Gaylord National Resort

1
2008
Symposia Series 1

• Gaylord National Resort Convention Center
• National Harbor, Maryland
• April 12, 2008

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Incretin Therapy Where Does It Fit in the
Management of Type 2 Diabetes?

• Charles F. Shaefer, Jr, MD
• Assistant Clinical Professor of Medicine
• Medical College of Georgia
• Augusta, Georgia

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How likely are you to prescribe an incretin
mimetic for a patient with type 2 diabetes who
is not at goal on oral medications?

1. Very likely
2. Likely
3. Somewhat likely
4. Not likely

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Faculty Disclosure

• Dr Shaefer consultant Pfizer Inc,
  sanofi-aventis speakers bureau Daiichi Sankyo,
  Inc., Forest Pharmaceuticals, Inc., Pfizer Inc,
  sanofi-aventis, Takeda Pharmaceuticals, Inc.

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Learning Objectives

• State the rationale for aggressive stepwise
  therapy for patients with type 2 diabetes
• Explain the mechanism of action and role of new
  therapies for type 2 diabetes used alone and in
  combination with conventional therapies
• Design a plan for optimizing therapy to achieve
  treatment goals for individual patients

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Diabetes Demographics in the United States
Population Aged 20 Years
Physician-Diagnosed Diabetes () Physician-Diagnosed Diabetes () Undiagnosed Diabetes () Undiagnosed Diabetes ()
Physician-Diagnosed Diabetes () Physician-Diagnosed Diabetes () Undiagnosed Diabetes () Undiagnosed Diabetes ()
1988-1994 2001-2004 1988-1994 2001-2004
Male 5.4 7.6 3.5 4.3
Female 5.4 7.1 2.6 1.8
White 5.0 6.2 2.6 2.8
Black 8.6 11.4 4.2 3.1
Mexican 9.7 11.8 4.7 3.3
Total 5.4 7.3 3.0 3.0
Adapted from National Center for Health
Statistics. Health, United States, 2006. With
Chartbook on Trends in the Health of Americans.
Hyattsville, Md 2006.
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Obesity Trends Among Adults in the United States

• BRFSS 1990, 1998, 2006(BMI ?30, or about 30 lb
  overweight for 54 person)

1990
1998
2006
No data lt10 10-14 15-19
20-24 25-29 30

• BMI body mass index BRFSS Behavioral Risk
  Factor Surveillance System.

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Estimated 2007 Direct and Indirect Costs of
Diabetes in the United States
Cost of Diabetes in Billions Total 174 Billion
Indirect 58 Billion ? Absenteeism ?
Productivity Unemployment due to disability ?
Productivity due to early mortality
Direct 116 Billion Diabetes care DM
complications Excess general medical costs

• Increase of 42 billion (32) over 2002
• In 2007, 1 of every 5 healthcare dollars spent on
  a person diagnosed with diabetes
• In 2007, 1 of every 10 healthcare dollars spent
  on diabetes

DM diabetes mellitus. ADA. Diabetes Care.
2008311-20.
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Natural History of Type 2 Diabetes
Insulin Resistance
Progressive b-cell Dysfunction
Microvascular Complications
Macrovascular Complications
Stratton IM, et al. BMJ. 2000321405-412.
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Proposed A1C Targets

Optimal Target A1C lt6 (normal range)
Organization A1C Target ()
AACE lt6.5
EASD lt6.5
ADA lt7 (general) lt6 (individual patient)
As close to normal (lt6) without significant
hypoglycemia. Prospective data on A1C and
macrovascular disease are less conclusive than on
AIC and microvascular disease. A1C
glycosylated hemoglobin AACE American
Association of Clinical Endocrinologists ADA
American Diabetes Association EASD European
Association for the Study of Diabetes.
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ACCORD Interim Results (Feb 6, 2008 NHLBI
Press Release)

• Baseline 10,251 patients mean age 62 years
  disease duration 10 years A1C 8.2
• Known CHD or at least 2 additional risk factors
• At 4 years of follow-up intensive vs standard
  Rx
• Achieved median A1C 6.45 vs 7.5
• Total deaths 257 vs 203
• Deaths per 1000 patient-years 14 vs 11
• 10 fewer nonfatal CV events, but more often
  fatal or sudden death
• Higher death rate not due to hypoglycemia or any
  drug
• single or combination therapy
• Discontinued intensive Rx arm of study as of Feb
  6, 2008

