1. Diabetic Management in the Hospitalized Patient
Ben W. Seale, M.D.
Medical Director of Inpatient Diabetes Management
St. Dominic’s Hospital

2. Disclosures I speak on behalf of the following: Abbott AstraZeneca
Janssen
Lilly
Sanofi

3. Goals Outpatient goals Inpatient Goals Reduce Morbidity
Reduce Mortality
Improve Outcomes
Inpatient Goals

4. The Holy Trinity

5. The Holy Trinity

6. The Holy Trinity

7. Outpatient Targets Diabetic Goals: ADA ACE Lipid goals:
Preprandial: < 110
Postprandial: < 180 < 140
Lipid goals:
LDL < 100, ( <70 if known CVD)
non-HDL < 130
TG < 150
HDL > 40 (men), > 50 (women)
Blood pressure goal:
< 130/80

8. Types of Hyperglycemia in Hospitalized Patients
Known history of diabetes
Existing, but unrecognized, diabetes
Stress hyperglycemia
Reference:
Clement S, Braithwaite SS, Magee MF, et al. Management of diabetes and hyperglycemia in hospitals. Diabetes Care. 2004;27:
Clement et al. Diabetes Care. 2004;27:

9. Hyperglycemia and Poor Hospital Outcome
Metabolic stress response
 stress hormones and peptides
Glucose
 Insulin
Reactive O2 species
Transcription factors
Secondary mediators
Immune dysfunction
FFA
Ketones
Lactate
Infection dissemination
Hyperglycemia is associated with a wide range of physiologic derangements. This slide illustrates how the adverse effects of hyperglycemia may contribute to suboptimal patient outcomes, including poor outcomes after MI, cardiac surgery, and stroke; high rates of infection in hospitalized patients; disability; poor wound healing; increased mortality in some patient populations; and adverse health economic outcomes such as longer lengths-of-stay and increased costs. The adverse physiologic effects of hyperglycemia include the following:
Reversible Immune dysfunction: Reduction of phagocytosis, chemotaxis, and adherence, reduced superoxide formation, reduced lymphocyte counts, glycosylation of immunoglobulins.
Cardiovascular effects: Vascular endothelial dysfunction, increased infarct size with myocardial infarctions, decreased coronary collateral flow, increased viscosity and blood pressure.
Thrombosis: Platelet hyperactivity, increased plasminogen activator inhibitor and decreased plasma fibrinolytic activity and tissue plasminogen activator activity.
Inflammation: Increases in inflammatory markers, including IL-6 and TNF.
Oxidative Stress: Increases in reactive oxygen species.
Brain Effects: Increased neuronal damage post ischemia, increased acidosis and lactate.
GI effects: Gastroparesis.
Cellular injury/apoptosis
Inflammation
Tissue damage
Altered tissue wound repair
Clement et al,
Diabetes Care 27: , 2004
Prolonged hospital stay
Disability / Death

10. Inpatient Targets Has often depended upon the facility / provider
Tight control
Loose control
Keep them out of trouble
Keep them out of DKA
What is diabetes?

11. Hyperglycemia and Hospital Mortality*
Mortality (%) * *
The medical records of 2030 consecutive adult patients were analyzed for the presence of hyperglycemia and any association with poor hospital outcomes.
New hyperglycemia was associated with a 16% mortality rate compared with 3% and 1.7% for patients with a prior history of diabetes or normoglycemia (P<.01).
The mortality rate was significantly higher for patients with new hyperglycemia regardless of whether they were admitted to the ICU (P<.01 for both ICU and non-ICU patients compared with those with diabetes or normoglycemia). Mortality rates were 10% for non-ICU patients with new hyperglycemia and 31% for ICU patients.
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:
*P<.01 compared with normoglycemia and known diabetes.
Umpierrez GE et al. J Clin Endocrinol Metab. 2002;87:

12. Hyperglycemia and Mortality in Hospitalized Patients
Prospective study of 903 patients admitted to the hospital
22% had known history of diabetes
9% had new onset hyperglycemia in the diabetes range (FPG >126 mg/dL)
19% had impaired fasting glucose mg/dL
50% normoglycemia
Baker ST et al. Med J Aust: 2008; 188:

