Manejo del Paciente Diabetico en la Unidad de Cuidados Intensivos y Sala General Guillermo E. Umpierrez, MD, FACP, FACE Professor of Medicine Director, Grady Hospital Clinical Research Unit Emory University School of Medicine Director, Diabetes & Endocrinology Section Grady Hospital CIN (Research Unit) Grady Health System

Hiperglucemia en el Hospital: Agenda Magnitud del Problema: Cual es la frecuencia e impacto de hiperglucemia y diabetes en el hospital? Cuales criterios diagnosticos debemos de utilizar? Que niveles de glucosa son recomendables? 2. Como debemos de manejar la hiperglucemia en UCI y en en sala generales? Insulina – Que tipo, regimen, y como comenzar? Incretinas – debemos de utilizarlas en el hospital? Alta hospitalaria– Cual es el papel de la HBA1c, que regimen utilizar? HbA1c? Umpierrez et al. J Clin Endocrinol Metabol. 97(1):16-38, 2012

Distribution of patient-day-weighted mean POC-BG values for ICU Results: A total of 49,191,313 POC-BG measurements (12,176,299 ICU; 37,015,014 non-ICU) were obtained from 3,484,795 patients (653,359 ICU; 2,831,436 non-ICU). The mean POC-BG was 167 mg/dL for ICU patients and 166 mg/dL for non-ICU patients. The prevalence of hyperglycemia (>180 mg/dL) was 32.2% in ICU patients and 32.0% in non-ICU patients. The prevalence of hypoglycemia (<70 mg/dL) was 6.3% in ICU patients and 5.7% in non-ICU patients. Data from ~12 million BG readings from 653,359 ICU patients - mean POC-BG: 167 mg/dL Swanson et al. Endocrine Practice, October 2011

Hyperglycemia: Scope of the Problem Diabetes No Diabetes 50 40 30 20 10 50 40 30 20 10 Patients, % 26% 78% Using a national database derived from electronic medical records at 39 medical centers, investigators analyzed patterns of blood glucose (BG) control and documented insulin therapy among 16,534 patients hospitalized with acute myocardial infarction from January 2000 to December 2005. Of the 4940 patients (30%) with recognized diabetes mellitus (DM), nearly half (2412 patients, 49%) had mean BG >200 mg/dL during the first 24 hours after hospital admission. When the entire hospitalization was considered, 34% of DM patients had mean BG >200 mg/dL, while 61% had mean BG between 110 and 200 mg/dL, and only 5% maintained mean BG <110 mg/dL. Among patients without recognized DM, 8% had mean BG >200 mg/dL during the first 24 hours. When the entire hospitalization was considered, 4% of patients without known DM had mean BG >200 mg/dL, while 65% had mean BG between 110 and 200 mg/dL, and 31% had mean BG <110 mg/dL. <110 110-140 140-170 170-200 >200 <110 110-140 140-170 170-200 >200 Mean BG, mg/dL Kosiborod M, et al. J Am Coll Cardiol. 2007;49(9):1018-183:283A-284A. Kosiborod M, Inzucchi S, Clark B, et al. National patterns of glucose control among patients hospitalized with acute myocardial infarction. J Am Coll Cardiol. 2007;49(9):1018-183:283A-284A.

Perioperative Hyperglycemia in Patients With and Without Diabetes Undergoing CABG Surgery  No-DM DM P-value # of pts 150 152 -- BMI 29±6 33±8 p<0.001 Admission BG 111±28 171±72 HbA1c 6.1±0.2 8.0±2 Pre-op BG 108±23 155±51 Intra-op BG 138±20 157±31 ICU BG 135±16 149±18 Periop BG >140 83% 98% P=0.48 Started CII 88% 94% P=0.06 Insulin dose, Units 61±84 161±229 Transition to basal insulin after CII 48% P<0.001 Pasquel et al, Endocrine Society 2014, submitted. Unpublished

Hyperglycemia*: A Common Comorbidity in Medical-Surgical Patients in a Community Hospital 12% 26% 62% In a more recent study that involved 2020 consecutive patients admitted to a community hospital in Atlanta, we found that 64% of patients had normal glucose values, 26% had a prior history of diabetes, and that 12% of patients with hyperglycemia, as determined by 2 or more FBG > 126 or RBG > 200, did not had a know history of diabetes prior to admission. Normoglycemia n = 2,020 * Hyperglycemia: Fasting BG  126 mg/dl or Random BG  200 mg/dl X 2 Known Diabetes New Hyperglycemia Umpierrez G et al, J Clin Endocrinol Metabol 87:978, 2002

