the ACE-I/ARB group. This effect persists after a more thorough comparison, adjusting for age, gender, comorbidities and other medications. In fact, it appears that no matter how you slice the data, what subgroups you’re looking at, ACE inhibitors or angiotensin receptor blockers had significant benefit, and that goes for the head-to-head comparison with other hypertension drugs as well.

Now, this is a retrospective study, so it has all the limitations that come with post hoc-ing your way through the data. (I imagine the folks who saw me try to render the plural of “virus” as “virii” will enjoy seeing “post hoc” turned into a verb). The authors mention that an intentional randomized controlled trial will be a much better measure of this effect, and they’re right. But go back to the near panic that people were in when the angiotensin story first hit: if you’d asked folks what they would have expected from a study like this, I don’t think you’d get many takers for the actual results we have. If these drugs do indeed upregulate the amount of ACE2 protein (an open question) then that’s not likely to be making things too much more severe if you can get a reasonably strong signal the other way in a study like this. It may be, in fact, that these results can eventually be taken at face value and that such drugs are actually protective.

Which is, as mentioned, an object lesson in just how much we know about human responses to disease and to drug therapies. One thing I’ve noticed in the comments section here in recent weeks (OK, I’ve noticed a lot of things, but this is a prominent one) are people coming in who take a very straightforward mechanistic view of medicine and drug research. This does this, therefore that does that, and this will obviously raise this and lower those, and we already know that that’s beneficial, QED. Honestly, I wish we could work this way. But we can’t.

After you’ve worked in the biomedical field for a while, you get a lot more cautious about what you know – or you damn well should, anyway. Swinging from paper to paper in Pubmed like Tarzan with his vines in an old movie works in reality about as well as it does if you try the vine trick yourself. You’ll actually end up dangling in the tropical breeze, fifty feet over a pile of sharp rocks. As you listen to your liana unraveling. The drug literature, the biochemistry literature, the medical literature are full of quicksand and crocodiles (to stick with the Tarzan movie metaphors), and it’s a stewpot of some solid results mixed in with the true-but-unextrapolatable, the partly true, the true from a particular angle in favorable lighting, the pretty much false, and no small amount of flat-out gibberish. So confidently proclaiming that hydroxychloroquine opens the zinc channels while azithromycin ripsnipes the frannistan or whatever doesn’t count for much.

It doesn’t count for all that much even if everything you’re saying is reasonable. That ACE2 hypothesis was not crazy at all – perfectly reasonable, one of thousands and thousands of perfectly reasonable hypotheses. We mow those things down like wheat in this business; you get used to it. A good sign these days when you’re listening to someone talk about this epidemic is the number of times they say “We don’t know yet”. The more of those, the better. Confident predictions are grounds for suspicion –  under these conditions, the people who are the most confident are probably fools.

79 comments on “Good News on the Coronavirus-Angiotensin Connection”

  1. colintd says:

    As per the Yeat’s poem https://poets.org/poem/second-coming :

    “The best lack all conviction, while the worst
    Are full of passionate intensity.” ….

    1. Derek Lowe says:

      We are seeing plenty of that these days. One longs to live an in era when for once that poem isn’t relevant.

      1. colintd says:

        Indeed. We all seem to be cursed with the the old “Chinese” (entirely apocryphal association) curse “May you live in interesting times.” Dull times suddenly have a lot to recommend them.

        1. Hap says:

          I’m sort of hoping the blood-dimmed tide doesn’t get loosed, thanks.

          1. Oudeis says:

            Don’t worry about the Sphinx, though. He’s 2000 years old and he’s already caught H1N1 from the indignant desert birds. All that slouching? His lung collapsed.

          2. Nick K says:

            ….Mere anarchy is loosed on the world…

            An alarming portent for things to come?

  2. jz78817 says:

    “(I imagine the folks who saw me try to render the plural of “virus” as “virii” will enjoy seeing “post hoc” turned into a verb). ”

    it’s a perfectly cromulent verbing.

    1. Tim says:

      As a sometime language prescriptionist, I think “post hoc-ing” is fine.

      Let’s be glad he didn’t do “p-hocing”.

      1. asterix says:

        “p-hocing”… I love it…

        How about “ab post hoc”?…

        1. Doctor Memory says:

          “Posthocraphal”

          1. Hap says:

            And the word has “crap” in it too. How appropriate.

          2. DrOcto says:

            Welcome to the posthocalypse

      2. Jeff Marotte says:

        I spit up my coffee laughing

  3. yyz says:

    ACE-I/ARB for everyone at mild stage of infection?
    How unpleasant would it be to give these drugs to everyone suspected or at risk?

