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

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Presentation on theme: "Insulin therapy in Type 2 Diabetes: Current and Future Directions."— Presentation transcript:

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

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

4 Pharmacologic Therapy for Type 2 Diabetes Sulfonylureas (glyburide, glipizide, glimepiride) Sulfonylureas (glyburide, glipizide, glimepiride) Biguanides (metformin) Biguanides (metformin) Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) Benzoic acid analogues (repaglinide) Benzoic acid analogues (repaglinide) Thiazolidinediones (troglitazone, rosiglitazone, pioglitazone) Thiazolidinediones (troglitazone, rosiglitazone, pioglitazone) Insulin (human insulin, insulin analogues) Insulin (human insulin, insulin analogues)

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

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

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

9 Types of insulin

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

11 Glargine: A New Long-Acting Insulin Analogue Modifications to human insulin chain Modifications to human insulin chain Substitution of glycine at position A21 Substitution of glycine at position A21 Addition of two arginines at position B30 Addition of two arginines at position B30 Unique release pattern from injection site Unique release pattern from injection site

12 Characteristics of Insulin Glargine Euglycemic clamp studies vs. NPH Euglycemic clamp studies vs. NPH Smooth continuous release from injection site Smooth continuous release from injection site Longer duration of action Longer duration of action Continued effect at end of 24-hour clamp study Continued effect at end of 24-hour clamp study No differences in the absorption rate from arm, leg, or abdominal sites No differences in the absorption rate from arm, leg, or abdominal sites No inflammatory reactions at any of the injection sites No inflammatory reactions at any of the injection sites Flat insulin profile Flat insulin profile As effective in lowering FPG levels as NPH insulin, with significantly reduced nocturnal hypoglycemia As effective in lowering FPG levels as NPH insulin, with significantly reduced nocturnal hypoglycemia

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

16 Very-rapid-acting insulin lispro, lispro, aspart aspart glulisine 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 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 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 decreases the postprandial rise in blood glucose reduce the frequency of hypoglycemia reduce the frequency of hypoglycemia It is more convenient because it can be injected immediately before meals It is more convenient because it can be injected immediately before meals No difference in A1C 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 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. 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 : The basic requirements are : Baseline dose of insulin (whether an intermediate or long-acting insulin or given via CSII) plus 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). 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 Conventional insulin therapy Intensive insulin therapy: Intensive insulin therapy: MSI MSI CSII CSII

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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. 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 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 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. 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 ) Cost (three times ) Weight gain Weight gain Risk of hypoglycemia (three times) 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. Intensive therapy should be started as early as possible following the diagnosis of type 1 diabetes.

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

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

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

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

35 MSI CSII 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. 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. 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. 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). 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) 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 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 More flexibility in the timing of meals Insulin absorption is less variable from day to day Insulin absorption is less variable from day to day

38 Disadvantages of CSII instead of MSI Disadvantages of CSII instead of MSI Cost Cost Infection at the site of needle insertion Infection at the site of needle insertion infusion-system failure infusion-system failure DKA is more common 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) Sulfonylureas (glyburide, glipizide, glimepiride) Biguanides (metformin) Biguanides (metformin) Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) Benzoic acid analogues (repaglinide) Benzoic acid analogues (repaglinide) Thiazolidinediones (troglitazone, rosiglitazone, pioglitazone) Thiazolidinediones (troglitazone, rosiglitazone, pioglitazone) Insulin (human insulin, insulin analogues) Insulin (human insulin, insulin analogues)

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

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

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

45 Summary of Key Findings Kumamoto trial: Kumamoto trial: Intensive insulin treatment reduced microvascular complications Intensive insulin treatment reduced microvascular complications Established glycemic threshold to prevent onset and progression of complications Established glycemic threshold to prevent onset and progression of complications UKPDS: UKPDS: Diet therapy alone inadequate in two thirds of patients Diet therapy alone inadequate in two thirds of patients Pharmacologic therapy plus nutrition/exercise necessary Pharmacologic therapy plus nutrition/exercise necessary Weigh benefit:risk ratio Weigh benefit:risk ratio No threshold for HbA 1c reduction in reducing complications No threshold for HbA 1c reduction in reducing complications Insulin does not increase macrovascular disease Insulin does not increase macrovascular disease

46 Strategies for Insulin Therapy in Elderly Patients Insulin therapy often considered a last resort in the elderly Insulin therapy often considered a last resort in the elderly Therapeutic goals: Therapeutic goals: Relieve symptoms Relieve symptoms Prevent hypoglycemia Prevent hypoglycemia Prevent acute complications of hyperglycemia Prevent acute complications of hyperglycemia Ways to facilitate insulin treatment: Ways to facilitate insulin treatment: Simple dose schedules Simple dose schedules Premixed preparations Premixed preparations Improved, more convenient delivery systems Improved, more convenient delivery systems