13. Association of Hyperglycemia with Mortality
Baker ST et al. Med J Aust: 188, ;2008

14. Mortality Among Non-diabetic Hyperglycemic Patients
Baker ST et al. Med J Aust: 188, ;2008

15. Hyperglycemia Impacts Rate of Infections
Rates of deep sternal wound infection in 4864 patients with diabetes who underwent an open-heart surgical procedure
Rate of infection, %
P=0.001
An increase in the 3-day postoperative BG average has a direct relationship with the incidence of deep sternal wound infections (DSWI). The investigators identified an apparent inflection point at 175 mg/dL, at which the incidence of DSWI begins to increase significantly.
Reference:
Furnary AP, Wu Y, Bookin SO. Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project. Endocr Pract. 2004;10(suppl 2):21-33.
3-day average postoperative blood glucose, mg/dL
Furnary et al. Endocr Pract. 2004;10(suppl 2):21-33.

16. Inpatient Approach

17. Inpatient Approach Two Conceptual groups ICU Patients Non-ICU Patients
IV Insulin
SQ Insulin
Non-ICU Patients
SQ insulin

18. Mortality After MI Reduced by Insulin Therapy
DIGAMI Study
Mortality After MI Reduced by Insulin Therapy
Standard treatment
IV Insulin 48 hours, then
4 injections daily .7
All Subjects .7
Low-risk and not previously on Insulin
(N = 620)
(N = 272) .6 .6
Risk reduction (28%)
Risk reduction (51%) .5
P = .011 .5
P = .0004 .4 .4 .3 .3
Slide 6-11
BARRIERS TO INSULIN THERAPY
Cardiovascular Risk
Mortality After MI Reduced by Insulin Therapy in the DIGAMI Study
Patients at high risk of cardiovascular disease are often thought to be inappropriate candidates for treatment with insulin because of the belief that hypoglycemia, hyperinsulinemia, or other metabolic effects of insulin might provoke or worsen the outcome of major cardiovascular events. This figure shows data from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial. This Swedish trial studied the short-term and long-term effects of intensive insulin treatment of patients with diabetes who were enrolled in the trial at the time of a myocardial infarction. The subjects were immediately randomized to continued management according to the judgment of their physicians, or to intravenous infusion of insulin and glucose for 48 hours followed by a four-injection regimen subsequently for as long as 5 years. Other aspects of management of the infarction included treatment with b-blockers, angiotensin-converting enzyme inhibitors, fibrinolytic agents, and aspirin in high proportions of both groups. The rationale underlying the study was the old observation that, in animal experiments and studies of small numbers of humans, infarct size and outcome are improved by insulin-glucose infusion, in part because of suppression of otherwise elevated free fatty acid levels in plasma. The figure shows the cumulative total mortality rates in the whole population of 620 subjects randomized to the two treatments, as well as the rates for a predefined subgroup of subjects who were judged likely to survive the initial hospitalization and were not previously using insulin. The whole population showed an 11% actual and a 28% relative risk reduction with intensive insulin treatment after 5 years, and the subgroup showed a 15% actual and a 51% relative risk reduction. Most of the benefit was apparent in the first month of treatment and presumably was partly due to immediate intravenous infusion of insulin; however, the survival curves tended to separate further over time, suggesting an ongoing benefit from intensive treatment. This study suggests that insulin is an entirely appropriate treatment for patients with type 2 diabetes and high cardiovascular risk, especially at the time of myocardial infarction.
Malmberg K, Rydén L, Hamsten A, Herlitz J, Waldenström, Wedel H, and the DIGAMI study group. Effects of insulin treatment on cause- specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. Eur Heart J. 1996;17: ; Nattrass M. Managing diabetes after myocardial infarction: time for a more aggressive approach. BMJ ;314:1497; Malmberg K, and the DIGAMI study group. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ. 1997;314: .2 .2 .1 .1 1 2 3 4 5 1 2 3 4 5
Years of Follow-up
Years of Follow-up
Malmberg, et al. BMJ. 1997;314:
6-11

19. Van Den Berghe Study
Van den Berghe, G. et al. N Engl J Med 2006;354:
1200 patients admitted to the SICU
3 days or more in ICU
<3 days in ICU
Control received standard insulin (SSI, Target <200)
Intensive arm received IV insulin (Target )
Average glucose 103

20. Van Den Berghe Study Intensive (N=765) Conventional (N=783) BG Targets
<110 mg/dl
<200 mg/dl
Achieved glucose *
% pts with BG < 40 5
0.7
The maximal dose of insulin was arbitrarily set at 50 IU/hr
When the patient left the ICU,a conventional approach was adopted (maintenance of blood glucose at a level between mg per deciliter).
Patients were randomized on admission to the ICU.
Van den Berghe G, et al. N Eng J Med 2001;345:
van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367

