New Approaches to Managing Inpatient Hyperglycemia ACP Meeting MTP Session, April 24th, 2009 Review of Recent Developments in Context Greg Maynard MD, MSc Clinical Professor of Medicine and Chief, Division of Hospital Medicine, University of California, San Diego

Disclosure of Financial Relationships Greg Maynard MD, MSc Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients.

Outline Glycemic Target Controversies Transition from Infusion Ward Glycemic Control Hypoglycemia Larger Context

AACE - Consensus Conference Blood Glucose Targets Upper Limit Inpatient Glycemic Targets: ICU: 110 mg/dl (6.1 mmol/L) Non-critical care (limited data) Pre-prandial: 110 mg/dl (6.1 mM) Maximum: 180 mg/dL (10 mM) The current ADA guideline for pre-prandial plasma glucose is now < 126 mg/dL AACE- Endocrine Practice 10 (1): 77-82, 2004 ADA- Diabetes Care 27: 553-591, 2004 Diabetes Care 31:S12-S54, 2008 - The language around glycemic targets has softened in the 2008 version of the ADA Standards.

Negative Studies of Infusion Insulin Recent negative studies Glucontrol, VISEP, JAMA Meta-Analysis Vol 300 (8):933-944. Caveats Discontinued early Poor protocols drove results (viewed as suboptimal) Delta Glucose less than desirable Very high hypoglycemia rates seen in these studies….3 x hypoglycemia rate seen in U.S.

NICE – SUGAR March 26, 2009 NEJM Vol 360 (13) Open Label RCT, Multinational 6104 critically ill patients Intensive infusion (81-108 mg/dL) vs “Conventional” control (144 – 180 mg/dL) 90 day survival – primary end point

Blood Glucose Values, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

Probability of Survival Odds Ratios for Death, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

NICE - SUGAR 90 day mortality 27.5% vs 24.9% Severe hypoglycemia 6.8% vs 0.5% Glucose control (median) 107 vs 141 mg/dL Insulin infusion 97% vs 69% No difference – 30 day mortality, ICU days, hospital days, days of mechanical ventilation, days of renal replacement, organ failures

Summary Data from Randomized Clinical Trials of Intensive Insulin Therapy in Critically Ill Patients Inzucchi S and Siegel M. N Engl J Med 2009;360:1346-1349

Severe Hypoglycemia (< 40 mg / dL) with Different Infusion Protocols Leuven I (Surgical) 5.1% Leuven 2 (Medical) 19% Glucontrol (Med / Surg) 8.6% VISEP (Medical) 17% Yale (Surgical) 0% Yale (Medical) 4.3% Glucommander (Surgical) 2.6% NICE – SUGAR (Med / Surg) 6.8% 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 et al, N Engl J Med 358:125-39, 2008 Goldberg PA, et al. Diabetes Care. 2004;27:461; Goldberg PA, et al. J Cardiothorac Vasc Anes. 2004;18:690; Davidson PC. Diabetes Care. 2005;28:2418. NICE – SUGAR investigators NEJM 2009 360 (13) 1283-1297

UCSD Insulin Infusion 200 Med Surg patients >16,000 values Upper Limit – 150 mg /dL Mean BG126 Median BG121   below 90 6.1% 91-150 76.6% above 150 17.3% % below 70 < 2% Only 2 patients with any glucose < 40 mg/dL

NICE-SUGAR vs UCSD NICE - SUGAR UCSD Target Range (mg / dL) 80 – 110 90 – 150 Median Glucose 118 121 Severe Hypoglycemia 6.8% < 2%

AACE - Consensus Conference Blood Glucose Targets Upper Limit Inpatient Glycemic Targets: ICU: 110 mg/dl (6.1 mmol/L) Non-critical care (limited data) Pre-prandial: 110 mg/dl (6.1 mM) Maximum: 180 mg/dL (10 mM) The current ADA guideline for pre-prandial plasma glucose is now < 126 mg/dL AACE- Endocrine Practice 10 (1): 77-82, 2004 ADA- Diabetes Care 27: 553-591, 2004 Diabetes Care 31:S12-S54, 2008 - The language around glycemic targets has softened in the 2008 version of the ADA Standards.

AACE - Consensus Conference Blood Glucose Targets Upper Limit Inpatient Glycemic Targets: ICU: 110 mg/dl (6.1 mmol/L) Non-critical care (limited data) Pre-prandial: 110 mg/dl (6.1 mM) Maximum: 180 mg/dL (10 mM) The current ADA guideline for pre-prandial plasma glucose is now < 126 mg/dL AACE- Endocrine Practice 10 (1): 77-82, 2004 ADA- Diabetes Care 27: 553-591, 2004 Diabetes Care 31:S12-S54, 2008 - The language around glycemic targets has softened in the 2008 version of the ADA Standards.

