Umpierrez GE et al. Diabetes Care 2007;30:2181-2186.

Inpatient Hyperglycemia

• A common finding in hospitalized patients, even those without a previous history of diabetes

• Associated with increased inhospital complications, length of hospital stay and mortality

• Improved glycemic control reduces risk of MOF, serious infection, and mortality

Umpierrez G et al, J Clin Endocrinol Metabol 87:978, 2002, , Krinsley JS. Mayo Clin Proc. 2003;78:1471-1478, Van-Den Berge et al, NEJM 345:1359, 2001, Van-Den Berge et al, NEJM 354:449-61, 2006

Glycemic Control in Non-ICU Settings

• Few prospective randomized clinical trials in general medicine/surgical services

• 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 regimens– Delayed starting basal/bolus insulin therapy

• Basal and nutritional insulin use is advocated as preferred insulin regimen

Umpierrez et al, J Hospital Medicine, 1:143-144, 2006; Clement el al. Diabetes Care 27:553-591, 2004; Umpierrez et al, Am J Med, 120:563-567, 2007.

Methods for Managing Hospitalized Methods for Managing Hospitalized Persons With DiabetesPersons With Diabetes

• ICU:ICU: Continuous variable-rate IV insulin dripContinuous variable-rate IV insulin drip

• Non-ICU:Non-ICU: Basal/bolus therapy (MDI)Basal/bolus therapy (MDI)

• NPH and regular insulinNPH and regular insulin• Long-acting and rapid-acting insulinLong-acting and rapid-acting insulin

Sliding scale short-acting insulin Sliding scale short-acting insulin

5

Glycemic Control in Non-ICU Settings

Conventional Insulin Rx Limitations

B L S HS B

Reg

NPH

Insu

lin

Eff

ect

Meals

NPH

Reg

• Lacks flexibility

• Poor match between regular insulin and meals - Initial hyperglycemia - Late hypoglycemia

• Fasting hyperglycemia

6

Sliding-scale insulinconcerns:

Reactive approach:↑ Hyperglycemia

Insulin stacking:↑ Hypoglycemia

Sliding-Scale Regular Insulin

Adapted from the following sources: DeWitt DE, Dugdale DC. JAMA. 2003;289:2265-2269; Skyler JS. In: DeFronzo RA, ed. Current Therapy of Diabetes Mellitus.1998.

86

Insu

lin E

ffec

t

Time (h)

0 2 4 6 8 10 12 14 16 18 20 22 24

BG = 280

BG = 220

BG = 257

BG = 200

Insu

lin E

ffec

t

Time (h)

0 2 4 6 8 10 12 14 16 18 20 22 24

BG = 280

BG = 220

BG = 257

BG = 200

7

MDIs of InsulinGlargine QD + Rapid-acting Analog AC

21:0018:00

Breakfast Lunch Dinner

12:008:00

Time

GlargineInsu

lin A

ctio

n

Objectives• To determine whether inpatient glycemic

control, as measured by mean daily BG, is different between insulin glargine once daily plus glulisine before meals versus SSRI four-times daily in patients with type 2 diabetes

• To determine the safety of a basal bolus insulin regimen vs. SSRI

Methods

• 130 insulin-naïve diabetic subjects

• Inclusion Criteria:

– Age 18 – 80 yrs

– Known history of type 2 DM > 3 months

– BG > 140 mg/dL and < 400mg/dL

– Previous Rx: diet alone or diet + OADs

Exclusion Criteria

• New Onset or undiagnosed diabetes

• DKA or HHNS• Preadmission insulin

use• Admission to MICU or

SICU• Use of glucocorticoids

• Creatinine > 3 mg/dl• Mental illness or

incompetence• HIV• Pregnancy or lactation

Measured Outcomes

1) Differences in glycemic control as measured by mean daily BG

2) Differences between treatment groups in the following measures:

- number of hypoglycemic events (< 60 mg/dl)

- number of severe hyperglycemia (> 300 mg/dl)

- length of hospital stay

- mortality

Basal–Bolus Insulin Regimen

• D/C oral antidiabetic drugs on admission

• Starting total daily dose (TDD): – 0.4 U/kg/d x BG between 140-200 mg/dL– 0.5 U/kg/d x BG between 201-400 mg/dL

• Half of TDD as insulin glargine (Lantus®) and half as glulisine (Apidra®)– Insulin glargine - once daily, at the same time of the

day. – Insulin glulisine - three equally divided doses (AC)

• Hyperglycemia (FPG >140 mg/dL) without hypoglycemia, increase glargine dose by 20%

• Hypoglycemia (BG < 60 mg/dL), decrease glargine dose by 20%

• Consider using the total supplemental dose, nutritional intake, and results of BG to adjust insulin regimen

