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What is Known About Promoting Intestinal Adaptation in Adults with Short Bowel
Syndrome?
Ezra Steiger, MD: Dr O’Keefe has always been a lot of fun for me to listen to with the
combination of his not South African, maybe middle African, South African, London
accent, but whatever he says sounds like it’s the absolute truth.
Stephen JD O'Keefe, MD, MSc, FRCP: You’re so kind, Ezra. Good evening, ladies and
gentlemen. Thank you so much for coming here and keeping away from the bright lights
of, I was going to say Pittsburgh, of Phoenix to attend this meeting, and we hope we’re
making it your worthwhile.
My talk’s going to be quite different from Steve’s. If you wanted to learn something, you
should listen to Steve. What I’m talking about is more sort of research oriented and the
whole design of this meeting was supposed to be a journal club. So, I’m going to
present some very interesting publications, some 5 or 6 years old, some very, very
recent, in fact, some last month, that have come out on new avenues of treatment that
we’ve got for short bowel syndrome. And I’m talking about those patients with short
bowel intestinal failure, in other words, they’re IV-dependent.
So, Steve did a very nice job outlining the mechanism of adaptation, and this is a little
illustration that I drew just to sort of outline some of the important factors associated
with adaptation. So if this is the normal situation where you’ve got villi here and blood
flow and a food layer going through the lumen. What happens, everything is
exaggerated in short bowel. Basically, there’s hyperphagia and as Steve said, basically
patients with short bowel eat twice as much as normal. So the amount of food that we
give them is twice normal requirement rates.
That actually has an effect on increasing blood flow and then it increases generation
and hyperproliferation. And the mechanisms behind that are still rather unclear, but
probably what’s fair to say is that it’s not one specific mechanism but a whole multitude
of mechanisms that are interacting.
So the question that I have to try and answer in my talk is, can we do anything better
than what Steve has told us about so far, routine management principles? In other
words, can we super adapt these patients? And there are a number of mechanisms that
we can investigate. First of all, is the amino acid glutamine, which is the main energy
source for the small bowel mucosa. It’s not glucose, it’s actually the amino acid
glutamine. And this also increases proliferation as well, and so, therefore, in rat models
and so on, it’s been shown that it does have a proliferation effect. Can we utilize that?
Growth hormone is a trophic agent, not just to the bowel but to most parts of the body,
but some elegant studies have actually shown villus hyperplasia after growth hormone
treatment, and patients with acromegaly have the same effect.
What’s fascinating now and more gut-specific, is the ileal brake peptides that Steve
mentioned just now, particularly GLP-2 and GLP-1. They’re both derived from glucagon
but they’re slightly different mechanistically. And GLP-2 is of particular interest because
it has a specific hyperproliferative effect on the bowel. And then there are a whole host
of other growth factors such as EGF, TGF-alpha, KGF, and so on and so forth, that are
also somehow related. If you get contact between nutrients in the mucosa, you
stimulate the release of these growth factors and it all works together to produce
adaptation.
So, starting first with growth hormone. As you know, it’s stimulated by secretions from
the pituitary. It has effects, first of all, on the intestine, mainly through the production of
IGF-1, and experimental studies and human studies have shown that it actually
increases cell proliferation, mucosal growth, mesenchymal cell proliferation and
collagen deposition. All things that might, in fact, help our patients.
Unfortunately, it is pleiotropic and has effect throughout the body and we know this from
patients with acromegaly, who produce too much growth hormone and they get
increased bone growth, they get effects on the liver and body growth, in general. These
things counteract the good effects over here.
This is one little study that was interesting where somebody had a patient who had an
enterocutaneous fistula and they treated them for 7 days with recombinant HGH, human
growth hormone, and observed on biopsies taken from the stoma, a significant increase
in villus height from day 4 to day 7, associated with other trophic effects in the body as
well. So there’s no doubt that it has positive effects on the bowel. And studies such as
this led a number of investigators around the country, probably the best work came from
Doug Wilmore’s group in Boston, where they examined using a combination of growth
hormone glutamine and an optimal diet, in trying to get the patients on home TPN and
off IV fluids completely.
