1. Challenging Cases
2012: in the Treatment of Type 2 Diabetes
Faculty
Rattan Juneja, MD
Associate Professor of Clinical Medicine
Indiana University School of Medicine
Medical Director, Indiana University Diabetes Center
Case #1: Joan Sullivan: 52-year-old woman, Chief of Endocrinology, Wishard Memorial Hospital
maternal history of type 2 diabetes Indianapolis, IN
Learning Objectives
Vital signs and clinical and laboratory findings
This activity is designed for specialists in primary care and endocrinology.
Initial presentation One year later, after counseling, There are no prerequisites for this activity. At the conclusion of this
diet, and exercise activity, participants should be able to:
Age, years 52 53 • Preserve beta cell function, delay disease progression, and
minimize the risk of diabetes-related complications by formulating
Body weight, kg (lb.) 77.6 (171) 78.5 (173) an individualized treatment plan that addresses the multiple
Hb A1c 7.0% 7.5% pathophysiologic mechanisms of diabetes.
Blood pressure, mm Hg 118/78 122/82 • Recognize the fundamental features, benefits, and risks underlying
Fasting plasma glucose, mg/dL 122 140 (retest: 145) current treatment recommendations when developing individualized
treatment plans.
Total cholesterol, mg/dL 195 212
• Employ multiple strategies to identify and reduce clinical inertia to
LDL cholesterol, mg/dL 119 136 achieve optimal patient outcomes.
HDL cholesterol, mg/dL 35 34
• Foster good patient self-management by establishing a
Triglycerides, mg/dL 205 212 collaborative relationship with patients based on respect for
Proteinuria Negative Negative individual patient preferences, needs, and values.
• Establish a comprehensive conceptual framework for disease
management of diabetes, hypertension, and hypercholesterolemia
At her initial presentation, Mrs Sullivan There may also be biological reasons for so as to provide effective primary care based on current standards.
was prescribed a program of counseling, the difficulty in losing weight, such as a
diet, and exercise based on her laboratory mismatch between insulin production and CME Information
results and weight. However, despite blood glucose peaks. This mismatch is due Release Date: June 25, 2012.
Valid for credit through June 24, 2013.
counseling for diet and exercise, she has to a reduction or loss of first-phase insulin
This activity has been planned and implemented in accordance with the
been unsuccessful in her attempts to lose production. The diminution of first-phase Essential Areas and Policies of the Accreditation Council for Continuing
weight, her weight has increased, and her insulin release occurs because: (1) the Medical Education (ACCME) through the joint sponsorship of Indiana
glycemic control has worsened. On her patient is producing maximal quantities University School of Medicine and Heath Focus, Inc. Indiana University
School of Medicine is accredited by the ACCME to provide continuing
return visit 1 year later, her fasting plasma of insulin to take care of the glucose the medical education for physicians. Indiana University School of Medicine
glucose value was 140 mg/dL. On repeat, it body is producing from gluconeogenesis designates this enduring activity for a maximum of 4 AMA PRA Category
1 Credits™. Physicians should claim only the credit commensurate with
was 145 mg/dL. She therefore satisfies the (basal glucose production); and (2) there the extent of their participation in the activity.
criteria for type 2 diabetes.1 Most likely, her is a loss of meal-stimulated insulin release To receive credit, participants must review the slides and audio
components of this website, and submit the activity evaluation form
beta cell function has continued to decline. (loss of the incretin effect) (see Figure 1). and posttest (passing score = 75% or higher).
As a result, insulin release in response Length of time to complete the activity: 4 hours
This scenario is common in patients to food ingestion is delayed, which in Disclosure Information
with insulin resistance. Regardless of some instances may even precipitate late Commercial Support
their sincerity and intent to carry out postprandial hypoglycemia, which in turn Indiana University School of Medicine and Health Focus, Inc.
gratefully acknowledge the unrestricted educational grant provided by
the required lifestyle modifications, could precipitate hunger. This loss of first- Eli Lilly & Company, Merck, Novo Nordisk, Sanofi.
patients’ efforts often produce little phase insulin release is considered to be
success. There are many reasons for this, the earliest detectable evidence of impaired Faculty Disclosure
In accordance with the Accreditation Council for Continuing Medical
including social and environmental beta cell function. Education (ACCME) Standards for Commercial Support, educational
factors, such as the time required for programs sponsored by Indiana University School of Medicine (IUSM) must
demonstrate balance, independence, objectivity, and scientific rigor. All
exercise, familial and social patterns What is the best therapeutic approach faculty, authors, editors, and planning committee members participating
of overeating and underactivity, to improve Mrs Sullivan’s glycemic in an IUSM-sponsored activity are required to disclose any relevant
lack of access to skilled counseling control in the short term AND to financial interest or other relationship with the manufacturer(s) of any
commercial product(s) and/or provider(s) of commercial services that
and support, unhealthy nutritional maintain or improve her beta cell are discussed in an educational activity. Dr. Juneja reported that he has
environments (eg, the higher cost function in the long term? received consulting fees and/or honoraria from Alere, Amylin, Boehringer
Ingelheim, Merck, Eli Lilly & Company, and Sanofi.
of healthy foods and the ubiquitous
Staff: Hassan Danesh, PhD, Monica Armin, and Dr. Deborah Teplow have
presence of cheap fast foods and junk According to current guidelines from disclosed that they have no potential or actual conflicts of interest.
foods), and other barriers that challenge the American Diabetes Association CME Reviewer: Statements of disclosure of relevant financial
patients’ achievement of their goals. (ADA; Figure 2), initiation of metformin relationships have been obtained from Charles Clark Jr, MD. Dr. Clark
has disclosed that he has no potential or actual conflicts of interest.
