New Insulins and Insulin Delivery Systems Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia

American Diabetes Association. Facts and Figures. Available at: Accessed January 18, Diagnosed Type 1 Diabetes 0.5 – 1.0 Million Diagnosed Type 2 Diabetes 10.3 Million Undiagnosed Diabetes 5.4 Million Prevalence of Diabetes in the US

l Maintain near normal glycemia l Avoid short-term crisis l Minimize long-term complications l Improve the quality of life Hours Goals of Intensive Insulin Therapy

ACE / AACE Targets for Glycemic Control A1C (HbA 1c ) < 6.5 % Fasting/preprandial glucose< 110 mg/dL Postprandial glucose< 140 mg/dL ACE / AACE Consensus Conference, Washington DC August 2001

Specific Goals in Management of Diabetes l Fasting or premeal BG 70 to 140 mg/dL l Post-meal < 140 to 160 mg/dL l A1C < 6.5 to 7.0% l Blood Pressure < 130/80 l LDL 45 mg/dL l Triglycerides < 150 mg/dL

Insulin The most powerful agent we have to control glucose

Patient J.L., December 15, 1922 February 15, 1923 The Miracle of Insulin

Progression of Type 1 Diabetes Adapted from: Atkinson. Lancet. 2002;358: Age (y) Precipitating Event Beta-cell mass Genetic predisposition Normal insulin release Glucose normal Overt diabetes No C-peptide present Progressive loss of insulin release C-peptide present Antibody

Options in Insulin Therapy for Type 1 Diabetes l Current –Multiple injections –Insulin pump (CSII) l Future –Implant (artificial pancreas) –Transplant (pancreas; islet cells)

Type 2 Diabetes … A Progressive Disease Over time, most patients will need insulin to control glucose

Type 2 Diabetes: Two Principal Defects Reaven GM. Physiol Rev. 1995;75: Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S; Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127. Insulin resistance  -cell dysfunction/ failure ± Environment± IGT Genes Type 2 diabetes Glucose Toxicity Glucose Toxicity

A1C in the UKPDS

UKPDS:  -Cell Function for the Patients Remaining on Diet for 6 Years Years After Diagnosis  -Cell Function (%  ) Adapted from UKPDS Group. Diabetes. 1995; 44: N=376

Multiple factors may drive progressive decline of  -cell function  -cell (genetic background) Hyperglycaemia (glucose toxicity) Protein glycation Amyloid deposition Insulin resistance “lipotoxicity” elevated FFA,TG

Management of Type 2 DM Step Therapy l Diet l Exercise l Sulfonylurea or Metformin l Add Alternate Agent l Add hs NPH vs TZD l Switch to Mixed Insulin bid l Switch to Multiple Dose Insulin Utilitarian, Common Sense, Recommended Prone to Failure from Misscheduling and Mismanagement

Management of Type 2 DM Stumble Therapy l WAG Diet l Golf Cart Exercise l Sample of the Week Medication –Interrupted –Not Combined l Poor Understanding of Goals l Poor Monitoring HbA1c >8% (If Seen )

Consider A New Treatment Paradigm l Treatment designed to correct the dual impairments l Vigorous effort to meet glycemic targets l Simultaneous rather than sequential therapy l Combination therapy from the outset l Early step-wise titrations to meet glycemic targets

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 Continue FPG <110 mg/dl A1C <6.5% FPG >110 mg/dl A1C >6.5% Add Insulin

Comparison of Human Insulins / Analogues Insulin Onset ofDuration of preparations action Peak action Regular30–60 min2–4 h6–10 h Lispro/aspart5–15 min1–2 h 4–6 h NPH/Lente1–2 h4–8 h10–20 h Ultralente2–4 hUnpredictable16–20 h Glargine1–2 hFlat~24 h

Dissociation & Absorption of NovoLog  Insulin Aspart (NovoLog  ) Regular Human Insulin Peak Time = min Peak Time = min Capillary Membrane Subcutaneous Tissue

Meal SC injection Time (min) Regular Lispro Time (min) Plasma insulin (pmol/L) Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625–629; Mudaliar, et al. Diabetes Care. 1999;22:1501–1506. Short-Acting Insulin Analogs Lispro and Aspart Plasma Insulin Profiles Regular Aspart

