management of type 2 diabetes focus on insulin therapy

Management of Type Diabetes: Focus on Insulin Therapy International Diabetes Center Presentation Overview • Insulin secretion – Beta-cell decompensation • Insulin – Types of Insulin (Basal and Bolus) – Action times – Insulin Analogs • Insulin Regimens – Rationale for selecting certain types of insulin regimens – Adjusting Insulin International Diabetes Center % of Normal Function Glucose (mg/dL) Metformin Thiazolidinediones Medical Nutrition 350 300 250 200 150 100 50 250 200 150 100 50 Secretagogue Post Meal Glucose Fasting Glucose (11.1 mmol/L) (7.0 mmol/L) Most individuals with type diabetes will eventually require insulin therapy Insulin Resistance Insulin Level At risk for Diabetes -10 -5 Beta cell dysfunction 10 15 20 25 30 Years of Diabetes Adapted from: UKPDS 33: Lancet 1998; 352, 837-853 DeFronzo RA Diabetes 37:667, 1988 Saltiel J Diabetes 45:1661-1669, 1996 Robertson RP Diabetes 43:1085, 1994 Tokuyama Y Diabetes 44:1447, 1995 Polonsky KS N Engl J Med 1996;334:777 International Diabetes Center Insulin Use in Type Diabetes • Insulin utilized to overcome both relative insulin deficiency and insulin resistance • Purpose of insulin regimen is to mimic normal insulin secretion patterns • Approximately 40-50% of patients will require insulin for glycemic control • Start dose conservatively and adjust dose based on patterns of BG – High dose insulin (>1.0 U/kg) often required to overcome insulin resistance International Diabetes Center Insulin Processing PC2 Endopeptidase A-chain C-peptide Proinsulin B-chain Mature Insulin S PC3 Endopeptidase S 21 S S S S + C-peptide 30 Insulin supplied in vial or cartridge DiMarchi et al., Peptides-Chemistry and Biology 1992:26-28 Howey et al., Diabetes 1994;43:396-402 International Diabetes Center Overcoming Insulin Resistance Insulin Glucose G G G G GG G G G G G G Nucleus G Insulin Receptor Glucose Transporter (GLUT4) Insulin Sensitive Cell (Muscle or Fat) International Diabetes Center Normal Insulin Secretion Serum insulin (mU/L) Meal Meal Meal 50 40 Bolus insulin needs 30 20 10 Basal Insulin Needs 0 10 12 14 16 18 20 22 24 Time (Hours) International Diabetes Center Insulins Types Examples Bolus (Meal) Insulin Rapid-acting Short-acting Insulin lispro, Insulin aspart Regular Basal (Background) Insulin Intermediate-acting Long-acting NPH, Lente Glargine Pre-Mixed Insulin NPH/Regular NPL/Lispro NPA/Aspart 70/30, 50/50 Mix 75/25 Mix 70/30 International Diabetes Center Bolus/Pre-meal Insulin Type of Insulin Rapid-acting Onset Peak Monitor effect at: 5-15 mins 1-2 hrs hrs 30-45 mins 2-3 hrs hrs (Lispro, Aspart) Regular International Diabetes Center Advantages of Rapid Acting Insulin Analogs • Modification of human insulin – Increased rate of subcutaneous absorption (more physiological) • Reduced rates of hypoglycemia • Convenience - increased flexibility – Taken with meal (onset of action ~ 10 minutes) – Reduced risk of exercise-induced hypoglycemia – Limits need for snacks – Can be used to cover snacks International Diabetes Center Starting Physiologic Regimen: 0-0-0-G Serum insulin (mU/L) Start 0.1 U/kg at BT, increase dose until FPG target is reached or up to to 0.4 U/kg Start self-monitoring BG 50 Glargine 40 30 20 SMBG SMBG 10 Glargine 0 10 12 14 16 18 20 22 24 Hours International Diabetes Center Next Step: - - RA - G Serum insulin (mU/L) Add 0.1 U/kg RA before largest meal, increase dose until pre-BT target is reached or 0.2 U/kg for RA RA Glargine 50 40 30 20 SMBG SMBG 10 RA SMBG Glargine 0 10 12 14 16 18 20 22 24 Hours International Diabetes Center Next Step: RA - - RA - G Serum insulin (mU/L) Add 0.1 U/kg RA before next largest meal, increase dose until hours post meal target is reached or 0.2 U/kg for RA RA RA Glargine 50 40 30 