The document outlines clinical guidelines for managing hyperglycemia in hospitalized patients, focusing on non-critical care settings. It highlights the prevalence of hyperglycemia among patients, diagnostic criteria, and the association between hyperglycemia and clinical outcomes, emphasizing the importance of appropriate management strategies. Recommendations include the use of HbA1c testing, target glucose levels, and insulin regimens for effective glycemic control in hospitalized patients.

1. Clinical Guidelines for the Management of Hyperglycemia in Hospitalized Patients in a Non-Critical Care Setting Work in Progress The Endocrine Society, European Endo Society, American Heart Association, American Diabetes Association, Society of Hospitalist Medicine, American Association of Diabetes Educators

2. Inpatient Hyperglycemia in non-critical care setting What is the frequency of hyperglycemia and diabetes? What diagnosis criteria should we use? What is the association between hyperglycemia and outcomes? How should we manage hyperglycemia in non-ICU setting?

3. Hyperglycemia: Scope of the Problem Kosiborod M, et al. J Am Coll Cardiol. 2007;49(9):1018-183:283A-284A. No Diabetes 26% Diabetes 50 40 30 20 10 0 <110 110-140 50 40 30 20 10 0 <110 110-140 140-170 170-200 >200 78% 140-170 170-200 >200 Mean BG, mg/dL Patients, %

4. Hyperglycemia*: A Common Comorbidity in Medical-Surgical Patients in a Community Hospital 62% 12% 26% Normoglycemia Known Diabetes New Hyperglycemia Umpierrez G et al, J Clin Endocrinol Metabol 87:978, 2002 n = 2,020 * Hyperglycemia: Fasting BG  126 mg/dl or Random BG  200 mg/dl X 2

5. New and Stress hyperglycemia Patients with hyperglycemia without a previous history of diabetes should be tested with a hemoglobin A1C during the hospital stay or with an oral glucose tolerance test after discharge to confirm the diagnosis of diabetes. Less than 35% of patients had normal glucose tolerance after 3 to 12 months of follow-up. Norhammar et al. Lancet 2002; 359(9324): 2140-4. Arora et al. Endocr Pract 2009; 15(5): 425-30. Greci et al. Diabetes Care 2003; 26(4): 1064-8.

6. IGT and Undiagnosed T2DM are Common in Acute MI and Stroke Norhammar A, et al. Lancet 2002;359:2140−4. Matz K, et al. Diabetes Care 2006;792−7. 2-hour OGTT 70 60 50 40 30 20 10 0 Norhammar (n=181) Matz (n=238) Patients (%) 66 39 Myocardial infarction Stroke IGT Undiagnosed T2DM 35 23 31 16

7. Epidemiology of Inpatient Hyperglycemia in non-critical care setting What is the frequency of hyperglycemia and diabetes? What diagnosis criteria should we use? What is the association between hyperglycemia and outcomes? How should we manage hyperglycemia in non-ICU setting?

8. ADA 2010 - Categories of Increased Risk for Diabetes* ADA Clinical Practice Recommendations, January 2019 NORMAL IFG or IGT PREDIABETES DIABETES FPG < 100 mg/dl FPG > 100 - 125 mg/dl (IFG) FPG > 126 mg/dl 2-h PG < 140 mg/dl 2-h PG > 140 - 199 mg/dl (IGT) 2-h PG > 200 mg Random PG > 200 + symptoms A1C 5.7% to 6.4% ≥ 6.5%

9. A1C for Diagnosis of Diabetes in the Hospital Inhospital hyperglycemia is defined as an admission or inhospital BG > greater 140 mg/dl. HbA1c > 6.5% can be identified as having diabetes, and patients with A1C 5.7%-6.4% can be considered as being at risk for diabetes. Implementation of A1C testing can be useful: assess glycemic control prior to admission assist with differentiation of newly diagnosed diabetes from stress hyperglycemia designing an optimal regimen at the time of discharge

10. Comparison of sensitivity and specificity achieved for the diagnosis of diabetes based on FPG, at various levels of HbA1c, from NHANES III and 1999–2004 NHANES J Clin Endocrinol Metab, July 2008, 93(7):2447–2453

11. Factors influencing A1c

12. Epidemiology of Inpatient Hyperglycemia in non-critical care setting What is the frequency of hyperglycemia and diabetes? What diagnosis criteria should we use? What is the association between hyperglycemia and outcomes? How should we manage hyperglycemia in non-ICU setting?

