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Therapeutic Options Insulins. Insulin Preparations. ClassAgents Human insulinsRegular, NPH, lente, ultralente Insulin analoguesAspart, glulisine, lispro, glargine Premixed insulinsHuman 70/30, 50/50 Humalog mix 75/25 Novolog mix 70/30. Human Insulin. 21 amino acids. A-chain.

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Therapeutic Options Insulins

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Therapeutic options insulins

Therapeutic OptionsInsulins


Insulin preparations

Insulin Preparations

ClassAgents

Human insulinsRegular, NPH, lente, ultralente

Insulin analoguesAspart, glulisine, lispro, glargine

Premixed insulinsHuman 70/30, 50/50

Humalog mix 75/25

Novolog mix 70/30


Human insulin

Human Insulin

21 amino acids

A-chain

B-chain

30 amino acids

Monomers

Dimers

Self-aggregation

in solution

Hexamers

Zn++

Zn++


Modified human insulin

Modified Human Insulin

Regular InsulinShort acting

Hexamers in Zn2+ buffer

Neutral Protamine Hagedorn (NPH) InsulinIntermediate acting

Medium-sized crystals in protamine-Zn2+ buffer

Lente and Ultralente InsulinIntermediate andLarge crystals in acetate-Zn2+ bufferlong acting


Profiles of human insulins

Profiles of Human Insulins

2

3

4

5

6

7

8

9

12

13

14

15

16

17

18

19

20

21

22

23

24

0

1

10

11

Regular 6–8 hours

Plasma

insulin

levels

NPH 12–20 hours

Ultralente 18–24 hours

Hours


Insulin analogues

Insulin Analogues

Human Insulin

Dimers and hexamers

in solution

A-chain

B-chain

Aspart

Limited self-aggregation

Monomers in solution

Asp

Glulisine

Limited self-aggregation

Monomers in solution

Glu

Lys

Lispro

Limited self-aggregation

Monomers in solution

Lys Pro

Gly

Glargine

Soluble at low pH

Precipitates at

neutral (subcutaneous) pH

Arg Arg


Insulin aspart a rapid acting insulin analogue

Insulin AspartA Rapid-Acting Insulin Analogue

20 Healthy Subjects, 10-h Euglycemic Clamp

Insulin aspart

Regular insulin

Plasma Insulin

Insulin Action

Glusose

infusion rate

(mg/min)

500

400

300

200

100

0

pmol/L

700

600

500

400

300

200

100

0

0

100

200

300

400

500

600

0

100

200

300

400

500

600

Minutes

Mudaliar SR et al. Diabetes Care. 1999;22:1501-1506


Insulin lispro a rapid acting insulin analogue

Insulin LisproA Rapid-Acting Insulin Analogue

10 Patients With Type 1 Diabetes Following a Meal

Regular insulin

Insulin lispro

Plasma Insulin

pmol/L

Plasma Glucose

mg/dL

200

400

Meal

and

insulin

Meal

and

insulin

300

150

200

100

100

0

0

-60-30 0 306090120150 180210240

-60 -30 030 6090120150 180210240

Minutes

Heinemann L et al. Diabet Med. 1996;13:625-629


Therapeutic options insulins

Insulin Action Profiles in Type 1 Diabetes

20 Patients

4

3

2

1

0

Glucose infusion

(mg/kg/min)

Ultralente

NPH

Glargine

0

4

8

12

16

20

24

Hours

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


Action profiles of insulin analogues

Action Profiles of Insulin Analogues

2

3

4

5

6

7

8

9

12

13

14

15

16

17

18

19

20

21

22

23

24

0

1

10

11

Aspart, glulisine, lispro 4–6 hours

Regular 6–8 hours

Plasma

insulin

levels

NPH 12–20 hours

Ultralente 18–24 hours

Glargine 24 hours

Hours


Human insulins and analogues typical times of action

Human Insulins and AnaloguesTypical Times of Action


Normal daily plasma insulin profile

Normal Daily Plasma Insulin Profile

U/mL

100

B

L

D

80

60

40

20

1200

2400

1800

0800

0600

0600

Time of day

B=breakfast; L=lunch; D=dinner

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


Evening basal insulin bedtime nph

Evening Basal InsulinBedtime NPH

1200

2400

0600

1800

0800

0600

U/mL

100

B

L

D

Normal pattern

80

NPH

60

40

20

Time of day

B=breakfast; L=lunch; D=dinner


Starting basal insulin for type 2 diabetes bedtime nph added to diet

Starting Basal Insulin for Type 2 DiabetesBedtime NPH Added to Diet

12 Patients Treated for 16 Weeks

Plasma

glucose

(mg/dL)

400

Diet only

Bedtime NPH

300

NPH

200

100

0

0800

1200

1600

2000

2400

0400

0800

Time of day

Cusi K et al. Diabetes Care. 1995;18:843-851


Starting basal insulin for type 2 diabetes suppertime 70 30 added to glimepiride

Starting Basal Insulin for Type 2 DiabetesSuppertime 70/30 Added to Glimepiride

Placebo + insulin (N=73)