SMBG 20 RA SMBG 10 SMBG RA SMBG Glargine 0 10 12 14 16 18 20 22 24 Hours International Diabetes Center Final Step: RA - RA - RA - G Serum insulin (mU/L) Add 0.1 U/kg RA before mid-day meal, increase dose until post meal target is reached or total daily dose reaches 1.5 U/kg Consider additional injection of RA for snacks RA RA RA Glargine 50 40 30 20 RA SMBG RA SMBGRA 10 SMBG SMBG Glargine 0 10 12 14 16 18 20 22 24 Hours International Diabetes Center Starting Insulin at Diagnosis of Diabetes • • • HbA1c >11% Fasting plasma glucose > 300 mg/dL (16.7 mmol/L) Casual plasma glucose > 350 mg/dL (19.4 mmol/L) International Diabetes Center International Diabetes Center Conventional (Mixed) Insulin Stage R/N-0-R/N-0 or RA/N-0-RA/N-0 R/N Serum insulin (mU/L) R/N 50 Overinsulinization Overinsulinization 40 Overinsulinization 30 SMBG SMBG 20 Reg 10 SMBG SMBG Reg NPH 0 10 12 14 SMBG NPH 16 18 20 22 24 Time (Hours) Additional SMBG required to differentiate relative versus absolute hypoglycemia International Diabetes Center International Diabetes Center Alternative and New Means of Administering Insulin • • • Insulin Infusion Pump Inhaled Insulin Islet Transplant International Diabetes Center Insulin Infusion Pump CLOSING THE LOOP International Diabetes Center Innovations: Inhaled Insulin Therapy RAi-RAi-RAi-G • • • Pulmonary inhalation system Uses dry powder preparation Insulin action - similar to rapid acting insulins (lispro, aspart) • Generally requires use of background insulin • Limited dosing flexibility • Significant maintenance needs International Diabetes Center Islet Transplants • Islet Transplants – Experimental – Requires one-two pancreases – Not likely to be used in type diabetes International Diabetes Center ag en t) al n or /- M on ot he r O A M N T ap y O th A er Co ap m y bi na tio n O A P lu s BT In su In su li n (+ l i Summary: Optimal Clinical Effectiveness of Therapeutic Interventions Change in HbA1c* -1.0 -2.0 -3.0 >-4.0 >4 % *Difference from placebo; based on package insert data and assorted references International Diabetes Center % of Normal Function Glucose (mg/dL) Metformin Thiazolidinediones Medical Nutrition 350 300 250 200 150 100 50 250 200 150 100 50 Insulin Secretagogue Post Meal Glucose Fasting Glucose (11.1 mmol/L) (7.0 mmol/L) Insulin Resistance Insulin Level At risk for Diabetes -10 -5 Beta cell dysfunction 10 15 20 25 30 Years of Diabetes Adapted from: UKPDS 33: Lancet 1998; 352, 837-853 DeFronzo RA Diabetes 37:667, 1988 Saltiel J Diabetes 45:1661-1669, 1996 Robertson RP Diabetes 43:1085, 1994 Tokuyama Y Diabetes 44:1447, 1995 Polonsky KS N Engl J Med 1996;334:777 International Diabetes Center Type Master DecisionPath Entry Criteria Therapies Insulin Deficiency: Symptomatic, Lean Fasting 11% HbA1c 11% ~2% Combination Oral Agent Stage Combination Oral Agent Stage Secretagogue Note: Each stage requires a preset BG target: and a timeline to reach that goal Insulin Resistance Sensitizers ~1% + Sensitizer Combination Oral Agent/Insulin Stage Combination Oral Agent/Insulin Stage ~2-4% Oral Agent + Insulin Physiologic Insulin Stage Basal/Bolus Insulin RA - RA - RA - G > 4% International Diabetes Center ... International Diabetes Center Normal Insulin Secretion Serum insulin (mU/L) Meal Meal Meal 50 40 Bolus insulin needs 30 20 10 Basal Insulin Needs 0 10 12 14 16 18 20 22 24 Time (Hours) International Diabetes. .. et al Diabetes Care 20 01 ;24 :1 120 -1 121 (abstract #465) International Diabetes Center Basal Insulin Insulin Onset Peak Monitor effect at: NPH/Lente 2- 4 hrs 4-8 hrs - 10 hrs hrs No peak 12- 24 hrs... certain types of insulin regimens – Adjusting Insulin International Diabetes Center % of Normal Function Glucose (mg/dL) Metformin Thiazolidinediones Medical Nutrition 350 300 25 0 20 0 150 100 50 25 0