1

c

Distribution of patient-day-weighted mean POC-BG values for ICU & non-ICU settings

Swanson et al. Endocrine Practice, October 2011

DATA from ~49 million POC-BG testing (12 M ICU; 37 M non-ICU) from 3.5 million patients (653,359 ICU; 2,831,436 non-ICU). The mean POC-BG was 167 mg/dL for ICU patients and 166 mg/dL for non-ICU patients.

2

Distribution of patient-day-weighted mean POC-BG values for ICU & non-ICU settings

DATA from ~49 million POC-BG testing (12 M ICU; 37 M non-ICU) from 3.5 million patients (653,359 ICU; 2,831,436 non-ICU). The mean POC-BG was 167 mg/dL for ICU patients and 166 mg/dL for non-ICU patients.

Swanson et al. Endocrine Practice, Pub Ahead of Print, October 2011

Kosiborod M, et al. J Am Coll Cardiol. 2007;49(9):1018-183:283A-284A.

No Diabetes

26%

Diabetes 50

40

30

20

10

0 <110 110-140

50

40

30

20

10

0 <110 110-140 140-170 170-200 >200

78%

140-170 170-200 >200

Mean BG, mg/dL

Pat

ient

s, %

3

Comparison  of  sensi-vity  and  specificity  achieved  for  the  diagnosis  of  diabetes  based  on  FPG,  at  various  levels  of  HbA1c,  from  NHANES  III  and  1999–2004  NHANES  

J  Clin  Endocrinol  Metab,  July  2008,  93(7):2447–2453  

4

Norhammar A, et al. Lancet 2002;359:2140－4. Matz K, et al. Diabetes Care 2006;792－7.

2-hour OGTT

70

60

50

40

30

20

10

0

Norhammar (n=181)

Matz (n=238)

Pati

ents

(%)

66

39

Myocardial infarction

Stroke

IGT Undiagnosed T2DM

35 23

31

16

5

~2x

Mor

talit

y R

ate

(%)

Mean Glucose Value (mg/dL)

Krinsley JS. Mayo Clin Proc. 2003;78:1471-1478.

N=1826 ICU patients.

0

5

10

15

20

25

30

35

40

45

80-99 100-119 120-139 140-159 160-179 180-199 200-249 250-299 >300 0

5

10

15

20

25

30

35

40

45

0

5

10

15

20

25

30

35

40

45

~4x ~3x

Day of surgery: 241 mg/dL POD #1: 206 mg/dL POD #2: 195 mg/dL POD#3: 188 mg/dl

Day of surgery: 199 mg/dL POD #1: 176 mg/dL POD #3: 185 mg/dL POD#3: 181 mg/dl

DSWI, deep sternal wound infection; SCI, subcutaneous insulin; CII, continuous insulin infusion.

4.0

3.0

2.0

1.0

0.0

DSWI (%)

87 88 89 90 91 92 93 94 95 96 97 Year

Patients with diabetes

Patients without diabetes

Furnary AP, et al. Ann Thorac Surg. 1999;67:352–362.

CII (N=3554) SCI

6

Blood Glucose (mg/dL)

<150 150- 175

200- 225

175- 200

>250 225- 250

P<0.0001

*P<0.001

Postop Mortality

BG <200 n=662

1.8%

BG >200

n=1369

5.0% * P

osto

p M

orta

lity

(%)

Adjusted for 19 clinical and operation variables

Furnary AP et al. Circulation. 1999:100 (Suppl I): I-591.

1.4 1.7 2.1

3.8

5.8

8.6

0

2

4

6

8

10

CABG, coronary artery bypass graft.

First Postop Glucose >200

•  2x LOS •  3x Vent duration •  7x mortality !!!

*P<0.01 Van den Berghe et al. N Engl J Med. 2001;345:1359-1367. Relative Risk Reduction (%)

Intensive Glucose Management in RCT

Trial N Setting Primary

Outcome ARR RRR Odds Ratio

(95% CI) P-value

Van den Berghe 2006

1200 MICU Hospital mortality

2.7% 7.0% 0.94* (0.84-1.06)

N.S.

