1. Insulin Therapy of Type 2 Diabetes
Jack L. Leahy
University of Vermont College of Medicine
Division of Endocrinology, Diabetes and Metabolism
Burlington, Vermont

2. Global Projections for the Diabetes Epidemic: 2003-2025NA
EUR
23.0 M
36.2 M
↑57.0%
48.4 M
58.6 M
↑21%
EMME WP
19.2 M
39.4 M
↑105%
SEA
43.0 M
75.8 M
↑79%
39.3 M
81.6 M
↑108%
AFR
SACA
7.1M
15.0 M
↑111%
World
2003 = 194 M
2025 = 333 M
↑ 72%
14.2 M
26.2 M
↑85%
2003
2025
M = million, AFR = Africa, NA = North America, EUR = Europe,
SACA = South and Central America, EMME = Eastern Mediterranean and Middle East,
SEA = South-East Asia, WP = Western Pacific
Diabetes Atlas Committee. Diabetes Atlas 2nd Edition: IDF 2003.

3. Standards of Care - American Diabetes Association
Glycemia: HbA1c <7.0%, FPG mg/dL, PP <180 mg/dL.
Blood Pressure: <130/80.
Lipids: LDL <100 mg/dL; TG <150 mg/dL.
Yearly:
Dilated eye exam; urinary protein; foot exam; flu shot.
Other:
Aspirin usage; pneumococcal vaccine.
AACE goals - HbA1c 6.5%, FPG 110 mg/dL, PP 140 mg/dL
NCEP - LDL ≤ 70 mg/dL
ADA. Diabetes Care 2005;29:S4-S42

4. Consensus Algorithm Update 2009
Tier 1: Well-validated core therapies
Lifestyle + Metformin
plus
Basal Insulin
At diagnosis:
Lifestyle + Metformin
Lifestyle + Metformin
plus
Intensive Insulin
Lifestyle + Metformin plus
Sulfonylureaa
Step 1
Step 2
Step 3
Tier 2: Less well-validated therapies
Check A1C every 3 months until <7%. Change treatment if A1C is ≥7%
Lifestyle + Metformin plus
Pioglitazone
No hypoglyceamia
Oedema / CHF
Bone Loss
Lifestyle + Metformin plus
Pioglitazone plus Sulfonylurea
Lifestyle + Metformin plus
GLP-1 agonist
No hypoglyceamia
Weight loss
Nausea / vomiting
Lifestyle + Metformin plus
Basal Insulin
Nathan DM et al. Diabetes Care 2009;32:

5. Clinical Inertia: Failure to Advance Therapy When Required
Percentage of subjects advancing when A1C < 8%
At insulin initiation, the average patient had:
100
5 years with A1C > 8%
10 years with A1C > 7% 80
66.6% 60
44.6%
% of Subjects
35.3% 40
18.6% 20
Diet
Sulfonylurea
Metformin
Combination
Brown JB et al. Diabetes Care 2004;27:

6. Learning Objectives
To discuss the “nuts and bolts” of successful insulin therapy strategies in type 2 diabetes:
Highlight and discuss timely and controversial topics.
Use clinical trial data to:
Compare available long-acting (basal) insulins.
Identify expected dosages of basal insulins.
Discuss the importance of patient-driven algorithms for adjustment of basal insulin dosages.
Introduce the concept of “incomplete” basal-bolus insulin therapy - so called “Basal Plus”.

7. Basal Insulin Therapy Basal insulin Nondiabetic Type 2 diabetes
Glucose
Insulin
400
120
100
300 80
U/mL
mg/dL
200 60 40
100 20
6:00
10:00
14:00
18:00
22:00
2:00
6:00
6:00
10:00
14:00
18:00
22:00
2:00
6:00 B L D B L D
Time
Time
B = breakfast; L = lunch; D = dinner.
Polonsky KS et al. N Engl J Med 1988;318:

8. Basal Insulin Profiles Glucose Infusion Rates
N=20 T1DM
Mean  SEM 4 8
Mg/Kg/min
mol/Kg/min
s.c. insulin
NPH
Glargine
4.0
3.0
2.0
1.0 12 20 16 24
≈15% with some peak
Time (hours)
Lepore M et al. Diabetes 2000;49:

9. NPH
Glargine

10. Insulin Detemir: Structure
Lys
Thr
Tyr
Phe
Gly
Arg
Glu
Val
Leu
Ala
His
Ser
Gln B1 B3
A21
B29
Pro
Cys
Asn
lle
Asp A1
C14 fatty acid chain
(Myristic acid)

