8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

1/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

2/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

3/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

4/32

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.

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

5/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

6/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

7/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

8/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

9/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

10/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

11/32

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.

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

12/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

13/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

14/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

15/32

Results

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

16/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

17/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

18/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

19/32

Blood Glucose Values on Admissionand During Treatment

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

20/32

Glycemic Control

*

*

Duration of Treatment (days)

Ran

domizati

on

1 32 4

Glar+Glu

SSI

5 6 7 8 9 10

* p

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

21/32

RABBIT 2 Surgery: Glycemic Control

P

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

22/32

*

*

*

*

ean e ore mea s an atbedtime

during treatment

Breakfast Lunch DinnerBedtime

Glar+Glu

SSI

*p

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

23/32

Postoperative Complications

SSI = sliding scale insulin.

P=0.003

P=NS

P=0.05 P=0.10

P=0.24

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

24/32

Hospital Complications

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

25/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

26/32

Length of Stay

P=0.25

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

27/32

P=0.16

ICU Admissions

P=0.003

SSI = sliding scale insulin. ICU=intensive care unit

Postsurgical ICU Admission ICU Length of Stay

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

28/32

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

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

29/32

Hypoglycemia

P

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

30/32

23.1

4.7

0

5

10

15

20

25

Insulin Glargine

+ Insulin

Glulisine

SSI

Patient

s,%

P

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

31/32

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=

8/7/2019 RABBIT-2 Surgery_[12_2010] (1)

32/32

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.