Note: Although it offers CME credits, this activity is not intended to
1 C M E c a se st u di es av ai l abl e at: w w w. 2012chall e n g i n g c a s e s i n d i a b e te s . c o m provide extensive training or certification in the field.

2. monotherapy is the recommended
approach.2,3 Metformin monotherapy The Incretin Effect in Subjects Without and
is usually successful in lowering With Type 2 Diabetes
hemoglobin A1c (Hb A1c) levels to less
than 7.0% in patients whose initial Hb Control Subjects Patients with Type 2 Diabetes
A1c levels are equal to or greater than (n=8) (n=14)
7.5%. However, it may not be the most
advantageous approach because it is
0.6 0.6
80 80
Incretin The incretin effect
not likely to achieve the dual goals of Effect 0.5 is diminished 0.5
therapy: improve glycemic control and in type 2 diabetes.
IR Insulin, mU/L
IR Insulin, mU/L
60 60
preserve beta cell function. 0.4 0.4
nmol/L
nmol / L
40 0.3 40 0.3
Figure 3 shows beta cell function over
time, estimated using Homeostasis 0.2 0.2
Model Assessment (HOMA), in patients 20
0.1
20
0.1
who participated in the United Kingdom
Prospective Diabetes Study (UKPDS).4 0 0 0 0
Time zero represents the time at which 0 60 120 180 0 60 120 180
patients were given the diagnosis of Time, min Time, min
type 2 diabetes and started treatment. Oral glucose load
It was estimated that beta cell function Intravenous (IV) glucose infusion
had already declined by approximately
50% in these patients, but treatment with
Adapted with permission from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
metformin, a sulfonylurea, or insulin
did not prevent further decline in beta Figure 1. Demonstration of the Incretin Effect.
cell function. The graphic on the left is from patients without diabetes. As can be seen, insulin production is much greater
in response to oral glucose than IV glucose, because the incretin hormones GLP-1 and GIP are produced
Figure 4 illustrates the implications of when glucose stimulates the intestine. In contrast, in patients with type 2 diabetes the incretin effect is
declining beta cell function on Hb A1c diminished, either due to deficiency or decreased action, or both, of GLP-1.
levels among patients in A Diabetes Position Statement
Outcome Progression Trial (ADOPT).5
These patients had mean initial Hb A1c
values of approximately 7.3%, and the
introduction of metformin, glyburide,
or rosiglitazone rapidly reduced Hb A1c
values to acceptable levels. However,
during the subsequent years, Hb A1c
levels progressively worsened, so that
most patients had Hb A1c levels of
greater than 7.0% again within 3 years
to 5 years, despite continued treatment.
All 3 monotherapies tested reduced
mean Hb A1c levels soon after initiation
in patients with newly diagnosed type
2 diabetes. However, Hb A1c levels
progressively worsened during the
ensuing years, so that mean levels were
greater than 7.0% within 4 to 5 years of
treatment initiation.
Using metformin monotherapy, we
would expect Mrs Sullivan’s Hb A1c level
to decline to less than 7.0% soon after
initiation of treatment. But it is likely a
Consider beginning at this stage in patients with very high HbA1c (e.g., $9%). bConsider rapid-acting, nonsulfonylurea secreta-
Figure 2dAntihyperglycemic therapy in type 2 diabetes: general recommendations. Moving from the top to the bottom of the figure, potential
gogues (meglitinides) in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas.
that it would return to a level above sequences of antihyperglycemic therapy. In most patients,glargine, detemir) in combination with noninsulin agents. dCertain noninsulin agents mayafter, diagnosis
c
Usually a basal insulin (NPH, begin with lifestyle changes; metformin monotherapy is added at, or soon be
7.0% within a few years, requiring the (unless there are explicit contraindications). insulin.
continued with If the HbA1c target is not achieved after ;3 months, consider one of the five treatment options combined
with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist, or basal insulin. (The order in the chart is determined by historical
addition of a second drug at that time. introduction 2. Algorithm for Individualized Management of Type 2 Diabetes According to the drug characteristics, with
Figure and route of administration and is not meant to denote any specific preference.) Choice is based on patient and ADA.
Unfortunately, Mrs Sullivan’s beta cell the over-riding goal of improving glycemic control while minimizing side effects. Shared decision making with the patient may help in the selection of
The algorithm recommends initial monotherapy using metformin, followed by addition of a second
therapeutic options. The figure displays drugs commonly used both in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may be
function is likely to have deteriorated used in place of sulfonylureas. Other drugsA1c target levels are not achieved.
antihyperglycemic agent if Hb not shown (a-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where
available in selected patients but have modest efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin,
select initial drug from other classes depicted and proceed accordingly. In this circumstance, while published trials are generally lacking, it is
reasonable to consider three-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-line
2 To e a r n C M E c redi t, compl ete the pos ttes t and whenaHbA1ctiisovery high (e.g., 2 0 1 2 c h a l ltherapeutic c a s e s ishould includessome m insulin before moving to more
therapy, especially e v l u a n a t www. $9.0%). The e n g i n g regimen n d i a b e te . c o basal
complex insulin strategies (Fig. 3). Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a two-
drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycemia (e.g., HbA1c $10.0–12.0%). DPP-4-i, DPP-4
inhibitor; Fx’s, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; HF, heart failure; SU, sulfonylurea. aConsider beginning at this
stage in patients with very high HbA1c (e.g., $9%). bConsider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregular
meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. cSee Table 1 for additional potential adverse effects and risks, under

3. over this time, and deteriorating beta
cell function could make treatment
more challenging.