ACCORD Action to Control Cardiovascular Risk in
Diabetes CHD coronary heart disease CV
cardiovascular.
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ADVANCE Interim Results (February, 2008 The
George Institute for International Health Press
Release)

• Interim results based on glucose control levels
  (lt6.5) similar to those in ACCORD
• N 11,140 5-year average follow-up
• The interim results from ADVANCE provide no
  confirmation of the adverse mortality trend
  reported from the ACCORD study
• Doctors and patients should feel
  reassuredhowever, we need to await more
  definitive analyses and reports from both studies
  before drawing final conclusions

ADVANCE Action in Diabetes and Vascular Disease
preterAx and diamicroN-MR Controlled Evaluation
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STENO2 Effect of Intensive Multifactorial
Intervention on Number of CV Events (13.3-year
mean follow-up)
Total Mortality on Intensive Rx Reduced by 46
Number of CV Events
Death FromCV Causes
Stroke
MyocardialInfarction
CABG
PCI
Revascu-larization
Amputation
CABG coronary artery bypass graft PCI
percutaneous coronary intervention. Gaede P, et
al. N Engl J Med. 2008358580-591.
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No A1C Threshold in Type 2 Diabetes
Epidemiologic Data From the UKPDS
80
Myocardial infarction
Microvascular end points
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AACE Goal
Adjusted Incidence per 1000 Person-Years ()
40
20
?
0
5
6
7
8
9
10
11
Updated Mean A1C ()
UKPDS United Kingdom Prospective Diabetes
Study. Stratton IM, et al. BMJ. 2000321405-412.
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CV Risk Factor Control in Adults With Diabetes
NHANES III (1988-1994)/NHANES 1999-2000
NHANES III, n 1204
NHANES 1999-2000, n 370
48.2
50
P lt.001
44.3
40
37.0
35.8
33.9
29.0
30
Patients ()
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10
7.3
5.2
0
A1C lt7
BP lt130/80 mm Hg
TC lt200 mg/dL
Good control
Achieved all 3 indicated goals. BP blood
pressure NHANES National Health and Nutrition
Examination Survey TC total cholesterol.
Saydah SH, et al. JAMA. 2004291335-342.
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Standards of Medical Care in Type 2 Diabetes
2008 ADA Glycemia Goals

• A1C lt7
• Preprandial glucose 70-130 mg/dL
• Postprandial glucose (PPG) lt180 mg/dL
• At diagnosis metformin and lifestyle changes
• Add therapy to reach A1C of lt7
• Add therapy to maintain A1C of lt7
• Target PPG if A1C goals are unmet, despite
  reaching preprandial glucose

ADA. Diabetes Care. 200831(Suppl1)S12-S54
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ADA/EASD Consensus Algorithm for Type 2 Diabetes
Diagnosis
Lifestyle Intervention MET
Add Glitazone (no hypoglycemia)
Add SFU (least expensive)
Add Basal Insulin (most effective)
Intensify Insulin
Add Glitazone
Add Basal Insulin
Add SFU
Add Basal or Intensify Insulin
Intensive Insulin MET /- Glitazone
Check A1C every 3 months until lt7 and then at
least every 6 months. Although 3 oral agents
can be used, initiation and intensification of
insulin therapy is preferred based on
effectiveness and expense.1. Nathan DM, et al.
Diabetes Care. 2006291963-1972. 2. ADA.
Diabetes Care. 200831S12-S54
MET metformin
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Standards of Medical Care in Type 2 Diabetes
2008 ADA Weight Recommendations

• Weight loss is an important therapeutic
  objective1
• 85 of patients with type 2 diabetes are
  overweight/obese2
• Lifestyle measures (physical activity, behavior
  modification) are important1
• Moderate weight loss (5 in short-term studies)
  is associated with benefits1
• Decreased insulin resistance
• Improvement in glycemia, lipemia
• Reduced blood pressure
• It is important to control body weight to reduce
  risks related to diabetes1
• Sustained weight loss is difficult1

