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Antidiabetic Therapies and HCC
Thursday, Feb. 21, 2019 · 7:02 p.m. · 34m 22s
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special place for me i mentioned this briefly uh i came here at two thousand one
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doesn't want assistant and it was actually the time that i learned that i could do surgery
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uh no offence but it was a good for a lot of patients i think uh and that's when i turned towards madison
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uh and um the and now i'm here today back again uh and i will have to
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walk over to that little house i think it's uh the rural just or somewhere outside of this
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but anyways i'm here to talk about anti diabetic their piece in h. c. c. uh and uh it again and
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and on or to do so i wanna give a brief background uh on h. t. c. which is almost not necessary
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it's to see is a disease that exhibits this a large regional difference
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fill touch on it but he did get a lot of samples from asia
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and of course that's also related to the distributors of a hepatitis b. virus which causes
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the global level a lot of uh h. c. c. this is all data two thousand seven
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seven thousand h. c. c. deaf third most common cancer related deaf global thing
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so this is the u. k. a cool word and actually looked at patients liking for
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liver transplantation you can see the fallout from two thousand to two thousand and ten um
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and uh you see the change of the ideology that's being
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a given uh for being referred for liver transplantation and and
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one a spectral force law mentioned is that the orange bar increases so uh this
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is thought to be non alcoholic ready the disease and this is something we see
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uh today the more ah this goes out to two thousand and ten and on the right hand side the
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graph shows you that patients at present for liver transplantation
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the old exhibit more metabolic risk factors which gives them
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co morbidity is the relevance to the surgeon um uh and the medical treatment uh they get up front
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so there's the incidence in germany they will but constitute a presents a the data over time and
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the different age groups that are being shown in this is the uh uh the uh um uh
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incidence for uh h. c. c. in males and females and you can see
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uh again over up until two twenty thirteen but there you see
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a slight increase uh also the younger uh populations here in germany
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um and wise this patients are getting older today we live longer but we're
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also becoming more obese uh and uh at a global level that's a big problem
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if you're obese in uh is this is a massive obesity b. m. i. above
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thirty five you have a tremendously increased risk of cancer different organs and delivers down
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uh uh the liver is does this work yet the livers down here actually has the now which are uh the biggest
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increase uh so there's the relative risk of death related to
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cancer of that uh just obesity is a big driver of cancer
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uh and and again i'm a little older data uh a
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followup user fourteen years v. a. population so it's mostly men
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uh with a diabetes and you can see they separate two entities they separate h. c. c.
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and nash kind looks the same if you've to to have to diabetes uh your competitive incidence
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of your natural h. c. c. is um uh it all doubled um independently of other
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and the line alcoholic liver diseases a viral hepatitis or demographic features
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and i thought i think that's very striking and and uh reminds us of uh of
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the risk factor of type two diabetes that is poses type two diabetes for these patients
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uh and uh service awesome mentioned uh the global prevalence spot
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behind now to start to affect globally a twenty five percent
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of the population maybe less in africa and that's a problem those patients are
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not all dying of h. c. c. so major problems are cardiovascular a risk
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uh uh factors cardiovascular disease non liver cancer scholar answers
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of major concern in these patients with a lover uh
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in h. c. c. is a one percent in this graph um i i think we'll learn more over time
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so for sure the severity of the underlying the disease germans your mortality risk and this is three
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strata you have patients with known apple the have isolates details is commonly considered considered as non nash
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no ballooning no information on your liver biopsy and
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you have nash we have the more severe inflamed um
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a a liver tissue which normally also exhibits more fibrosis um
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and you can see that the green bar goes up from non
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f. o. d. two isolates details and so you cardiovascular risk
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kicks in once developed fatty liver and then actually the liver related
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risk emerges once you have information in your liver that makes sense and that's what we think
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tries fibrosis and then determines your uh a little
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related a risk uh and this increases over time
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so something that was mention before it's important that nash is one of those
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each allergies where you develop h. c. c. outside of cirrhosis this is one of
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the major job just because a robotics have uh have been defined as a well
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uh established risk group to be screened it for and uh as bill mentioned it's difficult to
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screen the non surrounded population after the is such a disease that gives you h. c. c. in
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no uh sir roger glover uh and this is from a recent mete
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analysis on the top a graph shows you that uh there's no differences
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answer if you take all h. t. season compare the charges nash was non nash
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however if you look at specifically the non somebody agencies and this is the lower the b. graph
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uh you see that there is a trend sixty one increase throughout all these studies
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uh one is negative but most of them are on the side but papers nash
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as the ideology that increases your risk to develop non uh sir roddick h. c. c.