Pharmacokinetic Comparison Aspart vs Lispro Aspart Lispro Free Insulin (pmol/L) Time (hours) Hedman, Diabetes Care 2001; 24(6):

Limitations of NPH, Lente, and Ultralente l Do not mimic basal insulin profile –Variable absorption –Pronounced peaks –Less than 24-hour duration of action l Cause unpredictable hypoglycemia –Major factor limiting insulin adjustments

Asp Gly Arg Extension Substitution Arg Insulin Glargine (Lantus) A New Long-Acting Insulin Analog l Modifications to human insulin chain –Substitution of glycine at position A21 –Addition of 2 arginines at position B30 l Gradual release from injection site l Peakless, long-lasting insulin profile

Lepore, et al. Diabetes. 1999;48(suppl 1):A Time (h) after SC injection End of observation period 2030 Glargine NPH Glucose utilization rate (mg/kg/h) Glargine vs NPH Insulin in Type 1 Diabetes Action Profiles by Glucose Clamp

Overall Summary: Glargine l Insulin glargine has the following clinical benefits –Once-daily dosing because of its prolonged duration of action and smooth, peakless time- action profile (mean 23.5 hours) –Comparable or better glycemic control (FBG) –Lower risk of nocturnal hypoglycemic events –Safety profile similar to that of human insulin

GlyThrGluPheTyrProLysThr GlyThrGluPheTyrProLysThr Insulin Detemir (CH 2 ) 4 NH CO R Primary Structure of Lys(B29)-N-  - Tetradecanoyl, Des(B30)-Insulin

28 Brunner GA, et al. Exp Clin Endocrinol Diabetes. 2000;108: Elapsed time (min) Detemir-high Detemir-low Placebo Glucose infusion rate (mg/kg/min) Insulin Detemir in Nondiabetic Subjects— Pharmacokinetics by Glucose Clamp

Lowers A1C as effectively Lowers FPG significantly more Provides significantly lower intra-subject variation of fasting blood glucose (more predictable) Produces a smoother nocturnal glucose profile Causes a lower incidence of hypoglycaemia Associated with some weight loss Causes no safety concerns Insulin detemir in comparison to NPH : Conclusions From Phase 2 and 3 Studies

4: :0012:0016:0020:0024:004:00 BreakfastLunchDinner Plasma insulin (U/ml) Plasma insulin ( µ U/ml) Time 8:00 Physiological Serum Insulin Secretion Profile

4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine or Detemir Lispro Lispro Lispro Aspart Aspart Aspart or Plasma insulin Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs

The Basal/Bolus Insulin Concept l Basal insulin –Suppresses glucose production between meals and overnight –40% to 50% of daily needs l 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

Insulin Therapy in Type 2 Diabetes Indications l Significant hyperglycemia at presentation l Hyperglycemia on maximal doses of oral agents l Decompensation –Acute injury, stress, infection, myocardial ischemia –Severe hyperglycemia with ketonemia and/or ketonuria –Uncontrolled weight loss –Use of diabetogenic medications (eg, corticosteroids) l Surgery l Pregnancy l Renal or hepatic disease

Starting With Basal Insulin Advantages l 1 injection with no mixing l Insulin pens for increased acceptance l Slow, safe, and simple titration l Low dosage l Effective improvement in glycemic control l Limited weight gain 6-37

Treat to Target Study: Glargine vs NPH Added to Oral Therapy of Type 2 Diabetes l Type 2 DM on 1 or 2 oral agents (SU, MET, TZD) l Age 30 to 70 l BMI 26 to 40 l A1C 7.5 to 10% and FPG > 140 mg/dL l Anti GAD negative l Willing to enter a 24 week randomized, open labeled study Riddle et al, Diabetes June 2002, Abstract 457-p

Treatment to Target Study: NPH vs Glargine in DM2 patients on OHA l Add 10 units Basal insulin at bedtime (NPH or Glargine) l Continue current oral agents l Titrate insulin weekly to fasting BG < 100 mg/dL - if mg/dL, increase 2 units - if mg/dL, increase 4 units - if mg/dL, increase 6 units - if mg/dL, increase 8 units

