1. Insulin Therapy in Type 2 Diabetes: Current and Future Directions

2. 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

3. Prevalence of Type 2 Diabetes Mellitus
MMWR. 1997;46:

4. Incidence of Type 2 Diabetes Mellitus
MMWR. 1997;46:

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. 1994;272:

7. Link Between Obesity and Type 2 Diabetes: Nurses’ Health Study
Colditz GA, et al. Ann Intern Med. 1995;122:

8. Link Between Obesity and Type 2 Diabetes: Nurses’ Health Study (cont’d)
Colditz GA, et al. Ann Intern Med. 1995;122:

9. ADA Treatment Guidelines
Biochemical Index Normal Goal Action Suggested
Preprandial glucose <90 mg/dL mg/dL <80 or >140 mg/dL
Bedtime glucose <120 mg/dL mg/dL <100 or >160 mg/dL
HbA1c <6%* <7% >8%
*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 Monotherapy
Very symptomatic
Severe hyperglycemia
Ketosis
Latent 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 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

15. Improvement in HbA1c in the VA CSDM
P<0.001 vs. placebo in intensive treatment group
Abraira C, et al. Diabetes Care. 1995;18:

16. 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 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:

17. The Kumamoto Trial: Effects of Conventional vs
The Kumamoto Trial: Effects of Conventional vs. Intensive Insulin Therapy
Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:

18. UKPDS: Effect of Intensive Therapy on Glycemia
UKPDS Group. Lancet. 1998;352:

19. UKPDS 10-Year Cohort Data: Reductions With Intensive vs
UKPDS 10-Year Cohort Data: Reductions With Intensive vs. Conventional Therapy
UKPDS Group. Lancet. 1998;352:

20. 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

21. Pharmacokinetics of Current Insulin Preparations
Effective
Onset Peak Duration
Insulin lispro <15 min 1 hr 3 hr
Regular hr 2-3 hr 3-6 hr
NPH/Lente 2-4 hr 6-12 hr hr
Ultralente 4-8 hr Varies hr
Barnett AH, Owens DR. Lancet. 1997;349: 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:

22. 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

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/Insulin Combination Therapy
Johnson JL, et al. Arch Intern Med. 1996;156:

26. Comparison of Insulin Regimens Among Oral Treatment Failures
Yki-Jarvinen H, et al. N Engl J Med. 1992;327:

27. Total Direct Costs of Type 2 Diabetes
Rathman W. Drug Benefit Trends. 1998;10:24-27.

28. Total Indirect Costs of Type 2 Diabetes
Rathman W. Drug Benefit Trends. 1998;10:24-27.

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 <15 min 1 hr 3 hr
Regular hr 2-3 hr 3-6 hr
NPH/Lente 2-4 hr 7-8 hr hr
Ultralente 4 hr Varies hr
Insulin glargine* 1-2 hr Flat/Predictable 24 hr
*Investigational
Barnett AH, Owens DR. Lancet. 1997;349: 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:
Coates PA, et al. Diabetes. 1995;44(Suppl 1):130A.

31. 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

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. 1998;41(suppl 1):A245.

34. Exogenous Insulin Concentration of Insulin Glargine in Normal Volunteers
Owens DR, et al. Diabetologia. 1998;41(suppl 1):A245.

35. 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.

36. Safety of Insulin Glargine in Type 1 and Type 2 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 Advantages of newer insulin pens
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. 1998:Abstract 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 (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