Case Presentation: Inpatient Glycemic Control · Intensive Glucose Management in RCT . Trial ... IV insulin in ICU until patients were able to eat ... Regular Insulin. Sliding. Basal

1

Guillermo E. Umpierrez, MD, FACP, FACE

Professor of Medicine

Director, Grady Hospital Clinical Research Unit

Emory University School of Medicine

Director, Diabetes & Endocrinology Section

Grady Health System

Inpatient Glycemic Control

Case Presentation:

64 y/o male with a 3 cm thyroid nodule, FNA biopsy suspicious for papillary thyroid carcinoma. He has an 12 yr history of T2DM treated with metformin.

In the pre-surgery holding area, his BG is 324 mg/dL, A1C: 9.2%, normal TSH and Free T4.

Given this patient’s history and laboratory values, what is the best treatment option for glycemic management?

1. Hold surgery and reschedule after glycemic control improved

2. Move to ICU/step-down and start continuous IV insulin drip?

3. Cover with sliding-scale insulin and proceed with surgery?

4. Start basal bolus regimen – long + rapid acting analogs?

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

Swanson et al. Endocrine Practice, October 2011

Data from ~12 million BG readings from 653,359 ICU patients - mean POC-BG: 167 mg/dL

Hyperglycemia*: A Common Comorbidity in Medical-Surgical Patients in a Community Hospital

62%

12%

26%

Normoglycemia

Known Diabetes

New Hyperglycemia

Umpierrez G et al, J Clin Endocrinol Metabol 87:978, 2002

n = 2,020

* Hyperglycemia: Fasting BG 126 mg/dl or Random BG 200 mg/dl X 2

2

Diagnosis & recognition of hyperglycemia and diabetes in the hospital setting

Admission

Assess all patients for a history of diabetes

Obtain laboratory BG testing on admission

Umpierrez et al. J Clin Endocrinol Metabol. 97(1):16-38, 2012

BG<140 mg/dl

No POC

BG testing

History of diabetes

BG monitoring

No history of diabetes

Start POC BG

testing x 24-48h

Check A1C

A1C ≥ 6.5%

BG >140 mg/dl

A1C for Diagnosis of Diabetes in the Hospital

HbA1c should be measured in non-diabetic subjects with hyperglycemia (BG>140 mg/dl) and in subjects with diabetes if not done within 2-3 months prior to admission.

In the presence of hyperglycemia, a patient with HbA1c >6.5% can be identified as having diabetes.

Implementation of A1C testing can be useful:

assess glycemic control prior to admission

assist with differentiation of newly diagnosed diabetes from stress hyperglycemia

designing an optimal regimen at the time of discharge

Umpierrez et al, J Clin Endocrinol Metabol, 2012

What is the association between hyperglycemia and

hospital outcomes? 111-145

146-199

200-300

>300

Me

an

BG

(m

g/d

L)

Nondiabetics 153,910

Odd Ratio Odd Ratio

History Diabetes

Diabetics 62,868

No History Diabetes

Falciglia et al, Crit Care Med 2009

216,775 consecutive first admission

177 surgical, medical, cardiac ICUs

73 geographically diverse VAMC

Mortality Risk Greater in Hyperglycemic Patients without History of Diabetes

3

Thirty Day Mortality and Hospital Complications in Diabetic and Non-diabetic subjects Undergoing General Non-Cardiac Surgery

†p = 0.1 * p= 0.001

#p=0.017

†

*

* *

* #

*

%

A Frisch et al. Diabetes Care, May 2010

Adverse Events Stratified by Perioperative Hyperglycemia

BG at any point on the day of surgery, post-op day 1 and 2 N= 11,633, colorectal and bariatric surgery;

29.1% with hyperglycemia

Diabetes No Diabetes

*

*

*

*

§

§ p <0.05 * P <0.01

Known et al. Ann Surg 2013

Proportion of Patients (%)

BG > 180 mg/dl

BG < 180 mg/dl

Hyperglycemia: An Independent Marker of In-Hospital Mortality in Patients with Undiagnosed Diabetes

Total In-patient Mortality

Normoglycemia Known New Diabetes Hyperglycemia

1.7% 3.0%

16.0% *

Mort

alit

y (

%)

* p < 0.01

Umpierrez GE et al, J Clin Endocrinol Metabol 87:978, 2002

What target glucose should we aim in the hospital?