Treatment to Target Study; A1C Decrease

Treat to Target Study: Glargine vs NPH Added to Oral Therapy of Type 2 Diabetes l Nocturnal Hypoglycemia reduced by 40% in the Glargine group (532 events) vs NPH group (886 events) Riddle et al, Diabetes June 2002, Abstract 457-p

Advancing Basal/Bolus Insulin l Indicated when FBG acceptable but –A1C > 7% or > 6.5% and/or –SMBG before dinner > 140 mg/dL l Insulin options –To glargine or NPH, add mealtime aspart / lispro –To suppertime 70/30, add morning 70/30 –Consider insulin pump therapy l Oral agent options –Usually stop sulfonylurea –Continue metformin for weight control –Continue glitazone for glycemic stability?

Novo Nordisk devices in diabetes care First pen (NovoPen 1) launched in 1985 Committed to developing one new insulin administration system per year.

Lilly Insulin Pens

Novo FlexPen ® l 3-mL prefilled disposable pen offers precise dosing

82% of DNEs Preferred FlexPen ® Source: Diabetes Nurse Educators In-Depth Study—Reactions to FlexPen. NovoLog ® FlexPen ® ®

Novo Innolet ® Large push button with low resistance Large-scale numbers 1 unit increments Support shoulder Maximum dose 50 units Clear & uncomplicated dial, dials forward and back Contains 300 units Novolin ® 70/30, NPH, or R Audible clicks NovoFine ® disposable needle Needle storage compartment

InDuo™ - Integration Feature l Combined insulin doser and blood glucose monitor

InDuo™ - Doser Remembers Feature l Remembers amount of insulin delivered and time since last dose Benefit l Helps people inject the right amount of insulin at the right time

Starting MDI l Starting insulin dose is based on weight 0.2 x wgt in lbs or 0.45 x wgt in kg l Bolus dose (aspart/lispro) = 20% of starting dose at each meal l Basal dose (glargine/NPH) = 40% of starting dose at bedtime

Starting MDI in 180 lb person l Starting dose = 0.2 x wgt. in lbs. 0.2 x 180 lbs. = 36 units l Bolus dose = 20% of starting dose at each meal 20% of 36 units = 7 units ac (tid) l Basal dose = 40% of starting dose at bedtime 40% of 36 units = 14 units at HS

Correction Bolus l Must determine how much glucose is lowered by 1 unit of short- or rapid-acting insulin l This number is known as the correction factor (CF) l Use the 1700 rule to estimate the CF l CF = 1700 divided by the total daily dose (TDD) ex: if TDD = 36 units, then CF = 1700/36 = ~50 meaning 1 unit will lower the BG ~50 mg/dl

Correction Bolus Formula Example: –Current BG:220 mg/dl –Ideal BG: 100 mg/dl –Glucose Correction Factor: 50 mg/dl Current BG - Ideal BG Glucose Correction factor =2.4u

Options to MDI l A Simpler Regimen l Insulin Pump l Premixed BID (DM 2 only)

Human Insulin Time-action Patterns Time (h) Baseline level Regular insulin Premix 70/30 SC injection Normal insulin secretion at mealtime NPH insulin Change in serum insulin

A More Physiologic Insulin Time (h) SC injection Baseline Level Normal insulin secretion at mealtime NPH insulin NovoLog  NovoLog  Mix 70/30 Change in serum insulin

Analog Mix 70/30: Serum Insulin Levels in Type 2 Diabetes BreakfastLunch 0 6:00 PM 10:00 PM 8:00 AM 6:00 PM 1:00 PM Dinner C max Serum insulin (mU/L) 100 Time * * NovoLog ® Mix 70/30 70/30 Premix McSorley. Clin Ther. 2002;24(4): * P<0.05.

