Challenges in the Management
of T2DM—Exploring the Role of GLP-1
Receptor Agonists: Southern Region
Frank Svec, MD, PhD
Clinical Professor of Medicine
Tulane University School of Medicine
New Orleans, Louisiana
Kevan Chambers
Announcer
Medscape Diabetes & Endocrinology
Challenges in the Management
of T2DM—Exploring the Role of GLP-1
Receptor Agonists: Southern Region
• During today’s discussion, we will present 2 interactive
questions
• You may also submit a question at any time during the
program by using the “Ask a Question” box in the lower righthand corner of your screen
• We hope to be able to answer at least some of your questions
at the end of the program
• There will be a brief assessment at the end of the program
asking about the changes that you might make in your
practice, on the basis of your participation today. Your
responses will help us to improve the content of this and
future educational programs
Frank Svec, MD, PhD
Clinical Professor of Medicine
Tulane University School of Medicine
New Orleans, Louisiana
Ralph A. DeFronzo, MD
Professor of Medicine
Chief of Diabetes Division
University of Texas Health Science Center
at San Antonio
San Antonio, Texas
Staff Physician
Department of Medicine
Audie L. Murphy Division
South Texas Veterans Health Care System
San Antonio, Texas
Program Goal
• Review the incidence and prevalence of type 2
diabetes mellitus (T2DM)
• Evaluate evidence-based guidelines for the
management of diabetes
• Focus on the role of glucagon-like peptide (GLP)-1
receptor agonists to help you tailor therapies to
your patients with T2DM
Age-Adjusted Percentage of US Adults
With Diagnosed Diabetes
1994
1999
2008
Centers for Disease Control and Prevention: National Diabetes
Surveillance System. http://www.cdc.gov/diabetes/statistics.
Missing Data
<4.5%
4.5-5.9%
6.0-7.4%
7.5-8.9%
≥9.0%
Incidence of T2DM
• Approximately 20 million individuals with T2DM in
the United Statesa
• Additional 4-5 million individuals with
undiagnosed diabetesa
• 60 million individuals with prediabetes (ie, impaired
glucose tolerance, impaired fasting glucose)b
aCenters
for Disease Control and Prevention. 2008.
bNational Institute of Diabetes and Digestive and Kidney Diseases. 2008.
Obesity Trends* Among US Adults
1990
1999
2008
No Data
*BMI ≥ 30 kg/m2, or about 30 lb overweight for 5’4” person.
Centers for Disease Control and Prevention. 2008.
<10%
10–14%
15–19%
20–24%
25–29%
≥30%
In your region, what percentage of your
patients are obese?
A. ≤ 25%
B. 26%-50%
C. 51%-75%
D. ≥ 76%
Initial Presentation
Case 1
• 49-year-old man with a
1-year history of T2DM
• Waiter in the French
Quarter; 2 meals/day;
weight conscious
• Father died of coronary
disease; older brother
has coronary disease
• Initial glycated
hemoglobin (A1c) 9.1%;
BMI = 29.5 kg/m2
• A1c today 8.1%; BMI = 28.8
kg/m2; LDL = 87 mg/dL;
HDL = 33 mg/dL
• Metformin 1000 mg twice
daily and statin
• Is concerned about heart
disease; wants to lose
weight; nervous about
insulin
Case Presentations, Continued
Case 2
• 67-year-old woman with
a long history of T2DM
• Cared for at Charity
Hospital before
Hurricane Katrina;
moved to Mississippi;
back to New Orleans
• Old medical records lost
• On insulin?
• Lumbar disk disease and
hypertension
• Cannot exercise
• 2 meals/day; snacks;
drinks on the weekend
• Does not check blood
glucose values at home
• BMI = 33.2 kg/m2; A1c
7.9%; LDL = 138 mg/dL;
SCr = 1.6 mg/dL; blood
pressure = 137/88 mm Hg
• ACE inhibitor/thiazide,
sulfonylurea
Polling Question #1 Results
T2DM Epidemic and Complications
• 4000 new cases of diabetes are diagnosed daily
• 800 deaths from individuals with T2DM daily
• 200 individuals with T2DM experience an
amputation daily
• 50 individuals with T2DM develop blindness daily
Rodgers G. http://www.nih.gov/news/radio/nov2009/20091110NDEP.htm
Ethnic Disparities
• Highest incidence of diabetes among American Indiansa
• High incidence of diabetes among Hispanics,
Mexican Americans, and African Americansb,c
• Lowest incidence of diabetes among whites
aLee
ET, et al. Diabetes Care. 2002;25:49-54.
bCDC. MMWR Morb Mortal Wkly Rep. 2004;53:941-944.
cAHRQ. http://www.ahrq.gov/research/diabdisp.htm.
