2. Diabetes Management in the Hospital Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia

3. Diabetes in Hospitalized Patients 1997 3.5 Million US Hospitalizations 15% of Admissions 14 Million Hospital Days 20% of All Hospital Days 36% First Diagnosed in Hospital 66% No Documentation by Physician 27% Labeled Hyperglycemia 2% Diagnosed on Chart

4. Diabetes in Hospitalized Patients 1997 Costs $ 23,500 Each vs. $12,200 for Non-$ 23,500 Each vs. $12,200 for Non- diabetics diabetics 60% of All Diabetes-Related Costs60% of All Diabetes-Related Costs Only 5% DKA, HHNKCOnly 5% DKA, HHNKC 48% Diabetes Complications48% Diabetes Complications 52% Other Conditions52% Other Conditions

5. Diabetes in Hospitalized Patients High-risk for Bacterial Infection –Surgery –Catheters –Intravenous Access –Anaesthesia Problems with wound healing Problems with tissue and organ perfusion

6. Infections in Diabetes l One BG >220 mg/dl results in 5.8 times increase in nosocomial infection rate l Two hours hyperglycemia results in impaired WBC function for weeks Pomposelli, New England Deaconess, J Parenteral and Enteral Nutrition 22:77-81,1998

7. Causes for High Risk for Infection l Short Term Effect of Hyperglycemia –Immune Function –Pathogen Growth –Vascular Permeability l Long Term Effect of Hyperglycemia –Vascular Disease –Neurologic Disease

8. Evidence for Immediate Benefit of Normoglycemia in Hospitalized Patients l Numerous Publications on in Vitro Evidence –Neutrophil Dysfunction –Complement Inhibition –Altered Redox State (Pseudohypoxia) –Glucose Rich Edema as Culture Media l Six Recent Clinical Publications supporting good glucose control in the hospital setting

9. Perioperative Glycemic Control Hill, Peart-Vigilance, Kao, Brancati (Johns Hopkins) Diabetes Care (22)9:1408-1414, 1999 l 411 CABG 1990-1995 l Mean of BG in First 36-h Post-op l Quartiles of BG Results l 24.3% Infection Rate l Relative Risk vs. Quartile 1 (BG 121-206 mg/dl) –Quartiles 2,3,4: 1.17, 1.86, 1.72 l Case-Control Analysis –Patients Subsequently Infected Had Significantly Higher BGs Throughout Pre- Infection Course

10. Open Heart Surgery in Diabetes Portland St. Vincent Medical Center Protocol Ordered by Surgeon Administered by Nursing Staff No Change Except Insulin Administration Control Group l N=968 l 1987-1991 l SubQ Insulin q 4 h l Goal 200 mg/dl l Standard Deviation 36 l All Mean BG’s <200 47% Study Group l l N=1499 l l 1991-1997 l l IV Insulin l l Goal 150-200 mg/dl l l Standard Deviation 26 l l All Mean BG’s <200 84% Furnary et al, The 34th Meeting of The Society of Thoracic Surgeons New Orleans, LA January 26, 1998

11. Open Heart Surgery in Diabetes Portland St. Vincent Medical Center Perioperative Blood Glucose Furnary et al, The 34th Meeting of The Society of Thoracic Surgeons New Orleans, LA January 26, 1998

12. Incidence of DSWI: 1987-1997 CII Furnary, et al, The 34th Meeting of The Society of Thoracic Surgeons New Orleans, LA January 26, 1998

13. Open Heart Surgery in Diabetes Portland St. Vincent Medical Center Mortality l All(99/2467) 4.0% l SQI 6.1% l CII 3.0% Recent Experience l 1994-1997 DSWI as in non-diabetics l 1996-7 No DSWI in last 15 mo. Furnary et al, The 34th Meeting of The Society of Thoracic Surgeons New Orleans, LA January 26, 1998

14. Benefit of CII and Normoglycemia l Avoids Accelerated Glycosylation ImmunoglobulinsC3 Component New Collagen l Preventing Granulocyte Dysfunction Abnormal Adherence Impaired Phagocytosis Delayed Chemotaxis Depressed Bactericidal Capacity l Reverses Phagocyte Impairment

