Insulin Deficiency and Insulin Resistance

1
Therapeutic OptionsInsulins
2
Insulin Preparations

• Class Agents
• Human insulins Regular, NPH, lente, ultralente
• Insulin analogues Aspart, glulisine, lispro,
  glargine
• Premixed insulins Human 70/30, 50/50
• Humalog mix 75/25
• Novolog mix 70/30

3
Human Insulin
21 amino acids
A-chain
B-chain
30 amino acids
Monomers
Dimers
Self-aggregation in solution
Hexamers
Zn
Zn
4
Modified Human Insulin
Regular Insulin Short acting Hexamers in Zn2
buffer Neutral Protamine Hagedorn (NPH)
Insulin Intermediate acting Medium-sized crystals
in protamine-Zn2 buffer Lente and Ultralente
Insulin Intermediate andLarge crystals in
acetate-Zn2 buffer long acting
5
Profiles of Human Insulins
Regular 68 hours
Plasma insulin levels
NPH 1220 hours
Ultralente 1824 hours
Hours
6
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
7
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.
1999221501-1506
8
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 30 60 90 120 150 180 210 240
-60 -30 0 30 60 90 120 150 180 210 240
Minutes
Heinemann L et al. Diabet Med. 199613625-629
9
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. 2000492142-2148
10
Action Profiles of Insulin Analogues
Aspart, glulisine, lispro 46 hours
Regular 68 hours
Plasma insulin levels
NPH 1220 hours
Ultralente 1824 hours
Glargine 24 hours
Hours
11
Human Insulins and AnaloguesTypical Times of
Action
Insulin Preparations Onset of Action Peak Duration of Action
Aspart, glulisine, lispro 15 minutes 12 hours 46 hours
Human regular 3060 minutes 24 hours 68 hours
Human NPH, lente 24 hours 410 hours 1220 hours
Human ultralente 46 hours 816 hours 1824 hours
Glargine 24 hours Flat 24 hours
12
Normal Daily Plasma Insulin Profile
?U/mL
100
B
L
D
80
60
40
20
1800
1200
2400
0600
0600
0800
Time of day
Bbreakfast Llunch Ddinner
Polonsky KS et al. N Engl J Med.
19883181231-1239
13
Evening Basal InsulinBedtime NPH
?U/mL
100
B
L
D
Normal pattern
80
NPH
60
40
20
Time of day
Bbreakfast Llunch Ddinner
14
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. 199518843-851
15
Starting Basal Insulin for Type 2
DiabetesSuppertime 70/30 Added to Glimepiride
Placebo insulin (N73)
Glimepiride insulin titrated to FPG 140 mg/dL
(N72)
Fasting Glucose
Insulin Dosage
mg/dL
Units /day
100
300

250




75
Plt0.001


200

50
150
25
Plt0.001
100
0
0
12
16
8
4
20
24
0
12
16
8
4
20
24
Weeks
FPGfasting plasma glucose

Riddle MC et al. Diabetes Care. 1998211052-1057
16
Split-Mixed RegimenHuman Insulins
NPH Regular
NPH Regular
?U/mL
100
B
L
D
80
Normal pattern
60
40
20
Time of day
Bbreakfast Llunch Ddinner
17
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
0600
1800
2400
1200
0600
0600
1800
2400
1200
B
L
D
B
L
D
Time of day
Bbreakfast Llunch Ddinner
Henry RR et al. Diabetes Care. 19931621-31
18
Multiple Daily InjectionsHuman Insulins
NPH Regular
Regular
Regular
NPH
?U/mL
100
B
L
D
80
60
Normal pattern
40
20
Time of day
Bbreakfast Llunch Ddinner
19
Multiple Daily InjectionsNPH Regular for Type
2 Diabetes
10 Patients With Diabetes, 10 Normal Controls
Baseline oral agents
Insulin 8 weeks
Normal
Plasma Glucose
Serum Insulin
N
R
R
N
R
R
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
L
D
B
L
D
Sn
Sn
Sn
Sn
Sn
Sn
Time of day
Bbreakfast Snsnack Llunch Ddinner
Lindström TH et al. Diabetes Care. 19921527-34
20
Multiple Daily InjectionsNPH Regular or Aspart
for Type 1 Diabetes
Plasma Glucose
mg/dL
16
mmol/L
14
250
12
10
200
8
150
6
Serum Insulin
NPH regular insulin
A
N
A
A
100
mU/L
Insulin aspart
80
60
40
20
0
0600
1200
1800
2400
0600
B
L
D
Bbreakfast Llunch Ddinner
Time of day
Home PD et al. Diabetes Care. 1998211904-1909
21
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

22
Basal-Bolus Insulin TreatmentWith Insulin
Analogues
Lispro, glulisine, or aspart
?U/mL
100
Glargine
B
L
D
80
60
Normal pattern
40
20
Time of day
Bbreakfast Llunch Ddinner
23
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
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
High anxietyabout injections
Troubledby ideaof moreinjections
Troubledby ideaof moreinjections
Avoidinjectionsbecause of anxiety
Zambanini A et al. Diabetes Res Clin Pract.
199946239-246
25
Barriers to Insulin TherapyCardiovascular Risk
Is Not Supported by Trials
Type 2 Diabetes in the UKPDS Risk of myocardial
infarction Conventional treatment 17.4
events/1000 pt-yr Intensive insulin 14.7
events/1000 pt-yr (P0.052) Type 1 and 2
Diabetes in the DIGAMI Study Long-term survival
after acute myocardial infarction Conventional
treatment 44 mortality Intensive insulin 33
mortality (P0.011)
UKPDS Group. Lancet. 1998352837-853 Malmberg
K. BMJ. 19973141512-1515
6-14
26
Barriers to Insulin TherapySevere Hypoglycemia
Type 1 Diabetes in the DCCT Conventional insulin
35 of pts 19 events/100 pt-yr A1C 9, 6.5 yr
Intensive insulin 65 of pts 61 events/100
pt-yr A1C 7.2, 6.5 yr Type 2 Diabetes in the
UKPDS Intensive policy insulin 37 of pts 2.3
pts/yr A1C 7.0, 10 yr
DCCT Research Group. Diabetes. 199746271-286
UKPDS Group. Lancet. 1998352837-853
6-14
27
Barriers to Insulin TherapyWeight Gain
Type 1 Diabetes in the DCCT Intensive insulin
10.1 lb more A1C 7.2, 6.5 yr than 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. 199746271-286
DCCT Research Group. N Engl J Med.
1993329977-986 UKPDS Group. Lancet.
1998352837-853
28
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

29
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

31
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. 2001357331-335
32
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
? A1C ()(mean baseline, 8.7)
2
1
0
-1
Baseline
Week 8
Week 12
Week 4
Cefalu WT et al. Ann Intern Med. 2001134203-207
33
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 Plt0.001
8
6
4
2
0
Baseline
12 weeks
Baseline
12 weeks
Weiss SR et al. Diabetes. 199948(suppl 1)A12
34
Buccally Absorbed Insulin in Type 2 Diabetes
33 Patients With Oral Insulin tid Added to
DietChange from baseline -1.7Placebo-subtracted
difference -2.2
A1C ()
11
Oral insulin Placebo
10
9
8
7
Baseline
60 days
30 days
90 days
Schwartz S et al. Diabetes. 200150(suppl 2)A130
35
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