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Silvio E. Inzucchi MD Yale University

4th Annual Optimal Glycemic Control for the Hospitalized Patient Conference Freeport, Maine November 5, 200 9. Inpatient Management of Hyperglycemia. The Swinging Pendulum. Silvio E. Inzucchi MD Yale University. Glycemic Control in the Hospital: An Elusive Goal.

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Silvio E. Inzucchi MD Yale University

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  1. 4th Annual Optimal Glycemic Control for the Hospitalized Patient Conference Freeport, Maine November 5, 2009 Inpatient Management of Hyperglycemia The Swinging Pendulum Silvio E. Inzucchi MD Yale University

  2. Glycemic Control in the Hospital: An Elusive Goal  NutritionMeal interruptionsMonitored complianceInsulin ‘stacking’ Mental status “Stress hyperglycemia”D/C outpatient regimensIV D5/ TPN / PPNSteroids, pressors  Physical activity Fear of hypoglycemia Metchick LN et al. Am J Med 113:317, 2003

  3. Hospital Mortality Rate & Glucose Control in a Medical-Surgical ICU N=1826 ICU patients Mortality Rate (%) Mean Glucose Value During ICU Stay (mg/dL) Krinsley JS. Mayo Clin Proc. 2003;78:1471–1478.

  4. Mean Glucose & In-Hospital Mortality in Patients with AMI (Reference: Mean BG 100-110 mg/dl) N=16,871 Kosiborod M et al. Circulation 2008:117:1018

  5. Hyperglycemia: An Independent Marker of ICU Mortality 31%* 30 20 10 0 ICU Mortality Mortality (%) 11% 10% Normoglycemia Known New Diabetes Hyperglycemia Umpierrez et al. J Clin Endocrinol Metab 87:978, 2002 *P<0.01

  6. ?

  7. Illness leads to Stress Hyperglycemia Illness  Stress hormones • cortisol, epinephrine  Glucose Production + FFAs  Glucose  Fatty Acids  Lipolysis  Glucose Uptake FFAs

  8. Hemodynamic insult Electrolyte losses Oxidative stress Myocardial injury Hypercoagulability Altered immunity  Wound healing  Inflammation  Endothelial function “Stress Hyperglycemia” Exacerbates Illness Illness Illness  Stress hormones • cortisol, epinephrine  Glucose Production + FFAs  Glucose  Fatty Acids  Lipolysis  Glucose Uptake FFAs

  9. Portland CT Surgery DiabetesProject: Insulin Infusion after Cardiac Surgery 2467 diabetic patients admitted for open heart surgery in a single institution between 1/87-11/97 Study group: 1499 patients (9/91-11/97) receiving the Portland Continuous Insulin Infusion protocol. Goal: 151-200 mg/dl immediately post-op x 3 days. Historical controls: 968 patients (1/87-9/91) who received Q4h regular insulin sliding scale “coverage.” Goal: ~200 mg/dl. Furnary AP et al. Ann Thorac Surg 67:352, 1999

  10. The ‘Portland Protocol’: Glucose Control & Sternal Infections 2.0% 19/968 RR = 0.34 (95% CI 0.14-0.74) P=0.01 Deep Wound Infection Rate (%) 19/968 0.8% 12/1948 12/1498 SQI = subcutaneous insulin; CII = continuous insulin infusion. Furnary AP et al. Ann Thorac Surg 67:352, 1999

  11. The ‘Portland Protocol’: Glucose Control & Sternal Infections 4.0 Insulin infusion 3.0 Patients with DM DSWI(%) 2.0 Patients without DM 1.0 0.0 87 88 89 90 91 92 93 94 95 96 97 Year DSWI = deep sternal wound infection; CII = continuous insulin infusion. Furnary AP et al. Ann Thorac Surg 67:352, 1999

  12. The Diabetes Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study 620 DM / AMI patients Insulin-Glucose Infusion x 24-h (Target: 126-196 mg/dl) + Multi-dose insulin injections x 3 mos. Conventional Diabetes Care Malmberg K et al. BMJ 314: 1512-1515, 1997

  13. DIGAMI Study: CVD Mortality Post-AMI .7 .7 All Subjects (N = 620) Subjects at low CV risk and w/ no prior insulin therapy (N = 272) .6 .6 .5 .5 .4 .4 .3 .3 RRR=28% P=.011 RRR=51% P=.0004 .2 .2 .1 .1 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Years of Follow-up Years of Follow-up Standard treatment Intensive management Malmberg K et al. BMJ 314: 1512-1515, 1997