UKPDS: β-Cell Loss Over Time
To prevent long-term loss of beta cell 100
function and reduce glycemic levels in
the short term, I recommend starting
patients on monotherapy (usually using
β-Cell Function (%)*
75 Patients treated
metformin) and then introducing a with insulin,
second oral agent as soon as metformin is metformin,
titrated to the maximum tolerated dosage, 50 sulfonylureas‡
regardless of the patient’s Hb A1c level.
The second drug should have a different
mechanism of action than the first drug, 25
IGT†
Postprandial
Type 2 Type 2 Diabetes
Diabetes
have no risk or low risk of hypoglycemia, Hyperglycemia
Phase I Type 2 Phase III
and facilitate weight loss or weight Diabetes
Phase II
maintenance, according to patient needs. 0
This approach is more similar to the -12 -10 -6 -2 0 2 6 10 14
glycemic control algorithm recommended Years From Diagnosis
by the American Association of Clinical *
Dashed line shows extrapolation forward and backward from years 0 to 6 from diagnosis based on
Endocrinologists/American College of
Homeostasis Model Assessment (HOMA) data from UKPDS.
†
IGT=impaired glucose testing
Endocrinology (AACE/ACE) (Figure 5).6 ‡
The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a subset of the
UPKDS population and were determined by the HOMA model.
This algorithm recommends that patients Lebovitz HE. Diabetes Rev. 1999;7:139-153.
start with dual therapy if their Hb A1c is
equal to or lower than 7.6%. Figure 3. Beta Cell Function Estimated Using the HOMA Model for Patients With Pre-diabetes and Type
2 Diabetes.
Although Mrs Sullivan’s Hb A1c level is
just below the recommended threshold Long-term Efficacy of Monotherapy: ADOPT
for use of 2 drugs, for reasons discussed,
I would advocate planning to use dual
Long-term Efficacy of Monotherapy: ADOPT
therapy with her. However, therapies
often need to be introduced gradually.
8.0
Note also that the Hb A1c goal in the Treatment difference (95% Cl)
AACE/ACE algorithm (6.5%) is lower Rosiglitazone vs metformin
-0.13 (-0.22 to -0.05); P=.002
than the ADA-recommended goal of 7.6
Rosiglitazone vs glyburide
7.0%, and that all guidelines recommend -.042 (-0.50 to -0.33); P<.001
adding a second antihyperglycemic 7.2
agent if the goal is not reached within 2
A1C, %
months to 3 months. 6.8
Although there is no direct clinical Annualized slope (95% Cl)
6.4
trial evidence to support the approach Rosiglitazone, 0.07 (0.06 to 0.09)
outlined above, it is clear that the Metformin, 0.14 (0.13 to 0.16)
traditional approach—monotherapy, 6.0 Glyburide, 0.24 (0.23 to 0.26)
followed by waiting until the Hb A1c 0
level returns to unacceptable levels, and 0 1 2 3 4 5
then adding the second drug—appears Years
to perpetuate beta cell failure and fails
to provide long-term glycemic control Reproduced with permission from Kahn SE, et al. N Engl J Med. 2006;355:2427-2443.
in most patients. For this reason, the
dual-therapy approach is advocated by
experts on the basis of indirect evidence Figure 4. Mean Hb A1c Levels in Patients in the ADOPT Trial.
from the UKPDS data and other
studies, such as the Insulin Resistance healthy, has a long life-expectancy with pursuing more stringent glycemic goals
Atherosclerosis Study.7,8 few comorbidities, and appears to be than the standard of less than 7.0%, such
motivated and capable of self-care. as an Hb A1c level of 6.5%.
Beyond considerations of beta cell Principles of individualizing Hb A1c
function, we should consider how Hb targets and therapeutic approaches (see Tighter glycemic targets, as well as
A1c targets should be individualized. next case and Figure 8)9,10 should lead us lower body weight, blood pressure, and
This patient is relatively young and to discuss with Mrs Sullivan the goal of blood lipid levels, have been advocated
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4. in such patients as a way to prevent or
forestall disease progression and the
development of complications, and to
preserve quality of life.9, 10
Oral diabetes therapies need to be
initiated gradually and titrated to
optimize compliance, minimize
adverse effects, and reduce the risk
of hypoglycemia. One important
barrier to good self-management
is adverse effects. By immediately
beginning dual-agent therapy at full
dosages, Mrs Sullivan could have
adverse effects that she may consider
intolerable and be less motivated to
adhere to recommended treatment.
This problem is especially prevalent
with the use of metformin.
