Slide 1
I’m going to start out by talking about the type 2 diabetes pathophysiology, the
current landscape for the treatment of type 2 diabetes. And I’ll begin a little bit of the
discussion about where the GLP-1 agonists might fit in to this.
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Slide 2
I want to start our program with a patient case. So in this patient case, we have a 44year-old Hispanic female who comes for a diabetes coaching session. And one of the
things she says when she comes in is “I feel like I can’t lose any weight. I’m really
stuck and I know that losing weight is important. I’ve tried and I just can’t seem to
make any progress.” She has type 2 diabetes for the past three years and also
dyslipidemia and hypertension, and she’s been overweight most of her adult life.
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Slide 3
Current medications include metformin 1000 twice a day, ramipril 5 she takes in the
morning, along with chlorthalidone 25 milligrams. Pravastatin 40, which she takes in
the morning. Fish oil capsules, which she takes two capsules twice a day. Calcium plus
vitamin D for her bones. She has no known drug allergies, no previous drug reactions.
And she actually has a prescription drug plan that helps to pay for some of her
medications with a 3-tiered plan.
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Slide 4
She works as an administrative assistant. She’s kind of concerned about losing her
job, though, because there’s been talk of downsizing in her company, but luckily her
insurance comes through her husband’s employment. She lives with her husband and
three teenaged kids. She eats a very carbohydrate-rich breakfast, often skips lunch
because at work she’s very busy. And she makes traditional Cuban meals for dinner
for her family most nights of the week. She tries to attend a fitness class, but she
admits that this is kind of sporadic and she probably only does it two to three times a
month. She denies ever using tobacco and she enjoys a glass of wine, but probably
only a few times a year on social occasions with the family.
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Slide 5
Physical examination. So this is her most recent physical examination and vital signs.
Her blood pressure is 138 over 90; a heart rate of 86 and it’s regular. She’s not in any
pain. As you can see, she’s overweight. Her BMI is 33.8. Her last A1C measured just a
few days ago was 8.4% with a fasting blood glucose of 146. Serum creatinine and
BUN are within normal limits but her estimated creatinine clearance is 67 mils per
minute. Liver function tests are normal and her cholesterol panel looks pretty good.
LDL of 88, HDL of 27, and triglycerides of 198.
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Slide 6
So which of the following medications would be the most appropriate addition to this
patient’s antidiabetic regimen at this time? And remember, she takes metformin
twice a day. Do you think it would be best to add a basal insulin to this lady’s
regimen? Would you be recommending adding a DPP-4 inhibitor, a GLP-1 agonist, a
sulfonylurea, or a thiazolidinedione? And those are the most common things that
would be added to metformin in most patients. So what would you recommend in
this patient’s case?
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Slide 7
Many of you would recommend a GLP-1 agonist. We’ll come back and explore that
more.
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Slide 8
When we look at the clinical practice guidelines, you’ll see there are some differences
between different organizations about which of these therapies they might
recommend next. We’ll come back and talk about that.
Type 2 diabetes is actually a fairly complex disorder. It involves two primary
things but many organ systems that kind of contribute to hyperglycemia. The one of
this is the person does not produce enough insulin relative to what their body needs
to keep them in euglycemia. So they don’t produce enough insulin at the right time.
And the reasons why they don’t produce it is one is beta-cell dysfunction. But why do
they develop beta-cell dysfunction? Well, part of that is from hormones that are
secreted by the gut. These are the incretin hormones and GLP-1 is one of those. And
along with another hormone, GIP. So these hormones stimulate the beta cells to
release insulin at an appropriate time and they also help to maintain beta-cell health.
So that’s part of the pathogenesis of type 2 diabetes.
Then there’s this insulin resistance part of the equation, and most of that
comes from adiposity. As people begin getting heavier, they get more insulin
resistance. And of course, there’s some genetic variability that contributes to that as
well, so some people who are obese are more prone to developing greater resistance
relative to that, as well as the beta-cell dysfunction. To combine those two things
together kind of sets you up for hyperglycemia. And there are other mechanisms that
are all at play here, including hyperinsulinemia and also insulin resistance at the site
of muscle and brain tissue. So complex mechanisms here.
Slide 9
We look at the kind of natural history of type 2 diabetes – before people are
diagnosed with type 2 diabetes, there is a period of time when people are at high risk
for type 2 diabetes, and what you see during this period of time is that their
postprandial blood glucose begins to rise when they eat. And this is related to some
degree of beta-cell dysfunction. This early-phase release of insulin is impaired, and so
after they eat their blood glucoses are higher, but their fasting blood glucoses look
pretty good. And so they’re not diagnosed with type 2 diabetes yet because their
fasting blood glucoses look okay. It’s during this period of time when they’re able to
secrete more insulin, and their insulin resistance, although it’s rising, their insulin
release is sufficient to keep, at least, their fasting blood glucose under control.
When they first get diagnosed with diabetes, it’s when their fasting blood
glucose is elevated. And the reason why it becomes elevated is because now beta-cell
dysfunction has grown to such a point that it’s not enough insulin to meet the insulin
resistance that’s underlying this. And as diabetes progresses over the years – and this
is number of years of onset in here – the insulin level progressively declines and the
insulin resistance remains. And of course, because insulin secretion declines, both
fasting plasma glucose and postprandial blood glucose increase. This is the natural
course of type 2 diabetes. So there’s a decline in beta-cell function that results in
lower insulin secretion, and this is also mirrored in a decline in incretin effects, the
incretin function of the gut. As the gut sends less of a signal to the beta cells, they
produce less insulin and we have more and more beta-cell dysfunction over time.
Slide 10
What do the clinical practice guidelines say about the treatment of type 2 diabetes?
Well, there are two major organizations that publish guidelines in the United States
that many clinicians follow. One is the American Association of Clinical
Endocrinologists and the other is the American Diabetes Association, and both have
recently published guidelines, 2011, 2012. Each say that good glycemic control is
important, but their benchmark for what they consider to be the goal of therapy for
most patients is slightly different. The AACE guidelines recommend to go as low as
possible, and that would be 6.5% on an A1C or less, whereas the ADA say major
clinical trials achieved about a 7%, and that’s all that should be achieved in practice
unless you can get below that without causing any hypoglycemia. So the benchmarks
are slightly different. And that’s true for both postprandial and fasting blood glucose
goals. So you’ll see the AACE guidelines a little more stringent fasting and
postprandial blood glucose goals compared to the ADA guidelines.
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Slide 11
If you wanted to draw a little graphic of this, this is kind of what they would look like.
The ADA guidelines is less than 7% in terms of the overall glycemic control that’s
measured by an A1C, but then postprandial blood glucoses could be as high as 180
and the fasting one should be around 110 or less and somewhere in this range,
whereas the AACE guidelines have this kind of graphical representation. And
particularly, if you’ll notice, the postprandial blood glucoses are far more aggressive.
They key in on achieving really good postprandial blood glucose control.
Slide 12
Now, we have a lot of choices. And when I first started in diabetes education about 20 years
ago, I could only talk about two things: insulin and sulfonylureas. We’ve come a long way. So
for any of you that have been in practice for more than 15 years, you’ve seen an explosion in
the number of medications that are available to treat type 2 diabetes. Now, that’s a great
thing; we have more tools, but it also means we need to use these tools appropriately in the
right circumstances, since we have so many more choices.
Insulins, I think you’re all familiar with them. There’s a wide variety and a lot of
delivery forms. We have pumps and pens and still vials and syringes a lot of patients use.
Sulfonylureas have been around for a long time. There haven’t been any new agents
introduced here in more than a decade. The thiazolidinediones were introduced in the 1990’s
and we know quite a bit about them. There are growing concerns about some of their
adverse effects in recent years but they’re still an available option for us. The glinides, also
introduced in the 1990’s. These stimulate insulin production and sort of like sulfonylureas but
their mechanism of action and they’re much shorter duration of effect. The alpha-glucosidase
inhibitors inhibit the breakdown of complex carbohydrates, and therefore we don’t have as
high a peak of blood glucose so they affect postprandial blood glucose. Then there’s the
amylin analog. Amylin is also secreted by the pancreas, and so pramlintide, which is the
amylin analog, mimics that hormone which is a natural hormone that also addresses
postprandial blood glucose excursions. The DPP-4s, the dipeptidyl peptidase-4 inhibitors, and
there are several of them in this class now, inhibit the hormone that breaks down the incretin
hormones. And we have the GLP-1 agonists, which mimic the action of GLP-1. We have bile
acid sequestrants, which are approved for type 2 diabetes, by lowering both cholesterol and
blood glucose and affecting outcomes. And the last and the most recent, and the one that I
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have not seen prescribed yet myself, is the dopamine receptor agonist bromocriptine, which
is now being used for type 2 diabetes as well. So we’ve got a laundry list of medications that
we could use for patients with type 2 diabetes.
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Slide 13
And these medications work in a variety of ways. They work by stimulating the
pancreas to produce more insulin. They overcome insulin resistance. They regulate
the liver in terms of glucose production. And glucagon, they influence satiety and
how much food we take, as well as gastric emptying. So they have a variety of affects
throughout the body. And because each drug has a different effect, we often use
them in combinations.
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Slide 14
So some things that have been kind of problematic with many of the therapies
that we have, certainly our traditional therapies, the ones that stimulate insulin,
or even insulin itself, and even the thiazolidinediones, are kind of associated with
weight gain. And that’s one of the issues that our patients already have. Most of
them are overweight. That’s one of the reasons why they’ve developed type 2
diabetes. Many of these therapies are associated with hypoglycemia. Not all of
them, but certainly the ones that stimulate insulin secretion. And hypoglycemia in
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of itself is a problem, and not only produces symptoms short term in emergency
room visits and hospitalizations, but it may have long term consequences if the
patients have repeated hypoglycemia. It affects quality of life but it also affects
perhaps the development of dementia, for example. So it is a real issue we have to
deal with. Many of these therapies are not easily tolerated. Metformin causes a lot of
GI side effects, so do the GLP-1 agonists. The long term safety concerns of some of
these therapies we know with rosiglitazone we’ve become more and more concerned
about the cardiovascular outcomes, potential development of heart failure,
osteoporosis, and even cancer has now become a concern perhaps with some of
these therapies, including insulin. Most therapies except for insulin really don’t
maintain good glycemic control over the long haul. Insulin we can always increase the
dose, but many of the therapies we have just don’t maintain good glycemic control
for long periods of time. Some of the newer agents we don’t know yet because they
haven’t been around long enough. But certainly, our traditional agents, it’s kind of
problematic. We might get two, three, four years, but then we have to add on
additional therapies.
