1. Basal Bolus: The Strategy for Managing All Diabetes Fall, 2003 Paul Davidson, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia

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

3. Step Therapy l Diet l Exercise l Sulfonylurea or Metformin l Add Alternate Agent l Add hs NPH l Switch to Mixed Insulin bid l Switch to Multiple Dose Insulin Utilitarian, Common Sense, Recommended Prone to Failure from Misscheduling and Mismanagement

4. Stumble Therapy l YAG Diet l Golf Cart Exercise l Sample of the Week Medication –Interupted, –Not Combined l Poor Understanding of Goals l Poor Monitoring HbA1c >8% (If Seen) Informed Patient Refers Self Elsewhere

5. PETS Therapy Step--Spelled Backwards All at once, nothing first, Just like bubbles, when they burst. l Start with Fast to Glucose <126 mg/dL –Glargine, Wt x 0.1 units qd l Feed PSMF Diet l Add SU, MF, TZD, Repaglanide + prn Lispro for BG <150 l “Normal” BG from Day 1 l Monitor BG qid l See Patient Monthly, HFP l HbA1c Bimonthly GI Problems: Cut MF Hypoglycemia: Cut SU Hypoglycemia Again: Cut Repaglinide Allow 2 Month to See TZD Effect

6. MIMICKING NATURE WITH INSULIN THERAPY All persons need both basal and mealtime insulin control to control glucose 6-19 (endogenous or exogenous)

7. 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 –More weight gain

8. 15 10 15202530 1 5101520 Asp Gly Arg Extension Substitution Arg Insulin Glargine 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

9. Glucose Infusion Rate n = 20 T1DM Mean ± SEM SC insulin 4.0 3.0 2.0 1.0 0 24 20 16 12 8 4 0 04812162024 Time (hours) mg/kg/min µmol/kg/min Lepore M, et al. Diabetes. 2000;49:2142–2148. NPH Ultralente Glargine CSII

10. Lepore, et al. Diabetes. 1999;48(suppl 1):A97. 6 5 4 3 2 1 0 010 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

11. Treat 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 Based on average FBG of 6th and 7th day - 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

12. The Treat-to-Target Trial Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients Riddle, Rosenstock, Gerich D IABETES C ARE 2003 26;3080-2083

13. Percentage of Patients in Target (A1C < 7%) The Treat-to-Target Trial Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients Riddle, Rosenstock, Gerich D IABETES C ARE 2003 26;3080-2083

14. 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 –Glimepiride 2 mg

15. The Treat-to-Target Trial Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients Riddle, Rosenstock, Gerich D IABETES C ARE 2003 26;3080-2083

16. The Treat-to-Target Trial Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients Riddle, Rosenstock, Gerich D IABETES C ARE 2003 26;3080-2083

17. The Treat-to-Target Trial. Bedtime Glargine vs NPH With Mealtime Regular 4 3 2 1 0 48 36 24 12 0 Nocturnal Hypoglycemia Weight Gain * ** Weight (kg) NPH Glargine Patients (%) *P <.0007 **P <.02 (compared to NPH) Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100. 6-52

18. Treatment to Target Study: NPH vs Glargine in DM2 patients on OHA l 57% had HbA1c <7% l Nocturnal Hypoglycemia reduced by 42% in the Glargine group l 33% had HbA1c <7% without any nighttime hypoglycemia in glargine group l Results significantly better than with NPH

19. Body Weight in pounds x 0.1 Average am BG x 2 after five days Add to Glargine (BG-100)/10 Repeat weekly Example: 200# 20 units glargine q hs AM BG averages 200 on 6th and 7th day Add (BG-100)10 to glargine, i.e. increase to 20 to 30 units q hs 2nd week--average 130 increase glargine from 30 to 33 Establishing Basal Requirement for Glargine

20. 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 –Comparable or better glycemic control (FBG) –Lower risk of nocturnal hypoglycemic events –Safety profile similar to that of human insulin