Therapeutic Options Insulins. 1 Insulin Preparations ClassAgents Human insulinsRegular, NPH, lente,...

Therapeutic OptionsInsulins

2

Insulin Preparations

Class Agents

Human insulins Regular, NPH, lente, ultralente

Insulin analogues Aspart, glulisine, lispro, glargine

Premixed insulins Human 70/30, 50/50Humalog mix 75/25Novolog mix 70/30

3

Human Insulin

A-chain

B-chain

Zn++

Zn++

Self-aggregationin solution

Monomers

Dimers

Hexamers

21 amino acids

30 amino acids

4

Modified Human Insulin

Regular Insulin Short actingHexamers in Zn2+ buffer

Neutral Protamine Hagedorn (NPH) Insulin Intermediate actingMedium-sized crystals in protamine-Zn2+ buffer

Lente and Ultralente Insulin Intermediate andLarge crystals in acetate-Zn2+ buffer long acting

5

Profiles of Human Insulins

0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Plasmainsulinlevels

Regular 6–8 hours

NPH 12–20 hours Ultralente 18–24 hours

Hours

6

Insulin Analogues

Human InsulinDimers and hexamers

in solution

A-chain

B-chain

Lys Pro

Gly

Arg Arg

Asp

LisproLimited self-aggregation

Monomers in solution

AspartLimited self-aggregation

Monomers in solution

GlargineSoluble at low pH

Precipitates atneutral (subcutaneous) pH

GluGlulisine

Limited self-aggregationMonomers in solution

Lys

7

500

400

300

200

100

0

Insulin AspartA Rapid-Acting Insulin Analogue

Plasma Insulin

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

Insulin Action pmol/L

700

600

500

400

300

200

100

0

Minutes

0 100 200 300 400 500 600 0 100 200 300 400 500 600

Glusoseinfusion rate(mg/min)

Insulin aspartRegular insulin

20 Healthy Subjects, 10-h Euglycemic Clamp

8

Insulin LisproA Rapid-Acting Insulin Analogue

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

Insulin lisproRegular insulin

-60 -30 0 30 60 90 120 150 180 210 240

Minutes

mg/dLpmol/L400

-60 -30 0 30 60 90 120 150 180 210 240

Mealand

insulin

Mealand

insulin

Plasma Insulin Plasma Glucose

10 Patients With Type 1 Diabetes Following a Meal

300

200

100

0

200

150

0

100

9

0 4 8 12 16 20 24

Insulin Action Profiles in Type 1 Diabetes

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

Glucose infusion(mg/kg/min)

20 Patients

4

3

2

1

0

Glargine

NPHUltralente

Hours

10

Action Profiles of Insulin Analogues

0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Plasmainsulinlevels

Regular 6–8 hours

NPH 12–20 hours

Ultralente 18–24 hours

Hours

Glargine 24 hours

Aspart, glulisine, lispro 4–6 hours

11

Human Insulins and AnaloguesTypical Times of Action

Insulin Preparations

Onset of Action Peak Duration of Action

Aspart, glulisine, lispro

~15 minutes 1–2 hours 4–6 hours

Human regular 30–60 minutes 2–4 hours 6–8 hours

Human NPH, lente

2–4 hours 4–10 hours 12–20 hours

Human ultralente

4–6 hours 8–16 hours 18–24 hours

Glargine 2–4 hours Flat ~24 hours

12Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

0600 0600

Time of day

20

40

60

80

100 B L D

Normal Daily Plasma Insulin Profile

B=breakfast; L=lunch; D=dinner

0800 18001200 2400

U/mL

13

Time of day

20

40

60

80

100 B L D

Evening Basal InsulinBedtime NPH


0600 06000800 18001200 2400

NPHNormal pattern

U/mL

14

Starting Basal Insulin for Type 2 DiabetesBedtime NPH Added to Diet

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

300

200

00800 1200 1600

Time of day

2000 2400 0400 0800

400

100

Diet onlyBedtime NPH

Plasmaglucose(mg/dL)

NPH

12 Patients Treated for 16 Weeks

15

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

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

0

100

150

200

250

300*

*

12 1684 20 24

Weeks

Fasting Glucose

00

25

50

75

100

12 1684 20 24

*P<0.001

Insulin Dosage

**

* * **

Placebo + insulin (N=73)

