Achieving Glycemic Control in the Hospital Setting Part 1 of 3

Diabetes and Hospitalization: Scope of the Problem Prevalence of diabetes is estimated at 12%-25% of hospitalized patients and may be underestimated by as much as 40%1 29% of all cardiac surgery patients2 1-3 days longer hospital stay2 In 2007, more than $58 billion in cost for hospital inpatient care3 Diabetes and Hospitalization: Scope of the Problem Review as stated References Clement S, Braithwaite SS, Magee MF, et al. Management of diabetes and hyperglycemia in hospitals. Diabetes Care. 2004;27(2):553-591. ACE Position Statement. Endo Pract. 2004;10:77-82. American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2007. Diabetes Care. 2008;31(3):596-615. 1. Clement S et al. Diabetes Care. 2004;27(2):553-591; 2. ACE Position Statement. Endo Pract. 2004;10:77-82; 3. American Diabetes Association. Diabetes Care. 2008;31(3):596-615.

2007 Total Direct Cost=$27 billion Hospitalizations Account for the Largest Portion of the Direct Cost of Diabetes Care 2007 Total Direct Cost=$27 billion 50% Hospitalizations Account for the Largest Portion of the Direct Cost of Diabetes Care The direct cost of diabetes in 2007 reached a total of $27 billion. The health care expenditures attributable to this total can be broken down into numerous categories as seen on the slide Hospitalizations (specifically, hospital inpatient days) make up the largest part of the direct cost Reference American Diabetes Association. Economic costs of diabetes in the U.S. in 2007. Diabetes Care. 2008;31(3):596-615. American Diabetes Association. Diabetes Care. 2008;31(3):596-615.

Hyperglycemia Is Prevalent at Hospital Admission 38% of patients at admission have hyperglycemia —Of those patients, nearly one-third have no history of diabetes Hyperglycemia Is Prevalent at Hospital Admission The medical records of 2030 consecutive adult patients admitted to a community hospital in Georgia over a 15-week period (July 1, 1998 to October 20, 1998) were reviewed to determine the prevalence of in-hospital hyperglycemia and its impact on survival and functional outcome in patients with and without a history of diabetes Because 144 patients did not have a blood glucose value, only 1886 patients were eligible for the study Hyperglycemia was defined as an admission or in-hospital fasting blood glucose level of 126 mg/dL or more, or random blood glucose levels of 200 mg/dL or more on 2 or more occasions Results on admission indicate that 1168 patients were normoglycemic (62%) and 718 were hyperglycemic (38%). Of those who were hyperglycemic, 223 (31%) did not have a previous history of diabetes Reference Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87(3):978-982. Single-center, retrospective chart review of 1886 patients hospitalized over 15 weeks in a community teaching hospital. Hyperglycemia defined as BG 126 mg/dL on admission or while fasting, or random BG 200 mg/dL on 2 occasions. Umpierrez GE et al. J Clin Endocrinol Metab. 2002;87(3):978-982.

Admission and Change in Glucose Within 24 Hours Predict Mortality Risk N=1469 with AMI (n=1219 without diabetes) 9% in 30-day mortality per 10 mg/dL BG in first 24 hr (P=.002)* 30-Day mortality (%) Admission and Change in Glucose Within 24 Hours Predict Mortality Risk The Complement and Reduction of Infarct Size after Angioplasty or Lytics (CARDINAL) study looked at the prognostic significance of BG change in the first 24 hours post AMI Goyal et al demonstrated that admission glucose and changes in glucose level within the first 24 hours predict the risk of mortality at 30 days in patients with AMI and without a history of diabetes The risk of 30-day mortality decreased by 9% per 10 mg/dL reduction in glucose within the first 24 hours after AMI Patients with hyperglycemia on admission whose BG increased 24 hours after admission experienced marked increases in mortality. Patients with admission BG levels of 170 mg/dL or greater whose BG values increased were associated with the highest 30-day mortality rates Glucose measurements did not predict outcomes in patients with AMI and a history of diabetes. The authors suggested that this might be related to the relatively small number of patients with AMI and diabetes in the study Reference Goyal A, Mahaffey KW, Garg Jyostsna, Nicolau JC, Hochman JS, Weaver WD, et al. Prognostic significance of the change in glucose level in the first 24 h after acute myocardial infarction: results from the CARDINAL study. Euro Heart J. 2006;27:1289-1297. <125 125 to <140 140 to <170 ≥170 Baseline Blood Glucose (mg/dL) BG (24-hr vs baseline) ≥30 mg/dL drop in BG <30 mg/dL drop in BG Actual increase in BG Goyal A et al. Eur Heart J. 2006;27:1289-1297. *Multivariate analysis. AMI=acute myocardial infarction.