21. Van Den Berghe Study Intensive treatment Conventional treatment
100
Intensive treatment 96 92
Survival in ICU (%)
Conventional treatment 88 84
Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival
At 12 months, with a total of 1,548 patients enrolled, mortality during intensive care was reduced from 8.0% with conventional treatment to 4.6% with intensive insulin therapy (P < 0.04, with adjustment for sequential analyses).
Death in ICU >5 days was reduced from 20.2% to 10.6% (48% reduction)
Critiqued for high mortality rate in conventional group and concomitant use of TPN
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359–1367. 80 20 40 60 80
100
120
140
160
Days After Admission
Conventional: insulin when blood glucose > 215 mg/dL.
Intensive: insulin when glucose > 110 mg/dL and maintained at 80–110 mg/dL. 21
van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367. 21

22. Van Den Berhge Study Conventional Intensive (N=605) (N=595) ICU DEATHS
Total (26.8) (24.2) P 0.31
In ICU >3 days (38.1) (31.3) P 0.05
IN-HOSPITAL DEATHS
Total (40.0) (37.3) P 0.33
In ICU >3 days (52.5) (43.0) P 0.09
In ICU < 3 days
No significant differences across groups based on apache scores or causes of death.

23. Van Den Berhge Study
Intensive therapy to achieve blood glucose levels of 80–110 mg/dL reduced mortality (-34%), sepsis (-46%), dialysis (-41%), blood transfusion (-50%), and polyneuropathy (-44%)
Mortality
Sepsis
Dialysis
Blood Transfusion
Polyneuropathy
N = 1,548
Reduction (%)
Intensive Insulin Therapy in Critically Ill Surgical Patients: Morbidity and
Mortality Benefits
Intensive insulin therapy also reduced overall in-hospital mortality by 34%, bloodstream infections by 46%, acute renal failure requiring dialysis or hemofiltration by 41%, the median number of red-cell transfusions by 50%, and critical-illness polyneuropathy by 44%. Patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care.
The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than 5 days (20.2% with conventional treatment vs. 10.6% with intensive insulin therapy, P = 0.005).
The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus.
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359–1367.
34%
41%
44%
46%
50%
van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367. 23

24. VISEP Trial Blood Glucose Overall Survival
[Brunkhorst. NEJM.Jan. 2008/p131/Fig 1A; p134/Fig 2A]
Blood Glucose
Overall Survival
100
Conventional therapy (n=290) 80
200
150 60
Probability of Survival (%)
Mean Blood Glucose (mg/dL)
Intensive therapy (n=247)
100 40
Conventional therapy 50 20
Intensive therapy
N=573 pts with sepsis, MICU. Randomized to conventional vs intensive insulin (van den Berghe criteria) and LR vs Hepastarch volume replacement.
Mortality 28d 24.7 v 26 intensive v conventional
Mortality 90d 39.7 v 35.4
Hypoglycemia 17% vs 4.1% 10 20 30 40 50 60 70 80 90 1 2 3 4 5 6 7 8 9 10 11 12 13 14
100
Days
Days
Data from 537 patients:
247 received IIT goal: 80 – 110 mg/dL: mean BG 112 mg/dL
290 received CIT goal: 180 – 200 mg/dL: mean BG 151 mg/dL
IIT, intensive insulin therapy; CIT, conventional insulin therapy.
Brunkhorst FM et al. N Engl J Med. 2008;358: 24

25. VISEP Trial IIT (n=247) CIT (n=290) P Mortality rate, % 28 days
[Brunkhorst. NEJM.Jan. 2008/p / Table 2]
[Brunkhorst/p130/c1/ line 21-33]
IIT (n=247)
CIT (n=290) P
Mortality rate, %
28 days
90 days
24.7
39.7
26.0
35.4
0.74
0.31
% of Patients with glucose ≤40 mg/dL
17.0%
4.1%
<0.001
SOFA* score (mean) % CI
0.16
*SOFA – sequental organ failure assessment
Brunkhorst FM et al. N Engl J Med. 2008;358: 25

26. NICE-SUGAR Multi-center, randomized, controlled trial
Assessed 90-day mortality rates in patients with
Tight glucose control ( mg/dl)
Less tight control ( mg/dl)
Results:
90-day mortality 27.5 vs 24.9% (p = 0.02)
No difference in 30-day mortality
Increased CV death in tight control group
More hypoglycemia: 6.6 vs 0.5% (p < 0.001)

