Download Insulin Deficiency and Insulin Resistance

Therapeutic Options
Insulins
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
1
Human Insulin
21 amino acids
A-chain
B-chain
30 amino acids
Monomers
Dimers
Zn++
Self-aggregation
in solution
Hexamers
Zn++
2
Modified Human Insulin
Regular Insulin
Hexamers in Zn2+ buffer
Short acting
Neutral Protamine Hagedorn (NPH) Insulin Intermediate acting
Medium-sized crystals in
protamine-Zn2+ buffer
Lente and Ultralente Insulin
Large crystals in acetate-Zn2+ buffer
Intermediate and
long acting
3
Profiles of Human Insulins
Regular 6–8 hours
NPH 12–20 hours
Ultralente 18–24 hours
Plasma
insulin
levels
0
1
2
3
4
5
6
7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Hours
4
Insulin Analogues
A-chain
Human Insulin
B-chain
Dimers and hexamers
in solution
Aspart
Asp
Limited self-aggregation
Monomers in solution
Glu
Lys
Lys Pro
Gly
Glulisine
Limited self-aggregation
Monomers in solution
Lispro
Limited self-aggregation
Monomers in solution
Glargine
Arg Arg
Soluble at low pH
Precipitates at
neutral (subcutaneous) pH
5
Insulin Aspart
A Rapid-Acting Insulin Analogue
20 Healthy Subjects, 10-h Euglycemic Clamp
Plasma Insulin
pmol/L
Glusose
infusion
rate
(mg/min)
500
400
300
Insulin aspart
Regular insulin
Insulin Action
700
600
500
400
300
200
200
100
100
0
0
100
200
300
400
500
600
0
0
100
200
300
400
500
600
Minutes
Mudaliar SR et al. Diabetes Care. 1999;22:1501-1506
6
Insulin Lispro
A Rapid-Acting Insulin Analogue
10 Patients With Type 1 Diabetes Following a Meal
Regular insulin
Insulin lispro
pmol/L
Plasma Insulin
400
mg/dL
Meal
and
insulin
300
Plasma Glucose
200
150
Meal
and
insulin
200
100
100
0
-60 -30
0
30
60
90 120 150 180 210 240
0
-60 -30
0
30
60 90
120 150 180 210 240
Minutes
Heinemann L et al. Diabet Med. 1996;13:625-629
7
Insulin Action Profiles in Type 1 Diabetes
20 Patients
Glucose infusion 4
(mg/kg/min)
Ultralente
NPH
3
2
1
Glargine
0
0
4
8
12
16
20
24
Hours
Lepore M et al. Diabetes. 2000;49:2142-2148
8
Action Profiles of Insulin Analogues
Aspart, glulisine, lispro 4–6 hours
Plasma
insulin
levels
Regular 6–8 hours
NPH 12–20 hours
Ultralente 18–24 hours
Glargine 24 hours
0
1
2
3
4
5
6
7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Hours
9
Human Insulins and Analogues
Typical 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
10
Normal Daily Plasma Insulin Profile
U/mL
100
B
L
0800
1200
D
80
60
40
20
0600
1800
2400
0600
Time of day
B=breakfast; L=lunch; D=dinner
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239
11
Evening Basal Insulin
Bedtime NPH
U/mL
100
B
L
D
80
Normal pattern
NPH
60
40
20
0600
0800
1200
1800
2400
0600
Time of day
B=breakfast; L=lunch; D=dinner
12
Starting Basal Insulin for Type 2 Diabetes
Bedtime 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
13
Starting Basal Insulin for Type 2 Diabetes
Suppertime 70/30 Added to Glimepiride
Placebo + insulin (N=73)
Glimepiride + insulin titrated to FPG 140 mg/dL (N=72)
mg/dL
Fasting Glucose
300
*
250
*
Insulin Dosage
Units /
100
day
75
*P<0.001
200
*
25
0
4
8
12
16
20
24
*
*P<0.001
100
0
*
*
50
150
*
*
0
4
8
12
16
20
24
Weeks
FPG=fasting plasma glucose
Riddle MC et al. Diabetes Care. 1998;21:1052-1057
14
Split-Mixed Regimen
Human Insulins
NPH
Regular
U/mL
100
B
NPH
Regular
L
D
80
Normal pattern
60
40
20
0600
0800
1200
1800
2400
0600
Time of day
B=breakfast; L=lunch; D=dinner
15
Split-Mixed Regimen
NPH + Regular for Type 2 Diabetes
Diet only
Insulin 6 months
Plasma Glucose
mg/dL
400
N+R
Serum Insulin
pmol/L
N+R
1000 N + R
N+R
800
300
600
200
400
100
200
0
0
0600
B
1200
L
1800
D
2400
0600
Time of day
0600
B
1200
L
1800
D
2400
0600
B=breakfast; L=lunch; D=dinner
Henry RR et al. Diabetes Care. 1993;16:21-31
16
Multiple Daily Injections
Human Insulins
NPH
Regular Regular
U/mL
100
B
L
Regular
NPH
D
80
60
Normal pattern
40
20
0600
0800
1200
1800
2400
0600
Time of day
B=breakfast; L=lunch; D=dinner