Their experimental design was rather complex and difficult to follow but unfortunately,
as I’ll show you in a minute, most of the studies that we do are rather complex. First of
all, you have to screen the patients, then you have to stabilize them, because a lot of
patients who we’re referred from around the country are on TPN and don’t really need it.
So, we’ve got to trim them down, make sure that they absolutely need it, and we do that
by looking at urine and gradually reducing the amount of IV fluids to find out how much
they need. Once they’re stabilized on a specific regimen, they were then randomized to
1 of 3 groups. First of all, glutamine and diet alone. The second group was growth
hormone and diet alone, and then the third group was a combination of all 3, growth
hormone, glutamine, and diet.
And they only gave this for a 4-week period and measured at the end of that 4-week
period, what had happened, and then they discharged them home and followed them at
home, not on growth hormone any more but those who had been given glutamine and
diet before, continued on it, or just diet alone, or glutamine and diet in the third group as
well. And then they reassessed them at 3 months follow-up.
And, basically, the treatment arms were .1 mg/kg/day of somatotropin, which is a
synthetic molecule of growth hormone. They gave glutamine as 5 g at 6 takings during
the day, and their diet consisted of a high-protein, low-fat, high-complex carbohydrate
diet. And this was also spread out evenly throughout the day, 6 more intakes. And that’s
one of the critical things we do to all our short bowel patients, is to break up a big meal
into short frequent intakes.
And they, basically, between weeks 1 and 3, if they were stable with regard to
hydration, electrolyte in the blood, weight and enteral balance, defined as more than
500 mils, positive intake minus stomal output, and they maintained a urine output. They
then progressively reduced the PN quantity hoping that these values would stay the
same. And then they went into this outpatient follow-up for 3 months.
And this shows the 3 groups who were reasonably balanced. There were 9 subjects in
the glutamine and diet group, 16 in the growth hormone and diet, and 16 on the growth
hormone, glutamine, and diet. What’s important to look at always with these patients is
the severity of their disease. And Steve has told you, if you’ve got 60 to 80 cm of small
bowel, you’re going to be at risk of needing IV fluids, but it depends upon whether you
have the colon, and most of these patients still had residual colon. So, in comparison to
many of the other studies that have been done, these patients weren’t as severe as a
lot of patients that we actually deal with.
Nonetheless, the results were that they managed to complete 40 studies. All groups
showed a reduction in PN after the 4-week active treatment but the growth-hormone–
treated patients had the biggest reductions in IV requirements, between 6 and 8 liters
per week. And in addition, they actually cut down the number of calories that they
required by 4000 to 6000 calories per week.
They did, in fact, notice a decrease in urine so they were not really optimized, and they
did notice a lot of side effects, and that’s being a problem with all growth hormone
treatment. That peripheral edema, fluid retention, and muscular aches and pains are
very common. They then went into the 3-month follow-up and they found that reduction
in PN requirement in the growth hormone, glutamine, diet, remain significantly greater
than the corresponding reduction in the other 3 groups. Suggesting that pretreatment
with growth hormone actually had a long-term effect. They also noticed that body weight
decreased after they had stopped growth hormone treatment and, basically, they
concluded that treatment with growth hormone with this diet—and the diet was probably
the most important thing that they did because it, again, it was a very high-calorie diet,
about 4000 calories per day, divided into 6 units and they continued on the usual
antimotility drugs and so on and so forth—permitted significantly more, but if they added
in growth hormone, it permitted significantly more weaning from PN than the glutamine
and diet. And only subjects receiving the combination of growth hormone, glutamine
and diet maintained this effect for at least 3 months.
The second study I’d like to mention was that conducted from Bernard Messing’s group
in Paris, who also have a very large home TPN program. And they noted that the dose
of growth hormone used by Byrne and others was approximately 20 times higher than
the current dose used for replacement therapy in growth hormone-deficient adults.
