The document discusses different types of insulin available to manage diabetes, including rapid-acting, short-acting, intermediate-acting, long-acting, and premixed insulins. It reviews insulin protocols and addresses patient selection for different regimens. The document also discusses designing and adjusting insulin regimens, including using a basal-bolus approach to better mimic normal physiology.
2. Objectives
1. Discuss the different types of insulin
preparations available to manage types 1 and 2
diabetes
2. Review the various insulin protocols and address
appropriate patient selection for each
3. Address how to design and adjust insulin
regimens
Monday, July 16, 2012 2
3. What Type of Insulins Are
Available?
Monday, July 16, 2012 3
4. Normal Pancreas
‘Bolus’ Insulin
(Meal Associated)
Insulin Effect
Basal Insulin
(~0.5-1.0 U/hr.)
Insulin is released in response to varying blood glucose levels
Monday, July 16, 2012 and hypoglycemia does not occur 4
5. Basal vs Bolus Insulin
BASAL INSULIN BOLUS INSULIN
• Suppress hepatic glucose • Meal-associated CHO
production (overnight and disposal
intermeal) • Storage of nutrients
• Prevent catabolism (lipid
• Help suppress inter-meal
and protein)
hepatic glucose
– Ketosis
production
– Unregulated amino
acid release
• Reduce glucolipotoxicity
Monday, July 16, 2012 5
11. Rapid-Acting Analogs and
RHI in Obese Subjects
6
Glulisine
* Lispro
GIR, mg.kg-1.min-1
5
* Regular human insulin
4 N=18
BMI=30 kg/m2 to 40 kg/m2
3
2
1
0
0 60 120 240 360 480 600
Time, min
Dosage=0.3 U/kg GIR=Glucose Infusion Rate
* p< .05 GIR-t20% vs RHI and Lispro
Monday, July 16, 2012 11
Frick AD et al. ADA 64th Scientific Sessions, 2004. Abstract 526.
12. Fatty Meals---Rapid
Acting Insulin
HYPERGLYCEMIA
INSULIN ACTIVITY
GLUCOSE LEVELS
TIME
Monday, July 16, 2012 12
13. Effect of Premixing on Rapid-
Acting Analog Properties
Tmax 49-53 min
Aspart 1,2
Tmax 2.4 hours
70/30 NovoLog Mix 3
Plasma Insulin Levels
-60 0 60 120 180 240 300 360 420 480 540
Time (min)
1. Hedman CA et al. Diabetes Care
Monday, July 16, 2012
2001;24:1120-1121 2. Home PD et al. Eur J Clin Pharm 13
1999;55:199-201 3. Novo Nordisk, data on file
14. Effect of NPH on GIR
mg/dl
90
mmol/l
5.0
80 4.5
GLUCOSE
70 Plasma Glucose
INFUSION 4.0
RATE 4.0 24
PEN DOWN
20
3.0
µmol/Kg/min
16
mg/Kg/min
0.3 U/Kg NPH s.c.
2.0 MIX
12
1.0 8
0 4
PEN UP
0
Monday, July 16, 2012 0 1 2 3 4 5 6 7 8 9 14
Lepore M. et al., unpublished data Time (hours)
16. Bolus vs Basal Insulin
• Bolus insulins • Basal insulins
– Regular – NPH
– Humalog (lispro) – Lente
– NovoLog (aspart) – Ultralente
– Apidra (glulisine) – Lantus (glargine)
– Levemir (detemir)
L Combination insulins
— 70/30
and 50/50
— Humalog mix (75/25 or NPL)
— NovoLog mix (70/30 or NPA)
Monday, July 16, 2012 16
17. Basic Insulin Regimen: Split-
Mixed Regimen or Premix
• Does not
Endogenous insulin mimic normal
Regular
physiology
NPH
Hyperglycemia • Requires meal
consistency
• Snacking may
result in weight
gain
• Hypo- and
hyperglycemia
B L D HS B
Monday, July 16, 2012 17
18. Basal-Bolus or Physiologic
Insulin Therapy
Endogenous insulin
Bolus insulin
Insulin Effect
Basal insulin
B L D HS
Adapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY:
Monday, permission 18
Marcel Dekker, Inc; 2002:193
19. Case---History
25 year old student comes to clinic for management
of type 1 diabetes. He was diagnosed
approximately 3 years ago and has been managed
with twice daily NPH insulin and lispro. He is
frustrated because his glucose values fluctuate
considerably, and he is having multiple episodes
of hypoglycemia.
