CLINICAL EVIDENCE FOR GLUCOSE CONTROL IN THE INPATIENT SETTING

1. CLINICAL EVIDENCE FOR GLUCOSE CONTROL IN THE INPATIENT SETTING First RCT- landmark paper that was the bases for previous guidelines.First RCT- landmark paper that was the bases for previous guidelines.

2. Number of US Hospital Discharges with Diabetes as Any-Listed Diagnosis

3. Hyperglycemia and Mortalityin the Medical Intensive Care Unit

4. Mortality Increases with Increases in Average BG Levels One of the true pioneers in this field has been Dr. Anthony Furnary, a cardiovascular surgeon in Portland, Oregon, who is responsible for the Portland Diabetic Project. He has been documenting a cohort of thousands of patients since the early 1990s and has been treating his diabetic cardiovascular surgery patients with continuous IV insulin since 1992. Diabetes is a risk factor for death after coronary artery bypass grafting (CABG). Its relative risk may be related to the level of perioperative hyperglycemia. The Portland Diabetic Project has demonstrated that continuous insulin infusions can reduce in-hospital mortality after CABG associated with diabetes. Mortality Increases with Increases in Average BG Levels One of the true pioneers in this field has been Dr. Anthony Furnary, a cardiovascular surgeon in Portland, Oregon, who is responsible for the Portland Diabetic Project. He has been documenting a cohort of thousands of patients since the early 1990s and has been treating his diabetic cardiovascular surgery patients with continuous IV insulin since 1992. Diabetes is a risk factor for death after coronary artery bypass grafting (CABG). Its relative risk may be related to the level of perioperative hyperglycemia. The Portland Diabetic Project has demonstrated that continuous insulin infusions can reduce in-hospital mortality after CABG associated with diabetes.

5. Hyperglycemia and Mortality in 259,040 Critically Ill Patients SETTING:: 173 U.S. medical, surgical, and cardiac intensive care units. PATIENTS:: 259,040 admissions from October 2002 to September 2005; unadjusted mortality rate, 11.2%. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: A two-level logistic regression model determined the relationship between glycemia and mortality. Age, diagnosis, comorbidities, and laboratory variables were used to calculate a predicted mortality rate, which was then analyzed with mean glucose to determine the association of hyperglycemia with hospital mortality. Hyperglycemia was associated with increased mortality independent of illness severity. Compared with normoglycemic individuals (70-110 mg/dL), adjusted odds of mortality (odds ratio, [95% confidence interval]) for mean glucose 111-145, 146-199, 200-300, and >300 mg/dL was 1.31(1.26-1.36), 1.82(1.74-1.90), 2.13(2.03-2.25), and 2.85(2.58-3.14), respectively. Furthermore, the adjusted odds of mortality related to hyperglycemia varied with admission diagnosis, demonstrating a clear association in some patients (acute myocardial infarction, arrhythmia, unstable angina, pulmonary embolism) and little or no association in others. Hyperglycemia was associated with increased mortality independent of intensive care unit type, length of stay, and diabetes. SETTING:: 173 U.S. medical, surgical, and cardiac intensive care units. PATIENTS:: 259,040 admissions from October 2002 to September 2005; unadjusted mortality rate, 11.2%. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: A two-level logistic regression model determined the relationship between glycemia and mortality. Age, diagnosis, comorbidities, and laboratory variables were used to calculate a predicted mortality rate, which was then analyzed with mean glucose to determine the association of hyperglycemia with hospital mortality. Hyperglycemia was associated with increased mortality independent of illness severity. Compared with normoglycemic individuals (70-110 mg/dL), adjusted odds of mortality (odds ratio, [95% confidence interval]) for mean glucose 111-145, 146-199, 200-300, and >300 mg/dL was 1.31(1.26-1.36), 1.82(1.74-1.90), 2.13(2.03-2.25), and 2.85(2.58-3.14), respectively. Furthermore, the adjusted odds of mortality related to hyperglycemia varied with admission diagnosis, demonstrating a clear association in some patients (acute myocardial infarction, arrhythmia, unstable angina, pulmonary embolism) and little or no association in others. Hyperglycemia was associated with increased mortality independent of intensive care unit type, length of stay, and diabetes.