Consequently, in both controlled studies it was reported that all patients experienced
some adverse effects with particular intracellular fluid accumulation. This meant that
they had to actually reduce the amount of growth hormone given, and so they used half
the actual dose. And their experimental design was slightly different. There was a 3week active treatment, and basically patients were randomized to either placebo or
growth hormone. They were given this for 3 weeks and then they had a washout period
of 1 week and then they were switched around. It was a crossover trial. And the total
time was 49 days.
As I said, it was the lower dose and the tests that they did was that they measured
intestinal macronutrient absorption after each treatment, which was really the primary
endpoint.
When we look at the type of patients that they looked at, as I said before, it is important
to see that, that their average small bowel length was actually quite small and only half
of them had colons remaining. So these were actually a more severe group than those
studied by Byrne and colleagues.
When they looked at the progress during the treatment period, after 3 weeks there was
no change in food intake or stool output in those given growth hormone, and that’s
important because you can change output by changing input. But when they looked at
absorption, it was very significant that they had a significant increase in energy
absorption, nitrogen absorption, and carbohydrate absorption. They had a numeric
increase in fat absorption but not significant and D-xylose as a mechanism of smallbowel absorption was also significantly increased. So, generally, quite positive effects.
There were a number of other control studies that were performed and they, of course,
everybody does meta analyses in these sort of things to try and squeeze out a little bit
more. And 5 randomized control trials qualified for meta analysis, those of Ellegård,
Scolapio, Szkudlarek, Seguy, and Byrne. And again, it’s important to see what types of
patients they were. Ellegård had 10 patients, they had Crohn’s disease, so the response
also will depend. The most common cause of loss of massive amounts of bowel now is
mesenteric infarction. And that means actually that the remaining bowel is actually
healthy. On the other hand, the second most common cause is loss through Crohn’s
disease. And there nearly always the remaining bowel is affected. So you might expect
some difference in outcome. And they mainly had Crohn’s disease patients, 130 cm,
half of them had colon.
Scolapio’s patients were a little bit more sick, from the Mayo Clinic. Eight patients, mean
of 71 cm, only 2 had colons.
This unpronounceable name, 8 patients, 6 of 8 had Crohn’s disease, 100 cm, half had
colon. And then we talked about these 2 here. So they are a bit of a mixed bunch but
meta analysis has to take care of that.
So when they came to actually analyzing its effect on, first of all, lean body mass, they
could only find 3 of these studies that could be included but overall, there was a net
improvement in lean body mass in the meta analysis of those 3. The same thing when
they looked at effect on energy absorption, there was a significant increase in energy
absorption.
And then, finally, here they could only find 2 of the studies where they could actually
look at fat absorption, and in those 2 studies, fat absorption was significantly improved.
And this was part of a Cochrane study, where the authors have to come up with a
conclusion, is this significant or not? Is this thing going to be useful in clinical practice?
And they concluded that the results suggest a positive effect of human growth hormone
on weight gain and energy absorption. However, in the majority of trials, the effects are
short-lived, returning to baseline shortly after cessation of therapy. The temporary
benefit calls into question the clinical utility of this treatment. To date, the evidence is
inconclusive to recommend this therapy.
And I think this is important because it has now been marketed as absorptive, you’re
probably all aware of it. And you can only give it for a short period of time. I think it’s 6
months, maximum. And that is the problem, is this safety concern. That they’re worried
that if you carry it on forever, all your patients are going to get acromegaly.
So we must have a better way. So why not go for something that is gut-specific, namely
glucagon-like peptide-2. This is actually principally secreted from the terminal ileum in
the colon, from L cells, endocrine cells. It slows gastric emptying, reduces gastric
secretion, increases mucosal blood flow, stimulates the growth of small and large
intestine, and increases epithelial proliferation and inhibits apoptosis. All the things that
normal adaptation is supposed to do. So in many ways, it looked absolutely ideal.