Diagnosis & recognition of hyperglycemia and diabetes in the hospital setting Admission Assess all patients for a history of diabetes Obtain laboratory BG testing on admission No history of diabetes BG<140 mg/dl (7.8 mmol/L) Initiate POC BG monitoring according to clinical status No history of diabetes BG >140 mg/dl Start POC BG monitoring x 24-48h Check A1C A1C ≥ 6.5% History of diabetes BG monitoring Umpierrez et al. J Clin Endocrinol Metabol. 97(1):16-38, 2012

A1C for Diagnosis of Diabetes in the Hospital HbA1c should be measured in non-diabetic subjects with hyperglycemia (BG>140 mg/dl or 7.8 mmol/L) and in subjects with diabetes if not done within 2-3 months prior to admission. In the presence of hyperglycemia, a patient with HbA1c > 6.5% can be identified as having 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 Umpierrez et al, J Clin Endocrinol Metabol, 2012

Hyperglycemia in the ICU: Lecture Agenda Scope of the Problem: What is the frequency of hyperglycemia and diabetes? Why should we care about hyperglycemia in the ICU? Mechanisms for hyperglycemia in acute critical illness and ICU 2. How should we manage hyperglycemia in the ICU and non-ICU settings? Insulin regimens Incretin-base regiments Other agents?

Hyperglycemia and Hospital Complications: What glucose level predicts complications? N= 55,530 patients records in ICU and non-ICU, Emory University Hospital. Composite of complications: pneumonia, acute renal or respiratory failure, acute MI, bacteremia, and death. Patients with admission BG >400 mg/dL, DKA, and GFR <15 were excluded.

Thirty Day Mortality and Hospital Complications in Diabetic and Non-diabetic subjects Undergoing General Non-Cardiac Surgery * * * % * * † # †p = 0.1 * p= 0.001 #p=0.017 A Frisch et al. Diabetes Care, May 2010

Adverse Events Stratified by Perioperative Hyperglycemia Diabetes No Diabetes § * * * The Surgical Care and Outcomes Assessment Program is a Wash- ington State quality improvement benchmarking-based initiative. We evalu- ated the relationship of perioperative hyperglycemia (>180 mg/dL) and insulin administration on mortality, reoperative interventions, and infections for pa- tients undergoing elective colorectal and bariatric surgery at 47 participating hospitals between fourth quarter of 2005 and fourth quarter of 2010. Results: Of the 11,633 patients (55.4 ± 15.3 years; 65.7% women) with a serum glucose determination on the day of surgery, postoperative day 1, or postoperative day 2, 29.1% of patients were hyperglycemic. After controlling for clinical factors, those with hyperglycemia had a significantly increased risk of infection [odds ratio (OR) 2.0; 95% confidence interval (CI), 1.63–2.44], reoperative interventions (OR, 1.8; 95% CI, 1.41–2.3), and death (OR, 2.71; 95% CI, 1.72–4.28). Increased risk of poor outcomes was observed both for patients with and without diabetes. Those with hyperglycemia on the day of surgery who received insulin had no significant increase in infections (OR, 1.01; 95% CI, 0.72–1.42), reoperative interventions (OR, 1.29; 95% CI, 0.89– 1.89), or deaths (OR, 1.21; 95% CI, 0.61–2.42). A dose-effect relationship was found between the effectiveness of insulin-related glucose control (worst 180–250 mg/dL, best <130 mg/dL) and adverse outcomes. Conclusions: Perioperative hyperglycemia was associated with adverse out- comes in general surgery patients with and without diabetes. However, patients with hyperglycemia who received insulin were at no greater risk than those with normal blood glucoses. Perioperative glucose evaluation and insulin ad- ministration in patients with hyperglycemia are important quality targets. * BG > 180 mg/dl BG < 180 mg/dl * P <0.01 Proportion of Patients (%) § p <0.05 BG at any point on the day of surgery, post-op day 1 and 2 N= 11,633, colorectal and bariatric surgery; 29.1% with hyperglycemia Known et al. Ann Surg 2013

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

Inpatient Hyperglycemia: ICU and non-ICU Lecture Outline What is the frequency of hyperglycemia and diabetes? What is the association between hyperglycemia and outcomes? Does treatment of hyperglycemia in ICU and non-ICU matters? What is the evidence for intensive glycemic control? How should we manage hyperglycemia in non-ICU setting

Portland Diabetes Project: Insulin Infusion Reduces DSWI SCI CII [Furnary.AnnThorac Surg.Feb.1999/p357/Fig 3] 4.0 SCI Group: Day of surgery: 241 mg/dL POD #1: 206 mg/dL CII Group: Day of surgery: 199 mg/dL POD #1: 176 mg/dL 3.0 DSWI (%) 2.0 1.0 0.0 87 88 89 90 91 92 93 94 95 96 97 Year Prospective study of 2,467 consecutive diabetics who underwent open heart surgery. DSWI, deep sternal wound infection; SCI, subcutaneous insulin; CII, continuous insulin infusion. Furnary AP, et al. Ann Thorac Surg. 1999;67:352–362.

