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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