Extra days=hospitalization charges (approximate) Hyperglycemia Increases the Length of Stay and Overall Hospitalization Charges 3.04=$11,200 2.28=$8400 Extra days=hospitalization charges (approximate) 1.52=$5600 0.76=$2800 Hyperglycemia Increases the Length of Stay and Overall Hospitalization Charges The association between perioperative hyperglycemia and outcomes in patients with and without diabetes has not been well defined This review examines a historic cohort study of 1574 patients who underwent coronary artery bypass grafting between 1998 and 1999. Of that cohort, 545 (34.6%) were patients with diabetes Outcomes included 30-day mortality, 30-day infections, and resource utilization as measured by days to discharge, hospitalization charges, and hospitalization costs In this review, perioperative blood glucose level was defined as the average of all blood glucose values obtained on the day of and the day after surgery After adjusting for diabetes status and calculated preoperative or mediastinitis risk scores, each 50-mg/dL increase in blood glucose was not statistically associated with higher mortality (odds ratio [OR], 1.37; 95% confidence interval [CI], 0.98-1.92; P=.071), or higher infection rate (OR, 1.23; 95% CI, 0.94-1.60; P=.14) Each 50-mg/dL blood glucose increase was associated with longer postoperative hospital stays by 0.76 days (95% CI, 0.36-1.17 days; P<.001), increased hospitalization charges by $2824 (95% CI, $1599-$4049; P<.001), and increased hospitalization cost by $1769 (95% CI, $928-$2610; P<.001) Reference Estrada CA, Young JA, Nifong LW, Chitwood WR Jr. Outcomes and perioperative hyperglycemia in patients with or without diabetes mellitus undergoing CABG. Ann Thorac Surg. 2003;75(5):1392-1399. 50 100 150 200 Blood glucose (mg/dL) From a retrospective observational cohort study of 1574 patients who had undergone coronary artery bypass grafting between 1998 and 1999, 545 (34.6%) with diabetes. Each increase in BG level of 50 mg/dL was associated with an additional hospital stay of 0.76 days and increased hospitalization charges of $2824 (based on 1998-1999 data). Estrada CA et al. Ann Thorac Surg. 2003;75(5):1392-1399.

Association Between Mean Blood Glucose and In-Hospital Mortality 0.8 No diabetes All patients 0.6 Diabetes Unadjusted association Mortality rate 0.4 0.2 20 15 Multivariable-adjusted association (Reference: Mean BG 100 to <110) Association Between Mean Blood Glucose and In-Hospital Mortality The objective of this study was to identify the most prognostically important measure of hyperglycemia during AMI and to establish whether this metric is a superior predictor of prognosis than admission hyperglycemia alone The ability of models to predict mortality improved as the time window increased from admission, to 24 hours, to 48 hours, and to the entire hospitalization (C index = 0.62, 0.64, 0.66, and 0.70, respectively) Mean BG showed a J-shaped relationship with in-hospital mortality In the normal glucose range, patients without diabetes had a lower mortality rate than those with diabetes; however, at ~130 mg/dL the risk of mortality markedly increased and actually became worse in the patients without diabetes Measures of persistent hyperglycemia better predict mortality than admission hyperglycemia in hospitalized patients with AMI Reference Kosiborod M, Inzucchi SE, Krumholz HM, Xiao L, Jones PG, Fiske S, et al. Glucometrics in patients hospitalized with acute myocardial infarction: defining the optimal outcomes-based measure of risk. Circulation. 1008;117:1018-1027. Odds ratio (OR) 10 5 1 <70 80 to <90 100 to <110 120 to <130 140 to <150 160 to <170 180 to <190 200 to <210 220 to <230 240 to <250 260 to <270 280 to <290 ³300 Mean Blood Glucose (mg/dL) Kosiborod M et al. Circulation. 2008;117:1018-1027.