6. Hyperglycemia is Associated With Increased Risk-Adjusted Mortality

7. Mortality Risk is Greater in Hyperglycemic Patients Without History of Diabetes SETTING:: 173 U.S. medical, surgical, and cardiac intensive care units. PATIENTS:: 259,040 admissions from October 2002 to September 2005; unadjusted mortality rate, 11.2%. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: A two-level logistic regression model determined the relationship between glycemia and mortality. Age, diagnosis, comorbidities, and laboratory variables were used to calculate a predicted mortality rate, which was then analyzed with mean glucose to determine the association of hyperglycemia with hospital mortality. Hyperglycemia was associated with increased mortality independent of illness severity. Compared with normoglycemic individuals (70-110 mg/dL), adjusted odds of mortality (odds ratio, [95% confidence interval]) for mean glucose 111-145, 146-199, 200-300, and >300 mg/dL was 1.31(1.26-1.36), 1.82(1.74-1.90), 2.13(2.03-2.25), and 2.85(2.58-3.14), respectively. Furthermore, the adjusted odds of mortality related to hyperglycemia varied with admission diagnosis, demonstrating a clear association in some patients (acute myocardial infarction, arrhythmia, unstable angina, pulmonary embolism) and little or no association in others. Hyperglycemia was associated with increased mortality independent of intensive care unit type, length of stay, and diabetes. SETTING:: 173 U.S. medical, surgical, and cardiac intensive care units. PATIENTS:: 259,040 admissions from October 2002 to September 2005; unadjusted mortality rate, 11.2%. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: A two-level logistic regression model determined the relationship between glycemia and mortality. Age, diagnosis, comorbidities, and laboratory variables were used to calculate a predicted mortality rate, which was then analyzed with mean glucose to determine the association of hyperglycemia with hospital mortality. Hyperglycemia was associated with increased mortality independent of illness severity. Compared with normoglycemic individuals (70-110 mg/dL), adjusted odds of mortality (odds ratio, [95% confidence interval]) for mean glucose 111-145, 146-199, 200-300, and >300 mg/dL was 1.31(1.26-1.36), 1.82(1.74-1.90), 2.13(2.03-2.25), and 2.85(2.58-3.14), respectively. Furthermore, the adjusted odds of mortality related to hyperglycemia varied with admission diagnosis, demonstrating a clear association in some patients (acute myocardial infarction, arrhythmia, unstable angina, pulmonary embolism) and little or no association in others. Hyperglycemia was associated with increased mortality independent of intensive care unit type, length of stay, and diabetes.

8. Hyperglycemia is Linked to Mortality Regardless of Diabetes Status Hyperglycemia, Not Diabetes per se, Affects Mortality It appears that (acute) hyperglycemia may be a more important predictor of adverse outcome than is a diagnosis of diabetes, a situation of chronic hyperglycemia. RegardLess of diabetes status, patients with glucose levels of =200 mg/dL were at greater risk for mortality at 180 days (bars on right)Hyperglycemia, Not Diabetes per se, Affects Mortality It appears that (acute) hyperglycemia may be a more important predictor of adverse outcome than is a diagnosis of diabetes, a situation of chronic hyperglycemia. RegardLess of diabetes status, patients with glucose levels of =200 mg/dL were at greater risk for mortality at 180 days (bars on right)

9. Mortality in Inpatients with �New Hyperglycemia� Hyperglycemia Is an Independent Marker of Inpatient Mortality in Patients With Undiagnosed Diabetes New hyperglycemia was defined as an admission or in-hospital fasting glucose level of 126 mg/dL (7 mmol/L) or more or a random blood glucose level of 200 mg/dL (11.1 mmol/L) or more on 2 or more determinations. Hyperglycemia was present in 38% of patients admitted to the hospital, of whom 26% had a known history of diabetes, and 12% had no history of diabetes before admission. Newly discovered hyperglycemia was associated with a higher in-hospital mortality rate (16%) compared with patients with a history of diabetes (3%) and patients with normoglycemia (1.7%; both P < 0.01). In addition, new hyperglycemic patients had longer hospital stays and a higher admission rate to an intensive care unit, and were less likely to be discharged to home, frequently requiring transfer to a transitional care unit or nursing home facility. The results indicate that in-hospital hyperglycemia is a common finding and represents an important marker of poor clinical outcome and mortality in patients with and without a history of diabetes. Patients with newly diagnosed hyperglycemia had a significantly higher mortality rate and a lower functional outcome than patients with a known history of diabetes or normoglycemia. 1. Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87:978�982. Hyperglycemia Is an Independent Marker of Inpatient Mortality in Patients With Undiagnosed Diabetes New hyperglycemia was defined as an admission or in-hospital fasting glucose level of 126 mg/dL (7 mmol/L) or more or a random blood glucose level of 200 mg/dL (11.1 mmol/L) or more on 2 or more determinations. Hyperglycemia was present in 38% of patients admitted to the hospital, of whom 26% had a known history of diabetes, and 12% had no history of diabetes before admission. Newly discovered hyperglycemia was associated with a higher in-hospital mortality rate (16%) compared with patients with a history of diabetes (3%) and patients with normoglycemia (1.7%; both P < 0.01). In addition, new hyperglycemic patients had longer hospital stays and a higher admission rate to an intensive care unit, and were less likely to be discharged to home, frequently requiring transfer to a transitional care unit or nursing home facility. The results indicate that in-hospital hyperglycemia is a common finding and represents an important marker of poor clinical outcome and mortality in patients with and without a history of diabetes. Patients with newly diagnosed hyperglycemia had a significantly higher mortality rate and a lower functional outcome than patients with a known history of diabetes or normoglycemia. 1. Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87:978�982.

