1. DIABETES MANAGEMENT 2006: INTEGRATING NEW MEDICINES AND NEW DEVICES
Robert B. Baron MD MS
Professor and Associate Dean
UCSF School of Medicine
Declaration of full disclosure: No conflict of interest

2. Diabetes Mellitus in the US: Health Impact of the Disease
6th leading cause of death
Renal failure*
Life expectancy
-5 to 10 yr
Blindness*
Diabetes
Cardiovascular disease 2x to 4x
Nerve damage in 60% to 70% of patients
Amputation*
*Diabetes is the no. 1 cause of renal failure, new blindness, and nontraumatic amputations

3. Diabetes Mellitus: U.S. Impact
16.7 Million (8.3%)
IFG
12.3 Million
(6.3%)
~1 Million Type 1
~16 Million Type 2
TOTAL:
29 Million
(14.4%)
1/3
Undiagnosed
(4.9 Million)
2/3
Diagnosed

4. Screening for Diabetes
ADA: >45, especially if BMI >25. <45 if overweight and have risk factor for DM (inactive, FH, high risk ethnicity, baby >9 lb, HTN, low HDL or high TG, PCOS, vascular disease). Screen with FPG or 2-h OGTT
Diabetes Care, 2006
USPSTF: Insufficient evidence to recommend for or against. However, recommend screening in adults with hypertension and lipid disorders
Ann Intern Med, 2003

5. Diagnosis of Diabetes Two measures of any of the following:
Random glucose: 200 mg/dl with symptoms (poly’s, weight loss)
Fasting glucose: 126 mg/dl
2-hr glucose: 200 mg/dl during OGTT
Diabetes Care 2006

6. HbA1C for Screening ?
HbA1c 2SD above mean has sensitivity of 66 % and specificity of 98 % and compares favorably to FPG
Different nondiabetic reference ranges due to different glycated hemoglobin fractions
Precision and accuracy may not be sufficient in all labs
Affected by hemoglobinopathies, anemia, transfusions, uremia, pregnancy

7. Diagnosis of Pre-Diabetes
Two measures of any of the following:
Fasting glucose mg/dl
2-hr glucose mg/dl during OGTT

8. DPP: % Developing DM After 3 Years
% developing Diabetes

9. Prevention of Type 2 DM: RCTs
Trial Description Results (RR)
Da Qing1 Diet &/or exercise 31 to 46%
Finnish Prevention
Study (FPS)2 Intensive lifestyle 58 %
Diabetes Prevention Meformin %
Program (DPP)3 Lifestyle 58 %
STOP- NIDDM4 Acarbose 25 %
TRIPOD5 Troglitazone %

10. Recommendations for Adults
Glycemic Control
A1C: <7.0
Preprandial: mg/dl
Postprandial: <180 mg/dl
Blood Pressure: <130/80 mmHg
Lipids
LDL: <100 mg/dl
TG: <150 mg/dl
HDL: >40 mg/dl
ADA Diabetes Care 2006

11. Treatment of Type 2 Diabetes
Step 1: Lifestyle Changes
Step 2: Oral Monotherapy
Step 3: Combination Oral Therapy
Step 4: Oral Therapy plus Insulin
Step 5: Insulin Alone
Step 6: Insulin plus Thiazolidinedione/Metformin
Target metabolic values need to be individualized

12. Attaining Glycemic Goals Using Monotherapy in Obese Patients With Type 2 Diabetes
Turner RC et al. JAMA. 1999;281:

13. Treatment of Type 2 Diabetes Improved Glycemic Control
Delay
digestion of
carbohydrates
Acarbose/
Miglitol
SFUs/Insulin
Metformin
Decrease
Hepatic
Glucose
Output
Improved Glycemic Control
Increase
Insulin
Secretion
Decrease
insulin
resistance
Thiazolidinediones

14. Generic Oral Hypoglycemic Slide
Change from Drug A to B, C, or D
Add Drug A to B, or B to A
HgA1c
Add Drug C
Add Drug D
Time

15. Adding Instead of Switching
Continue glyburide
Switch to metformin 1
Glyburide+ metformin
+0.2% –
0.4% * * * * – 1
Change in Mean HbA1c (%) –
1.7% – 2 – 3 9 13 17 21 25 29
Treatment (wk)
DeFronzo, et al. N Engl J Med. 1995;333: ,
5-2

