Diabetes Update New Insulins and Insulin Delivery Systems Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia
Prevalence of Diabetes in the US Diagnosed Type 2 Diabetes 10.3 Million Diagnosed Type 1 Diabetes 0.5 1.0 Million Undiagnosed Diabetes 5.4 Million American Diabetes Association. Facts and Figures. Available at: http://www.diabetes.org/ada/facts.asp. Accessed January 18, 2000. 3
Causes of Death in People With Diabetes 50 40 %of Deaths 30 20 10 0 Ischemic Other Heart Disease Heart Disease Diabetes Cancer Stroke Infection Other Geiss LS, et al. In: Diabetes in America, 2nd ed. 1995. Bethesda, MD: National Institutes of Health; 1995:chap 11. 4
Goals of Intensive Diabetes Management Near-normal glycemia HbA1c less than 6.5 to 7.0% Avoid short-term crisis Hypoglycemia Hyperglycemia DKA Minimize long-term complications Improve QOL ADA: Clinical Practice Recommendations. 2001.
Relative Risk of Progression of Diabetic Complications by Mean HbA1C Based on DCCT Data RELATIVE RISK 15 13 11 9 7 5 3 1 6 7 8 9 10 11 12 Retinop Neph Neurop Microalb Skyler, Endo Met Cl N Am 1996 HbA 1c
HbA1c and Plasma Glucose 26,056 data points (A1c and 7-point glucose profiles) from the DCCT Mean plasma glucose = (A1c x 35.6) 77.3 Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002
Emerging Concepts The Importance of Controlling Postprandial Glucose
ACE / AACE Targets for Glycemic Control HbA 1c < 6.5 % Fasting/preprandial glucose Postprandial glucose < 110 mg/dl < 140 mg/dl ACE / AACE Consensus Conference, Washington DC August 2001
Natural History of Type 2 Diabetes Glucose 350 300 mg/dl 250 200 150 100 Post-prandial glucose Fasting glucose Relative to normal (%) 250 200 150 100 50 0 At risk for diabetes Beta-cell dysfunction Insulin resistance -10-5 0 5 10 15 20 25 30 Years Insulin level R.M. Bergenstal, International Diabetes Center
Major Metabolic Defects in Type 2 Diabetes Peripheralinsulin resistance in muscle and fat Decreased pancreatic insulin secretion Increased hepatic glucose output Haffner SM, et al. Diabetes Care, 1999
Insulin Resistance: An Underlying Cause of Type 2 Diabetes Obesity and inactivity Aging Medications Genetic abnormalities Type 2 diabetes INSULIN RESISTANCE Rare disorders PCOS Reaven GM. Physiol Rev. 1995;75:473-486 Clauser, et al. Horm Res. 1992;38:5-12. Hypertension Dyslipidemia Atherosclerosis
Type 2 Diabetes: Two Principal Defects Genes Genes Insulin resistance β-cell dysfunction/ failure ± Environment ± Environment IGT IGT Glucose Toxicity Type 2 diabetes Glucose Toxicity Reaven GM. Physiol Rev. 1995;75:473-486 Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S; Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127.
HbA 1c in the UKPDS 9 HbA 1c (%) 8 7 Conventional Intensive 6 0 6.2% upper limit of normal range 0 3 6 9 12 15 Years from randomisation
UKPDS: β-cell Function for the Patients Remaining on Diet for 6 Years 100 β-cell Function (% β) 80 60 40 20 0 N=376-10 -9-8 -7-6 -5-4 -3-2 -1 0 1 2 3 4 5 6 Years After Diagnosis Adapted from UKPDS Group. Diabetes. 1995; 44:1249-1258.
UKPDS: Benefits of Glycemic Control in Type 2 Diabetes Risk reduction over 10 years Any diabetes-related endpoint 12% P = 0.029 Microvascular endpoints 25% P = 0.0099 Myocardial infarction 16% P = 0.052 Cataract extraction 24% P = 0.046 Retinopathy at 12 years 21% P = 0.015 Microalbuminuria at 12 years 33% P < 0.001 UKPDS 33. Lancet. 1998;352:837-853.