But the problem is that if you use the natural hormone it only lasts a couple of minutes,
so that’s not going to be any use in clinical practice. So our clever research chemists
come along and they just switch an alanine for a guanine in the actual peptide itself and
that makes it resistant to peptidase destruction within the body and it increases its halflife to a number of hours. And that means that it can actually then be given as a single
injection per day.
And there are a number of phase I and phase II human studies that have been
performed, and this is the drug here, and it’s been named teduglutide. And they’ve
shown, very clearly, that it increases villus height, crypt depth and plasma citrulline.
Plasma citrulline is an important index of enterocyte function because citrulline can only
be synthesized by the small bowel. And if you don’t eat then you measure the level in
the blood and it shows you how much enterocyte function you’ve got remaining. And if it
increases, obviously it’s increasing the efficacy of the remaining bowel. It also has been
shown to increase fluid energy electrolyte absorption in short bowel patients. Most of
this work was done by Palle Jeppesen and colleagues in Denmark.
And then, finally, NPS designed this study involving 26 centers, 139 patients to
randomize 84 patients. So these were all around the world and the problem with short
bowel intestinal failure is that it’s not that common and all the studies that I’ve talked
about so far have only had about 7 or 8, or 10 patients. But you can’t really achieve
strong endpoints with that so we had to go around the world looking for centers who
could actually add in patients.
And this is recently published in Gut and, first of all, there was an optimization period, as
I said. You’ve got to make sure that the patients are in stable condition and they
absolutely need TPN. You then observe them on that and make sure that renal function
remains stable. And only at that stage that they randomized and they were randomized
to 2-drug dose levels of teduglutide, .05 and .1 versus placebo. And they had this for a
3-month period.
So the primary endpoint was kind of clever. Many things, even Lomotil, can actually
reduce the amount of PN requirement but it’s only about, on the order of about 1% to
5% every 6-month period. So it’s not really clinically significant. So a bunch of us got
together and decided that a 20% reduction in PN infusions would probably be
meaningful in clinical practice. So in somebody who requires say, for instance, 3 liters of
fluid, of TPN, 5 days a week, it would mean that they would come off one day of TPN
per week, which we thought might be clinically meaningful. Secondary endpoints, fluid
balance, plasma citrulline, lean body mass, and safety.
So, basically, the patients were adults and they had to have short bowel from major
resection. It had to be at least 12 months out so that the adaptation period was over.
Normal nutritional status. Normal 24-hour urine output. You must always measure the
sodium in the urine as well, to make sure you’re not sodium deprived. Creatinine BUN
very important, must remain within normal or just slightly above normal; 1.5 was
accepted. And LFTs, one didn’t want to have patients with liver failure because that
would make it very difficult to interpret.
Exclusion criteria, patients with cancer, alcohol abuse, clinical study, in other studies for
30 days, use of these type of drugs before, and the usual exclusion criteria. We
continue to allow patients to use antimotility drugs, H2 antagonists, all the basically
normal clinical practice was continued.
And the primary endpoint, after the 6-month period, showed that on those patients put
on placebo, only one achieved a 20% reduction in PN infusions. However, the low dose,
16 of the 35, in other words, 45% actually achieved a clinically meaningful reduction.
And kind of surprisingly, the higher dose didn’t do as well, only 8, or 25% of subjects,
and that was not significant. The combined groups of teduglutide together was
significant. And this was considered, no one could quite understand it at the time, but it
probably was a design fault, and if you look at the PN requirements at start, it was much
higher in this group and it probably accounts for that. But nonetheless, this was the
significant finding in the lower-dose group.
And when you look at citrulline, it really didn’t change on placebo, plasma citrulline,
whereas, both drugs it did significantly increase, showing that enterocyte function was
increased. And lean body mass against placebo also significantly increased in both
dose levels. And most interestingly, 3 patients were actually totally weaned from IV
fluids. And they were a mixed bunch. Some had been on TPN for 16 years, others for 4
years. And they had a variable amount of small bowel and large bowel remaining. This
patient, you might think would come off because they had 100% colon, they didn’t. This
patient had no colon and 75 cm, which is really quite remarkable because rarely—that
usually means that somebody is PN dependent.