  14. Conventional IV insulin if BG >215 mg/dl Target: 180-200 mg/dl Intensive IV insulin if BG >110 mg/dl Target: 80-110 mg/dl 39% insulin BG=153 mg/dl 99% insulin BG=103 mg/dl Intensive Insulin Therapy in the Surgical ICU: The Leuven Study 1548 SICU patients Primary Outcomes: ICU Mortality Van Den Berghe G et al. N Engl J Med 345:1359, 2001

  15. The Leuven SICU Study Baseline Characteristics CharacteristicConventional Intensive(N=783) (N=765)Male sex 557 (71%) 544 (71%)Age (years) 62 ±14 63 ±14BMI (kg/m2) 25.8 ±4.7 26.2 ±4.4Reason for ICUCardiac surgery 493 (63%) 477 (62%)Non-cardiac 290 (37%) 288 (38%)APACHE score (1st 24˚) 9 (IQR, 7-13) 9 (IQR, 7-13)APACHE >9 458 (58%) 429 (56%)History of DM 103 (13%) 101 (13%)On insulin therapy 33 (4%) 39 (5%)Blood glucose>110 mg/dl 598 (76%) 557 (73%) >200 mg/dl 101 (13%) 81 (11%) Van Den Berghe G et al. N Engl J Med 345:1359, 2001

  16. Intensive Insulin Therapy in the Surgical ICU: The Leuven Study 100 96 92 88 84 80 0 100 96 92 88 84 80 0 Intensive treatment Intensive treatment In-Hospital Survival (%) Survival in ICU (%) Conventional treatment Conventional treatment MORTALITY  42% P<0.04 MORTALITY  34% P<0.01 0 50 100 150 200 250 0 20 40 60 80 100 120 140 160 B Days After Admission A Days After Admission Van Den Berghe G et al. N Engl J Med 345:1359, 2001

  17. Follow-Up Studies • DIGAMI 2 • Group 1 - Intensive* Inpt + Outpt† vs. • Group 2 - Conventional Inpt + Outpt vs. • Group 3 - Intensive Inpt + Conventional Outpt • Methodological flaws (under-recruited; small separation in glucose between groups; lower mortality than expected.) • Results: No significant difference in mortality between groups (Group 1 vs. Group 3: HR=1.09 [0.77-1.54]; P=0.62) * Insulin infusion, target BG 126-180 mg/dl x 24 hrs †MDI, target FPG 90-126 mg/dl Malmberg K et al. Europ Heart J 2005

  18. Follow-Up Studies • LEUVEN 2 • MICU • Insulin infusion: 80-110 mg/dl vs. 180-215 mg/dl • Mean BG: Intensive: 111 mg/dl Conventional: 153 mg/dl • Intent to treat analysis - Hospital mortality: 24.2% vs. 26.8% (P=0.30) • - Morbidities:  ICU & hospital LOS,  ventilator dependence • Predefined ‘long-stayer’ analysis (>3 days in ICU) - Hospital mortality: 31.3% vs. 38.1% (P=0.05) Van den Berghe G et al. N Engl J Med. 2006;354:449-461.

  19. NICE-SUGAR Study • Conventional • IV insulin if BG >180 mg/dl • Target: 140-180 mg/dl Intensive IV insulin if BG >108 mg/dl Target: 81-108 mg/dl 69% insulin BG=144 mg/dl 97% insulin BG=115 mg/dl 6104 ICU* patients Primary Outcome: 90-day mortality * 1/3 surgical, 2/3 medical 20% diabetes Finfer et al. N Engl J Med 2009

  20. NICE-SUGAR: Outcomes 1.0 180 Conventional 160 0.9 140 Conventional Probability of Survival BG, mg/dL 0.8 Intensive 120 108 0.7 Intensive 100 P=.03 0.6 80 0 0 Base-line 10 0 20 30 40 50 60 70 80 90 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Days After Randomization Days After Randomization • 90-day mortality: IIT: 829 patients (27.5%), CIT: 751 (24.9%) • Absolute mortality difference: 2.6%(95% CI, 0.4-4.8) • Odds ratio for death with IIT: 1.14 (95% CI, 1.02-1.28; P=.02) 3054 received IIT goal: 81-108 mg/dL (time weighted BG = 118 mg/dL) 3050 received CIT goal: <180 mg/dL (time-weighted BG = 145 mg/dL) Finfer S, et al. N Engl J Med. 2009;360::1283