Aspart Mix 70/30: Serum Glucose Levels in Type 2 Diabetes Aspart Mix 70/30 70/30 Premix DinnerBreakfastLunch *Glucose excursions 0-4 h, P<0.05. McSorley. Clin Ther. 2002;24(4):

Analog Mix 70/30 vs 75/25 vs 70/30 Premix: Serum Insulin Levels in Type 2 Diabetes Lispro Mix 75/25 70/30 Premix Aspart Mix 70/ Time (h) Serum insulin (mU/L) Hermansen. Diabetes Care. 2002;25(5):

Case #2: DM 2 on 70/30 l 60 year old black male l DM2 age 56; Ht 69”; Wgt 180 l Failed oral agents l On 70/30 BID: 10 u am and pm l HbA1c 8.4% SMBG 144 on 0.8 tests/day l Increased 70/30, tried 3xday, still not at goal

Case #2: DM 2 on 70/30 l Finally agrees to MDI l Starting dose: 0.2 x wgt in # (36 u) l Bolus: 20% pre-meal (7 u ac tid) l Basal: 40% Bedtime or anytime (14 u HS) l Correction Factor: 1700 divided by TDD (50mg/dl) l Does great - A1C 6.4% l Current dose: 4 u am, 4 u noon, 10 u pm, 16 u Lantus HS

4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Basal infusion Bolus Plasma insulin Variable Basal Rate: CSII Program

PARADIGM PUMP Paradigm. Simple. Easy.

Pump Infusion Sets

Metabolic Advantages with CSII l Improved glycemic control l Better pharmacokinetic delivery of insulin –Less hypoglycemia –Less insulin required l Improved quality of life

CSII Reduces HbA 1c n = 58n = 107n = 116n = 50n = 25n = 56 Mean dur. = 36 Adolescents Adults Mean dur. = 36Mean dur. = 54Mean dur. = 42Mean dur. = 12 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. BellRudolphChanteleauBodeBolandChase Pre-pumpPost-pump HbA 1c

-28%-18%-16%-17% * P <0.001 * * * * n = 389n = 389n = 298n = 246n = 187 Insulin Reduction Following CSII

l Monitoring –A1C = (0.21 x BG per day) l Recording 7.4 vs 7.8 l Diet practiced –CHO: 7.2 –Fixed: 7.5 –WAG: 8.0 l Insulin type (Aspart) CSII Factors Affecting A1C Bode et al. Diabetes 1999;48 Suppl 1:264 Bode et al. Diabetes Care 2002;25 439

Insulin aspart versus buffered R versus insulin lispro in CSII study: Bode et al: Diabetes Care, March 2002 Insulin aspart Buffered regular human insulin (Velosulin ® ) Screening Insulin lispro –2016 weeks 146 patients in the USA; 2–25 years with Type 1 diabetes; 7%  HbA 1c  9%; previously treated with CSII for 3 months

Glycemic Control with CSII NovoLog® Human insulin Humalog® HbA 1c (%) BaselineWeek 8Week 12Week 16 0 Bode, Diabetes 2001 ; 50(S2):A106 Type 1 Diabetes

Self-Monitored Blood Glucose in CSII NovoLog®Buffered RegularHumalog® Blood Glucose (mg/dl) * * * Bedtime2 AM Before and 90 min. after breakfast Before and 90 min. after lunch Before and 90 min. after dinner Type 1 Diabetes Bode, Diabetes 2001 ; 50(S2):A106

Episodes/month/patient insulin asparthuman insulininsulin lispro p < 0.05 Symptomatic or Confirmed Hypoglycaemia 30% relative reduction Bode et al: Diabetes Care, March 2002

Insulin aspart Buffered human insulin Insulin lispro Patients with trouble-free use (%) Insulin aspart versus buffered R versus insulin lispro in CSII study: pump compatibility Data on file (study ANA 2024)

Lispro Average = 140 SD = 118 Aspart Average = 118 SD = 73 DM 1 CSII Patient: Lispro to Aspart

Glycemic Control in Type 2 DM: CSII vs MDI in 127 patients l A1C CSIIMDI Baseline End of Study (24 wks) Raskin et al. Diabetes 2001;50 Suppl 2:A128