11. Dose Dependency of Action Profiles of Insulin Detemir7
Detemir 0.1 U/kg 6
Detemir 0.2 U/kg 5
Detemir 0.4 U/kg
Glucose infusion 4
Detemir 0.8 U/kg
rate (mg/kg/min)
Detemir 1.6 U/kg 3 2 1 2 4 6 8 10 12 14 16 18 20 22 24
Time since insulin injection (h)
DETEMIR DOSE (U/kg)
0.1
0.2
0.4
0.8
1.6
DURATION OF ACTION (h)
5.7
12.1
19.9
22.7
23.2
Plank J et al. Diabetes Care 2005;28:

12. Insulin Glargine Trials Showing Effective Reduction in HbA1c10 9 8 7 6 5
9.5
8.85
8.80
8.71
8.80
8.61
HbA1c (%)
7.14
7.15
7.14
6.96
6.96
6.80
Treat-To-Target
LANMET
APOLLO
LAPTOP
Triple Therapy
INITIATE
Baseline
Study endpoint

13. Less Hypoglycemia with Insulin Glargine vs NPH
3500
3000
2500
2000
1500
1000
NPH
Insulin glargine
Hypoglycemia events per 100 patient-years
T1DM
p=0.004 between treatments
HbA1c
200
150
100 50
Hypoglycemia events per 100 patient-years
T2DM
p=0.021 between treatments
HbA1c
Mullins P et al. Clin Ther 2007;29:1607−19.

14. Key Questions
Is there a difference between Glargine and Detemir?

15. Head to Head Comparison of Glargine Versus Detemir in Type 2 Diabetes 52-weeks. Once daily Glargine or Detemir - could be titrated to BID Detemir (55%). Baseline A1c 8.6% n = 582
Hemoglobin A1c (%) 4 6 8 5 7
7.2
7.1
P = NS
Glargine
Detemir
Rosenstock J et al. Diabetologia 2008;51:

16. Summary of Results
55% of patients on insulin Detemir were titrated to twice daily injections
All patients on insulin Glargine received only 1 injection per day
Average daily doses:
Detemir once daily 0.78 U/kg.
Detemir twice daily 1.0 U/kg.
Glargine once daily 0.44 U/kg
3.9 kg weight gain with Glargine versus 3.0 kg with Detemir - no difference between Glargine and twice daily Detemir.
Rosenstock J et al. Diabetologia 2008;51:

17. Key Questions Is there a difference between Glargine and Detemir?
When to start basal insulin versus adding another agent?

18. Consensus Algorithm Update 2009
Tier 1: Well-validated core therapies
Lifestyle + Metformin
plus
Basal Insulin
At diagnosis:
Lifestyle + Metformin
Lifestyle + Metformin
plus
Intensive Insulin
Lifestyle + Metformin plus
Sulfonylureaa
Step 1
Step 2
Step 3
Tier 2: Less well-validated therapies
Check A1C every 3 months until <7%. Change treatment if A1C is ≥7%
Lifestyle + Metformin plus
Pioglitazone
No hypoglyceamia
Oedema / CHF
Bone Loss
Lifestyle + Metformin plus
Pioglitazone plus Sulfonylurea
Lifestyle + Metformin plus
GLP-1 agonist
No hypoglyceamia
Weight loss
Nausea / vomiting
Lifestyle + Metformin plus
Basal Insulin
Nathan DM et al. Diabetes Care 2009;32:

19. Exenatide vs Once-Daily Insulin Glargine: Self-Monitoring Blood Glucose Profiles (n=549)
Blood glucose (mg/dL)
3 AM
100
120
140
160
180
200
220
240
Baseline (week 0)
Endpoint (week 26)
Exenatide
5 µg bid 1st 4 weeks, then 10 µg bid
Insulin glargine
10 U/d, titrated to target FPG <100 mg/dL
Prebreakfast
Prelunch
Predinner
Prebreakfast
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 2005;143:

20. Key Questions Is there a difference between Glargine and Detemir?
When to start basal insulin versus adding another agent?
Do what with oral agents?

21. Combined Effects of Metformin with Insulin Therapy in Type 2 Diabetes
Sasali A and Leahy JL. Curr Diab Rep 2003;3:

22. Key Questions Is there a difference between Glargine and Detemir?
When to start basal insulin versus adding another agent?
Do what with oral agents?
Continue OHA - “add on” therapy, not “substitution” therapy.

23. Key Questions Is there a difference between Glargine and Detemir?
When to start basal insulin versus adding another agent?
Do what with oral agents?
Continue OHA - “add on” therapy, not “substitution” therapy.
What are expected doses of basal insulin (Glargine or NPH)?

