Insulin Therapy

in Type 2 Diabetes:
Current and Future
Directions
Issues in the Management of
Type 2 Diabetes
Type 2: Deterioration of beta cells over time
Increasing prevalence with increasing risk factors, eg, obesity
Hyperglycemia affects morbidity, mortality, and resources
Tight glycemic control with insulin may reduce costly complications
30% to 40% of patients ultimately require insulin
Regimen-related limitations with current insulin formulations and
delivery systems
Newer semisynthetic insulins and delivery systems may improve
compliance and achieve better glycemic control with less
hypoglycemia
Prevalence of Type 2 Diabetes Mellitus
MMWR. 1997;46:1014-1018.
29.8
25.2
20
25
30
35
1990 1992 1994
CDC NHIS Results
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Incidence of Type 2 Diabetes Mellitus
MMWR. 1997;46:1014-1018.
3.7
2.1
1
2
3
4
5
1990 1992 1994
CDC NHIS Results
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Risk Factors for Type 2 Diabetes
Nonmodifiable
Genetic factors
Age
Ethnicity
Modifiable
Weight
Physical activity
Trend in Prevalence of Obesity*:
NHANES Data
Kuczmarski RJ, et al. JAMA. 1994;272:205-211.
*BMI 27.3 mg/m
2
for women; 27.8 kg/m
2
for men
20
22
24
26
28
30
32
34
36
NHES (1960-
1962)
NHANES I
(1971-1974)
NHANES II
(1976-1980)
NHANES IIIb
(1988-1994)
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Link Between Obesity and Type 2 Diabetes:
Nurses Health Study
Colditz GA, et al. Ann Intern Med. 1995;122:481-486.
0
20
40
60
80
100
120
< 22 22-
22.9
23-
23.8
24-
24.9
25-
26.9
27-
28.9
29-
30.9
31-
32.9
33-
34.9
> 35
BMI (kg/m
2
)
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Link Between Obesity and Type 2 Diabetes:
Nurses Health Study (contd)
Colditz GA, et al. Ann Intern Med. 1995;122:481-486.
0
10
20
30
40
50
60
70
80
<22.0 22.0-24.9 25.0-28.9 29+
BMI (kg/m
2
) at Age 18 Years
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Loss of 5-10 kg
Loss or gain of 4.9 kg or less
Gain of 5-6.9 kg
Gain of 7-10.9 kg
Gain of 11-19.9 kg
Gain of 20 kg or more
ADA Treatment Guidelines
Biochemical Index Normal Goal Action Suggested


Preprandial glucose <90 mg/dL 80-120 mg/dL <80 or >140 mg/dL


Bedtime glucose <120 mg/dL 100-140 mg/dL <100 or >160 mg/dL


HbA
1c
<6%* <7% >8%
*Depending on assay norms
Medical Nutrition Therapy
for Type 2 Diabetes
Diet
Improved food choices
Spacing meals
Individualized carbohydrate content
Moderate calorie restriction
Exercise
Pharmacologic Therapy
for Type 2 Diabetes
Sulfonylureas (glyburide, glipizide, glimepiride)
Biguanides (metformin)
Alpha-glucosidase inhibitors (acarbose, miglitol,
voglibose)
Benzoic acid analogues (repaglinide)
Thiazolidinediones (troglitazone, rosiglitazone,
pioglitazone)
Insulin (human insulin, insulin analogues)
Treatment Algorithm
Nonpharmacologic therapy
Monotherapy
Sulfonylureas/Benzoic acid
analogue
Biguanide
Alpha-glucosidase inhibitors
Thiazolidinediones
Insulin
Combination therapy
Insulin
Very symptomatic
Severe hyperglycemia
Ketosis
Latent autoimmune diabetes
Pregnancy
Considerations in Pharmacologic
Treatment of Type 2 Diabetes
Efficacy (HbA
1c
lowering capacity)
Mechanisms of action of drugs
Impact on weight gain
Complications/tolerability
Frequency of hypoglycemia
Compliance/complexity of regimen
Cost
Tight Glycemic Control:
Reducing the Risk of Complications
Epidemiologic evidence in type 2 diabetes to link
microvascular disease and hyperglycemia first
suggested in DCCT
Type 2 diabetes studies: Veterans Affairs Cooperative Study
on Type 2 Diabetes (VA CSDM), United Kingdom Prospective
Diabetes Study (UKPDS), and Kumamoto trial
Intensive blood glucose control with insulin, sulfonylurea, or metformin
reduced risk of micro- and macrovascular complications
Glycemic threshold to prevent onset and progression of microvascular
complications: HbA
1c
<6.5%, FBG <110 mg/dL,
2-hr postprandial glucose <180 mg/dL
Improvement in HbA
1c
in the VA CSDM
P<0.001 vs. placebo in intensive treatment group
Abraira C, et al. Diabetes Care. 1995;18:1113-1123.
6
7
8
9
10
0 3 6 9 12 15 18 21 24 27 30
Months
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1
c

