advantages of tight ! ! glycemic control in the hospital ...diabetestechnology.org/fda/bergenstal-...
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��� ���
Richard M. Bergenstal, MD Executive Director International Diabetes Center at Park Nicollet Minneapolis, MN
President, Medicine & Science American Diabetes Association
Advantages of Tight Glycemic Control in the Hospital Setting
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Disclosure Statement Richard M. Bergenstal, MD
• Amylin
• Merck
• Pfizer
• ResMed
• Takeda
• Hygieia
Roche
LifeScan / J&J
Abbott
Bayer
• Medtronic
• Intuity
• DexCom / Edwards
•
I have participated in clinical research and/or served as a consultant for:
I have inherited Merck stock I am a volunteer officer of the American Diabetes Association
RMB receives no personal compensation for any of these activities and all contracts are with the non-profit Park Nicollet Institute for Research and Education
• Eli Lilly • Novo Nordisk • sanofi-aventis • MannKind
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1986 ADA recommended 10% not 15% total error?
But by 1993 this goal was not achieved.
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Complications Risk in Diabetes The Impact of Intensive Glycemic Control
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International Diabetes Center
Park Nicollet
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DCCT was presented at ADA June 1993 and this ADA SMBG Consensus meeting was Sept 1993
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I believe the American Diabetes Association feels that:
SMBG is one important component of safely improving glucose control
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2009
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NHS Diabetes publishes Self-Monitoring of Blood Glucose report
26 February 2010
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% of Individuals Achieving A1c
<7%
Status of Glucose Control in the US A1C Measures from NHANES
Hoerger TJ, et al. Diabetes Care. 2008;31:81-86.
1999-2000 2001-2 2003-4 0
25
50
75
100
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Severe Hypoglycemia Rates in INT & STD Groups
intensive
standard
Pts
w h
ypog
lyce
mia
eve
nts
(%)
INT
STD
15% vs. 5% 3-fold increase
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Self-reported Antecedents to Hypoglycemia Events
Reason % (n=875 events)
Delayed/missed meal or ate fewer carbohydrates 58% (510)
None 17% (148)
Took incorrect dose of glucose lowering medication 9% (82)
Cognitive decline 8% (70)
Intercurrent illness 5% (44)
Ingested alcohol 3% (26)
Recent weight loss 3% (29)
Started or increase of other medication 3% (28)
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Why Can’t We Improve Glycemic Control & Do it Safely?
HbA1c if elevated
tells you a change in therapy is needed
SMBG if displayed
to show a pattern
tells you what change in therapy to make
Maybe We Rely Too Much on the HbA1c
Alone for Clinical Decision Making
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I believe the American Diabetes Association feels that:
SMBG is one important component of safely improving glucose control
There is room for improvement in both SMBG accuracy and the clinical use of SMBG data – Patients in the hospital setting have the most potential
to benefit from improved meter accuracy. In addition, improved accuracy would add some benefit in most outpatient settings
– Teaching professionals and patients how to effectively use SMBG data needs at least equal emphasis
The role of CGM (inpatient & outpatient) deserves intense study and continued innovation to define its role in management in both settings.
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Special thanks to my colleagues
for data and slides
Silvio E. Inzucchi MD Etie S. Moghissi, MD
Mary Korytkowski MD
Anthony Furnary, MD
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Diabetes and Hospitalization Scope of the Problem
Prevalence of diabetes is estimated at 12% to 25% of hospitalized patients and may be significantly underestimated
50% of patients admitted to CCU have diabetes or pre-diabetes
29%-50% of all cardiac surgery patients
1-3 days longer hospital stay
ACE Position Statement. Endo Pract. 2004;10:77-82. Clement S. Diabetes Care. 2004;27:553-591. Diabetes Care. 2006, 29; 1955-1962
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Inpatient Glucose Management The Past
Acute hyperglycemia was considered to be benign
Sliding scale was the norm
No published standards of care or guidance from medical societies
Hyperglycemia in the hospital was essentially ignored
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“Stress hyperglycemia”���D/C outpatient regimens ���
IV D5/ TPN / PPN ���Steroids, pressors ���↓ Physical activity ���
Fear of hypoglycemia���
↓ Nutrition���Meal interruptions ���
Monitored compliance���Insulin ‘stacking’���Δ Mental status
Metchick LN et al. Am J Med 113:317, 2003
Glycemic Control in the Hospital: An Elusive Goal
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DSWI = deep sternal wound infection; 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 DM
Patients without DM
Insulin infusion
Furnary AP et al. Ann Thorac Surg 67:352, 1999
The ‘Portland Protocol’: Glucose Control & Sternal Infections
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39% insulin
BG=153 mg/dl 99% insulin
BG=103 mg/dl
Van Den Berghe G et al. N Engl J Med 345:1359, 2001
Intensive Insulin Therapy in the Surgical ICU: The Leuven Study
1548 SICU patients
Intensive IV insulin if BG >110 mg/dl
Target: 80-110 mg/dl
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100
96
92
88
84
80
0 0 20 40 60 80 100 120 140 160
Intensive treatment
Conventional treatment
Intensive treatment
Conventional treatment
Surv
ival
in IC
U (%
)
100
96
92
88
84
80
0 0 50 100 150 200 250
In-H
ospi
tal S
urvi
val (
%)
A Days After Admission B Days After Admission
MORTALITY ↓ 42% P<0.04
MORTALITY ↓ 34% P<0.01
Intensive Insulin Therapy in the Surgical ICU: The Leuven Study
Van Den Berghe G et al. N Engl J Med 345:1359, 2001
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Mortality Rate (%)
Mean Glucose Value During ICU Stay (mg/dL)
Krinsley JS. Mayo Clin Proc. 2003;78:1471–1478.