    1. Derek Lowe says:

      Might be a bridge too far – what we don’t have is a comparison between these patients and the ones who didn’t have hypertension at all. It could be that these just mitigate the some of the intersection of high blood pressure and coronavirus in ways that the other drugs don’t, and that might not apply to those with normal BP.

      1. Barry says:

        And the benefit might only be detectable in those who had been on ACE inhibitors or ARBs for months. Retrospective studies leave a lot of questions

      2. Adrian says:

        The two most common risk factors for non-mild COVID-19 are age and obesity.

        For people at risk due to obesity the only question should be why they aren’t already taking ACE-I/ARB no matter whether COVID-19 exists at all – 130/80 as limit for hypertension basically implies that an obese adult will always get an ACE-I/ARB prescription from a cardiologist or GP.

        The answer might include non-medical reasons like lack of health insurance, but rarely medical reasons.

        And more speculative, a large part of the racial differences in mortality in the US might end up being explained medically by something like fewer ACE-I/ARB prescriptions .

        1. Irene says:

          “For people at risk due to obesity the only question should be why they aren’t already taking ACE-I/ARB no matter whether COVID-19 exists at all – 130/80 as limit for hypertension basically implies that an obese adult will always get an ACE-I/ARB prescription from a cardiologist or GP.”

          Hypertension is common but far from universal in obese adults. It’s hardly malpractice to omit prescribing hypertensive meds to people who have absolutely normal blood pressure.

    2. Trottelreiner says:

      Problem is, ACE-1 inhibitors also lead to bradykinin piling up, and inflammed aurways and coughing (a possible result) are not that nice to have these days.

      Personally, I guess the sartans (ARBs) would be better, given the circumstances, but IANA doctor.

      1. david Bartos says:

        yes, but ACE2 breaks up bradykinin. ACE2 knockdown by Covid appears to be the source of the pneumonia/ARDS like condition we are seeing. Knocking down ACE2, with pure viral S protein, induces pneumonia/ARDS like pathology in mice, as does high dose Angiotensin II infusion (ACE2, of course, breaks down the proinflammatory Angiotensin II, converting into the anti-inflammatory Ang 1-7). ACE inhibitors and ARBs both cause upregulation of ACE2, b different, likley synergistic, mechanisms.
        Last, all the proven risk factors for Covid mortality are associated with low baseline ACE2 levels.

  4. Algirdas Velyvis says:

    “azithromycin ripsnipes the frannistan” perfectly summarizes contributions of ignoramuses that descended on this blog since March. Derek, it’s your house and your rules, but why you keep comments section open this last month is beyond me.

    1. loupgarous says:

      I can’t speak for Derek, but the only antidote for bad speech (also known as BS) is good speech. It’s probably better to let those who believe azithromycin is a Swiss Army knife of a molecule that exerts every imaginable mechanism of action against SARS_CoV2 when taken with hydroxychloroquine to say their say.

      Examining what they say closely, all the sales pitches for AZ, HCQ, et cetera are developing into textbook illustrations of what the late, great Irving Langmuir called “pathological science”:
      The maximum effect that is observed is produced by a causative agent of barely detectable intensity, and the magnitude of the effect is substantially independent of the intensity of the cause.
      The effect is of a magnitude that remains close to the limit of detectability, or many measurements are necessary because of the very low statistical significance of the results.
      There are claims of great accuracy.
      Fantastic theories contrary to experience are suggested.
      Criticisms are met by ad hoc excuses.
      The ratio of supporters to critics rises and then falls gradually to oblivion.

      1. li zhi says:

        I was just reading up on Luc Montagnier and his crack-pot “research” on EMR teleportation/homeopathy of DNA. His work has been characterized as pathological science (Nobel Prize for HIV). Homeopathic “science” has not faded away. So, there seems to be an alternative path for pathologics to morph (or just persist long enough) into “pseudo-science”. The fact that 3 pounds of fat often seems to behave rationally ought to be much celebrated – as the exception rather than the rule.

    2. JasonP says:

      @ Algirdas Velyvis

      We can’t all be experts at everything, so using one’s knowledge and skills to educate is a noble endeavor. One thing I suspect most all would agree with – education is the CURE for ignorance. Can you contribute to the solution?

      1. x says:

        You can cure ignorance, but you can’t fix stupid, which is too often the root cause of ignorance.

  5. loupgarous says:

    Derek, post-hoc as a verb isn’t all that bad, when color commentators in are paid by television networks to use “defense” as a verb (when “defend” is sittig there waiting to be used).

