Combination Therapy for Type 2 Diabetes Springfield, IL, Nov 15, 2003 Paul Davidson, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia

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

Goals of Intensive Diabetes Management A Normal HbA1c Is Not Everything. It Is the Only Thing!

TYPE 2 DIABETES... A PROGRESSIVE DISEASE Natural History and Treatment 0 Years of Diabetes Relative  -Cell Function Plasma Glucose Insulin resistance Insulin secretion 126 mg/dL Fasting glucose Post-meal glucose Wt Loss Sensitizes Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota Secretors Insulin Exercise

TYPE 2 DIABETES... A PROGRESSIVE DISEASE Progressive Decline of  -Cell Function in the UKPDS  10 99 88 77 66 55 44 33 22 1 Years  -Cell Function (%  ) Adapted from UK Prospective Diabetes Study (UKPDS) Group. Diabetes. 1995; 44:

Basal vs Mealtime Hyperglycemia in Diabetes Riddle. Diabetes Care. 1990;13: Plasma Glucose (mg/dL) Time of Day Type 2 Diabetes Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal  AUC from normal basal >1875 mgm/dL. hr; Est HbA1 c >8.7%

When Basal Corrected Plasma Glucose (mg/dL) Time of Day Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 900 mgm/dL. hr; Est HbA1 c 7.2%

When Mealtime Hyperglycemia Corrected Plasma Glucose (mg/dL) Time of Day Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 1425 mgm/dL. hr; Est HbA1 c 7.9

When Both Basal & Mealtime Hyperglycemia Corrected Plasma Glucose (mg/dL) Time of Day Basal hyperglycemiaMealtime hyperglycemia 6-18 Normal Basal vs Mealtime Hyperglycemia in Diabetes  AUC from normal basal 225 mgm/dL. hr; Est HbA1 c 6.4%

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

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

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 –IV Insulin 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

Mean Hemoglobin A1C PETS Rx

Insulin The agent we have to control glucose only most powerful

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

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

Short-Acting Analogs Lispro and Aspart l Convenient administration immediately prior to meals l Faster onset of action l Limit postprandial hyperglycemic peaks l Shorter duration of activity –Reduce late postprandial hypoglycemia –Frequent late postprandial hyperglycemia l Need for basal insulin replacement revealed

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

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

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

Glucose Infusion Rate n = 20 T1DM Mean ± SEM SC insulin Time (hours) mg/kg/min µmol/kg/min Lepore M, et al. Diabetes. 2000;49:2142–2148. NPH Ultralente Glargine CSII

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 mg/dL, increase 2 units - if mg/dL, increase 4 units - if mg/dL, increase 6 units - if mg/dL, increase 8 units

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 ;

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 ;

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 ;

The Treat-to-Target Trial. Bedtime Glargine vs NPH With Mealtime Regular Nocturnal Hypoglycemia Weight Gain * ** Weight (kg) NPH Glargine Patients (%) *P <.0007 **P <.02 (compared to NPH) Rosenstock, et al. Diabetes. 1999;48(suppl 1):A

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 ;

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

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

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

Goals of Intensive Diabetes Management l Near-normal glycemia –HbA1c less than 6.5% l Avoid short-term crisis –Hypoglycemia –Hyperglycemia –DKA l Minimize long-term complications l Improve QOL

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

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 (e.g. corticosteroids) l Surgery l Pregnancy l Renal or hepatic disease

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

Advancing to Multiple Dose Insulin l Indicated when FBG acceptable but –HbA1c > 6.5% l Insulin options –Add mealtime lispro/aspart l Oral agent options –Stop sulfonylurea –Continue metformin for weight control –Continue glitazone for insulin sensativity

Goals in Management of Type 2 Diabetes l Fasting BG <126 mg/dl –Less Than 4 Months l HbA1c <7.0% –Less Than 8 Months i.e. 6%

Managing Type 2 Diabetes Four Months or Less to Goal 1

Managing Type 2 Diabetes Goal 2 (HbA1c <7.0%)

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

Routine Hospital Care for Type 2 Diabetes The Case for GEMS l Usually metformin contra-indicated l Glargine 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

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

Intravenous Insulin with Severe Illness Three major recent studies DIGAMI: Prospective Randomised Study of Intensive Insulin Treatment on Long Term Survival After Acute Myocardial Infarction in Patients with Diabetes Mellitus Malmberg, et al. BMJ. 1997;314: Portland: Continuous Insulin Infusion Reduces Mortality in Patients with Diabetes Undergoing Coronary Artery Bypass Grafting Furnary et al J Thorac Cardiovasc Surg 2003;123: Leuven: Intensive Insulin Therapy in Critically Ill Patients Van den Berghe et al N Engl J Med 2001; 345:

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

Cardiovascular Risk Mortality After MI Reduced by Insulin Therapy in the DIGAMI Study Malmberg, et al. BMJ. 1997;314: All Subjects (N = 620) Risk reduction (28%) P =.011 Standard treatment 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 Years of Follow-up

Mortality of DM Patients Undergoing CABG Fumary et al J Thorac Cardiovasc Surg 2003;123:

Intensive Insulin Therapy in Critically Ill Patients l 1548 Patients l All with BG >200 mgm/dl l Randomized into two groups –Conventional group (BG ) –Intensive group (BG ) Maintained on IV insulin while in ICU Goal BG <110 mg/d l 1.74 X mortality in conventional group Van den Berghe NEJM 2001;345:1359