RCTs with demonstrating convincing benefit of TGC on general med – surg wards:

? New AACE / ADA Guidelines ? GOOD BAD BAD The point – the goal is somewhere in the middle … exactly where is not clear but too high and too low are definitely not good. Hypoglycemia Hyperglycemia Somewhere in the Middle <40 70 110 140 170 >200 17

Transitions

Transition from Infusion Insulin Ramos, Childers, Maynard – SHM Abstract

UCSD new Transition Protocol Need SC insulin when infusion stops? YES- DM1 DM 2 or A1c ≥ 6 and infusion rate ≥ 1 unit / hour On high dose steroids and rate ≥ 1 unit / hour NO- Type 2 DM with infusion rate < 1 unit / hour Stress hyperglycemia with HbA1c < 6 Even if high infusion rates

Step by Step Stable enough for transition? Need SC insulin with transition? Calculate TDD If taking in nutrition on infusion: IR x 20 = TDD If not taking nutrition on infusion, infusion only serving basal needs IR x 40 = TDD Give 40-50% of TDD as basal glargine BEFORE you stop the insulin infusion

Run Chart: Outcome Measures Glycemic control 48 hrs post transition with and without protocol. Transition Time Insulin Infusion Day 1 Day 2

Outcome Measures Severe Hypoglycemia (<40 mg/dL) 3 of 114 transitions or 2.6%. Protocol followed 1 of 66 patients or 1.5% Protocol not followed 2 of 48 patients or 4.2% Protocol followed (n=65) Basal recommended: 1/30 or 3.3% No basal recommended: 0/35 or 0% Protocol not followed (n=48) Basal recommended: 1/39 or 2.8% No basal recommended: 1/9 or 11.1% 23

Methods for Managing Hospitalized Non-ICU Patients With Diabetes Basal/bolus therapy (MDI) Long-acting and rapid-acting insulin NPH and Regular insulin Sliding Scale Short-Acting Insulin 24

Randomized Basal Bolus versus Sliding Scale Regular Insulin Therapy in patients with type 2 Diabetes (RABBIT-2 Trial) Study Type: Prospective, randomized, open-label trial Patient Population: 130 subjects with DM2 Oral hypoglycemic agents or insulin therapy Study Sites: Grady Memorial Hospital, Atlanta Jackson Memorial Hospital, Miami

(RABBIT-2 Trial) Basal / Bolus arm D/C oral antidiabetic drugs on admission Starting total daily dose (TDD): 0.4 U/kg/d x BG between 140-200 mg/dL 0.5 U/kg/d x BG between 201-400 mg/dL Half of TDD as insulin glargine and half as rapid-acting insulin (lispro, aspart, glulisine) Insulin glargine - once daily, at the same time/day. Rapid-acting insulin- three equally divided doses (AC) Smiley & Umpierrez, Southern Med J, June 2006

Mean Blood Glucose Levels During Insulin Therapy * * * ¶ ¶ ¶ ¶ * p<0.01 ¶ p<0.05 Day 3: P=0.06 Umpierrez, Diabetes Care 30: 2007

Basal–Bolus Insulin Regimen in Noncritically Ill Patients 29

Blood Glucose Levels in Patients Who Failed SSRI: Transition to Basal Bolus Insulin P: NS P: 0.02 ¶ ¶ ¶ ¶ ¶ Failure was defined as 3 consecutive BG values > 240 mg/dL during SSRI Umpierrez, Diabetes Care 30: 2007

RABBIT 2 Improved glycemic control with basal / bolus insulin regimen compared to SSRI Subset that failed with SSRI controlled with basal / bolus No difference in hypoglycemia (3% of patients in each arm) Umpierrez, Diabetes Care 30: 2007

Effect of Structured Insulin Orders and an Insulin Management Algorithm - UCSD 400 bed academic center All adult monitored stays on Med / Surg wards with dx of DM or Documented Hyperglycemia n = 9,314 > 7 readings n = 5,530 What is effect of implementing a structured insulin order set? What is the incremental effect of an insulin management protocol? Insulin Use Patterns Glycemic Control Hypoglycemia Maynard et al, JHM January 2009; 4: 3-15

The Use of Basal Insulin Increases (sliding scale only regimens decline) UCSD clinicians have done a good job of switching to regimens that have some scheduled basal insulin in them, but we still see a lot of variability. The first generation order set was introduced 10/03, and the computerized order entry version was initiated at UCSD Thornton 1/04, then at Hillcrest in the summer of ’04. 72% of 477 insulin regimens SSI only in May-Oct 2003 vs 26% of 499 in Mar-Aug 2004 72% of 477 insulin regimens SSI only in May-Oct 2003 vs 26% of 499 in Mar-Aug 2004

% of 9,314 Patient-Stays with Uncontrolled Hyperglycemia

A Win / Win Situation 5,530 patients with DM or Hyperglycemia and > 7 POC Glucose readings TP3:TP1 RR Uncontrolled Patient-Day 0.77 (0.74 - 0.80) RR Uncontrolled Patient-Stay (70% controlled vs 60%) 0.73 (0.66 - 0.81) RR Hypoglycemic Patient-Day (prevents 208 / year) 0.68 (0.59 – 0.80) RR Hypoglycemic Patient-Stay 0.77 (0.64 – 0.92) Maynard et al, JHM January 2009; 4: 3-15

Methods for Managing Hospitalized Non-ICU Patients With Diabetes Basal/bolus therapy (MDI) Long-acting and rapid-acting insulin NPH and Regular insulin Sliding Scale Short-Acting Insulin 36