10. Admission Hyperglycemia Is Also AssociatedWith Adverse Outcomes in Non-ICU Settings Admission Hyperglycemia is Associated with Adverse Outcomes in Patients Admitted to Non-Intensive Care Settings Similar findings have been reported in patients with community-acquired pneumonia; ie, increased mortality and increasing complications with increasing BG levels. Hyperglycemia on admission was independently associated with adverse outcomes in patients with community-acquired pneumonia. These increased risks were evident at lower glucose levels than previously reported. Admission Hyperglycemia is Associated with Adverse Outcomes in Patients Admitted to Non-Intensive Care Settings Similar findings have been reported in patients with community-acquired pneumonia; ie, increased mortality and increasing complications with increasing BG levels. Hyperglycemia on admission was independently associated with adverse outcomes in patients with community-acquired pneumonia. These increased risks were evident at lower glucose levels than previously reported.

12. Benefits of Tight Glycemic Control: Observational Studies and EarlyIntervention Trials Summary of early trials � most of them non-RCTSummary of early trials � most of them non-RCT

13. Portland Diabetic Project Incidence of DSWI and Impact of Implementation of Insulin Infusion Protocols; 1987-1997 Portland Diabetic Project: Incidence of DSWI and Impact of Implementation of Insulin Infusion Protocols The Portland Diabetic Project is a prospective, nonrandomized, interventional research study of the effects of hyperglycemia and the effect of pharmacologic management on patients in reducing adverse outcomes associated with cardiac surgical procedures in patients with diabetes. Data presented here are from 2,467 consecutive patients who were treated with either sliding-scale subcutaneous insulin or a continuous insulin infusion. The glycemic target was < 200 mg/dL. There was a significant downward trend (p = 0.03) in the incidence of deep sternal wound infection rate after the implementation of a continuous insulin infusion protocol in patients with diabetes undergoing open heart surgical procedures. 1. Furnary AP, Zerr KJ, Grunkemeier GL, et al. Continuous intravenous insulin infusion reduces the need for deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg. 1999;67:352�362. Portland Diabetic Project: Incidence of DSWI and Impact of Implementation of Insulin Infusion Protocols The Portland Diabetic Project is a prospective, nonrandomized, interventional research study of the effects of hyperglycemia and the effect of pharmacologic management on patients in reducing adverse outcomes associated with cardiac surgical procedures in patients with diabetes. Data presented here are from 2,467 consecutive patients who were treated with either sliding-scale subcutaneous insulin or a continuous insulin infusion. The glycemic target was < 200 mg/dL. There was a significant downward trend (p = 0.03) in the incidence of deep sternal wound infection rate after the implementation of a continuous insulin infusion protocol in patients with diabetes undergoing open heart surgical procedures. 1. Furnary AP, Zerr KJ, Grunkemeier GL, et al. Continuous intravenous insulin infusion reduces the need for deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg. 1999;67:352�362.

