A.%20Update%20on%20Type%202%20Diabetes

1
A. Update on Type 2 Diabetes
2
Natural History of Type 2 Diabetes
Post-meal glucose

300
IGT
Diabetes
Glucose (mg/dL)
Fasting glucose
100
-15
-10
-5
0
5
10
15
20
25
RelativeFunction ()
Insulin resistance
100
75
50
ß-cell
25
0
-15
-10
-5
0
5
10
15
20
25
Years of Diabetes
Adapted from International Diabetes Center
(Minneapolis, Minnesota).
3
Prevalence of Diabetes in the United States 2005
Estimates

• CDC estimates that 1 in 14 Americans, 20.8
  million, live with diabetes. Of these
• 14.6 million Americans have been diagnosed
• 6.2 million Americans do not know they have it

Centers for Disease Control and Prevention.
National diabetes fact sheet general information
and national estimates on diabetes in the United
States, 2005. Atlanta, GA U.S. Department of
Health and Human Services, Centers for Disease
Control and Prevention, 2005. Available at
http//www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf
.
4
The Prevalence of Obesity and Diabetes Continues
to Increase
The Prevalence of Obesity and Diabetes
Continues to Increase
Obesity
2004
1994
No Data
lt10
10-14
15-19
20-24
25
Obesity defined as BMI 30 or 30 lbs overweight
for 5'4" person
Behavioral Risk Factor Surveillance System,
Centers for Disease Control and Prevention.
Available at http//www.cdc.gov/nccdphp/dnpa/obes
ity/trend/maps/ and http//www.cdc.gov/diabetes/st
atistics/prev/state/. Accessed January 20, 2006.
5
Type 2 Diabetes Diagnostic Criteria

• American Diabetes Association (same since 1998)
• Symptoms of diabetes and non-fasting plasma
  glucose of 200 mg/dL
• OR
• By FPG (fasting plasma glucose) test
• Plasma glucose 126 mg/dL after 8h fast
• OR
• By OGTT (oral glucose tolerance test)
• Plasma glucose rises to at least 200 mg/dL 2
  hours after swallowing 75 g anhydrous glucose
  dissolved in water

American Diabetes Association. Diabetes Care.
200629S43-S48.
6
Pre-Diabetes Diagnosis

• High blood glucose (hyperglycemia) that does not
  meet diabetes diagnostic criteria
• Almost always precedes type 2 diabetes
• Criteria for diagnosis
• Impaired Fasting Glucose (IFG)
• FPG test of 100 to 125 mg/dL
• Impaired Glucose Tolerence (IGT)
• OGTT test of 2h plasma glucose 140 to 199 mg/dL

American Diabetes Association. Diabetes Care.
200629S43-S48.
7
Type 2 Diabetes

• American Diabetes Association (ADA) 2006
  classification
• Type 2 diabetes results from a progressive
  insulin secretory defect on the background of
  insulin resistance
• ADA 2006 diagnosis
• Fasting Plasma Glucose (FPG), or Fasting Blood
  Sugar (FBS), test is the preferred to diagnose
  diabetes in nonpregnant adults
• A1C (also known as glycosylated hemoglobin or
  HbA1c) test is not recommended for diagnosis

American Diabetes Association. Diabetes Care.
200629S43-S48.
8
B. 24h Glucose Monitoring
9
ADA Recommendations for Goals of Type 2 Diabetes
Treatment

• Measurements GOAL
• HbA1C () lt 7
• Preprandial capillary plasma glucose (mg/dL)
  90-130
• Peak postprandial plasma glucose (mg/dL) lt
  180
• Blood pressure (mmHg) lt 130/80
• LipidsLDL lt 100 mg/dLTriglycerides lt
  150 mg/dLHDL gt 40 mg/dL
• Key concepts
• A1C is primary target for glycemic control
• More stringent glycemic control (A1C lt 6.0) will
  lessen severe complications while increasing
  risks of hypoglycemia