As shown in Figure 6, metabolic defects
* May not be appropriate for all patients
in diabetes include increases in the ** patients with diabetes and A1c 6.5%,
For
appearance of glucose in the blood, as pharmacologix Rx may be considered
*** f A1c goal not achieved safely
I
well as defects in the disposal or use of  Prefered initial agent
1 DPP4 if  PPG and  FPG or GLP-1 if  PPG
glucose. Figure 7 shows that different 2 if metabolic syndrome and/or nonalcoholic
TZD
fatty liver disease (NAFLD)
classes of oral antihyperglycemic 3 AGI if  PPG
4 Blinide if  PPG or SU if  FPG
agents target different aspects of the 5 Low-dose secretagogue recommended
6 Discontinue insulin secretagogue with
a)
glucose control system. Metformin multidose insulin
b) Can use pramlintide with prandial insulin
primarily reduces glucose output 7 Decrease secretagogue by 50% when added to
GLP-1 or DPP-4
from the liver, thereby reducing 8 If A 8.5%, combination Rx with agents
© AACE 1ccause hypoglycemia Update.used with be reproduced
December 2009 should be May not
that
glucose appearance, so a good choice caution
9 If A1c 8.5%, in patients on Dual Therapy,
for a second drug would be one that Figure 5. From the AACE/ACE Algorithm for Glycemic Control.6 insulin should be considered
affects glucose disposal, such as a
thiazolidinedione (TZD), a dipeptidyl
peptidase-4 (DPP-4) inhibitor, or a Normal and Abnormal Glucose Control
GLP-1 agonist. 11 Nutrient Appearance vs Disappearance
What is a good strategy for initiating
treatment with metformin?
Plasma glucose
Metformin is often associated with changes only when
adverse side effects, especially diarrhea, appearance (Ra)
causing difficulties in tolerability and does not match
Meal
lack of compliance. These problems disappearance (Rd). Derived
often can be overcome by introducing Hepatic Glucose
Glucose
the drug at a low dosage and titrating In diabetes, appearance Production
the dosage to the maximum that can be is increased and disposal Ra
tolerated (not exceeding a maximum is impaired.
of 2000 mg to 2500 mg per day). The Plasma
Glucose
problem can also be mitigated by using Therapies may address Ra,
an extended-release formulation of the Rd, or both. Rd
drug, but titration is still important.
At any dosage, if the diarrhea becomes
intolerable, I advise the patient to
back off to the last dosage they found
tolerable, wait 1 week, and then try
again. If, despite this approach, they Figure 6. Normal and Abnormal Glucose Control.
still are unable to tolerate the dosage In type 2 diabetes, hepatic glucose production is increased and disposal of blood glucose is impaired. Both
required to achieve target Hb A1c levels, effects contribute to high blood glucose levels.
4 To e a r n C M E c redi t, compl ete the pos ttes t and e v a l u a ti o n a t www. 2 0 1 2 c h a l l e n g i n g c a s e s i n d i a b e te s . c o m

5. especially if they are already taking an
extended-release formulation, I might No Single Class of Oral Antihyperglycemic
consider a metformin formulation Monotherapy Targets All Key Pathophysiologies
that is released more slowly in the
intestines, such as Glumetza. Incretin
Alpha- Meglitinides3 SUs4,5 Mimetics/
How would you discuss the treatment Glucosidase TZDs 6,7
Metformin 8
DPP-4
Inhibitors1,2 Inhibitors
plan with Mrs Sullivan?
Major Pathophysiologies
It is important to combine active
Insulin
deficiency   
pharmacologic treatment with patient
education and counseling about the  
goals of therapies, the therapeutic
Insulin
resistance *
strategy, and future treatment plans,
such as the plan to introduce a second Excess hepatic
  
agent after metformin therapy is glucose output
established. The goals of education
Intestinal
and counseling are to increase Mrs
Sullivan’s understanding of the disease
glucose
absorption  
process and the potential of her diabetes 1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.
to worsen, and enhance her confidence 3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007.
5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.
in her ability to follow an effective 7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.
8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.
treatment plan. * Applies only to GLP1 agonists
My discussion with Mrs Sullivan Figure 7. Pathophysiologic Processes Targeted by Different Antihyperglycemic Agents.
will include several important topics, Although metformin improves insulin resistance, its main effect is to reduce hepatic glucose output.
including:
• Why treatment is necessary and amount of glucose that enters your body, Because metformin can cause diarrhea, I’m
important and (2) improve the way your body uses the going to start you at a low dosage and then
• Goals of treatment glucose to produce the energy you need to gradually increase it, because the diarrhea
• Rationale for the treatment plan carry out your daily activities. goes away in most people once their body
• How to manage side effects gets used to the medication. I want you to
• Plans for monitoring What is the rationale for the treatment start taking 500 mg metformin as a single
• Managing any barriers or challenges plan? pill with every evening meal. Taking it
she anticipates To achieve these goals, we need to use 2 with the evening meal does 2 things: (1) it
different drugs that work together. The makes the diarrhea less bothersome, and (2)
More specifically, here is an example of safest drug – the one that has been around your liver tends to make the most glucose
how I would cover these issues with Mrs for the longest time – is metformin. Its main at nighttime, so taking metformin in the
Sullivan: effect is to reduce the amount of glucose evening will have the greatest effect.
that your liver produces. Our first step is
Why is treatment necessary and to get you started on metformin during Metformin will lower your blood sugar
important? this first month. After 2 to 3 months, without making it go below normal limits
Your blood sugar level (known as Hb A1c) your Hb A1c level may drop below 7.0% or because it only reduces the glucose your
is 7.5%, indicating that your blood sugar even 6.5%. But from the results of many liver is making, and, therefore, doesn’t
level is above the level known to increase studies, I know that it is likely that your carry the risk of making your blood sugar
your risk for damage to your eyes, nerves, blood sugar level may not stay low for very bottom out. The goal is to eventually get
and kidneys. So, we need to bring this long; therefore, we also need to use a drug you on the maximum dosage because it
blood sugar level down. that improves how your body uses glucose. is most effective that way. So, I will ask
you to gradually increase the amount you
What are our goals of treatment? So, I plan to introduce a second drug at your take in weekly increments. You start now
There are 2 main goals in bringing this blood next visit. This drug targets a different part by taking 500 mg for the first week with
sugar down. One goal is to reduce the chances of the disease process in a different way than your evening meal. Next week, you’ll take
that you’ll have complications related to high metformin. We will, however, need to make 500 mg in the morning with breakfast
glucose values. Keeping your Hb A1c values sure that the 2 drugs together do not cause and 500 mg in the evening with dinner.
below 7.0% will do that. your blood sugar to go too low. During the third week, you’ll take 500 mg
in the morning and 1000 mg (2 pills) in
The second goal is to help your body use What are the possible side effects of the the evening. And by the fourth week, you’ll
glucose efficiently for energy. To do this, medicine and how can they be avoided take 1000 mg (2 pills) in the morning and
we need to do 2 things: (1) decrease the or managed? 1000 mg (2 pills) in the evening.
