Dialogue and Diagnosis - American Osteopathic Association

Volume 2 Number 2 September 2012
Injectable treatments for patients
with type 2 diabetes
Exploring injectable treatments
Initiating and adjusting injectable insulin therapy
Introducing and titrating GLP-1 agonist therapy
Supported by a publication grant
from Novo Nordisk
AN OFFICIAL PUBLICATION OF THE AMERICAN OSTEOPATHIC ASSOCIATION

Dialogue
and
Diagnosis
Volume 2, Number 2 September 2012
Editor in chief
Gilbert E. D’Alonzo Jr., DO
Supplement editor
Jay H. Shubrook Jr., DO
Director of publications
Diane Berneath Lang
Assistant director for
special publications
Walter Wachel
Creative director
Nancy L. Horvat
Art director
Leslie M. Huzyk
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American Osteopathic
Association
President
Ray E. Stowers, DO
President-elect
Norman E. Vinn, DO
Executive director
John B. Crosby, JD
Dialogue and Diagnosis is a publication
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Copyright 2012 by the American
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InsideOut
Jay H. Shubrook Jr., DO
Diabetes
mellitus:
a primary care
challenge
The management of patients with
type 2 diabetes mellitus (T2DM) is a
growing challenge for osteopathic
physicians for several reasons. First,
diabetes mellitus is extremely com -
mon, affecting 1 in 8 Americans. 1 The
prevalence of diabetes mellitus—
primarily T2DM—is projected to
increase 64% by 2025. 2
Each year in the United States, more
than 28 million ambulatory care visits
involve patients with diabetes
mellitus, 1 the vast majority of whom
are managed in primary care settings.
Second, office visits of patients with diabetes
mellitus are complex and often
require more time than scheduled in a
typical office schedule. Third, the
increasing number of treatment
options has complicated what used to
be simple treatment algorithms. Finally,
patients often have agendas focused
on their acute complaints, while physicians
may be focused on chronic
disease management and the achievement
of intermediate outcomes, such
as improved levels of glycosylated
hemo globin (HgA 1c ), low-density
lipoprotein cholesterol, and blood pressure.
These issues must be negotiated as
part of the primary care management
of this chronic disease.
Type 2 diabetes mellitus is a relentlessly
progressive disease that requires
ongoing patient self-care and
education, as well as physician surveillance
and collaborative supervision.
Research from the past decade has resulted
in a much greater understanding
of the pathophysiologic mechanisms
of T2DM and has led to an explosion
of treatment options. Despite the wide
range of medications to address the
multiple pathophysiologic defects in
T2DM, nearly 50% of people with diabetes
mellitus have poor control of
their disease. Understanding these
treatment gaps as opportunities is necessary
to improve diabetes control. 3,4
A physician’s attitudes, beliefs, and
knowledge about diabetes mellitus can
influence disease management. Suspicion
about the safety and efficacy of
current treatments may be a barrier to
aggressive management. Lack of time
in the clinical setting may hamper the
physician’s ability to recognize and address
the need for treatment intensification.
Insufficient knowledge of new
medications can also be detrimental to
treatment. Primary care physicians
need to be knowledgeable about a vast
array of conditions, but it is not possible
to keep up to date with the details
of all acute and chronic diseases and
their treatments.
Furthermore, both physicians and
patients have expressed resistance to
injectable treatments. 5 Specifically, primary
care physicians are less likely to
use insulin and more likely to intensify
treatment slowly, compared to diabetes
specialists. 6,7 One study found that
92% of primary care physicians treating
patients with T2DM had concerns
about patient adherence, 80% about
hypoglycemia, and roughly half about
patient pain resulting from fasting
serum glucose tests (54%) and
injections (47%). 8
Although sometimes seen by
patients as “the cause” of diabetic complications
or as the marker of failure in
diabetes treatment, insulin is being
used more often in treatment and earlier
in the course of the disease. Some re-
(continued on page 33)
Dialogue and Diagnosis // September 2012

Introducing and adjusting
injectable insulin therapy
for patients with type 2
diabetes mellitus
Joseph M. Tibaldi, MD, FACP
D
iabetes mellitus affects more than 26 million
people in the United States, 1 and the Centers for
Disease Control and Prevention projects that
more than 48 million people will have this disease
in the United States by 2050. 2 Diabetes mellitus is the
leading cause of kidney failure, cardio vascular disease,
nontraumatic lower-limb amputations, and new cases of
blindness among U.S. adults. 1 Despite numerous
therapeutic options, glycemic control in the United States
has not improved in recent years. 3,4
Dialogue and Diagnosis // September 2012
1

One of the reasons for
this lack of metabolic
control in patients with
type 2 diabetes mellitus
(T2DM) is a continued
clinical inertia regarding
treatment intensification
and adjustment 5 and an
underuse of insulin in
T2DM patients. 6
Poor glycemic control may be
reflected in the failure of self-management
by patients with diabetes mellitus,
and inadequate intervention
strategies by clinicians. 7-11 Attaining
target glucose levels under various
daily conditions—while avoiding
hypoglycemia, dramatic excursions
in blood glucose, and weight gain—
can be difficult to achieve. Physicians
need to overcome clinical inertia and
intensify therapy in an appropriate
and timely manner. 7 Because T2DM
is a progressive disease, many
patients will ultimately need insulin
therapy to achieve and maintain adequate
glycemic control. Insulin
remains essential treatment for
patients with T2DM after oral
therapy alone becomes inadequate.
The present article offers a case
report to highlight the need for
intensification and adjustment of
insulin therapy in patients with
T2DM. It also reviews factors that can
impact achievement of treatment
goals, challenges in adding
medications to therapeutic regimens,
and special challenges related to
ethnic minorities and patient
education.
Report of case
Sam is a 46-year-old Hispanic man
who presented to his primary care
physician for follow-up treatment for
his T2DM. He went unwillingly but
came at the urging of his wife who
helped him realize that disease
control is important for staying
healthy. His experience with diabetes
has not been good. He had vivid
memories from early childhood of his
grand mother receiving insulin injections
from his mother. His
grandmother lost her vision soon
after starting insulin. She could not
fill the syringe by herself and
required help with her therapy.
As Sam aged, he remained slim
and active. Nevertheless, diabetes
mellitus still developed in Sam. Three
years ago, when his glycosylated
hemoglobin (HbA 1c ) level was found
to be 7.3%, he grudgingly agreed to
begin self-monitoring of his blood
glucose levels and to take metformin
twice daily. Much to his surprise, his
glucose control improved, and his
HbA 1c level was 6.3%. A year later,
despite following his nutritionist’s
suggestions and exercising even
more, Sam’s fasting plasma glucose
level (FPG) level increased, and his
HbA 1c level rose to 7.7%. He initially
refused additional medications, but
he later agreed to use glipizide (a sulfonylurea),
noting that he preferred a
medication that had been “tried and
true” for many years and he did not
want to take injections.
The addition of glipizide to Sam’s
therapy worked only transiently. At
the time of his follow-up to his
primary care physician, he had not
seen the doctor for 9 months because
his FPG values had remained between
220 and 250 mg/dL and he did not
want to know the next steps. He said
he did not want to “take shots” and
suffer as his grandmother had.
His physician was empathetic.
Sam’s weight was stable and his body
mass index was 24. His blood
pressure was 118/76 mm Hg, despite
2
Dialogue and Diagnosis // September 2012

the fact that he was obviously upset
at the time it was measured. His
HbA 1c level was 9.1%. As his phenotype
was not typical for T2DM, and
his treatment had little durability
despite his significant lifestyle efforts
the consideration for atypical types
of diabetes was entertained. These
patients may be the “thin diabetics”
and often have family history of
other autoimmune diseases. Nearly
10% of adults (>35 y/o) who think
they have T2DM actually have a
slowly progressive form of T1DM.
Autoimmune antibodies (GAD65)
were ordered as was the test for
endogenous glucose production
(c-peptide in conjunction with serum
glucose). Alternatively, people from
ethnic minorities, especially men of
African descent can have a form of
T2DM that is prone to go to diabetic
ketoacidosis. This has been termed
ketosis prone T2DM or “Flatbush diabetes”—named
after a street in the
Bronx in which this pattern was first
described.
Islet-cell cytoplasm autoantibodies
and glutamic acid decarboxylase
autoantibodies (GADAs) can occur in
patients with apparently typical
T2DM. Data from the United
Kingdom Prospective Diabetes Study
25, or UKPDS 25 12 showed that
among patients older than 45 years,
the presence of GADAs was highly
predictive of the likelihood of insulin
requirements. In the ADOPT trial,
10% of the T2DM study population
had GAD antibodies. 13
The (GAD65) antibody was negative
and his c-peptide was normal
despite mild hyperglycemia (FSG
140 mg/dl).
Sam’s physician explained that in
light of his significant hyperglycemia
and the fact he has contributed so
significantly to his control that
insulin would be the safest and most
effective therapy. The physician also
explained that insulin has been a
“tried and true” life-saving therapy
for almost a century. Also as a
hormone replacement it may have
less side effects and drug interactions
than most oral medications.
As a side note, if Sam were not
slim and if he had a preponderance
of postprandial hyperglycemia
without an elevated fasting blood
glucose level, then the short-acting
glucagon-like peptide-1 (GLP-1)
receptor agonist exenatide would be a
treatment option. Because the longeracting
GLP-1 receptor agonists lower
both fasting and postprandial blood
glucose levels, they would also be
options in this type of case, especially
if weight loss is a consideration.
However, because Sam was relatively
slim with high FPG and HbA 1c levels,
insulin was his best option for therapeutic
addition.
Sam was instructed regarding how
to use an insulin pen, including the
appropriate injection sites (ie,
abdomen, outer arms, and thighs).
See Figure 1. Upon placing the needle
on the pen, he was shown how to do
a 2-unit “air-shot” (ie, dialing up the
pen to 2 units and ejecting a drop of
insulin into the air to ensure that the
injection would deliver the correct
Figure 1. Site selection
for insulin injection.
The most common injection site is
the abdomen or stomach. Other sites
that can be used include the back of
the upper arms, the upper buttocks
or hips, and the outer side of the
thighs. These sites are recommended
because they have a layer of fat just
below the skin to absorb the insulin
but not many nerves, which means
that injection at the site will be more
comfortable to the patient than
injection in other parts of the body.
Injection at these sites also make it
easier for the patient to inject into the
subcutaneous tissue.
amount of insulin with no air
bubbles). When administering the
injection, he was advised to count to
6 to ensure that the full dose of
insulin was delivered prior to
withdrawing the needle from the
injection site. The needle for the pen
was short and 32 gauge. Sam was
amazed how small and thin the
needles were and was pleasantly surprised
that he did not feel pain with
the injection. Part of the education
provided to Sam was to stress that the
needle should be changed with each
injection.
Sam began injecting 10 units of a
basal insulin analog every night at
bedtime. The PREDICTIVE 303 algorithm
was given to Sam to enable
him to self-titrate his insulin
(Table 1). 14 He had always checked
his fasting blood glucose levels daily
and was amenable to being even
more involved with his therapy, with
the assurance that he would receive
guidance from his physician.
Increased self-monitoring of blood
glucose levels gave him further feedback
and a sense of empowerment.
His fasting blood sugar (FBS) goal was
between 80 and 130 mg/dL, which
was individualized to his situation
and which is a bit more lenient than
Dialogue and Diagnosis // September 2012
3

FPG (mg/dL)
Response
80 Reduce dose by 3 units 3
80-110 No Change 0
110 Increase dose by 3 units 3
Table 1. Change in glycosylated hemoglobin levels
Patient self-titration of basal insulin analog, with dose adjustment every 3 days on basis of
fasting plasma glucose level. 14,31
the clinical trial goal of 80-110 mg/dL
in the PREDICTIVE trial (see below
for discussion of American
Association of Clinical Endocrinologists
and the American Diabetes Association
guidelines). He was advised to
increase the insulin dose by 3 units in
his insulin dose every 3 days until his
mean FBS was in that range. Sam was
also told to continue using his oral
diabetes medications (eg, sulfo -
nylurea) but was advised to call his
physician should he experience
hypoglycemia. Any blood glucose
level 80 mg/dL necessitated a reduction
of 3 units in dose. However, if
the total insulin dose exceeded 30
units, a 10% drop was recommended.
Sam returned 6 weeks later. He was
found to have achieved his FBS goal
with 36 units of insulin. He told his
physician, “Shots aren’t bad after all.”
At his next visit, 14 weeks after beginning
insulin therapy, a repeat HbA 1c
measurement yielded a result of
6.9%.
Unfortunately, with the first ice
storm of the winter Sam fell and
broke his leg. Without his exercise
routine, Sam’s FPG level began to rise.
On the basis of guidance from the
PREDICTIVE 303 algorithm, Sam
added another 6 units of basal insulin
to regain control over his FBS. After
the cast was removed from his leg, his
activity level increased and he was
able to reduce the basal insulin dose
to 36 units. Although Sam
experienced many changes and challenges
with his medications, he
expressed confidence that he had the
tools to control his diabetes mellitus
as he had the flexibility to match his
medication with his life circum -
stances.
Sam did well for the next 2 years.
He then received a promotion at
work, and his mealtimes became
more erratic. He continued his exercise
routine and followed his dietary
recommendations, but he noted that
his bedtime plasma glucose levels had
risen to more than 200 mg/dL. He
continued up-titration of the insulin
dose to lower his evening glucose
levels. The dose increased to 55 units
of basal insulin. He began noting
occasional morning (fasting) plasma
glucose values of approximately
60 mg/dL. Most upsetting to him was
that if his lunch was delayed because
of his job, hypoglycemia would
occur. He began carrying candy in his
jacket for such occasions.
On Sam’s return to his physician,
it was determined that the basal
insulin dose was excessive. Sam
agreed to add a second type of
insulin, prandial or meal time
insulin, to better cover his meal time
insulin needs and to alleviate the
hypoglycemia caused by excessive
basal insulin and to allow him to
regain control of his diabetes mellitus.
The sulfonylurea was stopped. He
was given a second pen with a rapidacting
insulin to take within 15
minutes of starting dinner, and he
was asked to test his blood glucose
levels before and 2 hours after dinner.
The starting dose of prandial
insulin was 6 units. Instruction was
given on how to titrate the dinner
dose every 3 days by 1 unit—until his
2-hour postprandial glucose level was
less than 180 mg/dL. If Sam were to
eat a larger meal, perhaps at a restaurant,
he would take an additional 2
units to compensate for the extra
food. He would also continue during
the next 3 days to titrate the basal
insulin dose to achieve a FPG level
between 80 and 130 mg/dL. The
basal insulin dose was decreased to 45
units. Only 1 type of insulin was to
be titrated on a given day.
After these adjustments in therapy,
life quickly returned to normal for
Sam. His hypoglycemia abated, and
his glucose goals were achieved.
Considerations for
insulin therapy
Insulin should be considered for any
patient undergoing triple therapy if
his or her HbA 1c levels are not at goal
for more than a few (no more than
2 to 3) months. 15 The AACE
recommends insulin for patients
with HbA 1c levels 10%, regardless
of whether the patients are symptomatic.
The AACE also recommends
insulin for patients with HbA 1c levels
more than 9% above normal if the
patients are symptomatic. 15
Introducing insulin
Patients’ fear, discomfort, and lack of
adherence with insulin therapy, as
well as certain societal factors, can
impact achievement of treatment
goals. 16 Patients failing to initiate prescribed
insulin therapy commonly
have misconceptions regarding
insulin risk. One study indicated that
35% of such patients believe that
insulin causes blindness, renal failure,
amputations, heart attacks, strokes, or
early death. Many patients see the
need for insulin as personal failure in
self-care. Common characteristics
among patients who fail to initiate
4 Dialogue and Diagnosis // September 2012

