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RAndomized Study of Basal Bolus
Insulin Therapy in the InpatientManagement of Patients With Type
2 Diabetes Undergoing GeneralSurgery
(RABBIT 2 Surgery)
G Umpierrez, D Smiley, S Jacobs, L Peng,A Temponi, C Newton, D Umpierrez,
P Mulligan, D Olson, J McLeod, M Rizzo
Emory University School of Medicine, Atlanta, GA1
NCT00596687
Umpierrez et al, Diabetes Care in Press
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Diabetes and Surgery
Patients with diabetes are more likely to undergosurgery than people without diabetes 1, 2 .
Surgery in diabetic patients is associated with longerhospital stay, greater perioperative morbidity andmortality, and higher health care resource utilization
than nondiabetic subjects1-3
. RABBIT-2 Medicine reported that in patients with
T2DM admitted to general medicine wards, treatmentwith basal bolus insulin regimen with glargine oncedaily and glulisine before meals improved glycemiccontrol without increasing the risk of severehypoglycemia compared to SSI regimen 4.
1. Clement et al. Diabetes Care 2004; 27(2): 553-97; 2. Smiley et al. South Med J2006; 99(6): 580-9;
3. Frisch et al. Diabetes Care 2010; 2010 Apr 30. [Epub ahead of print]: 4. Umpierrez GE, et al. Diabetes
Care. 2007;30(9):2181-2186
SSI=sliding-scale insulin
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Glycemic Control in Non-ICU Settings
No previous prospective randomized trialsevaluated the optimal management ofhyperglycemia in diabetic patients undergoinggeneral surgery
Fear of hypoglycemia and lack of establishedtreatment algorithms in non-ICU areas leadsto:
Holding patients diabetic regimen
Reliance on sliding scale insulin regimen
Basal and nutritional (bolus) insulin use isadvocated as preferred insulin regimen
Umpierrez G et al, JCEM87:978, 2002,, 2. Clement et al. Diabetes Care 2004; 27(2): 553-97; 3. Smiley et al.
South Med J2006; 99(6): 580-9; 4. Frisch et al. Diabetes Care 2010; 2010 Apr 30. [Epub ahead of print]: 5.Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181-2186
ICU=intensive care unit
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Hypothesis
Treatment with basal bolus regimenwith glargine once daily plus glulisinebefore meals will improve glycemiccontrol and reduced perioperative
complications compared to SSI four-times daily in patients with type 2diabetes undergoing general surgery.
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Objectives
To determine whether inpatient glycemiccontrol, as measured by mean daily BG, wasdifferent between basal bolus insulin regimenand SSI in general surgery patients with T2DM
To determine differences in a composite ofpostoperative complications including woundinfection, pneumonia, bacteremia, andrespiratory and acute renal failure between
basal bolus and SSI in general surgery patientswith T2DM
BG=blood glucose; T2DM=type 2 Diabetes Mellitus
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Study Type: Multi-center, prospective, open-label randomized clinical trial
Study Sites: Grady Memorial Hospital,Veterans Affairs Medical Center and Emory
University Hospital, Atlanta, GA Treatment Groups:
Group 1: basal/bolus regimen withglargine once daily and glulisine before
meals (n=104) Group 2: sliding scale insulin (SSI) using
human regular insulin four times daily (n=107)
Research Design and Methods
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Inclusion Criteria
Ages 18 - 80 years
Type 2 DM for > 3 months
BG between 140 400 mg/dL w/o DKA
Undergoing general surgery
Not in ICU
Patients on diet, any combination of oral
antidiabetic agents, or low-dose insulintherapy at a total daily dose 0.4 units/kgprior to admission.
DKA=diabetic ketoacidosis
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Exclusion Criteria
New Onset orundiagnoseddiabetes
DKA or HHS
Cardiac Surgery
Admission toMICU or SICU
Impaired renalfunction(Creatinine > 3
mg/dL) Mental illness or
incompetence
Pregnancy orlactation
Clinically relevanthepatic disease
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Measured Outcomes
Primary: Differences between treatment groups in mean daily BG concentration
Composite of postoperative complications including wound infection,pneumonia, bacteremia, respiratory failure, and acute renal failure.
Secondary:
Differences between treatment groups in any of the following measures:
Occurrence of mild and severe hypoglycemia (2.5 mg/dl)
Admission to the ICU
Death
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211 Patients with type 2 DM that underwent general surgery
Glargine + Glulisine(Gla+Glu)
N= 104
TDD: 0.5 U/kg
Half as glargine once dailyHalf as glulisine before meals
Sliding scale insulin(SSI)
N= 107
OPEN-LABELED RANDOMIZATION
SSI
4 times/day for BG >140 mg/dl
Patients
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Treatment arm: BasalBolus Insulin
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 y/oand/or with a serum creatinine 2.0 mg/dL.
Half of TDD as insulin glargine and half as insulinglulisine*
Insulin glargine - once daily, at the same time ofthe day.
Insulin glulisine- three equally divided doses (AC)
The goal of insulin therapy was to maintain fasting and pre-meal glucose concentration between 100 mg/dl and 140 mg/dl
*If a patient was not able to eat, insulin glargine was given but,insulin glulisine was held until meals were resumed.