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Slide 15
So our older glucose-lowering agents; they’ve been around for quite some time.
Metformin is our workhorse by all the guidelines. It can lower blood glucose pretty
substantially and it’s weight neutral or may lead to some weight loss in some patients. And
it’s got good outcomes data. So it’s our workhorse in patients with type 2 diabetes, but
not everybody can tolerate it because it does have GI side effects. And it is generically
available.
Sulfonylureas have been around for a long time. We’re using less of these now. I
think in part because they do cause hypoglycemia and they do cause some weight gain for
some patients. And they are available as generics so they’re inexpensive, but some of the
adverse effects have led to us using them less and less relative to some of the newer
agents.
TZDs, they’re not available generically. They’re expensive, and I’ve already told you
about some of the issues – development of heart failure, weight gain, osteoporosis is
becoming an increasing concern of these. And the risk of potentially increasing the risk of
cardiovascular events, particularly with rosiglitazone, perhaps not with pioglitazone but
with rosiglitazone, has emerged as concerns.
The glitinides, they’re relatively short-acting secretagogues, so they’re similar in
terms of the sulfonylureas. Don’t cause hypoglycemia quite as much but also can be
associated with weight gain.
And the alpha-glucosidase inhibitors have a lot of GI side effects, but they do
address postprandial glucose quite well, but they’re not as potent as some of our other
agents in terms of A1C lowering because they address only postprandial blood glucose.
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Slide 16
So our newest oral agents are the DPP-4 inhibitors, and we’ve got several in this class.
Again, they address primarily postprandial blood glucose, so their effect on the A1C is not
as potent as some of the other drugs that address both fasting and postprandial. But they
are weight neutral. They’re fairly well tolerated, so they’ve gained some popularity over
the sulfonylureas because of these issues. Unfortunately, they’re only available as brand
name products so they’re more expensive than the sulfonylureas.
Colesevelam, which is the bile acid sequestrant, is approved for type 2 diabetes. It’s
not particularly potent and it does have a lot of GI side effects like all the bile acid
sequestrants tend to have and it’s not available generically.
Bromocriptine is also a new agent, not very potent. Addresses primarily
postprandial blood glucoses and it has a tremendous pill burden. You have to take six of
these a day. So it hasn’t really taken off in the marketplace yet. And there are some side
effects such as nausea, dizziness, and fatigue from this.
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Slide 17
And then we have our injectable therapies. You all know about the insulins, of course. But
the GLP-1s are injectable therapies. They lower blood glucose at least as good as
metformin and the sulfonylureas do. They ‘re associated with some weight loss. Most
patients will have some weight loss on these. They seem to improve cardiovascular risk
factors, so the weight, lipids, and blood pressure. But they are an injection. They do come
with GI side effects and they are not available generically yet.
Pramlintide addresses mainly postprandial blood glucose. It does require injections
and also causes GI side effects and is not available generically.
Insulin is our go-to agent when you really need to lower blood glucose a lot.
Because this is the one that has no dose limit; can really lower your blood glucose very
significantly. And so when we come to the clinical practice guidelines, you’re going to see
insulin being favored in patients whose A1Cs are quite elevated.
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Slide 18
So what do those guidelines say? Well, the American Association of Diabetes
Educators has this – that if someone is diagnosed with type 2 diabetes the first
thing we should be doing is starting with lifestyle modification and metformin.
It’s the go-to drug unless there are contraindications. And then if the patient is
not able to achieve an A1C goal of less than 7, then you’re to add on additional
therapies. And they have Tier 1 therapies on this slide, which are the wellvalidated therapies, things that have been shown in long-term clinical trials to
change outcomes. And then they have Tier 2 therapies, which are drugs that
have not yet been well validated in long-term clinical trials to change outcomes,
but do lower blood glucose. And so the ADA would favor these Tier 1 agents
being added to metformin.
Now, not everyone can take metformin. Some people develop GI side
effects. Some people don’t have adequate renal function to take metformin. And
of course, the sulfonylureas, they’re associated with hypoglycemia and weight
gain, which for many patients we really want to avoid. And, of course, the TZDs
in recent years have really a lot of side effects that we’ve become increasingly
concerned about. So now we’re left with – do we add basal insulin, which is a
good option for many patients who are on metformin, or do we add a GLP-1
agonist?
Those are, in my mind, the two kinds of things I think about when I have
someone on metformin and they’re not at goal.
Slide 19
The ADA guidelines assumes, though – there are some things that you should realize
– assumes that all patients have an A1C that’s not at goal but not all that elevated. In
other words, they assume people are at like 8. But some patients have an A1C that’s
14 or 12, and in those cases it really wouldn’t be appropriate just to add a
sulfonylurea to that. That wouldn’t get them to goal. So it doesn’t take into account
that different patients are at different levels of glycemic control. It also doesn’t really
take into account hypoglycemic risks. It doesn’t look at other factors that may cause
blood glucose fluctuations during the day. They don’t, say, address postprandial
versus fasting blood glucose and use combinations that way. And they really don’t
talk about how the medications might have positive impacts or negative impacts on
other diseases the patient might have. So if they’re at a high risk for cardiovascular
disease, would we want to use agents that influence cardiovascular risk factors, for
example? That’s not a part of what they consider. They put a lot of heavy weight in
their algorithm on long-term clinical trials and on drug costs. The drug cost factor.
And those are important things to consider.
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Slide 20
The alternative guidelines, the American Association of Clinical Endocrinologists
diabetes algorithm, stratifies what drugs you use based on A1C. So how out of control
is the patient is an important consideration. And they consider both fasting and
postprandial blood glucose. They consider costs, but they also put a premium on side
effects from these medications. They put a lot of emphasis on the risk of
hypoglycemia and weight gain. They do say that most patients should start with
metformin, but many patients should probably start with a combination therapy right
off the bat, depending on what their blood glucose levels are. And what you combine
it with depends on whether they’ve got high postprandial blood glucoses or what
other comorbidities they have. And they think that all of the classes of medication
should be considered.
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Slide 21
So if you look at their guidelines, this is kind of what the algorithm looks like. It’s
much more complicated because it considers so many more factors. They consider all
the patient-related variables. If you’ll notice, though, the one important factor that’s
right at the top is where is the patient’s A1C? Because if it’s over here in the 9%
range, you’re beginning to think about insulin or triple therapies.
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Slide 22
So if the person’s A1C is close to goal and their goal is 6.5, then monotherapy is
probably going to be sufficient for most patients and metformin is the drug of choice,
and if they can’t tolerate that or they don’t have good enough renal function, then
they suggest alternatives. And that can include DPP-4 inhibitors or the GLP-1 agonist
as monotherapies.
If they’re asymptomatic but their blood glucoses are about 7.5, for example,
then they start saying consider dual therapies because one drug is probably not going
to get you to goal. And they list some combinations. And if it gets to 9% or above and
the patient is symptomatic, then you’re really talking about triple therapy or, in my
mind, you’re talking about insulin plus two orals. And that’s the way their diabetes
guideline is structured. It’s more based on where their blood glucose is that and how
is their postprandial as well as their fasting, and what combinations make sense.
Slide 23
So, the ACE/AACE algorithm for the management of hyperglycemia in patients with
type 2 diabetes emphasizes what? Risk of hypoglycemia? Do they put a lot of
emphasis on long-term safety data? Do they put a lot of emphasis on patient out-ofpocket cost? Or do they put a lot of emphasis on postprandial blood glucose
lowering?
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Slide 24
Okay. You know, I was a little torn, and you should have been a little torn about the
answers. And I’m just like you. I think 1 and 4 are equally important in these
guidelines. So the risk of hypoglycemia is certainly something they address in the
guidelines, but also postprandial blood glucose. Which one they value more, I don’t
know. But they do not consider as strongly patient out-of-pocket costs, because they
do talk about all of these new drugs and these new agents, which are costly. And they
don’t emphasize long-term safety data quite the same way as the ADA guidelines do.
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Slide 25
Okay, so AACE diabetes algorithm emphasizes glucose lowering and tolerability over
long-term outcomes. And just to kind of depict that a little bit, this is obviously the
queen of England walking by someone who’s had an adverse outcome. And so it’s
important to recognize that each of the two organizations actually, I think have a lot
of value. And I consider them both equal and important ways of looking at the
diabetes algorithm.
Slide 26
Long-term outcomes matter. They’re important. We need to know that drugs
have a long-term beneficial effect for our patient. But we’ve got so many
choices, how do we use them appropriately together? And that means
addressing both postprandial and fasting blood glucose in combinations and
considering insulin perhaps earlier than we have in the past. And so I actually
think both guidelines have it kind of right. I wish they would be able to come to
some consensus between the two organizations. So we know good glycemic
control matters. It matters for both type 1 and type 2 diabetes. This is data
from the UKPDS trial that shows in the long-term, the risk of cardiovascular
disease and diabetes-related death and microvascular complications are
reduced with good glycemic control.
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Slide 27
And that’s been validated again in a long-term follow-up study to the UKPDS. This is a
10-year follow-up study that shows that those benefits persist over the long haul. So
if we achieve good glycemic control now, it will have long-term, lasting benefits in
terms of complications for patients.
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Slide 28
So when helping patients and prescribers pick the best medicine for diabetes, which
of the following do you emphasize? Do you emphasize avoiding hypoglycemia? Do
you avoid weight gain for patients with type 2 diabetes? How about avoiding
injections? Is that something you try to do at all costs? Limiting out-of-pocket cost or
lowering glucose as much as possible? You want to go for the most potent agent
there is.
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Slide 29
Now, there’s no right or wrong answer on this, by the way, we’re just curious as to
what you emphasize. So most of you like to get the most bang for your buck. You like
to lower the blood glucose as much as possible when recommending an agent, and I
think that is an important consideration. I don’t want to overlook the fact – I’ve
thrown this in as a little curve ball to you. Some of the agents that don’t lower A1C as
much is the reason why are that they address postprandial glucose. And drugs that
are addressing postprandial glucose may not have as much of an effect on the A1C,
but they really address a very important part of the glucose control equation. And
we’re learning more and more about postprandial glucose and its effect on long-term
outcomes. So I hope you don’t look at lowering glucose as much as possible as only
A1C lowering, but postprandial glucose lowering. And I agree with you that avoiding
hypoglycemia is a real issue, a real concern. And it can really negatively affect
patients’ lives and willingness to take therapies.