(
%
)
Standard
Intensive
VA CSDM: Results at Endpoint
Baseline Endpoint P Value

HbA
1c
9.3% 6.9% <0.001
Fasting serum glucose 206 mg/dL 118 mg/dL <0.001
Insulin dose 22.9 U 133.0 U
Blood pressure* 136/81 mmHg 137/80 mmHg
Total cholesterol* 5.9 mg/dL 5.2 mg/dL 0.003
HDL cholesterol* 1.1 mg/dL 1.0 mg/dL
LDL cholesterol* 3.5 mg/dL 3.4 mg/dL
Triglycerides* 2.3 mg/dL 2.0 mg/dL 0.06

*Results at 2 years
Abraira C, et al. Diabetes Care. 1995;18:1113-1123.
The Kumamoto Trial: Effects of
Conventional vs. Intensive Insulin Therapy
Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117.
32%
44%
28%
32%
7.7%
19.2%
7.7%
11.5%
0
10
20
30
40
50
Primary
Prevention
Secondary
Prevention
Primary
Prevention
Secondary
Prevention
Retinopathy Nephropathy
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Conventional
Intensive
UKPDS: Effect of Intensive Therapy on Glycemia
UKPDS Group. Lancet. 1998;352:837-853.
6
7
8
9
10
0 1 3 5 7 9 Years
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FPG, Conventional (N=1138)
FPG, Sulfonylurea (N=1573) or Insulin (N=1156)
HbA1c, Conventional
HbA1c, Sulfonylurea or Insulin
UKPDS 10-Year Cohort Data: Reductions With
Intensive vs. Conventional Therapy
UKPDS Group. Lancet. 1998;352:837-853.
-6%
-10%
-16%
(P= 0.052)
-25%
(P= 0.0099)
-12%
(P= 0.029)
-11%
-30
-20
-10
0
HbA1c All-Cause Mortality Diabetes-Related
Death
Any Diabetes-
Related
Complication
Myocardial
Infarction
Microvascular
Complication
Summary of Key Findings
VA CSDM:
Glycemic control achievable with intensive insulin treatment: control
maintained >2 years
Intensive treatment not associated with severe hypoglycemia, weight
gain, hypertension, or dyslipidemia
Kumamoto trial:
Intensive insulin treatment reduced microvascular complications
Established glycemic threshold to prevent onset and progression of
complications
UKPDS:
Diet therapy alone inadequate in two thirds of patients
Pharmacologic therapy plus nutrition/exercise necessary
Weigh benefit:risk ratio
No threshold for HbA
1c
reduction in reducing complications
Insulin does not increase macrovascular disease
Effective
Onset Peak Duration