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and if i look in in our data and this is a mostly driven by on mine landfill
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uh mentioned ham uh and uh peter got at the department has had a longstanding interest in h. c. c.
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uh they collect to do a a two thousand a one thousand two hundred h.
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p. c.'s in the in those two uh ten years two thousand to two thousand ten
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and when i broke them down and they gave me the data to look at each allergies and also some of the traditional risk factors
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i stratified according to national alcohol so most of the cases in our department or alcoholic and then chronic viral
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and i think uh some haven't really been characterised well uh in the only days uh but that
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shouldn't be the centre of this crap so shows four percent national population up to two thousand and ten
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and we see that there is a tremendous uh there's a higher rate of obesity type two diabetes things would expect
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more market infections epileptic stroke actually less trouble side opinion
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and this is something we see those patients with nash h. c. c. have more preserve liver function
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sometimes they're older and actually do get liver transplant patients less frequently so i think
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the identification treatment of these patients might be very different from what we see in other
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uh patients and uh and i think other groups have a
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report similar out a results from their mother sent trick accords
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so that was my introduction and i was asked to talk on anti diabetic therapies
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i'm not that apologised uh so please excuse any shortcomings uh and in questions i
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might not answer i guess that consumers have a hobby that apologists uh these days
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um however i think it's safe if i stated
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life style should be the baseline intervention to treat metabolic
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disorders um and uh a graph that you might have shown before that's
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mainly coins to what's uh narcotics deals appetite isn't that comes from controlled trials
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other stuff for trial so going to this graph shows you if you have more than ten percent of
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weight reduction you chief fibrosis regression in half or your patients
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the magic number that always comes up to seven percent of
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weight reduction sixty forty ninety percent resolve nash so that's good news
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you should probably exceed five percent to have some benefit and if you're below that the benefit is not that great
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weight reduction works this is one of the famous studies where it came from twenty three patients prospectively followed
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i always try to think of myself cancelling my patient to reduce seven fifty categories and move two
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hundred minutes per week probably would favour everyone of them uh this was an intensive study with behavioural therapy
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only eight percent last to follow up thirty percent lost weight and
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then they compared resolutions data hepatitis versus no resolution of seats appetites
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my way of reading this crap is always like this there are people that
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goes way and do not exhausted appetites and there are people that do not
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lose weight and exhausted appetites well the seven percent is a good cover of but
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it's not all about weight in it's difficult for patients and in the end twenty percent
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regress fibrosis so we cannot treat everybody up like this and this is an intensive um
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a treatment regimen and i think one of the reasons this is and
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this comes from the uh endocrinology just a cardiologist literature big study look ahead
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cardiovascular endpoint that's weight reduction intensified a
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protocol improve your mortality from cardiovascular endpoints
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standard group intensified lie so group big drop of weight in the first year in in the end it's below five
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percent so it's difficult to maintain weight loss uh and i
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think that's uh uh something most of us would agree on
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having said that we should still try it now i'm gonna show you some mouse data only gonna be a little bit of mouse data in here
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uh somehow stated that we generated we took my superman running we'll
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so it might start to run the country paddy immune phenotype changes you move
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c. three c. for positive cells outside of andover you look more closely
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c. for a it fifty fifty four positive cells go down n. k.