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Slide 30
Okay, so A1C increases over time with all the agents. I talked about this, the durability
of effect, and there are many clinical trials that have looked at this. When we use
most of our agents, no matter what, over time glycemic control worsens. And this is
the ADOPT trial here. They used rosiglitazone, metformin, and glyburide in this
particular trial. What you can see was glyburide was really the most effective off the
bat in terms of glucose lowering, but in the long run it was the worst in terms of
holding glycemic control. Metformin and rosiglitazone were a little bit better in terms
of holding, but you can still see the trend is upward. The TZDs appear to have a little
bit more glucose maintaining over time and it may be true with some of our newer
agents. But still, they don’t work forever.
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Slide 31
And there are probably many reasons why we need to use multiple agents in patients
with diabetes. I wish we could just use one, but type 2 diabetes is a polygenic
disease. It’s got multiple defects. It’s a progressive disease so we often need to add
on agents. Monotherapies just don’t cut it. Not for long, anyways. And unfortunately,
a little bit of hyperglycemia begets more hyperglycemia, and you can see patients
that go from a 9 A1C and blood glucoses in the high 100s/low 200s to suddenly
having blood glucoses in the 300s and 400s. It happens very rapidly because of this
glucose toxicity. So hyperglycemia can progressively cause beta-cell dysfunction very
rapidly and now you’ve got someone really out of control.
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Slide 32
So let’s turn our attention to the GLP-1 agonists.
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Slide 33
GLP-1 agonists are simulates with the effects of the GLP hormone, specifically the
GLP-1 hormone, which is secreted in the gut. So these are major hormones that
modulate pancreatic function. They not only regulate insulin secretion but also
glucagon.
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Slide 34
So this is our friendly blue man. When he eats food it stimulates his gut, and
specifically the L-cells in the gut to release GLP and GIP, and this has many effects.
One is to stimulate insulin secretion, first-phase insulin secretion. It suppresses
glucagon so the liver doesn’t overproduce glucose, and slows gastric emptying so the
patient feels fuller and they don’t eat as much and therefore their blood glucoses are
lower and they lose some weight. And it seems to, at least in animal models, to
increase beta-cell mass and beta-cell health and maintain beta-cell function over
time.
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Slide 35
These hormones are regulated pharmacologically in two ways. There’s the DPP-4s
and there is the GLP-1 agonists. The DPP-4s inhibit the enzyme that breaks down
endogenous GLP-1 and GIP. GLP-1 agonists are pharmacologically providing the
hormone in a pharmacological way and don’t depend on that mechanism of
inhibiting that enzyme. It’s providing that hormone directly, so it’s mimicking the
action of the GLP-1s. And we have the two products there.
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Slide 36
My next question to you is: In what ways do the GLP-1 agonists and DPP-4 inhibitors
differ? How are they different? Is it they are different tolerability profiles? Is it their
glucose-lowering potential? Is it the route of administration that’s different? Is it their
effects on weight that’s different? Is it all of the above or frankly, they’re alike in all of
those regards so it’s none of the above? They’re essentially the same. What do you all
think?
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Slide 37
Okay, let’s see what you say. Well, you’re a very smart crowd. You knew that all these
things are different, and indeed they are.
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Slide 38
There are some things that are common. They both work on the incretin hormone
system so they both increase, because they affect incretin hormones, they both
increase insulin secretion from the pancreas. That’s true. And they both affect
glucagon secretion; they both suppress that. But beyond that, they’re different.
One is the potency of it is somewhat different because GLP agonist are
obviously supplying this. It’s an agonist. DPP-4 depends on you secreting GLP-1
yourself and then inhibiting it so that it stays around longer. So they have different
effects on gastric emptying. GLP-1s affect that. GLP-1s tend to have you lose weight.
DPP-4s are weight neutral. Side effects, the DPP-4s tend to be better tolerated. The
GLP-1 agonists, patients will experience some nausea and some will have vomiting.
Hypoglycemia, neither of them are associated, at least in monotherapy, to cause
hypoglycemia. One is orally administered and one is subcutaneous. So those are
some key differences.
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Slide 39
GLP-1 agonists, because remember, patients over time are losing the ability to
secrete these hormones, so it corrects some of that pathophysiologic defect, just like
insulin. We give insulin because patients are not secreting enough. We’re giving a
GLP-1 agonist to kind of replace what their body could have secreted. Now this is a
pharmacological dose. It is much larger than what had been secreted from the L-cells,
so it has a very robust effect. Again, it’s postprandial glucose. It really affects insulin
secretion then. It does cause some weight loss, and it appears to have some positive
effects on cardiovascular risk factors. What we don’t know yet is does it change
cardiovascular outcomes, because that’s going to take some long-term clinical trials.
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Slide 40
I just want to show you some quick slides, some data. Curtis is going to show you a
lot more data on the GLP-1s in his presentation. And here are some quick things. As
you can see, compared to a DPP-4 – sitagliptin is a DPP-4 and liraglutide is a GLP-1 –
the glucose lowering and the reduction in glucose is much greater with a GLP-1 and
the effects on weight are much greater with a GLP-1.
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Slide 41
If we were to compare liraglutide with exenatide – the combination of
liraglutide or exenatide with metformin, plus or minus a sulfonylurea in there,
you’ll see that liraglutide, which is a longer-acting agent, has a little bit more
glucose lowering than exenatide the twice-a-day regimen. It has more of an
effect on fasting blood glucose than others but if we look at nausea and side
effects, they’re about the same.
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Slide 42
There’s a new product now with exenatide, which is the extended release. It’s a oncea-week product. And Dr. Triplitt is going to tell you more about that later, but it’s also
a much longer-acting agent than the exenatide twice a day, the original product that
came out. And what you see here is that a longer-acting agent, just like liraglutide is,
produces more glucose lowering. So the A1C is a little bit lower. Most of that’s
through it seems to have more of an effect on fasting blood glucose. With a longeracting agent, at least in this trial, we saw that the incidence of nausea was somewhat
less.
42
Slide 43
Exenatide twice a day given over a long period of time has a positive effect on
cardiovascular risk factors. So you see here is not only are triglycerides down quite a
bit but also serum lipids look better. HDL is up; LDL is down. Systolic and diastolic
pressures are down a little bit. Probably most of this is mediated through weight loss,
so as people lose weight some of these parameters look better.
43
Slide 44
And this is a trial with liraglutide, which shows essentially the same sorts of things.
The patients lose a little bit of weight and therefore their blood pressure, their
triglycerides start to look better over time. So these are very positive things that we
would hope over a long period of time would have a positive effect on long-term
outcomes. Still don’t know yet; we need long-term clinical trials.
44
Slide 45
Now, with every therapy there’s a downside. And I think one of the things that we’re
watching right now is how big of a problem is pancreatitis with some of these new
therapies. It’s been reported with DPP-4s. It’s been reported with the GLP-1 agonists.
So all the incretin-based therapies have been associated with it – hadn’t been a
causal relationship, but we’re watching it over time. Certainly if a patient develops
some symptoms that suggest they have pancreatitis, which is belly pain for the most
part, we really need to stop these agents and we need to investigate whether they
have elevated amylase levels or not, whether it is really due to this or not. And if
someone has a history of pancreatitis, I would probably right now avoid one of these
agents. One of the things that we’ll talk about and we’ll test on this a little bit later is
in patients who have a history of MEN-2, which is the multiple endocrine neoplasia
syndrome type 2, and these are people who have medullary carcinomas of the
thyroid cancer. It’s a very rare cancer. These types of patients shouldn’t be receiving
the GLP-1 agonists. These drugs may, may cause an increase in stimulation of this
tissue – the medullary cancerous tissue, because it was observed in rat models. So
these are the two areas we are keeping an eye on as these are new drugs. We don’t
know how much of an issue it is in the long run.
45
Slide 46
So with that, I’m going to return to the case. Remember, she’s 44 years old. She’s got
type 2 diabetes. She’s been overweight for 20 years.
46
Slide 47
She’s on ramipril, metformin, chlorthalidone, pravastatin, fish oil and calcium.
47
Slide 48
And these were her parameters. Her A1C is 8.4. Let me point that out to you now.
Fasting blood glucose is 146 and she’s got a BMI of 33. And her blood pressure is a
little borderline for someone with type 2 diabetes.
48
Slide 49
So which of the following medications would be the most appropriate to add to her
regimen at this time? And she’s on metformin. What do you think now? Add basal
insulin? Add a DPP-4? Add a GLP-1? Add a sulfonylurea? Add a TZD?
49
Slide 50
So we’ve got a few more of you. So maybe I’ve shared with you some data that really
changed your opinion about the GLP-1.
50
Slide 51
In what ways are GLP-1 agonists and DPP-4 inhibitors different? Now you should all
get this question right. Is it tolerability, are they different in tolerability? Glucoselowering potential? Route of administration? Is it all of the above or are they really
the same?
51
Slide 52
It’s all of the above.
Thank you very much.
52
Slide 1
When we were preparing these talks, one of the things we were talking about is
clinical pearls. And that’s one of the reasons why I’m here. So as you think about
clinical pearls, what are the kinds of things that you think about? Well, some of the
things that I think about are things that I want my patient to know and that I need to
know before my patient asks me. So one of the things to think about is, as you’re
sitting there, “What if my patient asks me about this? What if my patient asks me
about that? Do I have the answer for them or do I have to go, oh, I’m not quite sure, I
think it should be okay.”
1
Slide 2
2
Slide 3
So as we go forward, I’m going to be explaining some of the benefits of GLP-1
therapy. We’re going to talk about adverse events. We’re going to talk about drug
interactions. We’re going to make sure you know the dosing. We’re going to know
how to adjust that medication. And we’re going to talk about administration
techniques. So we have a lot of ground to cover.
3
Slide 4
So let’s start with a case. You have in front of you a 44-year-old Hispanic female and
she presents to the diabetes coaching session. So she’s there at the visit, so that’s the
first step. So now it’s up to you to take her from point A to point B. So she’s had
diabetes. She has hypertension. She has dyslipidemia. And she’s obese.
4
Slide 5
Does that sound like anyone you know with type 2 diabetes? This is a very common
presentation, right? The other thing is that not everything in the case is absolutely
controlled. So as you look at her, one of the things you see – what are the things that
you see that right away, we need to work on that. Anything? She’s perfect, send her
home? No. All right. Hopefully you guys are looking at blood pressure. Hopefully you
guys are looking at her weight; her A1C is certainly not at goal. Fasting plasma
glucose is high. We have a little bit to work on maybe with triglycerides, but overall
we need to talk about how are we going to help this patient that presents to us.
5
Slide 6
So what may be helped by addition of the GLP-1 agonist to metformin? One, does it
help glucose only? Two, does it help glucose and weight? Three, does a GLP-1 agonist
help glucose, weight, and hypertension? Or number four, does it help glucose,
weight, hypertension and dyslipidemia?