Glimepiride + insulin titrated to FPG 140 mg/dL (N=72)

Fasting Glucose

Insulin Dosage

mg/dL

Units /day

100

300

*

*

250

*

*

*

75

*P<0.001

*

*

*

200

50

150

25

*P<0.001

100

0

0

4

8

12

16

20

24

0

4

8

12

16

20

24

Weeks

FPG=fasting plasma glucose

Riddle MC et al. Diabetes Care. 1998;21:1052-1057


Split mixed regimen human insulins

Split-Mixed RegimenHuman Insulins

1200

2400

1800

0800

0600

0600

NPH

Regular

NPH

Regular

U/mL

100

B

L

D

80

Normal pattern

60

40

20

Time of day

B=breakfast; L=lunch; D=dinner


Split mixed regimen nph regular for type 2 diabetes

Split-Mixed RegimenNPH + Regular for Type 2 Diabetes

Diet only

Insulin 6 months

Plasma Glucose

Serum Insulin

pmol/L

mg/dL

N + R

N + R

N + R

N + R

1000

400

800

300

600

200

400

100

200

0

0

0600

1200

1800

2400

0600

0600

1200

1800

2400

0600

B

L

D

B

L

D

Time of day

B=breakfast; L=lunch; D=dinner

Henry RR et al. Diabetes Care. 1993;16:21-31


Multiple daily injections human insulins

Multiple Daily InjectionsHuman Insulins

0800

0600

1200

2400

0600

1800

NPH

Regular

Regular

Regular

NPH

U/mL

100

B

L

D

80

60

Normal pattern

40

20

Time of day

B=breakfast; L=lunch; D=dinner


Multiple daily injections nph regular for type 2 diabetes

Multiple Daily InjectionsNPH + Regular for Type 2 Diabetes

10 Patients With Diabetes, 10 Normal Controls

Baseline oral agents

Normal

Insulin 8 weeks

Plasma Glucose

Serum Insulin

R

R

N

R

R

N

R

R

mg/dL

pmol/L

300

300

250

200

200

150

100

100

50

0

0

0800

1200

1600

2000

2400

0400

0800

0800

1200

1600

2000

2400

0400

0800

B

Sn

L

Sn

D

Sn

B

Sn

L

Sn

D

Sn

Time of day

B=breakfast; Sn=snack; L=lunch; D=dinner

Lindström TH et al. Diabetes Care. 1992;15:27-34


Multiple daily injections nph regular or aspart for type 1 diabetes

Multiple Daily InjectionsNPH + Regular or Aspart for Type 1 Diabetes

16

Plasma Glucose

mg/dL

mmol/L

14

250

12

10

200

8

150

6

Serum Insulin

NPH + regular insulin

A

N

A

A

mU/L

100

Insulin aspart

80

60

40

20

0

0600

1200

1800

2400

0600

B

L

D

B=breakfast; L=lunch; D=dinner

Time of day

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


The basal bolus insulin concept

The Basal-Bolus Insulin Concept

  • Basal insulin

    • Controls glucose production between meals and overnight

    • Nearly constant levels

    • 50% of daily needs

  • Bolus insulin (mealtime or prandial)

    • Limits hyperglycemia after meals

    • Immediate rise and sharp peak at 1 hour postmeal

    • 10% to 20% of total daily insulin requirement at each meal

  • For ideal insulin replacement therapy, each component should come from a different insulin with a specific profile


Basal bolus insulin treatment with insulin analogues

Basal-Bolus Insulin TreatmentWith Insulin Analogues

0600

1800

0800

0600

1200

2400

Lispro, glulisine, or aspart

U/mL

100

Glargine

B

L

D

80

60

Normal pattern

40

20

Time of day

B=breakfast; L=lunch; D=dinner


Barriers to using insulin

Patient resistance

Perceived significance of needing insulin

Fear of injections

Complexity of regimens

Pain, lipohypertrophy

Physician resistance

Perceived cardiovascular risks

Lack of time and resources to supervise treatment

Medical limitations of insulin treatment

Hypoglycemia

Weight gain

Barriers to Using Insulin


Barriers to using insulin attitudes of patients with type 1 and type 2 diabetes

Barriers to Using InsulinAttitudes of PatientsWith Type 1 and Type 2 Diabetes

All Patients

Patients With High Anxiety

100

% of patients

80

70%

60

45%

42%

40

28%

14%

20

0

Avoidinjectionsbecause of anxiety

Troubledby ideaof moreinjections

High anxietyabout injections

Avoidinjectionsbecause of anxiety

Troubledby ideaof moreinjections

Zambanini A et al. Diabetes Res Clin Pract. 1999;46:239-246


Barriers to insulin therapy cardiovascular risk is not supported by trials

Barriers to Insulin TherapyCardiovascular Risk Is Not Supported by Trials

Type 2 Diabetes in the UKPDS

Risk of myocardial infarction

Conventional treatment17.4 events/1000 pt-yr

Intensive insulin14.7 events/1000 pt-yr (P=0.052)