His most recent A1C returned 7.8%.
Monday, July 16, 2012 19
21. Case Study--History
His current insulin regimen consists of 16 U of NPH plus 5 to
15 U of lispro prior to breakfast and 12 U of NPH with a
similar amount of lispro prior to supper. He would give
correction doses of lispro prior to lunch, bedtime and
occasionally at 2-4 AM. If he was ‘low’, he would eat
carbohydrate and not take lispro.
His home glucose log documented testing 4 to 5 times a day
with values ranging from 40 to 500 mg/dl.
How should his management be approached?
Monday, July 16, 2012 21
22. Case Study--Approach
• Set a reasonable goal for glycemic control
– Initial goal was to avoid hypoglycemia (glucose
targets 120-150 mg/dL)
• Trouble-shoot the insulin regimen
– Which type of insulin and which injection is
doing what?
– Good luck doing it with this patient!
Monday, July 16, 2012 22
23. Case Study--Approach
• Variables with injected insulin:
– Type of insulin and site of injection
– Type of food and gastric emptying
– Remembering to take injections
– Accuracy of HGM
• Designing an insulin regimen
– Think in terms of basal and bolus
Monday, July 16, 2012 23
24. Case Study--Approach
• We opted to use glargine as the basal
insulin and lispro as the bolus insulin
• Dose calculations:
– TDD: 48 to 73 U
– Basal (as NPH): 16+12=28 U CURRENT REGIMEN
– Glargine: 28 x 0.8=22.4 U 16/10 and 12/10 (N/H)
TDD≈48 U/day
PLUS up to 25 U H/D
Monday, July 16, 2012 24
25. Case Study--Approach
• Usual insulin regimens are 50:50 or 60:40
basal:bolus
– TDD: 48 to 73 U
– Glargine: 22 U
– Bolus: ~ 22 U (50:50 Rule)
• Per meal 22/3= 7.3 U/meal
• Designed regimen: Glargine 22 U/HS; lispro 7 U
BEFORE EACH MAJOR MEAL
Monday, July 16, 2012 25
26. Case Study--Approach
• Correction doses (‘sliding scale’)
– 1700 Rule (some modify this as the 1500 Rule
or the 1800 Rule)
– 1700/TDD = Expected amount of glucose
lowering per unit of insulin
• Our patient
– 1700/44 = 38 ∴ 1 U insulin would lower his
glucose 38 mg/dl
Monday, July 16, 2012 26
27. Case Study--Approach
• Our goal glucose is ~ 150 mg/dL
• Our patient is instructed to:
– Take 22 U glargine at bed time (or ~ 10:00 PM)
– Start with 7 U of lispro before meals
• For every 50 mg/dL glucose is above 150, add 1 U lispro or
for every 50 below 150, subtract 1 U lispro
– Have the patient monitor and adjust the regimen based
upon results of HGM
Monday, July 16, 2012 27
28. Carbohydrate Counting
• There is no literature to document superiority of
CHO counting
– Estimation aids many patients with T1DM
– Likely not effective in T2DM
• Establishing insulin:carbohydrate ratio
– [Correction factor] x 0.33 = CHO gm covered by 1 unit
of insulin
– Usual ratio is 10-15:1
– Adjust based upon 2 hour postprandial glucose values
Monday, July 16, 2012 28
29. Clinical Secrets
• Plan target glucose goals
• Think in terms of basal and bolus insulin
• Typical ratio of basal to bolus is 50:50 or 60:40
• Correction doses are generally given before meals
• 1700 Rule: 1700/TDD = Glucose lowering/unit insulin
• Adjust basal insulin based upon FBS and bolus
insulin based upon preprandial values
Monday, July 16, 2012 29
30. Summary of Key Dose
Concepts for Type 1 Diabetes
Parameter Formula Usual Range
Basal insulin None (weight 12-24 U/day
requirements based 0.2-0.5
U/kg)
Bolus requirements Basal dose ÷ 3 or 5-10 U/meal
(empiric) number of meals/d
Insulin:CHO ratio CF x 0.33 ~15
Correction factor 1700 ÷ TDD 30-50
NOTE: These are approximations on starting a physiologic insulin regimen and
must beJuly 16, 2012based upon SMBG values
Monday,
adjusted 30
31. When Should Insulin Be Added
In Patients With Type 2
Diabetes?
