Module 6: Rediscovering Insulin for Type 2 Diabetes

1
Module 6 Rediscovering Insulin for Type 2
Diabetes
2
Insulin Therapy for Type 2 Diabetes

• Type 2 Diabetes . . . A Progressive Disease
• Barriers to Insulin Therapy
• Mimicking Nature With Insulin Therapy
• Insulin Tactics
• Practical Guidelines

6-2
3
TYPE 2 DIABETES . . . A PROGRESSIVE DISEASEHbA1c
in the UKPDS
Cross-sectional Median Values (7.0 vs 7.9)
8.7
9
Conventional
Intensive
8.4
8.1
8
7.5
ADA action
7.4
suggested
Median HbA1c ()
7
ADA target
6.6
6
6.2 upper limit of normal range
0
0
3
6
9
12
18
Years From Randomization
Adapted from UK Prospective Diabetes Study
(UKPDS) Group. Lancet. 1998352837-853.
6-3
4
TYPE 2 DIABETES . . . A PROGRESSIVE
DISEASE Progressive Decline of ?-Cell Function in
the UKPDS
100
80
60
?-Cell Function ( ?)
40
20
0
?10
?9
?8
?7
?6
?5
?4
?3
?2
?1
0
1
2
3
4
5
6
Years
Adapted from UK Prospective Diabetes Study
(UKPDS) Group. Diabetes. 1995 441249-1258.
6-4
5
TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE
Messages From the UKPDS

• Sulfonylureas, metformin, and insulin all reduce
  microvascular complications by improving
  glycemic control
• There is no evidence that sulfonylureas or
  insulin increase cardiovascular risk
• Early ? almost from the outset ? combination
  therapy is needed to control glucose
• Earlier introduction of insulin therapy can be
  expected in the progressive management of Type 2
  Diabetes

6-5
6
TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE
Natural History of Type 2 Diabetes
Postmeal glucose
Plasma Glucose
Fasting glucose
126 mg/dL
Insulin resistance
Relative ?-Cell Function
Insulin secretion
?20
?10
0
10
20
30
Years of Diabetes
Adapted from International Diabetes Center (IDC).
Minneapolis, Minnesota.
6-6
7
TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE

• Over time,most patients will needinsulinto
  control glucose

6-7
8
Barriers to Insulin TherapyCommon Concerns

• Insulin therapy might cause
• Worsening Insulin Resistance
• More Cardiovascular Risk
• Weight Gain
• Hypoglycemia

