1. Achieving Glycemic Control in the Hospital Setting 143357 (Part 2 of 4)

2. Trial Blood Glucose* Target Primary Outcome NSettingIntensiveConventionalRRR † Van den Berghe 2006 1 1200MICU80-110180-200 Hospital mortality 7.0% ¶ Glucontrol 2007 2 1101ICU80-110140-180 ICU mortality -10% ¶ Gandhi 2007 3 399 Operating Room 80-110<200Composite4.3% ¶ VISEP 2008 4 537ICU80-110180-200 28-Day mortality 5.0% ‡¶ De La Rosa 2008 5 504 SICU MICU 80-110 180-200 28-Day mortality -13% ¶ NICE-SUGAR 2009 6 6104ICU81-108≤180 90-Day mortality -10.6 § *Blood glucose in mg/dL; † RRR=Relative risk reduction, intensive group vs conventional group; ‡ Personal communication; Dr. Frank Brunkhorst; § P.05). 1. Van den Berghe G et al. N Engl J Med. 2006;354(5):449-461; 2. Devos P et al. Intensive Care Med. 2007;33:S189; 3. Gandhi GY et al. Ann Intern Med. 2007;146(4):233-243; 4. Brunkhorst F et al. N Engl J Med. 2008;358(2):125-139; 5. De La Rosa G et al. Crit Care. 2008;12:R120; 6. The NICE-SUGAR Study Investigators et al. N Engl J Med. 2009;360(13):1283-1297. Selected Randomized Controlled Trials of Intensive Glucose Management in Critical Care Studies Showing No Benefit

3. Eligibility: Patients expected to require treatment in the ICU for 3 or more consecutive days NICE-SUGAR Study: Design Multicenter, open-label, randomized, controlled trial Examining the effects of blood glucose management on 90-day, all-cause mortality The 2 groups had similar baseline characteristics 42 Centers in Australia, New Zealand, and Canada Recruitment from December 2004 to November 2008 Last follow-up: November 2008 Conventional control group (target BG: ≤180 mg/dL) n=3054 n=3050 N=6104 The NICE-SUGAR Study Investigators. N Engl J Med. 2009;360(13):1283-1297. Intensive control group (target BG: 81-108 mg/dL)

4. NICE-SUGAR Study Results: Treatment and Glucose Measures Intensive Control Group Conventional Control GroupP Value Patients treated with insulin97.2%69.0%<.001 Median duration of treatment (IQR), days 4.2 (1.9-8.7) 4.3 (2.0-9.0).69 Mean insulin dose, units/day50.2±38.116.9±29.0<.001 Morning BG, mg/dL118±25145±26<.001 Time-weighted BG, mg/dL115±18144±23<.001 No. of patients with hypoglycemia (BG ≤40 mg/dL)/ total no. (%) 206/3016 (6.8%) 15/3014 (0.5%) <.001 IQR=interquartile range. The NICE-SUGAR Study Investigators. N Engl J Med. 2009;360(13):1283-1297.

5. NICE-SUGAR Study: Outcomes Outcome Measure Intensive Control Group Conventional Control GroupP Value 28-Day mortality22.3%20.8%.17 90-Day mortality27.5%24.9%.02 Mech. ventilation (Mean days + SD) 96% (6.6±6.6) 95.3% (6.6±6.5).17 (.56) Dialysis15.4%14.5%.34 Bloodstream infections12.8%12.4%.57 The NICE-SUGAR Study Investigators. N Engl J Med. 2009;360(13):1283-1297.

6. NICE-SUGAR Study: Trial Limitations Subjects eligible for inclusion were defined by a subjective rather than an objective criterion, which was the expected time in the ICU Medical staff and study personnel were not blinded to treatment arms Several patients in the intensive-control group had glucose levels above the target range Data regarding potential biological mechanisms underlying the observed outcomes in the intervention groups were not collected Data regarding the costs of the trial interventions were not collected The NICE-SUGAR Study Investigators. N Engl J Med. 2009;360(13):1283-1297.

7. NICE-SUGAR Study: Conclusions This large, international, randomized trial found that intensive glucose control did not offer benefits to critically ill patients 1 Blood glucose target of <180 mg/dL with the achieved target of 144 mg/dL resulted in lower (90-day) mortality than did a target of 81-108 mg/dL 1 Increased hypoglycemic events were observed with lower glucose targets 1 ADA and AACE position: good glucose management, through establishing patient-specific glycemic targets and individualizing care, are important objectives for patients in the hospital setting 2 1. The NICE-SUGAR Study Investigators. N Engl J Med. 2009;360(13):1283-1297. 2. Joint statement from the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) on the NICE-SUGAR study on intensive versus conventional glucose control in critically ill patients. American Diabetes Association Web site. http://www.diabetes.org/for-media/2009/joint-statement-from-ada-and.html. Accessed December 17, 2009.

8. How Have These Data Changed Management Paradigms?

9. Guidelines for Glycemic Control in Hospitalized Patients With initiation of insulin therapy, maintain between 140 and 180 mg/dL; potential for better therapeutic outcomes at the lower range 1 Somewhat lower targets might be recommended for selected patients, but targets <110 mg/dL are not recommended 1 Prolonged treatment with sliding-scale insulin as the sole regimen is discouraged 1 Consideration should be given to minimizing the risk of hypogylcemia (a never event), which is associated with adverse short- and long-term outcomes among inpatients 1,2 1. Moghissi ES et al. Endocr Pract. 2009;15(4):353-369; 2. Eliminating serious, preventable, and costly medical errors—never events [news release]. Centers for Medicare & Medicaid Services. http://www.cms.hhs.gov/apps/media/press/release.asp?Counter=1863. Accessed December 17, 2009. Intensive Care Unit BG≤180 mg/dL

10. Guidelines for Glycemic Control in Hospitalized Patients (cont’d) Reassess treatment regimen if BG <100 mg/dL Modify treatment if BG <70 mg/dL, unless caused by other known factors (eg, missed meal) Stable patients with successful prior history of tight glycemic control in outpatient setting might be good candidates for lower ranges Higher ranges might be appropriate for certain patients* * Patients who are terminally ill, patients with severe comorbidities, and patients in care settings where frequent BG monitoring is not possible. Moghissi ES et al. Endocr Pract. 2009;15(4):353-369. Noncritical Care Preprandial: <140 mg/dL Random: <180 mg/dL