insulin therapy include a sense of
personal failure, low self-efficacy,
injection phobia, hypoglycemia concerns,
inadequate health literacy, and
limited insulin self-management
training, as well as having health care
providers who inadequately explain
risks and benefits. 17
Recent data show that patients
who are non-adherent with clinic
visits and insulin therapy are more
likely to have higher HbA 1c levels and
face an increased risk for all-cause
mortality compared to adherent compliant
patients. 18 These data demonstrate
the importance of ensuring
that patients with diabetes mellitus
are knowledgeable and comfortable
with insulin therapy.
To facilitate psychological
receptiveness to injectable treatments
among patients, physicians can
encourage patients to self-monitor
their blood glucose, they can educate
patients about acceptable ranges for
blood glucose readings, and they can
discuss HbA 1c results with patients.
Providing patients with injectable
pen delivery devices and establishing
a structured program of support
during insulin initiation may also
help patients overcome their
anxieties about treatment. 19 Other
factors to consider for facilitating
insulin therapy include the
following:
Basal insulin analogs
Long-acting insulin analogs (eg,
insulin glargine and insulin detemir)
are now firmly established as key
tools in the battle against diabetes
mellitus, and ongoing clinical
research is focused on treatment
strategies to maximize the benefits of
these agents. Basal insulin analogs
provide relatively uniform insulin
coverage throughout the day and
night, primarily by controlling blood
glucose levels through the
suppression of hepatic glucose
production between meals and
during sleep. 20 These agents are traditionally
dosed once daily, at the same
time each day. Recent data from the
Outcome Reduction with Initial
Glargine Intervention (ORIGIN) trial
showed that insulin glargine had no
positive or negative effect on cardiovascular
outcomes and no association
with cancer in patients with type 2
diabetes. 21
Although basal insulin analogs are
associated with a lower risk of hypoglycemia
than human neutral protamine
Hagedorn (NPH) insulin,
hypo glycemia is a dose-limiting
adverse effect of these agents. 22
Patients using basal insulin therapy
are more likely to adhere to treatment
if they are prescribed a long-acting
basal analog (eg, detemir or glargine
vs NPH) 23 and if they are able to
administer insulin using a pre-filled
pen (compared to the use of a vial
and syringe). 24
Continuation of oral medications
along with basal insulin is a common
clinical practice. The use of
metformin mitigates insulinassociated
weight gain and provides
another mechanism of action by
which to control hyperglycemia.
Sulfonylureas may or may not be
continued, depending on the patient
and the physician’s clinical
experience. Sulfonylureas are insulin
secretagogues, and their use with
insulin may increase the risk of
hypogly cemia in some patients.
Physicians are more likely to stop the
use of sulfonylureas as the number of
insulin doses increase; they should
certainly consider discontinuing
them regardless of the number of
insulin doses if unacceptable
hypoglycemia occurs, because the
Address the patient’s beliefs about
insulin.
Assess the patient’s insulin
experiences.
Determine the best insulin regimen
for the patient.
Determine the best delivery device
for the patient.
Educate the patient about dose
adjustment.
Adjust the insulin regimen as
necessary.
Dialogue and Diagnosis // September 2012
5

sulfonylureas are most likely the
culprits.
Patients should be counseled
about the signs and symptoms of
hypoglycemia, including hypo -
glycemia prevention and treatment.
Patients expressing concern about the
possibility of insulin-related
hypoglycemia should be reassured
that the risk of this condition is low
for patients with T2DM who are
treated with basal insulin analogs, 24,25
even among older adults. 26 This risk
is low despite the fact that patients
with T2DM, because of an innate
insulin resistance, tend to require
higher doses of insulin than patients
with type 1 diabetes mellitus. In the
case of Sam, if hypoglycemia were to
occur, discontinuation of the sulfonylurea
would be advisable.
Patient self-titration
Basal insulin is most often initially
used in patients with T2DM who fail
to achieve optimal glycemic control
with oral antidiabetic drugs. Clinical
trials have shown that addition of a
basal insulin analog to an oral regi -
men is capable of lowering the HbA 1c
level by approximately 1.6%, with
better tolerability than NPH insulin. 27
Once-daily dosing with long-acting
insulin analogs is adequate in many
patients. 13,28 Basal insulin doses
should be titrated to reduce FPG
levels to between 80 and 110 mg/dL
(according to AACE guidelines) 29 or
between 70 and 130 mg/dL (accord-
ing to ADA guidelines) depending on
patient charac teristics. 30
Results of clinical trials suggest
that patients, even those previously
naïve to injectable insulin therapy,
can safely and effectively manage
their blood glucose levels themselves
if empowered and educated to do
so. 31,32 Offering patients the option
of a once-daily basal insulin analog
with a simple-to-use titration
algorithm is a safe and effective intervention
that may address some of the
concerns of physicians related to the
complexity of initiating insulin
therapy. 31,32
Regarding glucose self-monitoring,
physicians should consider urging
measurements of fasting levels and
“bracketing” 1 meal with preprandial
and postprandial measurements daily
on a repetitive basis. In addition, it
should be kept in mind that Medicare
allows 3 insulin measurements per
day. Patients can get more if needed
with additional documentation.
Intensification of insulin
therapy
Titration of the patient’s existing
insulin regimen is the first step in
intensification efforts to maintain
HbA 1c goals. However, as T2DM takes
its natural course of progression,
treatment regimens need to be monitored
and, when necessary, further
intensified to maintain acceptable
glycemic control. Physicians should
consider intensifying therapy beyond
titration of basal insulin when a
patient using basal insulin has an
HbA 1c level above goal despite having
achieved the FPG target. The addition
of a sulfonylurea or an increase in sulfonylurea
dose will not correct this
glycemic problem and may actually
increase the risk of hypoglycemia.
Sulfonylureas first lower FPG, then
lower PPG. Furthermore, simply
increasing the dose of basal insulin in
such a scenario is likely to expose the
patient to the risk of between-meal
hypoglycemia and persistent
postprandial hyperglycemia.
Clinical experience suggests that
the total daily insulin dose—on the
basis of unit per kilogram of body
weight—typically ranges from 0.5 to
2 units per kilogram per 24 hours for
patients with T2DM. Approximately
50% of a patient’s total daily insulin
dose is basal insulin, with the balance
allocated across mealtime glucose
spikes (ie, postprandial insulin). Thus,
if the patient has not achieved HbA 1c
goals, attention to postprandial
hyperglycemia is warranted. Adding
prandial insulin to basal insulin regimens
provides physiologic coverage
of insulin requirements by means of
switching to a premixed insulin
analog or addition of a rapid-acting
analog at mealtimes, as indicted in
6 Dialogue and Diagnosis // September 2012

Basal insulin alone
Sequential addition of
prandial insulin before
meals with high PPG levels
Basal Bolus insulin
(multiple daily injections
Consider gold standard;
allows customization
to food activity
Simple way to start
increasing number
of injections
Often with oral agents
continued
Premixed insulin
three times a day
Premixed insulin
twice a day
Premixed insulin
once a day
Provides basal
and prandial insulin
in a single injection
Figure 2. Sequential insulin strategies
for patients with type 2 diabetes
mellitus.
Adapted with permission from Inzucchi SE,
Bergenstal RM, Buse JB, et al; American
Diabetes Association (ADA); European
Association for the Study of Diabetes (EASD).
Management of hyperglycemia in type 2
diabetes: a patient-centered approach: position
statement of the American Diabetes Association
(ADA) and the European Association for the
Study of Diabetes (EASD). Diabetes Care.
2012;35(6):1364-1379.
Figure 2 and Table 2, provides considerations
regarding which type of
prandial coverage may be most suitable
for a given patient. While basalbolus
insulin therapy required more
injections, it tends to increase day-today
life flexibility.
Given Sam’s erratic schedule, premixed
insulin is not a desirable treatment
option for him. Because he will
likely need to titrate prandial insulin
doses according to meal times and
sizes, the addition of a prandial
insulin at the largest meal is the most
attractive option. Data from the Orals
Plus Apidra and LANTUS (OPAL)
trial 33 showed that a single bolus of
prandial insulin analog improved
HbA 1c levels when added to a basal
insulin analog and oral antidiabetic
agents (Figure 3).
Challenges in adding
medications to
therapeutic regimens
Recent data suggest that most
patients with diabetes mellitus have
negative perceptions of the initiation
of additional medications, viewing it
as evidence of personal failure and
increased burden. 34 Patients equate
medication intensification with
Requires some
consistency in food
intake/exercise
increased risk for diabetes-related
complications rather than a step in
reducing risk. They view de-escala -
tion of medication as their primary
goal. However, patients respond
favorably to an individualized medication
plan outlining future contingencies.
34 According to the international
Diabetes Attitudes, Wishes,
and Needs (DAWN) study, 35 more
than half (57%) of all patients with
T2DM are very worried about starting
insulin therapy.
Many factors contribute to this
worry. As previously noted, feelings
of failure or depression (regarding following
lifestyle changes and
adherence to therapy), as well as the
sense that using insulin means that
their diabetes has worsened, may lead
to resistance to insulin therapy. Many
patients who are resistant to insulin
therapy may also be reluctant to
accept the responsibilities of everyday
management of insulin therapy. 36
Insulin should be offered to patients
in a positive light—as a means to
improve their health. Reminding
them early in the disease that there
may be times insulin is needed in a
pinch, such as a critical illness or hospitalization,
may help. This approach
might facilitate their acceptance of
insulin therapy. Physicians can help
patients at the time of diagnosis by
explaining that diabetes mellitus is a
progressive disease, and that changes
in therapy over the course of a
lifetime in no way reflect badly on
the patient.
Premixed Insulin
Basal-Bolus Insulin
(1, 2, or 3 injections of same insulin) (4 injections; 2 types of insulin)
— Preference for few injections — Variable meal pattern
— Fixed daily routine — Variable daily routine
— Unwilling to monitor blood glucose* — Postprandial control an issue
— Limited cognitive function* — Able to comply with complicated
— Limited healthcare support system* regimen (eg, willing and good
*the last 3 apply when relaxed glucose
cognitive function)
targets are applied
— Support system available
Table 2. Criteria for choosing between premixed vs basal-bolus insulin.
Dialogue and Diagnosis // September 2012
7

