Insulin Therapy of Type 2 Diabetes

Jack L. Leahy
University of Vermont College of Medicine
Division of Endocrinology, Diabetes and Metabolism
Burlington, Vermont
 Global Projections for the Diabetes Epidemic:
2003-2025
NA EUR
23.0 M 48.4 M EMME WP
36.2 M 58.6 M
↑57.0% 19.2 M SEA 43.0 M
↑21%
39.4 M 39.3 M 75.8 M
↑105% 81.6 M ↑79%
AFR ↑108%
SACA
World 7.1M
14.2 M 15.0 M
2003 = 194 M 26.2 M ↑111%
2025 = 333 M ↑85%
↑ 72%

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.
 Standards of Care - American Diabetes
Association
• Glycemia: HbA1c <7.0%, FPG 90-130 mg/dL, PP
<180 mg/dL. AACE goals - HbA1c 6.5%, FPG 110
mg/dL, PP 140 mg/dL
• Blood Pressure: <130/80.
• Lipids: LDL <100 mg/dL; TG <150 mg/dL.
• Yearly: NCEP - LDL ≤ 70 mg/dL

– Dilated eye exam; urinary protein; foot exam; flu

shot.
• Other:
– Aspirin usage; pneumococcal vaccine.
ADA. Diabetes Care 2005;29:S4-S42
 Consensus Algorithm Update 2009
Tier 1: Well-validated core therapies
Lifestyle + Metformin Lifestyle + Metformin
At diagnosis: plus plus
Basal Insulin Intensive Insulin
Lifestyle
+ Lifestyle + Metformin
Metformin plus
Sulfonylureaa

Step 1 Step 2 Step 3

Tier 2: Less well-validated therapies Check A1C every
3 months until <7%.
Lifestyle + Metformin Lifestyle + Metformin Change treatment if
plus plus
Pioglitazone A1C is ≥7%
Pioglitazone
No hypoglyceamia plus
Oedema / CHF
Bone Loss
Sulfonylurea

Lifestyle + Metformin
plus Lifestyle + Metformin
GLP-1 agonist plus
No hypoglyceamia
Weight loss
Basal Insulin
Nausea / vomiting

Nathan DM et al. Diabetes Care 2009;32:193-203..

 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%

80 • 10 years with A1C > 7%

66.6%
% of Subjects

60 44.6%
35.3%
40
18.6%
20

0
Diet Sulfonylurea Metformin Combination

Brown JB et al. Diabetes Care 2004;27:1535-1540.

 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”.
 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;318:1231-1239.
 Basal Insulin Profiles
Glucose Infusion Rates
N=20 T1DM
s.c.
insulin Mean  SEM
4.0 24

20
3.0 NPH

mol/Kg/min
16
Mg/Kg/min

2.0 ≈15% with 12

some peak
8
1.0
4

0 Glargine 0

0 4 8 12 16 20 24
Time (hours)

Lepore M et al. Diabetes 2000;49:2142-2148.

NPH Glargine
 Insulin Detemir: Structure

C1
4 fa
(My tty ac
ri s i
tic d cha Phe Gly Arg
aci i Tyr Phe
d) n Thr Glu
Pro Gly
Lys Cys
Thr B29 A21 Asn Cys Val
Tyr
A1 Gly Leu
Gln
lle Tyr
Glu
Val Leu
Leu
Glu Ala
Gln
Gln Glu
Tyr
Cys Leu Val
Cys Thr Ser lle Cys Ser Leu
His
Ser
B3 Gly
Cys
B1 Phe Val Asp Gln His Leu
 Dose Dependency of Action Profiles of Insulin
Detemir
7
Detemir 0.1 U/kg
Glucose infusion

6
Detemir 0.2 U/kg
rate (mg/kg/min)

5
Detemir 0.4 U/kg
4 Detemir 0.8 U/kg
3 Detemir 1.6 U/kg

1
0
0 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 5.7 12.1 19.9 22.7 23.2
(h)

Plank J et al. Diabetes Care 2005;28:1107-1112.