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

mg/dL Units /day

*P<0.001

FPG=fasting plasma glucose

16

Time of day

20

40

60

80

100 B L D

Split-Mixed RegimenHuman Insulins


0600 0600 0800 18001200 2400

NPHRegular

NPHRegular

Normal pattern

U/mL

17

Split-Mixed RegimenNPH + Regular for Type 2 Diabetes

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

200

400

100

300

00

200

600

1000

400

800

0600 06001800 24001200

Time of day

0600 06001800 24001200

Diet onlyInsulin 6 months

Plasma Glucose Serum Insulin

B L D

N + R N + Rmg/dL pmol/L

B L D

N + R N + R


18

Time of day

20

40

60

80

100 B L D

Multiple Daily InjectionsHuman Insulins


0600 06000800 18001200 2400

Regular NPHNPHRegular

Normal pattern

U/mLRegular

19

Multiple Daily InjectionsNPH + Regular for Type 2 Diabetes

0

300

250

200

150

100

50

0800 1200 1600 2000 2400 0400 0800

Time of day

0800 1200 1600 2000 2400 0400 0800

Plasma Glucose Serum InsulinR NR R

0

300

200

100

Baseline oral agents Insulin 8 weeksNormal

mg/dL pmol/L

B L D B L D

R NR R

Sn Sn SnSn Sn Sn

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

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

10 Patients With Diabetes, 10 Normal Controls

20

Multiple Daily InjectionsNPH + Regular or Aspart for Type 1 Diabetes

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

100

80

60

40

200

mU/L

0600 1200 1800 2400 0600

Plasma Glucose

Serum Insulin

A A A N

NPH + regular insulin

B=breakfast; L=lunch; D=dinnerB L D

250

200

150

mg/dL14

12

10

86

mmol/L 16

Time of day

Insulin aspart

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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

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0600 0800 18001200 2400 0600

Time of day

20

40

60

80

100 B L D

Basal-Bolus Insulin TreatmentWith Insulin Analogues


Glargine

Lispro, glulisine, or aspart

Normal pattern

U/mL

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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

24

Barriers to Using InsulinAttitudes of Patients

With Type 1 and Type 2 Diabetes

0

20

40

60

80

100% of patients

High anxietyabout

injections

Troubledby ideaof more

injections

Avoidinjectionsbecause of anxiety

Troubledby ideaof more

injections

Avoidinjectionsbecause of anxiety

All Patients Patients With High Anxiety

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

14%

42%

28%

45%

70%

25

Barriers to Insulin TherapyCardiovascular Risk Is Not Supported by Trials

6-14

Type 2 Diabetes in the UKPDSRisk of myocardial infarctionConventional treatment 17.4 events/1000 pt-yrIntensive insulin 14.7 events/1000 pt-yr (P=0.052)

Type 1 and 2 Diabetes in the DIGAMI StudyLong-term survival after acute myocardial infarctionConventional treatment 44% mortality Intensive insulin 33% mortality (P=0.011)

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

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Barriers to Insulin TherapySevere Hypoglycemia

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

6-14

Type 1 Diabetes in the DCCTConventional insulin 35% of pts 19 events/100 pt-yrA1C ~9%, 6.5 yr

Intensive insulin 65% of pts 61 events/100 pt-yrA1C 7.2%, 6.5 yr

Type 2 Diabetes in the UKPDSIntensive policy insulin 37% of pts 2.3% pts/yr A1C 7.0%, 10 yr

27

Barriers to Insulin TherapyWeight Gain

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

Type 1 Diabetes in the DCCTIntensive insulin + 10.1 lb more A1C 7.2%, 6.5 yr than conventional insulin

Type 2 Diabetes in the UKPDSIntensive insulin + 8.8 lb moreA1C 7.0%, 10 yr than diet treatment

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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

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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

30

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

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Subcutaneous insulin: 16 U regular + 31 U long-actingInhaled insulin: 12 mg inhaled + 25 U ultralente

Inhaled Insulin in Type 1 Diabetes

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

10

Weeks

A1C (%)

0 4 8 12

73 Patients Taking Inhaled Insulin tid in Addition to Injected Long-Acting Insulin

9

8

7

6

32

Δ A1C (%)(mean baseline, 8.7%)

2

Baseline Week 8 Week 12Week 4


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

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-actingWeek 12 mean dose: 15 mg inhaled + 36 U ultralente

1

0

-1

33


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

10

8

6

4

0Baseline 12 weeks Baseline 12 weeks

–2.3%P<0.001

2

A1C (%)Oral agents alone Oral + inhaled insulin

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

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11A1C (%)

Baseline 60 days 90 days30 days

Buccally Absorbed Insulin in Type 2 Diabetes

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

Oral insulinPlacebo

33 Patients With Oral Insulin tid Added to DietChange from baseline -1.7%

Placebo-subtracted difference -2.2%

10

9

8

7

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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

Therapeutic Options Insulins. 1 Insulin Preparations ClassAgents Human insulinsRegular, NPH, lente,...

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