Insulin lispro <15 min 1 hr 3 hr
Regular 0.5-1 hr 2-3 hr 3-6 hr
NPH/Lente 2-4 hr 6-12 hr 10-16 hr
Ultralente 4-8 hr Varies 18-20 hr
Pharmacokinetics of Current
Insulin Preparations
Barnett AH, Owens DR. Lancet. 1997;349:97-51. White JR, et al. Postgrad Med. 1997;101:58-70.
Kahn CR, Schechter Y. In: Goodman and Gilmans The Pharmacological Basis of Therapeutics. 1990:1463-
1495.
Clinical Efficacy of Insulin Lispro
Worldwide clinical trials of insulin lispro in >10,000
patients with type 1 or type 2 diabetes
1-year parallel group comparisons or 6-month
crossovers (3 months on each insulin) studies
Dosage regimen: insulin lispro 10 min before and soluble
human insulin 30 to 45 minutes before meals, with NPH or
ultralente insulin as the basal insulin supplement
Strategies for Insulin Therapy in Elderly Patients
Insulin therapy often considered a last resort in the
elderly
Therapeutic goals:
Relieve symptoms
Prevent hypoglycemia
Prevent acute complications of hyperglycemia
Ways to facilitate insulin treatment:
Simple dose schedules
Premixed preparations
Improved, more convenient delivery systems
Combination Therapy:
Oral Agents Plus Insulin
Rationale
Combination of two agents with different mechanisms of action
More convenient and may be safer
Sulfonylurea + Insulin
BIDS therapy: bedtime insulin/daytime sulfonylurea
Useful in patients early in course of disease
Metformin + Insulin
Improves insulin sensitivity
Alpha glucosidase inhibitor (acarbose) + Insulin
Decreases postprandial glycemia
Thiazolidinediones + Insulin
Improves insulin resistance, improves insulin action in peripheral
tissues
Reduces insulin requirement
Meta-Analysis of Sulfonylurea/Insulin
Combination Therapy
Johnson JL, et al. Arch Intern Med. 1996;156:259-264.
* P< 0.05 vs. baseline val ue
1.4
-0.6
-0.25
0.8
-2.5*
-1.1*
-3
-2
-1
0
1
2
Fasting Serum Glucose
(mg/dL)
HbA1c (%) Weight (kg)
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sSulfonylurea + Insulin
Insulin Only
Comparison of Insulin Regimens
Among Oral Treatment Failures
Yki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433.
-0.9
-1.7*
2.2*
-1.9*
1.2*
-1.8*
1.8*
-1.6*
2.9*
-0.5
-4
-2
0
2
4
6
8
10
Change in HbA1c (%) Weight Change (kg)
* P< 0.001 vs. control group
P< 0.05 vs. other insulin treatment groups
Morning NPH (N= 32)
Evening NPH (N= 28)
Twice-daily injections (N= 29)
Multiple-daily injections (N= 30)
Control (N= 30)
Total Direct Costs of Type 2 Diabetes
Rathman W. Drug Benefit Trends. 1998;10:24-27.
15.6
1.8
6.2
37.2
0 10 20 30 40
Prescription Costs
Nursing Home
Outpatient Care
Hospital
US $ Billions
Total Indirect Costs of Type 2 Diabetes
Rathman W. Drug Benefit Trends. 1998;10:24-27.
27
11.2
8.5
0 10 20 30
Mortality
Long-Term
Morbidity
Short-Term
Morbidity
US $ Billions
Ideal Basal Insulin
Closely mimic normal pancreatic basal insulin
secretion
No distinct peak effect
Continued effect over 24 hours
Reduce nocturnal hypoglycemia
Once-daily administration for patient compliance
Predictable absorption pattern
Effective
Onset Peak Duration

Insulin lispro <15 min 1 hr 3 hr
Regular 0.5-1 hr 2-3 hr 3-6 hr
NPH/Lente 2-4 hr 7-8 hr 10-12 hr
Ultralente 4 hr Varies 18-20 hr
Insulin glargine* 1-2 hr Flat/Predictable 24 hr

