Insulin Therapy of Type 2 Diabetes Jack L. Leahy University of Vermont College of Medicine Division...

Insulin Therapy of Type 2 Diabetes

Jack L. LeahyUniversity of Vermont College of Medicine

Division of Endocrinology, Diabetes and MetabolismBurlington, Vermont

Global Projections for the Diabetes Epidemic: 2003-2025

23.0 M36.2 M↑57.0%

14.2 M26.2 M↑85%

48.4 M58.6 M↑21% 43.0 M

75.8 M ↑79%

7.1M15.0 M↑111%

39.3 M81.6 M

↑108%

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 PacificDiabetes Atlas Committee. Diabetes Atlas 2nd Edition: IDF 2003.

World

2003 = 194 M2025 = 333 M

↑ 72%

AFR

NA

SACA

EUR

SEA

WP

19.2 M39.4 M↑105%

EMME

2003 2025

Standards of Care - American Diabetes Association

• Glycemia: HbA1c <7.0%, FPG 90-130 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

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

Consensus Algorithm Update 2009

Check A1C every3 months until <7%. Change treatment if

A1C is ≥7%

Step 3

Tier 1: Well-validated core therapies

At diagnosis:

Lifestyle+

Metformin

Lifestyle + Metforminplus

Basal Insulin

Lifestyle + Metformin plus

Sulfonylureaa


Intensive Insulin

Step 1 Step 2


PioglitazoneNo hypoglyceamia

Oedema / CHFBone Loss


GLP-1 agonistNo hypoglyceamia

Weight lossNausea / vomiting

Tier 2: Less well-validated therapies


Pioglitazone plus

Sulfonylurea


Basal Insulin

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

0

20

40

60

80

100

% o

f Su

bje

cts

Percentage of subjects advancing when A1C < 8%

Clinical Inertia: Failure to Advance Therapy When Required

Diet

66.6%

Sulfonylurea Metformin

35.3%44.6%

Combination

18.6%

At insulin initiation, the average patient had:• 5 years with A1C > 8%• 10 years with A1C > 7%

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”.

B = breakfast; L = lunch; D = dinner.

Polonsky KS et al. N Engl J Med 1988;318:1231-1239.

100

200

300

400Glucose Insulin

6:00 10:00 18:0014:00 2:0022:00 6:00

Time

6:00 10:00 18:0014:00 2:0022:00 6:00

Time

20

40

60

80

100

120

B L DB L D

Nondiabetic Type 2 diabetes

mg

/dL

U/m

L

Basal insulin

Basal Insulin Therapy

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

Time (hours)

Basal Insulin ProfilesGlucose Infusion Rates

N=20 T1DM

Mean SEM

0

4

8

Mg/Kg/min

mol/Kg/min

s.c. insulin

NPH

Glargine

4.0

3.0

2.0

1.0

0

40 128 2016 24

12

16

20

24

≈15% with some peak

NPH Glargine

Insulin Detemir: Structure

Lys

Thr Tyr

Thr

Phe Phe Gly ArgGlu

Gly

Val

LeuTyr

Leu

AlaGlu

ValLeu

HisSer

GlyLeuHis

Gln

Val

ValPheB1B3

A21B29

ProCys

TyrAsn

Glu

Cys

Gln

Leu

GlnTyr

LeuSerCys

CysThr Ser lle

Gly

lle

Glu

Gln

Cys

Cys

Asp

A1

C14 fatty acid chain

(Myristic acid)

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

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

Time since insulin injection (h)

0 2 4 6 8 10 12 14 16 18 20 22 24

Glu

cose

infu

sio

n

rate

(m

g/k

g/m

in)

Detemir 0.1 U/kgDetemir 0.2 U/kgDetemir 0.4 U/kgDetemir 0.8 U/kgDetemir 1.6 U/kg

0

1

2

3

4

5

6

7

Dose Dependency of Action Profiles of

Insulin Detemir

Insulin Glargine Trials Showing Effective Reduction in HbA1c

Hb

A1

c (%

)

APOLLO LAPTOP Triple Therapy

LANMET

10

9

8

7

6

5Treat-To-

TargetINITIATE

7.147.156.96

7.146.80

8.71 8.85 8.809.5

8.808.61

6.96

Baseline Study endpoint

Mullins P et al. Clin Ther 2007;29:1607−19.

Less Hypoglycemia with Insulin Glargine vs NPH

6 7 8 9 10HbA1c

3500

3000

2500

2000

1500

1000

Hyp

ogly

cem

ia

even

ts p

er 1

00

patie

nt-y

ears

NPH Insulin glargine

200

150

100

50

06 7 8 9 10

HbA1c

Hyp

ogly

cem

ia

even

ts p

er 1

00

patie

nt-y

ears

T1DM

T2DM

p=0.004 between treatments

p=0.021 between treatments

Key Questions

• Is there a difference between Glargine and Detemir?

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

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

Hem

oglo

bin

A1c

(%

)

4

6

8

5

7 7.2 7.1

P = NS

Glargine Detemir

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?

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

Consensus Algorithm Update 2009

Check A1C every3 months until <7%. Change treatment if

A1C is ≥7%

Step 3

Tier 1: Well-validated core therapies

At diagnosis:

Lifestyle+

Metformin


Basal Insulin


Sulfonylureaa


Intensive Insulin

Step 1 Step 2


PioglitazoneNo hypoglyceamia

Oedema / CHFBone Loss


GLP-1 agonistNo hypoglyceamia

Weight lossNausea / vomiting

Tier 2: Less well-validated therapies


Pioglitazone plus

Sulfonylurea


Basal Insulin

Heine RJ et al. Ann Intern Med 2005;143:559-569.