24. Published Insulin Glargine Doses and Titration Algorithms
Treat-to-Target1
INSIGHT2
LANMET3
INITIATE4
Target FBG
<100 mg/dL
≤100 mg/dL
Algorithm
+ 2 to 8 U
every week
+ 1 U every day
+2 U or + 4 U
every 3 days
+2 U
Final dose Glargine
0.48 U/kg
0.42 U/kg (NPH)
0.41 U/kg
0.69 U/kg
0.66 U/kg (NPH)
0.60 to 0.64 U/kg
1. Riddle M, et al. Diabetes Care 2003;26:3080−6.
2. Gerstein HC, et al. Diabet Med 2006;23:736−42.
3. Yki-Järvinen H, et al. Diabetologia 2006;49:442−51.
4. Yki-Järvinen H, et al. Diabetes Care 2007;30:

25. Key Questions Is there a difference between Glargine and Detemir?
When to start basal insulin versus adding another agent?
Do what with oral agents?
Continue OHA - “add on” therapy, not “substitution” therapy.
What are expected doses of basal insulin (Glargine or NPH)?
Average dosage of Glargine or once daily NPH U/kg.
No maximal dose - consider mealtime when reach 0.7 U/kg.

26. Key Questions Is there a difference between Glargine and Detemir?
When to start basal insulin versus adding another agent?
Do what with oral agents?
Continue OHA - “add on” therapy, not “substitution” therapy.
What are expected doses of basal insulin (Glargine or NPH)?
Average dosage of Glargine or once daily NPH U/kg.
No maximal dose - consider mealtime when reach 0.7 U/kg.
How to start and titrate?

27. Recommendations for Starting and Adjusting Basal Insulin
Bedtime or morning long-acting insulin OR
Bedtime intermediate-acting insulin
Daily dose: 10 units or 0.2 U/kg
Increase dose by 2 units every 3 days until FBG is 70–130 mg/dL.
If FBG is >180 mg/L, increase dose by 4 units every 3 days.
Check FBG daily
Continue regimen and check HbA1c every 3 months
In the event of hypoglycemia or FBG level <70 mg/dL.
Reduce bedtime insulin dose by 4 units, or by 10% if >60 units.
Nathan DM et al. Diabetes Care 2009;32:

28. Published Insulin Glargine Doses and Titration Algorithms
Treat-to-Target1
INSIGHT2
LANMET3
INITIATE4
Target FBG
<100 mg/dL
≤100 mg/dL
Algorithm
+ 2 to 8 U
every week
+ 1 U every day
+2 U or + 4 U
every 3 days
+2 U
Final dose Glargine
0.48 U/kg
0.42 U/kg (NPH)
0.41 U/kg
0.69 U/kg
0.66 U/kg (NPH)
0.60 to 0.64 U/kg
1. Riddle M, et al. Diabetes Care 2003;26:3080−6.
2. Gerstein HC, et al. Diabet Med 2006;23:736−42.
3. Yki-Järvinen H, et al. Diabetologia 2006;49:442−51.
4. Yki-Järvinen H, et al. Diabetes Care 2007;30:

29. FPG / weekly means (mg/dL)
Optimizing Dose of Glargine Allows Achievement of FPG Target (LANMET study)
Study in 110 insulin-naïve subjects with type 2 diabetes receiving insulin glargine plus metformin
Time (weeks)
FPG / weekly means (mg/dL) 30 60 90
120
180 -4 4 8 12 16 20 24 28 36 32
210 40 80
150
Insulin dose (IU/day)
Adapted from Yki-Järvinen H, et al. Diabetologia 2006;49:442–51

30. Key Questions Is there a difference between Glargine and Detemir?
When to start basal insulin versus adding another agent?
Do what with oral agents?
Continue OHA - “add on” therapy, not “substitution” therapy.
What are expected doses of basal insulin (Glargine or NPH)?
Average dosage of Glargine or once daily NPH U/kg.
No maximal dose - consider mealtime when reach 0.7 U/kg.
How to start and titrate?
Why not start with premixed insulins?

31. Split-Mixed/Pre-Mixed Insulin Therapy
Breakfast
Lunch
Dinner
Regular
NPH
Plasma Insulin
4:00
8:00
12:00
16:00
20:00
24:00
4:00
Time

32. LAPTOP: Insulin Glargine Versus 70/30 Premixed Insulin in OHA Failures
N=371 insulin-naïve patients Insulin glargine + OADs vs twice-daily human NPH insulin (70/30) Follow-up: 24 weeks
Twice-daily premixed insulin
Insulin glargine + OADs
p=0.0003 9 5
5.7
1.3%
1.7% 4 8
p=0.0009 3
7.5%
Hypoglycaemia* (events/patient year)
HbA1c (%) 7
7.2%
2.6 2 6 1 5
*Confirmed symptomatic hypoglycaemia (blood glucose <60 mg/dl [<3.3 mmol/l])
Janka H et al. Diabetes Care 2005;28:254−259.