 Insulin Glargine Trials Showing Effective Reduction in
HbA1c

10

9.5
9 8.85 8.80 8.80
8.61 8.71
HbA1c (%)

7.14 7.15 7.14

6.96 6.96 6.80
7

5
Treat-To- LANMET APOLLO LAPTOP Triple INITIATE
Target Therapy

Baseline Study endpoint

 Less Hypoglycemia with Insulin Glargine vs
NPH
3500 NPH Insulin glargine
events per 100

3000
Hypoglycemia

patient-years

2500 T1DM
p=0.004 between
2000 treatments
1500
1000
6 7 8 9 10
HbA1c
200
events per 100
Hypoglycemia

patient-years

150 T2DM p=0.021 between

treatments
100

50

0
6 7 8 9 10
HbA1c
Mullins P et al. Clin Ther 2007;29:1607−19.
 Key Questions
• Is there a difference between Glargine and Detemir?
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

8
P = NS

Hemoglobin A1c (%)

7 7.2 7.1

4
Glargine Detemir

Rosenstock J et al. Diabetologia 2008;51:408-416

 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;51:408-416

 Key Questions
• Is there a difference between Glargine and Detemir?
• When to start basal insulin versus adding another agent?
 Consensus Algorithm Update 2009
Tier 1: Well-validated core therapies
Lifestyle + Metformin Lifestyle + Metformin
At diagnosis: plus plus
Basal Insulin Intensive Insulin
Lifestyle
+ Lifestyle + Metformin
Metformin plus
Sulfonylureaa

Step 1 Step 2 Step 3

Tier 2: Less well-validated therapies Check A1C every
3 months until <7%.
Lifestyle + Metformin Lifestyle + Metformin Change treatment if
plus plus
Pioglitazone A1C is ≥7%
Pioglitazone
No hypoglyceamia plus
Oedema / CHF
Bone Loss
Sulfonylurea

Lifestyle + Metformin
plus Lifestyle + Metformin
GLP-1 agonist plus
No hypoglyceamia
Weight loss
Basal Insulin
Nausea / vomiting

Nathan DM et al. Diabetes Care 2009;32:193-203..

 Exenatide vs Once-Daily Insulin Glargine: Self-
Monitoring Blood Glucose Profiles (n=549)
Exenatide Insulin glargine
5 µg bid 1st 4 weeks, then 10 µg bid 10 U/d, titrated to target FPG <100 mg/dL
240 240
Blood glucose (mg/dL)

220 220
200 200
180 180
160 160
140 140
120 Baseline (week 0) 120 Baseline (week 0)
Endpoint (week 26) Endpoint (week 26)
100 100

Pr
Pr

Pr

Pr
Pr

Pr
3

3
eb
eb

el

el
ed

ed
AM

AM
re
un

un
re

in

in
ak
ch

ch
ne
ak

ne
fa
fa

r
st
st

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;143:559-569.

 Key Questions
• Is there a difference between Glargine and Detemir?
• When to start basal insulin versus adding another agent?
• Do what with oral agents?
 Combined Effects of Metformin with Insulin
Therapy in Type 2 Diabetes

Sasali A and Leahy JL. Curr Diab Rep 2003;3:378-385.

 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.
 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)?
 Published Insulin Glargine Doses and Titration
Algorithms
Treat-to-Target1 INSIGHT2 LANMET3 INITIATE4

Target FBG <100 mg/dL ≤100 mg/dL <100 mg/dL <100 mg/dL

Algorithm + 2 to 8 U + 1 U every day +2 U or + 4 U +2 U

every week every 3 days every 3 days

Final dose 0.48 U/kg 0.69 U/kg 0.60 to 0.64

0.41 U/kg
Glargine 0.42 U/kg (NPH) 0.66 U/kg (NPH) 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;30:1364-9.
 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 0.5-0.6 U/kg.
– No maximal dose - consider mealtime when reach 0.7 U/kg.
 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 0.5-0.6 U/kg.
– No maximal dose - consider mealtime when reach 0.7 U/kg.
• How to start and titrate?
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
Check
FBG
daily

Increase dose by 2 units every 3 days until FBG In the event of hypoglycemia or FBG level
is 70–130 mg/dL. <70 mg/dL.
If FBG is >180 mg/L, increase dose by 4 units Reduce bedtime insulin dose by 4 units,
every 3 days. or by 10% if >60 units.