14. Glucose Control with IV Insulin Lowers Mortality Risk After Cardiac Surgery Portland Diabetic Project: Mortality This slide shows Dr. Furnary�s mortality data and how, as his glycemic target has been ratcheted lower over the years, the risk of mortality decreases significantly among patients with diabetes. All patients with diabetes undergoing CABG (N = 3554) were treated aggressively with either SC insulin (1987�1991) or continuous insulin infusion (1992�2001) for hyperglycemia. (This was a nonrandomized, prospective study.) Observed mortality and glucose control were both significantly better with continuous insulin infusion than with SC insulin therapy. Continuous insulin infusion independently reduced perioperative absolute mortality by 57% and risk-adjusted mortality by 50%. Improved survival was attributed to a reduction in cardiac-related deaths. Portland Diabetic Project: Mortality This slide shows Dr. Furnary�s mortality data and how, as his glycemic target has been ratcheted lower over the years, the risk of mortality decreases significantly among patients with diabetes. All patients with diabetes undergoing CABG (N = 3554) were treated aggressively with either SC insulin (1987�1991) or continuous insulin infusion (1992�2001) for hyperglycemia. (This was a nonrandomized, prospective study.) Observed mortality and glucose control were both significantly better with continuous insulin infusion than with SC insulin therapy. Continuous insulin infusion independently reduced perioperative absolute mortality by 57% and risk-adjusted mortality by 50%. Improved survival was attributed to a reduction in cardiac-related deaths.

15. Intensive Insulin Managementin Medical-Surgical ICU Non-RCT� Intensive Insulin Management in Medical-Surgical ICU Continuous IV insulin was used if glucose values exceeded 200 mg/dL on 2 successive occasions. This protocol resulted in significantly improved glycemic control and was associated with decreased mortality and with no significant increase in nursing requirements.Non-RCT� Intensive Insulin Management in Medical-Surgical ICU Continuous IV insulin was used if glucose values exceeded 200 mg/dL on 2 successive occasions. This protocol resulted in significantly improved glycemic control and was associated with decreased mortality and with no significant increase in nursing requirements.

17. Intensive Insulin Therapy in Critically Ill Patients: The Leuven SICU Study Randomized controlled trial: 1548 patients admitted to a surgical ICU, receiving mechanical ventilation. Patients were assigned to receive either: Conventional therapy: IV insulin only if BG >215 mg/dL Target BG levels: 180-200 mg/dL Mean daily BG: 153 mg/dL Intensive therapy: IV insulin if BG >110 mg/dL Target BG levels : 80-110 mg/dL Mean daily BG: 103 mg/dL First RCT- landmark paper that was the bases for previous guidelines.First RCT- landmark paper that was the bases for previous guidelines.

18. Intensive Insulin Therapy in CriticallyIll Patients: SICU Remarkable results!Remarkable results!

19. The slide shows results of trials of glucose management in critical care patients.1-10 Some early randomized trials suggested that intensive glucose lowering can improve outcomes.1,2 However, more recent studies in the critical care population were unable to replicate earlier studies, and identified severe hypoglycemia as a significant risk of intensive glucose control.3-10 In the study by Ghandi et al,7 intensive insulin therapy during cardiac surgery did not reduce perioperative death or morbidity. In the NICE-SUGAR study,10 critically ill patients treated in the intensive glucose control group (81-108 mg/dL) were 14% more likely to die (27.5% vs 24.9%) than were those in the conventional glucose control group (144-180 mg/dL). Severe hypoglycemia (blood glucose =40 mg/dL) occurred in 6.8% of the intensive-control group versus 0.5% of the conventional-control group (P<.001).The slide shows results of trials of glucose management in critical care patients.1-10 Some early randomized trials suggested that intensive glucose lowering can improve outcomes.1,2 However, more recent studies in the critical care population were unable to replicate earlier studies, and identified severe hypoglycemia as a significant risk of intensive glucose control.3-10 In the study by Ghandi et al,7 intensive insulin therapy during cardiac surgery did not reduce perioperative death or morbidity. In the NICE-SUGAR study,10 critically ill patients treated in the intensive glucose control group (81-108 mg/dL) were 14% more likely to die (27.5% vs 24.9%) than were those in the conventional glucose control group (144-180 mg/dL). Severe hypoglycemia (blood glucose =40 mg/dL) occurred in 6.8% of the intensive-control group versus 0.5% of the conventional-control group (P<.001).

20. Randomized controlled trial: 1,200 pts admitted to a medical ICU. Patients were assigned to receive either: Conventional therapy: IV insulin if BG > 215 mg/dL Target BG levels: 180-200 mg/dL Mean daily BG: 153 mg/dL Intensive therapy: IV insulin if BG > 110 mg/dL Target BG levels : 80-110 mg/dL Mean daily BG: 111 mg/dL

22. Severe Hypoglycemia in the Medical ICU - 2nd Leuven Study Conventional Intensive (605) (595) Hypoglycemia events # (%) 19 (3.1) 111 (18.7) Two or more episodes 5 (0.8) 23 (3.9) Glucose level (mg/dL) 31 � 8 32 � 5 Identified hypoglycemia as an �independent risk factor for death.� Van den Berghe G, et al. N Engl J Med. 2006;354:449-461.