6-8
9
BARRIERS TO INSULIN THERAPYInsulin Sensitivity
in Glucose Clamp StudiesImproved by Insulin
Treatment
Baseline
After Insulin
100
87
80
80
67
57
60
53
Glucose Disposal of Matched Control Values
40
40
20
0
Garvey
Andrews
Scarlett
Scarlett, et al. Diabetes Care. 19825353-363
Andrews, et al. Diabetes. 198433634-642
Garvey, et al. Diabetes. 198534222-234.
6-9
10
BARRIERS TO INSULIN THERAPYLipids and Blood
PressureImproved or Unchanged by Insulin
Treatment
6 Months Treatment in 2 Studies
Suppertime Suppertime 70/30 Twice-dailyChange 7
0/30 Glimepiride NPH Regular Weight
(kg) 4.0 4.3 8.7 Triglycerides () 34 26
60 HDL () 11 2 5 LDL () 2 2 1 BP
systolic (mm Hg) 2 2 No data BP diastolic (mm
Hg) 1 0 No data
Riddle, et al. Diabetes Care. 1998211052-1057.
Henry, et al. Diabetes Care. 19931621-31.
6-10
11
BARRIERS TO INSULIN THERAPYCardiovascular
RiskMortality After MI Reduced by Insulin
Therapy in the DIGAMI Study
IV Insulin 48 hours, then
4 injections daily
All Subjects
.7
.7
Low-risk and Not Previously on Insulin
(N 620)
(N 272)
.6
.6
Risk reduction (51)
Risk reduction (28)
.5
.5
P .011
P .0004
.4
.4
.3
.3
.2
.2
.1
.1
0
0
0
1
2
3
4
5
0
1
2
3
4
5
Years of Follow-up
Years of Follow-up
Malmberg, et al. BMJ. 19973141512-1515.
6-11
12
BARRIERS TO INSULIN THERAPYWeight Gain in the
UKPDS
Excess Weight vs Conventional Rx After 10 Years
kg lb Main study Glyburide 1.7 3.7
Insulin 4.0 8.8 Metformin substudy
Metformin 0 0 Glyburide 2-3 4-7
Insulin 4-5 9-11
Values estimated from published
illustrations. UK Prospective Diabetes Study
(UKPDS) Group. Lancet. 1998352837-853 UK
Prospective Diabetes Study (UKPDS) Group.
Lancet. 1998352854-865.
6-12
13
BARRIERS TO INSULIN THERAPYWeight Gain Is
Minimized by Metformin
Yki-Järvinen Avilés-Santa Bergenstal
Ins Ins Met Ins Ins Met Ins Ins Met No. of
subjects 24 19 22 21 22 20 Duration of study
(mo) 12 12 6 6 4 4 Insulin dosage at end
(U/d) 53 36 120 92 136 99 HbA1c at end
() 7.9 7.2 7.6 6.5 7.0 7.1 Weight gain
(kg) 4.6 0.9 3.2 0.5 0.5 ?1.4 Mean weight gain
(kg) Without metformin 2.8
With metformin 0
Avilés-Santa, et al. Ann Intern Med.
1999131182-188 Bergenstal, et al. Diabetes.
199847(suppl 1)A89. Abstract 347
Yki-Järvinen, et al. Ann Intern Med.
1999130389-396.
6-13
14
BARRIERS TO INSULIN THERAPYHypoglycemia in the
UKPDS
Percentage of Patients Yearly, by Actual Therapy
Any Episodes Major Episodes Main study
Diet 1.2 lt1 Glyburide 18 lt1
Insulin 36 2.3 Metformin substudy (obese
patients) Diet lt1 lt1 Metformin 4 lt1
Glyburide 18 lt1 Insulin 34 2.5
UK Prospective Diabetes Study (UKPDS) Group.
Lancet. 1998352837-853 UK Prospective Diabetes
Study (UKPDS) Group. Lancet. 1998352854-865.
6-14
15
BARRIERS TO INSULIN THERAPYReassurance About
Common Concerns

• Insulin Therapy in Type 2 DM
• Improves Insulin Sensitivity by Reducing
  Glucotoxicity
• Probably Reduces Cardiovascular Risk
• Causes Modest Weight Gain
• Rarely Causes Severe Hypoglycemia

6-15
16

• Mimicking Nature
• The Basal/Bolus Insulin Concept

6-16
17
MIMICKING NATURE WITH INSULIN THERAPYInsulin and
Glucose PatternsNormal and Type 2 Diabetes
Normal
Type 2 Diabetes
Glucose
Insulin
400
120
100
300
80
mg/dL
?U/mL
200
60
40
100
20
0600
1000
1800
1400
0200
2200
0600
0600
1000
1800
1400
0200
2200
0600
B
L
S
B
L
S
Time of Day
Time of Day
Polonsky, et al. N Engl J Med. 19883181231-1239.
6-17
18
MIMICKING NATURE WITH INSULIN THERAPY Insulin
and Glucose PatternsBasal vs Mealtime
Hyperglycemia in Early Type 2 Diabetes
Basal hyperglycemia
Mealtime hyperglycemia
250
200
Type 2 Diabetes
150
Plasma Glucose (mg/dL)
100
Normal
50
0
0600
1200
1800
2400
0600
Time of Day
Riddle. Diabetes Care. 199013676-686.
6-18
19
MIMICKING NATURE WITH INSULIN THERAPY