Hyperglycemia and surgical ICU morbidity and mortality

Intensive Glucose Management in RCT Trial N Setting Primary Outcome ARR RRR Odds Ratio (95% CI) P-value Van den Berghe 2006 1200 MICU Hospital mortality 2.7% 7.0% 0.94* (0.84-1.06) N.S. Glucontrol 2007 1101 ICU ICU mortality -1.5% -10% 1.10* (0.84-1.44) Ghandi 2007 399 OR Composite 2% 4.3% 1.0* (0.8-1.2) VISEP 2008 537 28-d mortality 1.3% 5.0% 0.89* (0.58-1.38) De La Rosa 2008 504 SICU -4.2% * -13%* NR NICE-SUGAR 2009 6104 3-mo mortality  -2.6% -10.6 1.14 (1.02-1.28) < 0.05 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). *not significant Griesdale DE, et al. CMAJ. 2009;180(8):821-827.

No. Events/Total No. Patients Intensive Insulin Therapy and Hypoglycemic Events in Critically Ill Patients No. Events/Total No. Patients Study IIT Control Risk ratio (95% CI) Van den Berghe et al 39/765 6/783 6.65 (2.83-15.62) Henderson et al 7/32 1/35 7.66 (1.00-58.86) Bland et al 1/5 1.00 (0.08-11.93) 111/595 19/605 5.94 (3.70-9.54) Mitchell et al 5/35 0/35 11.00 (0.63-191.69) Azevedo et al 27/168 6/169 4.53 (1.92-10.68) De La Rosa et al 21/254 2/250 10.33 (2.45-43.61) Devos et al 54/550 15/551 3.61(2.06-6.31) Oksanen et al 7/39 1/51 9.15 (1.17-71.35) Brunkhorst et al 42/247 12/290 4.11(2.2-7.63) Iapichino et al 8/45 3/45 2.67 (0.76-9.41) Arabi et al 76/266 8/257 9.18 (4.52-18.63) Mackenzie et al 50/121 9/119 5.46 (2.82-10.60) NICE-SUGAR 206/3016 15/3014 13.72 (8.15-23.12) Overall 654/6138 98/6209 5.99 (4.47-8.03) Hypoglycemic Events Favors IIT Favors Control 0.1 1 10 Griesdale DE, et al. CMAJ. 2009;180(8):821-827. Risk Ratio (95% CI)

NICE-SUGAR Trial: Hypoglycemia and Mortality Figure 3 Hazard Ratio for Death According to the Occurrence of Hypoglycemia on 1 Day or More Than 1 Day and Receipt or Nonreceipt of Insulin Therapy at the Time of the First Hypoglycemic Episode. The risk of death was increased among patients who had moderate hypoglycemia on more than 1 day, as compared with just 1 day (Panel A), and among patients who were not receiving insulin when hypoglycemia first occurred, as compared with those who were receiving insulin (Panel B). The interval from the first episode of hypoglycemia to death was shorter among patients who were not being treated with insulin when hypoglycemia first occurred (P=0.004 and P<0.001 for moderate and severe hypoglycemia, respectively). The size of the squares is proportional to the number of deaths. The NICE-SUGAR Study Investigators. N Engl J Med 2012;367:1108-1118

2009 AACE/ADA Recommended Target Glucose Levels in ICU Patients Starting threshold of no higher than 180 mg/dL Recommended 140-180 Acceptable 110-140 Not recommended <110 >180 Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009;15(4). 2012 Critical Society Guidelines ICU Target Glucose Goal < 150 mg/dl Start Insulin Therapy when BG  ≥  150 mg/dL Maintain BG values <180 mg/dL Jacobi, et al. Crit Care Med 2012;40:3251–3276 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. 2012 American College of Physicians (ACP) ICU Target Glucose Goal < 200 mg/dl Annals Intern Med 2012 Moghissi ES, Korytkowski MT, Dinardo M, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. American Association of Clinical Endocrinologists and American Diabetes Association Consensus Statement on Inpatient Glycemic Control. Endocr Pract. 2009;15(4). http://www.aace.com/pub/pdf/guidelines/InpatientGlycemicControlConsensusStatement.pdf. Accessed May 18, 2009. 21