P= P=0.026 BG< <BG<150 BG>150 ICU Mortality Effect of Average BG Van den Berghe et al (Crit Care Med 2003; 31: )

Protocol for Insulin in Hospitalized Patient l IV insulin while NPO l Basal insulin: Wt(#) x 0.1 Glargine hs l Bolus insulin: 1 unit rapid insulin per 10 Gm CHO eaten l Correction bolus for BG >150: (BG-100) / CF units rapid insulin CF = 7000 / Wt(#) l Do Not Use Sliding Scale Only l Any BG <80: D50 (100-BG) x 0.3 ml IV l Do Not Hold Insulin When BG Normal

If HbA 1c is Not to Goal i.e. 6.5% l SMBG –frequency –recording –memory meter l Diet –accurate CHO counting –appropriate CHO/insulin bolusing l l Infusion site areas l l Overtreatment of low BG l l Delayed or undertreatment of high BG

If HbA 1c Not to Goal i.e. 6.5% l SMBG –frequency –recording –memory meter l l Infusion site areas l l Overtreatment of low BG l l Delayed or undertreatment of high BG More than 4/day 2.8 x Wt / TDD 1700 Rule (100-BG) x 0.2 lDiet –accurate CHO counting –appropriate CHO/insulin bolusing

Improvement in HbA 1c with Increased BG Testing

If HbA 1c Not to Goal i.e. 6.5% l SMBG –frequency –recording –memory meter l l Infusion site areas l l Overtreatment of low BG l l Delayed or undertreatment of high BG More than 4/day 2.8 x Wt / TDD 1700 Rule (100-BG) x 0.2 lDiet –accurate CHO counting –appropriate CHO/insulin bolusing

Median slope = 2.82 Data: file: IPDC020510A1cCIRs2, 127 pts CARBOHYDRATE TO INSULIN RATIO CIR = 2.8 * BW# / TDD

If HbA 1c Not to Goal i.e. 6.5% l SMBG –frequency –recording –memory meter l l Infusion site areas l l Overtreatment of low BG l l Delayed or undertreatment of high BG More than 4/day 2.8 x Wt / TDD 1700 Rule (100-BG) x 0.2 lDiet –accurate CHO counting –appropriate CHO/insulin bolusing

Correction of Hypoglycemia with Glucose 100-BG X 0.15 Grams

If HbA 1c Not to Goal i.e. 6.5% l SMBG –frequency –recording –memory meter l l Infusion site areas l l Overtreatment of low BG l l Delayed or undertreatment of high BG More than 4/day 2.8 x Wt / TDD 1700 Rule (100-BG) x 0.2 lDiet –accurate CHO counting –appropriate CHO/insulin bolusing

Correction Factor The 1700 Rule CF = 1708 / TDD n = 179

Total Daily Wt Wt CIR Insulin CF (kg) (lb) (gm/unit) (unit) (mg/dL/unit) 149 ┼ 329 ┼ ┼ ┼ 313 ┼ ┼ ┼ 298 ┼ ┼ ┼ 284 ┼ ┼ ┼ 270 ┼ ┼ ┼ 258 ┼ ┼ ┼ 245 ┼ ┼ ┼ 234 ┼ ┼ ┼ 222 ┼ ┼ ┼ 212 ┼ ┼ ┼ 202 ┼ ┼ ┼ 192 ┼ ┼ ┼ 183 ┼ ┼ ┼ 174 ┼ ┼ ┼ 166 ┼ ┼ ┼ 158 ┼ ┼ ┼ 151 ┼ ┼ ┼ 143 ┼ 9 45 ┼ ┼ 137 ┼ 8 47 ┼ ┼ 130 ┼ 7 49 ┼ ┼ 124 ┼ 7 52 ┼ ┼ 118 ┼ 6 55 ┼ ┼ 112 ┼ 5 57 ┼ ┼ 107 ┼ 5 60 ┼ ┼ 102 ┼ 5 63 ┼ ┼ 97 ┼ 4 66 ┼ ┼ 92 ┼ 4 70 ┼ ┼ 88 ┼ 3 73 ┼ ┼ 84 ┼ 3 77 ┼ ┼ 80 ┼ 3 81 ┼ ┼ 76 ┼ 3 85 ┼ ┼ 72 ┼ 2 89 ┼ ┼ 69 ┼ 2 93 ┼ ┼ 66 ┼ 2 98 ┼ ┼ 63 ┼ ┼ ┼ 60 ┼ ┼ ┼ 57 ┼ ┼ ┼ 54 ┼ ┼ ┼ 51 ┼ ┼ 14 Accurate Insulin Management (AIM) Nomogram 1.Connect the columns with a straight line between weight and total daily dose of insulin (TDD). 2.Read correction factor (CF) and carbohydrate/insulin ratio (CIR). 3.Basal insulin is one-half total daily dose of insulin.

Future of Diabetes Management Improvements in Insulin & Delivery l Insulin analogs and inhaled insulin l Smart external pumps l Internal pumps l Real-time sensors l Closed-loop systems l Unconceived-of solutions

Conclusion Intensive therapy to target is the only way to treat patients with diabetes 4. Insulin Pump (CSII) 3. Glargine + Lispro/Aspart (MDI) 2. Glargine + Glinide or Sulfonylurea (GEMS) 1. Metformin and/or TZD + Glinide or Sulfonylurea (PETS)

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