Metformin Prevents Heart Attacks and Reduces Deaths in Type 2 Diabetes Heart Attacks Coronary Deaths 20 P=0.01 10 P=0.02 Incidence (per 1,000 patient years) 15 10 5 8 39% Reduction 6 4 2 50% Reduction 0 Conventional Metformin Therapy 0 Conventioal Therapy Metformin
anagement of Type 2 DM tep Therapy Diet Exercise Sulfonylurea or Metformin Add Alternate Agent Add hs NPH vs TZD Switch to Mixed Insulin bid Switch to Multiple Dose Insulin Utilitarian, Common Sense, Recommended Prone to Failure from Misscheduling and Mismanagement
Management of Type 2 DM Stumble Therapy WAG Diet Golf Cart Exercise Sample of the Week Medication Interrupted Not Combined Poor Understanding of Goals Poor Monitoring HbA1c >8% (If Seen)
Consider A New Treatment Paradigm Treatment designed to correct the dual impairments Vigorous effort to meet glycemic targets Simultaneous rather than sequential therapy Combination therapy from the outset Early step-wise titrations to meet glycemic targets
Goals in Management of Type 2 Diabetes Fasting BG < 110 mg/dl Post-meal < 140 mg/dl HbA1c < 6.5% Blood Pressure < 130/80 LDL < 100 mg/dl HDL > 45 mg/dl
Thiazolidinediones: Mode of Action Peroxisome Proliferator-Activated Receptors PPARγ Affects glucose, lipid and protein metabolism PPARα Affects lipoprotein metabolism (some TZDs) Saltiel & Olefsky. Diabetes 1996;45:1661 9
Thiazolidinediones: Rationale for Type 2 Diabetes Therapy Proven characteristics Target insulin resistance, a core defect Improve glycemic control Do not cause hypoglycemia Improve lipid profile (pioglitazone and troglitazone) Potential benefits Preservation of pancreatic b-cell function Prevention of progression from impaired glucose tolerance to type 2 diabetes Improvement in cardiovascular outcomes Saltiel & Olefsky. Diabetes 1996;45:1661 9 Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551 5
Change in Lipid Profile at Endpoint: ACTOS Added to Sulfonylurea from baseline at 16 weeks 20 10 (%) 0-10 SU + Placebo (n = 187) SU + ACTOS 30 mg (n = 189) * 12.00 10.15 7.02 6.57 4.07 2.33-0.95-15.89 * -20 Triglycerides Total cholesterol HDL cholesterol LDL cholesterol Baseline (mg/dl) 258.6 259.5 211.5 214.4 42.9 41.8 123.7 126.5 LOCF * p 0.05 vs. placebo Takeda Pharmaceuticals America, Data on file Study 010
Incidence of Edema 100 U.S. Placebo-controlled Studies 80 Placebo ACTOS (%) 60 40 20 0 7.5 4.8 1.2 2.1 2.5 3/259 29/606 Monotherapy 6.0 7.0 15.3 4/187 28/373 4/160 10/168 13/187 58/379 Combination with Combination with Combination with sulfonylurea metformin insulin 2 patients from combination therapy trials and 0 from the monotherapy trials discontinued due to edema Pioglitazone HCl Package Insert July, 1999
Approach to Combination Oral Therapy Intensifying of Oral Therapies metformin &/or glitazone + sulfonylurea/repaglinide &/or glucosidase inh sulfonylurea/repaglinide &/or glucosidase inh + metformin &/or glitazone FPG < 120 mg/dl HbA1c < 7.0% FPG > 120 mg/dl HbA1c >7.0% Continue Add Insulin
Insulin The most powerful agent we have to control glucose
Comparison of Human Insulins / Analogues Insulin Onset of Duration of preparations action Peak action Regular 30 60 min 2 4 h 6 10 h NPH/Lente 1 2 h 4 8 h 10 20 h Ultralente 2 4 h Unpredictable 16 20 h Lispro/aspart 5 15 min 1 2 h 4 6 h Glargine 1 2 h Flat ~24 h
Short-Acting Insulin Analogs Lispro and Aspart Plasma Insulin Profiles Plasma insulin (pmol/l) 400 350 300 250 200 150 100 50 0 0 30 60 Regular Lispro 90 120 150 180 210 240 Time (min) Plasma insulin (pmol/l) 500 450 400 350 300 250 200 150 100 50 0 0 50 100 Regular Aspart 150 200 250 300 Time (min) Meal SC injection Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625 629; Mudaliar, et al. Diabetes Care. 1999;22:1501 1506.