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cells go down and also macrophages go down a little bit of the cell
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seem to be going down so running for the mice changes your immune phenotype in
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the liver this is not plot this is liver tissue that was faxed another size
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uh an hour size and we can see changes if the mice are running so
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i think that's important because of this very important paper that comes out of
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this department where you actually have mice running mice are susceptible to develop too much
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pretend efficient mice develops to to put eyes h. c. c. and if they're exercising their developing this tool
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i think this makes perfect sense we're affecting information were potentially affecting too much growth
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and the difference in these graphs it's been publishing jay had
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a grey publication again um our um very uh a challenge
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so this is another mouse story that also reduced to more it's a
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different model chemically induction d. n. and c. c. l. for re toxic
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uh my still pick to morse if you give them antibiotics
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get it gots the realisation they're protected they get tremendously less
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cancer and this argues for an information together for signalling in the development of these cancers
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uh the office uh did some uh place under sell so it's non bone marrow derived cells
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in the liver that are important for this uh and i think that's that's also something that we can learn how to influence
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h. c. c. inflammation is important um and and h. this is a very inflammatory cancer
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so have said that to show a little trial we did again in mines small lifestyle intervention we did
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this is actually patients we got them running short exercise problem i don't
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wanna get into the details eight weeks of physical exercise in patients with nash
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you see a l. t. goes down and thirty not a great marker goes down
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we get some fibrosis marcus noble fibrosis marcus proceed three that probably
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dynamic they could probably manage money to dynamic changes if people start running
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it can go down we actually see changes and they got microbiology so
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remember the paper with the antibiotics this is a diversification patients that are running
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uh my sports physiologist says well you get your bowels moving that's
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good for your feces so the microbiology change and i think that's something
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i was asked to talk about the prevention of the therapy with life so you could potentially affect your h. c. c. risk
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those are non agency patients but of course changes and they got microbe iota
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prone from a tory or anti inflammatory effects exercise can be very important
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so this is enough for life style uh but i think you get my point we
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should get the patients moving because in animal models and what we know today it works
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and will also like the work to uh to uh prevent cancer so what about approve trucks
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there's a lot of antibiotics and i can't i'm not the person talking all of them
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and i'm just gonna show you some that have been studied uh with specific liver endpoints
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and i wanna focus a mate format because it's a baseline therapy for diabetes very important i wanna talk
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a little bit up higher good design 'cause it's been a great study that's been done couple years ago
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and then some more a recent uh data to lose the recruit type we can touch by me very briefly
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so make formant made foreman does not
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have a benefit for patients with nash there's been a lot of studies
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that looked at that uh and this is a matter analysis um so if
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you treat a patient of mine foreman placebo controlled you do not see improvements
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details you do not see information for because you do not see improvement fibrosis
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however you do see that my foreman reduces the h. c. c. the risk of h. t. c.
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development and that's pretty robust significant reduction in metaphor menus as well as non mat forming uses risk
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relative risk zero point two four you see there's a lot of studies here again that kind of show the same trend
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if you use my foreman in your diabetic patient reduces risk to develop h. c. c.
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i think that's very reassuring uh it's not directly related to the positive effect on the lever
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are on nash because that really can't we can say today that made form is a good track
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for to treat nash but there is something that for me does to prevent cancer in these patients
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saturn's patients with diabetes and happily dina should be on status because
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pro it's it has a good cardiovascular risk a profit for that
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and there's a big case control study that comes from time on
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a publishing but uh joe with apology in twenty eighteen again the compared
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cases and controls large number of patients never use it ever use that and they show that's that tons
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produce a protected from h. c. c. development and there is a dose dependent effect
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and there's a time dependent effect so that cross sectional data a case control study but i think those dependency in
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time dependencies all the longer you take a step in the more risk reduction you experience in terms of h. t. c.
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that's something that i also by and say well the staten really does something
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for my patient it's improved their p. uh there's really there's a real risk reduction
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so either ah medications the german system i i'm sure
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this was a cyst a health care system as well
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likes to choose cheap medication you have to use the drug that works and that's not the most intel expensive
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for example so familiar areas and ugly needs they
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actually increase the risk of cancer in patients with diabetes
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to a lesser extent an insulin 'cause insulin is really a driver of cancer and
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this is again a case control study ah but if you compare any use of insulin
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uh you get a significant increase in the risk of
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cancer and they're different organ kansas dissected down here livers