  21. Leuven-1 vs. NICE-SUGAR

  22. Intensive Glucose Control in the ICU: RCTs * Mean AM BG [mg/dL] (except for Glucontrol: mean overall BG [mg/dL]; †Intensive group vs. conventional group; §Sepsis patients only; I = Intensive arm; C = Conventional arm; NR = Not reported Inzucchi S, Siegel M. N Engl J Med. 2009;360:1346-1349.

  23. What are the risks of IV insulin? • Hypoglycemia

  24. Intensive Insulin Therapy and Mortality in Critically Ill Patients: A Meta-analysis Hypoglycemic Events Favors IIT Favors Control 0.1 1 10 Griesdale DE, et al. CMAJ. 2009;180:821 Risk Ratio (95% CI)

  25. Mean Glucose & In-Hospital Mortality in Patients with AMI (Reference: Mean BG 100-110 mg/dl) N=16,871 Kosiborod M et al. Circulation 2008:117:1018

  26. Hypoglycemia & Mortality in Insulin-treated vs. Non–Insulin-treated AMI Patients N=7338 no hypo N=482 hypo (BG <60) 20 18.4 Hypoglycemia P<.001 P=.92 No hypoglycemia 10.4 10.2 Mortality, % 9.2 Hypoglycemia was a predictor of higher mortality in patients not treated with insulin, but not in patients treated with insulin 10 0 No Insulin Treatment Insulin Treatment Kosiborod M, et al. JAMA. 2009;301:1556

  27. What are the risks of IV insulin? • Hypoglycemia • Stimulation of sympathetic nervous system • Stroke volume (myocardial 02 demand) • Potassium / phosphate shifts • Mitogenic effects (pro-atherogenic?) • Competing clinical priorities

  28. New AACE-ADA Consensus Statement on Inpatient Glycemic Control Moghissi E et al. Diabetes Care 2009, Endocrine Practice 2009

  29. Successful IV Insulin Protocol • Reaches and maintains BG successfully within a pre-specified target range. • Includes a clear algorithm for making temporary corrective changes in the IV insulin rate, as patient requirements change • Incorporates the ‘rate of change’ in BG, not just the absolute values. • Incorporates the current IV insulin rate. • Minimizes hypoglycemia; provides specific directions for its treatment when it occurs. • Provides specific guidelines for timing and selection of doses for the transition to SQ insulin.

  30. Target BG: 100-140 Begin IV insulin: BG ÷100 = ___ U/hr YALE INSULIN DRIP PROTOCOL STEP 1: Determine the CURRENT BG LEVEL - identifies a COLUMN in the table: STEP 2: Determine the RATE OF CHANGE from the prior BG level - identifies a CELL in the table - Then move right for INSTRUCTIONS: [Note: If the last BG was measured 2-4 hrs before the current BG, calculate the hourly rate of change. Example: If the BG at 2PM was 150 mg/dL and the BG at 4PM is now 120 mg/dL, the total change over 2 hours is -30 mg/dL; however, the hourly change is –30 mg/dL  2 hours = -15 mg/dL/hr.] **D/C INSULIN DRIP; BG q 30 min; when BG  100 mg/dl, restart drip @75% of original rate.

  31. Yale Insulin Infusion Protocol: Initial Results in the ICU Goldberg PA et al. Diabetes Care 2004;27:461

  32. Non-ICU Hospital Management

  33. Hyperglycemia & Patients on General Medical Wards Absolute risk of adverse outcome (death or prolonged stay) increased 15% per 18-mg/dL increase in glucose levels N=433 patients with COPD Exacerbations Mortality (%) Baker EH et al. Thorax. 2006;61:284-289.

  34. New AACE-ADA Consensus Statement on Inpatient Glycemic Control Moghissi E et al. Diabetes Care 2009, Endocrine Practice 2009

  35. Insulin Orders in the Hospital What to do depends on several questions How well is it controlling glucose? When is the patient to eat? Who is the patient? Which is the outpatient regimen? What is the current glucose? Why is the patient admitted? • A1c 6.5%? • A1c 9.5%? • Type 1? • Type 2? • NPO? • Full diet? • Orals? • Insulin? • Combo? • BG=142? • BG=442? • Sepsis? • A-Fib?