Monday, July 16, 2012 31
32. Natural History of Type 2
Diabetes
Postmeal
Plasma glucose
Glucose
126 mg/dL Fasting glucose
Insulin resistance
Relative β-Cell
Function Insulin secretion
−20 −10 0 10 20 30
Years of Diabetes
Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota.
Monday, July 16, 2012 32
33. Therapy In Type 2 Diabetes:
Estimated Improvement
HbA1c FBG
(mg/dL)
Monotherapy
Sulfonylurea 1.5% to 2% 50 to 60
Metformin 1% to 2% 50 to 60
Pioglitazone 0.6% to 1.9% 55 to 60
Rosiglitazone 0.7% to 1.8% 55 to 60
Glitazones (Troglit) 0.6% to 1.0% 20 to 40
Repaglinide 0.8% to 1.7% 30 to 40
Acarbose 0.5% to 1.0% 20 to 30
Sulfonylurea + Metformin ~1.7% ~65
Combination
Therapy
Sulfonylurea + Pioglitazone ~1.2% ~50
Sulfonylurea + Troglitazone ~0.9% to 1.8% ~40 - 60
Sulfonylurea + Acarbose ~1.3% ~40
Repaglinide + Metformin ~1.4% ~40
Pioglitazone + Metformin ~0.7% ~40
Rosiglitazone + Metformin ~0.8% ~50
Insulin Therapy
Monday, July 16, 2012 33
Oral Agents + Insulin Rx Open to Target Open to
Target
34. Evolution of Treatment
Strategies
Pre-1995 2000 Current
Diagnosis Diagnosis Diagnosis
Monotherapy Dual
Monotherapy Therapy
SU
Dual/Triple Basal
Triple
Stop SU Therapy Insulin +
Therapy
OHA
Stop OHA
Stop SU
Insulin
Insulin
Prandial and Basal
Monday, July 16, 2012 34
Insulin + OHA
35. ADA/EASD Position
Statement
Diagnosis
Lifestyle Intervention and Metformin
No HbA1c ≥ 7% Yes
Add Basal Insulin − Add Sulfonylurea − Add GLitazone −
(most effective) (least expensive) ( no hypoglycemia)
Check HbA 1c 16, 2012 3 months and act until HbA 1c is
Check
Monday, July every 35
<7% Nathan DM et al. Diabetes Care. 2006;29:1963-1972
36. How Is Insulin Employed in Type
2 Diabetes?
Different Regimens
Monday, July 16, 2012 36
37. Basal Insulin Regimen
Sensitizer Secretagogue Basal Insulin
Insulin Effect
B
Monday, July 16, 2012 L D HS 37
38. Basic Insulin Regimen: Split-
Mixed Regimen or Premix
Endogenous insulin
Regular
NPH
B L D HS B
Monday, July 16, 2012 38
39. Basal-Plus Insulin Therapy
Endogenous insulin
Bolus insulin
Insulin Effect
Basal insulin
B L D HS
Adapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY:
Monday, permission 39
Marcel Dekker, Inc; 2002:193
40. Inhaled Bolus Insulin
Therapy
Endogenous insulin
Bolus insulin
Insulin Effect
B L D HS
Adapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY:
Monday, permission 40
Marcel Dekker, Inc; 2002:193
41. Basal-Bolus or Physiologic
Insulin Therapy
Endogenous insulin
Bolus insulin
Insulin Effect
Basal insulin
B L D HS
Adapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY:
Monday, permission 41
Marcel Dekker, Inc; 2002:193
43. Basal Insulin Therapy
Sensitizer Secretagogue Basal Insulin
Insulin Effect
B
Monday, July 16, 2012 L D HS 43
44. Effects Of Basal Insulin
□ HS NPH+Gly+Met
r BID NPH
• HS NPH+Metformin
∆ HS NPH+Glyburide
Monday, July 16, 2012 44
Yki-Järvinen et al; Ann Int Med 1999;130:389
45. Flexible Timing Of Glargine
Compared With NPH Insulin
9.5
AM Glargine
9.0 HS Glargine
HS NPH
A1C (%)
8.5
8.3
8.0 8.1
7.8 *
7.5
0 4 8 12 16 20 24
Time (wk)
* Decrease in A1C from baseline for AM Glargine: P<0.001 vs HS NPH and P=0.008 vs HS
Glargine etJulyAnn Int Med 2003;138:952-959.