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6. If diarrhea is a problem and becomes should be avoided in patients with polypeptide. In turn, this stimulates
intolerable when you start taking 4 pills heart failure. Both drugs are associated glucose-mediated insulin release and
per day, for example, then you can go back with an increased risk of bone fracture,16 suppresses glucagon. These drugs
to 3 pills per day, 1 in the morning and 2 in and some experts have argued that do not suppress appetite and do not
the evening. Wait 1 week and then try the pioglitazone should be limited to a slow gastric emptying, thus their
4 pills again. If diarrhea is still intolerable, dosage of 30 mg per day to minimize use is not associated with nausea.
then go back to the 3 pills that you could the risk of bladder cancer.17 Although they lower Hb A 1c levels in
tolerate and that will be the dosage that you patients with diabetes, 21,22 they usually
will continue to use because we want you The GLP-1 receptor agonists, which are less potent than GLP-1 receptor
to take as much as you can tolerate up to a include exenatide, liraglutide, and agonists. The DPP-4 inhibitors also
maximum of 2000 mg per day. exenatide extended-release (a once- have little effect on body weight and
a-week formulation), increase insulin are considered weight neutral. 2 These
How will you know that the treatment secretion in a glucose-dependent agents may also be a good option for
is working? manner, decrease glucagon secretion, Mrs Sullivan, depending on whether
At this time, I also want you to see a and thereby reduce hepatic glucose her goal is to maintain her weight or
diabetes educator who will teach you how output, slow gastric emptying, and lose weight. Two key advantages of
to monitor your own blood glucose levels. suppress appetite.2 They are also the DPP-4 inhibitors are that they are
The purpose of this monitoring is so you associated with weight loss, making administered orally and are usually
can see for yourself if you are reaching them valuable treatment options for well tolerated. Furthermore, there is
your blood sugar target. Our treatment overweight or obese patients. But evidence that these agents improve
plan is designed to get your blood sugar patients need to be counseled about beta cell function, lower Hb A 1c levels
level between 70 mg/dL and 130 mg/dL how much weight loss to expect. A in patients already taking metformin,
before you eat. realistic weight loss associated with and are associated with low rates
GLP-1 receptor agonist therapy is 3 of hypoglycemia. 23-25 Cases of acute
With the knowledge that Mrs Sullivan kg to 5 kg, though some patients can pancreatitis have been reported in
is concerned about gaining weight, lose much more. These agents have patients receiving DPP-4 inhibitors.
what antihyperglycemic agents also been reported to improve beta cell
are the best choice to add after her function in some studies.18-20 CASE SUMMARY
appropriate metformin dosage is
established? GLP-1 receptor agonists do have Metformin is most often the first agent
several disadvantages. Most notably, recommended for treatment initiation.
The choices of add-on therapy for Mrs they are administered via injection and When considering dual therapy,
Sullivan are a sulfonylurea, a TZD, a are associated with gastrointestinal numerous factors affect the choice of
DPP-4 inhibitor, or a GLP-1 receptor side effects (nausea, vomiting, which antihyperglycemic agent to use
agonist. Since sulfonylureas are known diarrhea).2 However, the drugs are in combination with metformin. Mrs
to be associated with weight gain in better tolerated when the dose is Sullivan has achieved a reasonable
patients with type 2 diabetes and may titrated gradually. New, long-acting Hb A1c level (6.5%), which is within
actually worsen beta cell function, they formulations of GLP-1 receptor the targets recommended by the
would not be our choice here.2,12 agonists (once-weekly exenatide) may ADA and on the border for targets
be good options to minimize nausea recommended by AACE/ACE. In either
The TZDs, pioglitazone and (they are administered in a fixed dose case, a second drug is important to
rosiglitazone, have many characteristics and do not need titration) and for prevent the worsening of the Hb A1c
that would make them good agents for patients uncomfortable with frequent control that has been shown to occur
use in combination with metformin. injections. Cases of pancreatitis have with monotherapy alone.5,15 The second
These drugs activate peroxisome been reported in patients receiving agent should be one that works by a
proliferator-activated receptor-gamma GLP-1 receptor agonists, and patients different mechanism than metformin,
leading to direct improvements in should be cautioned about this risk. does not cause weight gain, and has
peripheral insulin sensitivity.13 There There is also an increase in medullary a low potential for hypoglycemia. A
is also evidence that they may improve c-cell hyperplasia in animal studies DPP-4 inhibitor would be a good choice
beta cell function,14,15 and they are reported with some of these agents; for Mrs Sullivan, but because she has
associated with very low incidence of thus, it is recommended that they expressed concerns about her weight,
hypoglycemia. However, both agents not be used in patients with multiple a GLP-1 receptor agonist might be a
are also associated with weight gain, endocrine neoplasia type 2. better choice for her because the GLP-1
so Mrs Sullivan would not benefit from agonists have more of an effect on Hb
either of these drugs.2 Furthermore, The DPP-4 inhibitors include A1c levels and also facilitate weight
rosiglitazone is now available only sitagliptin, saxagliptin, and linagliptin. loss. The recent availability of a once-
through an enrollment-based access They are oral agents that inhibit the weekly formulation of exenatide may
program because of the potential risk breakdown of incretin hormones and reduce concerns about the frequency of
for cardiovascular disease. Pioglitazone thus increase endogenous GLP-1 and required injections and also minimize
is also associated with edema and glucose-dependent insulinotropic nausea.
