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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.

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challenges in the management of t2dm exploring the role of glp 1 receptor agonists southern region
Challenges in the Managementof 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 region2
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
slide3

Frank Svec, MD, PhD

Clinical Professor of Medicine

Tulane University School of Medicine

New Orleans, Louisiana

slide4

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
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
Age-Adjusted Percentage of US Adults With Diagnosed Diabetes

1994

1999

2008

<4.5%

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.

incidence of t2dm
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
Obesity Trends* Among US Adults

1990

1999

2008

No Data

10–14%

15–19%

<10%

20–24%

25–29%

≥30%

*BMI ≥ 30 kg/m2, or about 30 lb overweight for 5’4” person.

Centers for Disease Control and Prevention. 2008.

in your region what percentage of your patients are obese
In your region, what percentage of your patients are obese?

A. ≤ 25%

B. 26%-50%

C. 51%-75%

D. ≥ 76%

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

Initial Presentation

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
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 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
t2dm epidemic and complications
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
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
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
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
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
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

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

exenatide sustained a1c reductions over 82 weeks

0.0

-0.5

Change in A1c (%)

-0.8% ± 0.1%

-1.0

-1.1% ± 0.1%

-1.5

0

10

20

30

40

50

60

70

80

90

Exenatide Sustained A1c Reductions Over 82 Weeks

Mean Baseline A1c

82-Week Completer

8.3%

82-Week ITT

8.4%

Open-label extension

Placebo-controlled

(All patients 10 mg BID)

Time (week)

Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.

82-wk completer, N = 314; 82-wk ITT, N = 551; Mean ±SE.

Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.

durability of exenatide weight
Durability of Exenatide: Weight

Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.

effects of glp 1 agonists on cardiovascular risk factors
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
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

Follow-up

Case 1

american diabetes association
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.

slide25

Lifestyle + MET + Intensive Insulin

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. 2009;32:193-203.

american association of clinical endocrinologists american college of endocrinology
American Association of Clinical Endocrinologists/American College of Endocrinology

Rodbard HW, et al. Endocr Pract. 2009;15:540-559.

slide27

Pathophysiologic Approach to Treatment of T2DM

Impaired Insulin Secretion

TZDs

GLP-1 analogues

DPP-4 inhibitors

Sulfonylureas

Metformin

Thiazolidinediones

Thiazolidinediones

Metformin

_

Hyperglycemia

Increased

Hepatic Glucose Production

Decreased Glucose

Uptake

DeFronzo RA. Diabetes. 2009;58:773-795.

consensus statements for t2dm
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.

glp 1 receptor agonists
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.

slide31

GLP-1 Actions in Peripheral Tissue

Heart

Neuroprotection

Brain

Appetite

Stomach

Stomach

Gastric

emptying

Cardioprotection

Cardiac output

GI Tract

GLP-1

_

Liver

Insulin secretion

β-cell neogenesis

β-cell apoptosis

Glucagon secretion

+

Glucose

production

Glucose

Uptake

Muscle

Drucker DJ. Cell Metab. 2006;3:153-165.

side effects glp 1 receptor agonists and dpp 4 inhibitors
Side Effects: GLP-1 Receptor Agonists and DPP-4 Inhibitors

Davidson JA. Cleve Clin J Med. 2009;76(suppl5):S28-S38.

side effects metformin and thiazolidinediones
Side Effects: Metformin and Thiazolidinediones

Seufert J, et al. Clin Ther. 2004;26:805-818.

next steps34
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
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. 2005;143:559-569.

slide36

Placebo BID

Exenatide 5 μg BID

Exenatide 10 μg BID

Change in A1c Seen With Exenatide in Phase 3 Clinical Trials

0.2

0.1

0.1

METa

MET + SFUc

SFUb

Change in A1c (%)

-0.4*

*

-0.5*

-0.6*

- 0.8

-0.8*

-0.8*

-0.9*

n

123 125 129

247 245 241

113 110 113

8.7 8.5 8.6

8.5 8.5 8.5

8.2 8.3 8.2

Baseline

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

slide37

Effects of Exenatide in Sulfonylurea-Treated Patients: Weight

Buse JB, et al. Diabetes Care. 2004;27:2628-2635.

follow up38
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

Follow-up

Case 2

medullary thyroid cancer and pancreatitis
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
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 region42

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

concluding remarks
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
Summary: T2DM Is 2 Diseases
  • Microvascular complications
  • Macrovascular complications
  • Two distinct pathogenic sequences
  • Two distinct clinical presentations
slide45

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slide46

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