Glycosylated Hemoglobin Level, %
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
Figure 3. Change in glycosylated hemoglobin levels
Change in glycosylated hemoglobin levels with addition of a single prandial dose of a
rapid-acting insulin in patients with type 2 diabetes mellitus who were treated with a
basal insulin analog and oral antidiabetic medications. 33
Many patients have misconcep -
tions about insulin therapy. Some of
these misconceptions relate to the
fact that insulin therapy was formerly
delayed until the patient had
advanced disease, often with complications.
Thus, physicians may hear
that the patient’s grandmother
started insulin therapy and shortly
thereafter was on dialysis or had an
amputation as a result of peripheral
neuropathy—family experiences that
cause the patient to associate the start
of insulin therapy with a bad out -
come. In Sam’s case, he associated
insulin therapy with his grand -
mother’s diabetic complication of
blindness.
It is important to ask patients
what they think they know about
insulin therapy. They should be
informed about advances in insulin
therapy−such as the availability of
insulin analogs that reduce hypo -
glycemia risks (a valid concern) and
that are convenient to dose (so as
not to pose a lifestyle constraint),
as well as the availability of insulin
pen delivery devices (which should
allay concerns about pain,
embarrassment, and worries
regarding correct dosing). All
P = .0001
Baseline
Endpoint
7.32 6.99
patients need to understand that
in T2DM, the ability of the body to
make insulin decreases over time.
Helping patients understand the
role of insulin in the management
of T2DM and in the context of the
disease process may go a long way
to avoiding patient resistance to
insulin use.
Challenges in ethnic
minorities
Type 2 diabetes mellitus is more
common among African Americans
and Mexican Americans than among
non-Hispanic whites, which necessitates
that primary care physicians
consider culturally competent
approaches to care. Mexican Americans
and non-Hispanic blacks are less
likely to achieve good glycemic
control compared with non-Hispanic
whites. 37 Data from the National
Health and Nutrition Examination
Survey reveal that the disparity in
diabetes-related mortality across education
levels widened from the late
1980s to 2005−both overall and in
the subgroups of men, women,
blacks, whites, and Hispanics. 38 Hispanics
are generally much more concerned
about adverse effects related
to diabetes medications than are
African Americans or non-Hispanic
whites. 39 Hispanics are also much
more likely to be resistant to the idea
of insulin therapy. 40,41
Ultimately, minority patients with
diabetes mellitus are more likely than
white patients with this condition to
have poor long-term outcomes,
leading to such complications as diabetic
retinopathy, lower extremity
amputations, and chronic kidney
disease. Increasing clinicians’ awareness
of such racial and ethnic disparities
and improving communication
between clinicians and minority
patients may enhance care among
these patients. 39,42,43 Language
barriers may hinder adequate care by
limiting or preventing communi -
cation (including the exchange of
important cultural information) and
by leading to misunderstanding of
physicians’ instructions, poor shared
decision-making, and ethical
compromises (eg, not obtaining full
informed consent). In the Translating
Research Into Action for Diabetes
(TRIAD) study, 44 23% of Spanish-
8 Dialogue and Diagnosis // September 2012

speaking Hispanic patients reported
language to be a barrier in communicating
with health care professionals.
Poor adherence to treatment, missed
appointments, and patient
dissatisfaction can all be attributed to
miscommunication.
Patient education and
support
The use of support groups for patients
with diabetes mellitus that focus on
management and education, creative
ways to adopt healthy foods that
complement ethnic diets, exercise
opportunities, and other advice is an
additional way to enhance self-management.
45,46 Encouraging patients to
use social networks of family
members, peer support groups, community
health workers, and one-onone
interactive education can
improve patient resilience to
stressors. Diabetes self-management
education programs for Hispanics
and Latinos, led by community
health workers, have been imple -
mented in a number of community
settings. These programs may
effectively improve behavioral skills,
such as physical activity and healthy
eating. 47
Key learning points
Effectively educate patients with
diabetes mellitus about the progression
of and treatment for the
disease.
Achieving good glycemic control
early prevents diabetic complica -
tions. The lowest possible HbA 1c
level, without unacceptable hypoglycemia
and untoward complications,
should be attained.
Optimal glycemic control should be
maintained to minimize the risk of
diabetic complications. When
choosing the treatment option for
each patient, consider the duration
of T2DM, stage of the disease,
current level of control, lifestyle
habits, and attitude toward disease
management.
Intensification of treatment
requires glucose monitoring and
medication adjustment every 2 to 3
months.
Lifestyle intervention remains the
foundation of care for all patients
with diabetes mellitus, and healthy
lifestyle choices should be
addressed at every office visit.
Most patients who have HbA 1c
levels greater than 7.5% will require
combination therapy with complementary
mechanisms of action.
Insulin should be prescribed for all
patients with HbA 1c levels greater
than 10% and for all symptomatic
patients with HbA 1c levels greater
than 9%.
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Joseph M. Tibaldi, MD, FACP, is an assistant
clinical professor of medicine at Weill Cornell
Medical College in New York, New York. Dr.
Tibaldi can be reached at jtibaldi@aol.com.
10 Dialogue and Diagnosis // September 2012

AFTER METFORMIN
Introducing and titrating
glucagon-like peptide-1 receptor
agonist therapy for patients
with type 2 diabetes mellitus
Jeffrey S. Freeman, DO
Metformin has remained the cornerstone of therapy
for patients with type 2 diabetes mellitus (T2DM)
who do not have contraindications to its use and
who can tolerate it. Metformin’s widespread use is
based on its glucose-dependent mechanism of action (with
a low risk of hypoglycemia), its lack of association with
weight gain, its durability of effect, its long history of safety,
and its generic availability. 1
Dialogue and Diagnosis // September 2012
11

In addition, metformin
may have beneficial
effects in reducing
cardiovascular risks 2
and cancer risks 3 in
patients with T2DM.
Traditionally, sulfonylureas (ie,
insulin secretagogues) or thiazolid -
ine diones (ie, insulin sensitizers) were
among the only other available oral
treatment options for individuals
with T2DM. In recent years, however,
a new generation of oral and
injectable antidiabetic therapies—
besides insulin—became available. 4
Now the clinician is faced with many
more treatment options and many
more safety, efficacy, and tolerability
issues to consider when personalizing
treatment for patients who require
combination therapy in addition to
metformin as T2DM progresses.
In the present article, I focus on a
rationale for the use of glucagon-like
peptide-1 (GLP-1) receptor agonists as
add-on therapy to metformin for
some patients with T2DM.
Case report
Julia is a 48-year-old woman with
T2DM who presents to a primary care
physician complaining of weight
gain. She understands that, as an
individual with diabetes mellitus, she
needs to try to maintain a healthy
weight to assist in attaining glucose
control. She was diagnosed with
T2DM 3 years ago, as she went
through menopause. A year before
this diagnosis, she could not
understand why she was gaining
weight, despite exercising a few times
per week. After the diagnosis, she
began metformin therapy and saw a
nutritionist. She learned to perform
self blood glucose monitoring and to
test fasting plasma glucose (FPG)
levels daily. She was pleased that she
was able to lose 3 pounds and
attained a glycosylated hemoglobin
(HbA 1c ) level of 6.2% after 6 months.
Her body mass index (BMI) at that
time was 31. For the next 18 months,
she maintained a healthy lifestyle
and an FPG level below 130 mg/dL,
as recommended by her family physician.
Initial therapy: lifestyle
intervention plus
pharmacotherapy
Typically, therapeutic strategies for
patients with T2DM begin with diet
and exercise modification, followed
by the gradual and sequential
addition of medications. The current
treatment paradigm acknowledges
intrinsic physiologic defects present
early in the course of the disease that
require efforts beyond lifestyle modification
alone, including pharmacologic
therapy, with metformin most
often being used as the initial therapy
(in the absence of contraindica -
tions). 1,5 Metformin has become the
cornerstone of therapy on the basis of
its efficacy, low risk of hypoglycemia,
low risk of weight gain, and generic
availability.
When treatment goals are not
achieved or maintained with
metformin and lifestyle modification,
treatment should be promptly intensified
to combination drug therapy
using agents with complementary
mechanisms of action. In addition,
lifestyle intervention (eg, physical
activity, healthy eating, nonuse of
tobacco, weight management, effective
coping) should be continued and
even intensified as the disease
progresses. 1,5 Other recommenda -
tions for improving the care of
patients with diabetes mellitus
include the following: 6
Explore patient’s goals for
treatment.
12 Dialogue and Diagnosis // September 2012

Figure 1. The simultaneously increasing rates of obesity
The simultaneously increasing rates of obesity and diabetes mellitus from 1994 to 2009, shown according to the percentages of adults
with these conditions in each state.
Source: Centers for Disease Control and Prevention, National Diabetes Surveillance System.
http://www.cdc.gov/diabetes/statistics/index.htm.
Set explicit goals with patients.
Identify and address barriers to care.
Integrate evidence-based guidelines
into care.
Incorporate care management
teams.
Implement a systematic approach
to support patients’ efforts at
behavioral changes.
Incorporate disease selfmanagement,
including medication
taking and management and selfmonitoring
of glucose levels and
blood pressure when clinically
appropriate.
Prevent disease complications
through self-monitoring of foot
health; patient participation in
screenings for eye, foot, and renal
complications; and immunizations.
Lifestyle modifications
The Centers for Disease Control and
Prevention has documented the dramatic
simultaneous increase in
prevalence of diabetes mellitus and
obesity in the United States
(Figure 1).
Lifestyle modification, primarily
calorie reduction and appropriate
physical activity, remains the cornerstone
of control of obesity in
patients with T2DM. 5 Ongoing therapeutic
lifestyle management should
be discussed with all patients with
diabetes mellitus throughout their
lives. Medical nutritional therapy
must be individualized, generally
requiring evaluation and teaching
by a trained nutritionist/registered
dietitian or a knowledgeable physician.
In addi tion to proper nutrition
and physical activity, lifestyle
manage ment includes the avoidance
of tobacco products and the promo -
tion of an adequate quantity and
quality of sleep.
Regular physical activity, that
includes both aerobic exercise and
strength training, is important to
improve a variety of cardiovascular
disease risk factors, to decrease the
risk of falls and fractures, to
improve functional capacity, and to
improve glucose control in individuals
with T2DM. Recommendations
for at least 150 minutes per week of
moderate-intensity exercise, such as
brisk walking or its equivalent, are
now well accepted and part of
national guidelines. 5 The main
Dialogue and Diagnosis // September 2012
13

physical activity recommendations
for patients with diabetes mellitus are
as follows:
Advise patients to perform at least
150 minutes per week of moderateintensity
aerobic physical activity
(ie, 50%-70% of maximum heart
rate), spread over at least 3 days per
week with no more than 2 consecutive
days without exercise.
In the absence of contraindications,
patients should be encouraged to
perform resistance training at least
twice per week.
Four-year results from the Look
AHEAD trial show that comprehensive
lifestyle intervention can
induce clinically significant weight
loss (ie, 5%) in overweight or
obese participants with T2DM. 7 This
weight loss was maintained in more
than 45% of the patients in the
trials. 7 Intentional weight loss is
known to decrease the need for
antidiabetic medications, primarily
by improving insulin resistance. 8
Pharmacotherapy
At Julia’s next 3-month checkup,
her FPG level mean increased to
160 mg/dL, and her HbA 1c level
was found to be increased to 7.4%.
Glimepiride 2 mg daily was added to
Figure 2. T2DM antihyperglycemic therapy: general recommendations
Possible progressions in antihyperglycemic therapy after metformin and before the full use of basal bolus insulin in patients with type 2
diabetes mellitus, including efficacy, hypoglycemia risk, weight effects, adverse effects, and costs. If a patient’s glycosylated hemoglobin
(HbA1c) target is not achieved after approximately 3 months, 1 of these 5 treatment options should be considered: metformin combined
with (1) a sulfonylurea, (2) a thiazolidinedione (TZD), (3) a dipeptidyl peptidase-4 (DPP-4) inhibitor, (4) a a glucagon-like peptide-1
(GLP-1) receptor agonist, or (5) basal insulin. The choice is based on patient and drug characteristics, with the goal of improving glycemic
control while minimizing adverse effects. Along with pharmacotherapy, healthy eating, weight control, and increased physical activity are
necessary components of treatment.
Adapted with permission of American Diabetes Association. 1
14 Dialogue and Diagnosis // September 2012

Figure 3. Key benefits and risks of antidiabetic medications
Key benefits and risks of antidiabetic medications: metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor
agonists, sulfonylureas, thiazolidinediones, and insulin. Abbreviation: CHF, congestive heart failure. 9
Source: Endocrine Practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists,
by American College of Endocrinology; American Association of Clinical Endocrinologists, Copyright 2012. Adapted with permission of
Aacecorp Inc.
metformin 1000 mg twice daily. Her
glucose reading improved, however
she quickly learned that if a meal was
delayed, hypoglycemia would ensue.
Within another 3 months, her HbA 1c
level was again below 7%, but she
had gained 5 pounds. She had also
curtailed exercise somewhat because
of her fear of hypoglycemia.
The American Diabetes Associa -
tion (ADA) and the European Association
for the Study of Diabetes
(EASD) 1 have recently updated their
recommend ations for the manage -
ment of hyperglycemia to take a
more holistic approach, encouraging
the individualization of treatment
goals and options for patients with
diabetes mellitus. As previously mentioned,
most patients with T2DM
begin pharmacotherapy with
metformin, but they eventually need
additional medications. Figure 2 summarizes
possible progressions in
therapy after metformin and before
the full use of basal bolus insulin. 1 If
the patient’s HbA 1c target is not
achieved after approximately 3
months of lifestyle treatments and
metformin, 1 of these 5 treatment
options should be considered:
metformin combined with (1) a sulfonylurea,
(2) a thiazolidinedione
(TZD), (3) a dipeptidyl peptidase-4
(DPP-4) inhibitor, (4) a GLP-1
receptor agonist, or (5) basal insulin.
The choice is based on patient and
drug characteristics, with the over -
riding goal of improving glycemic
control while minimizing adverse
effects. Shared decision-making with
the patient may help in the selection
of therapeutic options. 1 Figure 3
summarizes key benefits and risks of
the main classes of antidiabetic medications.
9
Limitations of insulin
secretagogues
One of the biggest concerns with
sulfonylureas is hypoglycemia. Medication
associate hypoglycemia is
likely under-recognized and under -
reported as a cause of morbidity and
mortality. 10-12 Hypoglycemia
adversely affects patients’ quality of
life and may influence adherence to
treatment—and, thus, the success of
the treatment. 13,14 Patients and their
friends, families, and neighbors
should be educated about the signs
and symptoms of hypoglycemia and
its treatment. 15
The use of sulfonylureas results in
a relatively rapid lowering of glucose
levels. However, the use of these
agents is not always successful in
maintaining glucose control over the
long-term. The progressive -cell
failure seen in T2DM results in even-
Dialogue and Diagnosis // September 2012
15