American Diabetes Association. Diabetes Care.
200629S43-S48.
10
Lowering A1C Reduces Complications in Type 1 and
Type 2 Diabetes
Kumamoto
DCCT
UKPDS
A1C
Retinopathy Nephropathy Neuropathy Macrovascular
disease
? 69 ? 70 Significantly improved
? 63 ? 54 ? 60 ? 41
? 1721 ? 2433 ? 16
Not statistically significant DCCT Research
Group. N Engl J Med. 1993329977-986 Ohkubo Y
et al. Diabetes Res Clin Pract. 199528103-117
UKPDS Group. Lancet. 1998352837-853
11
Glycemic Control Reduces Long-Term Risk of
Macrovascular Complications
Nonfatal MI, Stroke, or Death from CVD
Any CV Outcome
42 risk reductionP 0.02
0.12
0.12
0.10
0.10
57 risk reductionP 0.02
0.08
0.08
Cumulative Incidence
0.06
0.06
0.04
0.04
0.02
0.02
0.00
0.00
4
0
2
6
8
10
12
14
16
18
20
0
2
4
6
8
10
16
12
14
18
20
Years Since Entry
Years Since Entry
No. at Risk Conventional 714 688 618 92 Intensive
705 683 629 113
721 694 637 96 705 686 640 118
DCCT-EDIC Study Research Group. N Engl J Med
20053532643-2653
12
Glycemic Control Reduces Long-Term Risk of
Macrovascular Complications
No. at Risk Conventional 714 688 618 92 Intensive
705 683 629 113
721 694 637 96 705 686 640 118
DCCT-EDIC Study Research Group. N Engl J Med
20053532643-2653
13
Continuous Blood Monitoring System

• DexCom STS Continuous Glucose Monitoring System
  (FDA approved 2006)
• Indicated for detecting trends and tracking
  patterns in adults
• Intended for patients at home and in health care
  facilities
• Adjunctive device to complement information
  obtained from standard home glucose monitoring
  devices
• Minimed Guardian RT Continuous Glucose
  Monitoring System (FDA approved 2005)
• Indicated for continuous or periodic monitoring
  of glucose in the fluid under the skin in adults
  to improve diabetes management
• Alerts if glucose falls below or rises above
  preset values
• Values intended to provide indication of when a
  finger stick may be required
• All therapy adjustments should be based on
  measurements from a home glucose monitor

FDA Centers for Devices Radiological Health.
http//www.fda.gov/cdrh
14
C. Incretin Biology Science
15
Incretin Hormones Human Physiology

• Nutrient ingestion stimulates gastrointestinal
  tract L-cells peptide hormone secretion in
  response to
• GLP-1 glucagon-like peptide-1
• GIP glucose-dependent insulinotropic polypeptide
• Incretins
• Modulate insulin and glucagon release from
  pancreatic islet cell
• Rapidly degraded by dipeptidyl peptidase 4
  (DPP-IV) into inactive metabolites
• Lowered plasma GLP-1 in patients with
  pre-diabetes and type 2 diabetes

Toft-Neilsen M, et al. J Clin Endocrinol Metab.
2001 86 3717-23.Deacon CF, et al. Diabetes
1995 44 1126-31.Drucker DJ. Gastroenterology.
2002 122 531-44.
16
Incretin Hormones Their Actions

• Acute
• Enhance glucose-dependent insulin secretion
• Suppress glucagon secretion
• Slow gastric emptying
• Subacute
• Increase transcription of proinsulin and
  biosynthesis of insulin
• Increase expression of Glut-2 and glucokinase
• Chronic
• Stimulate proliferation and neogenesis of ß-cells
  from precursor ductal cells and inhibits ß-cell
  apoptosis

Drucker DJ. Mol Endocrinol 2003 17
161-71. Farilla L, et al. Endocrinology 2002
143 4397-408.
17
GLP-1 in Type 2 Diabetes

• GLP-1 given a continuous subcutaneous infusion
  for 6 weeks resulted in
• Lowered fasting plasma glucose by 77 mg/dL and
  mean plasma glucose by 100 mg/dL
• Decreased A1C percentages by 1.3
• Decreased body weight by 2-3 kg

Zander M, et al. Lancet. 2000359824-830.
18
Strategies to Increase Incretin Hormone