Diabetes and Cardiovascular Disease
• Increased incidence of atherosclerotic
cardiovascular complicationsa
• Incidence of myocardial infarction and
stroke increaseda
• High cost of managing micro- and
macrovascular complicationsb
aLotufo
PA, et al. Arch Intern Med. 2001;161:242-247.
bNational Institute of Diabetes and Digestive and Kidney Diseases. 2008.
Challenges to Diabetes Care
• Complications among undiagnosed individuals
with diabetes
• Cost of medication
• Patient propensity to lose weight
What is your greatest obstacle
to initiating therapy with GLP-1 receptor
agonists?
A. Not being up-to-date on current safety and efficacy
evidence supporting use of these agents in T2DM
B. Cost of medication/insurance/managed care issues
C. They offer no advantages over current
antidiabetic agents
D. Unfamiliarity with placement of this class within
treatment guidelines
E. Patients’ fear of injections or other patient-related
factors
Next Steps
Case 1
49-year-old man with 1-year history of T2DM; on metformin;
A1c, 8.1%; scared of insulin, worried about heart disease, and
wants to lose more weight
• Reinforce positive results; his BMI went down
• Continue to reinforce the importance of diet and exercise
• GLP-1 agonist should be considered, given that his A1c is not
at goal on metformin; he is worried about his heart, and wants
to lose weight
• Need to check serum creatinine level and liver function
• Ask about history of pancreatitis
Exenatide Sustained A1c Reductions
Over 82 Weeks
Mean Baseline A1c
8.3%
8.4%
Change in A1c (%)
82-Week Completer
82-Week ITT
0.0
Open-label extension
(All patients 10 mg BID)
Placebo-controlled
-0.5
-0.8% ± 0.1%
-1.0
-1.5
-1.1% ± 0.1%
0
10
20
30
40
50
60
70
80
90
Time (week)
Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.
Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.
82-wk completer, N = 314; 82-wk ITT, N = 551; Mean ±SE.
Durability of Exenatide: Weight
Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.
Effects of GLP-1 Agonists on
Cardiovascular Risk Factors
• A subset achieved 3.5 years of exenatide exposure
and had serum lipids available for analysis
(n = 151)
• Triglycerides decreased 12% (P = .0003)
• Total cholesterol decreased 5% (P = .0007)
• LDL-C decreased 6% (P < .0001)
• HDL-C increased 24% (P < .0001)
Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.
Follow-up
Case 1
• Warn him about the potential gastrointestinal side
effects of GLP-1 agonists (nausea, vomiting) and that
they generally abate over time
• Educate on the need to control glucose and weight
• Review cardiovascular risk parameters
• Test blood glucose twice daily – before breakfast,
before dinner
• DPP-4 inhibitors are a possibility, but they offer
modest glucose lowering and are weight neutral
Diabetes Algorithms and A1c Goal
A1c Goal
American Diabetes
Association
American Association of
Clinical Endocrinologists
European Association for
the Study of Diabetes
Emerging Evidence/Expert
Opinion
≤ 7%
≤ 6.5%
≤ 6.5%
≤ 6%
American Diabetes Association
• Lowering A1c to below or around 7% has been
shown to reduce microvascular and macrovascular
complications of T2DM
American Diabetes Association. Diabetes Care. 2009;32(suppl1):S13-S61.
Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.
American Diabetes Association/European
Association for the Study of Diabetes
At diagnosis: Lifestyle + MET
STEP 1
If A1c ≥7%
STEP 2
Tier 1: Well-validated core therapies*
Lifestyle + MET +
SFU
STEP 3
Lifestyle + MET +
Basal Insulin
OR Tier 2: Less-well-validated therapies*
Lifestyle + MET +
GLP-1 Agonist
Lifestyle + MET +
PIO
Lifestyle + MET +
PIO + SFU
Lifestyle + MET +
Basal Insulin
Lifestyle + MET + Intensive Insulin
MET = metformin; PIO = pioglitazone; SFU = sulfonylurea
*Validation based on clinical trials and clinical judgment
Adapted from: Nathan DM, et al. Diabetes Care. 2009;32:193-203.
American Association of Clinical
Endocrinologists/American College of
Endocrinology
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
Pathophysiologic Approach
to Treatment of T2DM
Impaired Insulin Secretion

Metformin
Thiazolidinediones
_
TZDs
GLP-1 analogues
DPP-4 inhibitors
Thiazolidinediones
Sulfonylureas
Metformin

Hyperglycemia
Increased
Hepatic Glucose
Production
DeFronzo RA. Diabetes. 2009;58:773-795.
Decreased
Glucose
Uptake
Consensus Statements for T2DM
• Consensus group of leading international
endocrinologists and diabetologists with extensive
clinical experience
• Recent medical literature and all currently approved
classes of medications should be considered
• Common goal is to improve glucose control through
individualization of therapy
Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.