Continue regimen and

check HbA1c every 3 months

Nathan DM et al. Diabetes Care 2009;32:193-203.

 Published Insulin Glargine Doses and Titration
Algorithms
Treat-to-Target1 INSIGHT2 LANMET3 INITIATE4

Target FBG <100 mg/dL ≤100 mg/dL <100 mg/dL <100 mg/dL

Algorithm + 2 to 8 U + 1 U every day +2 U or + 4 U +2 U

every week every 3 days every 3 days

Final dose 0.48 U/kg 0.69 U/kg 0.60 to 0.64

0.41 U/kg
Glargine 0.42 U/kg (NPH) 0.66 U/kg (NPH) 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;30:1364-9.
 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
210 80
FPG / weekly means (mg/dL)

180
60

Insulin dose (IU/day)

150

120
40
90

60
20

30

0 0
-4 0 4 8 12 16 20 24 28 32 36
Time (weeks)
Adapted from Yki-Järvinen H, et al. Diabetologia 2006;49:442–51
 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 0.5-0.6 U/kg.
– No maximal dose - consider mealtime when reach 0.7 U/kg.
• How to start and titrate?
• Why not start with premixed insulins?
 Split-Mixed/Pre-Mixed Insulin Therapy

Breakfast Lunch Dinner

Regular
Plasma Insulin

NPH

4:00 8:00 12:00 16:00 20:00 24:00 4:00

Time
 LAPTOP: Insulin Glargine Versus 70/30
Premixed Insulin in OHA Failures
N=371 insulin-naïve patients
Insulin glargine + OADs vs twice-daily human Twice-daily premixed insulin
NPH insulin (70/30) Insulin glargine + OADs
Follow-up: 24 weeks

p=0.0003

Hypoglycaemia* (events/patient year)

9 5 5.7
1.3% 1.7%
4
8

3 p=0.0009
HbA1c (%)

7.5%
7 7.2% 2.6
2
6
1

5 0
*Confirmed symptomatic hypoglycaemia
(blood glucose <60 mg/dl [<3.3 mmol/l])
Janka H et al. Diabetes Care 2005;28:254−259.
 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
 Change in A1C From Baseline to Study End

P<0.01 Baseline
10
Endpoint
9 - 2.4% - 2.8%
9.8% 9.7%
8
A1C (%)

7 7.4%
6.9%
6

5
Insulin Glargine + OADs PreMix

Raskin P et al. Diabetes Care 2005;28:260-265.

 Hypoglycemia
Documented Hypoglycemic Episodes (<56 mg/dL)

P<0.05
4

Episodes per patient year 3

3.4

0.7
0
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;28:260-265.

 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 0.5-0.6 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?
 Blood Glucose Profiles

Plasma Glucose (mg/dL) 350 Premix† Glargine

300

250 Baseline
200 * *
150 * *
*
100
Week 28

50
BB B90 BL L90 BD D90 Bed 3AM
Time of Day

Raskin P et al. Diabetes Care 2005;28:260-265.

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

 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

 Eleonor Study Results
100
9.0

pts achieving HbA1c <7.0 (%)

Group 1 p=NS
80
8.5
Group 2
55%
60 51%
HbA1c (%)

8.0

7.5 40

7.0 20
ADA/EASD target

6.5 0
0 Glargine 12 Glargine + 1 Glulisine + 36 Group Group
+ OHAs OHAs 1 2
Weeks

No clinically significant weight gain. Low rate of severe hypoglycemia

Del Prato S, et al. Diabetologia 2008;51 Suppl. 1:S452

 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 - 0.1 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
 Lispro, Aspart, Glulisine vs Regular
Insulin
Analog insulin
10
Insulin Activity

4
RHI

2 Timing of
food
absorbed
0
0 1 2 3 4 5 6 7 8 9 10 11 12

RHI = regular human insulin.

Hours

Adapted with permission from Howey DC et al. Diabetes 1994;43:396-402.

 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 - 0.1 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
 Robert Turner MA, MD, FRCP
Professor of Medicine
University of Oxford

1938-1999

“We don’t start insulin early

enough, or use it aggressively