Pharmacokinetic Comparison NovoLog vs Humalog 350 Free Insulin (pmol/l) 300 250 200 150 100 NovoLog Humalog 50 0 Hedman, Diabetes Care 2001; 24(6):1120-21 7 8 9 10 11 12 13 Time (hours)
Lispro Mix 75/25 Pharmacodynamics 12 Glucose infusion rate mg/kg/min 10 8 6 4 2 Lispro Lispro Mix 75/25 NPL 0 Heise T, et al. Diabetes Care. 1998;21:800 803. 0 4 8 12 16 20 24 Hours
Limitations of NPH, Lente, and Ultralente Do not mimic basal insulin profile Variable absorption Pronounced peaks Less than 24-hour duration of action Cause unpredictable hypoglycemia Major factor limiting insulin adjustments More weight gain
Insulin Glargine A New Long-Acting Insulin Analog Modifications to human insulin chain Substitution of glycine at position A21 Addition of 2 arginines at position B30 Gradual release from injection site Peakless, long-lasting insulin profile Gly 1 5 10 15 20Asp Substitution 1 5 10 15 20 25 30 Extension Arg Arg
Glargine vs NPH Insulin in Type 1 Diabetes Action Profiles by Glucose Clamp Glucose utilization rate (mg/kg/h) 6 5 4 3 2 1 0 0 10 Time (h) after SC injection NPH Glargine 20 30 End of observation period Lepore, et al. Diabetes. 1999;48(suppl 1):A97.
Glucose Infusion Rate 4.0 SC insulin n = 20 T1DM Mean ± SEM 24 mg/kg/min 3.0 2.0 1.0 0 Ultralente Glargine NPH CSII 20 16 12 8 4 0 µmol/kg/min Lepore M, et al. Diabetes. 2000;49:2142 2148. 0 4 8 12 16 20 24 Time (hours)
Plasma Glucose 220 SC insulin n = 20 T1DM Mean ± SEM 12 200 11 mg/dl 180 160 NPH Ultralente 10 9 mmol/l 140 Glargine 8 120 CSII 7 Lepore M, et al. Diabetes. 2000;49:2142 2148. 0 4 8 12 16 20 24 Time (hours)
Overall Summary: Glargine Insulin glargine has the following clinical benefits Once-daily dosing because of its prolonged duration of action and smooth, peakless timeaction profile (23.5 hours on repeat injections) Comparable or better glycemic control (FBG) Lower risk of nocturnal hypoglycemic events Safety profile similar to that of human insulin
Type 2 Diabetes A Progressive Disease Over time, most patients will need insulin to control glucose
Insulin Therapy in Type 2 Diabetes Indications Significant hyperglycemia at presentation Hyperglycemia on maximal doses of oral agents Decompensation Acute injury, stress, infection, myocardial ischemia Severe hyperglycemia with ketonemia and/or ketonuria Uncontrolled weight loss Use of diabetogenic medications (eg, corticosteroids) Surgery Pregnancy Renal or hepatic disease
6-16 Mimicking Nature The Basal/Bolus Insulin Concept
The Basal/Bolus Insulin Concept Basal insulin Suppresses glucose production between meals and overnight 40% to 50% of daily needs Bolus insulin (mealtime) Limits hyperglycemia after meals Immediate rise and sharp peak at 1 hour 10% to 20% of total daily insulin requirement at each meal