Insulin Dose Adjustment

BEFORE MEAL, Supplemental Sliding Scale Insulin (number of units) - Add to scheduled insulin dose. BEDTIME. Give half of Supplemental Sliding Scale Insulin. 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 ______________________________________________________________ ** Check appropriate column below and cross out other columns

SSRI Regimen

Lantus + Apidra SSRI

Age (yr) 56 ± 13 56 ± 11

Gender (M/F) 42/23 21/44

Race (B/W/H) 43/4/18 48/3/14

BMI (kg/m2) 32 ± 8 32 ± 9

A1c (%) 8.9 ± 2 8.7 ± 2.5

Creatinine (mg/dL) 1 ± 0.5 1.1 ± 0.5

BUN (mg/dL) 15 ± 7 17 ± 8

WBC 9.4 ± 4 8.7 ± 4

Hct (%) 37.5 ± 4 38 ± 5

LOS (days) 5.2 ± 6 5.1 ± 4

Characteristics of Enrolled Subjects

Blood Glucose Levels During Isulin Treatment

Days of Therapy

Blo

od

glu

cose

(m

g/d

L)

100

120

140

160

180

200

220

240

Admit 1 2 3 4 5 6 7 8 9 10

SSRI

Lantus + glulisine

Mean Blood Glucose Levels During Insulin Therapy

* p<0.01¶ p<0.05

¶* * *

¶ ¶ ¶

Day 3: P=0.06

Umpierrez et al, Diabetes Care 30:2181–2186, 2007

• Treatment successTreatment success– BG target of < 140 mg/dL was BG target of < 140 mg/dL was

achieved in 66% of patients on achieved in 66% of patients on Basal-Bolus (LantusBasal-Bolus (Lantus® + Apidra + Apidra®) ) and 38% regular insulin (SSI)and 38% regular insulin (SSI)

• Treatment failureTreatment failure– One out of 5 patients using SSI One out of 5 patients using SSI

remained with BG >240 mg/dL remained with BG >240 mg/dL and switched to Basal-Bolus and switched to Basal-Bolus (Lantus(Lantus® + Apidra + Apidra®))

Adapted from Umpierrez GE et al. Diabetes Care. 2007;30:2181-2186.

66%

38%

0%

25%

50%

75%

100%

Pa

tie

nts

wit

h B

G <

14

0 m

g/d

L,

%

Days of Therapy

Blo

od

Glu

cose

(m

g/dL

)

100

120

140

160

180

200

220

240

Admit 1 2 3 4 1 2 3 4 5 6 7

Sliding-ScaleSliding-ScaleInsulin DeliveryInsulin Delivery

LANTUS® + APIDRA®

260

280

300

Sliding-ScaleSliding-ScaleInsulinInsulin

Basal-Bolus

Basal–Bolus Insulin Regimen in Basal–Bolus Insulin Regimen in Noncritically Ill Patients Noncritically Ill Patients

Blood Glucose Change From Admission

1 2 3 4 5 6 7 8 9 10

Blo

od g

luco

se (

mg/

dL)

-100

-80

-60

-40

-20

0

Difference 18 23 35 41 40 58 39 44 34 37 between groups (mg/dL)

SSRILantus plus glulisine

Day of Insulin Treatment

DifferenceBetween groups

(mg/dL)

18 23 35 41 40 58 39 44 34 37

Mean Blood Glucose Levels in Patients Treated with Basal Bolus and SSRI

RABBIT-2 Trial: Insulin Dose

The mean daily insulin dose was significantly higher in the basal-bolus group than in the SSI group

Umpierrez GE et al. Diabetes Care 2007;30:2181-2186.

Insulin TypeMean Insulin Dose, units / day

Basal-Bolus Group SSI Group

Basal insulin 22 ± 2 -

Rapid-acting insulin 20 ± 1 -

Regular insulin - 12.5 ± 2

Hypoglycemia• Basal Bolus Group:

– 1,005 BG readings– Two patients (3%) had BG < 60 mg/dL– Four BG readings (0.4%) < 60 mg/dL – No BG < 40 mg/dL

• SSRI:– 1,021 BG readings – Two patients (3%) had BG < 60 mg/dL– Two BG readings (0.2%) < 60 mg/dL – No BG < 40 mg/dL

• None of the episodes of hypoglycemia in either group were associated with adverse outcomes

Basal bolus in DM surgical patients

• A randomized multicenter trial

• Compared the safety and efficacy of a basal-bolus insulin regimen with glargine once daily and glulisine before meals to sliding scale regular insulin (SSI) four times daily in patients with type 2 diabetes mellitus undergoing general surgery.

• Outcomes included differences in daily blood glucose (BG) and a composite of postoperative complications including wound infection, pneumonia, bacteremia, and respiratory and acute renal failure.

Guillermo E. Umpierrez Et All Diabetes Care 34:256–261, 2011

Main results-Rabbit 2 for surgery

A: Glucose levels during basal-bolus and SSI treatment. Changes in blood glucoseconcentration after the 1st day of treatment with basal-bolus with glargine once daily plus glulisine before meals (○) and with SSI 4-times daily (●). *P , 0.001, ŧP = 0.02, †P = 0.01.