tual loss of sulfonylurea efficacy,
which depends on the number of
remaining -cells. Therefore, sulfonylureas
are ineffective in the absence
of insulin-producing capacity. This
limitation was demonstrated in the
ADOPT study, 16 which assessed the
“durability” of glucose-lowering
effects among metformin, TZDs, and
sulfonylureas. Sulfonylureas had the
least durability, and TZDs had the
most durability. 16
Hypoglycemia is a major concern
with the use of either sulfonylureas
or insulin. The association between
these agents and hypoglycemia was
a perceived disadvantage of the previous
treatment algorithm issued by
the ADA and EASD. 17 That algorithm
did not take a holistic approach with
patients and did not incorporate
ambient HbA 1c levels, possible
contraindications, or risks of weight
gain or hypoglycemia into treatment
choices. 17 In the revised ADA/EASD
algorithm, 1 the use of sulfo nyl ureas
is not encouraged if avoidance of
hypoglycemia is the main objective
of therapy.
Twelve months after starting
glimepiride, Julia’s HbA 1c level was
again elevated, to 7.7%, her FPG
level was 170 mg/dL, and she had
gained another 5 pounds, increas -
ing her weight to 180 pounds and
her BMI to 32. She was frustrated
and depressed. When injectable
therapy was mentioned, Julia
quickly refused. Nevertheless, her
family physician discussed the
advantages of injectable therapy
using a GLP-1 receptor agonist. The
2 major advantages were
attainment of glycemic control
with the possibility of weight loss.
Adverse effects include possible
transient nausea and the potential
risk of pancreatitis. The risk of
Medullary thyroid tumors (a very
rare thyroid cancer), as noted in
rodents, was also discussed with
the patient. 18
Limitations of
thiazolidinediones
TZDs have been available for some
time and appear to be durable and
address insulin resistance in diabetes.
But these agents are being used less
often. With recent concerns about
the short-term tolerability (eg, weight
gain, fluid retention) 19 and long-term
safety (eg, risk of osteoporosis, 20 possible
association with bladder
cancer) 21 of TZDs, the advantage of
durability alone may not be enough
to support the use of pioglitazone in
addition to, or as a replacement for, a
sulfonylurea.
Increasing role of
incretin-based therapies
A distinct advantage of incretin-based
therapies—both oral DPP-4 inhibitors
and injectable GLP-1 RAs—is that
they work in a glucose-dependent
manner (ie, only when glucose levels
are high). Thus, incretin-based therapies
are associated with a very low
risk of hypoglycemia, 22 unless they
are used with agents that work in a
glucose-independent manner—
which is the reason that doses of sulfonylureas
and insulin may need to
be lowered if a GLP-1 RA is used with
these agents. 23
Although DPP-4 inhibitors are
weight neutral, GLP-1 RAs are associated
with a slow, progressive 24 (and
dose-dependent 25 ) loss in weight, primarily
a loss in adipose tissue. Given
Julia’s frustration with weight gain,
despite her efforts at lifestyle modification,
and her concerns about hypoglycemia,
the use of 1 of the available
GLP-1 receptor agonists (ie, exenatide
twice daily, liraglutide once daily, or
exenatide extended release once
weekly) is a reasonable therapeutic
option. Both the ADA/EASD
algorithm 1 and that of the American
Association of Clinical Endocrinologists
(AACE) 9 encourage the use of
incretin-based therapies in patients
for whom weight gain is problematic
and for whom avoiding hypoglyce -
mia is important. Figure 4 compares
and contrasts DPP-4 inhibitors and
Properties/Effects DPP-4 Inhibitors GLP-1 Receptor Agonists
Similarities
Glucose-dependent actions Yes Yes
Low risk of hypoglycemia, Yes Yes
except when used with
sulfonylureas
Use with caution in patients Yes Yes
with history of pancreatitis
Differences
Route of administration Oral Subcutaneous injection
Frequency of administration Once daily Varies by agent
Effects on weight Weight neutral Associated with weight loss
because of effects on satiety and
gastrointestinal emptying
Tolerability Well tolerated Gastrointestinal adverse effects
Figure 4. Comparison of properties and effects
Comparison of properties and effects of dipeptidyl peptidase-4 (DPP-4) inhibitors
and glucagon-like peptide-1 (GLP-1) receptor agonists. 26,27
16 Dialogue and Diagnosis // September 2012

Compounds Exenatide (approved 2005)
Liraglutide (approved 2010)
Exenatide extended duration (approved 2012)
Mechanism
Action(s)
Advantages
Disadvantages
Cost
GLP-1 RAs. 26,27 Figure 5 summarizes
features of the available GLP-1
receptor agonists, including mechanisms,
actions, advantages, and
disadvantages. 6
Glucagon-like peptide-1
receptor agonists
Efficacy when added to oral anti -
diabetic monotherapy
Given the combination of effective
glycemic control and weight benefits,
addition of a GLP-1 receptor agonist
may be a good option for early addon
therapy for patients receiving oral
antidiabetic monotherapy, such as
Julia. For example, for patients
receiving metformin monotherapy,
the addition of either liraglutide or
Activates GLP-1 receptors (-cells/endocrine
pancreas; brain/autonomic nervous system)
Insulin secretion up (glucose-dependent)
Glucagon secretion down (glucose-dependent)
Slows gastric emptying
Satiety up
Low hypoglycemia risk
Weight reduction
Improvement in cardiovascular risk factors
Potential for improved -cell mass/function
Gastrointestinal adverse effects (nausea,
vomiting, diarrhea)
Cases of acute pancreatitis observed
C-cell hyperplasia/medullary thyroid tumors
in animals (liraglutide, exenatide extended
duration)
Injectable
Long-term safety unknown
High
Figure 5. Summary of features
Summary of features of available glucagon-like peptide-1 (GLP-1) receptor agonists,
including mechanisms, actions, advantages, and disadvantages. Adapted with
permission from Diabetes Care. 6
glimepiride was shown to result in
similar levels of glycemic control,
though patients receiving glimepiride
had statistically significant greater
weight gain (P .001) and higher
rates of minor hypoglycemia. 28 Comparisons
of liraglutide vs sitagliptin in
patients not achieving adequate
glycemic control with metformin
monotherapy showed that liraglutide
offered sustained, more effective
glycemic control and weight reduc -
tion compared to sitagliptin. 29,30 In
addition, liraglutide was also associated
with greater treatment satisfaction
(independent of effects on
weight) at 1 year after treatment initiation.
29,30
Likewise, in trials lasting longer
than 1 year, exenatide twice daily was
generally well tolerated, producing a
durable reduction in HbA 1c levels and
a progressive reduction in weight in
patients with T2DM. 31 In patients
taking metformin, exenatide twice
daily was comparable to the use of
premixed insulin for glycemic
control, and it was better in terms of
hypoglycemia and weight control. 32
The recently approved long-acting
formulation of exenatide (exenatide
extended duration), which is given
once weekly, was more effective than
a TZD or DPP-4 inhibitor as an
adjunct to metformin in achieving a
combined endpoint of optimum
glucose control with weight loss—
without hypoglycemia. 33
Precautions and
contraindications
If an incretin-based medication is
selected it is important to review the
safety issues with the patient.
Prescribing information states that
incretin-based medications (both
DPP-4 inhibitors and GLP-1 receptor
agonists) should be stopped if “signs
of pancreatitis” develop (eg, persis -
tent abdominal pain that can radiate
to the back, with or without nausea
and vomiting), and that these agents
should not be used in patients who
have a history of pancreatitis. 18,34-36
Diabetes mellitus and obesity, in and
of themselves, increase the risks of
pancreatitis, and available data do
not suggest a difference between the
incidence of pancreatitis in patients
using incretin-based therapies vs
other classes of glucose-lowering
agents. 37 Julia was counseled about
the symptoms of pancreatitis and
advised to call her physician should
she experience these symptoms.
Liraglutide and exenatide
extended-release are contraindicated
in patients who have rare forms of
thyroid cancer (eg, multiple endo -
Dialogue and Diagnosis // September 2012
17

crine neoplasia syndrome type 2) or
a personal or family history of
medullary thyroid cancer. 38
Serum calcitonin is a wellaccepted
marker of C-cell proliferation,
particularly in medullary
thyroid carcinoma. Long-term
administration of GLP-1 receptor
agonists in rodents has been associated
with increased serum
calcitonin levels and C-cell tumor
formation. 38 However, recent data
do not support an effect of GLP-1
receptor activation on serum
calcitonin levels in humans. 39
Thus, concerns based on rodent
studies may not apply to humans.
Nevertheless, the long-term consequences
of treatment with GLP-1
receptor agonists will remain a
subject of further studies. In any
event, patients should be coun seled
to contact their physicians if they
have a lump or swelling in the neck,
hoarseness, trouble swallow ing, or
shortness of breath, because these
conditions may be signs of thyroid
cancer.
Treatment initiation
After this discussion, both Julia and
her physician agreed—the
advantages of GLP-1 receptor
agonists outweighed the risks. Julia
was shown the pen injection device
and potential injection sites, and
she began liraglutide treatment with
the initiation dose of 0.6 mg. This
dose was to be taken once daily in
either the morning or evening independent
of meals. Julia was told that
the same time frame should be
maintained for the injection.
Assuming no severe nausea after 1
week, the dose was to be increased
to 1.2 mg and maintained until the
patient’s next visit. If nausea was
noted after the initiation dose, that
dose was to be main tained until the
nausea abated. To alleviate the risk
of hypoglycemia, the patient’s dose
of glimepiride was decreased to 1 mg
daily. To ensure safety, she was asked
to test her glucose level a second
time before dinner—a time point
when hypoglycemia was previously
common.
Julia started taking liraglutide in
the morning, soon after she awakened.
Nausea was not an issue, so
she increased the dose to 1.2 mg
after the first week. She noted a
feeling of satiety, though she
believed that she was eating less.
When she returned to her family
physician 3 weeks after beginning
liraglutide, her FPG level was found
to be decreased, to 140 mg/dL. In
addition, the occurrence of her
daytime hypoglycemia was
reduced, though it still occasionally
occurred before dinner. Her family
physician asked Julia to increase
the liraglutide dose to 1.8 mg/dL
and to stop the glimepiride
altogether.
Patient follow-up
With the increase in liraglutide
dose to 1.8 mg/dL and the
cessation of glimepiride, Julia
noted FPG values between 120 and
130 mg/dL and pre-dinner glucose
values of 80 to 100 mg/dL, as well
as the disappearance of hypo -
glycemia and the need to snack to
prevent hypoglycemia. Three
months after the increase in
liraglutide dose, Julia’s HbA 1c level
was 6.9% and she had lost 8
pounds.
Julia has returned to the gym 3
times a week, and she now feels
back in control to manage her diabetes
mellitus.
Key Learning Points
Nutrition, physical activity,
and patient education
constitute the foundation of
any treatment program for
patients with T2DM.
Unless contraindicated,
metformin is a cornerstone
of antihyperglycemic therapy.
Many patients will require
medications in addition to
metformin to either achieve
or maintain glycemic control.
Treatment decisions should
be made in conjunction with
the patient, focusing on the
patient’s needs and
preferences.
The GLP-1 receptor agonists
may be an attractive
treatment option because
of their glucose-lowering
efficacy, their association with
weight loss, and their low risk
of hypoglycemia in patients
who are willing to use
injectable agents.
18 Dialogue and Diagnosis // September 2012

PATIENT
DIALOGUE
Are GLP-1 receptor
agonists like insulin?
Although both GLP-1 agonists and
insulin are administered by means of
subcutaneous injection and are relatively
potent in their glucoselowering
effects, they differ in several
important respects. Most
importantly, unlike insulin, GLP-1
receptor agonists are associated with
a very low risk of hypoglycemia.
Patients can be reassured that these
agents work only when glucose levels
are high. In contrast to the use of
insulin therapy, which is often associated
with weight gain, the use of
GLP-1 receptor agonists to manage
hyperglycemia may have the
additional benefits of lowering body
weight, systolic blood pressure, and
triglyceride levels—all of which may
be elevated in patients with T2DM.
Clinical trials comparing GLP-1
receptor agonists with insulin have
shown that GLP-1 receptor agonists
lower blood glucose levels to levels
similar to when insulin is adminis -
tered, but with less weight gain and
hypoglycemia. 32,40,41 In addition,
treatment satisfaction has been
reported to favor GLP-1 receptor agonists
over insulin, independent of
weight effects. 42
Availability, dosage, and
administration
Liraglutide is available as pen sets,
with each pen delivering a dose of
0.6 mg, 1.2 mg, or 1.8 mg. Patients
will use 2 pens per month at a dosage
of 1.2 mg daily and 3 pens per month
at a dosage of 1.8 mg daily. Patients
may administer injections at any
time of day, independent of meal -
times, but preferably at the same time
each day. The starting dosage is
0.6 mg daily, which is not a clinically
effective dose but rather a dose to
acclimate the patient to possible
gastrointestinal adverse effects (eg,
nausea, vomiting). If tolerated, the
GLP-1 receptor
agonists to manage
hyperglycemia may
have the additional
benefits of lowering
body weight, systolic
blood pressure, and
triglyceride levels.
starting dosage is increased to
1.2 mg daily. Some patients may
require further dosage escalation to
1.8 mg daily; glucose-lowering and
weight effects are dose related. 43
Exenatide is available in 5- and
10-g fixed-dose pen devices. 35,36
Patients typically start treatment with
a dosage of 5 g twice daily, administered
before meals. Patients may take
their doses before lunch and before
the evening meal if they do not eat
breakfast. The dosage may then be
titrated to 10 g twice daily as
indicated and tolerated. Exenatide
should be administered from 60
minutes to immediately before
meals—with less nausea reported
when given closer to the meal, but
with maximum satiety when given 1
hour before the meal. The 2 daily
doses should be at least 6 hours apart.
Exenatide extended release, which
was approved for use by the Food and
Drug Administration in January
2012, is administered once weekly. 36
It is available in single-dose trays,
with each tray providing an injection
of 2 mg exenatide. Thus, patients
receive 4 trays per month. Patients
may administer injections at any
time, without regard to mealtime.
Because of its very long half life,
Dialogue and Diagnosis // September 2012
19