6
Slide 7
We have a little more to build on here. The correct answer actually is number four. So
believe it or not, we know that GLP-1 therapy lowers triglycerides some, which is
probably one of the ones some of you missed. And the other one some of you missed
is actually a very interesting component of these drugs. They seem to actually help
people with hypertension lower their blood pressure slightly. So the average
reduction on the systolic/diastolic side, if the blood pressure is high, is around 2-4
millimeters of mercury. So this is another thing. Does that mean it’s going to get you
to goal? I didn’t say that. But what I did say, though, is that it’s certainly a positive
thing for your patient to help them on some of these cardiovascular aspects. Very
good.
7
Slide 8
So when that script comes into your pharmacy or you’re thinking about giving it to a
patient, one of the things I want you to think about are well-established versus nonwell-established reasons why you might give a drug. Everyone usually hangs their hat
on the left-hand side of this slide. They say, “Okay, I’m going to give you a medicine
because the mechanism of action, I want to make sure you don’t have
contraindications. I know it’s fairly safe for you and it fits into the budget.” Okay? And
on the right-hand side, though, are some of the things that we’re starting to really
incorporate into our diabetes treatment. We need to think about things such as
cardiovascular outcomes; why? Because four out of five people in your clinic with
diabetes are not going to die of their high sugar; they’re going to die of a
cardiovascular event. So because of that, a cardiovascular outcome is very important.
At a minimum, we should expect antihyperglycemics to be neutral. If they help them,
even better, but at a minimum we want them to be neutral. What about weight
effects? Most type 2s at your clinic, are they underweight, at weight, or overweight? I
work in San Antonio and most of the Hispanic patients I see are obese or, at a
minimum, overweight. So it’s something we need to deal with. Many are on statins.
Many have hypertension. And of course, one of the things that’s becoming more and
more important is the beta cell effect.
8
Slide 9
And one of the goals, really, is the fact that we want our patients to achieve the
clinical goal and we want to do this without causing lots of problems. So how would
you sum this statement up? How about, will the patient do it? Will the patient take
their medication? One of the things that I want you to think of is will this patient do
it. And some of that is you telling the patient to make sure that they have the proper
information to see if they’ll do it.
9
Slide 10
What medications, when used with an incretin-based therapy, might require a dose
adjustment? Which, in combination with a GLP-agonist, might actually require a dose
adjustment? Is it metformin, one? Insulin, two? Three, sulfonylureas and metformin?
Or four, insulin and sulfonylureas?
10
Slide 11
Very good. So the majority of you understand that hypoglycemia is something that we
need to think about when we add on to an incretin-based therapy. So if you have a
drug that’s on board that causes hypoglycemia, that may actually cause a dosage
adjustment. Sulfonylureas and insulin are the correct one. It looks like most of you
understood that. Now, some of you may have done sulfonylureas and metformin. We
know the sulfonylurea might need the dosage adjusted but the metformin is likely
not. So even though three sounds like it might be close we’re going to go with
number four.
11
Slide 12
So why are we talking about hypoglycemia? Why did most of you mention
hypoglycemia? It’s because it’s something that’s scary to your patient, right? So why
is it scary? Because these kind of statistics are out there everywhere. This is actually a
study. It was published in this little-known journal called The New England Journal of
Medicine. And it was published there because of the fact that it was so striking. And
one of the things that is striking is if you have someone who is over 65 years of age
and they looked at drug hospitalizations. This is right down our ally, drugs and you’re
admitted to the hospital, two out of the four top drugs actually are medications that
we use in diabetes. Now, the other ones we use a lot, too. We use anti-platelet
agents and we use warfarin in select patients, but two of them are directly related to
diabetes, and that’s insulin and oral hyperglycemic agents. So again, why were these
people admitted to the hospital? Hypoglycemia. 95% of these events were
hypoglycemic in nature and put that person into the hospital. So hypoglycemia is not
something that’s nebulous. It’s not something that is just kind of out there. We
shouldn’t just kind of consider it in therapy. If you want to get to goal in your patients,
you’re going to have to put hypoglycemia front and center for them.
12
Slide 13
This is why we consider GLP-1 agonists a potential drug that can help us with this
problem. So as you look at hypoglycemia, this actually two of the trials that are from
the liraglutide phase 3 trials. This happens to be LEAD-1. This is LEAD-1 and this is
LEAD-3, so if you look at the top, what you’re seeing is this is liraglutide plus a
sulfonylurea versus rosiglitazone and a sulfonylurea. And at the bottom, what we
have here is monotherapy of liraglutide versus glimepiride. If you’re looking at the
rates of hypoglycemia, it’s not that they’re absolutely zero, but you can see that if you
add on a sulfonylurea, the rates double. So what we’re seeing is 0.3 to 0.5, 0.25 to
about 0.47. And overall what you’re seeing is when you add on a sulfonylurea you
increase the risk of hypoglycemia. Now if it’s just minor hypoglycemia and it’s
something your patient can actually deal with and they understand how to treat it,
maybe that’s something that’s not going to fully prevent that person from actually
continuing therapy. But if they’re having more severe hypoglycemic reactions or
actually have to go to the emergency room, these are things that should be a
harbinger for you to actually say, “You know what? This is something serious. We
need to address it. We need to actually change therapy.”
13
Slide 14
What about GLP-1 agonists and drug interactions? Overall they’re pretty good in this
particular area, but one thing you guys need to know about, and of course that’s
slowing of the gastric emptying. GLP-1 agonists, unlike DPP-4 inhibitors, slow gastric
emptying, and what this means to your patient is they have something that’s timesensitive to get into their system, whether that be antibiotics, contraceptives,
narrow-threshold drugs, it’s important for us to understand that these drugs may be
delayed. It doesn’t necessarily mean they’re not going to get into the system, but
they’ll be delayed to get into the system. So drug interactions are something that
“will your patient do it?” If you have a patient who has in front of them levothyroxine,
something like that, it’s not that the levothyroxine won’t get into the system, it just
may be delayed slightly. But maybe you should put it before the drug is actually given.
14
Slide 15
“If a patient experiences some nausea with a GLP-1 agonist, what do you think you
should tell your patient?” Again, if a patient experiences some nausea on a GLP-1
agonist, what do you think you should tell them? Do you tell them to eat more
slowly? Number two, should you tell them to fill a prescription for metoclopramide?
Number three, should you tell them to take an antacid? Call their doctor in the
morning. Number four, should you tell them to take the medication at least an hour
before mealtime?
15
Slide 16
So take the medication at least an hour before mealtime. This is why we’re here. If
you take the medication – let’s just take one medication. Let’s take exenatide BID or
the immediate-release exenatide. And you move it more from the meal; what
happens? It actually slows down gastric emptying more. And the more you slow
down gastric emptying, the more GI side effects that person will actually have. So the
correct answer is actually eat slower. What happens is that the slower they eat, the
more likely it is that they’re going to feel full. That satiety signal is so important for
them. When that satiety signal comes, they’ll likely stop eating. So what happens is
that you eat slower, no nausea. So one of the things to think about is how fast your
patients eat as well. One of the things to think about is just eat slower. That’s actually
going to help them to feel that signal to stop eating. If you have to move it
someplace, exenatide would actually be moved closer to the meal. That should
actually help nausea a little bit, and we’re going to talk about it here in just a second.
16
Slide 17
One of the things about all of these drugs is that the nausea is dose-dependent. The first
thing you should look at is, “Can I reduce the dose?” The second thing is that it decreases
over time. If they’re able to tolerate the nausea, usually over time the nausea will get less.
And last is, is the nausea really a feeling of fullness? One of the things about the GLP-1
system is that it is deficient in type 2 diabetes and when we replace that GLP-1 or actually put
it all the way to pharmacologic doses, which is what GLP-1 agonists do, one of the things to
think about is that that may actually be satiety they’re feeling. Nausea and satiety are very
closely linked, so make sure that you discuss that with your patient. The other thing to think
about is if it’s really troublesome, leave it at a lower dose for a longer period of time, even if
the physician has recommended they go up to a higher dose. It’s important for them to be
experiencing no nausea. If you look at the package inserts, they’re quite clear about how you
should titrate the drug. You titrate the drug based on patient response. And the patient
response has to do with other things, glycemic control, etc., but number two, it really has to
do with nausea. So you shouldn’t go to the higher doses until you can tolerate the lower
doses. And if you’re actually on exenatide BID, you can administer it closer to the meal. It
really doesn’t mean much for the other drugs because they’re too long-acting. But for
exenatide BID, you can actually administer it closer to the meal. And last but not least, most
of the trials have shown that the longer-acting agents which would be liraglutide, or
potentially exenatide extended release, have a slightly better tolerable side-effect profile, a
little less nausea, a little less vomiting. This is clearly related to a little less gastric emptying.
So overall, what you need to know is that’s something you can consider in your patients as
well. If it’s absolutely intolerable, it’s time for an alternative. An alternative may be a DPP-4
inhibitor.
17
Slide 18
Now let’s go and talk about a direct comparison. You guys are like, “Well which one
should I recommend if they ask me?” So I’m like, “I want to recommend liraglutide.”
Why did you recommend liraglutide? Okay, maybe it’s because of nausea. If you look
at liraglutide here in the red versus exenatide 10 twice a day, what you’re seeing is
that there was actually less nausea with the liraglutide. One of the reasons for this is
in a step dose and the step dose is the 0.6. The 0.6 is not a therapeutic dose, but
rather a step dose to get them to the therapeutic dose of 1.2. So by doing that, you’re
actually able to lessen nausea. That might be one reason you would choose one of
the longer-acting drugs over the shorter-acting.
18
Slide 19
Also might have slightly less hypoglycemia. If you’re looking at LEAD-6, which is
actually a trial that looked at liraglutide versus exenatide, one of the things you’re
going to see is there was a little bit of spread of hypoglycemia in a patient per year.
Now, one of the things to think about is just because they had a hypoglycemic
episode is not necessarily a reason to take them off the drug. But there was a split.
You can see that exenatide had slightly more. Here were patients that were switched
from exenatide to liraglutide. And here are people on liraglutide. So again, a potential
reason for you to recommend a longer-acting GLP-1 agonist in your practice.
19
Slide 20
What about exenatide extended release versus exenatide BID? Well, one of the things
about this is you’re wondering about this newer drug, it’s a once-a-week product.
How does it fit in? How does it help your patient get to goal and what are the
differences? Though with exenatide extended release weekly, one of the things that
you saw is actually that it lowered A1C slightly more than exenatide BID and some
people would say it was slightly better tolerated. but I’m not quite sure about that.
