Jaime A. Davidson, MDClinical Professor of MedicineDivision of EndocrinologyDiabetes and MetabolismUniversity of Texas Southwestern Medical CenterDallas, Texas

Kevan ChambersAnnouncerMedscape Diabetes & Endocrinology

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

Challenges in the Managementof T2DM -- Exploring the Role of GLP-1 Receptor Agonists: Central 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 improve the content of this and future educational programs.

Jaime A. Davidson, MDClinical Professor of MedicineDivision of EndocrinologyDiabetes and MetabolismUniversity of Texas Southwestern Medical CenterDallas, Texas

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

CDC. Available at: http://www.cdc.gov/diabetes/statistics Accessed July 6, 2010.

1994 1999

2008

Missing Data < 4.5%

4.5%-5.9% 6.0%-7.4%

7.5%-8.9% ≥ 9.0%

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.

Incidence of T2DM

• Approximately 20 million individuals with T2DM in the United States[a]

• Additional 4-5 million individuals with undiagnosed diabetes[a]

• 60 million individuals with prediabetes (ie, impaired glucose tolerance, impaired fasting glucose)[b]

Obesity Trends* Among US Adults

*Body mass index (BMI) ≥ 30 kg/m2, or about 30 lb overweight for 5’4” personCDC. Available at: http://www.cdc.gov/diabetes/statistics Accessed July 6, 2010.

1990 1999

2008

No Data

< 10% 10%-14% 15%-19%

20%-24% 25%-29% ≥ 30%

In your region, what percentage of your patients with diabetes are obese?

A. ≤ 25%

B. 26%-50%

C. 51%-75%

D. ≥ 76%

Narayan et al, JAMA, 2003

Estimated Lifetime Risk Developing Diabetes for US-Born Individuals (2000)

Narayan KM, et al. JAMA. 2003;290:1884-1890.

Initial PresentationCase 1

A1c = glycated hemoglobin; BP = blood pressure; HDL = high-density lipoprotein; LDL = low-density lipoprotein; TG = triglyceride

• 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

• 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

Case Presentations (cont)

• 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

Case 2

SCr = serum creatinine

• 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

YearProj

ecte

d Po

pula

tion

(mill

ions

)

*Other includes American Indian, Alaskan Native, Native Hawaiian, other Pacific Islander, and 2 or more races.

0

20

40

60

80

100

120

2000 2010 2020 2030 2040 2050

Other*AsianBlackLatinos

Fastest Growing US Ethnic Minority Groups

US Census Bureau. Available at: http://www.census.gov/ipc/www/usinterimproj Accessed July 6, 2010.

*Adjusted for age (20–44 years, 45–64 years, 65+ years), sex, education, poverty index ratio, abdominal obesity, health insurance coverage, time since last blood pressure reading, and diabetes treatment

Effect of Ethnicity on A1c: NHANES 1999-2002

Saydah S, et al. Ethn Dis. 2007;17:529-535.

Projected Diabetes Cases in Texas (2000-2040)

Obesity Increases Mortality Risk

Body Mass Index

Women

Rela

tive

Risk

for D

eath

Body Mass Index

2.42.22.01.81.61.41.21.00.80.6

Cardiovascular diseaseCancerAll other causes

3.23.02.82.62.42.22.01.81.61.41.21.00.80.6Re

lativ

e Ri

sk fo

r Dea

th

Men

Calle EE, et al. N Engl J Med. 1999;341:1097-1105.

<19–25 25–30 >30 <19–25 25–30 >30

Polling Question #1 Results

Rodgers G. Available at: http://www.nih.gov/news/radio/nov2009/20091110NDEP.htm Accessed July 6, 2010.

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.

a. Lee ET, et al. Diabetes Care. 2002;25:49-54.b. CDC. MMWR Morb Mortal Wkly Rep. 2004;53:941-944.c. AHRQ. Available at: http://www.ahrq.gov/research/diabdisp.htm Accessed July 6, 2010.

Ethnic Disparities

• Highest incidence of diabetes among American Indians[a]

• High incidence of diabetes among Hispanics, Mexican Americans, and blacks[b,c]

• Lowest incidence of diabetes among whites

a. Lotufo PA, et al. Arch Intern Med. 2001;161:242-247.b. NIDDK. Available at: http://diabetes.niddk.nih.gov/DM/PUBS/statistics/ Accessed July 6, 2010.

Diabetes and Cardiovascular Disease

• Increased incidence of atherosclerotic cardiovascular complications[a]

• Incidence of myocardial infarction and stroke increased[a]

• High cost of managing microvascular and macrovascular complications[b]

Challenges to Diabetes Care

• Complications among undiagnosed individuals with diabetes

• Cost of medication

• Patient difficulty in losing 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

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

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

AACE = American Association of Clinical Endocrinologists; ADA = American Diabetes Association

Glucose Control and Weight Management

a. Malone M. Ann Pharmacother. 2005;39:2046-2055. 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. 2008;31:173-175. f. Holman RR, et al. N Engl J Med. 2007;357:1716-1730.

Therapeutic Option A1c < 7% Weight Sulfonylurea[a,b]

TZD[c,d]

Insulin[e,f]

Glucose Control and Weight Management (cont)

a. Bristol-Myers Squibb Company. Glucophage® XR full prescribing information. 2008.b. Merck. Januvia® full prescribing information. 2007. c. Drucker DJ. J Clin Invest. 2007;117:24-32.

