1. 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

2. 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.

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

4. 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: , 2004
Diabetes Care 31:S12-S54, The language around glycemic targets has softened in the 2008 version of the ADA Standards.

5. Negative Studies of Infusion Insulin
Recent negative studies
Glucontrol, VISEP, JAMA Meta-Analysis Vol 300 (8):
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.

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

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

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

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

10. 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:

11. Severe Hypoglycemia (< 40 mg / dL) with Different Infusion Protocols
Leuven I (Surgical) %
Leuven 2 (Medical) 19%
Glucontrol (Med / Surg) %
VISEP (Medical) 17%
Yale (Surgical) %
Yale (Medical) %
Glucommander (Surgical) %
NICE – SUGAR (Med / Surg) %
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: ;
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 (13)

12. UCSD Insulin Infusion 200 Med Surg patients >16,000 values Upper Limit – 150 mg /dL
Mean BG Median BG121  
below % %
above %
% below 70 < 2%
Only 2 patients with any glucose < 40 mg/dL

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

14. 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: , 2004
Diabetes Care 31:S12-S54, The language around glycemic targets has softened in the 2008 version of the ADA Standards.

15. 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: , 2004
Diabetes Care 31:S12-S54, The language around glycemic targets has softened in the 2008 version of the ADA Standards.

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

17. ? 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
< >200 17

18. Transitions

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

20. 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

21. 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

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

23. 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

24. 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

26. 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

27. (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 mg/dL
0.5 U/kg/d x BG between 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

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

29. Basal–Bolus Insulin Regimen in Noncritically Ill Patients29

30. 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

31. 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

32. 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, > 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

33. 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

34. % of 9,314 Patient-Stays with Uncontrolled Hyperglycemia

35. A Win / Win Situation 5,530 patients with DM or Hyperglycemia and > 7 POC Glucose readings TP3:TP1
RR Uncontrolled Patient-Day
0.77 ( )
RR Uncontrolled Patient-Stay (70% controlled vs 60%)
0.73 ( )
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

36. 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

37. 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

38. 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

39. 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

40. 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

41. (# 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

42. 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)

43. Hypoglycemia

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

45. 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: )

46. 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:

47. 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 Vol 21:

48. Hypoglycemia – 65 cases Severe (≤ 40 mg / dL) 11 17%
Nutrition / insulin mismatch %
Absent documentation %
Time next value (minutes) (8 – 600)
Time to resolution (minutes) (10 – 1,260)
Temporary harm %

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

52. 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.

53. 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

54. Inpatient DM Resources
SHM Glycemic Control Mentored Implementation Program

55. Questions / Comments