• Subcutaneous infusion of GLP-1 and/or GIP
• Use pump to deliver incretin hormones
  continuously
• Long-acting GLP-1 agonists (Incretin Mimetics)
• Exenatide (FDA approved)
• Pramlintide (FDA approved)
• Liraglutide
• Blocking degradation of GLP-1 (DPP-4 Inhibitors)
• Sitagliptin (FDA submission)
• Vildagliptin (FDA submission)
• Saxagliptin

19
DPP-4 Inhibitors
Since DPP-4 rapidly breaks down GLP-1, DPP-4
inhibitors prolong the physiologic actions of
GLP-1
20
C. Incretin Biology Clinical Trials
21
Injected Incretin Mimetics Recently Approved
Therapies for Type 2 Diabetes

• Pramlintide (FDA approved 2005)
• Synthetic form of amylin, which is produced by
  pancreatic beta cells
• Injected at mealtimes lowers A1C modestly
• No hypoglycemia or weight gain
• Primary side effect is nausea, which tends to
  improve over time
• Pramlintide and insulin must be stored and
  injected separately
• Approved in type 2 diabetes for insulin-injecting
  patients not achieving A1C goals
• Exenatide (FDA approved 2005)
• Synthetic version of exendin-4, a hormone first
  isolated from lizard saliva
• Injected at mealtimes, lowers elevated blood
  glucose modestly primarily by increasing insulin
  secretion
• No increased risk of hypoglycemia unless
  treatment includes a sulfonylurea
• Primary side effect is nausea, which tends to
  improve over time
• Modest weight loss
• Approved in type 2 diabetes in patients not
  achieving A1C goals using metformin, a
  sulfonylurea, or a combination of metformin and a
  sulfonylurea

22
Effects of Exenatide on Insulin and Glucagon
Secretion
Kolterman OG, et al. J Clin Endocrinol Metab.
2003 883082-3089.
23
Effect of Exenatideon Post-Prandial Blood Glucose
Kolterman OG, et al. J Clin Endocrinol Metab.
2003 883082-3089.
24
Change in A1C seen in Exenatide in Phase 3
Clinical Trials
25
Change in Weight in Exenatide Phase 3 Clinical
Trials
26
Exenatide vs. Insulin Glargine as Add-on Therapy
for Type 2 Diabetes
Heine, R J, et al. Ann Intern Med.
2005143559-569.
27
Liraglutide (NN2211)

• Compared with native GLP-1
• Has prolonged half-life of 11-15 hours
• Phase 2 clinical trials
• Insulin secretion increased
• Post-prandial glucagon secretion suppressed
• A1C decreased by 0.7-0.8
• Weight loss of 0.7 1.2 kg

Madsbad S, et al. Diabetes Care 2004 27
1335-42. Harder H, et al. Diabet Care 2004 27
1915-21.
28
Liraglutide (NN2211) vs Placebo

• Dose finding study in patients with diabetes
• 165 patients with diet-controlled type 2 diabetes
  and baseline A1C 8.1-8.5
• Liraglutide 0.65, 1.25, 1.9 mg Sub-Q daily vs.
  placebo for 14 weeks
• Fasting plasma glucose ? 16.7 mg/dL (plt0.001)
• A1C ? 1.74 (mean improvement in 3 groups,
  plt0.001)
• Reaching A1C lt 7 were
• 43 - 50 of patients taking liraglutide
• 8 of patients taking placebo
• Weight change -3 kg vs. 1.2 kg (p0.039)
• GI side effects were most common, highest
  incidence was diarrhea (19.5) and nausea (10)

Vilsboll T, et al. ADA 2006 Annual Meeting,
Abstract 115-OR
29
Sitagliptin (MK-0431)-Pioglitazone vs
Placebo-Pioglitazone in Patients with Type 2
Diabetes

• Patients
• All treated with pioglitazone (30-50 mg/day)
• Baseline A1C, 7-10
• First 24 weeks of treatment
• Sitagliptin 100 mg/day given to 353 patients
• Results in sitagliptin-pioglitazone patients
• Fasting plasma glucose ? 16.7 mg/dL (plt0.001)
• A1C ? 0.85 (plt0.001)
• 45 of patients reached A1C lt 7 vs. 23 taking
  placebo
• No change in weight
• Slightly greater percent had hypoglycemia or any
  GI adverse event