Glucontrol 2007

1101 ICU ICU mortality

-1.5% -10% 1.10* (0.84-1.44)

N.S.

Ghandi 2007

399 OR Composite 2% 4.3% 1.0* (0.8-1.2)

N.S.

VISEP 2008

537 ICU 28-d mortality

1.3% 5.0% 0.89* (0.58-1.38)

N.S.

De La Rosa 2008

504 SICU MICU

28-d mortality

-4.2% * -13%* NR N.S.

NICE-SUGAR 2009

6104 ICU 3-mo mortality

 -2.6% -10.6 1.14 (1.02-1.28)

< 0.05

*not significant

7

Favors IIT Favors Control Mixed ICU

Medical ICU

Surgical ICU

ALL ICU

Intensive Insulin Therapy and Mortality Among Critically Ill Patients

Griesdale DE, et al. CMAJ. 2009;180(8):821-827.

Griesdale DE, et al. CMAJ. 2009;180(8):821-827.

Favors IIT Favors Control

Hypoglycemic Events

Intensive Insulin Therapy and Hypoglycemic Events in Critically Ill Patients

No. Events/Total No. Patients Study IIT Control Risk ratio (95% CI) Van den Berghe et al 39/765 6/783 6.65 (2.83-15.62) Henderson et al 7/32 1/35 7.66 (1.00-58.86) Bland et al 1/5 1/5 1.00 (0.08-11.93) Van den Berghe et al 111/595 19/605 5.94 (3.70-9.54) Mitchell et al 5/35 0/35 11.00 (0.63-191.69) Azevedo et al 27/168 6/169 4.53 (1.92-10.68) De La Rosa et al 21/254 2/250 10.33 (2.45-43.61) Devos et al 54/550 15/551 3.61(2.06-6.31) Oksanen et al 7/39 1/51 9.15 (1.17-71.35) Brunkhorst et al 42/247 12/290 4.11(2.2-7.63) Iapichino et al 8/45 3/45 2.67 (0.76-9.41) Arabi et al 76/266 8/257 9.18 (4.52-18.63) Mackenzie et al 50/121 9/119 5.46 (2.82-10.60) NICE-SUGAR 206/3016 15/3014 13.72 (8.15-23.12) Overall 654/6138 98/6209 5.99 (4.47-8.03)

0.1 1 10

Risk Ratio (95% CI)

Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009;15(4). http://www.aace.com/pub/pdf/guidelines/InpatientGlycemicControlConsensusStatement.pdf.

Recommended 140-180

Acceptable 110-140

Not recommended <110

Not recommended >180

8

Leuven SICU Study1 Yale Insulin Infusion Protocol2

MICU Insulin Infusion Protocol

0

50

100

150

200

250

300

350

400

450

0 12 24 36 48 60 72

Hours

Blo

od G

luco

se (

mg/

dL)

Glucommander3

0 50

100 150

200 250

300 350

400 450

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

Hours

Glu

cose

(m

g/dL

)

1. Van den Berghe et al. N Engl J Med. 2001;345:1359-1367. 2. Goldberg PA et al. Diabetes Care. 2004;27:461-467. 3. Davidson et al. Diabetes Care. 2005;28:2418-2423. 4. Finfer S, et al. N Engl J Med. 2009;360(13):1283-1297.