4

Prospective study of 2,467 consecutive diabetics who underwent open heart surgery. 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

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

CII SCI

Portland Diabetes Project: Insulin Infusion Reduces DSWI

SCI Group: Day of surgery: 241 mg/dL

POD #1: 206 mg/dL

CII Group: Day of surgery: 199 mg/dL

POD #1: 176 mg/dL

Intensive Insulin Therapy in SICU: The Leuven Study

N= 1548 pts in a surgical ICU

Conventional IT

• Target BG: 180-200 mg/dL

• Mean daily BG: 153 mg/dL

Intensive IT

• Target BG: 80-110 mg/dL

• Mean daily BG: 103 mg/dL

Van-Den Berge et al, NEJM 345:1359, 2001

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

The NICE-SUGAR Study

Blood Glucose Level,

According to Treatment Group

IIT goal: 81 – 108 mg/dL (mean BG 118 mg/dL)

CIT goal: <180 mg/dL (mean BG 145 mg/dL)

Probability of Survival

90 days: Absolute mortality difference of 2.6% (95% CI, 0.4 to 4.8);

Odds ratio for death with IIT: 1.14 (95% CI, 1.02 to 1.28; p = 0.02).

829

751

RR= 1.14

NICE-SUGAR Trial. N Engl J Med. 360:1283-1297, 2009.

5

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).

2009 AACE/ADA Recommended Target Glucose Levels in ICU Patients

Recommended 140-180

Acceptable 110-140

Not recommended <110

Not recommended >180

Computerized algorithm (Glucommander) to reduce risk of hypoglycemia and protocol violations

GLUCO-CABG trial - first prospective RCT to determine the optimal BG target during the perioperative period in hyperglycemic subjects who undergo CABG.

100-140 mg/dl

141-180 mg/dl

GLUCO-CABG Trial – RCT to determine the optimal BG target during the peri-operative period (ICU stay, hospital stay, 90 day after

discharge) in hyperglycemic subjects who undergo CABG

NCT 01792830

Gluco-CABG: Methods

Patients with hyperglycemia during surgery, or after surgery were randomized to:

Intensive insulin therapy (100-140 mg/dL) Conservative insulin therapy (141-180 mg/dL)

Computerized algorithm (Glucommander) was used to guide continuous insulin infusion

IV insulin in ICU until patients were able to eat and/or for transfer to non-ICU services

Transition to SQ insulin (target <140 mg/dL) Diabetes → Basal bolus regimen Non-diabetes requiring CII ≥ 2 U/h → Basal bolus regimen

Non-diabetes requiring < 2 U/h → correction doses with SSI

GLUCO-CABG Trial Perioperative Blood Glucose Concentration

Data are means SEM

Intensive (n=151): Target BG 100-140 mg/dl Conservative (n=151): Target BG 141-180 mg/dl

Umpierrez GE, et al. 2014 ADA Scientific Meeting

100

120

140

160

180

200

Admit Rando- mization

OR ICU I.V.

ICU Non- ICU

After Discharge

Glu

cose

, m

g/d

l

* *

p<0.001 p<0.001

Intensive= 130±11 mg/dl (IQR 124-139) Conventional= 159±14 mg/dl (IQR 142-164)

i.v. ICU

Intensive= 132±14 mg/dl (IQR 124-139) Conventional= 154±16 mg/dl (IQR 142-164)

ICU

Intensive

Conservative

6

Percent of patients with hypoglycemia Intensive vs. Conventional glucose target

Hypogly

cem

ia,

%

Intensive insulin therapy (n=151): Target BG 100-140 mg/dl Conservative insulin therapy (n=151): Target BG 141-180 mg/dl


5

10

15

20

25

0

Data are means SEM, mg/dL

Hospital Non-ICU

After Hospital Discharge

< 40

5

1

< 70 < 70

CII No-CII

ICU

< 40

1 1 0 0 0 0

< 40

1 1

< 70

20

23

< 40 < 70

0 0

24

19

Intensive

Conservative

*

*p= 0.03

Perioperative Complications Intensive vs Conservative

Co

mp

lica

tio

ns,

%

Intensive Conservative

Composite of complications: death, wound infection, pneumonia, acute kidney injury (AKI), respiratory failure, and major cardiovascular events (MACE)


10

20

30

40

50

60

Wound Infection

Pneumonia AKI Composite Death Resp Failure

MACE

0

P= 0.08

42

52

1 3

P= 0.45

2 4

P= 0.62

2 5

P= 0.45

14

19

P= 0.27 P= 0.27 P= 0.27

11

19

34

32

Data are means SEM

Perioperative Complications: DM vs no-DM

Co

mp

lica

tio

ns,

%

Diabetes No-Diabetes

Composite of complications: death, wound infection, pneumonia, acute kidney injury (AKI), respiratory failure, and major cardiovascular events (MACE)


10

20

30

40

50

60

Wound Infection

Pneumonia AKI Composite Death Resp Failure

MACE

0

P= 0.48

49

45

5

0

P= 0.02

4 1

P= 0.17

4 3

P>0.9

20

12

P= 0.048 P= 0.49 P= 0.53

14 17

39 36

Data are means SEM

*

*

GLUCO-CABG trial - first prospective RCT to determine the optimal BG target during the perioperative period in hyperglycemic subjects who undergo CABG.