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at the top with the odds ratio of two point one so insulin also so familiar react to a lower extent
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uh it increases your risk of h. c. c. i think
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that's also important message uh it's not only the protective effect of
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meant for men but some of the drugs we is you might have to use insulin you're diabetics but again i think this might
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it could affect our type of monitoring these patients uh let's put it that way
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so no court struck class are the t. c. d.'s and uh that
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was the the pittance try that was published in the evening magellan twenty ten
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uh it's like a long time ago to ninety six weeks and it was a three on
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trial it compared to placebo where the spy up with his own versus white i mean he
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uh and if you look only at the first graph here the resolution of
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national to try was negative was tested that i agree there's on would be more
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other part isn't actually the pink one a more effective than
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a placebo and the uh p. value was point zero four
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in the three arm three group design it should have been point zero two five so that was
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negative however in this weather vitamin in story comes in by them he was superior to placebo too
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is all this logical features how good is on to do something
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good they results details is more frequently and they have less global information
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but but i mean it was pretty good too in this group um so this is the data with how good is on actually
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was not the most successful in non diabetic patients however by the menu was if a successful
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my name is therefore in the us guidelines it's not emphasise in the german guidelines
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'cause there's some problems with high those wider me some toxicity some concerns of cancer
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if you look in patients with diabetes and you just tied with his own
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the primary endpoint was highly significant it was mad resolution and the mask or just a logical
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improvement of nash in patients with diabetes so quietly does on in this population uh is effective
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and there was also some debate on the safety of
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prior good is on our again bladder cancer bone fractures um
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i think it's uh i'm experiencing a a renewal of somebody does a very
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prominent abbott was driving the user pipers especially in the special population with fatty liver
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um but it's something that's probably not up to everybody to use 'cause there's been some cautions uh that have been raised
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so how about the risk of h. c. c. this was pure
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treatment of national translating this again what does that mean for the patient
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to develop h. c. c. and again this is a a a
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a group that publish a lot on the same office pathology twenty twelve
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published risk of liver cancer that with e. i. e. the
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pilot is always rosy good is on in type two diabetes patients
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and you see that as a collective dosage effect protective you
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decreasing your h. c. c. risk uh and it's those dependent
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and it's time dependents along to take it the more of a risk reduction you're experiencing
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so that again is pretty reassuring that actually this type of
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drug will hope you uh to prevent or reduce crystal pages
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there are other trucks a peep are at the nests um that um
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like how good dozens of paper agnes try p. prime
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minister being trial off in phase three or phase two trials
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uh with the primary endpoint and indication in nashville actively in
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rolling and i know you're contributing your patients uh some of
00:19:32
those trials will be interesting to see we don't have an idea yet what to expect in terms of h. c. c. risk
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with these drugs but based on what we know from the older a peep ours you might well argue that this
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is also something that will benefit uh that will give the benefit to the patient terms of h. c. c. risk
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so another diabetic the treatment truck g. l. p. one and
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p. p. p. for a which has a different mechanism um
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introduces some uh some amount of weight loss especially in specific uh the g. l. p. one and honest
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um they're approved f. d. a. approved they're different ones to look a tight extended tightly regular tight
00:20:12
uh the seneca tight and uh you get a moderate reduction in blood glucose moderate weight loss
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but some eighties nausea vomiting based on their g. i. side effects the
00:20:25
um decreasing off the intent estimate intestinal a movement so this um gives them
00:20:31
the patient now the of course they're injectable is at this point so um
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you can argue that's not perfect drawing but they work well and there's been a
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again study that's been published um it's initiated for that was driven by u. k. investor
00:20:46
uh the route to tighten the least audiences small study twenty five
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patients in the control group versus twenty five patients in the treatment group
00:20:54
and they receive receive injections either placebo in an escalating dot's
00:20:58
'cause that way you avoid some of the g. i. side effects
00:21:02
um what's that was wrong here we go again and at the end forty eight
00:21:07
weeks you got a liver biopsy so this was a well done study with that
00:21:11
nash definition but we could uh rely on and you can actually see that
00:21:15
the the the record tight in nine of twenty three patients achieved the resolution
00:21:20
off nash compared to only two of twenty two placebo treated patients
00:21:25
patients lost weight and a. o. t. goes down so the dodgers feel strong
00:21:29
about l. t. that's good the weight of course that will also help the patient
00:21:33
and if you have an improvement in liver histology we think this could translate into a
00:21:38
benefit for the patients small study but significant effects i thought this is a great study
00:21:43
and uh there's another one that's coming up and there's
00:21:46
an indication for some appetite in obesity phase three study
00:21:50
um and this is a post hoc analysis because that's study was focused on
00:21:56
examining wake lots
00:21:59
couple of arms uh this multiple those as you can see here one two three four five versus placebo
00:22:05
um patients without diabetes but increased the uh my
00:22:10
and again this is a pasta talk analysis so they took the data and analysts patients
00:22:16
with regards to changes in a. o. t. 'cause this is not a histology base trial
00:22:20
but you can see that there's a dose dependent effect in non diabetics that are overweight on a l. t.'s
00:22:26
and this probably means it's also good for the little somehow and their follow
00:22:31
up study still doing a assessment of liver a specific endpoints with liver biopsy
00:22:36
so does dependent uh a weight loss l. to redirect the reduction and you can see a normalisation of l. t.