Nathan DM, et al. Diabetes Care. 2009;32:193-203.
Polling Question #2 Results
GLP-1 Receptor Agonists
• First-in-class exenatide approved in 2005
• Augment insulin secretion
• Inhibit glucagon secretion
• Lower fasting glucose and improve postprandial
glucose profile
Schnabel CA, et al. Vasc Health Risk Manag. 2006;2:69-77.
GLP-1 Actions in Peripheral Tissue
Heart
Neuroprotection
Brain
Appetite
Gastric
emptying
Stomach
Stomach
Cardioprotection
Cardiac output
GI Tract
GLP-1
_
Liver
Insulin secretion
β-cell neogenesis
Glucose
production
Drucker DJ. Cell Metab. 2006;3:153-165.
+
Muscle
Glucose
Uptake
β-cell apoptosis
Glucagon secretion
Side Effects: GLP-1 Receptor Agonists
and DPP-4 Inhibitors
Side effects
Weight
Administration
Other cardiac risk
factors
GLP-1 Receptor
Agonists
DPP-4 Inhibitors
Gastrointestinal
Well tolerated
> 85% patients
lose weight
Twice-daily
injection
↓ Triglycerides
↑ HDL
↓ Blood pressure
Davidson JA. Cleve Clin J Med. 2009;76(suppl5):S28-S38.
Weight neutral
Oral, once daily
Unknown
Side Effects: Metformin and
Thiazolidinediones
Metformin
Side effects
Gastrointestinal
Weight
Weight neutral
Renal impairment
Restricted > 1.4
mg/dL
Seufert J, et al. Clin Ther. 2004;26:805-818.
Thiazolidinediones
Fluid retention,
congestive heart
failure, bone
fractures
Weight gain
Next Steps
Case 2
67-year-old woman with a long history of T2DM; babysits
grandchildren; on sulfonylurea; A1c, 7.9%
• Emphasize the importance of exercise and diet
• Serum creatinine is high, so cannot use metformin
• Insulin is a common next step and may be considered, but
associated with weight gain and hypoglycemia
• GLP-1 agonists should be considered to help lower glucose
levels and may be associated with mild improvements in blood
pressure and lipid profile
Exenatide vs Insulin Glargine as
Add-on Therapy in T2DM
Change in Body Weight (kg)
A1c Level (%)
Exenatide group (n = 275)
Insulin glargine group (n = 260)
*
*
*
0 2 4
Heine RJ, et al. Ann Intern Med. 2005;143:559-569.
8
*
12
*
18
*
26
Change in A1c Seen With Exenatide
Placebo BID
in Phase 3 Clinical Trials
Exenatide 5 μg BID
Change in A1c (%)
Exenatide 10 μg BID
0.1
*
METa
-0.4*
- 0.8
0.1
0.2
MET + SFUc
SFUb
-0.5*
-0.8*
-0.6*
n
113 110 113
-0.9*
123 125 129
Baseline
8.2 8.3 8.2
8.7 8.5 8.6
-0.8*
247 245 241
8.5 8.5 8.5
Mean (SE): *P < .005
aDeFronzo
R, et al. Diabetes Care. 2005;28:1092-1100.
bBuse JB, et al. Diabetes Care. 2004;27:2628-2635.
cKendall D, et al. Diabetes Care. 2005;28:1083-1091.
MET = metformin; SFU = sulfonylurea
Effects of Exenatide in SulfonylureaTreated Patients: Weight
Buse JB, et al. Diabetes Care. 2004;27:2628-2635.
Follow-up
Case 2
• Illustrate the effects of binge alcohol consumption
(hypoglycemia, pancreatitis risk)
• Another agent may help control hypertension
• A statin may help lower LDL
• Encourage home blood glucose monitoring
• DPP-4 inhibitors can be considered, but insulin may
cause unwanted weight gain
Questions & Answers
Medullary Thyroid Cancer and Pancreatitis
• Liraglutide-induced medullary carcinoma is rare, but
need to evaluate the patient’s risk
• Increase in incidence of pancreatitis in patients with
T2DM, but unclear whether it is associated with use
of exenatide
Parks M, et al. N Engl J Med. 2010;362:774-777.
Differences in Glycemic Control
• Genetic variation on response to treatment
commonly seen
• Further studies are needed
Challenges in the Management
of T2DM—Exploring the Role of GLP-1
Receptor Agonists: Southern Region
Concluding Remarks
• Treatment of diabetes requires consideration of
multiple risk factors
• Obesity/overweight is a prime factor in the
development diabetes
• Glucose control is important and can be
accomplished without worsening adiposity
• Discussion of side-effect profile of any medication
ahead of time will enhance patient acceptance
Summary: T2DM Is 2 Diseases
• Microvascular complications
• Macrovascular complications
• Two distinct pathogenic sequences
• Two distinct clinical presentations
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