• Over time,
• most patients will need
• both basal and mealtime insulin
• to control glucose

6-19
20
MIMICKING NATURE WITH INSULIN THERAPYThe
Basal/Bolus Insulin Concept

• Basal Insulin
• Suppresses 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
• 10 to 20 of total daily insulin requirement at
  each meal
• Ideally, for insulin replacement therapy, each
  component should come from a different insulin
  with a specific profile

6-20
21
BARRIERS TO INSULIN THERAPYPractical Limitations
of Conventional Tactics

• Complexity of Starting Insulin Therapy
• Need to Mix and Inject Insulins
• Limitations of Insulin Preparations

6-21
22
INSULIN TACTICS Comparison of Human Insulins and
Analogues

• Insulin Onset of Duration ofPreparations
  Action Peak Action
• Lispro/Aspart 5-15 minutes 1-2 hours 4-6 hours
• Human Regular 30-60 minutes 2-4 hours 6-10 hours
• Human NPH/Lente 1-2 hours 4-8 hours 10-20 hours
• HumanUltralente 2-4 hours Unpredictable 16-20
  hours
• Glargine 1-2 hours Flat 24 hours

The time course of action of any insulin may vary
in different individuals, or at different times
in the same individual. Because of this
variation, time periods indicated here should be
considered general guidelines only.
6-22
23
INSULIN TACTICS Twice-daily Split-mixed Regimens
Regular
NPH
Insulin Effect
B
S
L
HS
B
6-23
24
INSULIN TACTICS Multiple Daily Injections
(MDI)NPH Regular
NPH at AM and HS Regular AC
NPH at HS Regular AC
Regular
Regular
NPH
NPH
Insulin Effect
Insulin Effect
B
S
L
HS
B
B
S
L
HS
B
6-24
25
INSULIN TACTICS Multiple Daily Injections
(MDI)Ultralente Regular
Regular
Ultralente
Insulin Effect
B
S
L
HS
B
6-25
26
INSULIN TACTICSLimitations of Human Regular
Insulin

• Slow onset of action
• Requires inconvenient administration 20 to 40
  minutes prior to meal
• Risk of hypoglycemia if meal is further delayed
• Mismatch with postprandial hyperglycemic peak
• Long duration of activity
• Up to 12 hours duration
• Increased at higher dosages
• Potential for late postprandial hypoglycemia

6-26
27
INSULIN TACTICSShort-acting Analogues Lispro
and AspartClinical Features

• Convenient administration immediately prior to
  meals
• Faster onset of action
• Limit postprandial hyperglycemic peaks
• Shorter duration of activity
• Reduce late postprandial hypoglycemia
• Frequent late postprandial hyperglycemia
• Need for basal insulin replacement revealed

6-27
28
INSULIN TACTICSShort-acting Insulin Analogues
Lispro and AspartPlasma Insulin Profiles
400
500
Aspart
Lispro
450
350
400
300
350
250
300
250
200
Plasma Insulin (pmol/L)
Plasma Insulin (pmol/L)
Regular
200
150
Human
150
Regular
100
100
Human
50
50
0
0
0
30
60
90
120
180
210
150
240
0
50
100
150
200
300
250
Time (min)
Time (min)
Meal SC injection
Meal SC injection
Heinemann, et al. Diabet Med. 199613625-629
Mudaliar, et al. Diabetes Care. 1999221501-1506.
6-28
29
INSULIN TACTICS Multiple Daily Injections
(MDI)NPH Mealtime Lispro
NPH at AM and HS Lispro AC
NPH at HS Lispro AC
6-29
30
THE ROLE OF INSULIN IN TYPE 2 DIABETES
Limitations of Human 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
• More weight gain

6-30
31
INSULIN TACTICS Multiple Daily Injections
(MDI)The Quest for Basal Insulin Replacement
Mealtime Lispro NPH and NPH at HS
Lispro
NPH
Insulin Effect
B
S
L
HS
B
Bolli, et al. Diabetologia. 1999 421151-1167.
6-31
32
INSULIN TACTICS The Ideal Basal Insulin . . .

