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Frank Svec, MD, PhDClinical Professor of MedicineTulane University School of MedicineNew Orleans, Louisiana
Kevan ChambersAnnouncerMedscape Diabetes & Endocrinology
Challenges in the Managementof T2DM—Exploring the Role of GLP-1 Receptor Agonists: Southern Region
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Challenges in the Managementof 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 right-hand 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
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Frank Svec, MD, PhDClinical Professor of MedicineTulane University School of MedicineNew Orleans, Louisiana
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Ralph A. DeFronzo, MDProfessor of MedicineChief of Diabetes DivisionUniversity of Texas Health Science Center at San AntonioSan Antonio, Texas
Staff PhysicianDepartment of MedicineAudie L. Murphy DivisionSouth Texas Veterans Health Care SystemSan Antonio, Texas
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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
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Age-Adjusted Percentage of US Adults With Diagnosed Diabetes
Centers for Disease Control and Prevention: National Diabetes Surveillance System. http://www.cdc.gov/diabetes/statistics.
1994 1999
2008
Missing Data <4.5%
4.5-5.9% 6.0-7.4%
7.5-8.9% ≥9.0%
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aCenters for Disease Control and Prevention. 2008.bNational Institute of Diabetes and Digestive and Kidney Diseases. 2008.
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
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Obesity Trends* Among US Adults
*BMI ≥ 30 kg/m2, or about 30 lb overweight for 5’4” person.Centers for Disease Control and Prevention. 2008.
1990 1999
2008
No Data
<10% 10–14% 15–19%
20–24% 25–29% ≥30%
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In your region, what percentage of your patients are obese?
A. ≤ 25%
B. 26%-50%
C. 51%-75%
D. ≥ 76%
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Initial Presentation
• 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
Case 1• 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
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Case Presentations, Continued
• 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
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
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Polling Question #1 Results
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Rodgers G. http://www.nih.gov/news/radio/nov2009/20091110NDEP.htm
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
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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.
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
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aLotufo PA, et al. Arch Intern Med. 2001;161:242-247.bNational Institute of Diabetes and Digestive and Kidney Diseases. 2008.
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
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Challenges to Diabetes Care• Complications among undiagnosed individuals
with diabetes
• Cost of medication
• Patient propensity to lose weight
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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
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Next Steps
• 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
Case 149-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
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Exenatide Sustained A1c Reductions Over 82 Weeks
82-wk completer, N = 314; 82-wk ITT, N = 551; Mean ±SE.
Time (week)
Placebo-controlled Open-label extension
0 10 20 30 40 50 60 70 80 90-1.5
-1.0
-0.5
0.0
-1.1% ± 0.1%
-0.8% ± 0.1%
Chan
ge in
A1c
(%)
(All patients 10 mg BID)
8.3%8.4%
Mean Baseline A1c
82-Week ITT82-Week Completer
Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.
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Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.
Durability of Exenatide: Weight
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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.
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Follow-up
• 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
Case 1
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Diabetes Algorithms and A1c Goal
A1c Goal
American Diabetes Association
≤ 7%
American Association of Clinical Endocrinologists
≤ 6.5%
European Association for the Study of Diabetes
≤ 6.5%
Emerging Evidence/Expert Opinion ≤ 6%
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American Diabetes Association
American Diabetes Association. Diabetes Care. 2009;32(suppl1):S13-S61.Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.
• Lowering A1c to below or around 7% has been shown to reduce microvascular and macrovascular complications of T2DM
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Lifestyle + MET + PIO + SFU
Lifestyle + MET + PIO + SFU
STEP 1 At diagnosis: Lifestyle + MET
STEP 2
STEP 3 Lifestyle + MET + Intensive Insulin
OR
If A1c ≥7%
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.