33. Analog Pre-Mixed Insulin Therapy
Breakfast
Lunch
Dinner
Plasma Insulin
4:00
8:00
12:00
16:00
20:00
24:00
4:00
Time

34. Change in A1C From Baseline to Study End
P<0.01
Baseline 10
Endpoint
- 2.4% 9
- 2.8%
9.8%
9.7% 8
A1C (%)
7.4% 7
6.9% 6 5
Insulin Glargine + OADs
PreMix
Raskin P et al. Diabetes Care 2005;28:

35. Hypoglycemia Documented Hypoglycemic Episodes (<56 mg/dL)1 2 3 4
3.4
Episodes per patient year
0.7
Insulin Glargine
PreMix
Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin
Raskin P et al. Diabetes Care 2005;28:

36. Key Questions Is there a difference between Glargine and Detemir?
When to start basal insulin versus adding another agent?
Do what with oral agents?
Continue OHA - “add on” therapy, not “substitution” therapy.
What are expected doses of basal insulin (Glargine or NPH)?
Average dosage of Glargine or once daily NPH U/kg.
No maximal dose - consider mealtime when reach 0.7 U/kg.
How to start and titrate?
Why not start with premixed insulins?
What if basal insulin is not enough?

37. Blood Glucose Profiles
350
300
250
200
150
100 50
Premix†
Glargine
Baseline
Plasma Glucose (mg/dL) * * * * *
Week 28 BB
B90 BL
L90 BD
D90
Bed
3AM
Time of Day
Raskin P et al. Diabetes Care 2005;28:

38. Stepwise Treatment of Type 2 Diabetes
Further intensification
Intensification
Basal Bolus
Insulin Initiation
Basal Plus
Add prandial insulin at main meal
Basal
Add basal insulin and titrate
Additional Oral agents
Lifestyle changes + Metformin
Progressive deterioration of -cell function

39. Eleonor Study
Aim: To determine if a Telecare program facilitates optimization of basal insulin Glargine followed by addition of one mealtime insulin injection of insulin Glulisine.
Protocol:
24-week, open label, multicenter, randomized study in Italy.
200 patients with type 2 diabetes.
Poor glycemic control (A1C 8.9±0.9%) on one or more oral hypoglycemic agents.
Adjust Glargine to FBG <126 mg/dL followed by adding Glulisine to meal with highest PPG value.
Del Prato S, et al. Diabetologia 2008;51 Suppl. 1:S452

40. pts achieving HbA1c <7.0 (%)
Eleonor Study Results 20 40 60 80
100
pts achieving HbA1c <7.0 (%)
51%
55%
p=NS
Group 1 2
9.0
Group 1
Group 2
8.5
8.0
HbA1c (%)
7.5
7.0
ADA/EASD target
6.5
Glargine + OHAs 12
Glargine + 1 Glulisine + OHAs 36
Weeks
No clinically significant weight gain. Low rate of severe hypoglycemia
Del Prato S, et al. Diabetologia 2008;51 Suppl. 1:S452

41. Basal Plus Mealtime Insulin
Use rapid-acting analogs, not regular insulin
Easier timing, less postprandial hypoglycemia
Can be taken up to 20 minutes after start eating
Start with 1 shot, at largest meal:
4 units, and titrate, OR
By weight U/kg
Titrate to:
<160 mg/dL 2 hours post-prandial OR
<130 mg/dL next meal or bedtime
Continue oral secretagogues until full basal-bolus regimen

42. Lispro, Aspart, Glulisine vs Regular Insulin
Analog insulin 10
Timing of
food absorbed 8 6
Insulin Activity 4
RHI 2 1 2 3 4 5 6 7 8 9 10 11 12
Hours
RHI = regular human insulin.
Adapted with permission from Howey DC et al. Diabetes 1994;43:

43. Basal Plus Mealtime Insulin
Use rapid-acting analogs, not regular insulin
Easier timing, less postprandial hypoglycemia
Can be taken up to 20 minutes after start eating
Start with 1 shot, at largest meal:
4 units, and titrate.
By weight U/kg
Titrate to:
<160 mg/dL 2 hours post-prandial OR
<130 mg/dL next meal or bedtime
Continue oral secretagogues until full basal-bolus regimen

44. “We don’t start insulin early enough, or use it aggressively enough”
Robert Turner MA, MD, FRCP
Professor of Medicine
University of Oxford
“We don’t start insulin early enough, or use it aggressively enough”