*Investigational
Pharmacokinetics of Current Insulin
Preparations Compared With Insulin Glargine
Barnett AH, Owens DR. Lancet. 1997;349:97-51. White JR, et al. Postgrad Med. 1997;101:58-70.
Kahn CR, Schechter Y. In: Goodman and Gilmans The Pharmacological Basis of Therapeutics. 1990:1463-
1495.
Coates PA, et al. Diabetes. 1995;44(Suppl 1):130A.
Structure of Insulin Glargine:
A New Long-Acting Insulin Analogue
Modifications to human insulin chain
Substitution of glycine at position A21
Addition of two arginines at position B30
Unique release pattern from injection site
1
1
15 10 5
5 10 15 20
20 Asn
25 30
Gly
Arg Arg
Substitution
Extension
Characteristics of Insulin Glargine
Euglycemic clamp studies vs. NPH
Smooth continuous release from injection site
Longer duration of action
Continued effect at end of 24-hour clamp study
No differences in the absorption rate from arm, leg, or
abdominal sites
No inflammatory reactions at any of the injection sites
Flat insulin profile
As effective in lowering FPG levels as NPH insulin, with
significantly reduced nocturnal hypoglycemia
Blood Glucose Profile of Insulin
Glargine in Normal Volunteers
Owens DR, et al. Diabetologia. 1998;41(suppl 1):A245.
70
75
80
85
90
95
100
105
110
-0.5 1 3 6 9 12 15 18 21 24
Time (hr)
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NPH Insuli n glargine (15 g zinc) Insul i n glargi ne (80 g zinc)
Exogenous Insulin Concentration
of Insulin Glargine in Normal Volunteers
Owens DR, et al. Diabetologia. 1998;41(suppl 1):A245.
0
25
50
75
0 2 4 6 8 10 12 14 16 18 20 22 24
Hours after i njections
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NPH Insulin glargine (15 g zinc) Insulin glargine (80 g zinc)
Efficacy of Insulin Glargine
in Type 1 and Type 2 Diabetes
Raskin P, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0404.
Rosenstock J, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0357.
*P=0.0001
Improvement in FPG After 4 Weeks
-50.4
-41.4
-14.4
-46.8
-52.2*
-60
-40
-20
0
Insulin
glargine
N= 168
NPH
N= 88
Insulin
glargine
(30 g
zi nc)
N= 55
Insul in
glargi ne
(80 g
zinc)
N= 51
NPH
N= 49
Type 1 Type 2
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Safety of Insulin Glargine
in Type 1 and Type 2 Diabetes
Type 1 Diabetes
Similar incidence of hypoglycemia between insulin glargine
and NPH after 4 weeks of treatment
Pattern of adverse events and injection site reactions also
similar
Type 2 Diabetes
No difference in frequency of hypoglycemia from NPH
No change in body weight
Other Long-Acting Insulin Analogues
Glycemic objectives:
Provide constant, reproducible supply of basal insulin
Adequately suppress hepatic glucose production
NovoSol Basal
First long-acting insulin analogue
Discontinued because of local inflammatory reactions
In development
Di-arginyl human insulin analogue (Gly, Arg)
C16 fatty-acid-acylated analogue
Need for Novel Delivery Systems of Insulin
Disadvantages of conventional subcutaneous injection:
Discomfort
Inconvenience
Systemic delivery
Inconsistent pharmacokinetics
Irreversible after injection
Insulin pumps: too complex, limited experience and utility
with type 2
Insulin pen: beneficial but underutilized
Systems in clinical testing
Inhaled formulation
Jet-injected systems
Insulin Pump
CSII: uses portable infusion pump connected to an
indwelling subcutaneous catheter to deliver short-
acting insulin
IIP shown to have significant advantages over
multiple daily injections
Reduces glycemic variability, clinical hypoglycemia, weight
gain
Extreme for routine practice but may be useful in special
circumstances
Not currently available in the United States
Insulin Pump
Insulin Pen
Benefits
More accurate dosing mechanisms
Faster and easier than conventional syringes
Improved patient attitude and compliance
Advantages of newer insulin pens
LCD display to show dosage setting
Dosage settings change quickly and easily
Safety button automatically resets after drug delivery
Insulin Pen
Inhaled Insulin Formulations
Gelfand RA, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0235.
Changesin Gl ycemic Parameters
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
HbA1c 2-hr PG
%

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Inhal ed human insuli n
Subcutaneously i njected
insuli n
Continuous Glucose Sensors
When available, may provide only mechanical means
of achieving normal glucose homeostasis
Will direct insulin delivery automatically on demand
(closed loop)
One technology uses reverse iontophoresis to
noninvasively extract and measure glucose levels
Technical challenge to develop
Conclusions
Type 2 diabetes: gradual deterioration of glycemic control
Significant morbidity and mortality; tight glycemic control reduces risk
of complications
Earlier institution of insulin may help attain initial glycemic control
Objectives of insulin therapy:
Achieve normal fasting glucose levels
Achieve normal postprandial glucose levels
Minimize hypoglycemia
Intensive insulin therapy should:
Provide good glycemic control
Produce little hypoglycemia
Improve lipid profile
Reduce risks and costs of treating complications
Conclusions (contd)
New delivery systems:
Reduce limitations of conventional insulin syringes
Improve patient compliance and disease management
New long-acting insulin analogues (eg, insulin
glargine):
Produce flat insulin profile with no peaks
Allow once-daily administration
Significantly reduce nocturnal hypoglycemia