23. To compare the effects of 2 regimens of insulin therapy on clinical outcome: Intensive Therapy group: Target BG: 80 - 110 mg/dLAchieved mean BG: 118 mg/dL (109-131 mg/dL) Conventional Therapy group: Target BG: 140 - 180 mg/dLAchieved mean BG: 147 mg/dL (127-163 mg/dL) Nondiabetic patients: 872 Diabetic patients: 210 Glucontrol trial in more details. Mixed ICU patients� failed to reproduce the Belgium study. The study was stopped because high rate of hypoglycemia and lack of benefit of intensive glycemic controlGlucontrol trial in more details. Mixed ICU patients� failed to reproduce the Belgium study. The study was stopped because high rate of hypoglycemia and lack of benefit of intensive glycemic control

26. Visep trial in more details� . Mixed ICU patients� also failed to reproduce the Belgium study. The study was stopped because high rate of hypoglycemia and lack of benefit of intensive glycemic control Visep trial in more details� . Mixed ICU patients� also failed to reproduce the Belgium study. The study was stopped because high rate of hypoglycemia and lack of benefit of intensive glycemic control

29. Intensive Insulin Therapy in Severe Sepsis and Severe Hypoglycemia (VISEP Study)

30. Intensive Glycemic Control in a Mixed ICU

31. Tight Glucose Control in CriticallyIll Patients: A Meta-Analysis 29 randomized controlled trials totaling 8432 patients Tight glucose control vs usual care: no significant differencein mortality Overall: 21.6% vs 23.3%; intensive vs standard Decreased risk of septicemia; 10.9% vs 13.4%;RR, 0.76 Tight glucose control was significantly associated with: Higher risk of hypoglycemia (= 40 mg/dL)(13.7% vs 2.5%; RR, 5.13)

34. The most recent multinational study. Mixed ICU patients� not only that it also failed to prove the benefits of BG control BUT was associated with increased mortality (at 90 days)!The most recent multinational study. Mixed ICU patients� not only that it also failed to prove the benefits of BG control BUT was associated with increased mortality (at 90 days)!

35. Age: ~ 60 years Gender: ~ 36% female Diabetes: ~ 20% (BMI ~ 28 kg/m2) Interval, ICU admission to randomization: 13.4 hrs Reason for ICU admission: Operative* ~ 37% Non-operative� ~ 63% Sepsis: ~ 22% Trauma: ~ 15%

36. NICE-SUGAR: Intensive vs Conventional Glucose Control in Critically Ill Patients

37. NICE-SUGAR: Intensive vs Conventional Glucose Control in Critically Ill Patients

39. NICE-SUGAR: Intensive vs Conventional Glucose Control in Critically Ill Patients

40. NICE-SUGAR: Probability of Survival and OddsRatios for Death, According to Treatment Group

41. This large, international, randomized trial found that intensive glucose control did not offer any benefit in critically ill patients 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 There was increased hypoglycemia with lower glucose targets It is possible that the mortality difference in the two groups may have been related to the post-ICU care. It is possible that the mortality difference in the two groups may have been related to the post-ICU care.

44. Results of a recent meta-analysis that included the NICE-SUGAR study Overall no difference �but surgical patients appear to benefit from tight glycemic control

45. Results of a recent meta-analysis that included the NICE-SUGAR study. Overall no difference� but Surgical patients appear to benefit from tight glycemic control.Results of a recent meta-analysis that included the NICE-SUGAR study. Overall no difference� but Surgical patients appear to benefit from tight glycemic control.

49. Canadian meta-analysis� tight glycemic control is associated with a six-fold increased risk of hypoglycemiaCanadian meta-analysis� tight glycemic control is associated with a six-fold increased risk of hypoglycemia

50. Hyperglycemia is associated with poor clinical outcomes across many disease states in thehospital setting Despite the inconsistencies in the clinical trial results, good glucose management remains important in hospitalized patients It is likely that benefits on outcomes can bederived from somewhat higher glucose targets than previously proposed More conservative glucose targets would be predicted to result in lower rates of hypoglycemia

51. What Should We Take Awayfrom These Trials? Good glucose control, as opposed to near-normal control, is likely sufficient to improve clinical outcomes in the ICU setting Hyperglycemia and hypoglycemia are markers of poor outcome in critically and non-critically ill patients Importantly, the recent studies do not endorse a laissez-faire attitude toward inpatient hyperglycemia that was prevalent a decade ago