B: Glucose levels before meals and bedtime. Premeal and bedtime glucose levels were higher throughout the day in the SSI group (●) compared with basal-bolus regimen (○).

Guillermo E. Umpierrez Et All Diabetes Care 34:256–261, 2011

Summary

1.This is the first prospective randomized clinical trial aimed

to compare the efficacy and safety of a basal-bolus insulin

regimen with that of SSI in non–critically ill patients with

type 2 diabetes

2. Treatment with insulin glargine and glulisine results in a

significant improvement in glycemic control compared

with that resulting from the sole use of SSI

A basal-bolus insulin regimen is referred over SSI alone in

the management of non-critically ill patient with type 2

DM

Summary3. Significant differences in daily insulin dose between patients treated with the basal-bolus regimen compared

with that in the SSI treatment group.

Patients randomized to receive insulin glargine and glulisine received an approximately three times higher total insulin dose (40 units/day) than those treated with SSI (15 units/day)

4. Despite the higher insulin dose and improved glycemic control, the use of the basal-bolus insulin regimen was safe and was associated with a low rate of hypoglycemic events

Summary• Mean daily BG difference between groups ranged from 23 to 58

mg/dl during days 2 to 6 of therapy, with an overall blood glucose difference of 27 mg/dL

• A glucose target of < 140 mg/dL was achieved in 2/3 of patients treated with glargine and glulisine but only in 1/3 of those treated with SSR

• Despite increasing insulin doses, 14% of patients treated with SSRI had persistently elevated BG > 240 mg/dL

• In such patients, glycemic control rapidly improved achieving the glucose target of < 140 mg/dL after switching to the basal/bolus regimen

Conclusion

• Basal/bolus insulin regimen with glargine once daily and glulisine before meals is a better insulin regimen than SSRI in the management of type 2 diabetics in the non-ICU setting.

THANK YOU

Acknowledgements

Funding: Sanofi-Aventis

Back - up

• Basal/bolus insulin regimen with glargine once daily and glulisine before meals is a better insulin regimen than SSRI in the management of type 2 diabetics in the non-ICU setting.

• SSRI as a single insulin regimen should not be

used for the management of patients with type 2 diabetes.

Summary

• The use of the basal/bolus insulin regimen was safe and was associated with a low rate of hypoglycemic events

• The overall rate of hypoglycemia (< 60 mg/dL) occurred in 3% of patients in both treatment groups and none were associated with clinical adverse outcome

• There were no episodes of severe hypoglycemia (glucose < 40 mg/dL) in either treatment group

Summary5. Minimizing the rate of severe hypoglycemia events is of

major importance in hospitalized patients because they have been shown to be an independent risk factor for poor clinical outcomes

6. Many factors could explain the lack of glycemic control in the hospital

First, the overwhelming majority of hospitalizations in patients with hyperglycemia occur for a variety of comorbid conditions , with <10% of hospital discharges in the U.S. listing diabetes as the primary diagnosis

SummarySecond, physicians often perceive hyperglycemia as a consequence

of stress and acute illness and often delay treatment until blood glucose levels exceed 200 mg/dl

Third, fear of hypoglycemia constitutes a major barrier to efforts to improve glycemic control, especially in patients with poor caloric intake

Finally, physicians frequently hold their patient's previous outpatient antidiabetes regimen and initiate sliding-scale coverage with regular insulin, a practice associated with limited therapeutic success and suboptimal glycemic control

Summary7. The use of SSI was first introduced by Elliot P. Joslin shortly after the

discovery of insulin

regular insulin per sliding scale according to the amount of glycosuria

8. Potential advantages of SSI are convenience, simplicity, and promptness of treatment

the use of SSI, however, as a single insulin regimen in hospitalized subjects has never been associated with improved clinical outcome. Yet this remains the most popular default regimen in the majority of institutions across the country

Summary9. The following limitations in this study

Excluded patients without a known history of diabetes before admission

Excluded patients treated with insulin and corticosteroids because they were considered at higher risk of severe hyperglycemia if treated with SSI

Another limitation is that the study was not powered to demonstrate

differences in mortality or clinical outcome between treatment

groups

Summary 1. Basal-bolus insulin algorithm using insulin glargine once daily and

insulin glulisine before meals represents a simple and more effective regimen than SSI for glucose control in non–critically ill patients with type 2 diabetes

2. Despite the simplicity of SSI, this regimen fails to provide adequate glycemic control and should not be used in the management of hospitalized subjects with diabetes

3. Implementing standardized subcutaneous insulin order sets promoting the use of scheduled insulin therapy and discouraging the sole use of SSI are key interventions that might reduce complications associated with severe hyperglycemia and hypoglycemia in hospitalized patients