00:22:43
twenty five to forty percent in the v. room group and eighteen in the placebo group
00:22:47
so i think that the g. l. p. ones is a potentially promising glass to treat a patient with nash
00:22:54
if you asked me about habit to personal genesis have to go to the mouse again but there's some data that
00:23:01
uh there's a inflammatory driven cancer in inflammatory driven cancer setting you can
00:23:06
reduce to more volume into my number by giving sci tech like teen
00:23:11
uh and i'll turning a the immune response chemo texas which is potentially
00:23:16
good to control cancer so you have a reduction of cancer in these mice
00:23:25
anything else
00:23:28
was a lot of trucks being tested a lot of men clinical trials
00:23:33
some have come out as potentially promising
00:23:38
this was very nineties that was the first phase three trial that reported top one results to be positive
00:23:45
resolve the resolution of nash without worsening of fibrosis significantly more so compared to placebo
00:23:51
it's not a hundred versus twenty percent quite yet it's small numbers but it's significant
00:23:57
there was another big trout salon to to which i thought could have been a nice compound in so rod x. ray defeat
00:24:03
cool to treat population sunset products that truck failed it did not meet the primary endpoint i think we'll see a lot of
00:24:10
uh uh trials coming out of next time there's a lot of trials
00:24:13
going on so very innovative a space and uh i think a good place
00:24:17
to do signs these days let me summarise in finnish usual firms want
00:24:22
your comics i think in a patient with nash it's important to control obesity
00:24:29
have them exercise try to put them on a diet area trick surgery
00:24:33
this is a us driven story there's some very object surgery in in in germany but it's not at the same extent
00:24:40
but you have to try to control the obesity if you fail you have to try to address the cardiovascular risk
00:24:44
in these patients 'cause they die of a heart attack of a stroke with good medications for that trip to hypertension and
00:24:51
used happens for this to be the minutes to athens protect uh
00:24:55
and uh from h. c. c. or decreases the h. c. risk
00:24:59
nine diabetics met foreman is the h. t. c. uh a prodigious it's it's a good track to
00:25:05
to reduce your h. t. c. risk and also the stockings again reduce u. h. t. c. risk
00:25:09
if you're talking about liver target uh therapies we don't really know yet um if
00:25:14
you asked me i think it's a good thing to turn of information in the river
00:25:17
why didn't you might not be perfect i'm not using it how good is on i don't use it
00:25:22
the regular tight really um in germany you can prescribe the patient to achieve weight loss
00:25:29
um but i think it's important will contribute to our patients into uh the clinical trials and try to develop the field
00:25:34
and without them at my and thank you so much for the invitation
00:25:48
yeah sure that's how many possibilities and new things coming questions
00:25:58
you know
00:26:00
i had trials like that because because you love the competing courses
00:26:07
of that you might make the liver disease better but that you make the heart
00:26:11
disease was i don't know how do you how do you decide on your program
00:26:15
like what does the company depending on its well a there's design right now the
00:26:20
company's does with the f. b. i. says and they're too except that f. d. a.
00:26:24
endpoints which is resolution of nash with out worsening of fibrosis
00:26:29
war resolution of fibrosis without a a worsening of match
00:26:35
it's a little tricky you have to think about it what fibrosis goes away or nash goes away and also surrogate endpoints
00:26:42
which we think will translate into survival benefit for the patients
00:26:45
so drug that shows the benefit on histology will get conditional approval
00:26:50
you still have to show in these trials run out for five years and that and it's about is improved
00:26:56
it'll be tricky to keep the patients in the trials and
00:26:59
that's our uh that's our uh a job so to say
00:27:04
because um the real approval of the drug will be there if they show some level benefit
00:27:11
yeah there is a real challenge because uses maybe have the second biopsy
00:27:17
it is no improvement haven't we take these because we don't know if it's less able or drunk
00:27:24
for five more years tend to be so we'll see drugs that have conditional
00:27:29
approval under sub part h. that's the f. d. a. guidance um and um
00:27:37
this is not gonna be standard of care than that other drive truck trials will
00:27:40
have to compare to unless it really has a survival benefit at one point i
00:27:45
hopefully some of them will reach should be for five years so let's put it
00:27:47
that way that's uh because difficult in the metabolic the burden patient um i think there's
00:27:58
a lot of smart people trying to dissect that i think imaging can help us 'cause
00:28:02
we can look at different organs their inflamed what's the main driver of the mortality um
00:28:09
but it's a tough one
00:28:14
i think you're much come concerning your she's ye
00:28:17
match what is your opinion that to of course uh
00:28:22
do that series on the on the on the fact to us um and actually see you
00:28:27
using that type of who to your for of nash in patients with the grouping actually see because