13. Hyperglycemia and Pneumonia Outcomes BG (mg/dl) < 110 110 - <198 198 - <250 ≥ 250 * * * * * p: < 0.05 vs BG < 198 mg/dl (11 mmol/L) Admission glucose (mg/dl) % McAllister et al, Diabetes Crae 28:810-815, 2005 N= 2,471 patients with CAP

14. Community Acquired Pneumonia Outcomes in Patients with Diabetes % Hospitalization Mortality Pleural Effusion Concomitant Illnesses P: < 0.001 N= 660 (DM: 106 & non-DM: 554) No differences in microorganisms and bacteremia rates Falguera et al, Chest 128:3233-3239, 2005 * * * * 93 8 17 78 31 18 53 40 * Diabetes No Diabetes

15. A case control study of 108,593 patients who underwent noncardiac surgery. *Odds ratio for perioperative mortality is 1.19 (95% CI 1.1–1.3) per mmol/l increase of glucose level

16. Thirty Day Mortality and Inhospital Complications in diabetic and non-diabetic subjects † p = 0.1 * p= 0.001 #p=0.017 † * * * * # * % A Frisch et al. Diabetes Care, May 2010

17. Hyperglycemia and mortality Mean POSTSURGERY blood glucose and ODDS RATIOS for 30 day mortality in diabetic and non diabetic patients A Frisch et al. Diabetes 58 (suppl 1) A27, 2009

18. Hyperglycemia: An Independent Marker of In-Hospital Mortality in Patients with Undiagnosed Diabetes Total In-patient Mortality Normoglycemia Known New Diabetes Hyperglycemia 1.7% 3.0% 16.0% * Mortality (%) * P < 0.01 Umpierrez GE et al, J Clin Endocrinol Metabol 87:978, 2002

19. AACE/ADA Target Glucose Levels in Non – ICU Patients Glucose Target in non – ICU setting: Premeal glucose targets <140 mg/dL Random BG <180 mg/dL To avoid hypoglycemia, reassess insulin regimen if BG levels fall below 100 mg/dL Occasional patients may be maintained with a glucose range below and/or above these cut-points Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009;15(4). http://www.aace.com/pub/pdf/guidelines/InpatientGlycemicControlConsensusStatement.pdf

20. Epidemiology of Inpatient Hyperglycemia in non-critical care setting What is the frequency of hyperglycemia and diabetes? What diagnosis criteria should we use? What is the association between hyperglycemia and outcomes? How should we manage hyperglycemia in non-ICU setting?

21. ACE/ADA Task Force on Inpatient Diabetes. Diabetes Care. 2006 & 2009 Diabetes Care. 2009;31(suppl 1):S1-S110.. Antihyperglycemic Therapy Insulin Recommended OADs Not Generally Recommended IV Insulin Critically ill patients in the ICU SC Insulin Non-critically ill patients Recommendations for Managing Patients With Diabetes in the Hospital Setting

22. AACE/ADA Consensus Statement Non-insulin therapies in the hospital? Sulfonylureas are a major cause of hypoglycemia Metformin contraindicated in setting of decrease renal blood flow and with use of iodinated contrast dye Thiazolidinediones associated with edema and CHF α glucosidase inhibitors are weak glucose lowering agents Pramlintide and GLP1-directed therapies can cause nausea and have a greater effect on postprandial glucose Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009

23. Management of Hyperglycemia and Diabetes in non-ICU Setting Non-ICU Sliding Scale Short-Acting Insulin Basal/bolus therapy (MDI) NPH and Regular insulin Long-acting and rapid-acting insulin Premix insulin

24. Study Type: Prospective, multicenter, randomized, open-label trial Patient Population : 130 subjects with DM2 Diet and/or oral hypoglycemic agents Umpierrez et al, Diabetes Care 30:2181–2186, 2007

25. D/C oral antidiabetic drugs on admission Starting total daily dose (TDD): 0.4 U/kg/d x BG between 140-200 mg/dL 0.5 U/kg/d x BG between 201-400 mg/dL Half of TDD as insulin glargine and half as rapid-acting insulin (lispro, aspart, glulisine) Insulin glargine - once daily, at the same time/day. Rapid-acting insulin- three equally divided doses (AC) Ra ndomized B asal B olus versus Sliding Scale Regular I nsulin in patients with t ype 2 Diabetes Mellitus (RABBIT-2 Trial) Umpierrez et al, Diabetes Care 30:2181–2186, 2007

26. Umpierrez GE et al. Diabetes Care . 2007;30:2181-2186. Before meal: Supplemental Sliding Scale Insulin (number of units) Add to scheduled insulin dose Bedtime: Give half of Supplemental Sliding Scale Insulin Sliding Scale Insulin Regimen Blood Glucose (mg/dL) Insulin Sensitive Usual Insulin Resistant >141-180 2 4 6 181-220 4 6 8 221-260 6 8 10 261-300 8 10 12 301-350 10 12 14 351-400 12 14 16 >400 14 16 18

