Researchers have warned that
hydroxychloroquine (HCQ) and chloroquine (CQ), two similar drugs
repeatedly touted by President Trump to be promising treatments for COVID-19, may be deadly when combined with a common diabetes drug.
The new study was
published yesterday
online on scientific pre-print server BioRxiv and shows that 30-40% of
mice treated with a combination of HCQ or CQ and diabetes drug
metformin, died. Treatment with the same dose of either drug alone had
no effect on the survival of the mice.
HCQ and CQ are typically used to treat malaria and autoimmune
diseases such as rheumatoid arthritis and lupus, but have also shown
some early promise in the treatment of certain types of cancer, with
several
clinical trials ongoing.
“Our interest in this combination arose because both drugs
individually have been shown to have anti-tumor effects in pancreatic
cancer,” read a statement from two of the authors of the paper: Chi
Dang, director of the Ludwig Institute for Cancer Research and Anirban
Maitra, scientific director of the Center for Pancreatic Cancer Research
at MD Anderson Cancer Center. “To our utter surprise, both HCQ and CQ
when combined with metformin resulted in a surprising death rate in
30-40% of mice. In contrast there were no deaths in the single treatment
groups,” said the authors.
The work in the recently published study was done before the
coronavirus outbreak, with the researchers testing HCQ/CQ and metformin
for pancreatic cancer and coming up with this perhaps, serendipitous
finding. Due to this, some of the mice had pancreatic tumors, however
the drug combination proved fatal for the mice with and without
pancreatic cancer, at a similar rate.
“Even in mice that did not have any tumors, we found this deleterious
effect of the combination, underscoring that it is not dependent on the
presence of a tumor,” said the authors.
Although no work has yet been done in humans to evaluate this
interaction, there is also a plausible scientific reason by which these
two drugs may negatively interact. Both of them affect a process called
autophagy, which is where cells recycle proteins to enable them to make
more.
“Autophagy literally stands for “self-eating” and is a form of
“quality control” that most cells in our body engage in to recycle aging
proteins so as to synthesize new ones. HCQ and CQ are both agents that
inhibit autophagy and in fact this is the property that is important for
its use in tumors like pancreatic cancer,” said the authors.
Metformin, on the other hand can actually induce autophagy, so it is
possible that two drugs interfering with this recycling pathway at the
same time could be toxic.
The researchers looked to see whether this process was disrupted in
the mice dying after treatment with the combination and found increased
numbers of autophagosomes (essentially recycling bins, containing cell
proteins to be re-purposed), in the heart, liver and kidneys of the
mice. They also designed the dosage of both drugs so that the amount
they gave the mice should be proportional to how much humans typically
receive.
“In this study we used a method called “allometric scaling” which
uses the surface area of an average human being and an average mouse and
uses this to identify comparable doses. Importantly this does not
depend on the body weight which can lead to errors in estimation – most
oncology therapeutics are actually calculated based on surface area,”
said the authors.
So what do the researchers hope to achieve by publishing their work now?
“Our goal in communicating this work is not to scaremonger. We hope
that the lethality we observed in mice will not translate to humans but
instead there will be more “pharmacovigilance” or awareness regarding
potential drug interactions between HCQ/CQ and metformin,” said the
authors.
HCQ and CQ have been touted as a possible treatment for COVID-19,
despite very scant and even conflicting evidence that it works for
people with COVID-19, with some trials showing some promising effects of
the drug and others showing
no substantial benefit.
Dozens of other trials
are now up and running to properly evaluate HCQ/CQ in COVID-19, but the
results of these studies will take time. Despite this, President Trump
continues to
mention it universally positively in his press briefings, yesterday even
recommending that people take the drug.
“We have seen the escalating interest in HCQ for COVID-19, not only
for therapy but now increasingly for prophylaxis following exposure to
an infected family member or a patient. Because this drug is likely to
be used in spades – either as part of a clinical trial or what we call
“off label” – we wanted to get this information out at the earliest so
that physicians treating COVID-19 patients are at least aware of this
potential drug interaction,” said the authors.