Rosenstock J, et al. ADA 2006 Annual Meeting,
Abstract 556-P
30
Sitagliptin-Metformin vs Glipizide-Metformin
Stein P. ADA 2006 Annual Meeting.
31
Sitagliptin vs Glipizide-Metformin
Stein P. ADA 2006 Annual Meeting.
32
Vildagliptin (LAF237)

• Oral selective DDP-IV inhibitor
• Like sitagliptin
• Prolonged half life
• Can be administered once daily
• In rat models
• Increased beta cell mass
• Enhanced endogenous incretin activity
• Phase 2 clinical trials
• Tested vildagliptin add-on therapy in patients
  treated with metformin, or with pioglitazone
• Reduces fasting BG
• Reduces post-prandial BG and glucagon
• No change to 24-hour insulin secretion

American Diabetes Association 2005 Annual
Meeting, Abstracts 572-P and 2192-PO Ahrén B,
et al. Diabetes Care 2004 27 2874-80. Ahrén B,
et al. J Clin Endocrinol Metab 2004 89 2078-84.
33
Vildagliptin vs. Placebo in Patients with Type 2
Diabetes Taking Metformin
Hemoglobin A1C ()
Ahrén B, et al. Diabetes Care 2004 27 2874-80.
34
Vildagliptin (LAF237) Monotherapy

• Clinical trials with treatment naïve patients
  with type 2 diabetes
• Randomized, blinded 52 week study in 780 patients
  with mean baseline A1C 8.7
• Vildagliptin 50mg BID vs. metformin 1000mg BID
• Results
• A1C ? 1.0 vs. 1.4 (statistically identical)
• Weight change 0.3 kg vs. -1.9 kg
• Incidence of GI side effects lower (22 vs. 44)
  including diarrhea and abdominal pain
• Mild hypoglycemia lt1 in both groups

Dejager S, et al. ADA 2006 Annual Meeting,
Abstract 120-OR
35
Vildagliptin Superior GI Tolerability
36
Vildagliptin (LAF237) vs Rosiglitazone

• Monotherapy in treatment-naïve patients with type
  2 diabetes
• 697 patients and mean baseline A1C 8.7
• Randomized, blinded 24 week study
• Vildagliptin 50mg BID vs. rosiglitazone 8mg daily
• A1C ? 1.1 vs. 1.2 (non-inferior difference)
• Weight change -0.3 kg vs. 1.6 kg
• Changes in lipids compared to rosiglitazone TG ?
  9, LDL ? 16, and Total ? -14 but smaller HDL ?
• Incidence of LE edema was lower (2.5 vs. 4.9)
• Mild hypoglycemia lt1 in both groups

Rosenstock J, et al. ADA 2006 Annual Meeting,
Abstract 557-P
37
Vildagliptin (LAF237)

• Add on therapy to insulin
• 256 patients with type 2 diabetes
• Insulin injection gt 30 units/day)
• baseline A1C 7.5 - 11
• Randomized, blinded 24 week study
• Vildagliptin 50mg BID vs. placebo
• Baseline insulin dose ? 80 units/day
• A1C ? 0.5 vs. 0.2 (p0.022)
• Hypoglycemia was less frequent (33 vs. 45
  patients) and less severe (0 vs. 6 severe events)

Fonseca V, et al. ADA 2006 Annual Meeting,
Abstract 467-P
38
Sitagliptin (MK-0431)

• A competitive, reversible DDP-IV inhibitor
• In healthy volunteers
• Single 100mg dose or 50mg daily provides gt80
  inhibition of DDP-IV activity for 24 hrs
• Increased GLP-1 plasma levels 2-fold
• Well tolerated - did not cause hypoglycemia
• Half life of 8-14 hours
• Primarily eliminated unchanged in the urine

Herman GA, et al. Clin Pharmacol Ther 2005 78
675-88. Bergman A, et al. Clin Therapeutics 2006
28 55-72.
39
Sitagliptin (MK-0431)