Basal vs Mealtime Hyperglycemia in Diabetes 250 Basal hyperglycemia Mealtime hyperglycemia Plasma Glucose (mg/dl) 200 150 100 50 Type 2 Diabetes Normal 0 0600 1200 1800 2400 Time of Day 0600 AUC from normal basal >1875 mgm/dl. hr; Est HbA1 c >8.7% Riddle. Diabetes Care. 1990;13:676-686. 6-18
6-18 Basal vs Mealtime Hyperglycemia in Diabetes When Basal Corrected 250 Basal hyperglycemia Mealtime hyperglycemia Plasma Glucose (mg/dl) 200 150 100 50 Normal 0 0600 1200 1800 2400 0600 Time of Day AUC from normal basal 900 mgm/dl. hr; Est HbA1 c 7.2%
6-18 Basal vs Mealtime Hyperglycemia in Diabetes When Mealtime Hyperglycemia Corrected 250 Basal hyperglycemia Mealtime hyperglycemia Plasma Glucose (mg/dl) 200 150 100 50 Normal 0 0600 1200 1800 2400 0600 Time of Day AUC from normal basal 1425 mgm/dl. hr; Est HbA1 c 7.9
6-18 Basal vs Mealtime Hyperglycemia in Diabetes When Both Basal & Mealtime Hyperglycemia Corrected 250 Basal hyperglycemia Mealtime hyperglycemia Plasma Glucose (mg/dl) 200 150 100 50 Normal 0 0600 1200 1800 2400 0600 Time of Day AUC from normal basal 225 mgm/dl. hr; Est HbA1 c 6.4%
6-19 MIMICKING NATURE WITH INSULIN THERAPY Over time, most patients will need both basal and mealtime insulin to control glucose
6-37 Starting With Basal Insulin Advantages 1 injection with no mixing Insulin pens for increased acceptance Slow, safe, and simple titration Low dosage Effective improvement in glycemic control Limited weight gain
6-38 Starting With Basal Insulin Bedtime NPH Added to Diet 400 Diet only Bedtime NPH Plasma Glucose (mg/dl) 300 200 100 0 0800 1200 1600 2000 2400 0400 0800 Time of Day Cusi & Cunningham. Diabetes Care. 1995;18:843-851.
Treatment to Target Study: NPH vs Glargine in DM2 patients on OHA Type 2 DM on 1 or 2 oral agents (SU, MET, TZD) Age 30 to 70 BMI 26 to 40 A1C 7.5 to 10% and FPG > 140 mg/dl Anti GAD negative Willing to enter a 24 week randomized, open labeled study
Treatment to Target Study: NPH vs Glargine in DM2 patients on OHA Add 10 units Basal insulin at bedtime (NPH or Glargine) Continue current oral agents Titrate insulin weekly to fasting BG < 100 mg/dl - if 100-120 mg/dl, increase 2 units - if 120-140 mg/dl, increase 4 units - if 140-160 mg/dl, increase 6 units - if 160-180 mg/dl, increase 8 units
Treatment to Target Study; A1C Decrease 9 M ean H ba 1c% 8.5 8 7.5 7 8.6 7.5 7.1 6.9 6.5 0 5 10 15 20 W eeks in Study (N =691)
Patients in Target (A1c < 7%) P ercentage of P a tien ts 70 60 50 40 30 20 10 0 66.2 48.8 32.3 2.5 W eek 0 W eek 8 W eek 12 W eek 18
Treatment to Target Study: NPH vs Glargine in DM2 patients on OHA Nocturnal Hypoglycemia reduced by?% in the Glargine group
Advancing Basal/Bolus Insulin Indicated when FBG acceptable but HbA1c > 7% or > 6.5% and/or SMBG before dinner > 140 mg/dl Insulin options To glargine or NPH, add mealtime aspart / lispro To suppertime 70/30, add morning 70/30 Consider insulin pump therapy Oral agent options Usually stop sulfonylurea Continue metformin for weight control Continue glitazone for glycemic stability?