But overall what you can see was that nausea and vomiting, at least in this particular
trial, were less. But I do want to point out something I think is important, and that’s
injection site pruritus. So one of the things with the extended release is that the
mechanism has these little tiny beads and the beads actually have exenatide in them,
and so when you inject them, sometimes you can have a little bit of local reaction. It’s
usually not something that has your patient stop the drug but it’s something you
need to counsel them on. So again, local reaction is something to think about. And as
far as hypoglycemia, no difference.
20
Slide 21
The other thing to think about when you’re switching someone to exenatide extended
release is that at first they may come to you and say, “I noticed my fasting sugars are
10, 15, 20 points higher than they used to be. I don’t understand. I thought I was
supposed to be put on to this other drug and this other drug was supposed to work
better for me.” And the answer is it does if you look at the long-term data. Here is
exenatide extended release. You can see that the change in fasting plasma glucose was
much better than when you were on the exenatide twice a day. But what you see here
is this conspicuous little blip as people were switched from exenatide BID to the once
weekly. Now, what this is is simply that the exenatide once weekly is building up in the
blood. So as it builds up in the blood, you have this slight change in fasting plasma
glucose up. It’s not a reason for them to stop it, it’s just a counseling point in case
someone comes back into you and says, “I noticed this.” Another clinical pearl for you
in your practice.
21
Slide 22
And then last but not least, what about exenatide extended release versus
liraglutide? So in this particular trial, which is only in abstract form, just so you know,
exenatide extended releases two milligrams was given versus the liraglutide, and
what you see is that the A1C reduction was about the same; the liraglutide did
slightly better. And overall, even though exenatide was a little better tolerated, I
would say it’s pretty neutral from weight on down to anything else. Overall, I think
either of the long-acting ones would be something you could use in your practice
efficiently to try to help your patient get to goal.
22
Slide 23
What about pancreatitis? How many people have had a patient mention pancreatitis?
How many of us have had a clinician mention pancreatitis? I just want to reiterate
something I think is important. It’s that there doesn’t appear to be a higher risk of
pancreatitis with these drugs. They got slapped with it early on before we fully
understand that type 2 diabetes is a higher risk of pancreatitis. So there’s really no
difference between these drugs and other drugs that are currently on the market, but
the labeling has been changed and it is unlikely, at least for the short-term, that
anything is going to be done. Now long-term this may be changed back, and the
pancreatitis risk may be downgraded even further. But for right now it’s still a risk.
23
Slide 24
And so because of the fact that we sometimes have to practice a little bit defensively
– how many have seen an ad about pancreatitis on the TV? How about for a TZD? I
have seen these ads for pancreatitis. And one of the things is that they’re always
talking about is if you had pancreatitis drugs. So I just told you it’s probably not a
higher risk, but it is something that is a counseling point for you. So if you have
someone in front of you, you have to ask them a couple of clear questions. Number
one, do you have abdominal pain? Abdominal pain is not a real side effect of these
drugs, so abdominal pain is something that may mean pancreatitis. You need to send
them to the emergency room or the physician immediately. The other is severe
nausea and vomiting that won’t go away. Now, these drugs can cause that, but it’s
hard for us to address it so tell them to stop the drug and go to the emergency room
or to see their physician right away. So those are the two main things persistent,
severe nausea or vomiting or abdominal pain.
24
Slide 25
Which patients are not candidates for liraglutide? Is it number one, normal-weight
patients? Is it two, patients with renal impairment? Or is it three, a personal or family
history of medullary thyroid cancer?
25
Slide 26
Very good; so most of you understand that it is thyroid cancer. So medullary thyroid
cancer is not the same thing as all thyroid cancers. So let’s talk about that briefly.
26
Slide 27
So liraglutide and extended-release exenatide are actually contraindicated with
people with MEN, and the reason for this is simply we think, we don’t know for sure,
but that rodent models had a higher risk of this particular cancer. And we also know
that it may be how long that GLP-1 receptor agonist is around. So exenatide BID, for
example, does not have this on their package insert. It’s not a trick, it’s just that
exenatide is there and then it’s gone. Liraglutide and extended-release exenatide stay
on that receptor forever; basically, if you keep giving the drug, it will be on that
receptor. There might be a difference here as far as why actually it is a higher risk of
MEN in rodent models. The other thing to remember is that many of you may see
people with thyroid cancer. Most of the thyroid cancer, though, comes from different,
it’s usually called papillary or follicular thyroid cancer. It’s not truly medullary cancer.
And so if they come in and say I heard I can’t be on this because I have thyroid cancer,
you need to differentiate what kind of cancer they have. Usually people with MEN
know it.
27
Slide 28
It’s something that’s hereditary and usually something that they’re going to be able
to talk to you about. The other thing is that they recommend, though this is very nonspecific, maybe calling the health care professional if there’s a lump or swelling near
your neck. It is something you can certainly tell your patient when you’re counseling
them. But the other thing is they just want to know, “Well what do you think? What
do you think? Do you think I should go on this?” And the answer is probably you
could do it without problems. The human risk is certainly not there right now. We
don’t have any cases of this and it’s probably not going to be decided for sure for at
least ten years. But it’s not impossible, and that’s the important thing. A fourth of the
medullary thyroid carcinomas that they take out of patients actually have GLP-1
binding receptors in that cancer. And that means it’s not impossible, though you
should tell your patient the truth. It’s not impossible, but there have been absolutely
no cases to date showing this particular thing can actually happen. It’s a very rare
cancer.
28
Slide 29
And here is some of the signal we use to actually look for this particular cancer, and
it’s called calcitonin. It’s actually put out by these particular cells in the thyroid. And
with liraglutide over 104 weeks, you can see absolutely no signal that there might be
cancer. Up here way at 50 you see potential signal for that medullary thyroid cancer.
You can see that there’s nothing that actually goes anywhere near that. So overall, I
think we can feel positive that to date we’re pretty safe in this particular issue.
29
Slide 30
What if a dose of liraglutide is missed and it’s around eight hours from
administration? What should you do? Should you take the dose? Should you skip the
dose and take the next dose? Should you skip the dose and take the dose at the next
regularly scheduled time?
30
Slide 31
So the answer actually is take the dose. It’s less than 12 hours, and that’s why we’re
going to talk a little bit about how to counsel your patients on missed dose for the
GLP-1 agonists.
31
Slide 32
Exenatide twice a day is something that you should think about. We all know it’s a 5and 10-microgram dose, so you start with the 5 and when they tolerate you can go to
the ten. We should remember with exenatide that you’re usually going to do it in
relationship to meals. So it’s important, with relationship to meals. You’re going to
titrate to 10 when you can and you can reduce the dose if there’s nausea, and
remember you can get maximal satiety with the drug if you move it out to about an
hour before the meal. So that’s important with exenatide.
32
Slide 33
But what about missed doses? Well, it should be taken before meals so if it’s actually
injected after a meal you’re not going to get any satiety but it still will have some
glucose-lowering effects. It does decrease glucagon and it does increase insulin
secretion if your glucose is high, but it’s not going to have satiety. So we usually
actually recommend skipping the dose and going to the next dose and taking the
normal dose. So we never double the dose to catch up. Most pharmacists know you
never double the dose usually. Very rarely is that the case.
33
Slide 34
What about with liraglutide? Well liraglutide, as I said, has a step dosing so you’re
going to go 0.6 milligrams until they tolerate it and then to the therapeutic dose of
1.2 and, in some patients, they may benefit from an increase of the dose to 1.8
milligrams; slightly more A1C reduction but most of the studies show it’s fairly similar,
but definitely they’re going to lose a little more weight with the 1.8. And, importantly,
do I have to take this with breakfast? No. you can take it independent of meals but it
has to be every 24 hours, whenever your patient best remembers it.
34
Slide 35
So inject at the same time. If it’s less than 12 hours from the last dose, they should
take it, but the dose of liraglutide should be taken if it’s less than 12 hours but greater
than 12 hours, skip it and go to the next dose. Very simple. 12 hours is your key for
this drug.
35
Slide 36
What about exenatide extended release? So this comes in a tray. They’re actually
going to pick up the tray. It’s going to be once-weekly dosing and it can be given
weekly without regard to meals but they need to inject them the same day every
week. The titration is in the actual extended-release preparation, so there is no dose
other than 2 milligrams. That’s the only dose because it builds up over 6-8 weeks to
the therapeutic dose, which is equivalent 10 micrograms twice a day of the
exenatide.
36
Slide 37
So what about missed doses? This is where it gets a little more tricky. You have to
take the doses at least 3 days apart so if it’s less than 3 days to the next dose, you
have to skip the dose and wait for the next dose. But if it’s more than 3 days to the
next injection, you can actually take the injection. The other thing that’s tricky is
when you want to change the dosing day. You want to change the dosing day, it all
goes back to three days again. So you should have at least three days from the last
dose. So, for example, if you have someone who is dosing on Sunday and they want
to move it to Tuesday, what you’re going to have to do is tell them, “At your next dose
on Sunday do not take it, but then on Tuesday take your next dose.” This is actually
slightly different than if you had someone who came to you and said, I want to move
it four more days away from where I’m currently injecting it. So if they said “My
dosing day is Sunday but I want to move it to Friday,” you could simply tell them,
“Take it on Sunday and then when Friday comes, you need to take the dose again and
then from then on you take it every Friday.”
37
Slide 38
When you’re counseling someone this takes a little bit. So I think it’s important to tap
the powder to loosen it. The reason why you want to tap the powder is it can be kind
of compacted. It’s a little vial. You’re going to connect it to this orange vial connector.
I encourage you guys, if you guys are interested in counseling on this, you look on
line. But there’s an orange vial connector. You’re going to twist that on and you’re
going to inject the diluent from the syringe that’s included into the little vial. You’re
then going to shake it until it’s suspended. Once it’s suspended, it should be injected
immediately. You’re going to draw that fluid back into the syringe, and then what
you’re going to do is you’re going to push it up to – there’s a little dotted line on the
syringe. You attach the needle and then you’re going to inject it subcutaneously. It
needs to be, again, injected immediately.
38
Slide 39
After that injection, because these little beads congeal, 77% of people felt a little
bump underneath the injection site. So I want to make sure you know that once you
feel the little bump, it doesn’t mean anything bad. But some people had a little bit of
swelling in the area, and that’s something that’s going to be a counseling point you’re
going to have to talk to your patients about.
39
Slide 40
As we kind of come back to the case, what can a GLP-1 agonist help this patient with?
It can help with blood pressure. It can help with weight. It can help with the A1C. It
can help with the triglycerides. There are multiple things that we can actually help in
this particular patient.