Therapeutic Option A1c < 7% Weight Metformin[a]

DPP-4 inhibitor[b]

GLP-1 receptor agonist[c]

Riedel AA, et al. Diabetes. 2006;55(suppl1):A132.

Lessons Seen in Managed Care Patients Treated Over 4 Years

A1c

(%)

Time (months)

(n=2373) (n=1590) (n=5453)

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

Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.American Diabetes Association. Diabetes Care. 2009;32(suppl1):S13-S61.

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 analogsDPP-4 inhibitorsSulfonylureas Thiazolidinediones

Metformin

MetforminThiazolidinediones

_

Pathophysiologic Approach to Treatment of T2DM

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

TZDs = thiazolidinediones

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 248-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

American Association of Clinical Endocrinologists/American College of Endocrinology

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

Baseline Weight: 219 lbChange in Body Weight (lb)Change in A1c (%)

0 26 52 78 104 130 1564

5

6

7

8

9

10

Treatment (weeks)

-1.00.1%-1.10.1%

0 26 52 78 104 130 156-14

-10

-6

-2

-11.7 ± 0.9 lb

Treatment (weeks)

-3.5 ± 0.4 lb

Baseline A1c: 8.2 ± 0.1%

0

Sustained A1c Reduction and Weight Loss Over 3 Years With Exenatide

N = 217; Mean ± SEKlonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.

A1c

(%)

Wei

ght (

l b)

Time (weeks)

–5.0

–3.0

–1.0

00 2 4 6 8 10 12 14

Wei

ght R

educ

tion

From

Bas

elin

e (lb

)

0.65 mg/day

1.25 mg/day

1.90 mg/day

Placebo **P < .05 vs placebo

–7.0

Effect of Liraglutide Monotherapy on Weight

Data are meansVilsbøll T, et al. Diabetes Care. 2007;30:1608-1610.

OrganType 2 Diabetes

Defect[a]

Effect

Continuously Infused GLP-1[a,b]

GLP-1 Receptor Agonist[b-f]

insulin production

first-phase insulin response

a. Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190. b. Nielsen LL, et al. Regul Pept. 2004;117:77-88. c. Fehse F, et al. J Clin Endocrinol Metab. 2005;90:5991-5997. d. Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:3082-3089. e. Maekawa F, et al. J Neuroendocrinol. 2006;18:748-756. f. Rachman J, et al. Diabetes. 1996;45:1524-1530.

Only GLP-1 Receptor Agonists Mimic 5 Key Actions of a Pharmacologic Dose of Continuously Infused GLP-1

OrganType 2 Diabetes

Defect[a]

Effect

Continuously Infused GLP-1[a,b]

GLP-1 Receptor Agonist[b-f]

glucagon; glucose output

gastric emptying

food intake *

Only GLP-1 Receptor Agonists Mimic 5 Key Actions of a Pharmacologic Dose of Continuously Infused GLP-1 (cont)

*This effect is postulated to be mediated through the central nervous systema. Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190. b. Nielsen LL, et al. Regul Pept. 2004;117:77-88. c. Fehse F, et al. J Clin Endocrinol Metab. 2005;90:5991-5997. d. Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:3082-3089. e. Maekawa F, et al. J Neuroendocrinol. 2006;18:748-756. f. Rachman J, et al. Diabetes. 1996;45:1524-1530.

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.

Incidence of Pancreatitis in Persons With or Without Diabetes

a. Frey CF, et al. Pancreas. 2006;33:336-344.b. Forsmark CE, et al. Gastroenterology. 2007;132:2022-2044.c. Frossard JL, et al. Lancet. 2008;371:143-152.

• Recent estimates of the incidence of pancreatitis in the general US population are as follows:

• 0.33-0.44 events/1000 adults/year[a] • Severe disease develops in 15% 20% of those ‑

pancreatitis cases[b,c]

• Death occurs in 2%-4% of cases[b,c]

• Drug-induced pancreatitis is a relatively rare event (1.4%-2.0% of all cases)[c]

Patients Without Diabetes

Incidence of Pancreatitis in Persons With or Without Diabetes (cont)

Noel RA, et al. Diabetes Care. 2009;32:834-838.

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

Patients With T2DM

GLP-1 Receptor Agonists vs DPP-4 Inhibitors[a]

ActionInjectable GLP-1 Receptor Agonist Oral DPP-4 Inhibitor

Insulin secretion Enhanced*[b] Enhanced

Glucagon secretion Suppressed*[b] Suppressed

Postprandialhyperglycemia Reduced*[b] Reduced

Gastric emptying Slowed significantly*[b] No effectAppetite Suppressed*[b] No effectSatiety Induced*[b] No effect

Body weight Reduced Neutral

Beta-cell functionPreservation; 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. 2007;13(suppl)S2-S16.b. DeFronzo, RA, et al. Curr Med Res Opin. 2008;24:2943-2952.

Questions & Answers

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

Concluding Remarks

Concluding Remarks

• T2DM is a devastating disease, but it does not have to be; it is controllable.

• GLP-1 agonists are effective drugs.

Summary: T2DM Is 2 Diseases

• Microvascular complications

• Macrovascular complications

• Two distinct pathogenic sequences

• Two distinct clinical presentations

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