Fritsche A al. 16, 2012
Monday, 45
46. Treat to Target Trial
9 Subjects were oral agent
failures on SU alone or
SU+metformin and basal Insulin glargine
Mean A1C (%)
insulin was added and
8 NPH insulin
aggressively titrated
7
Target A1C (%) ~60% of patients
reached target
6
0 4 8 12 16 20 24
Monday, July 16, 2012 Weeks 46
Riddle et al. Diabetes Care. 2003;26:3080-3086
47. Achieving Glycemic Control
(Detemir v Glargine)
Detemir Glargine
A1C at endpoint 7.16 % 7.12%
(baseline adjusted)
Insulin dose at 0.63 u/kg (0.02-3.96) 0.40 u/kg
endpoint [0.43 u/kg (0.02-1.98)
detemir QD (45% of pts.)]
[0.85 u/kg (0.14-3.96)
detemir BID (55% of pts.)
Completion rate 80% 87%
In-clinic FPG (mg/ 129.6 129.6
dl)
Monday, July 16, 2012 47
Rosenstock J et al. ADA 2006; Abstract 555-P
48. Do Algorithms and Basal
Insulin Work?
Community
Center
Start SU
Without
Algorithm
Community University Center
Add metformin
Center + + Algorithm
Start Algorithm
insulin
Monday, July 16, 2012 48
Fanning et al. Diabetes Care 2004;27:1638-1646
50. Basic Insulin Regimen: Split-
Mixed Regimen or Premix
Endogenous insulin
Regular
NPH
B L D HS B
Monday, July 16, 2012 50
51. Aggressively Titrated
Premix
70/30+Met+Pio Met+Pio
Baseline A1C 8.1±1.0 7.9±0.9
EOS A1C 6.5±1.0 7.8±1.2
Percentage of Patients
With A1C (EOS)
<7.0% 76.3 24.1
≤6.5 59.1 11.5
≤6.0 33.3 2.3
≤5.5 14.0 0
FPG (mg/dl) 130±50 162±41
Monday, July 16, 2012 51
Raskin et al. Insulin 2007;2 (suppl A):S11
52. When and How Should Prandial
Insulin Be Added?
Monday, July 16, 2012 52
53. Contributions of FBG and
PPG to Overall Glycemia
PPG + FBG = HbA1c (%)
80
Contribution (%)
70
60
50
40
30
20
10
0
(<7.3)
1 2(7.3-8.4) 3(8.5-9.2) (9.3-10.2)
4 5(>10.2)
PPG
A1c Quintiles
FPG
Monday, July 16, 2012 53
Adapted from Monnier, Lapinski, Colette: Diab Care Mar 2003, pg 881
54. Basal-Plus Insulin Therapy
Endogenous insulin
Bolus insulin
Insulin Effect
Basal insulin
B L D HS
Adapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY:
Monday, permission 54
Marcel Dekker, Inc; 2002:193
55. Final Insulin Doses
Basal-Plus Regimen
● 26 week study (safety
35 Basal Insulin Dose analysis) (N=158)
● Baseline A1C was 7.4%
30
31 and fell to 7.0%
Insulin Dose (IU)
30
25 ● 26% achieved A1C < 6.5%
20
15 Rapid-Acting Dose
10
5 11
5
0
Baseline Endpoint Baseline Endpoint
Monday, July 16, 2012 55
Abstracts of the 66th Scientific Sessions of the ADA. Diabetes. 2006; V(suppl X): XX. Abstract XX.
Diabetes.
56. CHO Counting v Fixed
Regimen
Mean A1C Across Study Weeks
8.5
8.0
ALG
A1C (%)
Carb Count
7.5
7.0
6.5
0 2 6 12 18 24
Week
Monday, July 16, 2012 56
Abstracts of the 66th Scientific Sessions of the ADA. Diabetes. 2006; V(suppl X): XX. Abstract XX.