    At least you’re gerundizing (my own contribution) post-hoc on your own time.

    1. Some idiot says:

      Python at its best…!

    2. Paul says:

      There ain’t no noun that cain’t be verbed.

      Isn’t post-hoc reasoning what happens after you’ve drunk too much German wine?

      1. mayfin says:

        Is there something wrong me with me that I’ve just spent the last 30 seconds singing “Ain’t no noun that can’t be verbed” in the style of Bill Withers … ?

        1. SP says:

          The real offense isn’t the verbifying of words, it’s their renounification.

      2. loupgarous says:

        Or to quote Sir Ector and Sir Grummore (while in their cups) planning the “eddication” of Kay and Arthur in The Once and Future King, between draughts of something alcoholic…
        “Hic, haec, hoc”

      3. Bannem says:

        > There ain’t no noun that cain’t be verbed
        I’ve always had it as ” There ain’t no woyd that cain’t be voybed” ( has to be done in a fake Brooklyn accent . . . )

    3. 10 Fingers says:

      “Verbing weirds language”

      1. Diver Dude says:

        The much missed Calvin and Hobbes.

  6. Paul Wenthold says:

    Would that also apply then to ibuprofen? If I remember right, the concerns about ibuprofen were of the same type (it up-regulates a channel that the virus uses)

  7. smbeast says:

    …. It would be nice to see less verbal grab-ass, and more attention to facts and science (not necessarily-the-same-thing). For instance, what is MoA of chloroquine/hydroxychloroquine in anti-malarial, RA and lupus? Can this HCQ polypharmacology explain COVID-19 clinical observations to-date?

    1. Charles H. says:

      Assuming “MoA” is mechanism of action, any hypothesis would be premature. First you have to prove that there *is* an action WRT COVID to explain. The studies without control groups do not inspire that much confidence, especially when they remove from the study those who died or left the study for the ICU (though perhaps only one of the studies did that).

      OTOH, studies are reportedly in progress that should reveal whether there is an effect to explain.

      1. smbeast says:

        ….the question posed was ‘what is mechanism-of-action of chloroquine/hydroxychloroquine in anti-malarial, RA and lupus?’ (where there is proven activity, no?) Which of these mechanism(s) might explain in vitro CoV activity observed? or potential COVID-19 benefit? That’s all

    2. Paul says:

      IIRC, we don’t know the mechanism of action of HCQ. Lots of conjectures, though.

  8. Hólmsteinn Jónasson says:

    Soluble ACE2 administration may intercept the coronavirus https://portlandpress.com/view-large/figure/3013487/CS-2020-0163i001.tif

    1. JN says:

      I think this Phase 2 study involves a drug that works on this principle. I haven’t seen any commentary on APN01 but would be curious to see what those with a better understanding of all of this think: https://www.technologynetworks.com/drug-discovery/news/phase-2-clinical-trial-of-apn01-for-treatment-of-covid-19-inititated-332897

      My apologies if this was posted twice. I tried once but it did not seem to go through.

  9. David Young MD says:

    I take one exception to that. Labs have now made a verb out of “result”, but it is used only in the past tense. Lab tests are first “completed” and then they are “resulted.”

    Just drives me insane

    1. Madman says:

      I just hate being insanitized.

      1. eyesoars says:

        Is that what happens before or after drinking the bleach?

  10. Mark says:

    The lesson from this posting that should not be ignored is that a first look does not always pan out. There are a large number of internet experts who seize on some fact/drug/treatment that they favor which might work through a plausible mechanism and follow this up with unbridled enthusiasm often stating that clinical trials are not needed, just a waste of time, etc.

    1. M says:

      This is always true, and now it’s being combined with scientists and press offices willing to hype studies that have not been peer reviewed and the (presumed) need to report on every potential breakthrough by observers.

  11. expr says:

    A month ago I saw this video about ACE2 and COVID suggesting a mechanism by which ACE inhibitors and ARB’s could suppress SARS
    https://www.youtube.com/watch?v=1vZDVbqRhyM
    seemed like it was based on some animal studies
    anyone know if it makes any sense?

    1. Ally says:

      They apparently block the receptors the virus used to enter the cell.

  12. David says:

    “HARK-ing” (hypothesizing after results known) has been in medical literature since Kerr 1998 Pers Soc Psychol Rev. v2(3):196-217

  13. Alan Goldhammer says:

    There are now several large scale hydroxychloroquine trials being launched. Our local community hospital, owned by Johns Hopkins and right across the street from NIH here in Bethesda is routinely using hydroxychloroquine + azithromycin. I pity anyone who is trying to run a CT on an NME or some other repurposed FDA approved drug. We may never know what works and what doesn’t. It’s a shame that the biomedical research enterprise has come to this.

