Analogs as a Focus

Bruce W. Bode, MD, FACE

Atlanta Diabetes Associates

Atlanta, Georgia

ADA. Clinical Practice Recommendations. 2001.

Goals of Intensive Diabetes Management

• Near-normal glycemia

— HbA1c <6.5% to 7.0%

• Avoid short-term crisis

— Hypoglycemia

— Hyperglycemia

— DKA

• Minimize long-term complications

• Improve QOL

ACE/AACE Targets for Glycemic Control

HbA1c <6.5%

Fasting/preprandial glucose <110 mg/dL

Postprandial glucose <140 mg/dL

ACE/AACE Consensus Conference. Washington, DC. August 2001.

Insulin

The Most Powerful Agent We Have to Control Glucose

Fred Banting (1891-1941) Charles H. Best (1899-1978) John J.R. McLeod (1876-1935)Fred Banting (1891-1941) Charles H. Best (1899-1978) John J.R. McLeod (1876-1935)

James B. CollipJames B. Collip(1892-1965)(1892-1965)

Marjorie (?-?)Marjorie (?-?)

The Discovery of Insulin (Toronto 1921)

Patient J.L., December 15, 1922 February 15, 1923

The Miracle of Insulin

Comparison of Human Insulins/Analogs

Insulin Onset of Duration ofPreparations Action Peak Action

Regular 30-60 min 2-4 h 6-10 h

NPH/lente 1-2 h 4-8 h 10-20 h

Ultralente 2-4 h Unpredictable 16-20 h

Lispro/aspart 5-15 min 1-2 h 4-6 h

Glargine 1-2 h Flat ~24 h

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Pla

sma

insu

lin

Ideal Basal/Bolus Insulin Absorption Pattern

Rapid-acting Insulin Analogs: Medical Rationale

• Administration at mealtime

• Mimic physiologic insulin profile

• Improved postprandial glycemic control

• Lower risk of late hypoglycemia

Gly ThrGlu Phe Tyr Pro Lys Thr

Gly ThrGlu Phe Tyr Lys Pro Thr

23 24 25 26 27 28 29 30

Insulin

Lispro

Primary Structure of Lys(B28), Pro(B29)–Insulin

Gly ThrGlu Phe Tyr Pro Lys Thr

Gly ThrGlu Phe Tyr Asp Lys Thr

23 24 25 26 27 28 29 30

Insulin

Aspart

Primary Structure of Asp(B28)-Insulin

Dissociation and Absorption of NovoLog®

Insulin aspart (NovoLog®)

Regular human insulin

Peak time=80-120 min

Peak time=40-50 min

Capillarymembrane

Su

bcu

tan

eou

s ti

ssu

eS

ub

cuta

neo

us

tiss

ue

800

700

600

500

400

300

200

100

0

Se

rum

ins

ulin

(p

mo

l/L)

0.2 U/kg SQTime (h)

0 2 4 6 8 10

Insulin aspartRegular insulin

Heinemann L, et al. Diabetes Care. 1998;21:1910.

Insulin Aspart: Mean Serum Insulin Profiles During Euglycemic Clamp in Healthy Volunteers

Glucose Area Under the Curve

60

70

80

90

100

110

120

130

-30 Fast 30 60 90 120 240

Time (min)

Glucose (mg/dL)

None

RegularAspart

Home PD, et al. Diabetes Care. 1998;21:1904-1909.

BreakfastBreakfast LunchLunch DinnerDinner NPHNPH

mU/LmU/L

8080

6060

4040

2020

00

100100

06:0006:00 12:0012:00 18:0018:00 24:0024:00 06:0006:00

Ser

um

in

suli

nS

eru

m i

nsu

lin

1010

mmol/Lmmol/L

1616

1414

1212

88

66

1818

Pla

sma

glu

cose

Pla

sma

glu

cose

250250

200200

150150

300300

mg/dLmg/dL

Insulin aspart

Human regular

Insulin Aspart vs Human Regular: Glycemic Control

Prandial increment isthe increase in bloodglucose from premeal to 90 minutes postmeal

European trial North American trial

Incr

emen

t (m

mo

l/L

)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

P<0.001 P<0.001

NovoLog®

Regular human insulin

Raskin P, et al. Diabetes Care. 2000;23:583.Home PD, et al. Diabet Med. 2000;17:762.

