Transcript Insulin Therapy in Type 2 Diabetes: Current and Future

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
Rate (per 1000 population)
35
29.8
30
25.2
25
20
1990
1992
CDC NHIS Results
MMWR. 1997;46:1014-1018.
1994
Incidence of Type 2 Diabetes Mellitus
Rate (per 1000 population)
5
3.7
4
3
2.1
2
1
1990
1992
CDC NHIS Results
MMWR. 1997;46:1014-1018.
1994
Risk Factors for Type 2 Diabetes
Nonmodifiable
Modifiable
•
Genetic factors
•
Weight
•
Age
•
Physical activity
•
Ethnicity
Trend in Prevalence of Obesity*:
NHANES Data
36
US Population (%)
34
32
30
28
26
24
22
20
NHES (19601962)
NHANES I
(1971-1974)
NHANES II
(1976-1980)
*BMI  27.3 mg/m2 for women;  27.8 kg/m2 for men
Kuczmarski RJ, et al. JAMA. 1994;272:205-211.
NHANES IIIb
(1988-1994)
Age-Adjusted Relative Risk
Link Between Obesity and Type 2 Diabetes:
Nurses’ Health Study
120
100
80
60
40
20
0
< 22
2222.9
2323.8
2424.9
2526.9
2728.9
BMI (kg/m2)
Colditz GA, et al. Ann Intern Med. 1995;122:481-486.
2930.9
3132.9
3334.9
> 35
Link Between Obesity and Type 2 Diabetes:
Nurses’ Health Study (cont’d)
80
Age-Adjusted Relative Risk
70
60
50
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
40
30
20
10
0
<22.0
22.0-24.9
25.0-28.9
BMI (kg/m2) at Age 18 Years
Colditz GA, et al. Ann Intern Med. 1995;122:481-486.
29+
ADA Treatment Guidelines
Biochemical Index
Normal
Preprandial glucose
Bedtime glucose
HbA1c
*Depending on assay norms
Goal
Action Suggested
<90 mg/dL
80-120 mg/dL
<80 or >140 mg/dL
<120 mg/dL
100-140 mg/dL
<100 or >160 mg/dL
<6%*
<7%
>8%
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
Very symptomatic
Severe hyperglycemia
Ketosis
Latent autoimmune diabetes
Pregnancy
Insulin
Considerations in Pharmacologic
Treatment of Type 2 Diabetes
•
Efficacy (HbA1c 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: HbA1c <6.5%, FBG <110 mg/dL,
2-hr postprandial glucose <180 mg/dL
Improvement in HbA1c in the VA CSDM
10
HbA1c (%)
9
Standard
Intensive
8
7
6
0
3
6
9
12 15 18 21 24 27 30
Months
P<0.001 vs. placebo in intensive treatment group
Abraira C, et al. Diabetes Care. 1995;18:1113-1123.
VA CSDM: Results at Endpoint
Baseline
Endpoint
P Value
9.3%
6.9%
<0.001
206 mg/dL
118 mg/dL
<0.001
22.9 U
133.0 U
Blood pressure*
136/81 mmHg
137/80 mmHg
Total cholesterol*
5.9 mg/dL
5.2 mg/dL
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
HbA1c
Fasting serum glucose
Insulin dose
*Results at 2 years
Abraira C, et al. Diabetes Care. 1995;18:1113-1123.
0.003
0.06
The Kumamoto Trial: Effects of
Conventional vs. Intensive Insulin Therapy
Cumulative Development or
Progression (%)
50
Conventional
44%
Intensive
40
32%
32%
28%
30
19.2%
20
10
7.7%
11.5%
7.7%
0
Primary
Prevention
Secondary
Prevention
Retinopathy
Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117.
Primary
Prevention
Secondary
Prevention
Nephropathy
FPG (mmol/L) or HbA 1c (%)
UKPDS: Effect of Intensive Therapy on Glycemia
FPG, Conventional (N=1138)
FPG, Sulfonylurea (N=1573) or Insulin (N=1156)
HbA1c, Conventional
HbA1c, Sulfonylurea or Insulin
10
9
8
7
6
0
1
3
UKPDS Group. Lancet. 1998;352:837-853.
Years
5
7
9
UKPDS 10-Year Cohort Data: Reductions With
Intensive vs. Conventional Therapy
0
-6%
-10
-10%
-11%
-12%
(P= 0.029)
-16%
(P= 0.052)
-20
-25%
(P= 0.0099)
-30
HbA1c
All-Cause Mortality
Diabetes-Related
Death
UKPDS Group. Lancet. 1998;352:837-853.