16. Oral Agent “Failure” Why does this occur?
Changing HbA1c goals
Compliance, side effects
Wrong diagnosis (LADA--latent autoimmune diabetes in adults 10%)
Stress, diabetogenic medications
Natural progression of the disease

17. Natural History of Type 2 Diabetes
Obesity IFG* Diabetes Uncontrolled hyperglycemia
350
Post-meal Glucose
300
250
Glucose
(mg/dL)
200
Fasting Glucose
150
100 50
250
200
Insulin Resistance
Relative Function
(%)
150
100
Insulin Level` 50
Beta-cell failure
-10 -5 5 10 15 20 25 30
Years of Diabetes
*IFG = impaired fasting glucose

18. Natural History of Type 2 Diabetes
Thiazolidinedione - Biguanide
Lifestyle
Insulin SU
350
Post-meal
Glucose
300
Glucose
(mg/dL)
250
Fasting Glucose
200
150
100 50
250
200
Relative Function
(%)
Insulin Resistance
150
100
Insulin Level 50
Beta-cell failure
-10 -5 5 10 15 20 25 30
Years of Diabetes

19. Insulin Plus Oral Agents
Introduction of insulin
Bedtime
Intermediate/Long-acting insulins
NPH, UL, glargine
10 units
Self-monitoring of blood glucose (hypoglycemia education)
Insulin plus other oral agent combinations (maintain effect on insulin sensitivity)

20. When to go to > 1 shot per day
HgA1c >7
Glucose in AM at goal but g lucose before dinner >140
Options
Add premeal lispro/aspart
Add bid premixed insulin – 70/30, 75/25
Questions
Continue metformin
? Sulfonylurea, ? Thiazolidinedione

21. Function of Insulin in Regimens
Meal coverage (carbohydrates)
Basal insulin
Correction of high blood sugar

22. More Options Insulins Insulin Lispro (Humalog®) ‘96
Insulin Aspart (Novolog®) 9/00
Humalog ® Mix 75/25 1/00
Insulin Glargine (Lantus®) 4/00
Novolog ® Mix 70/30 5/02
Insulin Glulisine (Apidra®) 4/04
Insulin Detemir (Levemir®) 6/05
Insulin delivery devices and glucose meters

23. Insulin Pharmacokinetics
On July 6, 2005 Lilly announced Lente and Ultralente
will no longer be available in 2006.

24. Plasma Insulin (pmol/L) Plasma Insulin (pmol/L)
Short-acting Insulin Analogues: Lispro and Aspart Plasma Insulin Profiles
400
glulisine
500
Aspart
Lispro
450
350
400
300
350
250
300
Plasma Insulin (pmol/L)
200
250
Plasma Insulin (pmol/L)
Regular
200
150
Human
150
100
Regular
100
Human 50 50 30 60 90
120
150
180
210
240 50
100
150
200
250
300
Time (min)
Time (min)
Meal
SC injection
Meal
SC injection
Heinemann, et al. Diabet Med. 1996;13: ; Mudaliar, et al. Diabetes Care. 1999;22:
6-28

25. Rapid-Acting Insulins
Advantages
• Flexibility--given immediately before or after meals
• Postprandial control-better match with glucose peak
• Limited duration so less overlap with subsequent injections
Disadvantages
• Caution with adequate CHO intake (if < than predicted, susceptible to hypoglycemia
• Cost/insurance coverage

26. Activity Profile in Type 1 Diabetes
Lepore et al. Diabetes 1999;48(suppl 1):A97. Abst 416; Study 1015
(Hourly Mean Values) 6
(mg/kg/min) 5
Insulin Glargine 4
NPH insulin 3
Glucose 2
Utilization Rate 1 10 30 20
Time (h) after sc injection
= End of observation
period

27. Type 2 Diabetes: Unanswered Questions
When should insulin be started?
What insulin should you use in Type 2? What insulin regimen is best?
Which, if any, oral agents should be continued?