Admission Day 1 Day 5 Day 15

Blo

od G

luco

se (

mm

ol/L

) Intensive - Mean BG 103 mg/dL

Conventional - Mean BG 153 mg/dL

0

2

4

6

8

10

12

14

Last day

Strategies for Achieving Glycemic Targets in the ICU

NICE-SUGAR4

Van Den Berghe G, et al. N Engl J Med. 2001; Van Den Berghe G, et al. N Engl J Med. 2006;De la Rosa,et al, Crit Care 2008; Brunkhorst et al. N Engl J Med. 2008; Preiser JC, SCCM, 2007; Nice Sugar, NEJM 2009

Glycemic Values Achieved with IV Insulin Protocols

IIT: Intensive insulin therapy CIT: Control, conventional insulin therapy Results are expressed as mean BG during hospital stay, mg/dL

9

8.6%

1.  Van Den Berghe G, et al. N Engl J Med. 2001:345:1359; 2.  Van Den Berghe G, et al. N Engl J Med. 2006;354:449-461; 3.  Brunkhorst FM et al. N Engl J Med. 2008; 358:125-139; 4.  Preiser JC, SCCM, 2007; 5.  Finfer S, et al. N Engl J Med. 2009;360(13):1283-1297.

Hypoglycemia Rates in Intensive IV Insulin Protocols

Algorithm 1 Algorithm 2 Algorithm 3 Algorithm 4

BG (mg/dL) Units/hr BG (mg/dL) Units/hr BG

(mg/dL) Units/hr BG (mg/dL) Units/hr

<60 = Hypoglycemia (See below for treatment)

<70 Off <70 Off <70 Off <70 Off

70 - 109 0.2 70 - 109 0.5 70 - 109 1 70 - 109 1.5

110 - 119 0.5 110 - 119 1 110 - 119 2 110 - 119 3

120 - 149 1 120 - 149 1.5 120 - 149 3 120 - 149 5

150 - 179 1.5 150 - 179 2 150 - 179 4 150 - 179 7

180 - 209 2 180 - 209 3 180 - 209 5 180 - 209 9

210 - 239 2 210 - 239 4 210 - 239 6 210 - 239 12

240 - 269 3 240 - 269 5 240 - 269 8 240 - 269 16

270 - 299 3 270 - 299 6 270 - 299 10 270 - 299 20

300 - 329 4 300 - 329 7 300 - 329 12

330 - 359 4 330 - 359 8 330 - 359 14 >330 28

>360 6 >360 12 >360 16

24 300-329

Reduce insulin rate or hold insulin

infusion at a higher BG

concentration

Newton CA et al. ADA Scientific Meeting. June 2008; J Hospital Med, in press

Protocols

10

Furnary et al. Am J Cardiol 98:557–564, 2006; Bode et al Endocr Pract 2004;10(Suppl. 2):71–80

•  Calculate 24-h insulin requirement based on last 6 hr IV insulin (6-h total dose x 4)

•  Initial basal dose = 80% of the 24h insulin requirement •  Stop IV infusion of insulin 2 h after basal insulin dose •  Monitor blood glucose AC, HS, at 3:00 AM •  Use correction doses of rapid-acting insulin •  Revise total 24-h dose of insulin daily •  Basal and prandial insulin= 50% basal and 50% prandial

Yeldandi & Baldwin. DIABETES TECHNOLOGY & THERAPEUTICS 8 (6) 2006

BG < 60 mg/dl % BG 80-140 mg/dl Mean BG after surgery

Results:

During first day ~ half of BG values within target range of 100–140mg/dL before meals and 100–180 after meals

BG <70mg/dL occurred in 7.7% on the first day and in 26.8% on the first 3 days after transition

Avanzini et al. Diabetes Care 34:1445–1450, 2011

11

Grady / Emory Protocol. Smiley & Umpierrez, Ann. N.Y. Acad. Sci 1212:1-11, 2010

Grady / Emory Protocol. Smiley & Umpierrez, Ann. N.Y. Acad. Sci 1212:1-11, 2010

12

1. ACE/ADA Task Force on Inpatient Diabetes. Diabetes Care. 2006 & 2009 2. Diabetes Care. 2009;31(suppl 1):S1-S110..

Antihyperglycemic Therapy

SC Insulin Recommended for

most medical-surgical patients

OADs Not Generally Recommended

Recommendations for Managing Patients With Diabetes in Non-ICU Setting

Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel. Endocr Pract. 2009

13

Study Type: Prospective, multicenter, randomized, open-label trial

Patient Population: 130 subjects with DM2 Diet and/or oral hypoglycemic agents

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

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

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

•  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

Sliding Scale Insulin Regimen

14

Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181-2186.