6-46 Starting With Bolus Insulin Combination Oral Agents + Mealtime Insulin
Starting With Bolus Insulin Mealtime Lispro vs NPH or Metformin Added to Sulfonylurea 6-47 HbA 1c (%) 12 10 8 6 4 2 0 10.0% 2.3% 3.4 kg Su + LP (n = 42) 10.4% 1.9% 2.3 kg Su + NPH (n = 50) 10.2% 1.9% 0.9 kg Su + Metformin (n = 40) 12 10 8 6 4 2 0 Weight Gain (kg) Baseline HbA 1c Follow-up HbA 1c Follow-up Weight Browdos, et al. Diabetes. 1999;48(suppl 1):A104.
Case #1: DM 2 on SU with infection 49 year old white male DM 2 onset age 43, wt 173 lbs, Ht 70 inches On glimepiride (Amaryl) 4 mg/day, HbA1c 7.3% (intolerant to metformin) Infection in colostomy pouch (ulcerative colitis) glucose up to 300 mg/dl plus SBGM 3 times per day
Case #1: DM 2 on SU with infection Started on MDI; starting dose 0.2 x wgt. in lbs. Wgt. 180 lbs which = 36 units Bolus dose (lispro/aspart) = 20% of starting dose at each meal, which = 7 to 8 units ac (tid) Basal dose (glargine) = 40% of starting dose at HS, which = 14 units at HS Correction bolus = (BG - 100)/ SF, where SF = 1500/total daily dose; SF = 40
Correction Bolus Formula Current BG - Ideal BG Glucose Correction factor Example: Current BG: 220 mg/dl Ideal BG: 100 mg/dl Glucose Correction Factor: 40 mg/dl 220-100 40 =3.0u
Case #1: DM 2 on SU with infection Started on MDI Did well, average BG 138 mg/dl at 1 month and 117 mg/dl at 2 months post episode with HbA1c 6.1%
Strategies to Improve Glycemic Control: Type 2 Diabetes Monitor glycemic targets Fasting and postprandial glucose, HbA 1c Self-monitoring of blood glucose is essential Nutrition and activity are cornerstones of therapy Combinations of pharmacologic agents are often necessary to achieve glycemic targets
Intensive Therapy for Type 1 Diabetes Careful balance of food, activity, and insulin Daily self-monitoring BG Patient trained to vary insulin and food Define target BG levels (individualized) Frequent contact of patient and diabetes team Monitoring HbA 1c Basal / Bolus insulin regimen
Options in Insulin Therapy Current Multiple injections Insulin pump (CSII) Future Implant (artificial pancreas) Transplant (pancreas; islet cells)
Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal 1.0 Insulin 0.8 0.6 0 Time
Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal 1.0 Injections Insulin 0.8 0.6 0 Time
Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal 1.0 Injections Insulin 0.8 0.6 0 Time
Multiple Injection Therapy Glargine & Short-Acting Insulin Pre-Meal 1.0 Injections Insulin 0.8 0.6 0 Time
Case #2: DM 1 on MDI 46 year old white male power line supervisor DM 1 age 40 On MDI: 10 u lispro pre-meal, 20 u NPH HS HbA1c 7.4% SMBG avg 124 mg/dl based on 1.9 tests/day (fasting 171 mg/dl, noon 105 mg/dl, pm 125 mg/dl, HS 75 mg/dl)