52. Is Hypoglycemia Life Threatening? These recent studies and meta-analysis bring up 2 questions�These recent studies and meta-analysis bring up 2 questions�

53. Severe Hypoglycemia as an Independent Risk Factor for Mortality in the ICU

54. This study was a retrospective database review, including a case-control analysis that matched each patient with severe hypoglycemia with 3 controls. It included 102 patients with at least 1 episode of severe hypoglycemia extracted from a series of 5365 medical, surgical, and cardiac patients admitted consecutively between October 1, 1999, and June 15, 2006. A program of tight glycemic control was implemented on February 1, 2003; 2666 patients were treated before and 2699 after this date. Multivariable logistic regression analysis identified diabetes, septic shock, renal insufficiency, mechanical ventilation, severity of illness, and treatment in the tight glycemic control period as independent risk factors for the development of severe hypoglycemia (defined as glucose <40 mg/dL). Mortality was 55.9% among the 102 patients with severe hypoglycemia and 39.5% among the 306 controls (P=.006). Multivariable logistic regression analysis identified severe hypoglycemia as an independent predictor of mortality for the entire cohort (odds ratio, 2.28; 95% CI,1.41-3.70; P=.008). This study was a retrospective database review, including a case-control analysis that matched each patient with severe hypoglycemia with 3 controls. It included 102 patients with at least 1 episode of severe hypoglycemia extracted from a series of 5365 medical, surgical, and cardiac patients admitted consecutively between October 1, 1999, and June 15, 2006. A program of tight glycemic control was implemented on February 1, 2003; 2666 patients were treated before and 2699 after this date. Multivariable logistic regression analysis identified diabetes, septic shock, renal insufficiency, mechanical ventilation, severity of illness, and treatment in the tight glycemic control period as independent risk factors for the development of severe hypoglycemia (defined as glucose <40 mg/dL). Mortality was 55.9% among the 102 patients with severe hypoglycemia and 39.5% among the 306 controls (P=.006). Multivariable logistic regression analysis identified severe hypoglycemia as an independent predictor of mortality for the entire cohort (odds ratio, 2.28; 95% CI,1.41-3.70; P=.008).

55. Blood Glucose During Hospitalization and Incidence of Death Within 2 Years This study evaluated the associations between glycometabolic parameters at admission and during hospitalization and 2-year all-cause mortality risk in an unselected cohort of consecutive patients with diabetes admitted for unstable angina or non-Q-wave myocardial infarction to a university hospital during 1988-1998. For the 684 patients with blood glucose data during hospitalization available, 44 patients had at least 1 documented hypoglycemic event with glucose documented =3.0 mmol/L (=55 mg/dL), 364 had an intermediate glucose value (3.1-6.5 mmol/L or 56-119 mg/dL), and 276 had persistent hypoglycemia with the lowest glucose documented =6.6 mmol/L (or 120 mg/dL). Compared with the intermediate group, both the lowest and the highest groups had significantly higher adjusted 2-year mortality using a model that included on-arrival blood glucose as a covariate (HR, 1.93; 95% CI, 1.18-3.17; HR, 1.48; 95% CI, 1.09-1.99, respectively).This study evaluated the associations between glycometabolic parameters at admission and during hospitalization and 2-year all-cause mortality risk in an unselected cohort of consecutive patients with diabetes admitted for unstable angina or non-Q-wave myocardial infarction to a university hospital during 1988-1998. For the 684 patients with blood glucose data during hospitalization available, 44 patients had at least 1 documented hypoglycemic event with glucose documented =3.0 mmol/L (=55 mg/dL), 364 had an intermediate glucose value (3.1-6.5 mmol/L or 56-119 mg/dL), and 276 had persistent hypoglycemia with the lowest glucose documented =6.6 mmol/L (or 120 mg/dL). Compared with the intermediate group, both the lowest and the highest groups had significantly higher adjusted 2-year mortality using a model that included on-arrival blood glucose as a covariate (HR, 1.93; 95% CI, 1.18-3.17; HR, 1.48; 95% CI, 1.09-1.99, respectively).

56. Unadjusted Results Recent observational study published in JAMA in April 2009. Differences in outcome between patients with and without hypoglycemia (higher mortality overall); but mortality was twice as higher in patients with spontaneous hypoglycemia (non-insulin treated patients). Mortality was not increased in insulin treated patients with hypoglycemia. Recent observational study published in JAMA in April 2009. Differences in outcome between patients with and without hypoglycemia (higher mortality overall); but mortality was twice as higher in patients with spontaneous hypoglycemia (non-insulin treated patients). Mortality was not increased in insulin treated patients with hypoglycemia.