    I wonder if we rolled the clock back to 1988, things would have ground to a halt with the use of AZT to treat HIV. Tony Fauci ought to know better.

    1. Charles H. says:

      I think he has to be very careful when he says things that don’t support the president. And has to defer to him in many ways that are foolish. The job was always partially political, but in this environment, that may be the main part of the job.

  14. Zee Bendelstein says:

    Given the rarity with which plausible mechanistic stories lead to clinical success, to what extent are those kinds of stories really a red herring that lead us humans down the rabbit hole? Sure there are examples of mechanistic standouts – BRC-ABL springs to mind – but imagine if you could rerun drug discovery as led by a “non-mechanistic/non-target” primed species. Some bias to phenotypic screening. Would our armamentarium be meaningfully superior/inferior.

    1. Gilles Frydman says:

      The PIs involved in the STI-571 trials for both CML and GIST estimated that this was probably a once-in-a-lifetime success story. I heard both of them say so early on in the trials and I heard them warn us we shouldn’t believe this was going to become the new normal.

    2. PDINV says:

      “Given the rarity with which plausible mechanistic stories lead to clinical success, to what extent are those kinds of stories really a red herring that lead us humans down the rabbit hole?”

      That is wrong on so many levels and I don’t think that’s what DL meant. We get suprised. All the time so an open critical mind is essential. But I would never call plausible mechanistic stories that lead to clinical success a rarity. From the drugs that do work, we have a pretty good idea why for the vast majority of them.

      1. Zee Bendelstein says:

        I need to tone down the rhetoric.
        https://www.nature.com/articles/nrd4336
        Good paper showing majority of first-in-class drugs approved 1999-2013 target-based.
        Two things can be true at same time: -plausible mechanism-based rationale does in no way guarantee clinical success; – plausible mechanism-based rationale greatly increases probability vs. flying blind.

  15. James Millar says:

    All this attention on “post hoc-ing,” but I’m much more impressed with “unextrapolatable.”

  16. Carl Pham says:

    I thought post hoc (in English) was an adjective, in which case doesn’t it get turned into a verb by doubling the final constant and adding “ify” as in “post-hoccify?” The present participle would then be “post-hoccifying.” Of course this is all post-hoccification, since the cat is well out of the bag here.

    1. eyesoars says:

      Post-hoccification: n. the hairball the cat just spit up.

  17. CoxTH says:

    I have two hypotheses for the effects shown in this study:

    The first one is simply that the effects of untreated hypertension in the event of a SARS-CoV-2 infection are actually worse than the effects of (possibly) upregulated ACE expression.

    The second one would be that ACEi are actually able to interfere with virus binding to ACE, thus lowering the rate at which the virus is able to enter cells.

    1. Thomas says:

      And a third one is that one is more likely to catch lighter Covid-19 symptoms while not increasing the risks of going to the ICU. I.e. they make you cough more, so you go to the doctor sooner.
      (Just like mortality goes down as more tests are done).
      I do not think this one is likely. That is why we need proper research, as is being done already.

    2. Jeffrey Paul says:

      African Americans have a very high infection and mortality in this pandemic. It usually explained on socioeconomic terms. Is it possible that there is a biological basis for their susceptibility because they are known to have a ramped up RAS system ?

      1. Anonymous says:

        Black Americans disproportionately have higher rates of hypertension and diabetes. What I don’t know is how much socioeconomics is causative, but there is certainly a correlation. It’s a societal travesty that good health requires the degree of disposable income that it does

    3. Allchemistry says:

      In fact, non-ACEI/ARB patients were also treated for hypertension, but this information is a bit hidden in the text. E.g. Table 1 indicates that the mean blood pressure of ACEI/ARB and non-ACEI/ARB group were comparable. See also the in-hospital treatments of the two groups (Table 2).

  18. Hólmsteinn Jónasson says:

    good piece: “Severe Acute Respiratory Syndrome Coronavirus Viroporin 3a Activates the NLRP3 Inflammasome” .https://www.frontiersin.org/articles/10.3389/fmicb.2019.00050/full

  19. Nanochem says:

    Related with the topic: “Substituting Angiotensin-(1-7) to Prevent Lung Damage in SARSCoV2 Infection?”, Circulation, 2020, DOI: 10.1161/CIRCULATIONAHA.120.047297
    https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.047297

  20. Hinterhun says:

    Your insight onto azithromizin ripsniping the frannistan is surely worth pursuing. However I looked up frannistan and it seems all the information about it is in hindi. Could you please elaborate?