40
Slide 41
And then you’re going to counsel them. So as a recap, what are you going to counsel
this patient about for a GLP-1 agonist? You’re going to look at their medications. You
want to make sure there are no drug-drug interactions. Are they currently on drugs
that would be contraindicated? Metoclopramide, I would say this person has
gastroparesis. Have they injected before? If they’ve never injected, you’re going to
have to teach them how to inject. You do this first because otherwise the whole time
they’re going to be sitting in front of you going, “I’m too afraid of the needle to even
think about the rest of this.” What to expect from the medication. Dr. Sease is going
to go more into this about expectations for your patient. Pancreatitis is something
you should just announce to them, and then we know, we talked about the thyroid
for which two drugs? Liraglutide and exenatide extended release.
41
Slide 42
I usually tell our people to accentuate the positive. Just remember that by doing this
you’re going to get better glucose control and more energy. It’s a chance to lose
weight. It can improve cardiovascular risk factors and it’s a low risk of hypoglycemia.
42
Slide 43
These are pathophysiologically sound medications. They have a low risk of
hypoglycemia and they can be used in conjunction with almost any other
medications, but sulfonylureas and insulin we need to be careful with. And
last but not least, we need to make sure and counsel our patients about how
you’re going to expect this drug to act for them.
43
Slide 1
I’m going to talk about some of the trends related to medication adherence. I’m going
to focus particularly on medication adherence as it applies to your patients with type
2 diabetes, of course. I’m also going to spend some time relating to you what we
already know from clinical data about patient preferences as it relates to the GLP-1
agonist and how you as the pharmacist taking care of patients who are taking GLP-1
agonists – some of the tips that you can provide to your patients to help them to be
more successful with their diabetes management through improved adherence.
1
Slide 2
2
Slide 3
So the former Surgeon General, Everett Koop, he may have said it best when he said,
“Drugs don’t work in patients who don’t take them.” And that sounds like a pretty
commonsense kind of statement but I know everybody realizes exactly how big of a
problem medication adherence is.
3
Slide 4
And this slide, it really shows us what medication adherence is like in our patients
who have type 2 diabetes. As we know, a patient with type 2 diabetes is likely to
acquire at least four different types of medications. Those oftentimes are going to
include an antiplatelet drug to reduce their cardiovascular risk, a lipid-lowering drug
also to help lower their cardiovascular risk, an antihypertensive medication to lower
cardiovascular risk but also help protect their kidneys, and that’s all in addition to the
medication that they take to help lower their glucose. Well, most of our patients, do
they need just one agent from each of these classes? Yes, no? No. In one study, in
fact, for the average patient with type 2 diabetes they required, on average, about 12
medications. So this is a polypharmacy disease state, and so even for patients who
are able to afford their medications just fine, the fact that they are taking that many
drugs on a daily basis makes medication adherence a difficult thing. And so this really
lets us know exactly how big of an issue that we’re dealing with.
4
Slide 5
And so there are a number of reasons why we as pharmacists really should be in the
care of patients that have diabetes to help improve adherence. For one, diabetes is
an area of growth in terms of drug development, and this is despite our relatively
poor economy. We’ve had, over the past few years, significant increases in the
number of drugs, as we mentioned earlier. And that includes both oral medications
and injectable drugs. And health care providers, in addition to our patients, look to us
as the drug experts to help them understand what these new medications are, how
they work, and also how best to use them in order to avoid side effects that are
possible from these new agents. And as we’ve also mentioned a little earlier, there’s
been a lot in the news, and many law firm commercials calling attention of our
patients to possible safety concerns with certain medications. An example of this was
rosiglitazone, Avandia. It was once a very commonly prescribed drug. I think most of
us would say that that’s a fair statement. And then there was that news-making metaanalysis that really highlighted the potential for an increased risk of cardiovascular
outcomes among our type 2 patients taking that drug. And now today it’s only
available through the Avandia medication access program. And so we’ve really come
full circle. And to patients without any education from us, where do they get their
education? TV. They hear these commercials and they think, “Well, if that drug can
cause me to have a heart attack or have heart failure, why wouldn’t this new
medication that my doctor just prescribed for me cause me to have that same
effect?” Without us, they don’t know that the different medications have different
safety profiles and different potential risk. So that’s where we can step in to help
them understand better.
5
Slide 6
And so what are some things that the pharmacists can do? Well, regardless of the setting that
you’re working in, so many of you are working in the community setting, so this really sets you
up, whether you are doing it from a standpoint of a typical community pharmacy program or
you’re instituting some more advanced practices like medication therapy management programs,
there are things that you can do to help improve your patients’ adherence rates. One thing you
could try is providing regular medication checkups for your patients to ascertain several things,
including the appropriateness of each drug that they’re taking, the potential for drug-drug or
drug-disease interactions, as well as identify any adverse effects that they may be experiencing
and not even realize it’s related to a drug that they’re taking.
Another is to review the patient’s medication dosing schedule and their daily regimen,
insuring that the patient is taking the medication at the best time of day possible and in proper
relation to meals if that’s applicable to that drug. Those are things you can do to help decrease
the likelihood of adverse effects with some of our medications. And you can also help improve
the patient’s ability to remember to take their medication sometimes by looking at their dosing
regimen. A lot of times our patients think, “Oh, this medication that I’ve got to take, that’s
something that I’m going to be doing separate from the rest of my life.” They don’t necessarily
look at it as, “This is something that I need to include in my everyday life or make a part of what I
do.” And so sometimes just a simple discussion with the patient of “what’s something that you do
every day? Okay, let’s talk about how we can associate taking this new medication with that thing
that you already do every day.” So maybe if that person is going to be taking exenatide BID,
maybe you talk to them about, “Well I brush my teeth about 45 minutes before I eat my breakfast
every morning.” Well, that would be a perfect time to take the morning dose of the BID exenatide
regimen. Because that’s going to be within an hour of when they’re going to eat their breakfast.
And that puts it attached to something else. Sometimes for patients it will be something as simple
as that to help increase their adherence. For others, of course, they’re going to maybe require
some fancy adherence aids, and for those oral drugs I always recommend that patients use pill
boxes because that helps them remember for sure that they really took the drug that day. When
things become a big habit for us, our brains don’t necessarily register, “Oh yeah, I did that. That
was today,” not that it was yesterday. So I always encourage patients to do that for those oral
drugs that they’re taking.
6
Slide 7
Along with education about why each medication is important and how it works, we
also want to think about educating our patients about what to watch out for and also
proper monitoring. That’s also something that’s going to be important to help them
improve their adherence. For example, a patient who is starting basal insulin, they
would need to know that they should check at least their fasting blood glucose levels
in order to assure proper titration ability, whereas that’s different for a patient who is
newly starting a rapid-acting bolus insulin. They need to check some postprandials in
order for you to be able to titrate their insulin appropriately. And so that’s just a
highlight or an example of the type of thing that you want to make sure that you also
talk to your patients about. They need to know not only that they need to monitor
their blood sugar, for example, but they need education from us about when’s the
best time to do that in order to insure the most usability of that information.
7
Slide 8
Open communication is also key. In order to open up the communication lines between you
and your patients, there are a few things that you always want to keep in the back of your
mind. Think about what their education level is. Think about what kind of financial
constraints or concerns they may have on their minds. Patients should always be included in
their treatment decisions and feel that they’re a part of their health care team, as well as that
they are a part of their goal setting. Make sure patients understand what their goals are. So
often patients come to me in my practice setting and they have no earthly idea of what their
blood sugar should be. They don’t even know what an A1C is. So you, as their pharmacist,
making sure they know what an A1C is, to start with, much less what their goal is, is going to
help them know when they’re meeting it or not. Same thing is going to go for they need to
know what their blood pressure goal is. They need to know what their cholesterol goals are.
They need to know if they’re meeting them or not. If patients have never been told what
their goals are, how will they ever know if they’re there or how far away they are? So that’s
something that you can also educate them about and do that in a fairly quick manner.
Consider utilizing motivational interviewing in your conversations with your patients.
And in doing that, you want to remember to always promote positive beliefs and positive
attitudes. Don’t let your patients get down on themselves whenever they’re not meeting
goal. If a patient is coming in saying to you, - you know, I’ve had patients do this to me –
they’ll come in and say, “Julie, I haven’t been checking my blood sugar.” First of all, I say,
“Thank you for telling me that you haven’t been checking your blood sugar instead of
bringing in a log that had a lot of made-up numbers on it. Thank you very much. I can work
with that.” And then also I want to make sure that patients understand that it’s not important
to focus on what they haven’t done well, or what has not been successful for them in their
past, but what we can do going forward. What’s the next best step. Let’s pick something and
let’s focus on that as a positive thing we’re going to do between now and the next time you
come to see me. Let’s focus on why it is we’re doing this, what good you’re going to have
come out of this, as opposed to, oh, this is just something my doctor told me to do.”
8
Slide 9
Keeping patients’ concerns in mind is also key to successful patient interaction. Some
typical concerns that patients might have include inconvenience and inflexibility of
timeline and frequency of administration of their diabetes medications. They may
have already a desire to avoid injections and/or insulin, as well as side effects related
to their diabetes medications. Sometimes those fears go away easily whenever we
provide some education to our patients, but it’s important that we don’t just brush
them aside. It’s important that we validate our patients’ concerns so that they
recognize that we do see where they’re coming from. That’s going to get them to
help understand that we are on their team. And then once you’ve validated that their
concern is a real concern, then begin your conversation with them about how this is
how that doesn’t have to be such a big concern or a reason why you find it difficult to
be adherent with your medication regimen.
9
Slide 10
When you’re talking to patients, think about including their families in your
conversations if they have supportive families, particularly if you’re dealing with a
patient population like the one that we bring up in our case. That was a Hispanic lady.
I’ve seen in my patient population that among those patients, sometimes you have to
get their families on board or they’re going to have a really hard time becoming
adherent. And so I’ll talk about that a little bit more in just a few seconds. But before I
do, I want to point out a few other things about the way that you go about your
conversation with your patients and their families. Use plain language, nonmedical
jargon. You want to use as plain a language as possible. Talk slowly. Focus on the top
two or three major concepts that you’re trying to convey to your patient. Once you
get through about the first two or three major concepts that you’re trying to convey,
they’re going to check out. Or even if they don’t check out, they’re not going to be
able to hold on to the rest of the information. So pick the top two or three things that
you need to make sure that they understand and focus there. Save the next steps, the
next important facts for the next time you see your patient. Break things down into
bite-sized bits and ask patients to show you what it is that they have learned or teach
you back what you have just taught them. That way you can make sure that they
really understood from you. The best way to make sure you really know something is
to be able to teach it, right? Well, if your patient can teach back to you what you just
told them then you can feel pretty confident that they really understood it.