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7. The importance of lifestyle modifications His Hb A1c is now back up to 7.9%, and are important to you because everyone
within a comprehensive treatment plan Mr Hamilton has curtailed some of is unique and has individual interests
should be re-emphasized, preferably his favorite activities: He reveals that, and goals. What are one or two things
as part of a formal diabetes education although he used to love to work in that you want to achieve from the
program. This program should include his garden on evenings and weekends, treatment of your diabetes?
guidance on starting and maintaining he recently hired someone to mow the Patient: Well, I know I need to get my
an exercise regimen that includes at grass and just lets everything else go blood sugar down, but nothing
least 150 minutes of moderate-intensity because he gets tired too easily to do seems to work.
aerobic exercise spread out throughout yard work. In discussing treatment Physician: Yes, I agree that we need to
the week, and resistance training at options for him, Mr Hamilton states get your blood sugar level down, and
least twice per week.2 that he never wanted to use a glucose that the treatments you’ve had up
meter and just wants medication that to now have not worked as well as
CLINICAL RECOMMENDATIONS will allow him to eat his favorite foods we’d hoped. Your lab results already
without worrying about his blood show some signs of damage to your
• When selecting noninsulin sugar, though he is becoming concerned kidneys, probably caused by a high
therapies for patients with about his increasing weight. blood sugar level.
type 2 diabetes, incorporate
considerations for weight loss How would you develop a treatment In a very simple, nonjudgmental way,
and long-term maintenance of plan for Mr Hamilton that has a strong we’ve raised the issue of his difficulties
glycemic control, minimizing chance of success? in managing his care, expressed
hypoglycemia. empathy, and given him the opportunity
• Incorporate patient education into Mr Hamilton’s diabetes control is to express his goals in his own words.
every clinic visit, including how suboptimal, and probably has been for By echoing those goals back to him and
to minimize and respond to any some time. He clearly has difficulty reinforcing them, we have taken an
side effects of medications, the adhering to lifestyle modifications, important first step toward increasing
importance of continued lifestyle which are an important element his motivation to develop and adhere
modifications, and the rationale of diabetes treatment. If treatment to a plan that can be more successful
for each patient’s individualized goals are to be achieved, it is crucial in controlling his diabetes. We’ve also
treatment plan. that he embraces the treatment plan, reframed his statement that “nothing
believes it is realistic, and is willing seems to work” by introducing a
and capable of following it. A recent timeframe (“up to now”) and a relative
Case #2: Frederick Hamilton: Position Statement from the ADA and value (“as well as we’d hoped”). By
62-year-old man, given a the European Association for the Study reframing his treatment experience
diagnosis of type 2 diabetes 7 of Diabetes (EASD) has emphasized the from a failure to one that suggests the
years ago importance of using a patient-centered potential for change, we introduce hope.
approach to the treatment diabetes, Using a patient-centered approach like
Vital signs and clinical and laboratory findings stating that “recommendations should this helps many patients feel more
Body weight, kg (lb) 101.4 (223.5) be considered within the context of engaged in their treatment plan and
Blood pressure, mm Hg 134/84 the needs, preferences, and tolerances can improve their motivation to adhere
Hb A1c 7.9% of each patient; individualization to the recommended treatment plan.
Urinary albumin/creatinine ratio 30 mg/g on 2 of treatment is the cornerstone of
determinations success.”9 Mr Hamilton’s belief that nothing works
Mr Hamilton is a 62-year-old white man can be addressed through questioning
who works as a short-haul truck driver. Using a patient-centered approach that may help to elicit the reasons for this.
On his time off, he is devoted to his hobby requires us to have a conversation
of landscape gardening. He was given a with each patient to elicit their needs, Physician: Let’s talk about some problems
diagnosis of type 2 diabetes 7 years ago, preferences, and tolerances. As we you’ve run into so we understand a
at which time he was prescribed lifestyle review this case and develop a treatment little more about your situation. I’m
modification and glimepiride (initially 2 plan for Mr Hamilton, we will provide confident that we can find treatments
mg/day, then 4 mg/day). Two years later, examples of how to engage patients in that work better for you.
his Hb A1c was 8.1%, so pioglitazone was the kinds of conversations that establish • I know that you’re a truck driver. Does
added at 30 mg per day, then increased a patient-centered approach and foster this make it hard for you to get healthy
to 45 mg per day. Six months later, his better self-management. foods while you’re on the road?
Hb A1c was down to 7.1%, but his • Do you have trouble taking your
weight had increased to 105 kilograms. Physician: I know that a number of medicine at the right time?
His pioglitazone dose was reduced to factors, such as your job, have made • Are these medicines too expensive?
30 mg per day because of concerns managing your diabetes a challenge. Are you taking the full doses?
about the risk of bladder cancer at the I’m sure there are some things we • Have you had any problems with low
45 mg dose. can talk about to make some of this blood sugar? Is that a concern for you
easier. First, let’s discuss what goals while you’re driving?