28. Insulin tactics Minimize weight gain – metformin
Minimize risk of hypoglycemia – insulin analogs, optimize self management skills
Minimize insulin resistance – thiazolidinediones and metformin
Use oral agents to limit number of injections

29. More Options Incretin mimetics Exenatide (Byetta ®) 4/05
Amylinomimetics (amylin analog)
Pramlintide (Symlin ®) 3/05

30. Incretins in Type 2 DM Gut hormones released postprandially
Oral glucose elicits greater insulin response than IV glucose; “incretin effect” accounts for 50-70% of insulin response to oral glucose
2 main gut incretins
Glucose-dependent insulinotropic polypeptide (GIP)
Released by K cells in duodenum
Glucagon-like peptide-1 (GLP-1)
Released by L cells in small intestines
Levels are diminished in type 2 DM post-meal

31. Incretins in Type 2 DM (cont)
Rapidly degraded by dipeptidyl peptidase IV (DPP-IV)
GLP-1 analogs; “incretin mimetics”
Liraglutide (free fatty acid added to bind to albumin; injected daily)
Exenatide
DPP-IV inhibitors (oral)

32. Actions of GLP-1 Insulin secretion (Insulinotropic effects)
Potentiates glucose-induced insulin secretion
Enhances all steps of insulin biosynthesis
Upregulates insulin gene expression
Upregulates genes needed for beta-cell function (
Stimulates beta cell proliferation
Promotes differentiation of beta cells from progenitor cells
Inhibits glucagon secretion (Glucostatic effect)
Slows gastric emptying
Inhibits appetite and food intake

33. Exenatide (Byetta)
Synthetic Exendin-4, or exenatide
Exendin-4 originally isolated from Gila monster’s (Heloderma suspectum) saliva; lizard in Arizona
Analog of GLP-1
39 amino acid peptide
>50% overlap with human GLP-1
Resistant to DPP-IV degradation
Similar binding affinity at GLP-1 receptors

34. Exenatide (Byetta)
Indications: adults with type 2 DM who are taking metformin, sulfonylurea or combination
Peak concentration post injection achieved in 2.1 hr (injected SQ twice daily within 60 minutes of meal)
Metabolized primarily by kidneys
Not recommended in Clcr <30 ml/min
OK in hepatic impairment

35. Restores first-phase insulin response Slows gastric emptying
Exenatide: BG Effects
Lowers post-prandial BG
Restores first-phase insulin response
Slows gastric emptying
Lowers post-prandial glucagon ( hepatic glucose output)
 food intake
Lowers A1C

36. Clinical Data: Exenatide
3 large, 30 week clinical trials (randomized, double-blind, placebo-controlled) in patients with type 2 DM
On SFU: Buse et al. Diabetes Care. 2004;27:
On SFU & metformin: Kendall DM et al. Diabetes Care. 2005;28:
On metformin: DeFronzo RA et al. Diabetes Care. 2005;28:
Placebo BID
5 mcg exenatide BID
10 mcg exenatide BID
ITT
483
480
Age (y) 55
BMI 34 33
A1C
8.5
8.4
Duration of DM 8 7

37. A1C (%) Effect (change from baseline)
Placebo BID
5 mcg exenatide BID
10 mcg exenatide BID
MET
0.1
-0.4
-0.8
SFU
-0.5
-0.9
MET+SFU
0.2
-0.6
Changes in A1C from baseline vs placebo statistically significant
Effect on FBG less pronounced:  6-9 mg/dl (5 mcg dose);
10 mg/dl (10 mcg dose)
PPG 60% (5 mcg dose) & 90% (10 mcg dose)

38. Weight (change from baseline) & Hypoglycemia
Placebo BID
5 mcg exenatide BID
10 mcg exenatide BID
Weight (kg)
-1.4
-3.1
-4.2
Hypoglycemia (%)
MET
SFU
MET + SFU
5.3
3.3
1.26
4.5
14.4
19.2
35.7
27.8
Open-label extension study to 90 weeks: persistence in weight loss and A1C

39. Exenatide Dosing
Start 5 mcg SQ BID before morning and evening meal
When added to SFU, lower dose of SFU
After 1 month, can increase to 10 mcg SQ BID
Available in prefilled pen
Must be continuously stored refrigerated at 36-46°F
For oral medications dependent on threshold concentrations or rapid onset, take them 1 hour before

40. Side Effects GI
Nausea (44% vs 18% with placebo); incidence lessens over time; 3% dropout rate due to nausea
Vomiting (13% vs 4%)
Diarrhea (13% vs 6%)
Headache (9% vs 6%)
Hypoglycemia (see previous slide)

41. New Options for Insulin Delivery
Ideal Insulin Pen:
Ease of priming, loading cartridge
Sturdy/reliable
Change dose without wasting insulin
Easy to read numbers
Flexibility in dosing range (wide range, 1 vs 2-unit increments)
Not costly