Glycemic Targets in NON-ICU Setting Premeal BG target of <140 mg/dl (7.8 mmol/L) and random BG <180 mg/dl (10 mmol/L) for the majority of patients. Glycemic targets be modified according to clinical status. For avoidance of hypoglycemia, diabetic therapy be reassessed when BG<100 mg/dl (5.5 mmol/L). American College of Physicians recommended a target BG <200 mg/dl (11.1 mmol/L), Ann Intern Med 2012 Umpierrez et al. J Clin Endocrinol Metabol. 97(1):16-38, 2012

Hyperglycemia in the ICU: Lecture Agenda Scope of the Problem: What is the frequency of hyperglycemia and diabetes? Why should we care about hyperglycemia in the ICU? 2. How should we manage hyperglycemia in the ICU and non-ICU settings?

Strategies for Achieving Glycemic Targets in the ICU Leuven SICU Study1 Yale Insulin Infusion Protocol2 MICU Insulin Infusion Protocol (N=69) 50 100 150 200 250 300 350 400 450 12 24 36 48 60 72 Hours Blood Glucose (mg/dL) Glucommander3 2 4 6 8 10 14 16 18 20 22 Glucose (mg/dL) Van den Berghe et al. N Engl J Med. 2001;345:1359-1367. 2. Goldberg PA et al. Diabetes Care. 2004;27:461-467. 3. Davidson et al. Diabetes Care. 2005;28:2418-2423. 4. Finfer S, et al. N Engl J Med. 2009;360(13):1283-1297. Admission Day 1 Day 5 Day 15 Blood Glucose (mmol/L) Intensive - Mean BG 103 mg/dL Conventional - Mean BG 153 mg/dL Last day Strategies for Achieving Glycemic Targets in the ICU NICE-SUGAR4

Intensive IV Insulin Protocols Hypoglycemia Rates in Intensive IV Insulin Protocols Protocol Hypo definition % patients RR Leuven SICU1 <40 mg/dL 5.1% 7 Leuven MICU2 19% 6 Glucontrol3 8.6% -- VISEP4 17.4% 4.11 NICE SUGAR5 6.5% 13.7 GLUCO-CABG6 <40 mg/dl 0% Only BG < 40 mg/dl are usually reported in RCT… We must change this. Van Den Berghe G, et al. N Engl J Med. 2001:345:1359; Van Den Berghe G, et al. N Engl J Med. 2006;354:449-461; Brunkhorst FM et al. N Engl J Med. 2008; 358:125-139; Preiser JC, SCCM, 2007; Finfer S, et al. N Engl J Med. 2009;360(13):1283-1297; Umpierrez , ADA 2014

Glycemic Values Achieved with IV Insulin Protocols Protocol IIT CIT Leuven SICU 103 153 Leuven MICU 111 De la Rosa 120 149 Glucontrol 118 143 VISEP 112 151 NICE SUGAR 145 GLUCO-CABG 132 154 Every RCT has shown that you can achieved great BG control (even in the control group). Thus, better or different algorithms may not be the answer… IIT: Intensive insulin therapy; CIT: Control, conventional/Conservative insulin therapy Results are expressed as mean BG during hospital stay, mg/dL Van Den Berghe G, et al. N Engl J Med. 2001; Van Den Berghe G, et al. N Engl J Med. 2006;De la Rosa,et al, Crit Care 2008; Brunkhorst et al. N Engl J Med. 2008; Preiser JC, SCCM, 2007; Nice Sugar, NEJM 2009; Umpierrez 2014 (ADA, unpublished)

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

Insulin Therapy in patients with T2D D/C oral antidiabetic drugs on admission Insulin naïve: starting total daily dose (TDD): 0.3 U/kg to 0.5 U/kg Lower doses in the elderly and renal insufficiency Previous insulin therapy: reduce outpatient insulin dose by 20-25% Basal bolus regimen: Half of TDD as basal and half as rapid-acting insulin before meals Umpierrez et al, Diabetes Care 30:2181–2186, 2007; Baldwin et al, Diabetes Care 10:1970-4, 2011; Rubin et al, Diabetes Care 34:1723-8, 2011 28

Sliding Scale Regular Insulin Basal Bolus Insulin Regimen Inpatient Management in non-ICU Setting Sliding Scale Regular Insulin Basal Bolus Insulin Regimen In insulin naïve patients with T2DM, does treatment with basal bolus regimen with glargine once daily and glulisine before meals is superior to sliding scale regular insulin? RABBIT-2D TRIAL: - Research Question: Umpierrez et al, Diabetes Care 30:2181–2186, 2007