initial glucose lowering may take
longer in the formulation.
Patients should read the directions
carefully before administering
extended release exenatide. A stepby-step
set of directions is provided
with this medication. Patients
should be counseled to tap the
powder in the exenatide extended
release tray to loosen it, if necessary,
and to use the orange connector to
connect the vial to the syringe. 44
Diluent should be injected into the
vial, which should be shaken until
the drug is fully suspended. Patients
or caregivers should then withdraw
the suspension into the syringe,
attach the 23-gauge, 5/16-inch
needle, and push the plunger until
the top is even with the dotted line
on the syringe. The dose may be
injected subcutaneously into the
stomach, back of the arm, or thigh.
Approximately 77% of people feel a
bump after injection under the skin,
and about 1 in 5 individuals may
have a localized reaction from the
injection. 44 However, only approxi -
mately 1% of patients discontinued
exenatide extended release because of
injection site reactions. 44
Exenatide twice daily primarily
affects postprandial glucose levels.
The longer-acting agents (liraglutide
and exenatide extended release)
reduce both FPG levels and postprandial
glucose levels and, therefore,
result in greater lowering of glucose
levels. 45,46
Risks of hypoglycemia with the
use of GLP-1 receptor agonists are
low, because these agents work only
in the presence of hyperglycemia. 47
However, when GLP-1 receptor
agonists are added to existing sulfo -
nylurea therapy, the risks of sulfo -
nylurea-induced hypoglycemia may
be increased, 48 and downward dose
adjustment or discontinuation of the
sulfonylurea may be warranted.
Because the most common
adverse effects of GLP-1 receptor agonists
are gastrointestinal in nature
(eg, nausea, vomiting) and are doserelated,
patients should not be “force
titrated.” Rather, doses should be
gradually escalated as the patient tolerates
each dose level (up to 1.8 mg
daily maximum for liraglutide and
10 mcg twice daily maximum for exenatide
short-acting). 18,35 The only
dose level for exenatide once weekly
is 2 mg, which, because of the long
half-life of this agent, takes some
time to reach a steady state. Nausea
is less common with longer-acting
agents and dissipates in almost all
patients by 12 weeks. 18,36 Because
these drugs affect gastric emptying,
patients should be counseled to eat
very slowly so as not to have feelings
of bloating. These agents should
not be used in people with diabetic
gastroparesis, a form of diabetic
neuropathy.
If a dose of liraglutide is missed
and less than 12 hours have passed
from when the patient should have
taken it, the dose should be taken as
soon as possible. If a dose of
liraglutide is missed and more than
12 hours have passed from when it
should have been taken, the patient
should skip the missed dose and
resume the usual dosing schedule
with the next scheduled dose. The
patient should not double the dose
to “catch up.” 18 If a patient misses a
dose of exenatide extended release,
the dose should be taken as soon as
remembered, provided that the next
scheduled dose is at least 3 days from
the current time. However, if a dose
of exenatide extended release is
20 Dialogue and Diagnosis // September 2012

missed and the next scheduled dose
is less than 3 days from the current
time, the patient should wait until
the next regularly scheduled dose to
restart the medication. 44
Are there oral forms
of GLP-1 receptor
agonists?
Many patients are aware that several
new drugs are available to manage
the hyperglycemia of T2DM. Represented
prominently in the AACE
treatment algorithm 9 are DPP-4
inhibitors, primarily because of their
good tolerability and low risk of
hypoglycemia. However, important
differences exist between that class
of incretin-based medications and
GLP-1 receptor agonists. The DPP-4
inhibitors work to inhibit the enzyme
that degrades GLP-1. Although DPP-4
inhibitors may inhibit the degrada -
tion of GLP-1, many patients with
T2DM have an impaired incretin
effect, so ambient GLP-1 levels may
already be compromised in these
individuals. 49 This compromised
condition may partly explain the difference
in glucose-lowering potential
between DPP-4 inhibitors and GLP-1
receptor agonists, in favor of GLP-1
receptor agonists, 29,50,51 which
directly provide GLP-1 agonism at
pharmacologic or supraphysiologic
levels. 52 The DPP-4 inhibitors primarily
affect postprandial glucose
levels. 53
The differences in effects on GLP-1
levels may partly explain the
differences in weight effects between
GLP-1 receptor agonists and DPP-4
inhibitors. 29,33 Recent data suggest
that a reduced incretin effect and
fasting hyperglucagonemia may constitute
early steps in the pathophysiologic
development of T2DM,
detectable even in obese people who,
despite their insulin-resistant state,
have normal glucose tolerance. 54
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39. Hegedus L, Moses AC, Zdravkovic M, Le Thi
T, Daniels GH. GLP-1 and calcitonin
concentration in humans: lack of evidence of
calcitonin release from sequential screening in
over 5000 subjects with type 2 diabetes or
nondiabetic obese subjects treated with the
human GLP-1 analog, liraglutide [published
online ahead of print January 5, 2011]. J Clin
Endocrinol Metab. 2011;96(3):853-860.
40. Diamant M, Van Gaal L, Stranks S, et al.
Once weekly exenatide compared with insulin
glargine titrated to target in patients with type 2
diabetes (DURATION-3): an open-label
randomised trial. Lancet. 2010;375(9733):2234-
2243.
41. Russell-Jones D, Vaag A, Schmitz O, et al;
Liraglutide Effect and Action in Diabetes 5
(LEAD-5) met+SU Study Group. Liraglutide vs
insulin glargine and placebo in combination
with metformin and sulfonylurea therapy in type
2 diabetes mellitus (LEAD-5 met+SU): a
randomised controlled trial [published online
ahead of print August 14, 2009]. Diabetologia.
2009;52(10):2046-2055.
42. Grant P, Lipscomb D, Quin J. Psychological
and quality of life changes in patients using GLP-
1 analogues [published online ahead of print
May 20, 2011]. J Diabetes Complications.
2011;25(4):244-246.
43. Astrup A, Rossner S, Van Gaal L, et al;
NN8022-1807 Study Group. Effects of liraglutide
in the treatment of obesity: a randomised,
double-blind, placebo-controlled study
[published online ahead of print October 23,
2009]. Lancet. 2009;374(9701):1606-1616.
44. Medication Guide BYDUREONTM (by-DURee-on)
(exenatide extended-release for injectable
suspension). US Food and Drug Administration
Web site; January 2012.
http://www.fda.gov/downloads/Drugs/DrugSafe
ty/UCM289869.pdf. Accessed June 13, 2012.
45. Buse JB, Rosenstock J, Sesti G, et al; LEAD-6
Study Group. Liraglutide once a day versus
exenatide twice a day for type 2 diabetes: a 26-
week randomised, parallel-group, multinational,
open-label trial (LEAD-6) [published online
ahead of print June 8, 2009]. Lancet.
2009;374(9683):39-47.
46. Blevins T, Pullman J, Malloy J, et al.
DURATION-5: exenatide once weekly resulted in
greater improvements in glycemic control
compared with exenatide twice daily in patients
with type 2 diabetes [published online ahead of
print February 9, 2011]. J Clin Endocrinol Metab.
2011;96(5):1301-1310.
47. Monami M, Marchionni N, Mannucci E.
Glucagon-like peptide-1 receptor agonists in
type 2 diabetes: a meta-analysis of randomized
clinical trials [published online ahead of print
March 24, 2009]. Eur J Endocrinol.
2009;160(6):909-917.
48. Esposito K, Mosca C, Brancario C, Chiodini P,
Ceriello A, Giugliano D. GLP-1 receptor agonists
and HBA1c target of 7% in type 2 diabetes:
meta-analysis of randomized controlled trials
[published online ahead of print June 13, 2011].
Curr Med Res Opin. 2011;27(8):1519-1528.
49. Bagger JI, Knop FK, Lund A, Vestergaard H,
Holst JJ, Vilsboll T. Impaired regulation of the
incretin effect in patients with type 2 diabetes
[published online ahead of print January 20,
2011]. J Clin Endocrinol Metab. 2011;96(3):737-
745.
50. Pratley RE, Nauck M, Bailey T, et al; 1860-
LIRA-DPP-4 Study Group. Liraglutide versus
sitagliptin for patients with type 2 diabetes who
did not have adequate glycaemic control with
metformin: a 26-week, randomised, parallelgroup,
open-label trial. Lancet.
2010;375(9724):1447-1456.
51. Wysham C, Bergenstal R, Malloy J, et al.
DURATION-2: efficacy and safety of switching
from maximum daily sitagliptin or pioglitazone
to once-weekly exenatide. Diabet Med.
2011;28(6):705-714. doi: 10.1111/j.1464-
5491.2011.03301.x.
52. Holst JJ, Vilsboll T, Deacon CF. The incretin
system and its role in type 2 diabetes mellitus
[published online ahead of print August 20
2008]. Mol Cell Endocrinol. 2009;297(1-2):127-
136.
53. DeFronzo RA, Okerson T, Viswanathan P,
Guan X, Holcombe JH, MacConell L. Effects of
exenatide versus sitagliptin on postprandial
glucose, insulin and glucagon secretion, gastric
emptying, and caloric intake: a randomized,
cross-over study [published online ahead of print
September 10, 2008]. Curr Med Res Opin.
2008;24(10):2943-2952.
54. Knop FK, Aaboe K, Vilsboll T, et al. Impaired
incretin effect and fasting hyperglucagonaemia
characterizing type 2 diabetic subjects are early
signs of dysmetabolism in obesity [published
online ahead of print January 17, 2012].
Diabetes Obes Metab. 2012;14(6):500-510. doi:
10.1111/j.1463-1326.2011.01549.x.
Jeffrey S. Freeman, DO, is chair of the
Division of Endocrinology and
Metabolism in the Department of
Internal Medicine at the Philadelphia
College of Osteopathic Medicine in
Pennsylvania. He is a member of the
speakers’ bureaus for Novo Nordisk
Inc, Merck & Co Inc, Boehringer
Ingelheim, Eli Lilly and Company,
Amylin Pharmaceuticals Inc, and
AstraZeneca. Address correspondence
to Jeffrey S. Freeman, DO, 4190 City
Ave, Suite 324, Division of
Endocrinology and Metabolism,
Philadelphia College of Osteopathic
Medicine, Philadelphia, PA 19131-
1633, or send e-mail to him at
jeffreyfreemando@aol.com.
22 Dialogue and Diagnosis // September 2012

Adding glucagon-like peptide-1
receptor agonists to insulin therapy
for patients with type 2 diabetes
mellitus: why and how?
James R. LaSalle, DO
L
ong standing diabetes creates special challenges
for the physician and patient. The progressive
pathophysiologic nature of diabetes mellitus
results in the need for numerous medications to
address multiple metabolic defects, 1 with an increasing
likelihood of the need for insulin as -cell function declines. 2
The necessary polypharmacy creates adherence and
tolerability challenges for patients. 3
Dialogue and Diagnosis // September 2012
23

As diabetes mellitus
progresses, the risk of
diabetes-related
complications increases—
including diabetes-related
nephropathy—which may
influence the choice of
therapeutic agents. With
nephropathy the excretion
of the medication is
important, depending
on other routes of
elimination. 4-6
Furthermore, the risk of
hypoglycemia is increased with
patient age, duration of diabetes
mellitus, and impairment in renal
function. 7 Most osteopathic
physicians are relatively comfortable
with initiating a single injection of
basal insulin as add-on therapy to
oral antidiabetic agents when
glycosylated hemoglobin (HbA 1c )
levels are no longer controlled with
combination therapy. However,
physicians may be less certain about
what to do when basal insulin
therapy does not maintain treatment
goals. Hypoglycemia is a major
concern of both physicians and
patients and may impact treatment
intensification efforts 8,9 and patient
adherence. 10
The use of a single dose of a basal
insulin analog (eg, insulin glargine
or insulin detemir) is generally indicated
if oral antidiabetic therapy has
been insufficient to maintain treatment
goals. 11,12 The selection of
long-acting basal insulin may have
some benefits over other insulin
choices. Long-acting basal insulin
analogs are associated with a lower
risk of nocturnal hypoglycemia
than is neutral protamine Hagedorn
(NPH) insulin as a result of their relatively
peakless profile. 13 Initial recommended
dosing of these agents is
often 10 units at bedtime, titrated to
achieve fasting plasma glucose (FPG)
goals of less than 110 mg/dL. 11 Titrations
can be supervised by the health
care team or can be patient driven.
Available data show that even
insulin-naïve patients can safely and
effectively titrate insulin levels. 14
One warning about basal insuin titration—be
careful not to overbasalize
this insulin. Hemoglobin HbA 1c levels
consist of both FPG and post prandial
glucose (PPG) components. The
closer a patient is to HbA 1c goal (eg,
HbA 1c of 7% vs 9%), the greater the
proportion of hyperglycemia is
attributed to postprandial hyper -
glycemia. 15
In the present article, I offer a case
report to highlight the need for
intensification of therapy in obese
patients with long-standing type 2
diabetes mellitus (T2DM) that is no
longer being controlled with oncedaily
injections of basal insulin in
addition to oral agents. I also review
factors that can impact achievement
of treatment goals, challenges in
adding medications to therapeutic
regimens, and special challenges
related to patient education.
Report of case
Gloria is a 66-year-old African American
woman who is a retired
accountant. She presented to her
primary osteopathic physician for
follow-up treatment for her T2DM.
She has a substantial weight problem.
At a height of 5 feet 3 inches, she
weighs 238 pounds and has a body
mass index of 42.2, which places her
in the obese classification. She has
arthritic changes in her knees and
24 Dialogue and Diagnosis // September 2012