• Monotherapy
• 741 patients with type 2 diabetes (diet
  controlled) and baseline A1C 7-10
• Sitagliptin 100mg or 200mg daily vs. placebo for
  24 wks
• Fasting plasma glucose ? 17.1 to 21.3 mg/dL
  (plt0.001)
• A1C ? 0.79 to 0.94 (plt0.001)
• Post-meal insulin and C-peptide AUC significantly
  ?
• No clinically important change in weight over
  time
• No difference in the percent who experienced
  hypoglycemia or any GI adverse event

Aschner P, et al. ADA 2006 Annual Meeting,
Abstract 1995-PO
40
Sitagliptin (MK-0431)

• Add on therapy to metformin
• 701 patients with DM type 2 on metformin ?1500mg
  daily and baseline A1C 7 -10
• Sitagliptin 100mg daily vs. placebo for 24 weeks
• Fasting plasma glucose ? 16.9 mg/dL (plt0.001)
• A1C ? 0.67 (plt0.001)
• 47 of patient reached A1C lt 7 vs. 18 on
  placebo
• No additional weight loss over time
• No difference in the percent who experienced
  hypoglycemia or any GI adverse event

Karasik A, et al. ADA 2006 Annual Meeting,
Abstract 501-P
41
D. Gaps/Obstacles in Type 2 Diabetes Therapies
and Treatment Options
42
Classes of Therapies for Type 2 Diabetes

• Insulin and insulin analogues
• Insulin secretagogues
• Biguanides
• Alpha-glucosidase inhibitors
• Thiazolidinediones
• Incretin mimetics
• Dipeptidyl Peptidase (DPP)-4 inhibitors
• FDA approval requested for sitagliptin and
  vildagliptin

43
Recommendations for Treatment of Type 2 Diabetes

• Patients need to achieve glycemic control
• Patients need to be counseled on lifestyle
  changes by exercise and weight loss through
  dietary changes and calorie restriction
• Blood AIC should be measured
• Biannually in stable patients meeting glycemic
  goals
• Quarterly in patients not meeting glycemic goals
  or whose therapy has changed

American Diabetes Association. Diabetes Care.
200629S43-S48.
44
Consequences of Antihyperglycemic Therapy Use

• Patients frequently
• Gain weight
• Have increased risk of hypoglycemia especially
  when treated with insulin and insulin
  secretagogue
• Have inadequately controlled postprandial
  hyperglycemia
• Have wide glycemic fluctuations
• Lack long-term glycemic control
• Do not understand the importance of
• Rigorous adherence to diet and exercise programs
• Frequent blood glucose monitoring

45
Weight Management

• Overweight and obesity
• Strongly linked to the development of type 2
  diabetes
• Can complicate management of type 2 diabetes
• Independent risk factor for hypertension,
  dyslipidemia, cardiovascular disease
• Moderate weight loss
• Improves glycemic control
• Reduces CVD risk
• Can prevent the development of type 2 diabetes
• Primary approach for achieving weight loss
• Reduction in energy intake and an increase in
  physical activity (therapeutic lifestyle change)
• Decrease of 500 1,000 kcal/day will result in
  weight loss of 12 lb/week

American Diabetes Association. Diabetes Care.
200629S43-S48
46
Prevention or Delay of Type 2 Diabetes

• ADA recommendations for patients with impaired
  glucose tolerance (IGT). They
• Need to be taught benefits of modest weight loss
  and regular physical exercise
• Need follow-up counseling
• Need to be monitored for development of type 2
  diabetes
• Need to be counseled to lower risk of
  cardiovascular disease by being treated for
  hypertension, dyslipidemia and stopping smoking
• Should not be routinely treated with diabetes
  drugs until more information is known about
  cost-effectiveness

American Diabetes Association. Diabetes Care.
200629S43-S48.
47
Diabetes Strategies to Achieve Optimal Glycemic
Control

• Development and progression of complications can
  be delayed by treating patients with type 2
  diabetes for
• Obesity
• Glycemic control
• Hypertension and dyslipidemia
• Most patients with diabetes do not achieve
  treatment goals.
• While conventional treatments work well in some
  patients, in others they are associated with
  unmet needs including
• Weight gain
• Postprandial hyperglycemia
• Hypoglycemia
• Progressive loss of glycemic control and ß-cell
  function and mass
• Newer therapies may help more patients achieve
  treatment goals