Prebreakfast

Both medications lowered A1C from 8.2% to 7.1% from baselineWeight change: exenatide –2.3 kg, glargine +1.8 kg

Nausea: exenatide 57.1%, glargine 8.6%

Exenatide vs Once-Daily Insulin Glargine: Self-Monitoring Blood Glucose Profiles (n=549)

Blo

od

glu

cose

(m

g/d

L)

3 AM

100

120

140

160

180

200

220

240

Baseline (week 0)Endpoint (week 26)

3 AM

100

120

140

160

180

200

220

240

Baseline (week 0)Endpoint (week 26)

Exenatide5 µg bid 1st 4 weeks, then 10 µg bid

Insulin glargine10 U/d, titrated to target FPG <100 mg/dL

Prebreakfast

Prelunch

Predinner

Prelunch

Predinner

Key Questions



• 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




– Continue OHA - “add on” therapy, not “substitution” therapy.

Key Questions





• What are expected doses of basal insulin (Glargine or NPH)?

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.

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

every week

+ 1 U every day +2 U or + 4 U

every 3 days

+2 U

every 3 days

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

Published Insulin Glargine Doses and Titration Algorithms

Key Questions






– 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








• 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

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.

CheckFBGdaily

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;32:193-203.

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.

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

every week

+ 1 U every day +2 U or + 4 U

every 3 days

+2 U

every 3 days

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

Published Insulin Glargine Doses and Titration Algorithms

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

Adapted from Yki-Järvinen H, et al. Diabetologia 2006;49:442–51Time (weeks)

FP

G /

wee

kly

mea

ns (

mg/

dL)

0

30

60

90

120

180

-4 0 4 8 12 16 20 24 28 3632

210

0

20

40

60

80

150

Insulin dose (IU/day)

Key Questions









• Why not start with premixed insulins?

Split-Mixed/Pre-Mixed Insulin Therapy

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00

BreakfastBreakfast LunchLunch DinnerDinner

12:0012:008:008:00

TimeTime

Pla

sma

Insu

lin

Pla

sma

Insu

lin Regular

NPH

LAPTOP: Insulin Glargine Versus 70/30 Premixed Insulin in OHA Failures

Janka H et al. Diabetes Care 2005;28:254−259.

*Confirmed symptomatic hypoglycaemia (blood glucose <60 mg/dl [<3.3 mmol/l])

N=371 insulin-naïve patientsInsulin glargine + OADs vs twice-daily human NPH insulin (70/30)Follow-up: 24 weeks

Hypoglycaemia* (events/patient year)

0

1

2

3

4

5

p=0.0009

5

6

7

8

9

HbA1c (%)

7.5%7.2%

1.3% 1.7%

p=0.0003

Twice-daily premixed insulinInsulin glargine + OADs

2.6

5.7

Analog Pre-Mixed Insulin Therapy

4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00

BreakfastBreakfast LunchLunch DinnerDinner

12:0012:008:008:00

TimeTime

Pla

sma

Insu

lin

Pla

sma

Insu

lin

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

Change in A1C From Baseline to Study End

9.8%

6.9%7.4%

5

6

7

8

9

Insulin Glargine + OADs PreMix

Baseline

Endpoint

P<0.01

A1C

(%

)

- 2.4% - 2.8%

10

9.7%

HypoglycemiaDocumented Hypoglycemic Episodes (<56 mg/dL)

0.7

3.4

0

1

2

3

4

Epi

sode

s pe

r pa

tient

yea

r

P<0.05

Insulin Glargine PreMix


Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin

Key Questions









• Why not start with premixed insulins?

• What if basal insulin is not enough?

350

300

250

200

150

100

50


*

Pla

sma

Glu

cose

(m

g/dL

)

Week 28

Baseline

GlarginePremix†

Time of DayBB B90 BL L90 BD D90 Bed 3AM

**

**

Blood Glucose Profiles

Lifestyle changes + Metformin

Additional Oral agents

BasalAdd basal insulin and titrate

Basal PlusAdd prandial insulin at main meal

Basal BolusInsulin Initiation

Intensification

Further intensification

Progressive deterioration of -cell function

Stepwise Treatment of Type 2 Diabetes

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

Hb

A1c

(%

)

Group 1Group 2

9.0

6.5

7.0

7.5

8.0

8.5

0 12 36

ADA/EASD target

Weeks

Glargine + OHAs

Glargine + 1 Glulisine + OHAs

20

40

60

80

100

pts

ach

ievi

ng

Hb

A1c

<7.

0 (%

)

51%55%

0

p=NS

Group1

Group2

Eleonor Study Results

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

HoursRHI = regular human insulin.

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

10

8

6

4

2

0

0 1 2 3 4 5 6 7 8 9 10 11 12

Insu

lin

Act

ivit

y

RHI

Timing offood

absorbed

Analog insulin

Lispro, Aspart, Glulisine vs Regular Insulin

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

“We don’t start insulin early enough, or use it aggressively

enough”

Robert Turner MA, MD, FRCPProfessor of MedicineUniversity of Oxford

1938-1999

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Insulin Therapy of Type 2 Diabetes Jack L. Leahy University of Vermont College of Medicine Division...

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