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

1
Challenges in the Managementof T2DM -- Exploring
the Role of GLP-1 Receptor Agonists Central
Region
Jaime A. Davidson, MD Clinical Professor of
Medicine Division of Endocrinology Diabetes and
Metabolism University of Texas Southwestern
Medical Center Dallas, Texas Kevan
Chambers Announcer Medscape Diabetes
Endocrinology
2
Challenges in the Managementof T2DM -- Exploring
the Role of GLP-1 Receptor Agonists Central
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
  improve the content of this and future
  educational programs.

3
Jaime A. Davidson, MD Clinical Professor of
Medicine Division of Endocrinology Diabetes and
Metabolism University of Texas Southwestern
Medical Center Dallas, Texas
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
lt 4.5
Missing Data
4.5-5.9
6.0-7.4
7.5-8.9
9.0
CDC. Available at http//www.cdc.gov/diabetes/sta
tistics Accessed July 6, 2010.
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

a. CDC. Available at http//www.cdc.gov/diabetes/
pubs/pdf/ndfs_2007.pdf Accessed July 6, 2010. b.
NIDDK. Available at http//diabetes.niddk.nih.gov
/DM/PUBS/statistics/ Accessed July 6, 2010.
8
Obesity Trends Among US Adults
1990
1999
2008
No Data
lt 10
15-19
10-14
20-24
25-29
30
Body mass index (BMI) 30 kg/m2, or about 30 lb
overweight for 54 person CDC. Available at
http//www.cdc.gov/diabetes/statistics Accessed
July 6, 2010.
9
In your region, what percentage of your patients
with diabetes are obese?

• A. 25
• B. 26-50
• C. 51-75
• D. 76

10
Estimated Lifetime Risk Developing Diabetes for
US-Born Individuals (2000)
Narayan et al, JAMA, 2003
Narayan KM, et al. JAMA. 20032901884-1890.
11
Initial Presentation
Case 1

• Lost 6 lb on metformin A1c not at goal
• Sulfonylurea added but gained weight
• Today, A1c 7.9 BMI 31.2 kg/m2 BP 134/82 mm
  Hg LDL 86 mg/dL TG 162 mg/dL HDL 39
  mg/dL
• Exercises 3/week when not traveling eats out
  frequently raising PPG

• 56-year-old black man newly diagnosed with T2DM 9
  months ago 10-year history of dyslipidemia
• Initial A1c 8.2
• Metformin 1000 mg twice daily, but due to
  intolerability, reduced to 1500 mg daily
• Statin and niacin

A1c glycated hemoglobin BP blood pressure
HDL high-density lipoprotein LDL low-density
lipoprotein TG triglyceride
12
Case Presentations (cont)
Case 2

• Lifestyle changes initiated and metformin
  started SCr 1.3 mg/dL
• Glyburide added to metformin
• Today, A1c 7.9 BMI 36.7 kg/m2 BP 129/82 mm
  Hg LDL 99mg/dL TG 187 mg/dL HDL 33 mg/dL

• 48-year-old, obese Latina/Hispanic woman with a
  10-year history of T2DM
• Hyperlipidemia and hypertension (well treated),
  lumbar disc disease
• Angiotensin receptor blocker and
  hydrochlorothiazide

SCr serum creatinine
13
Fastest Growing US Ethnic Minority Groups
Other
Asian
Black
Projected Population (millions)
Latinos
Year
Other includes American Indian, Alaskan Native,
Native Hawaiian, other Pacific Islander, and 2 or
more races.
US Census Bureau. Available at
http//www.census.gov/ipc/www/usinterimproj
Accessed July 6, 2010.
14
Effect of Ethnicity on A1c NHANES 1999-2002
Adjusted for age (2044 years, 4564 years, 65
years), sex, education, poverty index ratio,
abdominal obesity, health insurance coverage,
time since last blood pressure reading, and
diabetes treatment
Saydah S, et al. Ethn Dis. 200717529-535.
15
Projected Diabetes Cases in Texas (2000-2040)
16
Obesity Increases Mortality Risk
Cardiovascular disease Cancer All other causes
lt1925
2530
gt30
lt1925
2530
gt30
Body Mass Index
Calle EE, et al. N Engl J Med. 19993411097-1105.
17
Polling Question 1 Results
18
T2DM Epidemic and Complications

• 4000 new cases of diabetes are diagnosed daily.
• 800 deaths occur from individuals with T2DM
  daily.
• 200 individuals with T2DM experience an
  amputation daily.
• 50 individuals with T2DM develop blindness daily.
  