And despite the fact that we were blinded as investigators, we all knew who was on the
drug because you just need to look at the stoma. And this is 1 of the patients that I had
personally on the study. This is the stoma, to start with. After 3 months, this is what the
stoma looked like, much, much enlarged. And after 6 months, you can see it’s quite
massive. And so you can actually see the drug working, it’s quite remarkable. And then,
1 month after withdrawal of the drug, basically, things shrank back to normal.
And when we looked at the villus architecture, there was a significant increase in villus
height and crypt depth, and also in the colon as well. So it definitely is a proliferative
agent. And when we look endoscopically, at the villi, you can actually see, this is just a
normal endoscope, you can see the size of the villi waving in the breeze. So it’s really
quite dramatic.
So, in summary, all 3 patients showed a significant decrease in PN volumes at 6-month
period. But only the .05% achieved that significant 20% reduction. Both drug levels
increased lean body mass in citrulline, and most importantly, there was no serious
adverse events compared to placebo.
The problem with interpretation of this study was that statistically, for some crazy
reasons, statisticians have decided to power everything on the high-dose group before
the study was commenced. And since that didn’t come through positive, the study was
actually considered negative, which seems crazy to me, but I’m just a
gastroenterologist.
So anyway, they went to the FDA to try and get the drug approved. It couldn’t be
approved because they needed a confirmatory study. So they went ahead and then
simply compared the 0.5, the lower-dose group, to placebo over a 6-month period,
basically using the same experimental design. And these exciting results have just been
published in Gastroenterology in December and basically, again, we had to use a
multinational, multicenter, randomized, double-blind, placebo-control, parallel-group, 2stage, phase III study, in patients recruited from 27 sites in 10 different countries across
Europe and North America.
And this is what it was, the screening, optimization, stabilization, then randomization to
teduglutide or placebo. The inclusion and exclusion criteria were basically the same as
before. And this was the basic disposition of patients, 86 patients randomized, 39 of
both randomized arms got through to the end, with the same number of dropouts in
each. The demographics really showed that the breakdown of the 2 groups was very
well-balanced. As I mentioned before, vascular disease was the most common cause of
severe short bowel followed by Crohn’s disease. The length of bowel between 60 and
80 cm; about 50% of them having colon remaining.
And this was the sort of key primary endpoint, looking at 20% reduction in IV fluids after
6-month therapy. Sixty-three percent of patients on teduglutide were cut down by 20%
or more; remember it could be 100%, whereas, only 30% on placebo achieved that
level. And if you look at the progress throughout that 6-month period, there is a
progressive reduction in IV fluid requirements. But, remember, we’re trying to wean
them so every few weeks, we basically measure urine output, and if urine output goes
up over baseline, we can then cut down the amount of PN. So we’re trying to keep urine
output the same, creatinine BUN in the blood also the same, so everything’s stable, but
we changed the PN to keep the urine constant, and that’s what happens.
This is actually fascinating that you see the placebo also had a continuous reduction,
and this outlines why it’s so critically important in any study in short bowel patients to
have a placebo group because, really, what you should be looking at is the difference
between these 2, in other words, this section here.
But why is this happening? And I think it’s just better control, that if you follow patients
under research conditions, you’re watching their every move. You’re measuring the
inputs, outputs, Palle will know how important that is, and you improve their quality of
control but not to the level of teduglutide.
What also translated was very important, was that 13 patients could drop out 1 day of
TPN in the teduglutide group, only half as much, 6 on the placebo group, 4 times as
many patients could actually drop off 2 days of TPN a week and 3 times as many, 3
days a week. So there was a progressive improvement in overall hydrational state.
Most importantly, we must look at adverse effects. There wasn’t any significant
differences between placebo and teduglutide but there is, as expected, more stomal
complications from what I actually showed you just now, more abdominal distention,
and probably because the gut is hypertrophying and so things are not moving through
so far. And a lot of these patients have underlying chronic pain and, obviously, it could
exacerbate that.