• Mimics normal pancreatic basal insulin secretion
• Long-lasting effect around 24 hours
• Smooth, peakless profile
• Reproducible and predictable effects
• Reduced risk of nocturnal hypoglycemia
• Once-daily administration for convenience

6-32
33
INSULIN TACTICS Insulin GlargineA New
Long-acting Insulin Analogue

• Modifications to human insulin chain
• Substitution of glycine at position A21
• Addition of 2 arginines at position B30
• Gradual release pattern from injection site
• Peakless, long-lasting insulin profile

Gly
1
5
10
15
20
Substitution
Asp
1
5
15
20
25
30
10
Extension
Arg
Arg
6-33
34
INSULIN TACTICS Glargine vs NPH Insulin in Type
1 DiabetesAction Profiles by Glucose Clamp
6
5
4
NPH
Glucose Utilization Rate (mg/kg/h)
3
2
Glargine
1
0
0
10
20
30
Time (h) After SC Injection
End of observation period
Lepore, et al. Diabetes. 199948(suppl 1)A97.
6-34
35
INSULIN TACTICS Insulin GlargineSummary of
Completed Trials

• Glucose-insulin clamp studies of Glargine vs NPH
• Smooth, continuous release from injection site
• Longer duration of action with effect for about
  24 hours
• Peakless profile
• Equivalent absorption rates at various injection
  sites
• Clinical efficacy equivalent to NPH, with
  significantly less nocturnal hypoglycemia

6-35
36
Overcoming ComplexitybyStarting With Basal
Insulin
6-36
37
INSULIN TACTICSStarting With Basal Insulin
Advantages

• 1 injection with no mixing
• Insulin pens for increased acceptance
• Slow, safe, and simple titration
• Low dosage
• Limited weight gain
• Effective improvement in glycemic control

6-37
38
INSULIN TACTICSStarting With Basal
InsulinBedtime NPH Added to Diet
Diet only
Bedtime NPH
400
300
200
Plasma Glucose (mg/dL)
100
0
0800
1200
1600
2000
2400
0400
0800
Time of Day
Cusi Cunningham. Diabetes Care. 199518843-851.
6-38
39
INSULIN TACTICSStarting With Basal Insulin

• Combination Oral Agents
• Evening Basal Insulin

6-39
40
INSULIN TACTICSCombination Oral Agents
InsulinSynergistic or Complementary Effects

• Sulfonylureas and Meglitinides
• Increase hepatic levels of endogenous insulin and
  enhance meal-mediated insulin release
• Metformin
• Improves insulin sensitivity at the liver and
  reduces hepatic glucose production
• Glitazones
• Improve insulin action in peripheral tissues and
  enhance glucose uptake
• ?-Glucosidase inhibitors
• Decrease postprandial glucose absorption

6-40
41
INSULIN TACTICSStarting With Basal Insulin
Ultralente Added to Sulfonylurea
Sulfonylurea
Sulfonylurea Ultralente
Normal
0600
1200
1800
2400
0600
B
L
S
Time of Day
Holman, et al. Diabet Med. 19874457-462.
6-41
42
INSULIN TACTICSStarting With Basal Insulin
Bedtime NPH Added to Glipizide
Baseline on Glipizide 20 mg/d
NPH titrated to FPG 120 mg/dL
FPG
HbA1c
300
10
248
220
8.9
9
8.6
200
140
7.8
8
mg/dL
Percent
113
7.1
100
7
0
6
Bedtime NPH Glipizide
Bedtime NPH Glipizide
Bedtime NPH
Bedtime NPH
Shank, et al. Diabetes. 199544165-172.
6-42
43
INSULIN TACTICSStarting With Basal Insulin
Suppertime 70/30 Added to Glimepiride
Placebo Insulin
Glimepiride Insulin titrated to FPG 140 mg/dL
FPG
Insulin Dosage
300
100

