2. Insulin therapy in Type 2 Diabetes: Current and Future Directions

3. When we started insulin?
Type 1
Sometimes Type 2

4. 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)

5. 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

6. All patients with type 1 diabetes need insulin treatment permanently, unless they receive an islet or whole organ pancreas transplant; many patients with type 2 diabetes will require insulin as their beta cell function declines over time.

7. Indications for insulin therapy
unexplained recent weight loss (irrespective of the initial weight),
a short history with severe symptoms,
the presence of moderate to heavy ketonuria.
pregnancy

8. Type 2 DM
Patient with persistent elevated FPG leves ( mg/dl) or ketonuria or ketonemia
FPG more than 300 mg/dl with polyuria, polydipsia and weight loss
Gestational diabetes
Uncontrolled diabetes with oral agents
Physician-patient option wish to receive insulin as initial therapy
Wasting state
Latent autoimmune diabetes in adult
Post MI
Renal failure
Allergy or serious reaction to oral agents

9. Types of insulin

10. Types of insulin Insulin glargine :
No real advantage with regard to A1C
Lower fasting blood glucose and fewer hypoglycemic episodes
Do not mix with other insulin

11. 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

12. 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

15. Insulin detemir
Its duration of action appears to be substantially shorter than that of insulin glargine,
Compare to NPH insulin detemir may be associated with slightly less nocturnal hypoglycemia and weight gain

16. Very-rapid-acting insulin
lispro,
aspart
glulisine
Onset of action within 5 to15 Peak action at 30 to 90 Duration of action of two to four hours.

17. Clinical Efficacy of Insulin Lispro
Worldwide clinical trials of insulin lispro in >10,000 patients with type 1 or type 2 diabetes
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

18. Advantages of very rapid acting to regular
decreases the postprandial rise in blood glucose
reduce the frequency of hypoglycemia
It is more convenient because it can be injected immediately before meals
No difference in A1C
Need to increase in the dose of NPH when a patient is switched from regular insulin to a very-rapid-acting insulin

19. The teratogenicity and long term safety profile of rapid-acting insulins in pregnancy are unknown, although many diabetologists do prescribe very-rapid-acting insulins during pregnancy.

20. CHOICE OF INSULIN REGIMEN
The basic requirements are :
Baseline dose of insulin (whether an intermediate or long-acting insulin or given via CSII) plus
Adjustable doses of pre-meal rapid-acting insulin (regular) or very-rapid-acting insulin analogs (lispro, aspart, or glulisine).

21. Method of Insulin Preparation
Conventional insulin therapy
Intensive insulin therapy:
MSI
CSII

25. Getting started
Start on a total daily dose of 0.2 to 0.4 units of insulin per kg per day, although most will ultimately require 0.6 to 0.7 units per kg per day.
One-half of the total dose as a basal insulin (2/3 in the morning 1/3 in the bed time
The remainder is given as rapid or very rapid-acting insulin, divided before meals.
The pre-meal dosing is determined by the usual meal size and content, as well as activity and exercise pattern.

26. Conventional insulin therapy

27. Methods of MSI

28. Major drawback to intensive therapy
Cost (three times )
Weight gain
Risk of hypoglycemia (three times)

29. When to start intensive therapy
Intensive therapy should be started as early as possible following the diagnosis of type 1 diabetes.

30. Residual beta cell function
Intensive insulin therapy
Residual beta cell function
lower risk of hypoglycemia

31. MANAGEMENT ISSUES Consistency SMBG The content and timing of meals,
The site of insulin injections,
The timing and frequency of exercise.
SMBG
Four to seven times daily

33. Insulin Pump
CSII: uses portable infusion pump connected to an indwelling subcutaneous catheter to deliver short-acting insulin

34. MSI or CSII Same efficacy, Same frequency of hypoglycemic events,
Same impact on quality of life for most patients

35. MSI CSII
For a patient who has been well controlled on his previous MSI (eg, A1C <7.0 percent), the initial total daily dose of insulin administered by pump may be 10 to 20 percent less than the total daily dose of the previous regimen.
Conversely, patients with inadequate glycemic control may be started with the same total daily dose as they had been using with their injection regimens.

36. In general, approximately one-half of the total daily dose is administered as basal rate.
For most patients, basal rates are in the range of 0.01 to units per kg per hour (ie, for a 60 kg woman approximately 0.6 to 0.9 units per hour).

37. Advantages of CSII instead of MSI
Slightly better glycemic control (lower A1C)
The use of very-rapid-acting insulin instead of regular may result in a lower A1C, less hypoglycemia, and less weight gain
More flexibility in the timing of meals
Insulin absorption is less variable from day to day

38. Disadvantages of CSII instead of MSI
Cost
Infection at the site of needle insertion
infusion-system failure
DKA is more common

39. Insulin Pump

40. Insulin therapy in Type 2 Diabetes: Current and Future Directions

41. 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)

42. 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

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

44. 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:

45. Summary of Key Findings
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

46. 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

47. 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

49. Meta-Analysis of Sulfonylurea/Insulin Combination Therapy
Johnson JL, et al. Arch Intern Med. 1996;156:

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

51. 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

52. 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

53. Insulin Pen

54. Inhaled Insulin Formulations
Gelfand RA, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0235.

55. 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

56. 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

57. 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

59. Type of insulin available
Regular insulin
Insulin analogues, Lispro, Glargine
Alternate delivery system pump , pulmonary, intranasal , ocular, rectal , transdermal
Combination with oral agents
Initiating insulin in patient on oral agents bedtime insulin

60. What regimens are best for type 1?
Newly diagnosed patients or latent autoimmune DM may do well receiving once or twice basal insulin
Physiological regimens or both prandial and basal insulin is required in severe insulin deficiency

61. Practical strategy to start insulin in type 2 DM
Continue oral agents at the same dose (eventually reduce)
Add single evening dose(5 -10 IU) for thin and (10-15 IU) for obese patients
Adjust dose weekly 2-4 IU

62. How dose the patient use supplement and adjustment ?
A conservative dose for type 1 is additional 1 IU per 50 mg /dl above the target
For type 2 DM 1IU per 30 mg/dl above the target
If patients are to inject supplements less than 3 hours after previous insulin they can decrease it 50%

63. Meal bolus insulin Exercise
* The dose should be decrease by 30% for postprandial exercise of less than one hour, 40 % for 1-2 hours, 50 % for more than two hours
Food
* Insulin requirement approximately 1 unit of insulin per 15 g carbohydrate

64. Experience
Each patient must educated for insulin and blood glucose and record data
Blood glucose and insulin logs should be reviewed weekly until goal

65. Discontinuation of insulin in T2DM
Reduce the dose by 10 to 15% of total dose
If the blood glucose rise, restore the initial dose
If the blood glucose dose not rise reduce 10 %- 15% every 1-2 weeks
When daily dose reached to u/kg consider discontinuing insulin

66. Benefits of combination therapy?
Reduces fasting and postprandial glucose
Directly suppresses hepatic glucose production
Reduce free fatty acid levels
Counteracts dawn phenomenon
Minimal education needed
Easily started on an outpatient state
Better compliance
Less total exogenous insulin needed