47 Combination Therapy: Oral Agents Plus Insulin Rationale Rationale Combination of two agents with different mechanisms of action Combination of two agents with different mechanisms of action More convenient and may be safer More convenient and may be safer Sulfonylurea + Insulin Sulfonylurea + Insulin BIDS therapy: bedtime insulin/daytime sulfonylurea BIDS therapy: bedtime insulin/daytime sulfonylurea Useful in patients early in course of disease Useful in patients early in course of disease Metformin + Insulin Metformin + Insulin Improves insulin sensitivity Improves insulin sensitivity Alpha glucosidase inhibitor (acarbose) + Insulin Alpha glucosidase inhibitor (acarbose) + Insulin Decreases postprandial glycemia Decreases postprandial glycemia Thiazolidinediones + Insulin Thiazolidinediones + Insulin Improves insulin resistance, improves insulin action in peripheral tissues Improves insulin resistance, improves insulin action in peripheral tissues Reduces insulin requirement Reduces insulin requirement

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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: Disadvantages of conventional subcutaneous injection: Discomfort Discomfort Inconvenience Inconvenience Systemic delivery Systemic delivery Inconsistent pharmacokinetics Inconsistent pharmacokinetics Irreversible after injection Irreversible after injection Insulin pumps: too complex, limited experience and utility with type 2 Insulin pumps: too complex, limited experience and utility with type 2 Insulin pen: beneficial but underutilized Insulin pen: beneficial but underutilized Systems in clinical testing Systems in clinical testing Inhaled formulation Inhaled formulation Jet-injected systems Jet-injected systems

52 Insulin Pen Benefits Benefits More accurate dosing mechanisms More accurate dosing mechanisms Faster and easier than conventional syringes Faster and easier than conventional syringes Improved patient attitude and compliance Improved patient attitude and compliance Advantages of newer insulin pens Advantages of newer insulin pens LCD display to show dosage setting LCD display to show dosage setting Dosage settings change quickly and easily Dosage settings change quickly and easily Safety button automatically resets after drug delivery 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 When available, may provide only mechanical means of achieving “normal” glucose homeostasis Will direct insulin delivery automatically on demand (“closed loop”) Will direct insulin delivery automatically on demand (“closed loop”) One technology uses reverse iontophoresis to noninvasively extract and measure glucose levels One technology uses reverse iontophoresis to noninvasively extract and measure glucose levels Technical challenge to develop Technical challenge to develop

56 Conclusions Type 2 diabetes: gradual deterioration of glycemic control Type 2 diabetes: gradual deterioration of glycemic control Significant morbidity and mortality; tight glycemic control reduces risk of complications Significant morbidity and mortality; tight glycemic control reduces risk of complications Earlier institution of insulin may help attain initial glycemic control Earlier institution of insulin may help attain initial glycemic control Objectives of insulin therapy: Objectives of insulin therapy: Achieve normal fasting glucose levels Achieve normal fasting glucose levels Achieve normal postprandial glucose levels Achieve normal postprandial glucose levels Minimize hypoglycemia Minimize hypoglycemia Intensive insulin therapy should: Intensive insulin therapy should: Provide good glycemic control Provide good glycemic control Produce little hypoglycemia Produce little hypoglycemia Improve lipid profile Improve lipid profile Reduce risks and costs of treating complications Reduce risks and costs of treating complications

57 Conclusions (cont’d) New delivery systems: New delivery systems: Reduce limitations of conventional insulin syringes Reduce limitations of conventional insulin syringes Improve patient compliance and disease management Improve patient compliance and disease management New long-acting insulin analogues (eg, insulin glargine): New long-acting insulin analogues (eg, insulin glargine): Produce flat insulin profile with no peaks Produce flat insulin profile with no peaks Allow once-daily administration Allow once-daily administration Significantly reduce nocturnal hypoglycemia Significantly reduce nocturnal hypoglycemia

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59 Type of insulin available 1. Regular insulin 2. Insulin analogues, Lispro, Glargine 3. Alternate delivery system pump, pulmonary, intranasal, ocular, rectal, transdermal 4. Combination with oral agents 5. 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 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 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) 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 Add single evening dose(5 -10 IU) for thin and (10-15 IU) for obese patients Adjust dose weekly 2-4 IU 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 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 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% If patients are to inject supplements less than 3 hours after previous insulin they can decrease it 50%

63 Meal bolus insulin Exercise 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 * 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 Each patient must educated for insulin and blood glucose and record data Blood glucose and insulin logs should be reviewed weekly until goal 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 Reduce the dose by 10 to 15% of total dose If the blood glucose rise, restore the initial dose If the blood glucose rise, restore the initial dose If the blood glucose dose not rise reduce 10 %- 15% every 1-2 weeks If the blood glucose dose not rise reduce 10 %- 15% every 1-2 weeks When daily dose reached to u/kg consider discontinuing insulin When daily dose reached to u/kg consider discontinuing insulin

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

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