250




75


200

mg/dL
U/d
50

150
25
100
0
0
12
16
8
4
20
24
0
12
16
8
4
20
24
Weeks of Treatment
Weeks of Treatment


P
lt .0001
P
lt .05
Riddle, et al. Diabetes Care. 1998211052-1057.
6-43
44
INSULIN TACTICSStarting With Basal Insulin
Bedtime NPH Various Oral Agents (FINFAT Study)
(5/24)
0
25
NPH at HS
21
20
Glyburide
?1
15
(2/24)
Metformin
HbA1c ()
Dropouts ()
10
8
?2
(1/24)
Gly Met
? 1.9
? 2.0
4
5
(0/24)
? 2.1
0
? 2.5
NPH at
AM
?3
0
4.6
5
60
53
3.9
4
3.6
40
36
3
Insulin Dose (U)
Weight (kg)
24
20
2
20
0.9
1
0
0
Yki-Järvinen, et al. Ann Intern Med.
1999130389-396.
6-44
45
INSULIN TACTICSStarting With Basal Insulin
Weight Gain With Different Insulin Regimens
Baseline BMI Treatment Comparison Weight
Gain (kg/m2) (mo) Regimen (kg)
Basal Insulin Chow 24 6 Baseline 2.1 Landstedt-Hal
lin 26 4 Baseline 1.9 Yki-Järvinen 28 3 Oral
agents 1.2 Cusi 30 4 Baseline 2.4 Riddle 33 6 Base
line 4.0 Mean 2.5 Mealtime
Insulin Landstedt-Hallin 26 4 Baseline 3.4 Feinglo
s 31 4 Oral agents 3.2 Mean 3.3 Basal
Mealtime Insulin Chow 24 6 Baseline 5.2 Yki-Järvin
en 2 injections 28 3 Oral agents 3.1
28 3 Oral agents 2.9 Henry 31 6
Baseline 8.7 Mean 5.7
4 injections
6-45
46
INSULIN TACTICSStarting With Bolus Insulin

• Combination Oral Agents
• Mealtime Insulin

6-46
47
INSULIN TACTICS Starting With Bolus
InsulinMealtime Lispro vs NPH or Metformin Added
to Sulfonylurea
12
12
Baseline
10.4
HbA1c
10.2
10.0
10
10
Follow-up
?1.9
?1.9
HbA1c
?2.3
8
8
Follow-up
6
6
Weight
HbA1c ()
Weight Gain (kg)
4
4
2
2
3.4 kg
2.3 kg
0.9 kg
0
0
Su Metformin
Su NPH
Su LP
(n 40)
(n 50)
(n 42)
Browdos, et al. Diabetes. 199948(suppl 1)A104.
6-47
48
INSULIN TACTICSAdvancing Basal/Bolus Insulin
Therapy

• Multiple Daily Insulin Injections
• (MDI)

6-48
49
INSULIN TACTICS Advancing With Multiple Daily
InjectionsNPH Regular, Twice Daily
Diet only
Insulin 6 months
Plasma Glucose
Serum Insulin
1000
400
NR
NR
NR
NR
800
300
600
pmol/L
200
mg/dL
400
100
200
0
0
0600
0600
1800
2400
1200
0600
0600
1800
2400
1200
B
L
S
B
L
S
Time of Day
Time of Day
Henry, et al. Diabetes Care. 19931621-31.
6-49
50
INSULIN TACTICSAdvancing With Multiple Daily
InjectionsBedtime NPH Mealtime Regular
Normal
BaselineOral Agents
Insulin 8 weeks
Plasma Glucose
Serum Insulin
N
R
R
N
R
R
R
R
300
300
250
200
200
pmol/L
mg/dL
150
100
100
50
0
0
0800
1200
1600
2000
2400
0400
0800
0800
1200
1600
2000
2400
0400
0800
B
L
S
B
L
S
Sn
Sn
Sn
Sn
Sn
Sn
Time of Day
Time of Day
Lindström, et al. Diabetes Care. 19921527-34.
6-50
51
INSULIN TACTICS Advancing With Multiple Daily
InjectionsBedtime Glargine vs NPH, With Mealtime
Regular
4
48
Glargine
NPH
3
36