Days of Therapy

BG

, mg/

dL

100

120

140

160

180

200

220

240

Admit 1

Sliding-scale

Basal-bolus

bP<.05.

a a a

b b b

b

2 3 4 5 6 7 8 9 10 aP<.05.

•  Sliding scale regular insulin (SSRI) was given 4 times daily •  Basal-bolus regimen: glargine was given once daily; glulisine was given before meals. 0.4 U/kg/d x BG between 140-200 mg/dL 0.5 U/kg/d x BG between 201-400 mg/dL

Days of Therapy

BG

, mg/

dL

100 120 140 160 180 200 220 240

Admit 1

Sliding-scale

Basal-bolus

260 280 300

3 3 4 5 6 7 2 4 2 1

Rabbit 2 Trial: Treatment Success With Basal-Bolus vs. Sliding Scale Insulin

  Basal Bolus Group:   BG < 60 mg/dL: 3%   BG < 40 mg/dL: none

  SSRI:   BG < 60 mg/dL: 3%   BG < 40 mg/dL: none

Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181-2186.

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

15

Study Type: Prospective, randomized, open-label trial

Patient Population: 130 subjects with DM2 Oral hypoglycemic agents or insulin therapy

Study Sites: Grady Memorial Hospital, Atlanta, GA Rush University Medical Center, Chicago, IL

Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009

BG

, mg/

dL

Duration of Therapy, d

Data are means ±SEM.

Detemir + aspart NPH + regular

Basal-bolus regimen: detemir was given once daily; aspart was given before meals. NPH/regular regimen: NPH and regular insulin were given twice daily, two thirds in AM, one third in PM.

Umpierrez GE, et al. J Clin Endocrinol Metab. 2009;94(2):564-569.

P=NS

100

120

140

160

180

200

220

240

Pre-Rx BG

0 1 2 3 4 5 6-10

 NPH/Regular   BG < 40 mg/dl: 1.6%   BG < 60 mg/dl: 25.4%

 Detemir/Aspart   BG < 40 mg/dl: 4.5%   BG < 40 mg/dl: 32.8%

Umpierrez et al, J Clin Endocrinol Metab 94: 564–569, 2009

DEAN Trial: Hypoglycemia

To determine risk factors for

hypoglycemic events during SC insulin

therapy

16

p-value*

variable BG < 60 mg/dl BG < 70 mg/dl

AGE 0.036 0.001

wt 0.027 0.001 A1C 0.521 0.658

Creatinine 0.011 0.002 Enrollment BG 0.166 0.319

Previous treatment 0.005 <.001 Previous insulin Rx <0.001 <.001

Treatment group <0.001 <.001 *p-values are from Wilcoxon Two-Sample Test

Summary of Univariate Analyses

Umpierrez et al, ADA Scientific Meeting, Poster #516, 2009

Umpierrez et al, Diabetes Care, Diabetes Care 34 (2):1–6, 2011

Study Type: Prospective, multicenter, randomized, open-label trial in general surgery (non-ICU)

Patient Population: 211 subjects with DM2 Diet and/or oral hypoglycemic agents or low dose insulin <0.4 U/kg/day

Primary outcome: Differences between groups in mean daily BG concentration

•  Composite of hospital complications: wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia.

Basal Bolus Insulin Regimen

 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 years of age or with a serum creatinine ≥ 2.0 mg/dL

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.

 Half of TDD as insulin glargine and half as insulin glulisine* –  Glargine - once daily, at the same time of the day –  Glulisine- three equally divided doses (AC)

17

Blood glucose levels Change in Daily Insulin Dose*

Fasting and pre-meal BG between 100-140 mg/dl in the absence 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 the absence of hypoglycemia

Decrease by 10%

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.