D/C oral antidiabetic drugs on admission Randomized Basal Bolus versus Sliding Scale Regular Insulin in patients with type 2 Diabetes Mellitus (RABBIT-2 Trial) 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 (glulisine) Insulin glargine - once daily, at the same time/day. Glulisine- three equally divided doses (AC) Umpierrez et al, Diabetes Care 30:2181–2186, 2007 30

Rabbit 2 Trial: Changes in Glucose Levels With Basal-Bolus vs Rabbit 2 Trial: Changes in Glucose Levels With Basal-Bolus vs. Sliding Scale Insulin 240 Hypoglycemia rate: Basal Bolus Group: BG < 60 mg/dL: 3% BG < 40 mg/dL: none SSRI: BG < 40 mg/dL: none 220 a 200 a a b b 180 b BG, mg/dL b Sliding-scale 160 140 Basal-bolus 120 100 Admit 1 2 3 4 5 6 7 8 9 10 Key Point: Patients randomized to basal-bolus therapy achieved better glycemic control compared with those receiving sliding-scale insulin delivery in a hospitalized, non–ICU setting. This multicenter, prospective, open-label, randomized study enrolled 130 nonsurgical, insulin-naïve patients with a known history of diabetes for >3 months, admitted to medical general services with a blood glucose level between 140 and 400 mg/dL. Patients were randomly assigned to receive either sliding-scale regular insulin (SSRI; n=65) 4 times daily or a basal-bolus regimen with insulins glargine and glulisine (n=65). The goal of insulin therapy was to maintain fasting and premeal blood glucose levels <140 mg/dL while avoiding hypoglycemia. Compared with the basal-bolus group, patients who received sliding-scale insulin delivery had higher mean fasting glucose (165 ± 41 vs 147 ± 36 mg/dL, respectively, P<.01), mean random glucose (189 ± 42 vs 164 ± 35 mg/dL, respectively, P<.001), and mean glucose (193 ± 54 vs 166 ± 32 mg/dL, respectively, P<.001) during the hospital stay. The overall BG difference between treatment groups was 27 mg/dL (P<.01), with a mean daily BG difference ranging from 23 to 58 mg/dL during days 2 through 6 of therapy (P<.01). aP<.05. Days of Therapy bP<.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 Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181-2186. Umpierrez GE, Smiley D, Zisman A, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care. 2007;30(9):2181-2186.

DEAN TRIAL: Inpatient Management in non-ICU Setting Basal Bolus Insulin Regimen NPH and Regular Insulin-Spilt-Mixed Regimen In patients with T2DM on diet, oral agents or insulin treatment, does treatment with basal bolus regimen with detemir once daily and aspart before meals is superior to NPH and Regular split-mixed insulin regimen? DEAN TRIAL: - Research Question: Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009

DEAN Trial: Changes in Mean Daily Blood Glucose Concentration 240 Detemir + aspart NPH + regular 220 200 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% DEAN Trial: Hypoglycemia P=NS 180 BG, mg/dL 160 140 120 In the DEAN (Detemir plus Aspart vs NPH Plus Regular in Medical Patients with T2DM) trial, investigators randomized 130 nonsurgical patients with a blood glucose (BG) between 140 and 400 mg/dL to receive detemir once daily and aspart before meals (n=67) or neutral protamine Hagedorn (NPH) and regular insulin twice daily (n=63). Patients treated with detemir/aspart received half of the total daily dose (TDD) as detemir and half as aspart insulin. Detemir was given once daily at the same time of the day. Aspart was given in 3 equally divided doses with each meal. To prevent hypoglycemia, if a patient was not able to eat a given meal, the dose of aspart was held. Insulin dosage was adjusted daily according to BG values. Patients treated with NPH/regular insulin received two thirds of TDD before breakfast and one third before dinner. The insulin dose was given as two thirds NPH and one third regular insulin in the morning with breakfast, and two thirds NPH and one third regular insulin in the evening with dinner. The slide shows the changes in mean daily BG concentration. The BG target of less than 140 mg/dL before meals was achieved in 45% of the detemir/aspart group and in 48% of the NPH/regular group (P=NS). 100 Pre-Rx 1 2 3 4 5 6-10 BG Duration of Therapy, d 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. Umpierrez GE, et al. J Clin Endocrinol Metab. 2009;94(2):564-569. Umpierrez GE, Hor T, Smiley D, et al. Comparison of inpatient insulin regimens with detemir plus aspart versus neutral protamine hagedorn plus regular in medical patients with type 2 diabetes. J Clin Endocrinol Metab. 2009;94(2):564-569.