Diabetes.
57. Insulin Doses
Rapid-Acting Basal Insulin
P=0.04 P<0.0001
120
100
110.2
Dose (IU)
94.3 103.4
80
86.8
60
40
20
0
ALG
Monday, July 16, 2012
Carb Count ALG Carb Count
57
Abstracts of the 66th Scientific Sessions of the ADA. Diabetes. 2006; V(suppl X): XX. Abstract XX.
Diabetes.
58. Inhaled Bolus Insulin
Therapy
Endogenous insulin
Bolus insulin
Insulin Effect
B L D HS
Adapted withJuly 16, 2012 from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY:
Monday, permission 58
Marcel Dekker, Inc; 2002:193
60. Inhaled Insulin (Exubera)
and OHA
Oral Agents Alone Oral Agents +
SU and/or Met Inhaled Insulin
10
9
−2.3%
HbA1c (%)
8
*
7
6
5
Baseline Follow-up Baseline Follow-up
(0) (12) (0) (12)
*P < Monday, July 16, 2012
.001 Weeks 60
Weiss, et al. Diabetes. 1999;48(suppl 1):A12.
61. FPG: Exubera vs SC
Insulin at End Point
Type 1 DM Type 2 DM
Standard Intensive On insulin
0
-5 194 203 201 209 152 158
Mean ∆ FPG (mg/dL)
-10 207 149
-15 190
-20
132
-25
-30
-35 163 Exubera SC
167
-40
Hollander PA, et al. Diabetes Care. 2004;27:2356-2362.
Data on file.
Monday, July 16, 2012 61
62. What Are the Side Effects of
Exogenous Insulin?
Monday, July 16, 2012 62
63. Hypoglycemia
Severe insulin reactions per 100 patient-yr
0 20 40 60 80 100 120
DCCT 62 Type 1
SDIS 110 diabetes
UKPDS 2.3
Type 2
VA CSDM 3
diabetes
VA IIIP 7.8
Adapted with permission from McCall A. In: Leahy J, Cefalu W eds. Insulin Therapy. New York, NY:
Marcel Dekker, Inc.; 2002:193
Monday, July 16, 2012 63
64. Total Weight Gain and
Total Insulin Dose
400
Total
insulin 300
dose
(U/d)
200
100
0
0 10 20 30 40 50
Monday, July 16, 2012 Total weight gain (lb) 64
Adapted from Henry RR, et al. Diabetes Care. 1993;16:21-31.
65. Weight v Delta A1C
Studies with Type 2 Diabetes
Glargine
NPH 2
7 7
Detemir
1. Yki-Jarvinen
Reduction in A1C (%)
Diabetes Care 3
3 9
2000;23:1131
2. Rosenstock
1.5 8 9
Diabetes Care 4
2001;24:631 3.
Riddle Diabetes Care
2003;26: 3079
4. Fritsche Ann Int 8
1
4
Med 2003;138: 952 1
5.Raslova
Diab Res Clin Pract 2 1
5 5
2004;66:193 6. 0.5 2
2
Haak Diab Obes Clin
6 6
Pract 2005;7:56
7. Study 1530
8. Study 1337
9. Study 1373;
0
Rosenstock, 2006 July 16, 2012
Monday, 1 2 3 4 65
Weight Gain (kg)
66. How Do The Various Approaches
Compare?