15. LOS and Charge $ comparison: Socioeconomic Costs of DSWI: 16 Hosp Days $26,000

16. VariableSQICIISavings # DSWI2,96810091,959 Additional LOS47,48816,41631,342 Additional $$78.4M$26.6M$51.7M # Deaths564192372 Estimated USA Socioeconomic Savings Assumes 742K cases*, 20% prevalence of DM & 2% DSWI with SQI *1998 Heart & Stroke Statistical update, AHA

17. DIGAMI Study Diabetes, Insulin Glucose Infusion in Acute Myocardial Infarction(1997) l Acute MI With BG > 200 mg/dl l Intensive Insulin Treatment l IV Insulin For > 24 Hours l Four Insulin Injections/Day For > 3 Months l Reduced Risk of Mortality By: 28% Over 3.4 Years 51% in Those Not Previous Diagnosed Malmberg BMJ 1997;314:1512

18. Cardiovascular Risk Mortality After MI Reduced by Insulin Therapy in the DIGAMI Study Malmberg, et al. BMJ. 1997;314:1512-1515. All Subjects (N = 620) Risk reduction (28%) P =.011 Standard treatment 0.3.2.4.7.1.5.6 01 Years of Follow-up 2345 Low-risk and Not Previously on Insulin (N = 272) Risk reduction (51%) P =.0004 IV Insulin 48 hours, then4 injections daily 0.3.2.4.7.1.5.6 01 Years of Follow-up 2345 6-11

19. ICU Survival l 1548 Patients l All with BG >200 mg/dl l Randomized into two groups –Maintained on IV insulin –Conventional group (BG 180-200) –Intensive group (BG 80-110) l Conventional Group had 1.74 X mortality Van den Berghe et al, NEJM 2001;345(19):1359

20. ICU Survival Intensive Therapy (80 to 110 mg/dL) resulted in: l 34% reduction in mortality l 46% reduction in sepsis l 41% reduction in dialysis l 50% reduction in blood transfusion l 44% reduction in polyneuropathy Van den Berghe et al, NEJM 2001;345(19):1359

21. Conclusion All hospital patients should have normal glucose

22. Insulin The agent we have to control glucose only most powerful

23. 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

24. Methods For Managing Hospitalized Persons with Diabetes l Continuous Variable Rate IV Insulin Drip Major Surgery, NPO, Unstable, MI, DKA, Hyperglycemia, Steroids, Gastroparesis, Delivery, etc l Basal / Bolus Therapy (MDI) when eating

25. Continuous Variable Rate IV Insulin Drip l Mix Drip with 125 units Regular Insulin into 250 cc NS l Starting Rate Units / hour = (BG – 60) x 0.02 where BG is current Blood Glucose and 0.02 is the multiplier l Check glucose every hour and adjust drip l Adjust Multiplier to keep in desired glucose target range (100 to 140 mg/dl)

26. Continuous Variable Rate IV Insulin Drip l Adjust Multiplier (initially 0.02) to obtain glucose in target range 100 to 140 mg/dL If BG > 140 mg/dL, increase by 0.01 If BG < 100 mg/dL, decrease by 0.01 If BG 100 to 140 mg/dL, no change in Multiplier l If BG is < 80 mg/dL, Give D50 cc = (100 – BG) x 0.3 l Give continuous rate of Glucose in IVF’s l Once eating, continue drip till 1 hour post SQ insulin

27. Glucose Management System

28. Glucommander l Based on 15 Year Experience with a Computer Based Algorithm for the Administration of IV Insulin l Developed for Marketing by MiniMed and Roche l GMS System l Shelved Pending FDA Approval of IV Use of Insulin l Useful and Safe for Any Application of IV Insulin

30. Glucommander Effectiveness l Initial blood glucose –Median 292 mg/dl –Range 181-1,568 l Time to achieve glucose < 180 mg/dl –Median 3 hours –Range 0.3 - 19.7 l Time to achieve three consecutive glucose results between 60 - 180 mg/dL –Median 3. 1 hours –Range 0.3 - 22.5