Bueno, Benitez eta al. 2012 ADA Scientific Meeting, New Orleans Randomized Controlled Study Comparing Basal Bolus with Insulin Analogs vs Human Insulins in General Medicine Patients Basal bolus with glargine QD + glulisine AC versus NPH b.i.d. & regular AC. - 0.4 U/kg/d x BG: 140-200 mg/dL - 0.5 U/kg/d x BG: 201-400 mg/dL Bueno, Benitez eta al. 2012 ADA Scientific Meeting, New Orleans

Basal Bolus Regimen Analogs vs. Human Insulins Algo claro es que el esquema basal-bolos funciona. El comportamiento de la medianas es similar y probablemente no hayan diferencias demostrables estadísticamente entre los 2 brazos de intervención Bueno, Benitez eta al. 2012 ADA Scientific Meeting, New Orleans

Hypoglucemias por brazo de intervención ALL N= 134 Analogs N=66 Human N=68 p-value Patients with Hypoglycemia, n (%) 49 (37) 23 (35) 26 (38) OR:1.16 p: 0.68 Severe Hypoglucemia, n (%) 22 (16) 5 17 OR:2.93 P:0.04 Mild Hypoglucemia, n (%) 95 44 51 Patients withn ≥2 episodes, n (%) 26 (19) 10 16 OR:2.08 P:0.2 Hasta ahora el numero y porcentaje de pacientes con hipoglucemias es igual en cada brazo, pero la distribución de los 38 episodios es diferente. Hubieron más episodios entre los que usaron humanas que en los que usaron análogos y el numero de episodios severos tambien fue mayor( más del doble. Bueno, Benitez eta al. 2012 ADA Scientific Meeting, New Orleans

Randomized study of basal bolus insulin therapy in the management of general surgery patients with T2DM (Rabbit Surgery) Research Question: In patients with T2DM on diet, oral agents or insulin treatment, does treatment with basal bolus regimen with glargine and glulisine is superior to SSRI? Primary Outcomes: Differences between groups in mean daily BG Composite of hospital complications: wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia Umpierrez et al, Diabetes Care 34 (2):1–6, 2011

Mean BG before meals and at bedtime during basal bolus and SSI therapy Glargine+Glulisine Sliding Scale Insulin * * * * Breakfast Lunch Dinner Bedtime *p<0.001 Umpierrez et al, Diabetes Care 34 (2):1–6, 2011

Postoperative Complications Glargine+Glulisine Sliding Scale Insulin P=0.05 P=0.10 P=0.24 P=NS * Composite of hospital complications: wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia. Umpierrez et al, Diabetes Care 34 (2):1–6, 2011

Percent of patients with hypoglycemia during basal bolus and SSI therapy BG <70 mg/dL BG <60 mg/dL BG <40 mg/dL 23 5 10 15 20 25 Insulin Glargine + Insulin Glulisine SSI P <0.001 12 2 5 10 15 20 25 Insulin Glargine + Insulin Glulisine SSI P <0.001 4 5 10 15 20 25 Insulin Glargine + Insulin Glulisine SSI P =0.057 There were no differences in hypoglycemia between patients treated with insulin prior to admission compared to insulin-naïve patients. Umpierrez et al, Diabetes Care 34 (2):1–6, 2011

Insulin Treatment in in Non-ICU Setting T2DM with BG > 140 mg/dl (7.7 mmol/l) NPO Uncertain oral intake Adequate Oral intake Basal insulin - Start at 0.2-0.25 U/Kg/day* - Correction doses with rapid acting insulin AC - Adjust basal as needed Basal Bolus TDD: 0.4-0.5 U/Kg/day ½ basal, ½ bolus - adjust as needed GROUP 1. Insulin Glargine Once Daily Plus Supplemental Insulin Glulisine Oral antidiabetic drugs (sulfonylureas, repaglinide, nateglinide, metformin, TZDs) will be discontinued on admission. Starting total daily insulin dose: 0.5 units per kilogram of body weight per day Half of total daily dose will be given as insulin glargine and half as insulin glulisine. Insulin glargine will be given once daily, at the same time of the day. Insulin glulisine will be given in three equally divided doses before each meal. To prevent hypoglycemia, if a subject is not able to eat, the dose of glulisine will be held. Do you need basal bolus in ALL patients?