27. Rabbit 2 Trial: Changes in Glucose Levels With Basal-Bolus vs. Sliding Scale Insulin Umpierrez GE, et al. Diabetes Care . 2007;30(9):2181-2186. Days of Therapy BG, mg/dL 100 120 140 160 180 200 220 240 Admit 1 Sliding-scale Basal-bolus b P< .05. a a a b b b b 2 3 4 5 6 7 8 9 10 a P< .05. Sliding scale regular insulin (SSRI) was given 4 times daily Basal-bolus regimen: glargine was given once daily; glulisine was given before meals. 0.4 U/kg/d x BG between 140-200 mg/dL 0.5 U/kg/d x BG between 201-400 mg/dL

28. Persistent hyperglycemia (BG>240 mg/dl) is common (15%) during SSI therapy Hypoglycemia rate: Days of Therapy BG, mg/dL 100 120 140 160 180 200 220 240 Admit 1 Sliding-scale Basal-bolus 260 280 300 3 3 4 5 6 7 2 4 2 1 Rabbit 2 Trial: Treatment Success With Basal-Bolus vs. Sliding Scale Insulin Basal Bolus Group: BG < 60 mg/dL: 3% BG < 40 mg/dL: none SSRI: BG < 60 mg/dL: 3% BG < 40 mg/dL: none Umpierrez GE, et al. Diabetes Care . 2007;30(9):2181-2186.

29. Study Type: Prospective, randomized, open-label trial Patient Population : 130 subjects with DM2 Oral hypoglycemic agents or insulin therapy Study Sites : Grady Memorial Hospital, Atlanta, GA Rush University Medical Center , Chicago, IL Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009

30. Detemir–Aspart Insulin Regimen D/C oral antidiabetic drugs on admission Starting total daily dose (TDD): 0.4 U/kg/d x BG between 140-200 mg/dL 0.5 U/kg/d x BG between 201-400 mg/dL Half of TDD as insulin detemir and half as aspart Insulin detemir - once daily, at the same time of the day. Insulin aspart - three equally divided doses (AC) Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009

31. NPH–Regular Split-Mixed Regimen D/C oral antidiabetic drugs on admission Starting total daily dose (TDD): 0.4 U/kg/d x BG between 140-200 mg/dL 0.5 U/kg/d x BG between 201-400 mg/dL Three-fifth of TDD as insulin NPH and two-fifth as regular NPH insulin– twice daily, 2/3 before breakfast, 1/3 before dinner Regular insulin- twice daily, 2/3 before breakfast, 1/3 before dinner Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009

32. DEAN Trial: Changes in Mean Daily Blood Glucose Concentration BG, mg/dL Duration of Therapy, d Data are means  SEM. Detemir + aspart NPH + regular Basal-bolus regimen: detemir was given once daily; aspart was given before meals. NPH/regular regimen: NPH and regular insulin were given twice daily, two thirds in AM, one third in PM. Umpierrez GE, et al. J Clin Endocrinol Metab . 2009;94(2):564-569. P =NS 100 120 140 160 180 200 220 240 Pre-Rx BG 0 1 2 3 4 5 6-10

33. Blood glucose (mg/dL) Detemir + Novolog NPH + Regular DEAN-Trial

34. NPH/Regular BG < 40 mg/dl: 1.6% BG < 60 mg/dl: 25.4% Detemir/Aspart BG < 40 mg/dl: 4.5% BG < 40 mg/dl: 32.8% Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009 DEAN Trial: Hypoglycemia To determine risk factors for hypoglycemic events during SC insulin therapy

35. *p-values are from Wilcoxon Two-Sample Test Summary of Univariate Analyses Umpierrez et al, ADA Scientific Meeting, Poster #516, 2009 p-value * variable BG < 60 mg/dl BG < 70 mg/dl AGE 0.036 0.001 wt 0.027 0.001 A1C 0.521 0.658 Creatinine 0.011 0.002 Enrollment BG 0.166 0.319 Previous treatment 0.005 <.001 Previous insulin Rx <0.001 <.001 Treatment group <0.001 <.001

36. RAndomized Study of Basal Bolus Insulin Therapy in the Inpatient Management of Patients with Type 2 Diabetes Undergoing General Surgery: RABBIT Surgery Trial Guillermo E Umpierrez, Dawn Smiley, Sol Jacobs, Limin Peng, Angel Temponi, Christopher Newton, Denise Umpierrez, Patrick Mulligan, Darin Olson, Jana MacLeod, Monica Rizzo. Umpierrez et al, Preliminary data- ADA Scientific Session 2010