100-140 mg/dl

141-180 mg/dl

Emory University

GLUCO-CABG Trial – RCT to determine the optimal BG target

during the peri-operative period (ICU stay, hospital stay, 90 day after discharge) in hyperglycemic subjects who undergo CABG

Conclusion: Intensive glucose control targeting a BG of 100-140 mg/dl in the ICU did not reduce peri-operative complications or mortality compared to a less strict glucose target of 141-180 mg/dl in hyperglycemic patients undergoing CABG surgery

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How should we manage hyperglycemia in non-ICU settings?

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

Antihyperglycemic Therapy

Insulin

Recommended

OADs

Not Generally Recommended

Recommendations for Managing Patients With Diabetes in the Hospital Setting

Inpatient Management in non-ICU Setting

Sliding Scale Regular Insulin

Basal Bolus Insulin Regimen

In insulin naïve patients with T2DM, does treatment with basal bolus regimen with glargine once daily and glulisine before meals is superior to sliding scale regular insulin?

RABBIT-2D TRIAL: - Research Question:

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

Rabbit 2 Trial: Changes in Glucose Levels With Basal-Bolus vs. Sliding Scale Insulin

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

Days of Therapy

BG

, m

g/d

L

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

Hypoglycemia rate:

Basal Bolus Group:

BG < 60 mg/dL: 3%

BG < 40 mg/dL: none

SSRI:

BG < 60 mg/dL: 3%

BG < 40 mg/dL: none

8

Inpatient Management in non-ICU Setting

Basal Bolus Insulin Regimen

NPH and Regular Insulin-Spilt-

Mixed Regimen

In patients with T2DM on diet, oral agents or insulin treatment, does treatment with basal bolus regimen with detemir once daily and aspart before meals is superior to NPH and Regular split-mixed insulin regimen?

DEAN TRIAL: - Research Question:

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

DEAN Trial: Changes in Mean Daily Blood Glucose Concentration

BG

, m

g/d

L

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

Does glucose control prevents hospital complications in non-ICU settings?

Inpatient Management

in General Surgery

Sliding Scale

Regular Insulin

Basal Bolus

Insulin Regimen

In patients with T2DM on diet, oral agents or insulin treatment,

does treatment with basal bolus regimen with glargine and glulisine is superior to SSRI?

RABBIT-2 Surgery Trial: - Research Question:

• Differences between groups in mean daily BG

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

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

9

*

*

* *

Mean BG before meals and at bedtime during basal bolus and SSI therapy

Breakfast Lunch Dinner Bedtime

*p<0.001

Glargine+Glulisine

Sliding Scale Insulin


Postoperative Complications

P=0.003

P=NS

P=0.05 P=0.10

P=0.24

Glargine+Glulisine

Sliding Scale Insulin


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

Insulin Treatment in in Non-ICU Setting

Do you need basal bolus in ALL patients? Do you need basal bolus in ALL patients?

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

Basal Plus Trial:

Basal + Correction vs. Basal Bolus

Basal plus supplements

Starting glargine*: 0.25

units/kg

Correction with glulisine

for BG >140 mg/dl per

sliding scale

Basal Bolus Regimen

Starting TDD*: 0.5 U/kg

Glargine: 0.25 U/kg

Glulisine: 0.25 U/kg in three equally divided doses (AC)

Correction with glulisine

for BG >140 mg/dl per

sliding scale

* Reduce TDD to 0.15 U/kg in

patients ≥70 yrs and/or serum

creatinine ≥ 2.0 mg/dL

* Reduce TDD to 0.3 U/kg in

patients ≥70 yrs and/or serum

creatinine ≥ 2.0 mg/dL Umpierrez et al, Diabetes Care, 2013

10

Duration of Treatment (days)

0 1 2 3 4 5 6 7 8 9 10

Blo

od G

lucose (

mg/d

L)

120

140

160

180

200

220

240Basal Plus

Basal Bolus

Basal-PLUS vs Basal Bolus: 300 medical & surgical non-ICU patients

Patients treated with diet, oral agents or with low-dose insulin ≤ 0.4 U/Kg/Day

Basal Plus: glargine once daily

0.25 U/kg plus glulisine supplements

Basal Bolus: TDD: 0.5 U/kg/d

Glargine 50% glulisine 50%

Umpierrez et al, Diabetes Care, 2013

Basal-PLUS vs Basal Bolus: Medicine and Surgery Patients

Medicine Surgery

BG AC & HS

Daily BG Daily BG

BG AC & HS

Smiley et al, Diabetes Care, 2013

Can you treat patients with oral agents in the hospital?