Any DiabetesRelated
Complication
Myocardial
Infarction
Microvascular
Complication
Summary of Key Findings
•
VA CSDM:
–
–
•
Kumamoto trial:
–
–
•
Glycemic control achievable with intensive insulin treatment: control
maintained >2 years
Intensive treatment not associated with severe hypoglycemia, weight
gain, hypertension, or dyslipidemia
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 HbA1c reduction in reducing complications
Insulin does not increase macrovascular disease
Pharmacokinetics of Current
Insulin Preparations
Onset
Peak
Effective
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
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 Gilman’s The Pharmacological Basis of Therapeutics. 1990:14631495.
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
–
–
•
Sulfonylurea + Insulin
–
–
•
Improves insulin sensitivity
Alpha glucosidase inhibitor (acarbose) + Insulin
–
•
BIDS therapy: bedtime insulin/daytime sulfonylurea
Useful in patients early in course of disease
Metformin + Insulin
–
•
Combination of two agents with different mechanisms of action
More convenient and may be safer
Decreases postprandial glycemia
Thiazolidinediones + Insulin
–
–
Improves insulin resistance, improves insulin action in peripheral
tissues
Reduces insulin requirement
Change From Baseline Values
Meta-Analysis of Sulfonylurea/Insulin
Combination Therapy
2
Sulfonylurea + Insulin
Insulin Only
1.4
0.8
1
0
-1
-0.25
-0.6
-1.1*
-2
-3
-2.5*
Fasting Serum Glucose
(mg/dL)
HbA1c (%)
* P< 0.05 vs. baseline value
Johnson JL, et al. Arch Intern Med. 1996;156:259-264.
Weight (kg)
Comparison of Insulin Regimens
Among Oral Treatment Failures
10
8
Morning NPH (N= 32)
Evening NPH (N= 28)
Twice-daily injections (N= 29)
Multiple-daily injections (N= 30)
Control (N= 30)
6
4
2.2*
2
2.9*
1.2* †
1.8*
0
-2
-0.5
-1.7*
-1.9*
-1.8*
-0.9
-1.6*
-4
Change in HbA1c (%)
* P< 0.001 vs. control group
†P< 0.05 vs. other insulin treatment groups
Yki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433.
Weight Change (kg)
Total Direct Costs of Type 2 Diabetes
Hospital
37.2
Outpatient Care
6.2
Nursing Home
1.8
Prescription Costs
15.6
0
10
20
US $ Billions
Rathman W. Drug Benefit Trends. 1998;10:24-27.
30
40
Total Indirect Costs of Type 2 Diabetes
Short-Term
Morbidity
8.5
Long-Term
Morbidity
11.2
Mortality
27
0
10
20
US $ Billions
Rathman W. Drug Benefit Trends. 1998;10:24-27.
30
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
Pharmacokinetics of Current Insulin
Preparations Compared With Insulin Glargine
Onset
Peak
Effective
Duration
Insulin lispro
<15 min
1 hr
3 hr
Regular
0.5-1 hr
2-3 hr
3-6 hr
2-4 hr
7-8 hr
10-12 hr
4 hr
Varies
18-20 hr
1-2 hr
Flat/Predictable
24 hr
NPH/Lente
Ultralente
Insulin glargine*
*Investigational
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 Gilman’s The Pharmacological Basis of Therapeutics. 1990:14631495.
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
Gly
1
5
10
15
20 Asn
1
5
10
15
20
Substitution
25
30
Extension
Arg Arg
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
Concentration (mg/dL)
Blood Glucose Profile of Insulin
Glargine in Normal Volunteers
110
105
100
95
90
85
80
75
70
-0.5
NPH
1
3
6
9
12
15
18
21
24
Time (hr)
Insulin glargine (15 µg zinc)
Insulin glargine (80 µg zinc)
Owens DR, et al. Diabetologia. 1998;41(suppl 1):A245.
Exogenous insulin (pmol/L)
Exogenous Insulin Concentration
of Insulin Glargine in Normal Volunteers
75
50
25
0
0
2
4
6
8
10
12
14
16
18
20
22
Hours after injections
NPH
Insulin glargine (15 µg zinc)
Owens DR, et al. Diabetologia. 1998;41(suppl 1):A245.
Insulin glargine (80 µg zinc)
24
Mean Change From Baseline
(mg/dL)
Efficacy of Insulin Glargine
in Type 1 and Type 2 Diabetes
Improvement in FPG After 4 Weeks
0
-20
-14.4
-40
-60
-52.2*
Insulin
glargine
N= 168
NPH
N= 88
Type 1
-50.4
-46.8
Insulin
glargine
(30 µg
zinc)
N= 55
Insulin
glargine
(80 µg
zinc)
N= 51
-41.4
NPH
N= 49
Type 2
*P=0.0001
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.
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 shortacting 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
% Change From Baseline
Changes in Glycemic Parameters
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
-50
Inhaled human insulin
Subcutaneously injected
insulin
HbA1c
2-hr PG
Gelfand RA, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0235.
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 (cont’d)
•
•
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