00:28:34
sometimes annoys to your file conan so it's quite difficult on the co factors of
00:28:40
or falcon and and to do grew your file called toxicity
00:28:43
these patients it's quite difficult and i know the question fall
00:28:48
match we sample call for example to to give you force
00:28:52
of different factors in me unity which in frequency meter
00:28:56
greeks endowment for example you pick to do goofy patents
00:28:59
human disrepute in yeah and who's who's used to it cools off this type of co factors could improve wants to
00:29:06
yes i see to its complex we it someone smart like phil today sectors with the model i
00:29:14
i can tell you that i think arterial hypertension sticks out as a drive
00:29:18
of fibrosis so if somebody is actually hypertension he is more likely advanced fibrosis
00:29:23
then yes happily paid emails i think it you wrap attention is important for fibrosis which drives cancer
00:29:28
to me i look at our age to see patients with nash older
00:29:33
have more preserve the function they have more commodities they are less likely to go to transfer because they're older um
00:29:41
but they have a more preservative of functions i think you can do more section and i think that's what
00:29:46
not sure about your experience in that that's what happening in our place and about the alcohol uh there was a big lancet
00:29:52
review which i think is a a has able to field
00:29:55
in terms of saying everything below a hundred grams week can be
00:30:02
considered as social drinking without additional time if you had one hundred grams a week
00:30:07
and this is within the nash definitions or white one could be a lot had twenty grand
00:30:12
uh your mortality takes off that's is that big lancet paper that came
00:30:16
out last year big and uh i think it's u. k. driven uh also
00:30:21
and it's difficult you agree as a patient drank then you
00:30:24
stop ten years ago noise obese and diabetic what drives this cancer
00:30:28
the patient doesn't matter to cancer out or uh
00:30:33
which i guess jeans you that that right tasting that you presented concerned of course
00:30:41
where you close and the nutrition and and and yeah i'm from the entrance of the
00:30:45
knowledge because they choose to use say that to you katie and katie and they
00:30:51
don't teach you more response could be influenced boise duty on the nutrition come different compartments
00:30:57
so i don't know what it is i i i don't know about nutrition that well
00:31:01
um i think there are people that are saying yes nutrition and uh if you talk
00:31:05
to get love japan for example you'll tell you gluten or a t. i. is uh
00:31:08
are and you know gen x. stimuli from wheat uh that i don't know but that what
00:31:13
the data it showed you with exercise i think that if you exercising that
00:31:18
that's what we did with the mice it was no intervention the diet exercise change demon phenotype
00:31:24
and i think that comes through insulin sensitivity at at at at one level it
00:31:30
does a lot of things maybe the micro by on is part of the puzzle
00:31:34
um and it's difficult to say what is the most single important again
00:31:39
to me the exercise is really something that's there's a lot of studies that look good exercise and cancer patients
00:31:44
breast cancer colon cancer were kind of that holds up that uh you do have a beneficial medium term mate
00:31:55
how
00:31:58
yes
00:32:01
so um i have to say that i am not an ease or or or you may i say something
00:32:07
yeah it's true that i ah we we probably step beeper or about the architect
00:32:13
which had a we so that it had an effect on our rights
00:32:16
that works erotic so we cut that ah on affect existing order pressure
00:32:21
are we observing a direct effect on hypertext really excels in
00:32:25
from baton from humans so the thing is that in our study
00:32:30
we found that these effects work independent of g. l. p. one
00:32:34
because it an independent we couldn't uh observe any expression of you'll be wanting to leave or
00:32:40
and when we used in heaters of these yuppie why would be effectively or with that we're not a ah remove still
00:32:47
um i don't know what's the um the g. e. e. one expression my energy answer i'm not sure that's the
00:32:53
right one is uh it acts on that got and the
00:32:56
got hormones that are actually changed through g. l. p. one
00:33:00
through different mentality of the got the forgot x. creates a lot of formant that are important for that
00:33:06
i couldn't tell you which ones the most important um but i'm sure there's some literature related to that
00:33:11
so you'll get a or monster related to the got in then act on the liver we see that we use
00:33:16
that in clinical trials ethics are by last that's very important said look for those uh if you're in your animal model
00:33:26
if you have nineteen
00:33:31
oh of course it is yeah well
00:33:37
well this is a case control study from time on uh i and i
00:33:44
so this is one of the problems it with these big studies ah but i think insolent
00:33:49
you reviewed you you are comparable breast rocking
00:33:57
so i. g. f. an insulin is a is a role factor in on i i i agree it could
00:34:01
be the stage of the diabetes that the length of a of the disease uh that that comes into it
00:34:12
oh
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