Monday, July 16, 2012 66
67. Comparison of Common
Insulin Regimens*
Variable Glargine* NPH1 Premix2,3 Detemir4
Efficacy Insulin Works
Hypoglycemia† 1.0 1.4X 2.5-5.0X 1.0
Insulin Dose 1.0 1.0 1.5-2.0X 1.6-2.1X
Weight Gain 1.0 1.0 1.5X 0.7-1.0X
*
Normalized to glargine; sponsored comparator trials
†
Confirmed hypoglycemia
1
Riddle MC et al. Diabetes Care 2003;26:3080-3086
2
Janka HU et al. Diabetes Care 2005;28:254-259
3
Raskin P et al. Diabetes Care 2005;28:260-265
4 Monday, July 16, 2012 67
Rosenstock J et al. ADA 2006; Abstract 555-P
68. Conclusions
• Adjunctive therapy with insulin in type 2 diabetes
is both safe and effective
• Instead of being the ‘last resort’, early insulin use
is being encouraged by national organizations
• Choice of insulin and/or regimen is dependent
upon:
– The patient
– Pre-existing glycemic control
– Duration of illness
Monday, July 16, 2012 68
Editor's Notes
Slide 6-23 INSULIN TACTICS Twice-daily Split-mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years. In some cases, premixed 70/30 insulin is used for this purpose. Patient profiles of insulin levels resulting from this method, as shown in this figure, do not come close to matching the normal endogenous secretory pattern, shown in the shaded background. Patients with type 1 diabetes using this “split-mixed” regimen rarely achieve reasonably good glycemic control by present standards, since they lack endogenous insulin to supplement the partially adequate profile of injected insulin. Type 2 diabetes patients who have substantial endogenous insulin may fare much better with this regimen, but may experience late morning or nocturnal hypoglycemia because of excessive levels of insulin at these times. Berger M, Jorgens V, Mühlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care . 1999;22(suppl 3):C71-C75; Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews . 1995;3:308-334.
Study 1010 Study 1010 was a phase I, randomized, double-blind, 3-way crossover, euglycemic clamp study to evaluate the effect of obesity on the pharmacodynamic and pharmacokinetic behavior of glulisine, lispro, and regular human insulin The population included 18 obese individuals with increased abdominal tissue thickness determined by an MRI of abdominal subcutaneous fat layer The subjects acted as their own controls (crossover design) Subjects were given a single 0.3 U/kg dose of insulin subcutaneously in a crossover manner Results — Glulisine displays a rapid- and short-acting profile in obese individuals, which is more consistently maintained over the body mass index range of 30 kg/m 2 to 40 kg/m 2 and a range of subcutaneous fat thickness compared with lispro and regular human insulin Frick AD, Burger F, Scholtz H, Becker RHA. Time-action profile of insulin glulisine vs regular human insulin and insulin lispro in obese subjects. American Diabetes Association 64th Scientific Sessions. June 4-8, 2004; Orlando, Fla. Abstract 526.
Slide 29 Twice-Daily Split-Mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years Patient profiles of insulin levels shown in this slide do not come close to matching the normal endogenous secretory pattern seen in the shaded background Dawn phenomenon refers to the early morning fall of tissue insulin sensitivity counteracted by increased insulin secretion in nondiabetic individuals but manifested as rising glycemia in diabetic patients In some patients with marked dawn phenomenon, NPH insulin may be beneficial. Early morning hyperglycemia may also be managed by dividing the dose of NPH insulin between dinner and bedtime Berger M et al. Diabetes Care . 1999;22(suppl 3):C71-C75 Edelman SV, Henry RR. Diabetes Reviews . 1995;3:308-334
Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
Slide 6-6 TYPE 2 DIABETES…A PROGRESSIVE DISEASE Natural History of Type 2 Diabetes The natural history of type 2 diabetes shows the progressive emergence of the disorder. Well before diagnosis, patients may have had significant hyperglycemia for years, perhaps more than a decade. Patients with type 2 diabetes have altered islet -cell function and impaired insulin action in varying degrees. Plasma glucose may rise above normal in early adulthood, and as age-related declines in -cell function occur—together with less physical activity and increases in adipose tissue mass—plasma glucose continues to rise. By the time diabetes is diagnosed, plasma glucose may range from 180 to 220 mg/dL. It has been estimated that only about one third of the population has acceptable glycemic control by current standards. Based on the progressive nature of diabetes, complications that may take years to develop are often already present at the time of diagnosis. Riddle MC. Tactics for type II diabetes. Endocrinol Metab Clin North Am . 1997;26:659-677; Skyler JS. Insulin therapy in type 2 diabetes mellitus. In: DeFronzo RA, ed. Current Therapies of Diabetes Mellitus . St Louis, Mo: Mosby-Year Book Inc; 1998:108-116.