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8. • Are there other problems, such as
family or social problems, that could Factors Influencing Individualization of A1c Targets
be creating some challenges for you in
controlling your diabetes?
A1c target
Patient: Well, driving does make it hard, and Most intensive Least intensive
my medicine doesn’t always make me feel
better. Like, sometimes when I take all my 6.0% 8.0%è
medicine, I feel weak and light-headed. Patient attitude and expected treatment
That worries me when I’m driving, so efforts
I sometimes skip taking it if I know I’m
Highly motivated, Less motivated,
going to be driving. Other times when I
adherent, nonadherent,
feel light-headed after taking my medicine,
I just eat something and it gets better, but
excellent poor self-care
I can’t always do that when I’m driving. self-care capabilities
capabilities
This conversation has helped us Risks associated with Low High
understand some of the reasons hypoglycemia
why he is having trouble getting his
Disease duration 0-10 20+
diabetes under control. We can use
this knowledge, along with his input, Life expectancy Long Short
to design an alternative treatment Important Absent Severe
plan that is more compatible with his comorbidities
lifestyle, potentially improving his
adherence to therapy.9 Established vascular Absent Severe
complications
These discussions can also help us to set Resources, support Readily available Limited
and adjust realistic Hb A1c goals that are system
achievable and that obtain the greatest
benefits without exposing him to excessive Figure 8. Factors that Influence the Selection of an Hb A1c Target for Individual Patients.9,10
risks of hypoglycemia or to treatment side
effects that may jeopardize compliance. occupation make it difficult for him to to bring him to an Hb A1c target of less
Factors based on recent opinions and comply with diet and exercise regimens. than 7%. Note that although the DPP-4
position statements influencing the selection He needs more aggressive treatment inhibitors are generally well tolerated,
of an Hb A1c target are shown in Figure that can help him achieve key clinical cases of pancreatitis have been reported
8.9,10 We have learned that Mr Hamilton has goals while enabling him to adhere to in patients using these drugs.
poor access to support resources, difficulty the treatment over time.
with compliance, high risks associated We may choose to switch to a GLP-1
with hypoglycemia, and some evidence of Our initial goal for Mr Hamilton is to receptor agonist in 6 months to 12 months
microvascular complications. Therefore, negotiate a plan that works for him, if Mr Hamilton shows good compliance
we may choose to individualize his target which should involve reducing his risk with all changes necessary to improve his
Hb A1c level to a goal of less than 7.0% to of hypoglycemia, thereby improving his diabetes control. One could argue that if
minimize worsening of his microvascular ability to comply with treatment. The Mr Hamilton has achieved his desired
complications; but at the same time, drug that is causing the hypoglycemia Hb A1c goals with a DPP-4 inhibitor and
given his fear of hypoglycemia , we need is glimepiride, so it should be pioglitazone, there would be no need
to choose a drug that mitigates that risk. discontinued. He can continue to take to change his medications. This would,
We also need to consider a drug that he the pioglitazone that had been added to indeed, be a suitable decision. However,
can take once a day with no relationship his treatment plan after 2 years since he if we want to work with him to achieve
to meals, since his eating habits can be seems to be tolerating that well. his personal goal of weight loss, then
inconsistent. switching the DPP-4 inhibitor to a GLP-1
To replace the glimepiride, we can receptor agonist would be a better choice
After factoring in Mr Hamilton’s consider a DPP-4 inhibitor. Even though for him. As shown in Figures 9 and 10,
individual needs, goals, and desires, they are less potent than GLP-1 receptor both liraglutide and extended-release
what are the best treatment options for agonists in terms of reducing Hb A1c exenatide were associated with weight
him? levels, the DPP-4 inhibitors have been loss in clinical trials.22,27 In contrast, the
reported to reduce blood sugar levels by DPP-4 inhibitors are considered weight
Mr Hamilton is already showing 0.5% to 0.8%.26 With improved adherence neutral. Another reason to consider this
early signs of microvascular damage, to treatment from better tolerance of a change would be if his blood sugar goals
probably related to poor glycemic DPP-4 inhibitor (versus a sulfonylurea), were not being met with the DPP-4/
control. In addition, his lifestyle and it is realistic to expect that we will be able pioglitazone combination.
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9. Although short-acting exenatide is
likely to reduce Mr Hamilton’s Hb A1c Liraglutide and Sitagliptin: Weight from Baseline
to desirable levels, it has a number of
characteristics that would be drawbacks
for this particular patient. He mentioned
that he doesn’t always know when he
will be able to eat because of his driving Liraglutide or sitagliptin added to metformin in patients not achieving adequate
schedule. Short-acting exenatide, glycemic control on metformin alone
however, needs to be administered
within a 60-minute window before 0 4 8 12 16 20 24
meals.28 Furthermore, when beginning 0
Change in bodyweight (kg)
treatment with short-acting exenatide, -0.5
many patients experience nausea.
-1.0
-1.5
This side effect could be especially
Both
-2.0 P0.0001
problematic considering Mr Hamilton’s -2.5
occupation and history of skipping -3.0
treatment doses to avoid potential side -3.5
effects. -4.0
-4.5
CASE SUMMARY LAG 1.2 mg LAG 1.8 mg SITA 100 mg
My approach would be to discontinue
glimepiride and start one of the Pratley R et al. Lancet. 2010;375:1447-1456.
established DPP-4 inhibitors at full
dose. I would arrange for Mr Hamilton Figure 9. Change in Body Weight Associated with Adding Liraglutide (1.2 mg or 1.8 mg) or Sitagliptin to
to participate in a formal educational Metformin in Patients with Type 2 Diabetes.
program on diabetes self-management,
even if he has participated in the past.