So, in summary, 63% of patients came and got down to 20% reduction over a 6-month
period, 54% of patients were able to drop off 1 infusion a week, and the majority of
adverse events were related to GI symptoms, as expected.
So, in conclusion, 24 weeks of teduglutide treatment was generally well-tolerated in
patients. Treatment which teduglutide reduced volumes and numbers of days of
parenteral support for patients with short bowel intestinal failure. And, obviously, this
drug offers a novel therapeutic approach to patients with intestinal failure due to
massive intestinal resection.
There were just a few other little studies that remained and I’m just about to finish.
This is hot off the press, as I said, it’s actually just published right now. And what
happened after the first study I talked about, the 3 different groups, they then went into
an unblinded, or at least an open-label 6-month follow-up period to really look for safety
and continual effects of the drug itself. And this is looking at the reduction from baseline
in IV fluids in the teduglutide; this is the high-dose group and this is in the low-dose
group. Both of them you can see, it didn’t taper off. Often you expect with a
pharmacological agent, that it goes down and then it levels off. But this continues to go
down and we’ve now done studies out to 2½ years, which, again, show this
persistence, which is absolutely fascinating and I don’t have all the answers for that.
What everybody wants to know is that how many patients have you weaned from TPN?
So far, I reported this at the E.S.P.E.N. meeting in Barcelona. Of the 173 patients
who’ve been treated with teduglutide so far in the phase III trials, 11 were weaned
completely. Analysis of those groups showed that the time of weaning varied from 12 to
110 weeks on the drug, which is again, amazing. You would have thought if it’s going to
have an effect, it would have a very quick effect. But no, it seems to be scattered all the
way along.
Etiology of those of short bowel was variable, so we couldn’t predict somebody with
Crohn’s disease would be more responsive. And possible indications for weaning. If you
have a protein, PN volume of less than 7 liters per week total at baseline, then you’re
more likely to be weaned. And if you have preservation of the colon, you’re also more
likely to wean. And, again, from what Steve told us, you would actually expect that that
group would be more responsive and one would be able to get them off.
Does this drive continue once you stop it? Charlene Compher did a very nice little study
following what happened to patients once they stopped taking the drug. And there was
a dichotomous response. Some patients need immediate PN volume increases,
whereas, some of them didn’t. And the characteristics discriminating these 2 were a
longer small bowel and colon, lower PN volume and reduction on the drug and a low
BMI. Again, important, a bit like the patients that you weaned. The group with the less
severe intestinal failure are more likely to respond.
So, Mr Chairman, my overall conclusions, before you shoot me down, is that both
growth hormone and GLP-2 analogues have the potential to enhance adaptation in the
remnant intestine of patients with short bowel intestinal failure on life-long IVs and PN.
GLP-2 analogues have the advantage that they are gut-specific, but there is concern
about long-term cancer risk due to the enhancement of mucosal proliferation, potential
exacerbation of obstruction, and biliary complications and short bowel intestinal failure.,
So with all that growth things won’t flow through as quickly.
But it is a proliferative agent. How much of a concern this is, we don’t know. From
animal studies, it doesn’t seem to be a concern. We know that all the lovely food you
had today is also proliferative and we don’t worry too much about that. But it does mean
that we’ve got to do frequent colonoscopies to check and make sure that this is not a
real problem.
Thank you very much.
Dr Steiger: Very good. Two excellent presentations and a lot of things to think about, but
let me start it off, some of the questions among ourselves. When do you think you would
start somebody on any growth factor?
Dr O'Keefe: That’s a very important question and I don’t have enough experience to be
able to say which patients it would be useful and it wouldn’t. I think the problem is that
we’ve only had growth hormone, you know, up until now.
My own personal feelings is that I think that it actually would be useful in reducing PN
requirements but I am worried that growth hormone has also other effects in the body
and so, therefore, the benefit I have not considered using it myself, but Steve might
have a different opinion.