hips, which, with her excess weight,
severely affect her mobility and even
threatens the performance of routine
activities of daily living. In addition,
she has developed severe foot pain
that occurs only at rest and affects
her ability to sleep. This type of foot
pain is often associated with diabetic
neuropathy. The patient is generally
adherent to her medication regimen,
which consists of the following:
—Metformin 2000 mg daily
—Glimepiride 4 mg daily
—Pioglitazone 15 mg daily
Her current laboratory values are as
follows:
—HbA 1c 7.8%
—FPG 139 mg/dL
—PPG 189 mg/dL
—Serum creatinine 1.2 mg/dL
Discussion: Gloria is young and
healthy enough that a HgA 1c of 7%
should be pursued. She is already on
multiple oral antidiabetic medications.
Metformin may be nearing the
end of its usefulness in this patient, as
her renal function is declining. Renal
function is dynamic in patients with
T2DM and requires close supervision,
as do the choices of antidiabetic
agents used in the patients. The Table
summarizes the metabolism/
clearance sites, with dosing adjust -
ments in cases of chronic kidney
disease, for commonly used medications
in patients with T2DM, as
adapted from Fonseca. 6
Gloria’s renal function should
continue to be monitored closely.
Many physicians underestimate the
importance of renal function in their
patients with diabetes mellitus,
assuming that it does not change
rapidly in this patient group. This
assumption potentially puts these
individuals at risk of serious complications.
With this consideration in
Metabolism/
Medication Clearance Site Dosing Adjustment/Notes
Glinides Hepatic Decreased dose
GLP-1 agonists
—Exenatide Hepatic/renal Decreased dose
—Liraglutide Hepatic/tissue Caution if prolonged nausea or
vomiting
Insulins Tissue/renal Decreased dose
Metformin Renal Discontinue if creatinine³ 1.4 mg/dL
in women,³ 1.5 mg/dL in men
Sulfonylureas Hepatic/renal Glipizide preferred; glyburide has
high risk of hypoglycemia; all need
decreased dose
Thiazolidinediones Hepatic No dose adjustment
(eg, pioglitazone)
Table. Metabolism and clearance sites, with dosing adjustments in cases of chronic
kidney disease, for medications commonly used in patients with type 2 diabetes
mellitus, as adapted from Fonseca. 6
Abbreviation: GLP-1, glucagon-like peptide-1.
mind, Gloria’s physician explained
that they would need to adjust her
therapy to keep her sugar levels in a
safer range.
A basal insulin was added to her
regimen. Glargine insulin was started
at a dose of 10 units to be adminis -
tered daily at 10 p.m. The patient was
instructed to check her FPG levels
each day and to titrate her basal
insulin dose based on an average of
the last 3 FPG levels. If her FPG 3-day
average was greater than 120 mg/dL,
she was to increase her insulin
glargine by 3-unit increments until
an FPG level of 120 mg/dL was
achieved.
Insulin glargine titration
continued according to schedule
until Gloria’s FPG levels stabilized at
or near 139 mg/dL. It seemed to
Gloria that no matter what she did,
adding more basal insulin did not
cause her FPG level to change.
When basal insulin is no
longer sufficient
Basal insulin analogs provide
sustained background insulin levels
for up to 24 hours in many, but not
all patients. Longer-acting insulin
analogs currently in development
may be able to provide even more
consistent and sustained levels in the
majority of patients. 16 Basal insulin
analogs have a flatter and more prolonged
effect than NPH insulin. 13
Increasing the basal insulin dose
causes an approximately 0.5%
decrease in HbA 1c level for each
0.1 U/kg/day increment in insulin
dose, up to a threshold of 0.5 U/kg.
Beyond this dose, the improvement
in HbA 1c reduction is less substantial,
and the risk of hypoglycemia
increases. 17 So at a dose of 0.5 U/kg it
may be a good time for osteopathic
physicians to reflect on additional
treatment options rather than further
titration of basal insulin.
Most primary care providers have
had to deal with this issue many
times. Insulin resistance and -cell
failure are common denominators in
patients with T2DM. The balance
may tip toward increasing -cell
failure as the pathophysiologic
features of T2DM progress and as FPG
levels stop responding to basal
insulin as glucose control is lost
Dialogue and Diagnosis // September 2012
25

during the day with each meal.
Increasing basal insulin doses in such
cases may not improve glucose
control and may lead to increased
weight and the risk of hypoglycemia.
Insulin resistance, -cell failure, and
over-basalization put the physician at
a critical point on the decision tree of
diabetes management.
Often the approach to patients not
achieving treatment goals with basal
insulin analogs is to add 1 or more
doses of prandial insulin in the form
of a rapid-acting insulin analog (eg,
insulin aspart, insulin lispro, or
insulin glulisine) or regular human
insulin. 13 Although many physicians
consider multiple-injection basalbolus
therapy to be the “gold
standard,” addition of a single prandial
dose to basal insulin therapy can
bring many patients to goal in a
simpler and more patient-friendly
manner. The Orals Plus Apidra and
LANTUS (OPAL) study 18 showed that
addition of a single bolus of rapidacting
insulin analog, administered at
either breakfast or main mealtime in
combination with basal insulin and
oral antidiabetic drugs, resulted in a
decrease in HbA 1c level from 7.32% to
6.99% (P.001). Meneghini and colleagues
19 compared 2 intensification
strategies for stepwise addition of
prandial insulin analogs in patients
whose T2DM was inadequately controlled
by basal insulin detemir.
They found an overall reduction in
HbA 1c of 1.2% with stepwise
addition of rapid-acting insulin
analogs to 1 or more meals, regardless
of whether preprandial or postprandial
glucose levels were the
target of titration efforts.
Limitations of adding prandial
insulin to improve glycemic control
include its greater complexity for
patients to self-titrate, its increased
risk of hypoglycemia, and its
likelihood of leading to weight
gain. 20 Another choice for improving
glycemic control would be use of a
premixed insulin analog. However
that option is probably even less
desirable for Gloria because, to be
most effective and tolerated, it necessitates
strict regularity in mealtimes
and meal carbohydrate content. Furthermore,
weight gain is more
common with premixed insulin supplementation
than with the basal
bolus insulin regimen previously discussed.
19
Pramlintide, an amylinomimetic,
is approved for use in insulin-treated
patients who have either type 1 diabetes
mellitus (T1DM) or T2DM and
elevated PPG levels. Pramlintide is
cosecreted with insulin from
pan creatic -cells and acts centrally
to slow gastric emptying, suppress
postprandial glucagon secretion, and
decrease food intake. These actions
comple ment those of insulin to regulate
blood glucose concentrations.
Pramlintide is associated with modest
beneficial effects on HbA 1c levels
when used as adjunctive therapy.
Pramlintide is effective at stabilizing
blood glucose levels and, once the
appropriate dosage is established, it is
an effective tool in managing T1DM
and T2DM. Pramlintide is also associated
with weight loss, which may be
attractive, but it carries with it an
increased risk of hypoglycemia and it
requires an additional injection
before every meal. Nausea is a
common adverse effect of this medication.
21 A patient education support
program may be needed for
successful use of this agent. Pramlintide
was not considered the best
choice for Gloria.
Basal insulin in
combination with
incretin-based therapies
A major challenge to implementing
intensive therapy in patients with
26
Dialogue and Diagnosis // September 2012

T2DM is achieving glycemic control
without undue risk of hypoglycemia
or weight gain. A new approach
would be to consider incretin-based
agents, which are not associated with
weight gain and which work in a
glucose-dependent manner (ie, only
in the presence of hyperglycemia).
Basal insulin and incretin-based
agents are complementary therapies
for patients with T2DM—insulin corrects
the basic pathophysiologic
defect and incretin-based agents
improve insulin secretion while
decreasing glucagon output.
Combining an incretin-based
therapy with insulin is an attractive
treatment option for Gloria. This
combination has the potential to
maximize glycemic control while
minimizing the risk of hypoglycemia,
to ameliorate the weight gain typical
of insulin therapy, and—in patients
on established insulin therapy—to
decrease insulin dose requirements
when used with a glucagon-like
peptide-1 (GLP-1) receptor agonist.
Insulin and DPP-4
inhibitors in combination
DPP-4 inhibitors are oral agents that
work by inhibiting the enzyme that
degrades native GLP-1 and thus
support maintaining what levels of
GLP-1 are still available in patients
with T2DM. As such, they are associated
with modest reductions in A1c,
and are often used as part of combination
therapy strategies, but can be
used as monotherapy in patients
without marked hyperglycemia.
These agents, sitagliptin, saxagliptin,
and linagliptin are not associated
with weight gain or with nausea, and
are generally well tolerated.
Of the DPP-4 inhibitors, sita -
gliptin is currently the only agent
approved for use with insulin.
Although not paralleling our patient’s
case directly, the TRANSITION study
examined whether patients using
metformin with or without other oral
agents and who were not at treat -
ment goals would do better with the
addition of sitagliptin with or without
a sulfonylurea, or sitagliptin with
or without a basal insulin (insulin
detemir). 22 The combination of oncedaily
insulin detemir with sitagliptin
showed clinically and statistically significant
better improve ment in
glycemic control compared to sita -
gliptin with or without a sulfonylurea
(P.001).
Saxaglitpin also improves
glycemic control in patients whose
glucose levels are poorly controlled
on insulin alone or on insulin and
metformin. A placebo-subtracted
HbA 1c reduction of 0.41% was
observed in a study by Barnett et al. 23
When saxagliptin and other DPP-4
inhibitors are used in combination
with a sulfonylurea or with insulin,
medications known to cause
hypoglycemia, the incidence of confirmed
hypoglycemia may be
increased. Therefore, a lower dose of
insulin secretagogue or insulin may
be required to minimize the risk of
hypoglycemia when used in combination
with DPP-4 inhibitors.
Linagliptin has not been studied
in combination with insulin therapy.
Insulin and GLP-1
receptor agonists
in combination
Another option that requires subcutaneous
injections—but fewer injec -
tions than basal bolus insulin—
include the GLP-1 receptor agonists.
There are 3 currently available GLP-1
receptor agonists: exenatide twice
daily, liraglutide once daily, and exenatide
extended release once weekly.
Exenatide twice daily and liraglutide
once daily are approved for use with
basal insulin. The concomitant use of
a GLP-1 receptor agonist and insulin
may be advantageous for mitigating
the weight gain associated with
insulin therapy. This is particularly
true for obese patients with longstanding
T2DM, as is the scenario in
Dialogue and Diagnosis // September 2012
27

our patient example. Patients using
insulin may be already comfortable
giving themselves injections, so the
addition of another 1 or 2 injections
may not be problematic for them.
The use of short-acting exenatide
has been studied in patients with
T2DM (baseline HbA 1c =7.1%-10.5%)
who were receiving insulin glargine
alone or in combination with metfor -
min and/or pioglitazone. 24 Adding
exenatide improved glycemic control
(-0.69 placebo-subtracted reduction
in A 1C ) and resulted in weight loss
(-2.7 kg different from placebo)
without increasing hypoglycemia in
these patients, but it increased
nausea, diarrhea, and vomiting. 24
quately controlled T2DM may cause
reduction of HbA 1c level without
clinically significant weight gain or
increased hypoglycemia risk. 25
Other investigators have
explored the addition of the oncedaily
GLP-1 receptor agonist, lira -
glutide, to metformin in patients
with T2DM, followed by treatment
intensification with insulin detemir
if HbA 1c levels remain at or above
7%. 26 This combination of agents
was well tolerated in the majority of
patients, resulting in good glycemic
control (61% achieved A 1C 7%;
mean change -1.7% from baseline
A 1C 7.7%), sustained weight loss (by
3.5 kg during run-in with lira -
glycemia or weight gain. The
incretin-based agents meet these criteria,
and—in addition to their efficacy
either alone or in combination
with other non-insulin agents—
they (exenatide and liraglutide) are
effective and well tolerated when
used in combination with insulin.
Addition of incretin-based agents
has the potential to spare the
patient from prandial (ie, mealtime)
injections. GLP-1 receptor agonists
are not substitutes for insulin, and
they have not been studied in combination
with prandial insulin.
If only a modest HbA 1c reduction
is needed (eg, if HbA 1c less than
7.5% with basal insulin), a DPP-4
inhibitor can be added to the
patient’s treatment regimen. How -
ever, if greater HbA 1c reduction is
needed or if weight loss is desirable
or needed, a GLP-1 receptor agonist
can be added. DPP-4 inhibitors are
able to cause a less than a 1%
decrease in HbA 1c level, whereas
GLP-1 receptor agonists tend to be
more potent and efficacious in
achieving goals for patients with
higher HbA 1c levels.
“Real-world” data suggest that
adding exenatide to existing use of
basal insulin is more commonly prescribed
in patients who have dia -
betes mellitus of longer duration,
compared to the opposite approach
of adding basal insulin to back -
ground exenatide therapy. Regard -
less of treatment order, long-term
(up to 24 months) combined
therapy with insulin glargine and
exenatide in patients with inade -
glutide, then by .16 kg with insulin
detemir and by .95 kg more without
detemir) and low hypoglycemia
rates. 26 Liraglutide is injected preferably
at the same time each day,
without regard to mealtimes.
Choosing agents
As previously noted, treatment combinations
should include agents
that improve glycemic control
without increasing the risk of hypo-
Dosing considerations
The incidence of hypoglycemia is
minimal when DPP-4 inhibitors are
added to insulin therapy, so a
change in insulin dose is generally
not necessary when these agents are
combined. Although GLP-1 receptor
agonists work via glucosedependent
mechanisms and are
associated with a low risk of
hypoglycemia when used alone,
their hypoglycemia risk is greater
when used with insulin or insulin
secretagogues (eg, sulfonylureas).
Therefore, when GLP-1 receptor
agonists are used with insulin, the
dose of insulin may need to be
reduced. Injections of a GLP-1
receptor agonist may be given at the
28 Dialogue and Diagnosis // September 2012