Basal Plus Correction vs. Basal Bolus Basal plus supplements Starting glargine*: 0.25 units/kg Correction with glulisine for BG >140 mg/dl per sliding scale Basal Bolus Regimen Starting TDD*: 0.5 U/kg Glargine: 0.25 U/kg Glulisine: 0.25 U/kg in three equally divided doses (AC) Correction with glulisine for BG >140 mg/dl per sliding scale * Reduce TDD to 0.15 U/kg in patients ≥70 yrs and/or serum creatinine ≥ 2.0 mg/dL * Reduce TDD to 0.3 U/kg in patients ≥70 yrs and/or serum creatinine ≥ 2.0 mg/dL Umpierrez et al, Diabetes Care 2013

Basal-PLUS vs Basal Bolus: 300 medical & surgical non-ICU patients glargine once daily 0.25 U/kg plus glulisine supplements Basal Bolus: TDD: 0.5 U/kg/d Glargine 50% glulisine 50% Preliminary results: Basal bolus 51 patients, basal-plus: 49 patients Umpierrez et al, Diabetes Care 2013

Differences in glycemic control and frequency of treatment failures in patients treated with basal bolus, basal plus and sliding scale regular insulin Umpierrez et al, Diabetes Care, 2013

Basal-PLUS vs Basal Bolus: Medicine and Surgery Patients Daily BG Daily BG BG AC & HS BG AC & HS Smiley et al, Diabetes Care 2013

What about Incretin-Based Therapy? Management of Patients With Diabetes in Non-ICU Settings Inpatient Management in non-ICU What about Incretin-Based Therapy? Basal Bolus or Basal Plus Regimens

DPP-4 Therapy in Hospitalized Patients Study Type: Multicenter, prospective, open-label randomized clinical trial Patient Population: Patients with T2D admitted to general medicine and surgery services at 3 hospitals: Emory University, Grady, and University of Michigan Treatment Groups* Group 1. Sitagliptin once daily (n=30) Group 2. Sitagliptin plus glargine insulin once daily (n=30) Group 3. Basal bolus regimen with glargine once daily and lispro before meals (n=30) * All groups received supplemental doses of lispro for BG > 140 mg/dl before meals Umpierrez et al. Care. 36(11):3430-5, 2013

Mean Daily BG During Treatment Randomi-zation Umpierrez et al. Care. 36(11):3430-5, 2013

Mean BG before meals and at bedtime during Treatment P=0.52 P=0.57 P=0.22 P=0.15 Data is mean ± SE Umpierrez et al. Care. 36(11):3430-5, 2013

Mean Daily Blood Glucose (mg/dL) Randomization Blood Glucose (<180 mg/dl and >180 mg/dl) and Mean Daily Glucose concentration p= 0.08 p= 0.91 Mean Daily Blood Glucose (mg/dL) Umpierrez et al. Care. 36(11):3430-5, 2013

Recommendations for Managing Patients With Diabetes After Hospital Discharge Use admission A1C to adjust therapy at discharge 10% ADD basal or REPLACE with basal/bolus 9% ADD basal insulin therapy 8% Adjust original therapy, ADD another agent or basal insulin 7% Return to original therapy Umpierrez G et al, J Clin Endocrinol Metabol, 2012

Discharge Insulin Algorithm Discharge Treatment A1C < 7% A1C 7%-9% A1C >9% Re-start outpatient treatment regimen (OAD and/or insulin) Re-start outpatient oral agents and D/C on glargine once daily at 50-80% of hospital dose D/C on basal bolus at same hospital dose. Alternative: re-start oral agents and D/C on glargine once daily at 80% of hospital dose Umpierrez et al, ADA Scientific Sessions, 2012

Hospital Discharge Algorithm Based on Admission HbA1C for the Management of Patients with T2DM 8.75% 7.9% % 7.35% Umpierrez et al, ADA Scientific Sessions, 2012

Hospital Discharge Algorithm Based on Admission HbA1C for the Management of Patients with T2DM Primary outcome: - change in A1C at 4 wks and 12 wks after discharge All Patients OAD OAD + Glargine Glargine+ Glulisine Glargine # patients, n (%) 224 81 (36) 61 (27) 54 (24) 20 (9) A1C Admission, % 8.7±2.5 6.9±1.5 9.2±1.9 11.1±2.3 8.2±2.2 A1C 4 Wks F/U, % 7.9±1.7* 7.0±1.4 8.0±1.4ψ 8.8±1.8ψ 7.7±1.7 A1C 12 Wks F/U, % 7.3±1.5* 6.6±1.1 7.5±1.6* 8.0±1.6* 6.7±0.8* BG<70 mg/dl, n (%) 62 (29) 17 (22) 17 (30) 23 (44) 5 (25) BG<40 mg/dl, n (%) 7 (3) 3 (4) 0 (0) 3 (6) The primary outcome: change in HbA1C at 4 and 12 wks after discharge. The HbA1c on admission was 8.67±2.5% and decreased to 7.86±1.7% at 4 wks and to 7.26±1.48% at 12 wks of follow-up (both, p<0.001). * p< 0.001 vs. Admission A1C; ψp=0.08 Umpierrez et al, ADA Scientific Sessions, 2012

Management of diabetes in non-critical care setting So… What really have we learned?