Rodgers G. Available at http//www.nih.gov/news/r
adio/nov2009/20091110NDEP.htm Accessed July 6,
2010.
19
Ethnic Disparities

• Highest incidence of diabetes among American
  Indiansa
• High incidence of diabetes among Hispanics,
  Mexican Americans, and blacksb,c
• Lowest incidence of diabetes among whites

a. Lee ET, et al. Diabetes Care.
20022549-54. b. CDC. MMWR Morb Mortal Wkly Rep.
200453941-944. c. AHRQ. Available at
http//www.ahrq.gov/research/diabdisp.htm
Accessed July 6, 2010.
20
Diabetes and Cardiovascular Disease

• Increased incidence of atherosclerotic
  cardiovascular complicationsa
• Incidence of myocardial infarction and stroke
  increaseda
• High cost of managing microvascular and
  macrovascular complicationsb

a. Lotufo PA, et al. Arch Intern Med.
2001161242-247. b. NIDDK. Available at
http//diabetes.niddk.nih.gov/DM/PUBS/statistics/
Accessed July 6, 2010.
21
Challenges to Diabetes Care

• Complications among undiagnosed individuals with
  diabetes
• Cost of medication
• Patient difficulty in losing weight

22
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

23
Next Steps
Case 1
56-year-old black man newly diagnosed with T2DM 9
months ago A1c 7.9 despite lifestyle,
metformin, and sulfonylurea gained weight, BMI
36.7 kg/m2

• How can we help patients achieve ADA and AACE
  glycemic goals?

AACE American Association of Clinical
Endocrinologists ADA American Diabetes
Association
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Glucose Control and Weight Management
Therapeutic Option A1c lt 7 Weight
Sulfonylureaa,b
TZDc,d
Insuline,f
P
P
P
a. Malone M. Ann Pharmacother. 2005392046-2055.
b. Pfizer. Glucotrol XL full prescribing
information. 2006. c. Takeda. Actos full
prescribing information. 2007. d.
GlaxoSmithKline. Avandia full prescribing
information. 2007. e. Nathan DM, et al. Diabetes
Care. 200831173-175. f. Holman RR, et al. N
Engl J Med. 20073571716-1730.
25
Glucose Control and Weight Management (cont)
Therapeutic Option A1c lt 7 Weight
Metformina
DPP-4 inhibitorb
GLP-1 receptor agonistc
P
P
P
a. Bristol-Myers Squibb Company. Glucophage XR
full prescribing information. 2008. b. Merck.
Januvia full prescribing information. 2007. c.
Drucker DJ. J Clin Invest. 200711724-32.
26
Lessons Seen in Managed Care Patients Treated
Over 4 Years
(n2373)
(n1590)
(n5453)
A1c ()
Time (months)
Riedel AA, et al. Diabetes. 200655(suppl1)A132.
27
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

28
American Diabetes Association
Nathan DM, et al. Diabetes Care.
2006291963-1972. American Diabetes Association.
Diabetes Care. 200932(suppl1)S13-S61.
29
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.
30
American Association of Clinical
Endocrinologists/American College of Endocrinology
Rodbard HW, et al. Endocr Pract. 200915540-559.
31
Pathophysiologic Approach to Treatment of T2DM
Impaired Insulin Secretion
TZDs GLP-1 analogs DPP-4 inhibitors Sulfonylureas
?
Metformin Thiazolidinediones
Thiazolidinediones Metformin ?
_
Hyperglycemia
Increased Hepatic Glucose Production
Decreased Glucose Uptake
TZDs thiazolidinediones
DeFronzo RA. Diabetes. 200958773-795.
32
Polling Question 2 Results
33
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.
34
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.
35
Side Effects GLP-1 Receptor Agonists and DPP-4
Inhibitors
GLP-1 Receptor Agonists DPP-4 Inhibitors
Side effects Gastrointestinal Well tolerated
Weight gt 85 patients lose weight Weight neutral
Administration Twice-daily injection Oral, once daily
Other cardiac risk factors ? Triglycerides ? HDL ? Blood pressure Unknown
Davidson JA. Cleve Clin J Med. 200976(suppl5)S28
-S38.
36
Side Effects Metformin and Thiazolidinediones
Metformin Thiazolidinediones
Side effects Gastrointestinal Fluid retention, congestive heart failure, bone fractures
Weight Weight neutral Weight gain
Renal impairment Restricted gt 1.4 mg/dL
Seufert J, et al. Clin Ther. 200426805-818.
37
Next Steps
Case 2
48-year-old Latina/Hispanic woman with a 10-year
history of T2DM A1c 8.0 despite lifestyle,
metformin, and glyburide BMI 36.7 kg/m²

• AACE/ACE diabetes algorithm for glycemic control
• Efficacy and safety of GLP-1 receptor agonists

38
American Association of Clinical
Endocrinologists/American College of Endocrinology
Rodbard HW, et al. Endocr Pract. 200915540-559.
39
Sustained A1c Reduction and Weight Loss Over 3
Years With Exenatide
Change in Body Weight (lb)
Change in A1c ()
Baseline A1c 8.2 0.1
Baseline Weight 219 lb
10
0
9
-3.5 0.4 lb
-2