Postprandial Blood Glucose Increment (Mean over the 3 Meals at 6 Months)

NovoLog®

Regular human insulin

100

Study 1 Study 2 Study 3 Study 4

0

200

300

400

500

Outliers

Median

Data from: Home. Eur J Clin Pharmacol. 1999;55:199-203.Heinemann. Diabet Med. 1996;13:683-684. Mudaliar. Diabetes Care. 1999;22:1501-1506.Heinemann. Diabetes Care. 1998;21:1910-1914.

Healthy Volunteers

Decreased Interindividual Variability in NovoLog® Values for Tmax

Tm

ax (

min

)

Frequency of events:

7.9

7.8

7.7

7.6

0

Hb

A1

c (

%)

NovoLog® Regularinsulin

NovoLog® Regularinsulin

8.0

8.1

8.20 per year0-10 per year10-30 per year>30 per year

Type 1 Diabetes

*Symptoms or blood glucose <45 mg/dL.Data on file, Novo Nordisk. Studies 035/EU, 036/US.

Study 035/EU Study 036/US

Frequency of Minor* Hypoglycemia Observed by Level of Glycemic Control

NovoLog® Regular human insulin

14

10

0

% Patients with MajorHypoglycemic Episodes

Nighttime

4

12

Daytime

8

6

2

P<0.005 NS

Data on file, Novo Nordisk. Studies 035/EU, 036/US.

Reduced Reporting of Major Nocturnal Hypoglycemia

%

Reduced Risk of Major Nocturnal Hypoglycemia

0.7

0.5

Relative Risk NovoLog Compared with Regular

Human Insulin

NovoLog®

HumanInsulin

(No. of Patients with Events)

Home 8%(54/707)

11%(39/358)

Raskin 4%(24/596)

8%(23/286)

Study 035/EU Study 036/US

Data on file, Novo Nordisk. Studies 035/EU, 036/US.

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Pla

sma

insu

lin

lispro lispro lispro

Aspart Aspart Aspartor oror

Rapid-acting Insulin Analogs Provide Ideal Prandial Insulin Profile

400

350

300

250

200

150

100

MealSC injection

50

00 30 60

Time (min)90 120 180 210150 240

Regular Lispro

500450400350300250

150

50

200

100

00 50 100

Time (min)150 200 300250

Pla

sm

a i

ns

uli

n (

pm

ol/

L)

Pla

sm

a i

ns

uli

n (

pm

ol/

L)

MealSC injection

Heinemann, et al. Diabet Med. 1996;13:625-629.Mudaliar SR, et al. Diabetes Care. 1999;22:1501-1506.

Regular Aspart

Short-acting Insulin Analogs:Lispro and Aspart Plasma Insulin Profiles

Pharmacokinetic Comparison: NovoLog® vs Humalog®

300

350

250

200

150

100

50

0

7 8 9 10 11 12 13

NovoLog®

Humalog®

Fre

e in

sulin

(p

mo

l/L)

Time (h)Hedman CA, et al. Diabetes Care. 2001;24:1120-1121.

Insulin Aspart vs Buffered R vs Insulin Lispro in CSII Study

Bode B, et al. Diabetes Care. 2002;25:439-444.

Insulin aspart

Buffered regular human insulin (Velosulin®)Screening

Insulin lispro

-2 weeks 16 weeks0 weeks

146 patients in the USA; 2-25 years with type 1 diabetes;

7%HbA1c9%; previously treated with CSII for 3 months

Glycemic Control with CSII NovoLog®

Human insulin

Humalog®

7.0

7.2

7.8

8.0

Hb

A1

c (

%) 7.6

7.4

Baseline Week 8 Week 12 Week 160

Bode B. Diabetes. 2001;50(S2):A106.

Type 1 Diabetes

Self-monitored Blood Glucose in CSII

NovoLog® Buffered regular Humalog®

80

100

120

140

160

180

200

220

Blo

od

glu

cose

(m

g/d

L)

* *

*

Bedtime 2 AMBefore and90 min after

breakfast

Before and90 min after

lunch

Before and90 min after

dinner

Type 1 Diabetes

*P<0.01 vs buffered regular insulin.Bode B. Diabetes. 2001;50(S2):A106.