57. Same information ----Same information ----

58. Investigators evaluated 16,871 acute myocardial infarction (MI) patients hospitalized from January 2000 to December 2005. Using logistic regression models and C indexes, 3 metrics of glucose control (mean glucose, time-averaged glucose, hyperglycemic index), each evaluated over 3 time windows (first 24 hours, 48 hours, entire hospitalization), were compared with admission glucose for their ability to discriminate hospitalization survivors from nonsurvivors. Models were then used to evaluate the relationship between mean glucose and in-hospital mortality. In unadjusted analysis, higher mean hospitalization glucose was strongly associated with higher in-hospital mortality. As shown in the figure on the left, when mean hospitalization glucose was analyzed in increments of 10 mg/dL, there was a clear J-shaped relationship between glucose values and mortality rates. Although in the normal glucose range, patients without recognized diabetes had a lower mortality rate than patients with diabetes, their risk increased much more steeply at higher glucose levels, surpassing the risk of patients with diabetes at approximately 130 mg/dL. After multivariable adjustment, the nature of these relationships persisted. As shown in the figure on the right, higher mean hospitalization glucose continued to be strongly associated with higher in-hospital mortality. There was a statistically significant, gradual increase in the odds of in-hospital mortality with each 10-mg/dL incremental rise in mean hospitalization glucose levels above the threshold of 120 mg/dL. The odds of death associated with higher mean glucose rose steeply in patients without recognized diabetes once mean glucose levels exceeded 120 mg/dL. Measures of persistent hyperglycemia were better predictors of mortality than was admission glucose. Mean hospitalization glucose appears to be the most practical metric of hyperglycemia-associated risk in patients with acute MI.Investigators evaluated 16,871 acute myocardial infarction (MI) patients hospitalized from January 2000 to December 2005. Using logistic regression models and C indexes, 3 metrics of glucose control (mean glucose, time-averaged glucose, hyperglycemic index), each evaluated over 3 time windows (first 24 hours, 48 hours, entire hospitalization), were compared with admission glucose for their ability to discriminate hospitalization survivors from nonsurvivors. Models were then used to evaluate the relationship between mean glucose and in-hospital mortality. In unadjusted analysis, higher mean hospitalization glucose was strongly associated with higher in-hospital mortality. As shown in the figure on the left, when mean hospitalization glucose was analyzed in increments of 10 mg/dL, there was a clear J-shaped relationship between glucose values and mortality rates. Although in the normal glucose range, patients without recognized diabetes had a lower mortality rate than patients with diabetes, their risk increased much more steeply at higher glucose levels, surpassing the risk of patients with diabetes at approximately 130 mg/dL. After multivariable adjustment, the nature of these relationships persisted. As shown in the figure on the right, higher mean hospitalization glucose continued to be strongly associated with higher in-hospital mortality. There was a statistically significant, gradual increase in the odds of in-hospital mortality with each 10-mg/dL incremental rise in mean hospitalization glucose levels above the threshold of 120 mg/dL. The odds of death associated with higher mean glucose rose steeply in patients without recognized diabetes once mean glucose levels exceeded 120 mg/dL. Measures of persistent hyperglycemia were better predictors of mortality than was admission glucose. Mean hospitalization glucose appears to be the most practical metric of hyperglycemia-associated risk in patients with acute MI.

59. Hypoglycemia is Associated with Cardiovascular Complications Tachycardia and high blood pressure Myocardial ischemia Silent ischemia, angina, infarction Cardiac arrhythmias Transiently prolonged corrected QT interval, Increased QT dispersion Sudden death Why is hypoglycemia bad? We MUST avoid hypoglycemia NOT ONLY because acute neuroglycopenia, AMS and risk of seizures, but due to CV complications. Why is hypoglycemia bad? We MUST avoid hypoglycemia NOT ONLY because acute neuroglycopenia, AMS and risk of seizures, but due to CV complications.