Patient instruction
Clearly discuss the reasons for your selection of a new medication, as in this case
report. A glucagon-like peptide-1 (GLP-1) receptor agonist was selected for this
patient on the basis of its efficacy in lowering blood sugar levels and its low
propensity for hypoglycemia and weight gain.
Patient discussion
Elucidate common adverse effects and warnings associated with the new medication
and how they apply to the patient. Make sure that the patient does not have a
previous history of medullary thyroid cancer. Discuss such common adverse effects as
nausea and vomiting, as well as the unlikely potential for pancreatitis. Also tell the
patient that nausea and vomiting may cause dehydration, and that the physician
should be alerted if vomiting persists for more than 12 hours. Abdominal pain is not
an adverse effect of GLP-1 receptor agonists, however, it should be reported to the
physician as it may be a sign of pancreatitis.
Initial follow-up
Reiterate the reasons for selecting the GLP-1 receptor agonist, and review its adverse
effect profile. Adjust medications based on efficacy and safety issues. Re-evaluation of
medications should be based on their efficacy on lowering blood sugar levels and
their effects regarding hypoglycemic events, nausea, vomiting, and dehydration.
Subsequent follow-up
Check or ask about the following measures of patient health: glycosylated
hemoglobin level, daily glucose monitoring logs (both fasting plasma glucose and
postprandial glucose), body weight, hypoglycemic events, gastrointestinal adverse
effects, and abdominal pain.
Figure. Recommendations for physician communication with patients with
type 2 diabetes mellitus when adding glucagon-like peptide-1 receptor
agonists to insulin therapy, based on the present case report.
same time and in the same general
area of the body as insulin injec -
tions, but they should not be at the
exact same site.
Patient counseling
Setting treatment targets with
patients when initiating a new medication
is always recommended.
When adding a GLP-1 receptor
agonist, patients can be told that a
1% reduction in HbA 1c level is a sign
that the drug is working well.
Patients can also be informed of the
possibility of weight loss with GLP-1
receptor agonists, but it is important
to reinforce the need to work with a
dietitian or a certified diabetes educator
to further improve/maintain
healthy dietary habits. Patients
should clearly understand that
GLP-1 receptor agonists are not the
same as insulin and do not replace
insulin.
Several tips may improve patient
adherence with GLP-1 receptor agonists.
For example, physicians can
recommend that patients not eat a
high-fat meal after injecting a GLP-1
receptor agonist, especially during
the early days of therapy to limit
gastrointestinal side effects. When
prescribing exenatide, physicians
should work with patients to determine
when they are most likely to
eat. The 2 main meals for dosing
purposes can then be established.
The Figure shows guidelines for
improving physician communication
with patients with T2DM when
adding GLP-1 receptor agonists to
insulin therapy.
Gloria
When basal insulin fails to control
FPG levels, this failure is usually the
result of spikes in postprandial sugar
levels. 14,17 The decision tree of the
American Diabetes Association and
European Association for the Study
of Diabetes 12 suggests that prandial
insulin can be added in such cases,
but there is an alternative that may
suit Gloria better.
Gloria is obese and, in most
cases, insulin—even analog
insulins—will cause weight gain.
Recently, GLP-1 receptor agonists
have been approved for use with
basal insulin. 27,28 The longer-acting
GLP-1 agents affect both PPG and
FPG levels (short-acting exenatide
affects primarily PPG), and they are
associated with either weight loss or
at least much less weight gain than
is linked to insulin. Furthermore,
GLP-1 agents are associated with
much less hypoglycemia than is
associated with insulin. 29 Thus, for
Gloria, adding a GLP-1 receptor
agonist may be an appropriate
therapy. I made certain to ask Gloria
about any personal or family history
of thyroid cancer, because GLP-1
receptor agonists are contra -
indicated in patients with personal
or family histories of medullary
thyroid cancers. I also alerted Gloria
that these agents have been associated
with nausea and vomiting.
These gastrointestinal adverse
effects generally occur in only a
small percentage of patients and
abate within a few days to weeks
after starting the medication. I
informed Gloria that abdominal
pain is not common with these
agents, but if this adverse event did
Dialogue and Diagnosis // September 2012
29

occur, she was instructed to stop
taking the drug and contact us
immediately. In a small percentage
of patients taking GLP-1 receptor
agonists, abdominal pain has been
associated with acute pancreatitis.
As her physician, I selected liraglitide
for Gloria, because its use does
not involve dose adjustments for
patients with renal insuffici ency, 30
and it can be injected once daily
without regard to caloric intake.
However, I will want to closely
monitor her serum creatinine since
its 1.2 mg/dL as changing renal function
is a real issue to consider in
patients with long-term diabetes.
I started Gloria on liraglitide
0.6 mg daily and titrated the dosage
to 1.2 mg daily during the next 7 to
10 days. As liraglitide was initiated, I
instructed Gloria to suspend her use
of glimepiride and to reduce her
dose of insulin glargine by 10%, in
order to reduce her risk of hypo -
glycemia. 27 With this treatment
regimen, Gloria did not experience
nausea, vomiting, or hypoglycemia,
and she was pleased that her FPG
levels began to decrease within days
of starting liraglitide. Within 12
weeks of liraglitide initiation,
Gloria’s HbA 1c level was at the
American Diabetes Association
target of 6.9%, and her weight had
not increased.
Future of insulin
supplementation
Although currently available insulin
analogs do not represent exact physiologic
replacements for endogenous
basal bolus insulin, the continued
evolution of insulin products and
delivery devices is substantially
improving the ease of insulin use
for patients with T2DM. The refinement
in insulin supplementation
that has occurred in the last 20
years is dramatic and ongoing. The
future holds additional possibilities
for improving glycemic control with
less hypoglycemia, less variability,
and potentially less weight gain and
greater patient convenience.
Currently under review by the
Food and Drug Administration is
insulin degludec, a very long-acting
insulin which is in Phase III clinical
trials. Insulin degludec forms
soluble multi-hexamers upon subcutaneous
injection, resulting in a
depot from which insulin is continuously
and slowly absorbed into circulation
to provide an ultralong and
steady action profile. 31 This longacting
insulin is administered once
daily, but because of its long halflife,
it can be considered to be a very
“forgiving” insulin—meaning that if
a patient forgets to take insulin at
the same time each day, some variability
in the dosing will not affect
blood glucose levels. Compared
with insulin glargine, insulin
degludec has much less pharmacodynamics
variability and, thus, a
more predictable glucose-lowering
effect from day to day. 32 In studies
of patients with either T1DM or
T2DM, insulin degludec was associated
with less nocturnal hypo -
glycemia compared to insulin
glargine. 33,34
Insulin degludec is also being
studied as part of combination
therapy with insulin aspart (as
essentially a bolus boost of rapidacting
insulin). When given once
daily in the evening, this combination
improved glucose control
throughout the day (as measured by
30 Dialogue and Diagnosis // September 2012

8-point glucose levels) and did so
signifi cantly better than insulin
glargine for postdinner hyper -
glycemia. 35
Another novel insulin, a
PEGylated formulation of insulin
lispro is in development but is not
far along and has less information
available. This PEGylated insulin
(LY2605541), which has entered the
Phase-II stage of clinical develop -
ment, has a long duration of action.
Compared to insulin glargine,
LY2605541 was associated with
improved glycemic control and
some weight loss in patients with
T1DM (ie, those with a mean baseline
weight of 183 lb [83 kg]. The
baseline weight is only important if
we know how much weight loss
patients achieved. 36 Studies with
this agent are currently recruiting
participants with T2DM. (Information
on this recruitment can be
found at http://clinicaltrials.gov/.)
There are also advances in prandial
(mealtime) insulin develop -
ment. A novel ultrarapid-acting
insulin in development is associated
with less variability among patients
than regular human insulin. 37 There
also is an investigational ultrarapidacting
inhaled insulin that achieves
maximum blood concentrations
within 15 minutes and has a very
short duration of action (~2-3
hours). 38
Insulin delivery by inhaler may
be possible in the future. Techno -
sphere technology is being investigated
as a way to make pulmonary
delivery of proteins and peptides
possible, essentially by using a dry
powder with nanometer-sized particles
to carry active drugs so that the
drugs rapidly dissolve upon lung
contact. In the use of this techno -
logy for prandial insulin delivery,
less weight gain and fewer hypo -
glycemic events were observed in
combination with a basal insulin,
compared to injectable prandial
insulin analog added to basal
insulin. 39 The safety and tolerability
profile was similar for both treat -
ment regimens, apart from
increased occurrence of cough and
changes in pulmonary function in
the group receiving inhaled insulin
plus insulin glargine. 39
Final notes
Advances in pharmaceutical development
have greatly increased the
therapeutic options available for
manage ment of T2DM and the
possibilities for combination
therapy strategies. Technological
develop ments also are increasing
the number of available injectable
therapies. Patients should be made
aware of these therapies as viable
options in their care. Patient education
and involvement can improve
treatment adherence and reduce the
rates of poor outcomes associated
with the epidemic of diabetes
mellitus.
References
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triumvirate to the ominous octet: a new
paradigm for the treatment of type 2 diabetes
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2. Wright A, Burden AC, Paisey RB, Cull CA,
Holman RR; UK Prospective Diabetes Study
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5. Ritz E. Limitations and future treatment
options in type 2 diabetes with renal
impairment. Diabetes Care. 2011;34 suppl
2:S330-S334.
6. Fonseca VA. Incretin-based therapies in
complex patients: practical implications and
opportunities for maximizing clinical outcomes:
a discussion with Dr Vivian A. Fonseca. Am J
Med. 2011;124(1 suppl):S54-S61.
7. Akram K, Pedersen-Bjergaard U, Borch-
Johnsen K, Thorsteinsson B. Frequency and risk
factors of severe hypoglycemia in insulin-treated
type 2 diabetes: a literature survey. J Diabetes
Complications. 2006;20(6):402-408.
8. Nakar S, Yitzhaki G, Rosenberg R, Vinker S.
Transition to insulin in Type 2 diabetes: family
physicians’ misconception of patients’ fears
contributes to existing barriers. J Diabetes
Complications. 2007;21(4):220-226.
(continued)
Dialogue and Diagnosis // September 2012
31