Severe Hypoglycemia in Critically Ill Patients: Risk Factors and Outcomes Mortality rates: 55.9% in patients with severe hypoglycemia (n=102), 39.5% in controls (n=306) Severe Hypoglycemia Mortality OR P OR (95% CI) Diabetes 3.07 <.0001 0.97 NS Septic shock 2.03 .0096 1.33 Serum creatinine ³3 mg/dL 1.10 1.30 .0204 Mechanical ventilation 2.11 .0032 2.43 Treatment in TGC period 1.59 .0279 0.67 APACHE II (modified) 1.07 1.14 Age 1.01 1.03 Severe hypoglycemia N/A 2.28 .0008 Severe Hypoglycemia in Critically Ill Patients: Risk Factors and Outcomes This retrospective database review was undertaken to determine the risk factors and clinical outcomes of severe hypoglycemia (<40 mg/dL) in the hospital setting From a database of 5365 medical, surgical, and cardiac patients admitted to Stamford Hospital between October 1999 and June 2006, 102 individuals had suffered at least 1 episode of severe hypoglycemia. 306 patients were identified as matched control cases The main finding of the study was that even a single event of severe hypoglycemia in the ICU patients studied increased the risk of death As shown in the chart above, 55.9% of the 102 patients who had experienced at least 1 episode of severe hypoglycemia died, while only 39.5% of the control patients died. These data represent a statistically significant increase in the risk of death for ICU patients experiencing severe hypoglycemia compared with the control group (P=.0057) Additionally, using a multivariate logistic regression model to analyze the entire cohort (5365 patients), severe hypoglycemia was identified as an independent contributor to mortality (OR, 2.28; 95% CI, 1.41-3.70; P=.0008) Reference Krinsley JS, Grover A. Severe hypoglycemia in critically ill patients: risk factors and outcomes. Crit Care Med. 2007;35(10):2262-2267. Single severe hypoglycemia episode independently associated with increased mortality risk APACHE=Acute Physiology and Chronic Health Evaluation; CI=confidence interval; TGC=tight glycemic control. Krinsley JS, Grover A. Crit Care Med. 2007;35(10):2262-2267.

Outcome Studies With Tight Glycemic Control in Critically Ill Patients Review as stated

Intensive Glucose Management in Critical Care: Studies Showing Benefit Study Setting N Outcome Intervention ARR† RRR DIGAMI 19951 CCU (AMI) 620 1-Year mortality IIP (D5W) + MDI: 126-196 mg/dL 7.5% 29% Furnary 19992,* CTICU 2467 Sternal infections IIP: 150-200 mg/dL 1.2% 66% Van den Berghe 20013 SICU 1548 ICU mortality IIP: 80-110 mg/dL 3.4% 42% Krinsley 20044,* ICU 1600 Hospital mortality SC or IV insulin, <140 mg/dL 6.1% Intensive Glucose Management in Critical Care: Studies Showing Benefit This slide summarizes several studies that have shown intensive glucose management benefits the overall survival and care of patients in the hospital setting The absolute and relative risk reductions observed in each study are listed; absolute risk reduction values shown are calculated values represented by the difference in the reported risk reduction values of the measured outcome in the respective trials References Malmberg K, Rydén L, Efendic S, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995;26(1):57-65. Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg. 1999;67(2):352-360. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367. Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc. 2004;79(8):992-1000. *Nonrandomized design. †Absolute risk reduction (calculated value); difference in reported risk reduction values of the measured outcome in the respective trials. ARR=absolute risk reduction; CCU=coronary care unit; CTICU=cardiothoracic ICU; D5W=dextrose 5% in water; IIP=insulin infusion protocol; IV=intravenous; MDI=multidose insulin; MICU=medical ICU; RRR=relative risk reduction; SC=subcutaneous; SICU=surgical ICU. 1. Malmberg K et al. J Am Coll Cardiol. 1995;26(1):57-65; 2. Furnary AP et al. Ann Thorac Surg. 1999;67(2):352-360; 3. Van den Berghe G et al. N Engl J Med. 2001;345(19):1359-1367; 4. Krinsley JS. Mayo Clin Proc. 2004;79(8):992-1000.

The Recent Evidence Conflicting reports questioning the benefit of tight control Increasing concerns regarding safety, hypoglycemia, and the potential for harm The Recent Evidence Review as stated

Tight Glucose Control in Critically Ill Patients: A Meta-analysis 29 Randomized controlled trials totaling 8432 patients Tight glucose control vs usual care: no significant difference in mortality Tight glucose control was significantly associated with: Higher risk of hypoglycemia (≤40 mg/dL) (13.7% vs 2.5% for usual care; RR, 5.13) Tight Glucose Control in Critically Ill Patients—A Meta-analysis This meta-analysis was undertaken to ascertain the benefits and risks of tight glycemic control. It was conducted with data from 8432 patients who were enrolled in 29 randomized controlled trials. The main findings of this analysis are summarized here: No significant differences were observed between hospital mortality rates among patients managed with tight glucose control compared with usual care (21.6% vs 23.3%, respectively; RR 0.93; 95% confidence interval [CI], 0.85-1.03) Tight glycemic control was associated with a higher risk of hypoglycemia than usual care (13.7% vs 2.5%, respectively; RR, 5.13; 95% CI, 4.09-6.43) For this meta-analysis, “tight glycemic control” was defined by a glucose goal <150 mg/dL that was achieved with the use of insulin infusion. For the “usual care” group, the glucose goal and method of administration of insulin varied between studies Reference Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA. 2008;300(8):933-944. Wiener RS et al. JAMA. 2008;300(8):933-944.