The reason for him to repeat the class is
Exenatide Once Weekly vs
to reinforce his self-management skills Twice Daily in T2DM
and help him recognize the critical
importance of blood glucose monitoring,
which he has been reluctant to do in the Exenatide once a week
past. He should return to the clinic after (n=148), baseline 102 kg
3 months so we can assess how this new Exenatide twice a day
treatment regimen is working for him.
(n=147), baseline 102 kg
0
It could be argued that stopping the
Least Square Mean (SE)
glimepiride completely might actually
Change in Weight , kg
-1
result in worsening of glycemic control.
This is indeed possible, but by getting -2
the patient engaged in a diabetes
self-management program, we might
-3
gain better glucose control than was
-4
being achieved with glimepiride.
There are data showing that seeing a -5
certified diabetes educator can result 0 3 6 10 14 18 22 26 30
in substantial Hb A1c reduction.2 My Time, wk
philosophy is that the best care for
patients with diabetes is the care they Reproduced with permission from Drucker D, et al. Lancet. 2008;372:1240-1250.
believe in.
By discontinuing the drug that causes Figure 10. Change in Body Weight in Patients with Type 2 Diabetes During Treatment with Twice-Daily or
hypoglycemia, we may even reduce Once-Weekly Formulations of Exenatide.
“defensive eating,” and we might find
that his Hb A1c level actually improves In addition to his elevated Hb A1c level, converting enzyme (ACE) inhibitor
after the change. We can always add in Mr Hamilton currently has high blood is a preferred choice in this setting
another agent—after a 3-month period— pressure, which should be treated. And because of their dual antihypertensive
if his glycemic control continues to he has evidence of microalbuminuria, so and renal-protective properties. These
deteriorate. It is in his best interest to give controlling both his diabetes and blood drugs should to be titrated up to target
him a chance to try his best. pressure is crucial. An angiotensin- blood pressure of less than 130/80 mm
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10. Hg and until his urine albumin declines
into the normal range. Low HDL-C
Elevated BP Inflammation
CLINICAL RECOMMENDATIONS
• Identify each patient’s goals
for treatment, preferences, and Abdominal Insulin
tolerances to optimize the chances Smoking adiposity resistance
for long-term success in the
treatment of type 2 diabetes.
• Use a nonjudgmental
conversational style to prompt Elevated LDL-C Elevated blood
Elevated glucose
patients to openly discuss their
triglycerides
individual concerns and barriers,
and echo those challenges back
to them, so they recognize that Figure 11. Hallmarks of Metabolic Syndrome.
you are incorporating their
concerns into the treatment plan
and working to overcome their
barriers. Goals to Prevent Complications
• Use existing guidelines as
a starting point for clinical Measure ADA Standard/Goal
decision-making, then
individualize glycemic targets A1c 7%
and treatment strategies to
Blood pressure 130/80, lower if kidney disease
develop a plan that works best
for each patient. Dilated eye exam At least once a year
Foot exam Check feet every day
Case #3: Frank Molson:
51-year-old man, metabolic Smoking Stop!!!
syndrome 100 md/dL if no known CVC
LDL (mg/dL)
Vital signs and clinical and laboratory findings 70 mg/dL if known CVD
Height, cm (in) 175 (5’9”) Triglycerides (mg/dL) 150
Body weight, kg (lb) 91.4 kg (201)
45 (men)
Waist circumference, cm (in) 104 cm (41) HDL (mg/dL)
55 (women)
Blood pressure, mm Hg 138/86
American Diabetes Association. Diabetes Care . 2011;34(supp 1):S11-S61
Hb A1c 7.6%
Fasting plasma glucose, mg/dL 146 Figure 12. Clinical Goals for Each Risk Factor According to the ADA.
LDL cholesterol, mg/dL 137
HDL cholesterol, mg/dL 39 Mr Molson was prescribed the following Mr Molson has most of the hallmarks
medications: of metabolic syndrome (Figure 11),
Total cholesterol, mg/dL 220
including a waist circumference
Triglycerides, mg/dL 220 • Lisinopril: 10 mg per day greater than 40 inches ( 102 cm), type
Urine albumin Negative • Metformin: 1000 mg twice daily 2 diabetes mellitus with ongoing poor
Serum creatinine 1.1 mg/dL (reference
• Sitagliptin: 100 mg once daily glycemic control, hypertension (blood
range = 0.9-1.3 • Simvastatin: 20 mg once daily pressure 130/85 while taking an
mg/dL) ACE inhibitor), elevated triglycerides
Because of his budgetary restrictions, (≥ 150 mg/dL), and low high-density
Frank Molson is a 51-year-old white he had been taking sitagliptin every lipoprotein (HDL) cholesterol levels
man. He is a self-employed construction other day, but recently has not renewed ( 40 mg/dL for men). 1 Together and
contractor with an unpredictable work his sitagliptin prescription because he individually, these characteristics are
schedule and a busy family life. He cannot afford the co-pay for (nongeneric) risk factors for cardiovascular disease,
has indicated that he would like some sitagliptin. and all need to be addressed. Clinical
advice on weight loss. He has a tight goals for each risk factor, according to
budget, and his insurance co-pay for Would you try to address all of Mr the ADA, are shown in Figure 12.
nongeneric medications is very high. Molson’s problems at one clinic visit?
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