27. NICE-SUGAR Study Design: Primary Outcome:
Multicenter-multinational RCT (Australia, New Zealand, and Canada) in 6104 ICU patients, randomized to:
Intensive, BG target: 4.5 and 6.0 mmol/L ( mg/dL),
Conventional, BG target: < 10.0 mmol/L (180 mg/dL)
Primary Outcome:
Death from any cause within 90d after randomization
Mean APACHE II score: ~ 21,
Reason for ICU admission: surgery: ~37%, medical: 63%,
History of DM: 20% (T1DM: 8%, T2DM: 92%)
At randomization: Sepsis: 22%, trauma: 15%, APACHE > 25: 31%
IIT goal: 81 – 108 mg/dL (mean BG 118 mg/dL)
CIT goal: <180 mg/dL (mean BG 145 mg/dL)
Nice Sugar, NEJM 2009;360:1283 27

28. NICE-SUGAR
90 day mortality: IIT: 829 patients (27.5%), CIT: 751 (24.9%)
Absolute mortality difference: 2.6% (95% CI, 0.4 to 4.8); Odds ratio for death with IIT was 1.14 (95% CI, 1.02 to 1.28; P = 0.02).
Nice Sugar, NEJM 2009;360:1283 28

29. Probability of Survival and Odds Ratios for Death, According to Treatment Group
Operative Admission
Diabetes
Severe Sepsis
Trauma
Apache Score
Corticosteroids
All deaths at day 90
Favors Favors
IIT Conventional
Nice Sugar, NEJM 2009;360:1283 29

30. 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:

31. Frequency of Hypoglycemia (<40mg/dl)
Study
Intensive Rx
Conventional Rx
van den Berghe (SICU)1
5.1%
0.8%
van den Berghe (MICU)2
18.7%
3.1%
VISEP (Septic Shock)3
17.0%
4.1%
GLUCONTROL4
8.6%
2.4%
NICE-SUGAR5
6.8%
0.5%
1van den Berghe G, et al. N Engl J Med. 2001;345: Preiser &Devos, Crit Care Med 2007;35:S503-S507
2van den Berghe G et al. N Engl J Med 2006;354: NICE-SUGAR Invest, N Engl J Med 2009;360: Brunkhorst et al., N Engl J Med 2008;358: 31

32. ADA/AACE Target Glucose Levels in ICU Patients
ICU setting:
Insulin infusion should be used to control hyperglycemia
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 ( mg/dl) may be appropriate in selected patients  
Targets <110 mg/dL are not recommended
[Devos.CurrOpin ClinNutr.2007/p206/ c2/line 40-46, p207/ c1/line 1-4]
Not recommended
< 110
Acceptable
Recommended
Not recommended
>180
ADA/AACE Inpatient Task Force
Endocrine Practice 2009;15;1-17 32

33. Okay, but what about the non-ICU setting?
[Devos.CurrOpin ClinNutr.2007/p206/ c2/line 40-46, p207/ c1/line 1-4]
Sliding scale, right? 33

34. Why no more sliding scale?
Is often prescribed on admission & continued throughout the hospital stay
without modification
Worsens glycemic control
Is reactive to hyperglycemia, not preventative
Causes hypoglycemia
St. Dominic’s Diabetes Center

35. Normal Prandial Insulin
Normal Basal Insulin

36. Premix analogue insulin
Endogenous basal insulin secretion
Endogenous prandial insulin secretion
Intermediate-acting insulin1
Premix analogue insulin2
Regular human insulin3
Basal insulin3
Rapid-acting insulin3
Rapid-acting insulin
Regular human insulin
Premix analogue insulin
Intermediate-acting insulin
Basal insulin

38. RABBIT 2 Trial
Prospective randomized trial of 130 insulin naïve Type 2 DM non-ICU inpatients
Admission blood glucose b/w mg/dl
Basal- bolus insulin ( glargine and glulisine) vs Regular insulin SS

39. (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 (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

40. RABBIT 2 Trial Umpierrez, et al Diabetes Care 30;2181-86,2007
Mean Blood glucose mg/dl
DAYS
Umpierrez, et al Diabetes Care 30; ,2007

41. Percent of Glucose values within target
(BG < 140 mg/dl)
66%
* P < 0.01 %
38%
Umpierrez et al. Diabetes Care 30:2181–86, 2007 41

