Glycemia Treatment Strategies Used In ACCORD Presented at the American Diabetes Association 68th Scientific Sessions on June 10, 2008.

OUTLINE Glycemia Levels Achieved in the Intensive and Standard Arms How Targets Were Achieved Changes in Body Weight Severe Hypoglycemia

Glycemia Levels Achieved

A1C Distribution Standard Rx Goal Intensive Rx Goal Dec

A1C Distribution: 12 Mo. Standard Rx Goal Intensive Rx Goal Dec

A1C Distribution: 24 Mo. Intensive Rx Goal Standard Rx Goal Dec

A1C Distribution: 36 Mo. Intensive Rx Goal Standard Rx Goal Dec

A1C Distribution: 48 Mo. Standard Rx Goal Intensive Rx Goal Dec December 2007

Median A1C and Interquartile Ranges The mean difference during the trial was 1.1%

How Targets Were Achieved

Achieving Glycemic Goals Intensive Group Standard Group Visits (1st 4 months) Monthly Monthly – Q 4 mo* Visits (after 4 months) Q 2 mo Q 2-4 mo* Phone Contact Research staff initiated (>1 inter-visit) Participant initiated Supplemental Contact Severe hypoglycemia/ A1C in action required range Severe hypoglycemia/ hyperglycemia A1C in action required range POC A1C Mandatory Optional Routine use of postprandial SMBG values to guide therapy Yes No * depending on the blood pressure group assignment

Achieving Glycemic Goals Intensive Group Standard Group SMBG Frequency 3-8/day (prn 3 am test) < 3/day Self Titration Frequently used Less frequently used Initial Minimum Rx Diet/lifestyle AND 2 oral agents Diet/lifestyle Insulin Use Encouraged, and multiple injections Generally < 2 injections/day

ACCORD Glycemia Formulary Metformin Rosiglitazone Glimepiride Repaglinide Acarbose Glargine Insulin Aspart Insulin 70/30, N, R Insulin Exenatide

Medications Ever Used During the Trial Intensive (N = 5128) Standard (N = 5123) Any Insulin (%)* 77 55 Bolus Insulin (%) 35 Metformin (%) 95 87 Secretagogue (%) 74 Thiozolidinedione% 92 58 Rosiglitazone (%) 91 Acarbose (%) 23 5 Exenatide/Sitagliptin (%) 18 Exenatide (%) 12 4 * % of Participants

Usage of Insulin at Last Visit Intensive (N=5128) Standard (N=5123) (units/kg) (% of participants) Total Insulin 0.69 66% 0.65 47% Basal Insulin 0.48 64% 0.45 41% Bolus Insulin 0.33 40% 0.35 20%

Design of Intensive Glycemia Intervention Group A1C Targets Intensification Thresholds A1C > 50% of SMBG Results/4 Days Intensive < 6% > 5.9% Fasting > 100 (5.6) OR 2 Hr PP > 140 (7.8) Even if the A1C is <6.0 Rx was reduced in the presence of significant hypoglycemia.

Design of Standard Glycemia Intervention Group A1C Targets Action Required Thresholds A1C Standard 7-7.9% >8.0% 6.5%-6.9% X 2 OR < 6.5% INCREASE RX DECREASE Rx if**: Any Fasting < 90 (5.0) Symptomatic Hypoglycemia On Insulin or Secretagogue **Decrease only insulin or insulin secretagogues.

Changes in Body Weight

Changes in Body Weight Since Baseline Decrease Increase

Severe Hypoglycemia

ACCORD Definition of a Severe Hypoglycemic Episode Hypoglycemia requiring medical or paramedical attention, AND Documented blood glucose < 50 mg/dl (2.8 mmol/L), or Prompt recovery with administration of oral CHO, IV glucose, or subcutaneous glucagon Each participant’s ‘Glucose Diary’ was reviewed at each clinic visit to identify the occurrence of one of these hypoglycemic events

Severe Hypoglycemia Monitoring & Management Severe hypoglycemia events monitored and reported by the clinics Systematic monitoring, review, and feedback used Monitors within and external to ACCORD Feedback on management and prevention provided; A1C goal relaxed, as indicated Multiple events required detailed review and preventative intervention

Number of Participants with Severe Hypoglycemia   Intensive N (%) Standard P Requiring Any Assistance 830 (16.2) 261 (5.1) <0.001 Requiring Medical Assistance 538 (10.5) 179 (3.5)

Number of Participants With One or More Severe Hypoglycemia Events Requiring Medical Assistance (n and %) Intensive Group Standard Group # Events ** n % 1 400 7.8 130 2.5 2 82 1.6 34 0.7 3 to 5 43 0.8 10 0.2 >5 6 0.1 **Cumulative number of events

Incidence of Severe Hypoglycemia per Year (1st event) % of Participants Year Post-randomization

Conclusion Different Glycemia Treatment Strategies Were Used Compared with the standard group, the intensive group had: Lower A1C goal (< 6% vs. 7 - 7.9%) More visits (q 1-2 mo + at least 1 interim call) Point of care A1C Greater use of multiple medications Greater use of insulin

Conclusion Different Glycemia Treatment Strategies Were Used Implementation of the Intensive Glycemia Strategy versus the Standard Glycemia Strategy was associated with: More weight gain and in larger number of participants More frequent episodes of severe hypoglycemia (either single and multiple) in a larger number of participants Higher rate of mortality