CSII vs MDI in DM 2 Patients Raskin et al. Diabetes 2001;50 Suppl 2:A128

Case 3: DM 2 Poorly Controlled l 58 year old female presented with a 12 year history of poorly controlled, insulin treated diabetes l Ht 66’’, Wt 174#, BMI 28, C-peptide 2.1 l A1C 10.4% on 165 units per day (70/30 BID) l Added troglitazone, metformin, glimepiride to MDI insulin l A1C range 7.7 to 12.6% over 3 years

Case 3: DM 2 Poorly Controlled l Admitted twice for IV insulin and fasting with short lived success (A1C to 7.6% but back up to 12.6%) l Tried weight watchers and appetite suppressants; no help l Decided to try CSII

Case 3: DM 2 on CSII, A1C Results

Case 3: DM 2 Poorly Controlled l Patient loves the pump l On 110 units per day consuming 2 meals only per day (1.4 units per kg or 0.6 units per lbs) l Also on rosiglitazone 4 mg/day

Normalization of Lifestyle l Liberalization of diet — timing & amount l Increased control with exercise l Able to work shifts & through lunch l Less hassle with travel — time zones l Weight control l Less anxiety in trying to keep on schedule

N = 165 Average Duration = 3.6 years Average Discontinuation <1%/yr Continued 97% Discontinued 3% Current Continuation Rate Continuous Subcutaneous Insulin Infusion (CSII) Bode BW, et al. Diabetes. 1998;47(suppl 1):392.

U.S. Pump Usage Total Patients Using Insulin Pumps

Current Pump Therapy Indications l Diagnosed with diabetes (even new onset DM 1) l Need to normalize blood glucose (BG) –A1C  6.5% –Glycemic excursions l Hypoglycemia

Poor Candidates for CSII l Unwilling to comply with medical follow-up l Unwilling to perform self blood glucose monitoring 4 times daily l Unwilling to quantitate food intake

Meal bolus am12 pm12 am Time of day Basal rate Pump Therapy Units Meal boluses l Insulin needed pre-meal – Pre-meal BG – Carbohydrates in meal – Activity level l Correction bolus for high BG Basal rate l Continuous flow of insulin l Takes the place of NPH or glargine insulin

Initial Adult Dosage Calculations Starting Doses –Based on pre-pump Total Daily Dose (TDD) Reduce TDD by 25-30% for Pump TDD –Calculated based on weight 0.24 x wgt in pounds (0.5 x wgt in kg) Bode BW, et al., Diabetes 1999,(Suppl 1):84. Bell D and Ovalle F, Endocrine Practice 2000, 6: Crawford, LM, Endocrine Practice 2000, 6:

Initial Adult Dosage Calculations Basal Rate –50% of pump Total Daily Dose –Divide total basal by 24 hours to decide on hourly basal –Start with only one basal rate –See how it goes before adding additional basals

Basal Dose Adjustment Rule of 30: Basal Rate(s) Adjustments Overnight –Check BG Bedtime 12 AM 3 AM 7AM –Adjust overnight basal if readings vary > 30 mg/dl

Meal (food) Bolus –Usually 50% of Pump Total Daily Dose –Marjorie C. Total Daily Dose 40 Units Basal Rate20 Units Meal Bolus (total)20 Units Initial Dosage Calculations

Meal (food) Bolus Method - Divide total bolus dose by 3 - Test BG before meal - Give correction bolus - Give pre-determined insulin dose for pre- determined CHO content - Test BG after meal

Individually determined CIR = (2.8 x wgt in lbs) / TDD Anywhere from 5 to 25 g CHO is covered by 1 unit of insulin Estimating the Carbohydrate to Insulin Ratio (CIR)

What Type of Bolus Should You Give? Immediate vs Square vs Dual Wave l 9 DM 1 patients on CSII ate pizza and coke on four consecutive Saturdays l Dual wave bolus (70% at meal, 30% as 2-h square): 9 mg/dl glucose rise l Single bolus: 32 mg/dl rise l Double bolus at -10 and 90 min: 66 m/dl rise l Square wave bolus over 2 hours: 79 m/dl rise Chase et al, Diabetes June 2001 #365

