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Insulin Therapy in Type 2 Diabetes: Current and Future Directions

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Title: Insulin Therapy in Type 2 Diabetes: Current and Future Directions


1
Insulin Therapy in Type 2 DiabetesCurrent and
Future Directions
2
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

3
Prevalence of Type 2 Diabetes Mellitus
MMWR. 1997461014-1018.
4
Incidence of Type 2 Diabetes Mellitus
MMWR. 1997461014-1018.
5
Risk Factors for Type 2 Diabetes
  • Nonmodifiable
  • Genetic factors
  • Age
  • Ethnicity
  • Modifiable
  • Weight
  • Physical activity

6
Trend in Prevalence of Obesity NHANES Data
BMI ? 27.3 mg/m2 for women ? 27.8 kg/m2 for men
Kuczmarski RJ, et al. JAMA. 1994272205-211.
7
Link Between Obesity and Type 2 DiabetesNurses
Health Study
Colditz GA, et al. Ann Intern Med.
1995122481-486.
8
Link Between Obesity and Type 2 DiabetesNurses
Health Study (contd)
Colditz GA, et al. Ann Intern Med.
1995122481-486.
9
ADA Treatment Guidelines
Biochemical Index Normal Goal Action
Suggested Preprandial glucose lt90 mg/dL 80-120
mg/dL lt80 or gt140 mg/dL Bedtime glucose lt120
mg/dL 100-140 mg/dL lt100 or gt160
mg/dL HbA1c lt6 lt7 gt8
Depending on assay norms
10
Medical Nutrition Therapy for Type 2 Diabetes
  • Diet
  • Improved food choices
  • Spacing meals
  • Individualized carbohydrate content
  • Moderate calorie restriction
  • Exercise

11
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)

12
Treatment Algorithm
Nonpharmacologic therapy
Very symptomatic Severe hyperglycemia Ketosis Late
nt autoimmune diabetes Pregnancy
Monotherapy Sulfonylureas/Benzoic acid
analogue Biguanide Alpha-glucosidase
inhibitors Thiazolidinediones Insulin
Combination therapy
Insulin
13
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

14
Tight Glycemic ControlReducing 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
    lt6.5, FBG lt110 mg/dL, 2-hr postprandial glucose
    lt180 mg/dL

15
Improvement in HbA1c in the VA CSDM
Plt0.001 vs. placebo in intensive treatment group
Abraira C, et al. Diabetes Care.
1995181113-1123.
16
VA CSDM Results at Endpoint
Baseline Endpoint P Value HbA1c 9.3 6.9 lt0.00
1 Fasting serum glucose 206 mg/dL 118
mg/dL lt0.001 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.
1995181113-1123.
17
The Kumamoto Trial Effects of Conventional vs.
Intensive Insulin Therapy
Ohkubo Y, et al. Diabetes Res Clin Pract.
199528103-117.
18
UKPDS Effect of Intensive Therapy on Glycemia
UKPDS Group. Lancet. 1998352837-853.
19
UKPDS 10-Year Cohort Data Reductions With
Intensive vs. Conventional Therapy
UKPDS Group. Lancet. 1998352837-853.
20
Summary of Key Findings
  • VA CSDM
  • Glycemic control achievable with intensive
    insulin treatment control maintained gt2 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 benefitrisk ratio
  • No threshold for HbA1c reduction in reducing
    complications
  • Insulin does not increase macrovascular disease

21
Pharmacokinetics of Current Insulin Preparations
  • Effective
  • Onset Peak Duration
  • Insulin lispro lt15 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. 199734997-51.
White JR, et al. Postgrad Med. 199710158-70.
Kahn CR, Schechter Y. In Goodman and Gilmans
The Pharmacological Basis of Therapeutics.
19901463-1495.
22
Clinical Efficacy of Insulin Lispro
  • Worldwide clinical trials of insulin lispro in
    gt10,000 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

23
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

24
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

25
Meta-Analysis of Sulfonylurea/InsulinCombination
Therapy
Johnson JL, et al. Arch Intern Med.
1996156259-264.
26
Comparison of Insulin RegimensAmong Oral
Treatment Failures
Yki-Jarvinen H, et al. N Engl J Med.
19923271426-1433.
27
Total Direct Costs of Type 2 Diabetes
Rathman W. Drug Benefit Trends. 19981024-27.
28
Total Indirect Costs of Type 2 Diabetes
Rathman W. Drug Benefit Trends. 19981024-27.
29
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

30
Pharmacokinetics of Current Insulin Preparations
Compared With Insulin Glargine
  • Effective
  • Onset Peak Duration
  • Insulin lispro lt15 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

Barnett AH, Owens DR. Lancet. 199734997-51.
White JR, et al. Postgrad Med. 199710158-70.
Kahn CR, Schechter Y. In Goodman and Gilmans
The Pharmacological Basis of Therapeutics.
19901463-1495. Coates PA, et al. Diabetes.
199544(Suppl 1)130A.
31
Structure of Insulin GlargineA 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

32
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

33
Blood Glucose Profile of Insulin Glargine in
Normal Volunteers
Owens DR, et al. Diabetologia. 199841(suppl
1)A245.
34
Exogenous Insulin Concentration of Insulin
Glargine in Normal Volunteers
Owens DR, et al. Diabetologia. 199841(suppl
1)A245.
35
Efficacy of Insulin Glarginein Type 1 and Type 2
Diabetes
P0.0001
Raskin P, et al. Presented at ADA 58th Annual
Meeting. 1998Abstract 0404. Rosenstock J, et al.
Presented at ADA 58th Annual Meeting.
1998Abstract 0357.
36
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

37
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

38
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

39
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

40
Insulin Pump
41
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

42
Insulin Pen
43
Inhaled Insulin Formulations
Gelfand RA, et al. Presented at ADA 58th Annual
Meeting. 1998Abstract 0235.
44
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

45
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

46
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
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