9. Larkin ME, Capasso VA, Chen CL, et al.
Measuring psychological insulin resistance:
barriers to insulin use. Diabetes Educ.
2008;34(3):511-517.
10. Karter AJ, Subramanian U, Saha C, et al.
Barriers to insulin initiation: the translating
research into action for diabetes insulin starts
project [published online ahead of print January
19, 2010]. Diabetes Care. 2010;33(4):733-735.
11. Handelsman Y, Mechanick JI, Blonde L, et al;
AACE Task Force for Developing Diabetes
Comprehensive Care Plan. American Association
of Clinical Endocrinologists Medical Guidelines
for Clinical Pract. for developing a diabetes
mellitus comprehensive care plan. Endocr Pract.
2011;17 suppl 2:1-53.
12. Hirsch IB. Insulin analogues [review] N Engl J
Med. 2005;352(2):174-183.
13. Inzucchi SE, Bergenstal RM, Buse JB, et al.
Management of hyperglycemia in type 2
diabetes: a patient-centered approach: position
statement of the American Diabetes Association
(ADA) and the European Association for the
Study of Diabetes (EASD) [published online
ahead of print April 19, 2012]. Diabetes Care.
2012;35(6):1364-1379.
14. Selam JL, Koenen C, Weng W, Meneghini L.
Improving glycemic control with insulin detemir
using the 303 Algorithm in insulin naive patients
with type 2 diabetes: a subgroup analysis of the
US PREDICTIVE 303 study. Curr Med Res Opin.
2008;24(1):11-20.
15. Monnier L, Lapinski H, Colette C.
Contributions of fasting and postprandial plasma
glucose increments to the overall diurnal
hyperglycemia of type 2 diabetic patients:
variations with increasing levels of HbA(1c).
Diabetes Care. 2003;26(3):881-885.
16. Owens DR. Insulin preparations with
prolonged effect [review]. Diabetes Technol Ther.
2011;13 suppl 1:S5-S14.
17. Monnier L, Colette C. Addition of rapidacting
insulin to basal insulin therapy in type 2
diabetes: indications and modalities. Diabetes
Metab. 2006;32(1):7-13.
18. Lankisch MR, Ferlinz KC, Leahy JL,
Scherbaum WA; Orals Plus Apidra and LANTUS
(OPAL) Study Group. Introducing a simplified
approach to insulin therapy in type 2 diabetes: a
comparison of two single-dose regimens of
insulin glulisine plus insulin glargine and oral
antidiabetic drugs. Diabetes Obes Metab.
2008;10(12):1178-1185.
19. Meneghini L, Mersebach H, Kumar S,
Svendsen AL, Hermansen K. Comparison of 2
intensification regimens with rapid-acting insulin
aspart in type 2 diabetes mellitus inadequately
controlled by once-daily insulin detemir and oral
antidiabetes drugs: the step-wise randomized
study. Endocr Pract. 2011;17(5):727-736.
20. Holman RR, Farmer AJ, Davies MJ, et al; 4-T
Study Group. Three-year efficacy of complex
insulin regimens in type 2 diabetes [published
online ahead of print October 22, 2009]. N Engl
J Med. 2009;361(18):1736-1747.
21. Edelman S, Maier H, Wilhelm K. Pramlintide
in the treatment of diabetes mellitus. BioDrugs.
2008;22(6):375-386. doi: 10.2165/0063030-
200822060-00004.
22. Hollander P, Raslova K, Skjoth TV, Rastam J,
Liutkus JF. Efficacy and safety of insulin detemir
once daily in combination with sitagliptin and
metformin: the TRANSITION randomized
controlled trial. Diabetes Obes Metab.
2011;13(3):268-275. doi: 10.1111/j.1463-
1326.2010.01351.
23. Barnett AH, Charbonnel B, Donovan M,
Fleming D, Chen R. Effect of saxagliptin as addon
therapy in patients with poorly controlled
type 2 diabetes on insulin alone or insulin
combined with metformin [published online
ahead of print March 1, 2012]. Curr Med Res
Opin. 2012;28(4):513-523.
24. Buse JB, Bergenstal RM, Glass LC, et al. Use
of twice-daily exenatide in Basal insulin-treated
patients with type 2 diabetes: a randomized,
controlled trial [published online ahead of print
December 6, 2010]. Ann Intern Med.
2011;154(2):103-112.
25. Levin PA, Mersey JH, Zhou S, Bromberger
LA. Clinical outcomes using long-term
combination therapy with insulin glargine and
exenatide in patients with type 2 diabetes
mellitus. Endocr Pract. 2012;18(1):17-25.
26. Devries JH, Bain SC, Rodbard HW, et al; on
behalf of the Liraglutide-Detemir Study Group.
Sequential intensification of metformin
treatment in type 2 diabetes with liraglutide
followed by randomized addition of basal insulin
prompted by A1C targets [published online
ahead of print May 14, 2012]. Diabetes Care.
2012;35(7):1446-1454.
27. Victoza (liraglutide) [prescribing
information]. Princeton, NJ: Novo Nordisk;
2012.
28. Medication guide, BYDUREON (tm) (by-DURee-on)
(exenatide extended-release for injectable
suspension). Food and Drug Administration Web
site; January 2012.
http://www.accessdata.fda.gov/drugsatfda_docs/
label/2012/022200s000mg.pdf. Accessed July 7,
2012.
29. Wang Y, Li L, Yang M, Liu H, Boden G, Yang
G. Glucagon-like peptide-1 receptor agonists
versus insulin in inadequately controlled patients
with type 2 diabetes mellitus: a meta-analysis of
clinical trials. Diabetes Obes Metab.
2011;13(11):972-981. doi: 10.1111/j.1463-
1326.2011.01436.x.
30. Liraglutide (Victoza) for type 2 diabetes. Med
Lett Drugs Ther. 2010;52(1335):25-27.
31. Jonassen I, Havelund S, Hoeg-Jensen T,
Steensgaard DB, Wahlund PO, Ribel U. Design of
the novel protraction mechanism of insulin
degludec, an ultra-long-acting basal insulin
[published online ahead of print April 7, 2012].
Pharm Res.
32. Heise T, Hermanski L, Nosek L, Feldman A,
Rasmussen S, Haahr H. Insulin degludec: four
times lower pharmacodynamic variability than
insulin glargine under steady-state conditions in
type 1 diabetes [published online ahead of print
May 17, 2012]. Diabetes Obes Metab. doi:
10.1111/j.1463-1326.2012.01627.x.
33. Garber AJ, King AB, Del Prato S, et al;
NN1250-3582 (BEGIN BB T2D) Trial
Investigators. Insulin degludec, an ultralongacting
basal insulin, versus insulin glargine
in basal-bolus treatment with mealtime insulin
aspart in type 2 diabetes (BEGIN Basal-Bolus
Type 2): a phase 3, randomised, open-label,
treat-to-target non-inferiority trial. Lancet.
2012;379(9825):1498-1507.
34. Heller S, Buse J, Fisher M, et al; BEGIN Basal-
Bolus Type 1 Trial Investigators. Insulin degludec,
an ultra-longacting basal insulin, versus insulin
glargine in basal-bolus treatment with mealtime
insulin aspart in type 1 diabetes (BEGIN Basal-
Bolus Type 1): a phase 3, randomised, openlabel,
treat-to-target non-inferiority trial. Lancet.
2012;379(9825):1489-1497.
35. Heise T, Tack CJ, Cuddihy R, et al. A newgeneration
ultra-long-acting basal insulin with a
bolus boost compared with insulin glargine in
insulin-naive people with type 2 diabetes: a
randomized, controlled trial [published online
ahead of print February 1, 2011]. Diabetes Care.
2011;34(3):669-674.
36. Devries JH, Bain SC, Rodbard HW, et al; on
behalf of the Liraglutide-Detemir Study Group.
Sequential intensification of metformin
treatment in type 2 diabetes with liraglutide
followed by randomized addition of basal insulin
prompted by A1C targets [published online
ahead of print May 14, 2012]. Diabetes Care.
2012;35(7):1446-1454.
37. Hompesch M, McManus L, Pohl R, et al.
Intra-individual variability of the metabolic effect
of a novel rapid-acting insulin (VIAject) in
comparison to regular human insulin. J Diabetes
Sci Technol. 2008;2(4):568-571.
38. Garg SK, Mathieu C, Rais N, et al. Two-year
efficacy and safety of AIR inhaled insulin in
patients with type 1 diabetes: an open-label ra
Other ndomized controlled trial. Diabetes
Technol Ther. 2009;11 suppl 2:S5-S16.
39. Rosenstock J, Lorber DL, Gnudi L, et al.
Prandial inhaled insulin plus basal insulin
glargine versus twice daily biaspart insulin for
type 2 diabetes: a multicentre randomised trial.
Lancet. 2010;375(9733):2244-2253.
James R. LaSalle, DO, is a speaker for
AstraZeneca, GlaxoSmithKline, and
Novo Nordisk. He serves on advisory
boards for AstraZeneca, Bristol-Myers
Squibb, GlaxoSmithKline, and Novo
Nordisk. Address correspondence to
James R. LaSalle, DO, Medical Director,
Medical Arts Research Collaborative,
950 N. Jesse James Road, Excelsior
Springs, MO 64024-1238 or e-mail
him at jlasalle4@aol.com.
32 Dialogue and Diagnosis // September 2012

InsideOut
(continued from inside front cover)
cent studies have supported the use of
insulin as the first treatment for
patients with T2DM. In addition, the
mantra “once on insulin always on insulin”
no longer seems to be the case.
Many patients only intermittently
need insulin, during acute illnesses or
periods of hyperglycemia.
The glucagon-like peptide-1 (GLP-1)
receptor agonists—injectable incretinbased
medications—have dramatically
changed the acceptability of injection
therapy. These agents, as is explained
in the present supplement, address crucial
issues in diabetes care and can improve
both fasting plasma and post -
prandial glucose levels. Unlike many
other antidiabetic medications, GLP-1
receptor agonists are associated with
weight loss. This promise of weight loss
has appeared to help many patients
“overcome” their fear of needles.
The American Diabetes Association/
European Association for the Study of
Diabetes 9 and American Association of
Clinical Endocrinologists 10 have updated
their treatment recommendations
to better reflect the variety of available
treat ment options. Current treatment
recommendations underscore the need
for lifestyle change and the use of pharmacologic
treatment at the time of
diagnosis. The recommendations also
emphasize efforts to achieve the lowest
possible HgA 1c level without unacceptable
hypoglycemia. In recognition of
the progressive, multifactorial nature of
diabetes mellitus, 11 recent treatment
recommendations emphasize the use
of combination therapy with agents
that have complementary mechanisms
of action.
This comprehensive approach to
diabetes management is based on evidence
that typical glycemic-control parameters,
such as HgA 1c level, fasting
plasma and postprandial glucose excursions,
and hypoglycemia, have an impact
on cardiovascular disease risk,
Dialogue and Diagnosis // September 2012
mortality, quality of life, and clinical
outcomes in individuals with diabetes
mellitus. 9
The present issue of Dialogue and
Diagnosis provides practical strategies
for introducing and adjusting
injectable treatments in patients with
diabetes mellitus and for improving patient
acceptance and adherence. Joseph
M. Tibaldi, MD, describes the “how
and when” of introducing insulin for a
patient whose T2DM has progressed.
His case report also highlights factors
that are indicative of patients with
atypical forms of diabetes mellitus.
These atypical forms may represent as
much as 10% of diabetes cases.
Jeffrey S. Freeman, DO, reviews the
new treatment algorithms for diabetes
mellitus, and he discusses the risks and
benefits of oral and injectable treat -
ments. He uses a case report to show
how a physician can decide on the progression
of treatment on the basis of
patient wishes while addressing both
glycemic and nonglycemic effects.
James R. LaSalle, DO, discusses the role
of the incretin-based agents in treating
patients with advanced diabetes mellitus.
He presents data supportive of the
use of incretin-based agents for patients
who are already taking insulin.
We hope that this monograph will
help the reader better understand the
application of both newer and older
treatments for patients with diabetes
mellitus throughout the full spectrum
of disease. The reader should gain an
appreciation of the nonglycemic benefits
of treatment and be better able to
use a shared medical-decision
approach in the care of patients with
T2DM.
References
1. Centers for Disease Control and Prevention.
National Diabetes Fact Sheet: National Estimates
and General Information on Diabetes and
Prediabetes in the United States, 2011. Atlanta,
GA: US Department of Health and Human
Services, Centers for Disease Control and
Prevention; 2011.
2. Rowley WR, Bezold C. Creating public
awareness: state 2025 diabetes forecasts
[published online ahead of print January 27,
2012]. Popul Health Manag. 2012;15(4):194-200.
3. Zafar A, Davies M, Azhar A, Khunti K. Clinical
inertia in management of T2DM [published
online ahead of print August 16, 2010]. Prim
Care Diabetes. 2010;4(4):203-207.
4. Ziemer DC, Miller CD, Rhee MK, et al. Clinical
inertia contributes to poor diabetes control in a
primary care setting. Diabetes Educ.
2005;31(4):564-571.
5. Peyrot M, Rubin RR, Lauritzen T, et al;
International DAWN Advisory Panel. Resistance
to insulin therapy among patients and providers:
results of the cross-national Diabetes Attitudes,
Wishes, and Needs (DAWN) study. Diabetes Care.
2005;28(11):2673-2679.
6. Grant RW, Wexler DJ, Watson AJ, et al. How
doctors choose medications to treat type 2
diabetes: a national survey of specialists and
academic generalists [published online ahead of
print March 2, 2007]. Diabetes Care.
2007;30(6):1448-1453.
7. Grant RW, Lutfey KE, Gerstenberger E, Link
CL, Marceau LD, McKinlay JB. The decision to
intensify therapy in patients with type 2
diabetes: results from an experiment using a
clinical case vignette. J Am Board Fam Med.
2009;22(5):513-520.
8. Nakar S, Yitzhaki G, Rosenberg R, Vinker S.
Transition to insulin in Type 2 diabetes: family
physicians’ misconception of patients’ fears
contributes to existing barriers. J Diabetes
Complications. 2007:21(4);220-226.
9. Handelsman Y, Mechanick JI, Blonde L, et al;
AACE Task Force for Developing Diabetes
Comprehensive Care Plan. American Association
of Clinical Endocrinologists Medical Guidelines
for Clinical Practice for developing a diabetes
mellitus comprehensive care plan. Endocr Pract.
2011;17 suppl 2:1-53.
10. American Diabetes Association. Standards of
medical care in diabetes-2012. Diabetes Care.
2012;35 suppl 1:S11-S63.
11. Defronzo RA. Banting Lecture. From the
triumvirate to the ominous octet: a new
paradigm for the treatment of type 2 diabetes
D&D
mellitus. Diabetes. 2009;58(4):773-795.
Jay H. Shubrook Jr., DO, is an associate
professor of family medicine and a
diabetologist. He serves as the director
of clinical research and director of the
Diabetes Fellowship at Ohio University
Heritage College of Osteopathic
Medicine. He is a Fellow of the
American College of Osteopathic Family
Physicians. He can be reached at
shubrook@ohio.edu.
33

Dialogue
and
Diagnosis
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TAKE 10
When it comes to injectable
treatments for patients with type 2
diabetes, here are 10 points to
consider:
1. Despite the wide range of
medications to address the multiple
pathophysiologic defects in T2DM,
nearly 50% of people with diabetes
mellitus have poor control of their
disease.
2. Patients failing to initiate prescribed
insulin therapy commonly have
misconceptions regarding insulin
risk.
3. A physician’s attitudes, beliefs , and
knowledge about diabetes mellitus
can influence disease management.
Suspicion about the safety and
efficacy of current treatments may
be a barrier to aggressive manage -
ment. Insulin should be offered to
patients in a positive light as a
means to improve their health.
Reminding them early in the in the
disease that there may be times
insulin is needed in a pinch, such as
a critical illness or hospitalization,
may help.
4. Because T2DM is a progressive
disease, many patients will ultimately
need insulin therapy to achieve and
maintain adequate glycemic control.
Patients with T2DM, because of an
innate insulin resistance, tend to
require higher doses of insulin than
patient with type 1 diabetes mellitus.
5. Regarding glucose self-monitoring,
physicians should consider urging
measurements of fasting levels
and “bracketing” 1 meal with
preprandial and postprandial
measurements daily on a repetitive
basis.
6. When choosing the treatment option
for each patient, consider the
durations of T2DM, stage of the
disease, current level of control,
lifestyle habits, and attitude toward
disease management.
7. Today’s physicians are faced with
many more treatment options and
many more safety, efficacy, and
tolerability issues to consider then
personalizing treatment for patients
who require combination therapy in
addition to metformin as T2DM
progresses.
8. Metformin has become the
cornerstone of therapy on the basis
of its efficacy, low risk of hypo -
glycemia, low risk of weight gain,
and generic availability.
9. Ongoing therapeutic lifestyle
management should be discussed
with all patients with diabetes
mellitus throughout their lives.
Medical nutritional therapy must be
individualized, generally requiring
evaluation and teaching by a
trained nutritionist/registered
dietician or a knowledgeable
physician. Lifestyle intervention
remains the foundation of care of all
patients with diabetes mellitus, and
healthy lifestyle choices should be
addressed at every office visit.
10. If an incretin-based medication is
selected it is important to review
the safety issues with the patient.