60. Current Recommendations These recent studies and meta-analysis bring up 2 questions�These recent studies and meta-analysis bring up 2 questions�

61. AACE-ADA Consensus Statementon Inpatient Glycemic Control

62. ICU setting: Starting threshold of no higher than 180 mg/dL Once IV insulin is started, the glucose level should be maintained between 140 and 180 mg/dL Lower glucose targets (110-140 mg/dL) may be appropriate in selected patients � Targets <110 mg/dL or >180 mg/dL are not recommended Based on the high rate of hypoglycemia and no difference in mortality in major trials, and the results of NICE �SUGAR that reported increased mortality� NEW TASK FORCE. The slide shows the recommendations for target glucose levels in critically ill patients in the intensive care setting, which were released on May 8, 2009, by the American Association of Clinical Endocrinologists and the American Diabetes Association, and published online in the June issues of Endocrine Practice and Diabetes Care. They include the following: Insulin therapy should be initiated for treatment of persistent hyperglycemia, starting at a threshold of no greater than 180 mg/dL. Once insulin therapy has been started, a glucose range of 140 to 180 mg/dL is recommended for the majority of critically ill patients. Intravenous insulin infusions are the preferred method for achieving and maintaining glycemic control in critically ill patients. Validated insulin infusion protocols with demonstrated safety and efficacy, and with low rates of occurrence of hypoglycemia, are recommended. With IV insulin therapy, frequent glucose monitoring is essential to minimize the occurrence of hypoglycemia and to achieve optimal glucose control. Based on the high rate of hypoglycemia and no difference in mortality in major trials, and the results of NICE �SUGAR that reported increased mortality� NEW TASK FORCE. The slide shows the recommendations for target glucose levels in critically ill patients in the intensive care setting, which were released on May 8, 2009, by the American Association of Clinical Endocrinologists and the American Diabetes Association, and published online in the June issues of Endocrine Practice and Diabetes Care. They include the following: Insulin therapy should be initiated for treatment of persistent hyperglycemia, starting at a threshold of no greater than 180 mg/dL. Once insulin therapy has been started, a glucose range of 140 to 180 mg/dL is recommended for the majority of critically ill patients. Intravenous insulin infusions are the preferred method for achieving and maintaining glycemic control in critically ill patients. Validated insulin infusion protocols with demonstrated safety and efficacy, and with low rates of occurrence of hypoglycemia, are recommended. With IV insulin therapy, frequent glucose monitoring is essential to minimize the occurrence of hypoglycemia and to achieve optimal glucose control.

63. 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 For the majority of noncritically ill patients treated with insulin, the premeal blood glucose (BG) target should generally be less than 140 mg/dL in conjunction with random BG levels less than 180 mg/dL, provided these targets can be safely achieved. To avoid hypoglycemia, consideration should be given to reassessing the insulin regimen if BG levels decline below 100 mg/dL. Modification of the regimen is necessary when BG values are <70 mg/dL, unless the event is easily explained by other factors (such as a missed meal). More stringent targets may be appropriate in stable patients in whom tight glycemic control was achieved previously. Less stringent targets may be appropriate in terminally ill patients or patients with severe comorbidities. Hypoglycemia is defined as any BG level <70 mg/dL. Severe hypoglycemia in hospitalized patients has been defined by many clinicians as BG <40 mg/dL, although this value is lower than the approximate 50 mg/dL level at which cognitive impairment begins in normal persons. Scheduled subcutaneous administration of insulin, with basal, nutritional, and correction components, is the preferred method for achieving and maintaining glucose control. Prolonged treatment with sliding-scale insulin as the sole regimen is discouraged. Noninsulin antihyperglycemic agents are not appropriate in most hospitalized patients who require treatment for hyperglycemia.For the majority of noncritically ill patients treated with insulin, the premeal blood glucose (BG) target should generally be less than 140 mg/dL in conjunction with random BG levels less than 180 mg/dL, provided these targets can be safely achieved. To avoid hypoglycemia, consideration should be given to reassessing the insulin regimen if BG levels decline below 100 mg/dL. Modification of the regimen is necessary when BG values are <70 mg/dL, unless the event is easily explained by other factors (such as a missed meal). More stringent targets may be appropriate in stable patients in whom tight glycemic control was achieved previously. Less stringent targets may be appropriate in terminally ill patients or patients with severe comorbidities. Hypoglycemia is defined as any BG level <70 mg/dL. Severe hypoglycemia in hospitalized patients has been defined by many clinicians as BG <40 mg/dL, although this value is lower than the approximate 50 mg/dL level at which cognitive impairment begins in normal persons. Scheduled subcutaneous administration of insulin, with basal, nutritional, and correction components, is the preferred method for achieving and maintaining glucose control. Prolonged treatment with sliding-scale insulin as the sole regimen is discouraged. Noninsulin antihyperglycemic agents are not appropriate in most hospitalized patients who require treatment for hyperglycemia.