Guillermo E. Umpierrez, MD Thank you! Guillermo E. Umpierrez, MD geumpie@emory.edu

Inpatient Management of Medical and Surgical Patients with Type 2 diabetes- ICU and non-ICU Guillermo E. Umpierrez, MD, FACP, FACE Professor of Medicine Director, Grady Hospital Clinical Research Unit Emory University School of Medicine Director, Diabetes & Endocrinology Section Grady Hospital CIN (Research Unit) Grady Health System

External Industry Relationships * Dr. Guillermo Umpierrez, Personal/Professional Financial Relationships with Industry External Industry Relationships * Company Name(s) Role Equity, stock, or options in biomedical industry companies or publishers None Board of Directors or officer Royalties from from external entity Industry funds to Emory for my research Sanofi-Aventis Merck Novo Nordisk Boehringer Ingelhein Investigator-Initiated Research Projects

Hyperglycemia in non-critical care setting: Lecture Agenda Scope of the Problem: What is the frequency and impact of hyperglycemia and diabetes? What diagnosis criteria should we use? What target glucose should we aim? 2. How should we manage hyperglycemia in ICU and non-ICU setting? Insulin regimens – Which and how to start? Incretin-base regimens – are they safe & effective? Discharge algorithm – What is the role of the admission HbA1c? Umpierrez et al. J Clin Endocrinol Metabol. 97(1):16-38, 2012

Hyperglycemia: A Predictor of Mortality Following CABG in Diabetics 10 [Furnary. Circulation.1999/ pI591/line 8-19] BG >200 P<0.0001 BG <200 8.6 n=1369 n=662 8 Postop 1.8% 5.0% * Mortality *P<0.001 5.8 6 Postop Mortality (%) Adjusted for 19 clinical and operation variables 3.8 4 First Postop Glucose >200 2x LOS 3x Vent duration 7x mortality !!! 2.1 1.7 2 1.4 <150 150- 175- 200- 225- >250 CABG, coronary artery bypass graft. 175 200 225 250 Furnary AP et al. Circulation. 1999:100 (Suppl I): I-591. Blood Glucose (mg/dL)

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

Pharmacologic Therapy in Non-ICU Setting Patients treated with insulin at home require scheduled SQ insulin therapy in the hospital (1) Avoid prolonged use of sliding scale insulin as sole method for glycemic management (2) Scheduled SQ insulin consists of basal or intermediate acting insulin in combination with RAI or Regular insulin administered before meals in patients who are eating(1) Include correction insulin as a component of scheduled SQ insulin for treatment of BG above desired range (2) GE Umpierrez, R Hellman, MT Korytkowski, M Kosiborod, GA Maynard, VM Montori, JJ Seley, GV den Berghe. J Clin Endocrinol Metabol. 97(1):16-38, 2012

Basal Bolus Insulin Regimen D/C oral antidiabetic drugs on admission Starting total daily dose (TDD): 0.5 U/kg/day TDD reduced to 0.3 U/kg/day in patients ≥ 70 years of age or with a serum creatinine ≥ 2.0 mg/dL Half of TDD as insulin glargine and half as insulin glulisine* Glargine - once daily, at the same time of the day Glulisine- three equally divided doses (AC) GROUP 1. Insulin Glargine Once Daily Plus Supplemental Insulin Glulisine Oral antidiabetic drugs (sulfonylureas, repaglinide, nateglinide, metformin, TZDs) will be discontinued on admission. Starting total daily insulin dose: 0.5 units per kilogram of body weight per day Half of total daily dose will be given as insulin glargine and half as insulin glulisine. Insulin glargine will be given once daily, at the same time of the day. Insulin glulisine will be given in three equally divided doses before each meal. To prevent hypoglycemia, if a subject is not able to eat, the dose of glulisine will be held. *If a patient was not able to eat, insulin glargine was given but, insulin glulisine was held until meals were resumed. Umpierrez et al, Diabetes Care 34 (2):1–6, 2011