Challenges in the Management of T2DM—Exploring the Role of GLP-1 Receptor Agonists: Southern Region

1
Challenges in the Managementof T2DMExploring
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 Medsc
ape Diabetes Endocrinology
2
Challenges in the Managementof T2DMExploring
the Role of GLP-1 Receptor Agonists Southern
Region

• During todays 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

3
Frank Svec, MD, PhD Clinical Professor of
Medicine Tulane University School of Medicine New
Orleans, Louisiana
4
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
5
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

6
Age-Adjusted Percentage of US Adults With
Diagnosed Diabetes
1994
1999
2008
lt4.5
Missing Data
4.5-5.9
6.0-7.4
7.5-8.9
9.0
Centers for Disease Control and Prevention
National Diabetes Surveillance System.
http//www.cdc.gov/diabetes/statistics.
7
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.
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Obesity Trends Among US Adults
1990
1999
2008
No Data
1014
1519
lt10
2024
2529
30
BMI 30 kg/m2, or about 30 lb overweight for
54 person. Centers for Disease Control and
Prevention. 2008.
9
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
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

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Case Presentations, Continued
Case 2

• 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

• 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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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/nov2009/2
0091110NDEP.htm
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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. 20022549-54. bCDC
. MMWR Morb Mortal Wkly Rep. 200453941-944. cAHR
Q. http//www.ahrq.gov/research/diabdisp.htm.
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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.
2001161242-247. bNational Institute of Diabetes
and Digestive and Kidney Diseases. 2008.
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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
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

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Exenatide Sustained A1c Reductions Over 82 Weeks
Open-label extension
Placebo-controlled
(All patients 10 mg BID)
Time (week)
Blonde L, et al. Diabetes Obes Metab.
20068436-447.
82-wk completer, N 314 82-wk ITT, N 551
Mean SE.
Blonde L, et al. Diabetes Obes Metab.
20068436-447.
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Durability of Exenatide Weight
Blonde L, et al. Diabetes Obes Metab.
20068436-447.
21
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 lt .0001)
• HDL-C increased 24 (P lt .0001)

Klonoff DC, et al. Curr Med Res Opin.
200824275-286.
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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

23
Diabetes Algorithms and A1c Goal
24
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.
200932(suppl1)S13-S61. Nathan DM, et al.
Diabetes Care. 2006291963-1972.
25
American Diabetes Association/European
Association for the Study of Diabetes
At diagnosis Lifestyle MET
STEP 1
If A1c 7
Tier 2 Less-well-validated therapies
STEP 2
OR
Tier 1 Well-validated core therapies
Lifestyle MET GLP-1 Agonist
Lifestyle MET PIO
Lifestyle MET SFU
Lifestyle MET Basal Insulin
Lifestyle MET Basal Insulin
Lifestyle MET PIO SFU
STEP 3
MET metformin PIO pioglitazone SFU
sulfonylurea Validation based on clinical trials
and clinical judgment Adapted from Nathan DM,
et al. Diabetes Care. 200932193-203.
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American Association of Clinical
Endocrinologists/American College of Endocrinology
Rodbard HW, et al. Endocr Pract. 200915540-559.
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Pathophysiologic Approach to Treatment of T2DM
Impaired Insulin Secretion
TZDs GLP-1 analogues DPP-4 inhibitors Sulfonylurea
s
?
Metformin Thiazolidinediones
Thiazolidinediones Metformin ?
_
Hyperglycemia
Increased Hepatic Glucose Production
Decreased Glucose Uptake
DeFronzo RA. Diabetes. 200958773-795.
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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.
2006291963-1972. Nathan DM, et al. Diabetes
Care. 200932193-203.
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Polling Question 2 Results
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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.
2006269-77.
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GLP-1 Actions in Peripheral Tissue
Heart
Neuroprotection
Brain
Appetite
Stomach
Stomach
Gastric emptying
Cardioprotection Cardiac output
GI Tract
GLP-1
_
Liver
Insulin secretion ß-cell neogenesis ß-cell
apoptosis Glucagon secretion

Glucose production
Glucose Uptake
Muscle
Drucker DJ. Cell Metab. 20063153-165.
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Side Effects GLP-1 Receptor Agonists and DPP-4
Inhibitors
Davidson JA. Cleve Clin J Med. 200976(suppl5)S28
-S38.
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Side Effects Metformin and Thiazolidinediones
Seufert J, et al. Clin Ther. 200426805-818.
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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

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Exenatide vs Insulin Glargine as Add-on Therapy
in T2DM
Exenatide group (n 275)
Insulin glargine group (n 260)
A1c Level ()
Change in Body Weight (kg)






0 2 4 8 12 18 26
Heine RJ, et al. Ann Intern Med. 2005143559-569.
36
Change in A1c Seen With Exenatide in Phase 3
Clinical Trials
0.2
0.1
0.1
MET SFUc
METa
SFUb
Change in A1c ()
-0.4

-0.5
-0.6
- 0.8
-0.8
-0.8
-0.9
n
247 245 241
123 125 129
113 110 113
8.5 8.5 8.5
8.7 8.5 8.6
8.2 8.3 8.2
Baseline
Mean (SE) P lt .005
aDeFronzo R, et al. Diabetes Care.
2005281092-1100.bBuse JB, et al. Diabetes
Care. 2004272628-2635.cKendall D, et al.
Diabetes Care. 2005281083-1091.
MET metformin SFU sulfonylurea
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Effects of Exenatide in Sulfonylurea-Treated
Patients Weight
Buse JB, et al. Diabetes Care. 2004272628-2635.
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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

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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 patients 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. 2010362774-777.
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Differences in Glycemic Control

• Genetic variation on response to treatment
  commonly seen
• Further studies are needed

42
Challenges in the Managementof T2DMExploring
the Role of GLP-1 Receptor Agonists Southern
Region
43
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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