RAndomized Study of Basal Bolus

Insulin Therapy in the Inpatient

Management of Patients With Type
2 Diabetes Undergoing General
Surgery
(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

 Diabetes and Surgery

• Patients with diabetes are more likely to undergo

surgery than people without diabetes 1,2 .
• Surgery in diabetic patients is associated with longer
hospital stay, greater perioperative morbidity and
mortality, and higher health care resource utilization
than nondiabetic subjects 1-3 .
• RABBIT-2 Medicine reported that in patients with
T2DM admitted to general medicine wards, treatment
with basal bolus insulin regimen with glargine once
daily and glulisine before meals improved glycemic
control without increasing the risk of severe
hypoglycemia compared to SSI regimen 4.

SSI=sliding-scale insulin
1. Clement et al. Diabetes Care 2004; 27(2): 553-97; 2. Smiley et al. South Med J 2006; 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
 Glycemic Control in Non-ICU Settings
• No previous prospective randomized trials
evaluated the optimal management of
hyperglycemia in diabetic patients undergoing
general surgery

• Fear of hypoglycemia and lack of established

treatment algorithms in non-ICU areas leads
to:
– Holding patient’s diabetic regimen
– Reliance on “sliding scale” insulin regimen

• Basal and nutritional (bolus) insulin use is

advocated
ICU=intensive as preferred insulin regimen
care unit
Umpierrez G et al, JCEM 87:978, 2002, 2. Clement et al. Diabetes Care 2004; 27(2): 553-97; 3. Smiley et al.
South Med J 2006; 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
 Hypothesis

• Treatment with basal bolus regimen

with glargine once daily plus glulisine
before meals will improve glycemic
control and reduced perioperative
complications compared to SSI four-
times daily in patients with type 2
diabetes undergoing general surgery.
 Objectives

• To determine whether inpatient glycemic

control, as measured by mean daily BG, was
different between basal bolus insulin regimen
and SSI in general surgery patients with T2DM

• To determine differences in a composite of

postoperative complications including wound
infection, pneumonia, bacteremia, and
respiratory and acute renal failure between
basal bolus and SSI in general surgery patients
with T2DM

BG=blood glucose; T2DM=type 2 Diabetes Mellitus

 Research Design and Methods

• 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 with
glargine once daily and glulisine before
meals (n=104)
• Group 2: sliding scale insulin (SSI) using
human regular insulin four times daily (n=
107)
 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 insulin
therapy at a total daily dose ≤ 0.4 units/kg
prior to admission.

DKA=diabetic ketoacidosis
 Exclusion Criteria

• New Onset or • Impaired renal

undiagnosed function
diabetes (Creatinine > 3
mg/dL)
• DKA or HHS
• Mental illness or
• Cardiac Surgery incompetence
• Admission to • Pregnancy or
MICU or SICU lactation
• Clinically relevant
hepatic disease
 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 (<70 mg/dl and <40 mg/dl,
respectively)
– Length of hospital stay
– Surgical complications (wound infection and dehiscence, bacteremia,
pneumonia, and acute renal failure defined as an increased in serum creatinine
>50% of baseline and/or a serum creatinine >2.5 mg/dl)
– Admission to the ICU
– Death
 Patients
211 Patients with type 2 DM that underwent general surgery

OPEN-LABELED RANDOMIZATION

Glargine + Glulisine Sliding scale insulin

(Gla+Glu) (SSI)
N= 104 N= 107

TDD: 0.5 U/kg SSI

4 times/day for BG >140 mg/dl
Half as glargine once daily
Half as glulisine before meals
Treatment arm: Basal–Bolus 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/o
and/or with a serum creatinine ≥ 2.0 mg/dL.
• Half of TDD as insulin glargine and half as insulin
glulisine*
• Insulin glargine - once daily, at the same time of
the 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.
 Treatment Arm: Basal Bolus
Insulin Dose Adjustment

Blood glucose levels Change in Daily Insulin

Dose*

Fasting and pre-meal BG between 100-140 mg/dl in the no change

absence of hypoglycemia

Fasting and pre-meal BG between 141-180 mg/dl in the Increase by 10%

absence of hypoglycemia

Fasting and pre-meal BG between >181 mg/dl in the Increase by 20%

absence of hypoglycemia

Fasting and pre-meal BG between 70-99 mg/dl in the Decrease by 10%

absence of hypoglycemia

Fasting and pre-meal BG between <70 mg/dl Decrease by 20%

* Daily insulin adjustment was primarily focused on glargine dose. The

treating physicians were allowed to adjust prandial (glulisine) insulin dose, and
to use the total supplemental dose, patient’s nutritional intake, and results of
BG testing to adjust insulin regimen.
Treatment Arm: Basal-Bolus Insulin
Dose Adjustment

• Fasting and pre-dinner BG between 100-140 mg/dL in

the absence of hypoglycemia the previous day: no
change

• 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: increase

insulin 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 <70 mg/dL: decrease insulin TDD by 20%

