Insulin Therapy in Type 2 Diabetes: Current and Future Directions

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

Prevalence of Type 2 Diabetes Mellitus MMWR. 1997;46:1014-1018.

Incidence of Type 2 Diabetes Mellitus MMWR. 1997;46:1014-1018.

Risk Factors for Type 2 Diabetes Nonmodifiable Genetic factors Age Ethnicity Modifiable Weight Physical activity

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;272:205-211.

Link Between Obesity and Type 2 Diabetes: Nurses’ Health Study Colditz GA, et al. Ann Intern Med. 1995;122:481-486.

Link Between Obesity and Type 2 Diabetes: Nurses’ Health Study (cont’d) Colditz GA, et al. Ann Intern Med. 1995;122:481-486.

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

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.

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 The Kumamoto Trial: Effects of Conventional vs. Intensive Insulin Therapy Ohkubo Y, et al. Diabetes Res Clin Pract. 1995;28:103-117.

UKPDS: Effect of Intensive Therapy on Glycemia UKPDS Group. Lancet. 1998;352:837-853.

UKPDS 10-Year Cohort Data: Reductions With Intensive vs UKPDS 10-Year Cohort Data: Reductions With Intensive vs. Conventional Therapy UKPDS Group. Lancet. 1998;352:837-853.

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

Pharmacokinetics of Current Insulin Preparations Effective Onset 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 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.

Comparison of Insulin Regimens Among Oral Treatment Failures Yki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433.

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

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

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

Pharmacokinetics of Current Insulin Preparations Compared With Insulin Glargine Effective Onset 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 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

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.

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

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.

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

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 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

Insulin Pen

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

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