Treatment of Hyperglycemia l If blood glucose is above 250 mg/dl –Take a correction bolus by pump –Check BG again in 1 hr l If still above 250 mg/dl –Take correction bolus by syringe –Change infusion set and reservoir –Check BG again in 1 hr l If BG has not decreased –Increase correction bolus by syringe –CALL PHYSICIAN

Prevention of Hypoglycemia l Monitor BG –4-6 times a day –Set appropriate BG target range l Set minimum BG level before sleep –Never < 90, unless pregnant

If A1C is Not to Goal l SMBG frequency and recording l Diet practiced –Do they know what they are eating? –Do they bolus for all food and snacks? l l Infusion site areas –Are they in areas of lipohypertrophy? l l Other factors: –Fear of low BG –Overtreatment of low BG Must look at:

If A1C Not to Goal and No Reason Identified l Place on a continuous glucose monitoring system (CGMS by Medtronic Minimed, Glucowatch by Cygnus) to determine the cause

Cygnus GlucoWatch G2 –Watch Component –Electrode Component –Initial calibration takes 2 hours –Senses glucose and gives an average every 10 minutes up to 13 hours (r = 0.84 home use) –Alarm for high, low and rapidly dropping blood sugars Cygnus GlucoWatch

GLUCOSE MONITORING SYSTEMS - EXTERNAL l Physician downloads data for retrospective analysis l Com-Station and software packages combine data from: –Sensor –Models 508 and 507C insulin pumps –Traditional glucose meters Physician Product

CGMS

CGMS Sensor

Patient with Type 1 Diabetes –Practicing MDI –HbA 1C of 8.5% –Complications of High BG Renal Retinal Neural Glucose Profiles :00 Midnight6:00 AM12:00 Noon 6:00 PM 12:00 Midnight Time Meal Glucose Concentration (mg/dl) Pre-Meal BG Tests

Glucose Profiles Glucose Monitor Pre-Meal BG Tests :00 Midnight6:00 AM12:00 Noon 6:00 PM 12:00 Midnight Time Meal Glucose Concentration (mg/dl) Patient with Type 1 Diabetes –Practicing MDI –HbA 1C of 8.5% –Complications of High BG Renal Retinal Neural

Reasons to Use CGMS l Improve glycemic control l Reduce risk of hypoglycemic events l Minimize risk of future hypoglycemia

GLUCOSE MONITORING SYSTEMS - Telemetry l “Real time” glucose readings l Wireless communication from sensor to monitor l High and low glucose alarms l FDA panel pending Consumer Product

Closed-loop control using an external insulin pump and a subcutaneous glucose sensor subcutaneous glucose sensor Insulin infusion pump (currently MiniMed 508) +

The Long-Term Sensor System: a prototype of implantable artificial pancreas Sensor Tip Abdominal Lead Assembly (ALA) Catheter Tip for Insulin Delivery Catheter Header with Inlet Port Sensor Connection to the Pump Inlet to Pump

Medtronic Minimed Artificial Pancreas

Blood Glucose Profile, Before, During and After Closed Loop using LTSS closed loop

Distribution of Blood Glucose One Week Before and During 48H-‘Closed-Loop 0 % 5 % > 240 mg/dl 26 % 45 % mg/dl 60 % 25 % mg/dl 14 % 25 % < 70 mg/dl During ‘Closed- Loop ’ Before Closed-Loop Reference Point Range Average Glucose (mg/dl) Daily Insulin Use (IU) E. Renard et al, Lapeyronie Hospital, Montpellier, France

Summary l Insulin remains the most powerful agent we have to control diabetes l When used appropriately in a basal/bolus format, near-normal glycemia can be achieved l Newer insulins and insulin delivery devices along with glucose sensors will revolutionize our care of diabetes

Billing l Get paid for what you do l Use your codes and negotiate for coverage l Detailed visit: l Prolonged visit with contact plus above: or (insulin start or pump start) l Prolonged visit w/o contact plus above: or 59 (faxes, phone calls, s)

Billing l Bill faxes as prolong visits with out contact or negotiate a separate charge l Bill meter download: l Bill CGMS: l Bill immediate A1C: 83036

Questions l For a copy or viewing of these slides, contact l