TDD=total daily dose

 Treatment arm: Sliding Scale
Insulin Regimen
• 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 Usual Insulin Resistant
(mg/dL) Insulin Sensitive
>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

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
Results
 Clinical Characteristics on
Admission
All SSI Glar+Glu P-
value

Number of patients, 211 107 104 NS

n
Male/Female, n 107/104 53/54 54/50 NS
Age (years) 58±11 57±10 58±12 NS
BMI, kg/m2 31.3±8 31.3±8 31.3±8 NS
Duration DM, yrs 6.5±6 6.8 ±6 6.3 ±6 NS
Admission BG mg/dL 190±92 184±80 197±104 NS
BG at randomization, 198±54 194±56 202±51 0.548
mg/dL

A1c at admission, % 7.72 ±2.2 8.08±2.4 7.38 ±1.9 0.070

 Diabetes Treatments on Admission

Treatment All SSI Glar+Glu P-value

Diet alone, n 17 11 6 NS
Oral antidiabetic agents, 153 80 73 NS
n
Insulin + oral antidiabetic 20 11 9 NS
agents, n
 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
Blood Glucose Values on Admission
and During Treatment
 Glycemic Control
Glar+Glu
SSI

* * p<0.001; † p=0.01 ‡p=0.02

*
† ‡ † †
ti

1 2 3 4 5 6 7 8 9 10
za
on mi
o
d

Duration of Treatment (days)

an
R
 RABBIT 2 Surgery: Glycemic Control
BG Level After First Day BG Reading <140 mg/dL

P<0.001
P<0.01

SSI = sliding scale insulin.

Mean BG before meals and at
bedtime
during treatment
Glar+Glu
SSI
*

*
* *

Breakfast Lunch Dinner

Bedtime
*p<0.001
 Postoperative Complications

P=0.003

P=0.05 P=0.10

P=NS P=0.24

SSI = sliding scale insulin.

Hospital Complications
 Treatment Failure with Sliding Scale
Insulin
Sliding-scale Basal-bolus
300

280

260
Blood Glucose (mg/dl)

240

220

200

180

160

140

120

100
1 2 3 1 2 3 4 5 6

Days of Therapy
12 patients (11.1%) treated with SSRI had persistent severe hyperglycemia
(3 consecutive BG>240 mg/dl). Patients were switched to basal bolus regimen
Length of Stay
P=0.25
 ICU Admissions
Postsurgical ICU Admission ICU Length of Stay

P=0.003
P=0.16

SSI = sliding scale insulin. ICU=intensive care unit

 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: 8.7±4 U/day

• Patients treated with SSI:
• 88.5% received < 20 U/day
• 39.4% received < 10 U/day
 Hypoglycemia
BG <70 mg/dL BG <40 mg/dL
P<0.001 P=0.057

• There were no differences in hypoglycemia between patients treated with

insulin prior to admission compared to insulin-naïve patients.
 Hypoglycemia
BG <70 mg/ dL BG <60 mg/ dL BG <40 mg/ dL
P<0.001 P=0.057
25 25 4.0

23.1 3.5 3.8

20 20
P =0.005 3.0
% % %2.5
, 15 ,s 15 ,
s
t * s
t
t
n n n 2.0
e
it e
it 10 e
it
10 12
a a a 1.5
P P P
1.0
5 5
4.7 1.9 0.5
0
0 0 0.0
I nsulin Glargine SSI I nsulin Glargine SSI I nsulin Glargine SSI
+ I nsulin + I nsulin + I nsulin
Glulisine Glulisine Glulisine

• There were no differences in hypoglycemia between patients treated with

insulin prior to admission compared to insulin-naïve patients.
• There were no differences in hypoglycemia between patients treated with
insulin on admission prior to surgery or those enrolled after surgery.
 Summary
• The use of glargine once daily and glulisine before meals at a
starting dose of 0.5 unit/kg/day is a better regimen than SSI in
general surgery patients with type 2 diabetes
• When compared to SSI, this regimen was associated with:
– Improved glycemic control measured as mean daily glucose
concentration
– Reduced perioperative complications observed as the composite of
postoperative complications including wound infection,
pneumonia, bacteremia, respiratory failure, and acute renal failure
– No increase in the number of severe hypoglycemia. A BG < 70
mg/dl was reported in 1.9 % of in the basal bolus vs. 0.3% of
readings in the SSI group, p=<0.001; but there were no differences
in the frequency of severe hypoglycemia.

SSI = sliding scale insulin.

 Conclusions
• Treatment with glargine once daily plus glulisine
before meals improved glycemic control and reduced
hospital complications compared to SSI in general
surgery patients with T2DM.
• Our study indicates that basal/bolus insulin regimen
is the preferred insulin regimen over SSI in the
hospital management of general surgery patients
with type 2 diabetes.