N=1826 ICU patients
Hospital Mortality Rate & Glucose Control in a Medical-Surgical ICU
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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% *
Pos
top
Mor
talit
y (%
) 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
Hyperglycemia: A Predictor of Mortality Following CABG in Diabetics
CABG, coronary artery bypass graft.
First Postop Glucose >200
• 2x LOS • 3x Vent duration • 7x mortality !!!
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Intensive Insulin Therapy in Patients with Severe Sepsis (VISEP Study)
N = 537
Multicenter, 2x2 factorial trial
Intensive group vs conventional group
• Mean morning blood glucose (112 mg/dL vs 151 mg/dL; P<0.001)
• Severe hypoglycemia (17.0% vs 4.1%, P<0.001)
• No difference in mortality
0 10 20 30 40 50 60 70 80 90 100
Days
0 P
roba
bilit
y of
Sur
viva
l 10
20
30
40
50
60
70
80
90
100
Conventional therapy (N=290)
Intensive therapy (N=247)
Brunkhorst FM, et al. N Engl J Med. 358:125-139, 2008.
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Tight Glucose Control in Critically Ill Patients A Meta-Analysis
29 randomized controlled trials totaling 8432 patients
Tight glucose control vs usual care: no significant difference in mortality
Tight glucose control was significantly associated with:
• Higher risk of hypoglycemia (≤ 40 mg/dL) (13.7% vs 2.5%; RR, 5.13)
Wiener RS et al. JAMA 300:933-944, 2008.
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Responding to New Evidence
AACE/ADA Inpatient Glycemic task Force Etie S. Moghissi, MD, FACP, FACE, AACE Chair Mary T. Korytkowski, MD , ADA Chair Monica DiNardo, MSN, CRNP, CDE Daniel Einhorn, MD, FACP, FACE Richard Hellman, MD, FACP, FACE Irl B. Hirsch, MD Silvio E. Inzucchi, MD Faramarz Ismail-Beigi, MD, Ph M. Sue Kirkman, MD; Guillermo E. Umpierrez, MD, FACP, FACE
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AACE-ADA Consensus Statement on Inpatient Glycemic Control May 2009
ENDOCRINE PRACTICE 15: 1-17, 2009 Diabetes Care 32: 1119-1131, 2009
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NICE-SUGAR Study: Design Multi-centre, open label, randomized, controlled trial
Examining the effects of blood glucose management on 90 day, all cause morbidity and mortality
6104 ICU patients • 3054 in intensive control group (target: 81 to 108 mg/dL)
• 3050 in conventional control group (target: ≤180 mg/dL)
The two groups had similar baseline characteristics
40 centers of Australia, New Zealand, and Canada
Recruitment April 2005 to November 2008
Last Follow-up November 2008
The NICE-SUGAR Study Investigators. N Engl J Med. 2009;360:1283-1297.
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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 day mortality: IIT: 829 patients (27.5%), CIT: 751 (24.9%) Absolute mortality difference: 2.6% (95% CI, 0.4 to 4.8); Odds ratio for death with IIT was 1.14 (95% CI, 1.02 to 1.28; P = 0.02).