Type 1 and 2 Diabetes in the DIGAMI Study

Long-term survival after acute myocardial infarction

Conventional treatment 44% mortality

Intensive insulin33% mortality (P=0.011)

UKPDS Group. Lancet. 1998;352:837-853; Malmberg K. BMJ. 1997;314:1512-1515

6-14


Barriers to insulin therapy severe hypoglycemia

Barriers to Insulin TherapySevere Hypoglycemia

Type 1 Diabetes in the DCCT

Conventional insulin 35% of pts19 events/100 pt-yr

A1C ~9%, 6.5 yr

Intensive insulin65% of pts61 events/100 pt-yr

A1C 7.2%, 6.5 yr

Type 2 Diabetes in the UKPDS

Intensive policy insulin37% of pts2.3% pts/yr

A1C 7.0%, 10 yr

DCCT Research Group. Diabetes. 1997;46:271-286; UKPDS Group. Lancet. 1998;352:837-853

6-14


Barriers to insulin therapy weight gain

Barriers to Insulin TherapyWeight Gain

Type 1 Diabetes in the DCCT

Intensive insulin+ 10.1 lb more

A1C 7.2%, 6.5 yrthan conventional insulin

Type 2 Diabetes in the UKPDS

Intensive insulin+ 8.8 lb more

A1C 7.0%, 10 yr than diet treatment

DCCT Research Group. Diabetes. 1997;46:271-286; DCCT Research Group. N Engl J Med. 1993;329:977-986; UKPDS Group. Lancet. 1998;352:837-853


Insulin injection devices

Insulin pens

Faster and easier than syringes

Improve patient attitude and adherence

Have accurate dosing mechanisms, but inadequate mixing may be a problem

Insulin Injection Devices


Insulin pumps

Insulin Pumps

Continuous subcutaneous insulin infusion (CSII)

  • External, programmable pump connected to an indwelling subcutaneous catheter to deliver rapid-acting insulin

    Intraperitoneal insulin infusion

  • Implanted, programmable pump with intraperitoneal catheter. Not available in the United States


New insulins in clinical development

New Insulins in Clinical Development

  • Long-acting insulin analogue –Insulin detemir

    • Acylated insulin analogue

    • Soluble, binds to albumin

  • Rapid-acting insulin analogue –Insulin 1964

    • Limited aggregation, like lispro and aspart

    • Rapid absorption from injection site

  • Inhaled insulins –Aerodose, AERx, Exubera

    • Liquid aerosol or particulate cloud

    • Delivered by portable devices

  • Buccally absorbed insulin –Oralin

    • Liquid aerosol

    • Delivered by portable device


Inhaled insulin in type 1 diabetes

Inhaled Insulin in Type 1 Diabetes

73 Patients Taking Inhaled Insulin tid in Addition to Injected

Long-Acting Insulin

Subcutaneous insulin: 16 U regular + 31 U long-acting

A1C (%)

10

Inhaled insulin: 12 mg inhaled + 25 U ultralente

9

8

7

6

0

4

8

12

Weeks

Skyler JS et al. Lancet. 2001;357:331-335


Inhaled insulin in type 2 diabetes

Inhaled Insulin in Type 2 Diabetes

26 Patients With Subcutaneous Regular Replaced by Inhaled Insulin tid, in Addition to Long-Acting Insulin

Baseline mean dose: 19 U regular + 51 U long-acting

Week 12 mean dose: 15 mg inhaled + 36 U ultralente

Δ A1C (%)(mean baseline, 8.7%)

2

1

0

-1

Baseline

Week 4

Week 8

Week 12

Cefalu WT et al. Ann Intern Med. 2001;134:203-207


Inhaled insulin in type 2 diabetes1

Inhaled Insulin in Type 2 Diabetes

69 Patients With Inhaled Insulin tid Added to Sulfonylurea and/or Metformin

Oral agents alone

Oral + inhaled insulin

A1C (%)

10

–2.3%

P<0.001

8

6

4

2

0

Baseline

12 weeks

Baseline

12 weeks

Weiss SR et al. Diabetes. 1999;48(suppl 1):A12


Buccally absorbed insulin in type 2 diabetes

Buccally Absorbed Insulin in Type 2 Diabetes

33 Patients With Oral Insulin tid Added to DietChange from baseline -1.7%Placebo-subtracted difference -2.2%

A1C (%)

11

Oral insulin

Placebo

10

9

8

7

Baseline

30 days

60 days

90 days

Schwartz S et al. Diabetes. 2001;50(suppl 2):A130


Summary insulin therapy

SummaryInsulin Therapy

  • Replaces complete lack of insulin in type 1 diabetes

  • Supplements progressive deficiency in type 2 diabetes

  • Basal insulin added to oral agents can be used to start

  • Full replacement requires a basal-bolus regimen

  • Hypoglycemia and weight gain are the main medical risks

  • New insulin analogues and injection devices facilitate use


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