1. ADA. Diabetes Care. 200831(Suppl1)S20-S21
2. NHANES 1999-2002.
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NHANES data from 2008 now indicate better
control of diabetes with respect to

1. A1C
2. Complications from diabetes
3. FPG
4. Weight control

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New NHANES Data Indicate an Encouraging Trend

• Mean A1C among persons diagnosed with diabetes
• 1999-2000 7.82
• 2001-2002 7.47
• 2003-2004 7.18
• Compared with 1999-2000, A1C levels were
• 0.308 (P .20) lower in 2001-2002
• 0.511 (P .03) lower in 2003-2004
• This trend is encouraging for future reduction
  of diabetes-related complications

Hoerger TJ, et al. Diabetes Care. 20083181-86.
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For overweight patients whose A1C is not
adequately controlled with 2 OADs, what is your
usual recommendation?

1. Addition of a third OAD
2. Substitution of 1 of the OADs with another oral
   agent
3. Immediate switch to insulin plus 1 or 2 OADs
4. Consideration of a non-insulin injectable agent

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OAD oral anti-diabetics.
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Change in A1C With Addition of a TZD in Diabetes
Poorly Controlled With SFU MET
Placebo/troglitazone
Troglitazone/troglitazone
14
0.10
13
0.095
12
0.09
11
Fasting Plasma Glucose Level ( mmol/L)
A1C Level
0.085
10
0. 08
9
Double-Blind
Open-Label
Double-Blind
Open-Label
0
0
0
12
16
20
24
36
48
0
12
16
20
24
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Duration of Study (week)
Duration of Study (week)
TZD thiazolidinedione. Yale JF, et al. Ann
Intern Med. 2001.134737-745.
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Case Study
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A Middle-Aged Woman Finds A1C Control to Be a
Challenge

• 58-year-old African-American woman diagnosed 6
  months ago with type 2 diabetes reports periodic
  episodes of light-headedness, racing heart, and
  nervousnesstypical symptoms of hypoglycemia.
• Physical examination
• Blood pressure 126/74 mm Hg
• Weight 174 lb height 5 ft 4 in BMI 29.9
  kg/m2
• Laboratory results
• A1C 7.8
• Creatinine 0.8 mg
• Serum lipids (mg/dL) LDL 142 HDL 51 TG 170
• Urinalysis and liver function tests are normal
• No evidence of retinopathy or neuropathy no
  history of cardiac symptoms

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A Middle-Aged Woman Finds A1C Control to Be a
Challenge (contd)

• Current medications
• Losartan 50 mg daily
• Glipizide 10 mg twice daily
• Metformin 1000 mg twice daily
• Atorvastatin 10 mg daily

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Which factor(s) in this patients presentation
could be the cause of her episodes of
light-headedness?

1. Inadequate control of A1C
2. Skipping glucose monitoring
3. Hypoglycemia associated with use of an SFU
4. Lack of attention to dietary and behavioral
   measures recommended by diabetes educator

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SFU sulfonylurea.
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Targets for Glycemic Control
ADA ACE
A1C () Normal 4-6 lt7.0 ?6.5
Fasting/preprandial (mg/dL) 90-130 lt110
Postprandial (mg/dL) (2-hour) lt180 lt140
ACE. Consensus Conference on Diabetes Mellitus,
Aug 2001 ADA. Clinical practice recommendations.
Diabetes Care 2004 27(suppl 1)S11-S35.
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Management Shift

• The patient is maintained on metformin 1000 mg
  twice daily
• The diabetes educator begins an intensive
  education program focusing on dietary and
  behavioral change, emphasizing the importance of
  healthful choices and weight control, encouraging
  regular moderate exercise, and reinforcing the
  patients leading role in the diabetes management
  team
• With the diabetes educators guidance, the
  patient learns to use the glucometer with
  confidence and agrees to monitor her FPG 3 times
  a week

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DPP Benefit of Lifestyle Changes Weight Loss
4
2
Placebo
-0
Change in Weight(kg)
-2
MET
-4
Lifestyle
-6
-8
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Year
Year
DPP Diabetes Prevention Program. DPP Research
Group. N Engl J Med. 2002346393-403.
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3-Month Follow-up