Nice Sugar, NEJM 360; march 26, 2009
829
751
RR= 1.14
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NICE-SUGAR Study Results: Treatment and Glucose Measures
Insulin Rx Intensive Control Group
Conventional Control Group
P Value
Patients treated with insulin 97.2% 69.0% <0.001
Median duration of treatment (IQR)
4.2 days
(1.9-8.7)
4.3 days
(2.0-9.0) 0.69
Mean insulin dose, units/day 50.2 + 38.1 16.9 + 29.0 <0.001
Morning BG, mg/dL 118 + 25 145 + 26 <0.001
Time-weighted
BG, mg/dL 115 + 18 144 + 23 <0.001
Hypoglycemia (BG ≤40 mg/dL), no. of patients/total no. (%)
206/3016
(6.8%)
15/3014
(0.5%) <0.001
The NICE-SUGAR Study Investigators. N Engl J Med. 2009;360:1283-1297.
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NICE-SUGAR Study: Outcomes
Outcome measure
Intensive Control Group
Conventional Control Group
P Value
28 Day Mortality 22.3% 20.8% 0.17
90 Day Mortality 27.5% 24.9% 0.02
Mech. Ventilation (Mean days + SD)
96% (6.6 + 6.6)
95.3% (6.6 + 6.5)
0.17 (0.56)
Dialysis 15.4% 14.5% 0.34
Bloodstream infections 12.8% 12.4% 0.57
The NICE-SUGAR Study Investigators. N Engl J Med. 2009;360:1283-1297.
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NICE SUGAR Study: Conclusions
This large, international, randomized trial, found that intensive glucose control did not offer any benefit in critically ill patients
Blood glucose target of < 180 mg/dL with the achieved target of 144 mg/dL resulted in lower (90 day) mortality than did a target of 81-108 mg/dL
There was increased hypoglycemia with lower glucose targets
The NICE-SUGAR Study Investigators. N Engl J Med. 2009;360:1283-1297.
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Mean Glucose & In-Hospital Mortality in Patients with AMI
(Reference: Mean BG 100-110 mg/dl)
Kosiborod M et al. Circulation 2008:117:1018
N= 16,871
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What Should We Take Away from these Trial?
Good glucose control, as opposed to near-normal control, is likely sufficient to improve clinical outcomes in the ICU setting
We need to have a renewed concern about hypoglycemia in critically ill patients
Importantly, the NICE-SUGAR results do not endorse a laissez-faire attitude toward inpatient hyperglycemia that was prevalent a decade ago
It is time to rethink the targets and measurement
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Moghissi ES, et al; AACE/ADA Inpatient Glycemic Control Consensus Panel . Endocr Pract. 2009;15(4).
What glycemic targets can be recommended in different patient populations?
TARGETS: Critically ill
Insulin infusion to control hyperglycemia
Starting threshold no higher than 180 mg/dL
Maintain BG between 140-180 mg/dL
• Possibly greater benefit at lower end of range
Somewhat lower targets may be appropriate in selected patients
Targets < 110 mg/dL not recommended
Recommended 140-180
May be appropriate
110-140
Not recommended < 110
Not recommended >180
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AACE/ADA Target Glucose Levels in Non–ICU Patients
Non–ICU setting: • Premeal glucose targets <140 mg/dL
• Random BG <180 mg/dL
• To avoid hypoglycemia, reassess insulin regimen if BG levels fall below 100 mg/dL
• Occasional patients may be maintained with a glucose range below and/or above these cut-points
Hypoglycemia = BG <70 mg/dL Severe hypoglycemia = BG <40 mg/dL
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
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1. ACE/ADA Task Force on Inpatient Diabetes. Diabetes Care. 2006 & 2009 1. Diabetes Care. 2009;31(suppl 1):S1-S110.
Antihyperglycemic Therapy
Insulin Recommended
OADs Not Generally
Recommended
IV Insulin Critically ill patients
in the ICU
SC Insulin Non-critically ill
patients
Recommendations for Managing Patients With Diabetes in the Hospital Setting
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Goldberg PA et al. Diabetes Care. 2004;27:461-467. Markovitz LJ et al. Endocr Pract. 2002;8:10-18. Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367. Malmberg K et al. Circulation. 1999;99:2626-2632. Malmberg K et al. Eur Heart J. 2005;26:650-661. Krinsley J. Mayo Clin Proc. 2004;79:992-1000. Ku SY et al. Jt Comm J Qual Patient Saf. 2005;31:141-147. Donaldson S et al. Diabetes Educ. 2006;32:954-62. DeSantis AJ et al. Endocr Pract. 2006;12:491-505. Texas Diabetes Council. Available at: http://www.dshs.state.tx.us/diabetes/pdf/algorithms/iv%20insulin%20infusion.pdf
IV Insulin Protocols
Yale
Markovitz
Leuven
Portland
Texas Diabetes Council
DIGAMI
University of Washington
Luther Midelfort Mayo Health System
Rush University Protocol
Northwestern University
Multiple published protocols are available that are effective and safe. Some examples include:
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Yale Insulin Infusion Protocol.: First 33 Uses
Goldberg PA, et al. Diabetes Care. 2004;27:461-467.