    1. loupgarous says:

      “Ferangistan” is a general Southwest Asian term for “land of the Franks”. Remember the Ferengi from Star Trek:The Next Generation, and later franchises? The ST:TNG episode introducing them to viewers explains that the first Earth trader to encounter the Ferengi named them after the overall Muslim and Farsi term for Western Europeans – based on how the British, French, Portugese, and all those Yankee traders – the “franks” – behaved when they visited Southwest Asia. It wasn’t a compliment.

  21. Greg O'Sullivan says:

    I was wondering whether this group has also collected or had access to which exact ACEI and/or ARB these patients were on? In light of the potential (both positive and/or negative) role(s) of additional off-targets for all of these drugs, might such a further stratification provide insights into the MoA before one is tempted to believe that inhibiting RAS is the underlying reason for the reduced mortality?

  22. steve says:

    Off topic but it’s not looking good for hydrochloroquine.”This nationwide retrospective study of the largest integrated healthcare system in the United States provides the largest dataset yet reported of the outcomes of Covid-19 patients treated with hydroxychloroquine, with or without azithromycin, anywhere in the world. Specifically, hydroxychloroquine use with or without co-administration of azithromycin did not improve mortality or reduce the need for mechanical ventilation in hospitalized patients. On the contrary, hydroxychloroquine use alone was associated with an increased risk of mortality compared to standard care alone.”
    https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1.full.pdf

    1. Znake Oil says:

      But Zinc, it’s all about the Zn(ake oil)

  23. David Edwards says:

    Reading this post gave me an idea, which, of course, is open to rejection on the basis that I don’t share Derek’s extensive med-chem knowledge.

    But, if this result that angiotensin medications have a protective effect turns out to be reliable, then here’s a possible approach – synthesise a peptide that has numerous instances of the relevant binding sites that the Covid-19 spike protein binds to, and clog up the virus spike proteins with this peptide.

    Of course, talking about this, and achieving a clinically safe molecule that will do the job, are separated by many orders of magnitude of difficulty, to the point where anyone succeeding in pulling this trick off will probably be in line for a slew of awards. I also suspect that Derek and others may have entertained this idea themselves, and subjected it to the bombardment of their med-chem knowledge to determine its viability.

    Even with all those provisos in place, though, I still thought the idea worth presenting, just in case the one in a million chance pays off, and such an approach, once acted upon by proper scientists, yields dividends. Clog up those spike proteins with something that stays bound thereto, and renders the virus incapable of binding to actual human cells, and surely the result will be a potentially useful weapon?

    Just in case this idea is being considered by people with proper expertise, and any of them are posting here, how likely is this to succeed? If it’s a non-starter, at least I tried to come up with a constructive idea.

    1. ex-Glaxoid says:

      Peptides are not stable to oral administration, so they have to be given IV, typically. So while that might work, it would be a tough compound to both make and administer. But that is basically what the antibody type drugs do, they bind to the “bad” stuff and trap it, so the concept works, but it is not a trivial undertaking to make or administer.

      On another front, many places are taking temperatures, but another Dr. suggested that testing people blood oxygen levels may catch early cases of CV before other symptoms appear. has anyone else heard of that? Given that a pulse oximeter only costs $30-50, that might be an alternative or complementary screening test for employees or other groups of people. Any thoughts on that.

      1. Michael says:

        This has been done before. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118126/ , although this is the S2 domain. And as for administration peptides can be administered in a nebulized formulation directly to the lung epithelial cells

  24. Cheng Hu says:

    Structure of how Sars-CoV-2 bind to full length human ACE2 published a few weeks ago;
    https://science.sciencemag.org/content/367/6485/1444/tab-pdf
    While most public attentions are on Remdesivir and vaccines development, far fewer initiatives were launched on targeting ACE2 to block Covid-19 infections.

  25. APNO1 is now in second phase clinical trials and I believe we finally have a winner but I want a dozen opinions to confirm or deny the efficacy of this drug.
    I invite as many medical: researchers, analysts, doctors, and nurses as well as journalists, around the world to visit human4us2.blogspot and read the APNO1 article. Leave me a message at human4usbillions@gmail.com or come back here and comment. The idea is to arrive at a consensus.
    Thanks for reading!

  26. Rob says:

    Is there good data anywhere on risk factors for severe disease or death? Age, for sure, but for example a majority of older people have high blood pressure. Is high bp an independent risk factor? Is asthma just a common sense part of the list, or is there actual data?

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