10
Slide 11
Cultural factors are a major important key to understanding some things about the
ways that patients think about their disease states and the ways that they can also
make a big impact in their ability to control their chronic disease states like diabetes.
Cultural factors pay a role in your patients’ lives. They can impact their diabetes care,
and everything from your patients’ faith or religious beliefs, their myths, to their
general lifestyle, their family orientation and their household gender roles – all of
those have the potential to significantly impact your patient’s ability to care for
themselves and their diabetes well.
11
Slide 12
This is really the point, too, what I have seen to be such an important factor in a free clinic
setting where I was previously. I had several patients who, they were Hispanic women, and
they would come in and sit down with me to discuss their diabetes, and they would
understand what I was trying to tell them even if we had to use an interpreter. And they had
the desire to adhere or comply to whether it be the dietary intervention that I was trying to
make, the lifestyle intervention that I was trying to make, or their medications – becoming
adherent and taking them appropriately. But several of these ladies, particularly when it
came to the dietary intervention, they met a major roadblock in that their gender role and
their role in their household dictated that their job was to provide the meals for their families
and that the meals for their families couldn’t be necessarily just what I was discussing with
them. It would have to be what their spouse felt was a good meal. And without that spouse
there to discuss or to hear what I was trying to say about ways that she might need to change
her diet, she had a really hard time incorporating into her daily lifestyle being able to prepare
the meals that her husband and the rest of her family would want to eat in addition to what
she needed, the changes that she needed to make in order to improve her diabetes care. And
so that was a major issue for several of those ladies, and that’s the type of thing that if you
keep that in mind and bring the patients’ families in and let the patient’s family hear what
you’re trying to tell them, those are ways, too, that you can help break down a major
roadblock sometimes. It has also been shown that this particular group of patients, Hispanic
patients, tends to worry about drug side effects more than other groups like African
Americans and Caucasians. And so that means that they may be more likely to refuse to take
a medication or simply not start that medication even if they don’t tell you that they’re not
going to start it. Even though it’s been prescribed for them.
12
Slide 13
It has been shown that Hispanic adults are likely to utilize religious beliefs as an
explanation of the cause of their type 2 diabetes, as well as folk beliefs about strong
emotions being causes for their type 2 diabetes. And these patients also tend to have
strong negative emotions about insulin therapy. So that’s something to keep in mind,
because if you have a patient who believes strongly that they’re going to be able to
do something other than take traditional medication in order to improve their
diabetes care, you need to be aware of that. That they may turn to that. That may be
something that you need to address in your interaction with them, not that you’re
saying that it wouldn’t necessarily help, but if you don’t recognize the fact that they
have that strong belief, then you may not realize the reason that they’re not being
adherent if they tend not to be adherent to their medication therapy.
13
Slide 14
Diabetes outcomes can be improved in Latino patients through increased cultural
awareness and competence among your health care providers. Yourselves. And also
we know that an increased use of Spanish-speaking diabetes educators can also be
helpful.
14
Slide 15
Language barriers can also be overcome by using community-based resources, such as local
churches, to identify an interpreter that the patient would feel comfortable using and comfortable
talking with. Involve family both to help educate that patient and also to bring the family on board
with the needs that their family member has. And seek out also for those patients Spanishspeaking physicians when possible.
15
Slide 16
So as we get ready to transition now into some of the information that we have,
clinical data that we have about the GLP-1 agonist and patient satisfaction. I want to
start off by getting you to answer another one of those questions for us. So in clinical
trials, patient satisfaction scores have been found to improve among patients taking a
GLP-1 agonist as compared with which of the following treatment alternatives?
Metformin, sitagliptin, insulin, or all of the above?
16
Slide 17
Okay. And you all went mostly with all of the above. And that’s actually true but let
me tell you why.
17
Slide 18
18
Slide 19
All right. So in this first study patient reported outcomes were evaluated for both
exenatide and insulin glargine, with a pre/post comparison being made for each of
those treatment alternatives. And as you can see from this slide, patients reported
improvements in diabetes symptoms, as well as the Short Form 36 Vitality Subscale,
as well as the Diabetes Treatment Satisfaction Questionnaire, after beginning
treatment with both exenatide and also insulin glargine. So whether it was that the
patient was started on exenatide or insulin glargine, they did experience improved
satisfaction in each of these different ways.
19
Slide 20
In another study, patients reported outcomes were evaluated for type 2 patients
treated with either liraglutide or glimepiride as add-on therapy to metformin.
Patients treated with liraglutide reported less hypoglycemia than with a sulfonylurea
and less hyperglycemia than with metformin as monotherapy. Patient satisfaction
with liraglutide was greater than with metformin alone and comparable to metformin
plus glimepiride combination therapy.
20
Slide 21
Liraglutide has also been compared with sitagliptin as add-on to metformin.
Liraglutide is either 1.8 milligrams or 1.2 milligrams daily and produced a significant
A1C reduction as compared to sitagliptin. Liraglutide also provided greater weight
loss and improved patient satisfaction as compared with sitagliptin.
21
Slide 22
And in a study comparing psychological and quality-of-life changes in patients using
either one of the GLP-1 agonists versus an insulin, patients treated with a GLP-1
agonist reported greater treatment satisfaction, a better well-being score, and
reduced anxiety and depression scores. And these changes, and what I think is the
biggest thing to highlight here is that these changes were found to be independent of
weight changes. So the patients’ satisfaction with their treatment was not necessarily
just with the weight loss that the GLP-1 agonist created, but that same statement,
that improved patient satisfaction with the GLP-1 agonist versus insulin held true
regardless of weight change.
22
Slide 23
And so as we go back to our case study, just to highlight a few of those things. We
know her well now, a 44 year old Hispanic female. She comes for her diabetes
coaching session. She’s got diabetes, hypertension, dyslipidemia, and obesity.
23
Slide 24
She’s currently taking metformin, ramipril, chlorthalidone, pravastatin, fish oil and
calcium. And now we know that she’s either taking exenatide twice a day or
liraglutide once daily.
24
Slide 25
She works part time. She lives with her husband and three teenaged children. She’s
the caregiver in terms of those dietary habits I’ve spoken some about this evening.
She’d like to exercise more but has a difficult time with that. And I also put a little bit
extra information in here about her family history. Her mother died at age 70. Prior to
that, she had diabetes and she actually developed renal failure before passing away.
Her father is deceased at age 56. He had hypertension and died of an acute
myocardial infarction, and her sister is 42. She also has diabetes and hypertension.
And during your interview with your patient, you find out a few things about her.
25
Slide 26
You find out that one of the major concerns that she has is the fact that before her
mother developed renal dysfunction and end up going on dialysis that she was
started on insulin only about a year before that. And your patient has the
misunderstanding that the insulin played a role in her mother’s development of renal
failure and needing dialysis.
26
Slide 27
And so during the interview with her, you were to identify barriers that are present in your particular
patient, remembering that these could be rooted in her cultural difference or her cultural beliefs
about diabetes itself as a disease state and what causes it, as well as an increased concern about the
side effects of her medications. You need to educate your patient in this instance that it probably had
nothing to do at all with the insulin itself in what happened with her mother, but what’s most likely to
have occurred is that her mother had diabetes for quite some time. She may have been poorly
controlled prior to beginning insulin therapy. It was those years of damage that went on that actually
led to her renal dysfunction, and that it was just a happenstance that she developed the renal
dysfunction that ended up ending her life not that long after insulin being added on. Maybe if insulin
had been added on earlier, her renal dysfunction could have been slowed. That’s the type of thing,
though, that without the education, without us explaining to patients that insulin didn’t cause her
renal dysfunction, that it was the diabetes that caused the renal dysfunction, those are the types of
beliefs that patients can sometimes have and the lack of the education about it.
You may also find that some patients have the misconception that using an injectable medication is a
punishment or it’s a sign of failure. And helping patients understand that diabetes is a progressive
disease that can result in the addition of other needed therapies or injectable therapies as time goes
on, no matter what they do, is an important thing for us to make sure that we explain to them. It’s also
imperative that insulin and other injectable therapies never be used as a threat. I think we’re better
today than what we used to be about that with patients, but that can still happen sometimes where
patients are told or they have the belief that “Well, if I don’t do what I’m supposed to do with my diet,
if I don’t do what I’m supposed to do with this medicine, I’m going to end up needing insulin and I
don’t want to end up needing insulin so if I get there I’ve done something wrong.” That’s something
that we definitely want to fight against. We want patients to understand that even if they do
everything right, they may still very well need an injectable therapy. They may still need two, three,
maybe more medications to control their blood glucose, and they may eventually need insulin. And
that that is not a punishment or something that happens because they didn’t do what they were
supposed to do, but that that’s a product of diabetes being a progressive disease state.
Patients also oftentimes are going to assume that injectable medications require a very
complex regimen that can overtake their life. Helping patients understand that particularly in type 2
diabetes, patients are often well controlled with just one or two daily injections, and that our newest
options that are out there come in very easy-to-use, prefilled pen devices that don’t necessarily have
to be a big burden on them. And that the needles that they’re going to use are very thin and short and
relatively painless. And not having to hit a vein, only having to be injected into the subcutaneous
tissue. Those types of things are sometimes fears that patients have that if we educate them about
that, it can really help to mitigate their fear about going on to that injectable medication.
27
Slide 28
Also be ready to, during your education with your patient, consider allowing them to
do a dry run using an appropriate needle size. Basically, give them a short needle
that’s appropriate, small diameter from a pen needle. And let them inject themselves
without necessarily injecting any medication. Let them do that in front of you. Let
them see how easy and relatively painless that’s going to be for them. That can
definitely take away a lot of fear for the patients. So much of the time what they’re
fearful of is that this is going to hurt, I’m not going to be able to do this right, I’m not
going to be able to figure this out. And that can really fix that problem for them.
28
Slide 29
So your patient asks you, “Well, you’ve told me all of that and I feel better about it,
but isn’t there an oral form of this drug? I mean you’ve got that right?” Well no.
29
Slide 30
That the DPP-4 inhibitors they do share several similarities with the GLP-1 agonists.
They don’t produce weight loss, and also I’ve highlighted another important point to
keep in mind. They, unlike the GLP agonists, don’t produce the same amount of
patient treatment satisfaction, and so that’s something to also keep in mind. And
they don’t produce the same amount of A1C reduction either. So while, no, you can’t
get a GLP-1 agonist except for injectable form, the DPP-4 inhibitors, they are similar in
several regards to GLP-1 agonists. They are available orally, but in using them you are
giving up some benefit in terms of A1C reduction, as well as patient treatment
satisfaction too.