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The Ideal IV Insulin Protocol
Easily ordered (signature only)
Effective (gets to goal quickly)
Maintains BG within a defined target range over several hours
Includes an algorithm for making temporary corrective increments or decrements of infusion rate
Safe (minimal risk of hypoglycemia)
Directions for treatment of hypoglycemia
Easily implemented
Can be executed by nursing staff in response to a single physician order
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1. ACE/ADA Task Force on Inpatient Diabetes. Diabetes Care. 2006 & 2009 1. Diabetes Care. 2009;31(suppl 1):S1-S110.
Antihyperglycemic Therapy
Insulin Recommended
OADs Not Generally
Recommended
IV Insulin Critically ill patients
in the ICU
SC Insulin Non-critically ill
patients
Recommendations for Managing Patients With Diabetes in the Hospital Setting
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RABBIT 2: Randomized Study of Basal-Bolus Insulin Therapy in the Inpatient Management of patients
with type 2 diabetes
1
240
220
200
180
160
140
120
100 2 3 4 5 6 7 8 9 10 Admit
Days of Therapy
Bloo
d G
luco
se (
mg/
dL)
* * *
† †
† †
Basal /bolus
SSI
*P < 0.01; † P < 0.05 SSI = sliding-scale regular insulin.
Umpierrez GE, et al. Diabetes Care. 2007;30:2181-2186.
Mean blood glucose difference between groups = 27 mg/dL (P<0.01)
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Hours
Insulin Level
“Basal-Bolus” Insulin Therapy
0 2 4 6 8 10 12 14 16 18 20 22 24
Rapid (Lispro, Aspart, Glulisine)
Long (Glargine, Detemir)
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Maintaining Physiologic Insulin Delivery in the Hospital --- 3 Part Insulin Order
Breakfast Lunch Dinner Bedtime
Basal insulin
Mealtime insulin (bolus)
Correction Dose or Supplemental Dose of Insulin
Insu
lin
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Estimating SC Insulin Dose
1. Calculate estimated total daily dose of insulin as follows:
– T2DM: 0.5 to 0.7 U/kg
– T1DM or type unknown: 0.3 to 0.5 U/kg
2. Divide total daily dose of insulin into 50% basal as glargine or detemir and 50% prandial as aspart, lispro, or glulisine
3. Divide prandial insulin into 3 equal doses to be given with meals
DeSantis AJ et al. Endocr Pract. 2006;12:491-505.
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Premeal Algorithm for Correction-Dose Insulin
To be administered in addition to scheduled insulin to correct premeal hyperglycemia
Additional Insulin
Premeal BG mg/dL
Low Dose
Medium Dose
High Dose Individualized
150–199 1 unit 1 unit 2 units
200–249 2 units 3 units 4 units
250–299 3 units 5 units 7 units
300–349 4 units 7 units 10 units
>349 5 units 8 units 12 units
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Hypoglycemia Is a Concern
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Addressing Safety Concerns of Inpatient Management of Hyperglycemia
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What are areas for future research?
Stress hyperglycemia (mechanisms, targets)
Severe hypoglycemia (causes, outcomes, risks, costs)
Comparisons of glycemic targets and outcomes in non-critically ill patient populations
Effect of glycemic variability on patient outcomes
Hospital systems and safety
Monitoring (meter accuracy, CGM)
Pediatric populations (targets)
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Continuous Glucose Monitoring in the Inpatient Setting
• Good control of blood glucose is recommended in the ICU and medical floors
• If glucose could be accurately measured more frequently (continuously) hypoglycemia may be minimized and even tighter glycemic control may prove beneficial
• Research in underway by Edwards Lifesciences, DexCom, Inc. and others evaluating the accuracy and utility of frequent IV glucose monitoring in the inpatient setting. Initial results presented at scientific meetings are very encouraging.
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How Will We Translate What We Are Learning Into Improved Practice and Outcomes?
FDA, ISO & CLIA-POC are gathering critical data and writing important standards or guidelines regarding glucose monitoring in the hospital and outpatient settings.
But where do people with diabetes, clinicians and educators look for guidance on diabetes management?
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How Will We Translate What We Are Learning Into Improved Practice Patterns and Outcomes?
FDA, ISO & CLIA-POC should find a way to Partner with the American Diabetes Association (and others) to translate new science and standards into changes in practice patterns for patients and health care professionals.