-1.0
0.1

-1.1
0.1
8
A1c ()
Weight (l b)
-6
7
-11.7 0.9 lb
6
-10
5
-14
4
0
26
52
78
104
130
156
0
26
52
78
104
130
156
Treatment (weeks)
Treatment (weeks)
N 217 Mean SE Klonoff DC, et al. Curr Med
Res Opin. 200824275-286.
40
Effect of Liraglutide Monotherapy on Weight
Time (weeks)
6
2
4
8
10
12
14
0
0
1.0
3.0
Weight Reduction From Baseline (lb)
0.65 mg/day
5.0
1.25 mg/day
1.90 mg/day

Placebo
P lt .05 vs placebo
7.0
Data are means Vilsbøll T, et al. Diabetes Care.
2007301608-1610.
41
Only GLP-1 Receptor Agonists Mimic 5 Key Actions
of a Pharmacologic Dose of Continuously Infused
GLP-1
Organ Type 2 Diabetes Defecta Effect Effect
Organ Type 2 Diabetes Defecta Continuously Infused GLP-1a,b GLP-1 Receptor Agonistb-f
insulin production
first-phase insulin response
a. Aronoff SL, et al. Diabetes Spectrum.
200417183-190. b. Nielsen LL, et al. Regul
Pept. 200411777-88. c. Fehse F, et al. J Clin
Endocrinol Metab. 2005905991-5997. d.
Kolterman OG, et al. J Clin Endocrinol Metab.
2003883082-3089. e. Maekawa F, et al. J
Neuroendocrinol. 200618748-756. f. Rachman J,
et al. Diabetes. 1996451524-1530.
42
Only GLP-1 Receptor Agonists Mimic 5 Key Actions
of a Pharmacologic Dose of Continuously Infused
GLP-1 (cont)
Organ Type 2 Diabetes Defecta Effect Effect
Organ Type 2 Diabetes Defecta Continuously Infused GLP-1a,b GLP-1 Receptor Agonistb-f
glucagon glucose output
gastric emptying
food intake

This effect is postulated to be mediated through
the central nervous system a. Aronoff SL, et al.
Diabetes Spectrum. 200417183-190. b. Nielsen
LL, et al. Regul Pept. 200411777-88. c. Fehse
F, et al. J Clin Endocrinol Metab.
2005905991-5997. d. Kolterman OG, et al. J
Clin Endocrinol Metab. 2003883082-3089. e.
Maekawa F, et al. J Neuroendocrinol.
200618748-756. f. Rachman J, et al. Diabetes.
1996451524-1530.
43
Side Effects Nausea

• With GLP-1 receptor agonists, food will stay in
  stomach longer, creating a sense of fullness.
• Patients need to understand that their bodies are
  adapting to the new physiology.
• Eating smaller portions of food can help reduce
  the likelihood of nausea/vomiting.

44
Incidence of Pancreatitis in Persons With or
Without Diabetes
Patients Without Diabetes

• Recent estimates of the incidence of pancreatitis
  in the general US population are as follows
• 0.33-0.44 events/1000 adults/yeara
• Severe disease develops in 15-20 of those
  pancreatitis casesb,c
• Death occurs in 2-4 of casesb,c
• Drug-induced pancreatitis is a relatively rare
  event (1.4-2.0 of all cases)c

a. Frey CF, et al. Pancreas. 200633336-344. b.
Forsmark CE, et al. Gastroenterology.
20071322022-2044. c. Frossard JL, et al.
Lancet. 2008371143-152.
45
Incidence of Pancreatitis in Persons With or
Without Diabetes (cont)
Patients With T2DM

• A recent epidemiologic study has reported that
  patients with T2DM are at nearly 3 times the risk
  of developing pancreatitis than those without
  diabetes.

Noel RA, et al. Diabetes Care. 200932834-838.
46
GLP-1 Receptor Agonists vs DPP-4 Inhibitorsa
Action Injectable GLP-1 Receptor Agonist Oral DPP-4 Inhibitor
Insulin secretion Enhancedb Enhanced
Glucagon secretion Suppressedb Suppressed
Postprandial hyperglycemia Reducedb Reduced
Gastric emptying Slowed significantlyb No effect
Appetite Suppressedb No effect
Satiety Inducedb No effect
Body weight Reduced Neutral
Beta-cell function Preservation proinsulin/insulin ratio improved clinically Preservation proinsulin/insulin ratio improved clinically
Exenatide had a greater effect than sitagliptin
in these parameters. a. Triplitt CL, et al. J
Manag Care Pharm. 200713(suppl)S2-S16. b.
DeFronzo, RA, et al. Curr Med Res Opin.
2008242943-2952.
47
Questions Answers
48
Challenges in the Managementof T2DM -- Exploring
the Role of GLP-1 Receptor Agonists Central
Region
49
Concluding Remarks
50
Concluding Remarks

• T2DM is a devastating disease, but it does not
  have to be it is controllable.
• GLP-1 agonists are effective drugs.

51
Summary T2DM Is 2 Diseases

• Microvascular complications
• Macrovascular complications
• Two distinct pathogenic sequences
• Two distinct clinical presentations

52
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