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Blood glucose levels Change in Daily InsulinDose*
Fasting and pre-meal BG between 100-140 mg/dl in theabsence of hypoglycemia
no change
Fasting and pre-meal BG between 141-180 mg/dl in the
absence of hypoglycemia
Increase by 10%
Fasting and pre-meal BG between >181 mg/dl in the
absence of hypoglycemia
Increase by 20%
Fasting and pre-meal BG between 70-99 mg/dl in theabsence of hypoglycemia
Decrease by 10%
Fasting and pre-meal BG between
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Fasting and pre-dinner BG between 100-140 mg/dL inthe absence of hypoglycemia the previous day: nochange
Fasting and pre-dinner BG between 140 - 180 mg/dL:increase insulin TDD by 10% every day
Fasting and pre-dinner BG >180 mg/dL: increaseinsulin TDD dose by 20% every day
Fasting and pre-dinner BG is between 70-99 mg/dL:decrease insulin TDD dose by 10% every day
BG
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D/C oral antidiabetic drugs on admission
Before meal: Supplemental human regular insulin (# of units)
Bedtime: Give half of Supplemental Sliding Scale Insulin (SSI)
Blood Glucose(mg/dL) Insulin Sensitive
Usual Insulin Resistant
>141-180 2 4 6
181-220 4 6 8
221-260 6 8 10
261-300 8 10 12
301-350 10 12 14
351-400 12 14 16
>400 14 16 18
Treatment arm: Sliding ScaleInsulin Regimen
If the mean daily BG>240 mg/dL or if three consecutive were >240 mg/dL on maximal SSI dose,
patients were switched to basal-bolus starting at TDD 0.5 u/Kg
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Results
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Clinical Characteristics onAdmission
All SSI Glar+Glu P-value
Number of patients,n
211 107 104 NS
Male/Female, n 107/104 53/54 54/50 NS
Age (years) 5811 5710 5812 NS
BMI, kg/m2 31.38 31.38 31.38 NS
Duration DM, yrs 6.56 6.8 6 6.3 6 NS
Admission BG mg/dL 19092 18480 197104 NS
BG at randomization,mg/dL
19854 19456 20251 0.548
A1c at admission, % 7.72 2.2 8.082.4 7.38 1.9 0.070
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Diabetes Treatments on Admission
Treatment All SSI Glar+Glu P-value
Diet alone, n 17 11 6 NS
Oral antidiabetic agents,n
153 80 73 NS
Insulin + oral antidiabeticagents, n
20 11 9 NS
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Surgeries
Type of surgery All SSI Glar+Glu P-value
Cancer 76 40 36 NS
GI-GU benign 59 28 31 NS
Vascular 31 15 16 NS
Trauma 38 20 18 NS
Others 7 5 2 NS
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Blood Glucose Values on Admissionand During Treatment
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Glycemic Control
*
*
Duration of Treatment (days)
Ran
domizati
on
1 32 4
Glar+Glu
SSI
5 6 7 8 9 10
* p
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RABBIT 2 Surgery: Glycemic Control
P
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*
*
*
*
ean e ore mea s an atbedtime
during treatment
Breakfast Lunch DinnerBedtime
Glar+Glu
SSI
*p
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Postoperative Complications
SSI = sliding scale insulin.
P=0.003
P=NS
P=0.05 P=0.10
P=0.24
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Hospital Complications
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Days of Therapy
BloodGlucose(m
g/dl)
100
120
140
160
180
200
220
240
260
280
300
Treatment Failure with Sliding ScaleInsulin
Sliding-scale Basal-bolus
12 patients (11.1%) treated with SSRI had persistent severe hyperglycemia(3 consecutive BG>240 mg/dl). Patients were switched to basal bolus regimen
1 2 3 1 2 3 4 5 6
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Length of Stay
P=0.25
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P=0.16
ICU Admissions
P=0.003
SSI = sliding scale insulin. ICU=intensive care unit
Postsurgical ICU Admission ICU Length of Stay
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Insulin Dose
Mean Insulin Dose, units / day
Basal-Bolus SSI
Total Daily Dose 33.4 45 12.3 7
Basal insulin 21.8 9
Rapid-acting insulin 14.8 8
Mean supplemental (correction) dose of glulisine: 8.74 U/day
Patients treated with SSI:
88.5% received < 20 U/day
39.4% received < 10 U/day
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Hypoglycemia
P
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23.1
4.7
0
5
10
15
20
25
Insulin Glargine
+ Insulin
Glulisine
SSI
Patient
s,%
P
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Summary
The use of glargine once daily and glulisine before meals at astarting dose of 0.5 unit/kg/day is a better regimen than SSI ingeneral surgery patients with type 2 diabetes
When compared to SSI, this regimen was associated with:
Improved glycemic control measured as mean daily glucoseconcentration
Reduced perioperative complications observed as the composite ofpostoperative complications including wound infection,pneumonia, bacteremia, respiratory failure, and acute renal failure
No increase in the number of severe hypoglycemia. A BG < 70mg/dl was reported in 1.9 % of in the basal bolus vs. 0.3% ofreadings in the SSI group, p=
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Conclusions
Treatment with glargine once daily plus glulisinebefore meals improved glycemic control and reducedhospital complications compared to SSI in generalsurgery patients with T2DM.
Our study indicates that basal/bolus insulin regimen
is the preferred insulin regimen over SSI in thehospital management of general surgery patientswith type 2 diabetes.