Lifestyle + MET + Basal Insulin
Lifestyle + MET + Basal Insulin
Lifestyle + MET + SFU
Lifestyle + MET + SFU
Lifestyle + MET + Basal Insulin
Lifestyle + MET + Basal Insulin
Tier 2: Less-well-validated therapies*
Lifestyle + MET + PIO
Lifestyle + MET + PIO
Lifestyle + MET + GLP-1 Agonist
Lifestyle + MET + GLP-1 Agonist
American Diabetes Association/European Association for the Study of Diabetes
Tier 1: Well-validated core therapies*
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American Association of Clinical Endocrinologists/American College of Endocrinology
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
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IncreasedHepatic Glucose Production
Impaired Insulin Secretion
Hyperglycemia
Decreased GlucoseUptake
TZDsGLP-1 analoguesDPP-4 inhibitorsSulfonylureas Thiazolidinediones
Metformin
MetforminThiazolidinediones _
Pathophysiologic Approach to Treatment of T2DM
DeFronzo RA. Diabetes. 2009;58:773-795.
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Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.Nathan DM, et al. Diabetes Care. 2009;32:193-203.
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
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Polling Question #2 Results
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Schnabel CA, et al. Vasc Health Risk Manag. 2006;2:69-77.
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
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Insulin secretion
β-cell neogenesis
β-cell apoptosis
Glucagon secretionGlucose production
Heart
GI Tract
Liver
MuscleDrucker DJ. Cell Metab. 2006;3:153-165.
BrainAppetite
Cardioprotection
Cardiac output
StomachGastric emptying
Neuroprotection
Glucose Uptake
_
+
Stomach
GLP-1
GLP-1 Actions in Peripheral Tissue
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Side Effects: GLP-1 Receptor Agonists and DPP-4 Inhibitors
GLP-1 Receptor Agonists DPP-4 Inhibitors
Side effects Gastrointestinal Well tolerated
Weight> 85% patients
lose weight Weight neutral
AdministrationTwice-daily
injection Oral, once daily
Other cardiac risk factors
↓ Triglycerides↑ HDL
↓ Blood pressureUnknown
Davidson JA. Cleve Clin J Med. 2009;76(suppl5):S28-S38.
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Metformin Thiazolidinediones
Side effects Gastrointestinal
Fluid retention, congestive heart
failure, bone fractures
Weight Weight neutralWeight gain
Renal impairmentRestricted > 1.4
mg/dL
Seufert J, et al. Clin Ther. 2004;26:805-818.
Side Effects: Metformin and Thiazolidinediones
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Next Steps
Case 267-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
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Exenatide vs Insulin Glargine as Add-on Therapy in T2DM
A1c
Leve
l (%
)
* **
**
*0 2 4 8 12 18 26
Chan
ge in
Bod
y W
eigh
t (kg
)
Heine RJ, et al. Ann Intern Med. 2005;143:559-569.
Exenatide group (n = 275)Insulin glargine group (n = 260)
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Mean (SE): *P < .005
SFUb MET + SFUcMETa
*
- 0.8
Chan
ge in
A1c
(%)
247 245 241
8.5 8.5 8.5Baseline
n 113 110 113
8.2 8.3 8.2
123 125 129
8.7 8.5 8.6
0.1
-0.4*
-0.8*
-0.5*
-0.9*
0.1 0.2
-0.6*-0.8*
Placebo BIDExenatide 5 μg BID
Exenatide 10 μg BID
MET = metformin; SFU = sulfonylureaaDeFronzo 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.
Change in A1c Seen With Exenatide in Phase 3 Clinical Trials
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Buse JB, et al. Diabetes Care. 2004;27:2628-2635.
Effects of Exenatide in Sulfonylurea-Treated Patients: Weight
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Follow-up
• 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
Case 2
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Questions & Answers
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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.
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Differences in Glycemic Control
• Genetic variation on response to treatment commonly seen
• Further studies are needed
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Challenges in the Managementof T2DM—Exploring the Role of GLP-1 Receptor Agonists: Southern Region
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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
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Summary: T2DM Is 2 Diseases
• Microvascular complications
• Macrovascular complications
• Two distinct pathogenic sequences
• Two distinct clinical presentations
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