• The patient reports no additional hypoglycemic
  episodes
• She records her FPG 3 times a week and takes her
  medications as prescribed
• Weight 174 lb (unchanged) despite dietary
  efforts
• Blood pressure 124/72 mm Hg
• FPG range 110-130 mg/dL
• A1C 7.4

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Next Steps

• Patient-clinician-diabetes educator
  communication has improved
• Patient has a better understanding of diabetes
  and has made substantial progress
• Importantly, however, her A1C is well above
  target despite therapy with an OAD
• The patient is distressed by her inability to
  reduce her weight and is resistant to any
  suggestion of a therapy that might increase her
  weight

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What is an appropriate next step for this
patient?

1. Add another OAD
2. Refer patient to a nutritionist and/or a personal
   trainer
3. Add an incretin mimetic
4. Add insulin

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Determinants of Glycemia in Diabetes
Plasma Glucose

• GI Tract
• Liver (HGO)

• Insulin

GLP-1 glucagon-like peptide-1 HGO hepatic
glucose output.
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GLP-1 Modulates Numerous Functions in Humans
GLP-1 Secreted upon the ingestion of food
Promotes satiety and reduces appetite
Alpha cells ? Postprandialglucagon secretion
Liver ? Glucagon reduces hepatic glucose output
Beta cellsEnhance glucose-dependent insulin
secretion and amylin secretion
Stomach Helps regulate gastric emptying
Drucker DJ. Diabetes. 199847159-169 Flint A,
et al. J Clin Invest. 1998101515-520. Larsson
H, et al. Acta Physiol Scand. 1997160413-422
Nauck MA, et al. Diabetologia. 1996391546-1553.
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Incretin Effect in Subjects Without and With
Type 2 Diabetes
Control Subjects (n 8)
Patients With Type 2 Diabetes (n 14)
Oral glucose load
Intravenous (IV) glucose infusion
The incretin effect is diminished in type 2
diabetes.
Incretin Effect
nmol/L
nmol / L
IR Insulin, mU/L
IR Insulin, mU/L
180
60
120
0
180
60
120
0
Time, min
Time, min
Nauck M, et al. Diabetologia. 19862946-52.
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The Beginning

• Exenatide
• Synthetic version of salivary protein found in
  the Gila monster
• More than 50 overlap with human GLP-1
• Binds to known human GLP-1 receptors on beta
  cells (in vitro)
• Resistant to DPP-4 inactivation
• Following injection, exenatide is measurable in
  plasma for up to 10 hours

Site of DPP-4 Inactivation
Kolterman OG, et al. Am J Health-Syst Pharm.
200562173-181 Nielsen LL, et al. Regul Pept.
200411777-88.
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Inhibition of DPP-4 Increases Active GLP-1
Meal
Intestinal GLP-1 release
Active GLP-1
DPP-4
GLP-1 inactive
DPP-4inhibitor
GLP-1 glucagon-like peptide1 DPP-4
dipeptidyl-peptidase4. Rothenberg P, et al.
Diabetes. 200049(suppl 1)A39.
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Exenatide Mimics Many Properties of GLP-1
GLP-1 Exenatide DPP-4 Inhibitor
?Glucose-dependent insulin secretion v v v
?Glucagon secretion?Hepatic glucose output v v v
Regulates gastric emptying?Rate of nutrient absorption v v Marginal
?Food intake v v No obvious effect
?Plasma glucose acutely to near-normal levels v v v
Resistant to DPP-4 degradation v
Duration in plasma following a subcutaneous (SC) injection Short Long
Drucker DJ, Nouck MA. Lancet. 20063681696-1705.
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Incretin System Offers Innovative Therapeutic
Approaches

• The observation that enteral nutrition was a more
  potent stimulus for insulin release than an
  isoglycemic IV challenge led to the incretin
  concept
• Incretins identified
• glucose-dependent insulinotropic polypeptide
  (GIP)
• GLP-1
• Plasma levels of GLP increase within minutes of
  eating
• Development of GLP-1 agonists to maintain
  incretin effect
• DPP-4 rapidly degrades GLP-1
• Development of specific protease inhibitors that
  prevent rapid fall of GLP-1