  36. “Prandial” Insulin Normal Secretory Pattern of Insulin in Eating Patients Insulin Level “Basal” Insulin S L E E P Breakfast Lunch Dinner

  37. Short (Regular) Intermediate (NPH, Lente) Pharmacokinetic Profiles of Available Insulin Formulations Rapid (Lispro, Aspart, Glulisine) Insulin Level Long (Glargine) Long (Detemir) 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours

  38. “Basal - Bolus” Insulin Therapy Rapid (Lispro, Aspart, Glulisine) Insulin Level Long (Glargine, Detemir) 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours

  39. Regular Insulin “Sliding Scale” (RISS) Therapy Short (Regular) Insulin Level 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours

  40. Basal/Bolus vs. Sliding-Scale Insulin in Non-ICU Hospitalized T2DM Patients • Primary endpoint: differences in the mean daily BG • Mean overall BG difference between the groups during hospital stay was 27 mg/dL (P<0.01) N=130 insulin-naïve medical service pts, BG 140-400 mg/dl Blood Glucose Levels During Insulin Treatment 240 220 * 200 * * * * 180 * Blood Glucose (mg/dL) * Sliding-scale 160 140 Basal/Bolus 120 100 3 4 5 6 7 8 9 10 2 Admit 1 Days of Therapy P<0.05 Adapted from Umpierrez GE et al. Diabetes Care. 2007;30:2181-2186.

  41. DEAN Trial: Changes in Mean Daily Blood Glucose Concentration 240 Detemir + aspart NPH + regular 220 200 N=130 non-surgical pts, BG 140-400 mg/dl P=NS 180 BG, mg/dL 160 140 120 100 Pre-Rx 0 1 2 3 4 5 6-10 Duration of Therapy, d BG Data are means SEM. 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. Adapted with permission from Umpierrez GE, et al. J Clin Endocrinol Metab. 2009;94(2):564-569.

  42. Insulin O A D s Well-controlled, eating pts- Continue home regimen - Consider dose ~25-50% Poorly-controlled pts- Adjust home regimen vs. - Basal-Bolus NPO pts- Type 1: Basal-CorrectionorIV insulin - Type 2: Basal-Correction Well-controlled, eating pts- Continue home regimen - Consider dose ~25-50%- Hold metformin? Poorly-controlled pts- Advance therapy vs. - Initiate insulin NPO pts- RISSBasal-Correction Admission Orders Adjust dose every 1-2 days to achieve BG target. Change strategy if needed. Anticipate the discharge regimen.

  43. Pre-discharge Checklist Diet information 2. Monitor / strips (& Rx) 3. Rx for / supplies of meds, insulin, needles 4. Treatment goals 5. Contact phone numbers 6. “Medi-Alert” bracelet 7. “Survival Skills” training

  44. “Survival Skills” How & when to take meds / insulin How & when to monitor How to treat hypoglycemia Basics regarding meal plan ‘Sick day’ management Date of next appointment How to access outpt. DM education When to call healthcare team

  45. Inpatient Management of Hyperglycemia SUMMARY 1. Hyperglycemia is a frequent occurrence in the hospital, in both patients with and without diabetes. It is also a predictor of adverse outcomes, including mortality. 2. Intensive glucose management in the critical care setting has led to improved outcomes in some single-center studies. Recent multi-center trials have questioned this benefit; one trial even suggested some risk. 3. Taken together, the data would suggest that good (140-180 mg/dl), but not stringent (80-110 mg/dl) glucose control is the most reasonable strategy in the ICU. 4. IV insulin infusion, using a validated protocol to minimize hypoglycemia, is the preferred approach in this setting.

  46. Inpatient Management of Hyperglycemia SUMMARY 5. Much less is known about the effects of tight glycemic control in non-critically ill patients. 6. Specific targets outside of the ICU are not evidence-based. BGs >180 mg/dl should likely be avoided. A pre-meal goal of <140 mg/dl is reasonable and achievable in most patients. 7. Physiological insulin replacement (“basal-bolus”) is an increasingly popular strategy. It is the most flexible approach, but requires a knowledgeable, trained staff. 8. The smooth transition to outpatient care is an important (but often forgotten) feature of quality hospital glucose management.

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