Stephen A McClave, MD: No. I think that’s fair.
Dr Steiger: I mean, when would you use it though, whether it’s GLP-2 or growth
hormone, would it be right after someone’s had a massive resection, or at what point in
their postoperative course would you consider the use of any of these factors?
Dr O'Keefe: Okay. So the problem is that we have only got clinical trials to look at and
they’ve basically excluded anybody immediately after surgery. So I think your point is a
very good one that you would expect it to have the most effect when the adaptation
process is occurring and that’s most rapidly within the first 6 months. So I think that
observation still needs to be made.
Dr Steiger: Didn’t the Cochrane review kind of suggest that, that maybe that would be a
useful time to think about using the growth factor?
Dr O'Keefe: Yes, they did, actually. And that was one of their suggestions but I don’t
think the study was ever done.
Dr.McClave: No. The other interesting would be the strategy that you wait till you see
what kind of maximal adaptation you’ve got and then, if it’s not, if the TPN requirement
is still large, then consider the agent. But none of the studies have focused that far out
in the adaptation period.
Dr O'Keefe: Yeah, I mean, I think that we’re still in the learning phase and it’s very
difficult to extrapolate from a research study environment to clinical practice because
you’re stuck with a certain drug level and routine and so on and so forth. So I think the
learning experience is going to be now that it has become available. I forgot to mention
that. That the drug was FDA-approved following the reports that I have shared with you
late last year. So it will be available shortly, in fact. I know that some of my colleagues
have actually started prescribing already.
But the attraction to me is to be able to get somebody off TPN completely. And I think a
lot of this is going to be driven by patients themselves. They’re going to say, “Look, I
can’t, this is horrific. I cannot think of having to live with an IV for the rest of my days. I
need to try something different.” How that will work out, your guess is as good as mine.
Dr McClave: The other thing that I thought was interesting, I wondered if baseline GLP
levels would determine response, with lower levels with type 1, would there be greater
response, but your data doesn’t support that at all. The best ones that respond have
less severe short bowel syndrome.
Dr O'Keefe: That’s what’s really quite strange and there are some very nice animal
experiments which have actually shown that, that you can super adapt despite the fact
that you’ve got full normal adaptation going on and normal high GLP-2 levels in short
bowel animals. That was Dr Ney’s studies, beautiful studies.
Dr Steiger: Why, if 0.05 is good, why isn’t 0.1 even better?
Dr O'Keefe: Well, you want to be here all night? That took us all by surprise. My own
feeling, I was going to say my gut feeling, is that they’re both equally effective but if they
are equally effective, why not go with a lower dose. I think in those studies, the reason
that the 0.1 dose didn’t come off as well is that the baseline TPN requirements were
higher in that group. Also, the higher you go—this has been shown in infliximab and
other sort of biological studies as well—is that you get up to a plateau and you actually
can decrease the effect if you give too much.
And another factor is that, say if the drug is working too strongly, then it might, in fact,
increase complications such as chronic obstruction, stomal enlargement, and so,
therefore, lead to less compliance and people being taken off the drug. And, certainly,
there was a hint of those complications being more common on the higher-dose group.
Dr Steiger: You had a slide that showed SOCS, is that one of the reasons why the
higher doesn’t work? Suppressor cytokine signaling?
Dr O'Keefe: I don’t know, educate me.
Dr Steiger: It was on your slide and there was some literature that I read showing that
the higher the dose of the growth hormone, the less effective it was because of the
suppressor cytokine signaling that interfered with its action on peripheral tissues, and
one of your slides showed that SOCS was being produced along with GLP-2.
Another thing related to the biochemistry is, why not use or study IGF-1? That seems to
be the common mechanism by which growth hormone and GLP-2 act.
Dr O'Keefe: That’s a good question. I’m not aware of any studies that have been done
with IGF-1 and—Does anybody know in the audience, have they had any experience
with any endocrinologists in the—No. It must be a stability factor or something like that
because it is a peptide so you should be able to synthesize it.