Case #2: DM 1 on MDI Lantus (glargine) 20 u HS added in place of NPH No change in behavior (diet, SMBG frequency) Seen three months later (8-16-01) HbA1c 6.3% SMBG average 104 mg/dl (fasting BG 91 mg/dl, noon 126 mg/dl, pm 116 mg/dl, HS 126 mg/dl NO HYPOGLYCEMIA HAPPY
Insulin Pens
Introducing InDuo The world s first combined insulin doser and blood glucose monitoring system A major breakthrough in Diabetes Care
InDuo - Integration Feature Combined insulin doser and blood glucose monitor
InDuo - Compact Size Feature Compact, discreet design Benefit Allows discreet testing and injecting anywhere, anytime
InDuo - Doser Remembers Feature Remembers amount of insulin delivered and time since last dose Benefit Helps people inject the right amount of insulin at the right time
Variability of Insulin Absorption CSII <2.8% Subcutaneous Injectable 10% to 52% Fraction at inj. site 1.00 0.75 0.50 0.25 Fast (n = 12) Semilente (n = 9) Intermediate (n = 36) Lauritzen. Diabetologia. 1983;24:326 329. 0 6 12 18 24 30 36 42 48 Hours after single SC injections Femoral region
Pump Therapy Basal & Bolus Short-Acting Insulin
Pump Therapy Basal & Bolus Short-Acting Insulin
Pump Therapy Basal & Bolus Short-Acting Insulin Combined with SMBG, physiologic insulin requirements can be achieved more closely Flexibility in lifestyle
History of Pumps
PARADIGM PUMP Paradigm. Simple. Easy.
Paradigm Pump: Advantages 29% smaller, water resistant Menu driven: bolus, suspend, basal, prime, utilities Reservoir based (easier to fill) Silent motor AAA batteries
Paradigm Pump: Advantages Various bolus options normal, square, dual, and easy bolus Enhanced memory Enhanced safety features (low reservoir alarm, auto off, etc.)
Pump Infusion Sets Softset QR Silhouette
Pharmacokinetic Advantages CSII vs MDI Uses only regular or very rapid insulin More predictable absorption than modified insulins (variation 3% vs 19 to 52%) Uses 1 injection site Reduces variations in absorption due to site rotation Eliminates most of the subcutaneous insulin depot Programmable delivery simulates normal pancreatic function Lauritzen. Diabetologia. 1983;24:326 329.
Metabolic Advantages with CSII Improved glycemic control Better pharmacokinetic delivery of insulin Less hypoglycemia Less insulin required Improved quality of life
Glycemic Control 10 Adolescent (37) Adult (166) HbA1c 9 8 8.9 7.6 8.2 8.5 8 8.1 7 7 7 6.9 6.9 6 Baseline 1 yr 2 yr 3 yr 4 yr Atlanta Diabetes Associates
CSII Reduces HbA 1c HbA 1c 10.0 9.5.09 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 Pre-pump Post-pump Bell Rudolph Chanteleau Bode Boland Chase n = 58 n = 107 n = 116 n = 50 n = 25 n = 56 Mean dur. = 36 Mean dur. = 36 Mean dur. = 54 Mean dur. = 42 Mean dur. = 12 Mean dur. = 12 Adults Adolescents Chantelau E, et al. Diabetologia. 1989;32:421 426; Bode BW, et al. Diabetes Care. 1996;19:324 327; Boland EA, et al. Diabetes Care. 1999;22:1779 1784; Bell DSH, et al. Endocrine Practice. 2000;6:357 360; Chase HP, et al. Pediatrics. 2001;107:351 356.