Drucker DJ. Diabetes Care. 2003262929-2940.
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Therapeutic Potential of the Incretin System

• GLP-1
• Short half-life (?2 minutes)
• Rapidly degraded by DPP-4
• DPP-4 inhibition
• Extends endogenous GLP-1 half-life
• Incretin mimetics
• Mimic many of the glucoregulatory effects of
  GLP-1
• May preserve ß-cell function
• Resistant to DPP-4
• GLP-1 analogs
• Exenatide

Drucker DJ. Diabetes Care. 2003262929-2940
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Next Step

• This patient is motivated to improve her A1C
  control and reduce her weight
• She remains anxious to avoid hypoglycemic
  episodes such as she experienced on SFU therapy
• She would prefer to avoid insulin, not because
  she is afraid of needles, but because she is
  aware from friends experience that people on
  insulin tend to get heavy fast

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What is an appropriate choice for the next step
in this patients care?

1. Long-acting insulin with continuation of 1 OAD
2. Trial of a GLP-1 agonist
3. Trial of a glitazone
4. Trial of a DPP-4 inhibitor

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43
GLP-1 Agonist Lowered A1C in Large Phase 3
Clinical Studies
Type 2 Diabetes
Placebo BID
5 µg Exenatide BID
10 µg Exenatide BID
SFU
MET SFU
MET
0.5
0.5
0.5
0.1
0.1
0
0
0

• A1C ()

-0.5
-0.5
-0.5
-0.4

- 0.8
-1
-1
-1

ITT N 1446 Mean SE P lt.005ITT
intention to treat. Buse JB, et al. Diabetes
Care. 2004272628-2635 DeFronzo RA, et al.
Diabetes Care. 2005281092-1100Kendall DM, et
al. Diabetes Care. 2005281083-1091.
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GLP-1 Agonist Helped Many Achieve A1C 7 Large
Phase 3 Clinical Studies
Type 2 Diabetes
Placebo (twice daily)
5 µg Exenatide (twice daily )
10 µg Exenatide (twice daily )
MET
MET SFU
SFU
60
60
60

46

40
40
40
32
Achieving A1C 7
20
20
20
13
0
0
0
Evaluable 30-week data N 1024 P lt.01Buse
JB, et al. Diabetes Care. 2004272628-2635
DeFronzo RA, et al. Diabetes Care.
2005281092-1100 Kendall DM, et al. Diabetes
Care. 2005281083-1091.
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Open-Label, Twice-Daily Exenatide vs Once-Daily
Insulin Glargine Self-Monitoring Blood Glucose
Profiles (n549)
Insulin Glargine10 U/d, titrated to target FPG
lt100 mg/dL
Exenatide5 µg BID 1st 4 weeks, then 10 µg BID
Both medications lowered A1C from 8.2 to 7.1
from baseline Weight change exenatide 2.3 kg,
glargine 1.8 kg Nausea exenatide 57.1,
glargine 8.6
Heine RJ, et al. Ann Intern Med. 2005143559-569.
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DPP-4 Efficacy Placebo-Subtracted A1C Reductions
in Combination Therapy Studies
Sitagliptin 100 mg Daily
Pioglitazone Combination
MET Combination
?65 Years
?65 Years
lt65 Years
lt65 Years
0
-0.2
Placebo-Subtracted Change in A1C ()
-0.4
-0.51
-0.6
-0.67
-0.67
-0.8
-0.78
-1.0
A1C glycosylated hemoglobin. Williams-Herman D,
et al. Presented at the 19th World Diabetes
Congress. 2006. Abstract 875.
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Exenatide versus Glargine in a 16-Week
Open-Label, Crossover Trial Patients Achieving
A1C 7 or 6.5
50
Exenatide 10 µg BID
Insulin glargine QD
40
40
38
30
of Patients
22
20
14
10
0
7
6.5
A1C ()
ITT population n 138 patients with baseline
A1Cgt7.
Barnett AH, et al. Clin Ther. 2007292333-2348.
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Weight Change Over Time Exenatide vs Insulin
Glargine
Crossover
Exenatide 10 µg BID
2
Insulin glargine QD
0
-2
? Weight (lb)
-4
-6
0
4
8
12
16
20
24
28
32
Time (week)
ITT population n 138 mean SE
Barnett AH, et al. Clin Ther. 2007292333-2348.
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Large Phase 3 Clinical Studies (ITT)Exenatide
Reduced Weight
? Weight (lb)
Placebo
Exenatide 5 µg BID
Exenatide 10 µg BID
SFU (N 377)
MET SFU (N 733)
MET (N 336)
0
10
20
30
0
10
20
30
0
10
20
30
0
-1

