insulin therapy in type 2 diabetes: current and future directions
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Insulin Therapy in Type 2 Diabetes:Current and Future Directions
Issues in the Management ofType 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
Rat
e (p
er 1
000
popu
latio
n)
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
Rat
e (p
er 1
000
popu
latio
n)
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/m2 for women; 27.8 kg/m2 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)
US
Pop
ulat
ion
(%)
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/m2)
Age
-Adj
uste
d Rel
ativ
e Ris
k
Link Between Obesity and Type 2 Diabetes:
Nurses’ Health Study (cont’d)
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/m2) at Age 18 Years
Ag
e-A
dju
ste
d R
ela
tive
Ris
k
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
HbA1c <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
MonotherapySulfonylureas/Benzoic
acid analogueBiguanide
Alpha-glucosidase inhibitors
ThiazolidinedionesInsulin
Combination therapy Insulin
Very symptomaticSevere hyperglycemiaKetosisLatent autoimmune diabetesPregnancy
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
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
HbA 1
c (%
)
Standard
Intensive
VA CSDM: Results at Endpoint
Baseline Endpoint P Value
HbA1c 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
PrimaryPrevention
SecondaryPrevention
PrimaryPrevention
SecondaryPrevention
Retinopathy Nephropathy
Cu
mu
lativ
e D
eve
lop
me
nt o
r P
rog
ress
ion
(%
)
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 9Years
FP
G (
mm
ol/L
) or
HbA
1c
(%)
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-RelatedDeath
Any Diabetes-Related
Complication
MyocardialInfarction
MicrovascularComplication
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 HbA1c reduction in reducing complications– Insulin does not increase macrovascular disease
EffectiveOnset 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 Gilman’s 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 value
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)
Ch
ange
Fro
m B
asel
ine
Val
ues Sulfonylurea + Insulin
Insulin Only
Comparison of Insulin RegimensAmong 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-TermMorbidity
Short-TermMorbidity
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
EffectiveOnset 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 Gilman’s 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
15105
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
8085
9095
100
105
110
-0.5 1 3 6 9 12 15 18 21 24
Time (hr)
Co
nce
ntr
atio
n (
mg/
dL)
NPH Insulin glargine (15 µg zinc) Insulin glargine (80 µg 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 injections
Exog
eno
us
insu
lin
(pm
ol/L
)
NPH Insulin glargine (15 µg zinc) Insulin glargine (80 µg zinc)
Efficacy of Insulin Glarginein 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
InsulinglargineN= 168
NPHN= 88
Insulinglargine(30 µgzinc)
N= 55
Insulinglargine(80 µgzinc)
N= 51
NPHN= 49
Type 1 Type 2
Mea
n C
hang
e Fr
om B
asel
ine
(mg/
dL)
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.
Changes in Glycemic Parameters
-50-45-40-35-30-25-20-15-10
-50
HbA1c 2-hr PG
% C
han
ge F
rom
Bas
elin
e
Inhaled human insulin
Subcutaneously injectedinsulin
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
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