37. Research Design and Methods Study Type: Multi-center, prospective, open-label randomized clinical trial Patient Population: Patients with type 2 DM admitted to general surgery services Study Sites: Grady Memorial Hospital, Veterans Affairs Medical Center and Emory University Hospital, Atlanta, GA Treatment Groups: Group 1: basal/bolus regimen with glargine once daily and glulisine before meals Group 2: sliding scale regular insulin (SSRI) four times daily Umpierrez et al, Preliminary data- Abstract submitted to ADA Scientific Session 2010

38. Primary outcome: Differences between groups in mean daily BG concentration Composite of hospital complications including: postoperative wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Secondary outcome: Differences between groups in any of the following measures: Mean fasting and pre-meal BG, number of hypoglycemic (BG < 70 mg/dL and < 40 mg/dL) and hyperglycemic (BG > 200 mg/dL) events , length of hospital stay, need for ICU care, and rate of complications including wound infection, pneumonia, acute renal failure, and mortality.

39. RABBIT SURGERY TRIAL 211 Patients with type 2 DM that underwent general surgery Glargine + Glulisine (Gla+Glu) N= 104 Group 1: 0.5 U/kg Half as glargine once daily Half as glulisine before meals Sliding scale insulin (SSRI) N= 107 OPEN - LABELED RANDOMIZATION Group 2: 4 times/day for BG >140 mg/dl

40. RABBIT 2 SURGERY Umpierrez et al, Preliminary data- Abstract to be submitted_ADA Scientific Session 2010

41. Rabbit Surgery Trial Glucose levels during Basal Bolus and SSRI Therapy * p<0.001 † p: 0.01 ŧ p: 0.02 SSI GLA+GLU

42. Glucose levels Before meals and Bedtime SSI Basal Bolus

43. Differences in BG Concentration Within Target During Hospital Stay and After 24 Hours of Treatment

44. Hospital Complications: Primary outcome

45. Umpierrez et al, Preliminary data- Abstract to be submitted_ADA Scientific Session 2010 Hypoglycemic Events

46. Treatment with glargine once daily plus glulisine before meals improved glycemic control and reduced hospital complications compared to SSRI in general surgery patients with T2DM. Our study indicates that basal/bolus insulin regimen is the preferred insulin regimen in the hospital management of general surgery patients with type 2 diabetes. Summary & Conclusion RABBIT 2 SURGERY

47. Management Recommendations All patients with T1DM must receive insulin treatment with basal bolus, multi-dose insulin combination of NPH plus regular insulin or continuous insulin pump. Patients treated with insulin at home should be continued with insulin therapy in the hospital. Scheduled subcutaneous basal bolus insulin regimen is preferred for the majority of non-critically ill patients with hyperglycemia. The practice of using sliding scale insulin (SSI) as a single form of therapy is undesirable.

48. Strategies for Preventing Hypoglycemia In-service training on new treatment modalities and the actions of new antihyperglycemic agents Braithwaite SS, et al. Endocr Pract. 2004;10(suppl 2):89-99. Reducing outpatient insulin dose in patients treated with insulin prior to admission Basal Bolus is preferred over SSRI and NPH/regular combination

49. D/C oral antidiabetic drugs on admission Starting total daily dose (TDD): 0.3 U/kg/d in elderly and renal failure (lean?) 0.4 U/kg/d x BG between 140-200 mg/dL 0.5 U/kg/d x BG between 201-400 mg/dL Half of TDD as insulin glargine and half as rapid-acting insulin (lispro, aspart, glulisine) Decrease outpatient insulin dose by 20-25% Basal Bolus Insulin Regimen in T2DM: Summary Umpierrez et al, Diabetes Care 2007; JCEM 2009; Diabetes 2010

50. Rabbit Surgery Trial Glucose levels during Basal Bolus and SSRI Therapy * p<0.001 † p: 0.01 ŧ p: 0.02 Mainly Basal (Glargine) Insulin

51. 4:00 16:00 20:00 24:00 4:00 8:00 12:00 8:00 Time Glargine once daily 0.25 U/kg Basal-PLUS Insulin Regimen Insulin Action Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy . New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342 Aspart, Lispro or Apidra before meals per sliding scale

52. A1C < 7% Re-start outpatient treatment regimen (OAD and/or insulin) A1C 7%-9% Re-start outpatient oral agents and D/C on glargine once daily at 50-80% of hospital dose A1C >9% D/C on basal bolus at same hospital dose. Alternative: re-start oral agents and D/C on glargine once daily at 50-80% of hospital dose Discharge insulin Algorithm Discharge Treatment

53. Needed Research Studies What is the role of medical nutrition therapy in non-critical care setting? How should glycemia be monitored in non-critical care setting? How should hyperglycemia be managed across transitions in care? What are the best predictors of hypoglycemia? What is the financial impact of glycemic control in non-critical care areas?