-2



-3



-4




-5

-6



-7
Time (week)
Mean (SE) 30-week data P lt.05 weight was a
secondary end point. Buse JB, et al. Diabetes
Care. 2004272626-2635 DeFronzo RA, et al.
Diabetes Care. 2005281092-110 Kendall DM, et
al. Diabetes Care. 2005281083-1091
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Follow-up After 3 Months on a GLP-1 Agonist

• A1C 6.6
• FPG 90-110 mg/dL
• Weight 157 lb BMI 26.9 kg/m2
• The patient is pleased her A1C is at target and
  her weight is dropping gradually due partly to
  her efforts at lifestyle changes and partly to
  the effects of the GLP-1 agonist
• She has had no additional hypoglycemic episodes
  and wants to continue her current therapy

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Importance of Postprandial Hyperglycemia
Meal
Meal
Meal
400
300
Diabetes
Glucose (mg/dL)
200
100
Without Diabetes
0600
1000
1400
1800
2200
0200
0600
Polonsky KS. N Engl J Med. 19883181231-1239.
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At Lower A1C Levels, PPG Contributes More to
Overall A1C Than FPG
Contribution ()
1
2
3
4
5
A1C Quintile
Monnier L et al. Diabetes Care. 200326881-885.
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Hypoglycemia Adverse EventsLarge Phase 3
Clinical Studies
Exenatide MET
Exenatide SFU
Exenatide MET SFU
PBO 5 µg 10 µg
12.6 19.2 27.8
247 245 241
PBO 5 µg 10 µg
3.3 14.4 35.7
123 125 129
PBO 5 µg 10 µg
5.3 4.5 5.3
113 110 113
Hypoglycemia
n

• No increased risk with exenatide MET vs placebo
• Higher risk in exenatide SFU-treated patients
• Consider reducing SFU dose
• Most episodes were mild to moderate in intensity

ITT 30-week data N 1446. Buse JB, et al.
Diabetes Care. 2004272628-2635 DeFronzo RA, et
al. Diabetes Care. 2005281092-1100 Exenatide
PI 2006 Kendall DM, et al. Diabetes Care.
2005281083-1091.
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After this explanation of the multihormonal
nature of diabetes, do you understand the
pathophysiologic rationale for treatment?

1. Much more clearly
2. Somewhat more clearly
3. As before
4. Less than before

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55
Information and Patient Education Links for
Healthcare Professionals

• American Association of Clinical Endocrinologists
  (www.aace.com)
• American Association of Diabetes Educators
  (www.diabeteseducator.org)
• American Diabetes Association (www.diabetes.org)
• International Diabetes Federation (www.idf.org)
• National Diabetes Education Initiative
  (www.ndei.org)
• National Diabetes Education Program
  (ndep.nih.gov)
• National Institute of Diabetes and Digestive and
  Kidney Diseases (www2.niddk.nih.gov)

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Q A
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PCE Takeaways
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PCE Takeaways

• Numerous hormones in addition to insulin
  contribute to glucose homeostasis
• Agents that mimic the effects of the incretin
  system offer the following benefits in patients
  with type 2 diabetes
• A1C control
• Postprandial glucose control
• Fasting glucose control
• Weight reduction with glucose control

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How comfortable are you now with initiating
incretin therapy in your patients with type 2
diabetes?

1. Very comfortable
2. Somewhat comfortable
3. Comfortable
4. Not at all comfortable

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60
2008
Symposia Series 1

• Gaylord National Resort Convention Center
• National Harbor, Maryland
• April 12, 2008

60
60