Inpatient Management in

non-ICU

Basal Bolus or

Basal Plus Regimens

What about Incretin-Based

Therapy?


DPP-4 Therapy in Hospitalized Patients

Study Type: Multicenter, prospective, open-label

randomized clinical trial

Patient Population: Patients with T2D admitted to general

medicine and surgery services at 3 hospitals: Emory

University, Grady, and University of Michigan

Treatment Groups* Group 1. Sitagliptin once daily (n=30)

Group 2. Sitagliptin plus glargine insulin once daily (n=30)

Group 3. Basal bolus regimen with glargine once daily

and lispro before meals (n=30)

* All groups received supplemental doses of lispro for BG > 140 mg/dl before meals

NCT01378117


11

Randomi-zation

Mean Daily BG During Treatment


Me

an D

aily

Blo

od

Glu

cose

(m

g/d

L)

Randomization Blood Glucose (<180 mg/dl and >180 mg/dl) and Mean Daily Glucose concentration

p= 0.91

p= 0.08


Inpatient Management in

non-ICU

Basal Bolus or

Basal Plus Regimens

Management of Patients With Diabetes a After Hospital Discharge

What Regimen Should We Use at

Hospital Discharge?

Use admission A1C to adjust therapy at discharge

7%

8%

9%

10%

Adjust original therapy, ADD another agent or basal insulin

Return to original therapy

ADD basal insulin therapy

ADD basal or REPLACE with basal/bolus

Umpierrez G et al. Endocrine Society Inpatient Diabetes Guidelines. J Clin Endocrinol Metabol, 2012

Recommendations for Managing Patients With Diabetes After Hospital Discharge

12

Methods: Prospective, multicenter open-label study aimed to determine the safety and efficacy of a hospital discharge algorithm based on admission HbA1c.

Umpierrez et al. D Care in press 2014

A1C < 7%

Re-start outpatient treatment regimen

(OAD and/or insulin)

A1C 7%-9%

Re-start outpatient oral agents and D/C on glargine once daily at 50% of hospital dose

A1C >9%

D/C on basal bolus at same hospital dose.

Alternative: re-start oral agents and D/C

on glargine once daily at 80% of hospital dose

Discharge Insulin Algorithm

Discharge Treatment

Umpierrez et al, D Care 2014, in Press

Hospital Discharge Algorithm Based on Admission HbA1C for the Management of Patients with T2DM

8.75%

7.9%

7.35% %


Hospital Discharge Algorithm Based on Admission HbA1C for the Management of Patients with T2DM

Primary outcome: - change in A1C at 4 wks and 12 wks after discharge

All Patients

OAD OAD + Glargine

Glargine+ Glulisine

Glargine

# patients, n (%) 224 81 (36) 61 (27) 54 (24) 20 (9)

A1C Admission, % 8.7±2.5 6.9±1.5 9.2±1.9 11.1±2.3 8.2±2.2

A1C 4 Wks F/U, % 7.9±1.7* 7.0±1.4 8.0±1.4ψ 8.8±1.8ψ 7.7±1.7

A1C 12 Wks F/U, % 7.3±1.5* 6.6±1.1 7.5±1.6* 8.0±1.6* 6.7±0.8*

BG<70 mg/dl, n (%) 62 (29) 17 (22) 17 (30) 23 (44) 5 (25)

BG<40 mg/dl, n (%) 7 (3) 3 (4) 0 (0) 3 (6) 0 (0)

* p< 0.001 vs. Admission A1C; ψp=0.08


13

Management of diabetes in non-critical care setting

So… What really have we learned?

Umpierrez et al. Endocrine Society Annual Meeting, 2014

What Glucose Level Predicts Hospital Complications?

Guillermo E. Umpierrez, MD

[email protected]

Thank you!

Documents

Case Presentation: Inpatient Glycemic Control · Intensive Glucose Management in RCT . Trial ... IV insulin in ICU until patients were able to eat ... Regular Insulin. Sliding. Basal