CSII Factors Affecting HbA 1c Monitoring HbA 1c = 8.3 - (0.21 x BG per day) Recording 7.4 vs 7.8 Diet practiced CHO: 7.2 Fixed: 7.5 Other: 8.0 Insulin type Lispro: 7.3 R: 7.7
CSII Usage in Type 2 Patients Atlanta Diabetes Experience 10.00 9.00 9.2 8.00 7.00 6.00 7.57 7.19 5.00 N = 11 Baseline 6 months 18 months P = 0.026 P = 0.040 Mean HbA 1c (%)
Glycemic Control in Type 2 DM: CSII vs MDI in 127 patients A1C 8.4 8.2 8.0 7.8 7.6 7.4 7.2 7.0 Baseline End of Study (24 wks) CSII MDI Raskin, Diabetes 2001; 50(S2):A106
DM 2 Study: CSII vs MDI Overall treatment satisfaction improved in the CSII group: 59% pre to 79% at 24 weeks 93% in the CSII group preferred the pump to their prior regiment (insulin +/- OHA) CSII group had less hyperglycemic episodes (3 subjects, 6 episodes vs. 11 subjects, 26 episodes in the MDI group)
CSII Reduces Hypoglycemia Events per hundred patient years 160 140 120 100 80 60 40 20 0 n = 55 Mean age 42 Pre-pump n = 107 Mean age 36 Post-pump Bode Rudolph Chanteleau Boland Chase n = 116 Mean age 29 n = 25 Mean age 14 n = 56 Mean age 17 Chantelau E, et al. Diabetologia. 1989;32:421 426; Bode BW, et al. Diabetes Care. 1996;19:324 327; Boland EA, et al. Diabetes Care. 1999;22:1779 1784; Chase HP, et al. Pediatrics. 2001;107:351 356.
Insulin Reduction Following CSII 60 50 40 30 20 10 48.1-28% -18% -16% -17% 39.3 * 40.1 * 39.8* 34.5 * 0 Baseline (MDI) 15 days 6 mos 18 mos 36 mos n = 389 n = 389 n = 298 n = 246 n = 187 * P <0.001
Normalization of Lifestyle Liberalization of diet timing & amount Increased control with exercise Able to work shifts & through lunch Less hassle with travel time zones Weight control Less anxiety in trying to keep on schedule
Current Continuation Rate Continuous Subcutaneous Insulin Infusion (CSII) Continued 97% N = 165 Average Duration = 3.6 years Average Discontinuation <1%/yr Bode BW, et al. Diabetes. 1998;47(suppl 1):392. Discontinued 3%
U.S. Pump Usage Total Patients Using Insulin Pumps 162,000 150,000 120,000 100,000 81,000 60,000 50,000 6,600 8,700 11,400 15,000 20,000 26,500 35,000 43,000 0 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 2000 2001
Pump Therapy Indications HbA 1c >7.0% Frequent hypoglycemia Dawn phenomenon Hectic lifestyle Shift work Type 2 Exercise Pediatrics Pregnancy Gastroparesis Marcus. Postgrad Med. 1995.
Poor Candidates for CSII Unwilling to comply with medical follow-up Unwilling to perform self blood glucose monitoring 4 times daily Unwilling to quantitate food intake
Current Candidate Selection Patient Requirements Willing to monitor and record BG Motivated to take insulin Willing to quantify food intake Willing to follow-up Interested in extending life
Pump Therapy Basal rate Continuous flow of insulin Takes the place of NPH or glargine insulin Units 6 5 4 3 2 1 Basal rate Meal boluses Insulin needed pre-meal Pre-meal BG Carbohydrates in meal Activity level Correction bolus for high BG Meal bolus 12 am 12 pm 12 am Time of day
What Type of Bolus Should You Give? 9 DM 1 patients on CSII ate pizza and coke on four consecutive Saturdays Dual wave bolus (70% at meal, 30% as 2-h square): 9 mg/dl glucose rise Single bolus: 33 mg/dl rise Double bolus at -10 and 90 min: 66 mg/dl rise Square wave bolus over 2 hours: 80 mg/dl rise Chase et al, Diabetes June 2001 #365
If HbA 1c is Not to Goal Must look at: SMBG frequency and recording Diet practiced Do they know what they are eating? Do they bolus for all food and snacks? Infusion site areas Are they in areas of lipohypertrophy? Other factors: Fear of low BG Overtreatment of low BG
Future of Diabetes Management
Improvements in Insulin & Delivery Insulin analogs and inhaled insulin External pumps Internal pumps Continuous glucose sensors Closed-loop systems
Pulmonary Insulin
6-55 Oral Agents + Mealtime Inhaled Insulin Effect on HbA 1c 10 Oral Agents Alone Oral Agents + Inhaled Insulin HbA 1c (%) 9 8 7 * 2.3% 6 *P <.001 5 Baseline (0) Follow-up (12) Weeks Baseline (0) Follow-up (12) Weiss, et al. Diabetes. 1999;48(suppl 1):A12.