31. Glucommander l Final Patient Data Set3,473 l Median patients per month 27 l Median glucose tests per patient 20

32. Glucommander Safety and Effectiveness l Time to end of treatment with the algorithm –Median 20 hours –Range 0.4 - 298 l Percentage of blood glucose < 60 mg/dL –1.5% of all data

33. Converting to SQ insulin l Establish Daily Insulin Requirement –IV Insulin First Night –(BG - 60) x Multiplier = Ins/hr Targeted to 120 –60 x Multiplier x 24 = Daily Insulin Requirement l Give One-Half Amount As Basal l Give p.c. Boluses Based on CHO Intake –Start at CHO/Ins 1 CHO = 1.5 units Short-acting l Monitor a.c. tid, hs, and 3 am l Supplement All BG >150 –(BG-100)/(1500/Daily Insulin Requirement)

34. Protocol for SQ Insulin in Hospitalized Patient l Bedtime: Wt (kg) x 0.2 = Units of Glargine l Meals Eaten: 1.5 units per 15 Gm CHO eaten l BG >150: (BG-100) / SF SF = 3000 / Wt (kg) l Do Not Use Sliding Scale Only l Any BG <80: D50 (100-BG) x 0.3 ml Maintain INT l Do Not Hold Insulin When BG Normal

35. GEMS--Glargine Evening Mealtime Secretagogue l Basal Dosing –(Weight in kg x 0..2) Glargine bedtime or anytime l Prior to Meals –Short Acting Secretagogue Rapaglinide 2 mg Nateglinide 120 mg

36. Conclusion Intensive therapy is the best way to treat patients with diabetes

37. QUESTIONS l For a copy or viewing of these slides, contact l WWW.adaendo.com WWW.adaendo.com

38. Clinical Experience with Glucommander l Summary –Glucommander provides a safe and effective method of treatment for achieving and maintaining glycemic control. –Glucommander provides a standardized treatment method, yet is applicable for controlling glycemia in a wide variety of medical conditions.

39. Enterally Fed Diabetics l Uncontrolled with Sliding Scale l Erratically Controlled with Intermittent Intermediate Acting or Mixed Insulin

40. Diabetes Management Tube Feeding, On Steroids

41. Reversing Glucose Toxicity l Import in Controlling Type 2 Diabetes l Well Established Practice of Using IV Insulin Under Close Supervision l Expense and Restriction of Hospitalization

42. GEMS--Glargine Evening Mealtime Secretagogue l Basal Dosing –(Weight in #`s x 0.1) Glargine hs l Prior to Meals –Short Acting Secretagogue Rapaglinide 2 mg Nateglinide 120 mg

43. The Case for GEMS Routine Hospital Care for Type 2 Diabetes l Usually metformin contra-indicated l Insulin required for normal am glucose –Stress or steroids l Interrupted and/or unreliable food intake l Nursing routine problems –Lispro insulin at time of tray –Reluctance to give lispro with normoglycemia l Supplemental lispro with elevated glucose l Short-acting secretagogue in half hour before tray –Little risk of hypoglycemia if limited intake

44. How to Initiate MDI l Starting dose = 0.4 to 0.5 x weight in kilograms l Bolus dose (lispro/aspart) = 20% of starting dose at each meal l Basal dose (glargine) = 40% of starting dose given at bedtime or anytime l Correction bolus = (BG - 100)/ Sensitivity Factor, where SF = 1500/total daily dose

45. How to Initiate MDI l starting dose = 0.2 x wgt. in lbs. l Wgt. 180 lbs which = 36 units l Bolus dose (lispro/aspart) = 20% of starting dose at each meal, which = 7 to 8 units ac (tid) l Basal dose (glargine) = 40% of starting dose at HS, which = 14 units at HS l Correction bolus = (BG - 100)/ SF, where SF = 1500/total daily dose; SF = 40

46. Correction Bolus Formula Example: –Current BG:220 mg/dl –Ideal BG: 100 mg/dl –Glucose Correction Factor: 40 mg/dl Current BG - Ideal BG Glucose Correction factor 220 - 100 40 =3.0u