*  

 †    ‡  *  

Duration of Treatment (days)

 †    †  

R   1 3 2 4

Glargine+Glulisine

Sliding Scale Insulin

5 6 7 8 9 10

* p<0.001; † p=0.01 ‡p=0.02

R=  Randomiza-on  

Umpierrez et al, Diabetes Care 34 (2):1–6, 2011

18

P=0.003

P=NS

P=0.05 P=0.10

P=0.24

Glargine+Glulisine

Sliding Scale Insulin

Umpierrez et al, Diabetes Care 34 (2):1–6, 2011

* Composite of hospital complications: wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia.

P=0.16

P=0.003

SSI = sliding scale insulin ICU=intensive care unit

Postsurgical ICU Admission ICU Length of Stay

23

5 0

5

10

15

20

25

Insulin Glargine + Insulin Glulisine

SSI

P <0.001

4 0 0

5

10

15

20

25

Insulin Glargine + Insulin Glulisine

SSI

P =0.057

BG <70 mg/dL BG <60 mg/dL BG <40 mg/dL

There were no differences in hypoglycemia between patients treated with insulin prior to admission compared to insulin-naïve patients.

Umpierrez et al, Diabetes Care 34 (2):1–6, 2011

12

2 0

5

10

15

20

25

Insulin Glargine + Insulin Glulisine

SSI

P <0.001

19

SSI: range of daily regular insulin= 9.7 to 14.4 units after 24hr treatment 88.5% of patients received <20 units and 39.4% <10 units per day.

Basal Bolus versus SSRI – non-ICU

20

Hospital Complications: Primary outcome

•  Sliding scale regular insulin (SSRI) was given 4 times daily •  Basal-bolus regimen: glargine was given once daily; glulisine was given before meals. TDD: 0.5 U/kg/d x BG Elderly (>70 yrs) and with serum creatinine > 2.0 mg/dl: TDD reduced to 0.3 U/kg/d

p-value*

variable BG < 60 mg/dl BG < 70 mg/dl

AGE 0.036 0.001

wt 0.027 0.001 A1C 0.521 0.658

Creatinine 0.011 0.002 Enrollment BG 0.166 0.319

Previous treatment 0.005 <.001 Previous insulin Rx <0.001 <.001

Treatment group <0.001 <.001 *p-values are from Wilcoxon Two-Sample Test

Hypoglycemia: Univariate Analyses

Umpierrez et al, ADA Scientific Meeting, Poster #516, 2009

Umpierrez et al, Diabetes Care 2007; JCEM 2009; Diabetes Care 2011

21

Initial Insulin Treatment in Medical and Surgical in Non-ICU

BG Target: fasting and pre-meal glucose concentration between 100 mg/dl and 140 mg/dl. * Reduced TDD to 0.15 U/kg/day if age ≥ 70 yr or creatinine ≥ 2.0 mg/dL

T2DM with BG > 140 mg/dl (7.7 mmol/l)

Basal insulin - Start at 0.2-0.25 U/Kg/day* - Correction doses with rapid

acting insulin AC - Adjust basal as needed

NPO Uncertain oral intake

Adequate Oral intake

Basal Bolus TDD: 0.4-0.5 U/Kg/day - ½ basal, ½ bolus - - adjust as needed

Glargine once daily

0.25 U/kg Insu

lin

Act

ion

Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:87; Nathan DM. N Engl J Med. 2002;347:1342

Glulisine before meals per sliding scale (correction)

Preliminary results: Basal bolus 51 patients, basal-plus: 49 patients

Umpierrez et al, not for reproduction

Basal Plus: glargine once daily 0.25 U/kg plus glulisine supplements

Basal Bolus: TDD: 0.5 U/kg/d Glargine 50% glulisine 50%

22

140-180

Recommended 140-180

Acceptable 110-140

Not recommended >180

Not recommended <110

110-140