GLUCOSE MONITORING SYSTEMS - Telemetry Consumer Product Real time glucose readings Wireless communication from sensor to monitor High and low glucose alarms FDA panel pending
losed-loop control using an external insulin ump and a subcutaneous glucose sensor + subcutaneous glucose sensor Insulin infusion pump (currently MiniMed 508)
Shift ~ ` ESC F1 F2 F3 F4 F5 F6 F7 F8 F 9 F10 F11 F12 Insert Delete Scroll Print 1 2 3 4 5 6 7 8 9 0 _ + - = { } Tab Q W E R T Y U I O P [ ] \ A S D F G H J K L : 1 2 Alt Alt,. / Shift Closed-Loop Setup for Canine Studies ; " Enter ' Z X C V B N M < >?
24-h Closed-Loop Control (diabetic canine) GLUCOSE (mg/dl) 500 400 300 200 100 start control adjust control parameters meals YSI GLC Sensor 0 6 am noon 6 pm midnight 6 am noon Closed Loop Resonse (U/h) 12 10 8 6 4 2 (U/h) µu/ml 100 75 50 25 Insulin (µu/ml) 0 0 6 am noon 6 pm midnight 6 am noon Time (h)
Implantable Pump Average HbA 1c 7.1% Hypoglycemic events reduce to 4 episodes per 100 pt-years
MiniMed 2007 System Implantable Insulin Pump Placement
Implantable Insulin Pumps Indications for Use! Diabetes out of control (frequent, rapid ρbg)! Frequent hypoglycemic episodes! Subcutaneous insulin absorption resistance! Injection or infusion site reaction
Long-Term Glucose Sensor
ONG TERM IMPLANTABLE SYSTEM Human Clinical Trial 350 300 250 Glucose (mg/dl) 200 150 100 50 0 26 Thu 27 Fri 28 Sat 29 Sun 30 Mon 31 Tue 1 Nov 2 Thu 3 Fri 4 Sat 5 Sun 6 Mon 7 Tue Source: Medical Research Group, Inc.
Combine Pump and Sensor Technology + LTSS => Long Term Sensor System ( Open Loop Control ) Using an RF Telemetry Link...
Medtronic MiniMed s Implantable Biomechanical Beta Cell
Today s Reality Open-Loop Glucose Control Sensor # - 6347
LONG TERM IMPLANTABLE SYSTEM Automatic Glucose Regulation in a Fully Pancreatectomized Canine Manual Control Automatic Control Begins Control Terminated Manual Control Glucose (mg/dl) 400 350 300 250 200 150 100 50 CLOSED LOOP CONTROL 16 Wed 17 Thu 18 Fri 19 Sat 20 Sun 21 Mon 22 Tue 23 Wed August 2000 Source: Medical Research Group, Inc.
Summary Insulin remains the most powerful agent we have to control diabetes When used appropriately in a basal/bolus format, near-normal glycemia can be achieved Newer insulins and insulin delivery devices along with glucose sensors will revolutionize our care of diabetes
Conclusion Intensive therapy is the best way to treat patients with diabetes
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