30
Slide 31
Be sure that you educate your patient, again, to manage the most prevalent side
effects that might come from her beginning the GLP-1 agonists.
31
Slide 32
And nausea is likely to be the most troublesome side effect that she’s going to
experience once she beings that therapy. You can help her tolerate its effect, though.
A couple of things to remember, recommend that she stay on that starting dose of 5
micrograms for exenatide immediate release or 6 milligrams of the liraglutide for an
additional month if the nausea is occurring. Don’t titrate until the nausea has
dissipated. Insure that your patients are administering their GLP-1 agonist no longer
than an hour prior to the meal, and that’s specific, really for the exenatide BID
regimens. Be sure, too, that they’re keeping that BID exenatide regimen no shorter
than six hours apart. Recommend that your patients eat slow, slower than they ever
had before. Again, we’re trying to give them an opportunity to feel full. And if they
don’t eat slowly, they may very well eat much more than they ever would have
before, and a full stomach that can’t empty will equal nausea. So help them to
understand the importance of eating very slow, slower than they ever have in their
entire lives. For patients with nausea on the shorter-acting BID exenatide, consider
also that you could switch over, potentially, to one of the longer-acting options,
whether that be liraglutide or the extended-release form of exenatide.
32
Slide 33
Next question. Hypoglycemia is most likely to occur with which of the following
diabetes drugs? Sitagliptin, glipizide, metformin, or exenatide?
33
Slide 34
Well, we were close. So we haven’t specifically mentioned that glipizide, a
sulfonylurea, will cause hypoglycemia. We somewhat have but maybe haven’t
focused here. But that is the correct statement, that sitagliptin, metformin, and
exenatide, any of those options, when used as monotherapy are really not that likely
to cause hypoglycemia but glipizide is a sulfonylurea, it sure can.
34
Slide 35
And so hypoglycemia is definitely an issue. It has been associated with a reduced
quality of life, increased fear and anxiety among patients, reduced productivity, and
increased healthcare costs.
35
Slide 36
And because of the GLP-1 agonist’s glucose dependent action hypoglycemia is rarely
reported with these agents except when they’re used with combinations of drugs like
sulfonylureas and insulin.
36
Slide 37
And again, it’s important that we make sure that our patients understand what they
can truly expect from their therapies.
37
Slide 38
Patients beginning GLP-1 agonist therapy can generally expect which of the following
outcomes? A weight loss of about 2 kgs, and A1C level reduction of around 1%, or a
weight loss of around 2 kgs with an A1C level reduction of around 2.5%. Three,
weight loss 5 kg with an A1C level reduction of around 1%, or four, weight loss of
around 5 kg and an A1C level reduction of around 2.5%.
38
Slide 39
I’m so glad that I have the opportunity to clear this up.
39
Slide 40
Okay, so again, it’s important for our patients to understand exactly what they can expect
from these medications. Otherwise they’re going to say, “It’s not working, it’s not doing what
it’s supposed to do. Why am I taking this drug?” Well, you need to be ready to explain to
them what a true expectation really is and to do that accurately. So these agents, they’re not
boundless in their effect. They are not a drug that you can start and titrate like insulin in
order to get an endless amount of A1C reduction. That’s not going to be the case with your
GLP-1 agonist. With traditional exenatide twice-a-day regimens, patients can expect an A1C
reduction of about 1%. They can expect a weight decrease of somewhere in the
neighborhood of 0.7 to 2.5 kilograms and the differences here really have to do with the
therapy that the drug is being added on to. So there are some slight differences dependent
upon whether it’s being added onto sulfonylurea with metformin, sulfonylurea monotherapy,
metformin monotherapy, and thiazolidinedione. But as a general statement, a kind of easy
summarization, easy thing to remember, exenatide twice a day you can expect that that’s
probably going to get you an A1C reduction of about 1% and you’re probably going to get a
weight loss of somewhere between 1 and 2, maybe 2 and a half kilograms. Exenatide, also, of
course, comes in the extended-duration therapy, the once-weekly therapy and with that you
can see a slightly greater A1C reduction and a slightly more weight loss, a little bit more in
line with what I’m about to show you with liraglutide in just a moment. And clinically
speaking, when you’re choosing between the exenatide twice a day regimen or the once
weekly extended duration regimen the thing that you’re really going to want to keep in mind
is the BID regimen is really more of a postprandial type of effect, so we don’t see as much
A1C reduction when you’re going after postprandials as you do when you’re using agents
that are longer-acting. They’re focusing more on all over glucose control, including fastings.
So when you’re thinking about choosing between the different exenatide preparations you
want to think about not necessarily just the A1C reduction but what does this patient need.
Do they need more postprandial control or do they need more overall glucose control? And
then you’re also going to have to think about the difference in terms of side-effect profile.
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Slide 41
And liraglutide. It can be expected to produce an A1C reduction of between 1 and
1.5% and a weight reduction of about 3.2 kilograms, probably 2.5 kilograms is a little
bit more realistic of an expectation. And again with this longer-acting agent, you see a
little bit more in terms of the A1C reduction and a little bit more in terms of the
weight loss because it is affecting overall glucose control. So that’s a little bit more in
line with your exenatide XR, your extended-release agent.
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Slide 42
And so just to summarize, optimizing therapy with the GLP-1 agonist is something
that you can help your patients do through education. Ask them what they already
know about the therapy or what they’ve heard about the therapy. Find out what their
preconceived notions are about it as an injectable therapy. Find out what their fears
are up front. And if their fears have to do with injections, well, that’s something that
you’re going to be able to pretty easily fix by showing them that pen device, by
showing them how short and how thin the needle is, and even letting them do a dry
run. That’s something that we can fix for them. Address the possibilities of side
effects with them. Let them know that nausea is a very real possibility but it’s not
something you just have to live with, it’s something that we can do something about.
Let them know that that’s the case and let them know that the right thing to do if
they’re experiencing a side effect is not to simply stop the drug but to talk to their
healthcare provider or to you as their pharmacist about that. Because you may very
well be able to mitigate that problem altogether for them. And make sure, too, that
they understand what a realistic expectation is for their medication therapy. Make
sure that they do understand what they can really expect. You don’t want them to go
home thinking, “Oh, this is going to be the weight loss drug. I’m going to end up 10
pounds less, 20 pounds less, 30 pounds less after the next few months pass.” That’s
not realistic. So make sure that they understand that and that they understand too
that the A1C reduction that they may expect is not limitless. That there is a limit to
that. Make sure that they understand those facts about the drug. Thank you much.
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Dr. Haines:
I’d like to ask the panel about a tricky area. So you have a patient who is complaining of GIRD, and
reflux disease. And maybe, in a patient with diabetes, this might be an autonomic neuropathy, you know. They might
have an underlying gastroparesis. What do you do about it? Do you think the GLP-1 agonists really should be avoided
in these patients? How do you kind of handle this situation? Certainly GIRD is a common problem, so is this a patient
population that you avoid things with or not?
Dr. Sease:
The times that I have seen gastroparesis be an issue with my patients is those folks that have had
diabetes for a very long period of time. I have usually seen it only really occurring in those patients, too, who had very
poor control. And so I have to answer honestly by saying that I would not necessarily use a GLP agonist in that patient,
but it’s not necessarily even from the standpoint of the adverse effect. I think that that’s very much a potential truth.
That patient has already got nausea, and now you’re going to add something that’s going to even further slow down
their ability to empty their gut. They’re going to have more nausea. I think that that’s pretty intuitive, and so I’d
probably ward off from doing that from that regard. But then also, the times that I’ve seen it it’s been in patients
whose A1C’s are significantly higher than the 1.5 to 2 A1C reductions that I need to be able to get them to goal, and
so in those instances it just made more sense to go to insulin anyway, because they needed significantly more A1C
reduction than a GLP agonist could get them.
Dr. Haines:
I was just going to say, in general, if a patient’s got a lot of GI symptoms to begin with, it’s probably
a therapy I wouldn’t be recommending for them only because it might increase that. So until we get those symptoms
under control, I probably wouldn’t be recommending that kind of therapy for them.
So the extended-time extended-release requires what kind of needle, Curtis? And you know, what kind of experience
do patients have with this new product relative to other GLP-1 agonists? What are the key differences here, I guess?
1
Dr. Triplitt:
It is a unique needle. The needle looks like it’s going to be a 23-gauge needle and it’s going to be
kind of short, but it says it’s 5/16ths. So when you look at the needle, what you’re going to notice is that it looks a
little bit different than your typical pen device needle that you use. The needle comes with the dosing tray, so you
shouldn’t worry about the patient actually trying to get this needle at the pharmacy. The other thing is that each
dosing tray comes with two needles just in case he accidently drops one. So the needles will be included in the dosing
tray for them. Once they look at it, I think you’re going to find that they’ll accept the therapy, especially since it is
once a week. But it is definitely different than the 31-gauge short needle that you would use for either exenatide BID
or liraglutide.
Dr. Haines:
And the needle needs to be a little bit larger because these are beads that are going through, so the
really small needles that we use for insulin therapies are not appropriate for the exenatide extended release because
of the actual beads that are coming through the needle itself.
Dr. Haines:
One person asked would you combine GLP-1 with a DPP-4? I don’t think that’s a very good
combination for a couple of reasons. One, the DPP-4 is not really going to, and we haven’t seen, at least in clinical
trials, add very much. It seems like a very expensive way to deliver incretin-based therapies, and the DPP-4 is not
going to inhibit the breakdown of the GLP-1 agonist because those are not broken down by the same mechanisms
that endogenous GLP-1 is. So it’s not a combination I would recommend. I don’t know if any of you have seen it done?
If you have, any sense of whether this would even make logical sense? It’s not one that I would recommend. So we’ve
cleared that up. If you see that being recommended, no data to support it and I would encourage that it not be done.
Some clarification on the GLP-1 agonists and this postprandial glucose versus fasting blood glucose. Can you
give us a better sense of where the exenatide BID, what its effects are relative to the fasting and some of the really
long-acting GLP-1s?
2
Dr. Triplitt:
So the difference between these drugs is the long-acting drugs seem to affect glucagon for 24 hours. When you look
at exenatide BID, what you find is that by the next morning the drug is gone. In fact, within 4-6 hours, exenatide BID is
gone. So this is the true difference between these drugs. Exenatide BID releases this drug very quickly, which means
for about four hours you’re giving a very nice postprandial effect, probably a better postprandial effect than some of
the other drugs. But by the next morning it’s gone, whereas the liraglutide and the extended-release exenatide are
actually going to have better fasting glucose control than the exenatide BID, which will probably have better
postprandial control.
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