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

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

Frank Svec, MD, PhDClinical Professor of MedicineTulane University School of MedicineNew Orleans, Louisiana

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

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

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%

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

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%

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

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 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

Polling Question #1 Results

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

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

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

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

• 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

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.

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

Durability of Exenatide: Weight

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

Case 1

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%

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

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*

American Association of Clinical Endocrinologists/American College of Endocrinology

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

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.

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

Polling Question #2 Results

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

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

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.

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

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

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)

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

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

Effects of Exenatide in Sulfonylurea-Treated Patients: Weight

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

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 Managementof 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

Thank you for participatingin this Regional CME activity.

Please take a few moments to read the brief assessment to help us assess the effectiveness of this medical education activity.

Thank you for participatingin this Regional CME activity.

To proceed to the online CME test, click on the Earn CME Credit link on this page.