DEAN-Trial Detemir + Novolog NPH + Regular Blood glucose (mg/dL) Duration of Therapy (days) Data are ± SEM Basal/bolus regimen: Detemir was given once daily and Novolog before meals. NPH/regular regimen: NPH and Regular insulin were given twice daily, 2/3 A.M., 1/3 P.M. 37

Hypoglycemia Detemir/Aspart Group: 22 patients (32.8%) had ≥ 1 BG < 60 mg/dL 3 patients (4.5%) had a < 40 mg/dL (0.2%) NPH/Regular Group: 16 patients (25.4%) had ≥ 1 BG < 60 mg/dL 1 patient (1.6%) had a BG < 40 mg/dL Severe hypoglycemia defined as a BG < 40mg/dL ADA, 68th Scientific Sessions, 2008; JCEM, in press 38 38

Blood Glucose Concentration During SSRI, NPH-regular, and Basal Bolus Regimen in Medical Patients with Type 2 Diabetes Umpierrez et al, Diabetes Care 30:2181–2186, 2007 Umpierrez et al, ADA, 68th Scientific Sessions, 2008; JCEM, in press 39

Percent of Glucose values within target (< 140 mg/dl) RABBIT-2 Trial DEAN Trial * 66% 48% 45% % % 38% * P < 0.01 Umpierrez et al. Diabetes Care 30:2181–86, 2007 Umpierrez et al. JCEM, in press 40

(# patients with BG < 60 mg/dl) Rate of Hypoglycemia (# patients with BG < 60 mg/dl) RABBIT-2 Trial DEAN Trial 32.8 25.4 % % 3 3 Umpierrez et al. Diabetes Care 30:2181–86, 2007 Umpierrez et al. JCEM, in press 41

Summary – Ward Glycemic Control Optimal Glycemic Target Uncertain My bias: Fasting should likely be < 150 mg/dL Upper limit of no sugars > 180 mg/dL reasonable Basal / Bolus regimens with Glargine / RAA-insulin more effective than sliding scale and present no higher risk of hypoglycemia Well executed order sets / protocols can improve glycemic control and reduce hypoglycemia. Detemir/aspart resulted in equivalent glycemic control to a split-mixed NPH and regular regimen (but hypoglycemia higher than with RABBIT 2 regimen and UCSD regimens)

Hypoglycemia

Precipitating factors Etiologic factor % of hypo cases Reduction in enteral intake 40 Insulin adjustment 6.1 Steroid withdrawal 0.4 Unclear 43 “Diverse causes” 10.4 Medication error none Varghese P, et al. J Hosp Med. 2007; 2:234-240)

Hypoglycemia follow-up 1/3 with documented BG rechecked within 60 minutes < 50% with documented euglycemia within 2 hours of low Average time to documented resolution was 4 hrs, 3mins (median 2 hrs, 25mins) Varghese P, et al. J Hosp Med. 2007; 2:234-240)

Provider Response to Insulin-Induced Hypoglycemia in Hospitalized Patients Case series – 52 patients Delays in treatment Suboptimal adjustment of regimens common Garg, et al. J Hosp. Med. 2007; 2:258-260

Iatrogenic Hypoglycemia – Risk Factors, Treatment, and Prevention 130 ward inpatients monitored for glucose 65 consecutive cases with iatrogenic hypoglycemic day Matched 1:1 with controls (monitored, similar hospital day, not hypoglycemic) Examine risk factors for hypoglycemia Study hypoglycemia treatment and adjustments made to prevent recurrence Maynard et al, Diabetes Spectrum 2008 Vol 21:4 241-247.

Hypoglycemia – 65 cases Severe (≤ 40 mg / dL) 11 17% Nutrition / insulin mismatch 32 49% Absent documentation 19 29% Time next value (minutes) 60 (8 – 600) Time to resolution (minutes) 180 (10 – 1,260) Temporary harm 2 3%

Hypoglycemic Cases vs Controls Univariate Unadjusted Statistically Different Lower weight: 73.4 vs 89.7 Kg Lower BMI: 26 vs 31 More CKD / ESRD: 35% vs 17% More CHF: 37% vs 15%

Hypoglycemia: Take Home Points Suboptimal response to hypoglycemia is the rule Nurses and physicians! Opportunities for prevention often missed. Make a change after hypoglycemic event. Mere Existence of a hypoglycemia protocol does not guarantee good management SC insulin protocols promoting basal / bolus regimens can achieve improved control safely ---hypoglycemia can even be reduced.

Society of Hospital Medicine Big Picture Context DM / Hyperglycemia very common Controversy over exact glycemic target distracts from larger issues Chaos and avoidable hyper- and hypo-glycemia are the rule Alternatives (SSI, laissez faire) don’t work and can be dangerous Standardization / team approach / protocols / order sets / metrics

Inpatient DM Resources http://www.aace.com/resources/igcrc/ http://www.hospitalmedicine.org/ResourceRoomRedesign/GlycemicControl.cfm SHM Glycemic Control Mentored Implementation Program

Questions / Comments