Dr McClave: Another question I had: In the literature, is the difference between GLP-1
and GLP-2, is the GLP-1 effect more limited to the stomach in slowing gastric emptying
and the effects aren’t as great on the rest of the small bowel?
Dr O'Keefe: I didn’t have time to share with you a small study, an uncontrolled study,
that was published from somebody in California, where they looked at GLP-1 and that’s
the native GLP-1, and actually showed reductions in IV requirements in a group, I think
it was 5 short bowel patients. But they were specifically looking at its effect on motility,
and as a sort of added thing, they measured stomal outputs which were actually
reduced. And I think that’s also an exciting possibility and I suspect that all ileal brake
peptides, that includes PYY as well, might well have some beneficial effects.
And if you are actually trying to mimic what the ileal brake does, then it makes sense to
use a battery of peptides and not just a single thing, just as we do with
chemotherapeutic agents. But, it’s the next study.
Dr Steiger: So you use growth hormone and GLP-2 together? Just kidding. But that was
out of Cedars-Sinai, I think, that description of exenatide.
Dr O'Keefe: Correct.
Dr Steiger: For the use in patients with short bowel that showed a dramatic reduction.
Dr O'Keefe: Yeah, but it was uncontrolled.
Dr Steiger: Uncontrolled.
Dr O'Keefe: I think you’ve got to be very careful with these studies. I and/or our nutrition
team can actually reduce PN requirements dramatically by good management principles
that Steve shared with us. So diet, I think diet really explain all the effects of the Byrne
group, that they really were experts at dietary manipulation. And what you’ve got to
teach your patients is that your normal anatomy is gone and so you can’t eat like a
normal human being. And we really only need 1 meal a day. Once you’ve lost your
small intestine, you’ve got to make it work as long over the 24-hour period as possible.
And that’s why that one study where they actually use the feeding tube and delivered it
at a slow, constant rate, they got dramatic effects.
So you’ve got to change your whole pattern of eating and I say go around nibbling like a
rabbit all day long, and that’s what you need to do to keep things working and keep
them in there as long as possible.
Dr McClave: As this drug becomes available, we’re going to get into some strange
situations. Patients that are years out from their massive small bowel resection, insisting
on trying the drug to see if they get additional benefits. Would you not treat that patient?
And then, the second question is, is there any subset of patients with short bowel that
you would not treat or there would be a contraindication?
Dr O'Keefe: Those are excellent questions. Basically, I would try it, and I think a lot of
the audience will have experience with these patients, and some patients get used to
their IV fluid infusions and we always try and cut them down, give them at least a few
days off during the week. Others are really resistant to that. They don’t want to be. They
say, “Look, I’m happy with what I’ve got.”
So those sort of patients are not really going to like a new approach. There are others
who usually young professionals, and people who get out and have a life, those are the
people who are going to demand it. They’re going to say, “Look, you’ve got this new
wonder drug, I need it now.” And there’s going to be overenthusiasm. So I think the
best, what we can do at the moment, is to advise what we’ve seen in clinical trials and
say that we’re still learning. It’s a learning experience and it’s an exciting new avenue
that we’ve got now to use. Whether it’ll work well or not, I mean, some patients it does
not work on. Which again, is interesting. Why? I don’t know.
Dr McClave: The side effects really sound minimal. No hypersensitivity reaction, nothing
that is really going to cause you to have to stop the drug.
Dr O'Keefe: They’ve measured antibody levels and over the now 2-year period and
showed no excess of drug-specific antibodies.
Dr Steiger: But your cautionary remarks about long-term use and cancer and all that still
is in effect?
Dr McClave: It’s like our biologics in IBD, if you treat for 6 months or a year, stop and
come back a year later and treat, would you anticipate antibodies, in a transfusion-like
reaction, or not?
Dr O'Keefe: Yeah, I think that there are a lot of lessons from the biologics in Crohn’s
disease that one can learn from. There’s a lot to learn.