42. Rate of Hypoglycemia (BG < 60 mg/dl) % 3 3
Umpierrez et al. Diabetes Care 30:2181–86, 2007 42

43. RABBIT 2 Trial n=9 SSI Failures
Mean Blood glucose mg/dl
66% in basal-bolus group achieved FBG < 140 vs 38% in SSI group. Compared to 45% in detemir/apart basal bolus and 48% in NPH/regular split mixed regimen.
DAYS

54. ADA/AACE Target Glucose Levels in non-ICU Patients
[Devos.CurrOpin ClinNutr.2007/p206/ c2/line 40-46, p207/ c1/line 1-4]
Non-ICU setting:
Pre-meal 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 or above these cut-points
Hypoglycemia= BG < 70 mg/dl
Severe hypoglycemia= BG < 40 mg/dl
ADA/AACE Inpatient Task Force
Endocrine Practice 2009;15:1-17 54

55. St. Dominic Hospital Glycemic Excellence Project

56. Comprehensive Plan Providers Nursing Pharmacy Dietary/Nutrition
Diabetic Education
Administration

57. Comprehensive Plan Joint Commission Center of Excellence Data tracking
A1c value obtained
Hypoglycemia
Minor: <70
Major: <40
Glucose readings at target
Fasting: <140
Random: <180
Major hyperglycemia (>350)
POD #1 glucose in CAB patients

58. Diabetes Pathway IUC / Intensive Insulin Protocols in place
The major changes were for non-ICU patients
Pathway
All patients have glucose checked on admit
In the ER…. or…..
On arrival to floor
>140 triggers A1c check (>6.5 triggers DM educator)
>180 triggers the diabetic pathway
Standardized insulin orders

59. Diabetes Pathway All oral DM medications stopped
Standardized glycemic order set ordered
Basal Insulin
Glargine (Lantus)
Detemir (Levemir)
NPH
Fast-acting Insulin
Lispro (Humalog)
Aspart (Novolog)
Glulisine (Apidra) R

60. Diabetes Pathway Basal Insulin Fast-acting Insulin
Given daily, typically at bedtime
Covers fasting requirements
Fast-acting Insulin
Prandial dose
Covers the carbohydrates in the meal
Hold if NPO
Correctional dose
“sliding-scale”
Corrects glucoses that are already high before the meal
Give if NPO

61. Why no more sliding scale?
Is often prescribed on admission & continued throughout the hospital stay
without modification
Worsens glycemic control
Is reactive to hyperglycemia, not preventative
Causes hypoglycemia
St. Dominic’s Diabetes Center

62. Diabetes Pathway Order set includes: A1c order Hypoglycemia Protocol
Diet Orders
General Healthful Diet
Consistent carbohydrate counts
Default for diabetics = 60/60/60
Diet may be modified
Sodium restriction
Protein restriction
Accuchecks
QAC  correctional insulin if needed
QHS  NO correctional insulin
Q6 (if NPO)
Insulin Pump Protocol

63. How to actually use it Use the electronic order set Choose doses
TDD from home
½ given as basal
½ given as prandial (divided into 3 meals)
0.5 units per kg
You can always allow your consult to manage the glucoses from that point forward

64. (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

65. Glycemic Order Set iForm

69. Glycemic Excellence Project
Intensive Insulin
Glucomander tabs (Dr. Bruce Bode)
Targets
DKA protocol
Subcutaneous insulin
Fasting glucose target: <140
Random glucose target: <180

71. Glycemic Excellence Project
Initial meeting in May, 2012
Order sets available in September, 2012
Initial JC paperwork in June, 2012
95% of nurses educated in Nov/Dec, 2012
Physician education through January, 2013
JC site visit in March, 2013
JC Center of Excellence in Inpatient Diabetes Management in April, 2013

72. Outpatient Meds - PEARLS
GLP-1 Agonists
Byetta, Victoza, Bydureon, Trulicity, Tanzeum
Nausea, vomiting (occ. Diarrhea)
Delayed gastric emptying
Pancreatitis

73. Outpatient Meds - PEARLS
SGLT-2 Inhibitors
Invokana, Farxiga, Jardiance
Glucosuria
Genital mycotic infections
UTI’s
Hypotension / orthostasis (especially with loop diuretics)
DKA
Can happen in Type 2
Present with DKA despite lower glucoses (200’s)
Insulin/fluids

74. THANK YOU

75. QUESTIONS ?????