17
Multiple Daily Injections
NPH + Regular for Type 2 Diabetes
10 Patients With Diabetes, 10 Normal Controls
Baseline oral agents
Normal
Insulin 8 weeks
Plasma Glucose
R
mg/dL
R
R
Serum Insulin
N
R
pmol/L
300
R
R
N
300
250
200
200
150
100
100
50
0
0800 1200 1600 2000 2400
B Sn L Sn D
Sn
0400 0800
B=breakfast; Sn=snack; L=lunch; D=dinner
Lindström TH et al. Diabetes Care. 1992;15:27-34
0
0800 1200
B Sn L
1600 2000 2400 0400
Sn D
Sn
0800
Time of day
18
Multiple Daily Injections
NPH + Regular or Aspart for Type 1 Diabetes
mmol/L 16
mg/dL
Plasma Glucose
14
12
10
250
200
8
6
150
Serum Insulin
A
mU/L 100
A
A
NPH + regular
insulin
Insulin aspart
N
80
60
40
20
0
0600
B=breakfast; L=lunch; D=dinner
1200
B
L
Home PD et al. Diabetes Care. 1998;21:1904-1909
1800
D
2400
Time of day
0600
19
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
20
Basal-Bolus Insulin Treatment
With Insulin Analogues
Lispro, glulisine, or aspart
U/mL
100
B
L
D
80
Glargine
60
40
Normal pattern
20
0600
0800
1200
1800
2400
0600
Time of day
B=breakfast; L=lunch; D=dinner
21
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
22
Barriers to Using Insulin
Attitudes of Patients
With Type 1 and Type 2 Diabetes
% of
100
patients
All Patients
Patients With
High Anxiety
80
70%
60
42%
40
20
0
45%
28%
14%
Avoid
injections
because
of anxiety
Troubled
by idea
of more
injections
High
anxiety
about
injections
Zambanini A et al. Diabetes Res Clin Pract. 1999;46:239-246
Avoid
injections
because
of anxiety
Troubled
by idea
of more
injections
23
Barriers to Insulin Therapy
Cardiovascular Risk Is Not Supported by Trials
Type 2 Diabetes in the UKPDS
Risk of myocardial infarction
Conventional treatment
Intensive insulin
17.4 events/1000 pt-yr
14.7 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
Intensive insulin
44% mortality
33% mortality (P=0.011)
UKPDS Group. Lancet. 1998;352:837-853; Malmberg K. BMJ. 1997;314:1512-1515
24
Barriers to Insulin Therapy
Severe Hypoglycemia
Type 1 Diabetes in the DCCT
Conventional insulin
A1C ~9%, 6.5 yr
35% of pts
19 events/100 pt-yr
Intensive insulin
A1C 7.2%, 6.5 yr
65% of pts
61 events/100 pt-yr
Type 2 Diabetes in the UKPDS
Intensive policy insulin
A1C 7.0%, 10 yr
DCCT Research Group. Diabetes. 1997;46:271-286;
UKPDS Group. Lancet. 1998;352:837-853
37% of pts
2.3% pts/yr
25
Barriers to Insulin Therapy
Weight Gain
Type 1 Diabetes in the DCCT
Intensive insulin
A1C 7.2%, 6.5 yr
+ 10.1 lb more
than conventional insulin
Type 2 Diabetes in the UKPDS
Intensive insulin
A1C 7.0%, 10 yr
+ 8.8 lb more
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
26
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
27
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
28
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
29
Inhaled Insulin in Type 1 Diabetes
73 Patients Taking Inhaled Insulin tid in Addition to Injected
Long-Acting Insulin
A1C (%)
Subcutaneous insulin:
16 U regular + 31 U long-acting
Inhaled insulin:
12 mg inhaled + 25 U ultralente
10
9
8
7
6
0
4
8
12
Weeks
Skyler JS et al. Lancet. 2001;357:331-335
30
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
2
Δ A1C (%)
(mean baseline, 8.7%)
1
0
-1
Baseline
Cefalu WT et al. Ann Intern Med. 2001;134:203-207
Week 4
Week 8
Week 12
31
Inhaled Insulin in Type 2 Diabetes
69 Patients With Inhaled Insulin tid
Added to Sulfonylurea and/or Metformin
Oral agents alone
A1C (%)
Oral + inhaled insulin
10
–2.3%
P<0.001
8
6
4
2
0
Baseline
Weiss SR et al. Diabetes. 1999;48(suppl 1):A12
12 weeks
Baseline
12 weeks
32
Buccally Absorbed Insulin in Type 2 Diabetes
33 Patients With Oral Insulin tid Added to Diet
Change from baseline -1.7%
Placebo-subtracted difference -2.2%
A1C (%) 11
Oral insulin
Placebo
10
9
8
7
Baseline
30 days
Schwartz S et al. Diabetes. 2001;50(suppl 2):A130
60 days
90 days
33
Summary
Insulin 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
34