Ep

iso

des

/mo

nth

/pat

ien

t

0

2

4

6

8

10

12

Insulin aspart Human insulin Insulin lispro

PP<0.05<0.05

PP<0.05<0.05

Symptomatic or Confirmed Hypoglycemia

30% relative reduction

Bode B, et al. Diabetes Care. 2002;25:439-444.

0

10

20

30

40

50

Insulin aspartBuffered human insulinInsulin lispro

Pat

ien

ts w

ith

tro

ub

le-f

ree

use

(%

)

Insulin Aspart vs Buffered R vs Insulin Lispro in CSII Study: Pump Compatibility

Data on file, Novo Nordisk. Study ANA 2024.

Long-acting Soluble Insulin Analogs: Medical Rationale

• Mimic basal physiological insulin profile

• Improved glycemic control

• More reproducible insulin delivery

• May be used in insulin pens

Limitations of NPH, Lente,and Ultralente

• Do not mimic basal insulin profile

— Variable absorption

— Pronounced peaks

— Less than 24-hour duration of action

• Cause unpredictable hypoglycemia

— Major factor limiting insulin adjustments

ThrPhe Tyr Pro Lys Thr

25 26 27 28 29 30

InsulinB-chain

Glargine ThrPhe Tyr Pro Lys Thr Arg Arg

AsnLeu Glu Tyr Cys Gly

AsnLeu Glu Tyr Cys Asn

16 17 18 19 20 21

InsulinA-chain

Glargine

Primary Structure of Gly(A21), Arg(B31), Arg(B32)-Insulin

Gly ThrGlu Phe Tyr Pro Lys Thr

Gly ThrGlu Phe Tyr Pro Lys Thr

23 24 25 26 27 28 29 30

Insulin

Detemir

(CH(CH22))44

NHNH

COCO

RR

Primary Structure of Lys(B29)-N--Tetradecanoyl, Des(B30)-Insulin

Basis of Effect of Insulin Glargine

• Isoelectric point change

• Precipitates at neutral tissue pH

— Acid in solution; cannot be mixed with other insulins

• Retarded absorption rate

• Corresponding longer duration of action

0

0

1

2

3

4

5

6

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

NPH

Glargine

Placebo

0.4 U/kg

Time (h)

Glu

cose

infu

sio

n r

ates

(mg

/kg

/min

)

Linkeschowa R, et al. Diabetes.1999;48(suppl 1):A97.

Insulin Glargine in Nondiabetic Subjects: Pharmacokinetics by Glucose Clamp

Overall Summary: Glargine

• Insulin glargine has the following clinical benefits:

— Once-daily dosing because of its prolonged duration of action and smooth, peakless time-action profile

— Comparable or better glycemic control (FBG)

— Lower risk of nocturnal hypoglycemic events

— Safety profile similar to that of human insulin

Basis of Effect of Acylated Insulin Analogs (Detemir)

• Bind to serum albumin

• Prolonged time in circulation

• Longer duration of action

Injectionsite

Hormone

Blood

Carrierprotein

Carrierprotein Hormonehormone

Carrierprotein

Tissue

Receptor

Receptorhormone

Use of a Serum Carrier Protein (eg, Albumin) to Extend Time of Action

Brunner GA, et al. Exp Clin Endocrinol Diabetes. 2000;108:100-105.

Elapsed time (min)

0.0

0.5

1.0

1.5

2.0

-100 100 300 500 700 900 1100 1300 1500

Detemir - high

Detemir - low

Placebo

Glu

cose

infu

sio

n r

ate

(mg

/kg

/min

)

Insulin Detemir in Nondiabetic Subjects:Pharmacokinetics by Glucose Clamp

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Glargineor

detemir

Pla

sma

insu

lin

Long-acting Insulin Analogs Provide Ideal Basal Insulin Profile

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Glargineor

detemir

lispro lispro lispro

Aspart Aspart Aspartor oror

Pla

sma

insu

lin

Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs

Insulin Receptor Affinity (%) IGF-1 Receptor Affinity (%)

Cells Solubilized Cells SolubilizedReceptors Receptors

Relative to human insulin Relative to human insulin

Receptor Binding Affinities

Human insulin 100 100 100 100

Insulin aspart 92 92 69 81

Insulin lispro 102 ND 142 156

Insulin glargine ND 86 ND 641

ND = not determined.

Insulin Analogs

Fulfilling the Promise of Recombinant DNA Technology:

Better BasalBetter Bolus

Better Blood Glucose