42. Durable Insulin Pens Maximum dosage: 35 units ½ unit increment
Use replaceable insulin cartridge
Use dial mechanism for dose
NovoPen® 3
Maximum dosage: 70 units
1 unit increment
metal material
NovoPen ® Junior
Maximum dosage: 35 units
½ unit increment
BD™ Pen and Pen Mini
1.5 cc cartridge
Maximum dosage: 30 or 15 units

43. Innovo® & InDuo™
InDuo: Integrates two daily activities combined into one device
Blood glucose monitoring (OneTouch® Ultra® meter) and Insulin Delivery Device (Innovo)
Supports an acceptance and understanding of the link between SMBG and insulin therapy
Device serves as a constant reminder to test whenever the patient injects
Memory function stores the time elapsed & amount of last insulin dose
Uses 3 cc cartridge
Maximum dosage: 70 units; 1 unit increments

44. www.opticlik.com OptiClik FDA approved 8/04
Reusable pen for Lantus & Apidra
1-unit increments; takes only BD pen needles
Supplied to physicians; not available in pharmacies

45. Disposable/Prefilled Insulin Pens
Hold 3 cc insulin
Discard when finished
Use dial mechanism for dose; need to prime (“air shot”)
Novolin® InnoLet®
Clock-like dial (egg timer-like) with large scale numbers; audible clicks
large grip and ergonomic shape that allows alternative grips, easy-to-push large button and support shoulder
Maximum dose: 50 units
1 unit increments
Regular, NPH and 70/30 insulin only

46. Disposable/Prefilled Insulin Pens, cont.
Novo Nordisk FlexPen ® (Novolog ®, Novolog ® Mix 70/30): up to 60 units; 1 unit increments
Eli Lilly pens (Humalog ®,Humalog ® Mix 75/25™, NPH, 70/30): up to 60 units; 1 unit increments

47. Needles 29 G: ½” (12.7mm) 31 G: 3/16” (5 mm) or 5/16” (8 mm) NovoFine®
Pen Needles BD
29 G: ½” (12.7mm)
31 G: 3/16” (5 mm) or 5/16” (8 mm)
Novo Nordisk
NovoFine®
30 gauge x 1/3” (8mm)
31 gauge x ¼” (6mm)
Caution with obese patients if use shorter needles
Syringes: 1/3, ½, 1 cc
Several times enlarged NovoFine® 30
[30 gauge x 1/3” (8mm)] Disposable Needle

49. Alternate Testing Sites

50. Alternative Site Testing: Cons
Lag time of 5-30 minute between forearm & finger
blood flow to finger is 3-5 x faster than arm
significant when BG changing rapidly
When not to use (use fingers)
BG rapidly changing
suspect low BG
hypoglycemic unawareness
within 1-2 hours after meals
Bruising at site

51. CGMS  (Continuous Glucose Monitoring System) System Gold™
Other Methods of SMBG
Continuous ambulatory blood glucose monitoring
CGMS  (Continuous Glucose Monitoring System) System Gold™
Medtronic MiniMed
72-hour; BG recorded q5min
24-hour glucose patterns
detect unrecognized hypoglycemia
Requires HCP support
Noninvasive: GlucoWatch G2 Biographer
Cygnus
Requires a prescription

52. Self-Monitoring of Blood Glucose (SMBG) - ADA Recommendations
Type 1 Diabetes : 3 x daily
Type 2 Diabetes: optimal frequency and timing not known; “sufficient to facilitate reaching glucose goals”
Postprandial BG may be necessary to reach A1C goals and/or reduce risk of hypoglycemia
Self-management training: how to use the data to adjust food intake, exercise or pharmacologic therapy
Diabetes Care 2006

53. Self-Monitoring:Outcomes
Improve overall control:
Best studies:
HbA1c 0.7% lower in type 1
HbA1c 0.6% lower in type 2
Meta-analysis
HbA1c 0.25% lower

54. Other Emerging Therapies
Pharmacologic
PPAR/PPAR dual agonists
Muraglitazar (Pargluva; Advisory committee met 9/9/05; recommended approval)
Tesaglitazar (Galida)
Alternative insulin dosage forms (IH, buccal; transdermal; nasal)
Inhaled insulin, Exubera
Islet cell transplants
Rimonabant (Acomplia)
Monitoring
Continous blood glucose monitoring