Slide 35 OAD Basal Insulin Therapy: Insulin Secretagogues or Sensitizers + Glargine at HS Based on advances in insulin therapy, future regimens for type 2 diabetes patients might include the use of an injectable, long-acting basal insulin analog in combination with oral agents or possibly with inhaled human insulin Addition of basal insulin glargine to a combination of oral agents can improve glycemic control, reducing glucotoxicity, which may in turn restore endogenous insulin response to SU and potentiate the effect of insulin sensitizers Alternatively, long-acting insulin glargine can provide a basal insulin profile to be associated in the future with prandial inhaled insulin, which mimics normal insulin effects in response to meals
Slide 29 Twice-Daily Split-Mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years Patient profiles of insulin levels shown in this slide do not come close to matching the normal endogenous secretory pattern seen in the shaded background Dawn phenomenon refers to the early morning fall of tissue insulin sensitivity counteracted by increased insulin secretion in nondiabetic individuals but manifested as rising glycemia in diabetic patients In some patients with marked dawn phenomenon, NPH insulin may be beneficial. Early morning hyperglycemia may also be managed by dividing the dose of NPH insulin between dinner and bedtime Berger M et al. Diabetes Care . 1999;22(suppl 3):C71-C75 Edelman SV, Henry RR. Diabetes Reviews . 1995;3:308-334
Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
Slide 35 OAD Basal Insulin Therapy: Insulin Secretagogues or Sensitizers + Glargine at HS Based on advances in insulin therapy, future regimens for type 2 diabetes patients might include the use of an injectable, long-acting basal insulin analog in combination with oral agents or possibly with inhaled human insulin Addition of basal insulin glargine to a combination of oral agents can improve glycemic control, reducing glucotoxicity, which may in turn restore endogenous insulin response to SU and potentiate the effect of insulin sensitizers Alternatively, long-acting insulin glargine can provide a basal insulin profile to be associated in the future with prandial inhaled insulin, which mimics normal insulin effects in response to meals
Over the 24-wk treatment period, A1C improved from 9.1% to 7.8% with morning insulin glargine, from 9.1% to 8.3% with bedtime NPH insulin, and from 9.1% to 8.1% with bedtime insulin glargine Improvement in A1C was more pronounced with morning insulin glargine than bedtime insulin glargine (p=0.008) or with NPH insulin (p<0.001) Results: Mean A1C Levels During Study Slide 10 Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:13:pages TBD
Slide 10 Mean A1C Concentrations During Study The forced-titration schedule of insulin glargine and NPH insulin produced a decline in mean A1C concentration, which reached a constant level after 18 weeks There were no between-treatment differences at end point (week 24) Mean A1C concentration was 6.96% for insulin glargine Mean A1C concentration was 6.97% for NPH insulin
Slide 29 Twice-Daily Split-Mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years Patient profiles of insulin levels shown in this slide do not come close to matching the normal endogenous secretory pattern seen in the shaded background Dawn phenomenon refers to the early morning fall of tissue insulin sensitivity counteracted by increased insulin secretion in nondiabetic individuals but manifested as rising glycemia in diabetic patients In some patients with marked dawn phenomenon, NPH insulin may be beneficial. Early morning hyperglycemia may also be managed by dividing the dose of NPH insulin between dinner and bedtime Berger M et al. Diabetes Care . 1999;22(suppl 3):C71-C75 Edelman SV, Henry RR. Diabetes Reviews . 1995;3:308-334
Objective : The exact contribution of postprandial and fasting glucose increments to overall hyperglycemia remain controversial. The discrepancies between the data published previously might be caused by the interference of several factors. To test the effects of overall glycemic control itself, the authors analyzed the diurnal glycemic profiles of type 2 diabetic patients investigated at different levels of HbA1c. Design and Methods – In 290 non-insulin and non-acarbose using patients with T2DM, plasma glucose (PG) concentrations were determined at fasting (8AM) and during postprandial and postabsorptive periods (at 11AM, 2PM and 5PM). The areas under the curve above fasting PG (FPG) concentration (AUC1) and >6.1 mmol/L (AUC2) were calculated for further evaluation of the relative contributions of postprandial PG (PPG) ([AUC1/AUC2] x 100 = %) and FPG ([AUC2-AUC1]/AUC2) x 100 = % increments to overall diurnal hyperglycemia. The data were compared over quintiles of A1c. Results – The relative contribution of PPG DECREASED progressively from the lowest (69.7%) to the highest quintile of A1c (30.5%, p<0.001 ), whereas the relative contribution of FPG INCREASED gradually with increasing levels of A1c: 30.3% in the lowest to 69.5% in the highest quintile (p<0.001). CONCLUSIONS: The relative contribution of PPG excursions is predominant in fairly controlled patients, whereas the contribution of FPG hyperglycemia increases gradually with diabetes worsening. These results could therefore provide a unifying explanation for the discrepancies as observed in previous studies. FIX FASTING FIRST!! “ Contributions of Fasting and Postprandial Plasma Glucose Increments to the Overall Diurnal Hyperglycemia of Type 2 Diabetic Patients” – Louis Monnier, MD; Helene Lapinski, MD; and Claude Colette, PhD. Diab Care 26:881-885, 2003.
Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
Mean insulin glargine dose remained unchanged (30 IU/d at baseline vs 31 IU/d endpoint) [Lankisch Abstract line 28-29]
At week 24, the A1C was significantly reduced in both the ALG and Carb Count groups ( P <0.0001) [Bergenstal Abstract line 18-19]
The ALG group had a higher mean dose of insulin glulisine than the Carb Count group (110.2 vs 94.3 U, respectively; P =0.04) [Bergenstal Abstract line 21-22]
Slide 23 Mimicking Nature: The Basal-Bolus Insulin Concept This slide shows the pattern of normal peripheral plasma insulin (endogenous insulin) throughout the day in a normal-weight nondiabetic individual superimposed with the basal-bolus insulin strategy profile The basal-bolus approach to insulin therapy combines basal insulin to meet the insulin requirement to suppress hepatic glucose production between meals and bolus insulin to meet the insulin requirement after eating. This strategy may reduce risk of hypoglycemia in individuals with erratic schedules or in individuals who have greater insulin requirements Insulin analogs, such as insulin glargine, lispro, and aspart, appear to mimic basal and bolus insulin better than other available preparations McCall A. In: Insulin Therapy . Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
Slide 6-55 INSULIN TACTICS: THE FUTURE Oral Agents + Mealtime Inhaled Insulin Effect on HbA 1c The concept of inhaled insulin has been explored for those patients with type 2 diabetes who resist initiating insulin therapy because it requires injections. As a response to this resistance, a dry powder aerosol delivery system of human insulin has been developed. Weiss et al examined the ability of mealtime inhaled insulin to improve glycemic control in 69 subjects. Patients were randomized to a 3-month treatment period of either continued oral agents alone (sulfonylurea and/or metformin) or in combination with 1 or 2 puffs of inhaled insulin before meals. The inhaled insulin doses were titrated based on glucose testing 4 times daily. Patients continuing on oral agents alone showed little change in HbA 1c at 12 weeks (–0.13%), while those receiving the inhaled insulin in addition to the oral agents exhibited a marked improvement in HbA 1c (–2.28%). Weiss SR, Berger S, Cheng S, Kourides I, Landschulz W, Gelfand RA, for the Phase II Inhaled Insulin Study Group. Diabetes . 1999;48(suppl 1):A12.
In addition to HbA 1c - lowering effects, inhaled insulin consistently reduced fasting plasma glucose (FPG) levels to a significantly greater degree than SC insulin (as measured by 95% CIs). The baseline levels expressed in mg/dL are at the top of the bar and levels at end point are at the bottom. Values in parentheses are converted to mmol/L. Results from 3 different studies comparing inhaled insulin with SC insulin are shown on this slide. In the standard and intensive insulin therapy studies, the adjusted difference between inhaled insulin and SC insulin were - 25.17 (95% CI, - 43.39 to - 6.95) and - 39.53 (95% CI, - 57.50 to - 21.56), respectively. In the on insulin study, the adjusted difference was - 15.88 (95% CI, - 26.61 to - 5.15). 1,2 These reductions appear to be unrelated to the basal insulin dose administered the night before FPG measurement, and the mechanism for these changes is currently under investigation. Hollander P, Blonde L, Rowe R, et al. Efficacy and safety of inhaled insulin in patients with type 2 diabetes: a 6 - month, randomized, comparative trial. Diabetes Care . In press. Data on file. Pfizer Inc, New York, NY.