Patients ()
2
24
1
12
Baseline
Baseline
8.5

1
8.8

1
11.1

4
10.6

4
0
0

?1


?2

Nocturnal
FPG
HbA1c
()
Hypoglycemia
(mmol/L)
P lt .01 (change from baseline to endpoint
within each group)P lt .02 (compared to
NPH) Rosenstock, et al. Diabetes. 199948(suppl
1)A100.
6-51
52
INSULIN TACTICS Advancing With Multiple Daily
InjectionsBedtime Glargine vs NPH, With Mealtime
Regular
48
4
Glargine
NPH
36
3

24
2
Weight (kg)
Patients ()
12
1

0
0
Nocturnal
Weight Gain
Hypoglycemia
P lt .0007P lt .02 (compared to
NPH) Rosenstock, et al. Diabetes. 199948(suppl
1)A100.
6-52
53

• Future
• Insulin Therapy

6-53
54
Insulin Tactics The Future

• Combination Oral Agents Basal Insulin Glargine
• Combination Oral Agents Bolus Inhaled Insulin
• Basal Insulin Glargine Bolus Inhaled Insulin

6-54
55
INSULIN TACTICS THE FUTUREOral Agents
Mealtime Inhaled InsulinEffect on HbA1c
Oral Agents
Oral Agents Alone
Inhaled Insulin
10
9
?2.3
8

HbA1c ()
7
6
5
Baseline
Follow-up
Baseline
Follow-up
(0)
(12)
(0)
(12)
Weeks
P lt .001 Weiss, et al. Diabetes. 199948(suppl
1)A12.
6-55
56
INSULIN TACTICS THE FUTUREGlargine at HS Oral
Agents or Inhaled Insulin
Secretagogue
Inhaled Insulin
Sensitizer
Glargine
Glargine
Insulin Effect
Insulin Effect
B
S
L
HS
B
B
S
L
HS
B
6-56
57

• Practical Guidelines for
• Insulin Therapy
• in Type 2 Diabetes
• Today!

6-57
58
PRACTICAL GUIDELINES Combination Therapy Regimens

• Usual patient
• Early combination of insulin secretagogue and
  insulin sensitizer
• Initially most simple and cost-effective
• Low-dose, once-daily sulfonylurea and metformin
• Full-dose sulfonylurea in combination with
  increasing doses of metformin
• For marked insulin resistance
• Combination of metformin glitazone
• If target HbA1c lt 7 not achieved
• Try triple therapy
• or
• Add basal insulin while continuing oral therapy

6-58
59
PRACTICAL GUIDELINESStarting Basal Insulin

• Continue oral agent(s) at same dosage (eventually
  reduce)
• Add single, evening insulin dose (around 10 U)
• NPH (bedtime)
• 70/30 (evening meal)
• Glargine (bedtime or anytime?)
• Adjust dose by fasting SMBG
• Increase insulin dose weekly as needed
• Increase 4 U if FBG gt140 mg/dL
• Increase 2 U if FBG 120 to 140 mg/dL
• Treat to target (usually lt120 mg/dL)

6-59
60
PRACTICAL GUIDELINESAdvancing Basal/Bolus
Insulin

• Indicated when FBG acceptable but
• HbA1c gt7 or gt7.5
• and/or
• SMBG before dinner gt180 mg/dL
• Insulin options
• To bedtime NPH, add morning NPH and mealtime
  Regular or Lispro
• To suppertime 70/30, add morning 70/30
• To Glargine, add mealtime Regular or Lispro
• Oral agent options
• Usually stop sulfonylurea
• Continue metformin for weight control?
• Continue glitazone for glycemic stability?

6-60