Misuse of the drug has already resulted in at least one fatality, after man in Arizona
died after ingesting fish tank cleaner containing CQ. Reports of poisoning were also been
reported in Nigeria, a day after President Trump first mentioned it in one of his briefings.
“There is very good safety data on both drugs individually, as well
as safety data on combination being used in patients who have autoimmune
diseases like lupus and rheumatoid arthritis. However, patients with
COVID-19 are a whole different ballgame and typically much sicker than
the average population. We have to remember that COVID-19 has been
associated with adverse effects on the heart and the blood vessels – how
all of these play out in addition to the two drugs interacting with
each other will need to be studied,” said the authors.
Last week, the
CDC reported
that people with underlying health conditions are at more risk of
severe COVID—19. People with diabetes are included in their initial
dataset and appear to be more likely to be hospitalized/need to go to
ICU than people with no underlying conditions, but with such small
numbers it is difficult to tell currently why exactly this is. The
report also had no information about how many of these people were
currently on medications of any sort, whether it be metformin or HCQ/CQ,
so currently there is no human data to back up the interaction seen in
mice. However, the authors of the new study stress that this work must
be done as soon as possible.
“Right now, the drugs are being used in a completely patchwork way.
We need a national database on every COVID-19 patient that is receiving
HCQ or CQ – either as part of a clinical trial or off label,” We ask
either the FDA or companies like Flatiron to create such a registry for
HCQ/CQ usage in COVID-19,” said the authors, stressing that the
databases should record all adverse events that patients experience,
including those reported by patients themselves and any other
medications that patients are on. “This will allow us to sift through
potential adverse drug interactions like metformin and others,” they
added.
There are also two major points to be taken into account when
interpreting the new study. Firstly, the research was done in mice, not
humans. Testing drugs on mice is an important step in the approval of
all new treatments to go into human clinical trials and promising drugs
which cause severe toxicities in mice, generally don’t make it into
human trials. However, some drugs
do behave differently in mice to in humans,
so although this result is indicative that HCQ/CQ and metformin may be
especially toxic when combined in people, evidence from humans is needed
to make a definitive conclusion.
Secondly, the study has not yet been peer-reviewed by other
scientists to check its credibility and accepted for publication in a
scientific journal. Most of the time during peer review, other
scientists suggest ways in which the results or methodology could be
improved to further support a study’s claims, sometimes they challenge
the conclusions of the study and request that the authors be more
conservative about their claims. Less commonly, they uncover significant
flaws in the study meaning that they think the research needs to be
completely overhauled parts repeated, or conclusions drastically
changed. Although it is impossible to tell what will happen with this
study during peer review, the scientists involved are all very
experienced with thousands of accepted scientific publications between
them, so that their work would be inherently flawed with little-to-no
merit at all is rather unlikely.
Neither the lack of peer review or that the work was done in mice
necessarily affect the implications of the work, but they do mean that a
small amount of additional caution is warranted when interpreting the
results, as is the case with all scientific pre-prints and work done in
mice without corresponding human studies.
Considering the considerable burden of COVID-19 currently, it is
understandable why many people want to view HCQ/CQ as a magic bullet, an
old, reasonably safe and cheap drug, capable of quickly helping people
who are seriously ill with COVID-19. But, the bottom line is that there
are several reasons why many scientists and physicians are urging
caution with HCQ/CQ. It isn’t because they think the drug is useless,
it’s just because there simply isn’t enough evidence to suggest it is
useful just yet.
This could change in weeks or months from now, as the results of new
trials come out. But, if the relationship between HCQ/CQ and metformin
found in mice is similar in humans, it serves as somewhat of a
cautionary tale that even in these extreme and unusual times, there is
merit to stepping back and thinking about how drugs may affect different
people in different ways and what may help one person, may harm
another.
https://www.forbes.com/sites/victoriaforster/2020/04/05/researchers-warn-that-covid-19-treatment-touted-by-trump-may-be-toxic-when-combined-with-diabetes-drug/#47112c3555f8
