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Section overview: Hyperglycemia in ACS
• Physiologic impact of hyperglycemia
– Epidemiology
– Glucometrics
– Pathophysiologic mechanisms
• In-hospital therapeutic strategies for insulin
–
–
–
–
Rationale
Insulin protocols
GIK
Guidelines
• Post-discharge, long-term glycemic control
Cardioprotective actions of insulin
Insulin
Glucose lowering
FFA
Anti-inflammatory
NFB, IB, MCP-1
ICAM-1, CRP
Anti-thrombotic
Antioxidant
ROS
Vasodilation and
Platelet inhibition
NO release
cAMP
eNOS
TF, PAI-1
Anti-apoptotic
Cardioprotective
Neuroprotective
Dandona P et al. J Am Coll Cardiol.
2009;53(suppl S):S14-S20.
Differing effects of insulin and acute hyperglycemia
on myocardial ischemia/reperfusion injury
Male rats
• 30 min myocardial
ischemia, 6 hr reperfusion
• GIK = glucose 200 g/L,
insulin 60 U/L, KCl
60 mmol/L
• HG = glucose 500 g/L
†
50
‡
40
Infarct size
(INF/AAR, %)
*
30
20
10
INF = infarct area
AAR = area at risk
*P < 0.01 vs vehicle
†P < 0.05 vs vehicle
‡P < 0.01 vs GIK
0
Vehicle
GIK
HG GIK + HG
Su H et al. Am J Physiol Endocrinol Metab. 2007;293:E629-E635.
Insulin therapy for critically ill patients:
Key advances and clinical settings
1931: Cruikshank
First report of high glycosuria
prevalence in AMI
2001: Van den Berghe et al
Surgical ICU
Mortality 34%
2003: Furnary et al
CABG patients
Mortality 57%
Cruikshank N. BMJ. 1931.
Van den Berghe G et al. N Engl J Med. 2001.
Furnary AP et al. J Thorac Cardiovasc Surg. 2003.
Van den Berghe G et al. N Engl J Med. 2006.
2006: Van den Berghe et al
Medical ICU
Morbidity
Intensive vs conventional glucose control in the
medical ICU: Study design
N = 1200 admitted to medical ICU and unable to receive oral nutrition
Intensive insulin treatment
Conventional insulin treatment
n = 595
Insulin infusion started when
glucose >110 mg/dL and
adjusted to maintain between
80 and 110 mg/dL
n = 605
Insulin infusion started when
glucose >215 mg/dL and
adjusted to maintain between
180 and 200 mg/dL
n = 386 stayed in ICU ≥3 days
n = 381 stayed in ICU ≥3 days
Primary outcome: All-cause in-hospital mortality
Van den Berghe G et al. N Engl J Med. 2006;354:449-61.
Intensive vs conventional insulin treatment in
the medical ICU: In-hospital mortality
Intent-to-treat
(N = 1200)
60
3 days in ICU
(n = 767)
P = 0.009
50
P = 0.33
40
Rate
(%) 30
20
10
0
Intensive treatment
Conventional treatment
Van den Berghe G et al. N Engl J Med. 2006;354:449-61.
Intensive vs conventional insulin treatment in
the medical ICU: Reduced morbidity
Weaning from
mechanical ventilation
4.0
Discharge from ICU
4.0
P < 0.001
Discharge from hospital
5.0
P = 0.002
4.0
3.0
3.0
P < 0.001
3.0
Cumulative 2.0
hazard
2.0
1.0
1.0
1.0
0.0
0.0
0.0
2.0
0
20
40
60
80
100
0
20
40
60
80
100
0
100 200 300 400 500 600
Days after admission to ICU
Intensive treatment
Conventional treatment
Van den Berghe G et al. N Engl J Med. 2006;354:449-61.
Yale-Mid America Heart Institute protocol:
Performance in ACS
Consecutive patients with admission BG >140 mg/dL, target
BG 90-120 mg/dL
Protocol performance
240
Mean 24-hr glucose
190
180.1
180
200
170
160
Median
glucose
120
(mg/dL)
160
Mean
24-hr 150
glucose 140
(mg/dL)
130
80
127.6
120
40
110
100
0
0
5
10
15
20
25
30
35
Time (post insulin infusion, hours)
40
PrePostimplementation implementation
(n = 138)
(n = 94)
Kosiborod M et al. Circulation. 2007;116:II-811A.
Insulin therapy for noncritically ill patients
Sliding-scale 1970s
• Routine BG monitoring
• Short-acting insulin, with dose
based on BG level
Basal-bolus 2007
• Single dose of long-acting insulin
(basal)
• Supplemental short-acting insulin
given before each meal (bolus)
Umpierrez GE et al. Diabetes Care. 2007;30:2181-6.
Glycemic control in patients treated with
sliding-scale insulin
Medical records review, N = 90 consecutive hospitalized patients
100
80
Patients
(%)
60
40
20
0
1
2
3
Day
Glycemic control*
Poor†
Inadequate
Inconsistent
*Target range (TR): 90-130 mg/dL, †50% of measurements
outside TR with 1 measurement >180 mg/dL
4
Good
5
Excessive
Golightly LK et al. Pharmacotherapy. 2006;26:1421-32.
RABBIT 2: Superior glycemic control with
basal-bolus vs sliding-scale insulin
N = 130 insulin-naive hospitalized nonsurgical patients with T2DM
240
220
*
200
Blood
glucose
(mg/dL)
*
*
180
†
†
†
†
Sliding scale
160
140
Basal-bolus‡
120
100
Admit 1
2
3
4
5
6
7
8
9
10
Days of therapy
*P < 0.01; †P < 0.05; ‡Long-acting insulin (glargine) once-daily + short-acting
insulin (glulisine) before meals, total dose 0.4 U/kg (BG 140-200 mg/dL) or
0.5 U/kg (BG 201-400 mg/dL)
Umpierrez GE et al.
Diabetes Care. 2007;30:2181-6.
RABBIT 2: Glycemic control rapidly improved
after switching to basal-bolus insulin regimen
n = 9 patients with BG >240 mg/dL on sliding-scale insulin
300
←Switch from sliding-scale
260
Blood
glucose
(mg/dL)
to basal-bolus insulin
220
180
140
100
Admit
1
2
3
4
1
2
3
4
5
6
7
Days of therapy
Sliding scale
Glargine + glulisine
Umpierrez GE et al. Diabetes Care. 2007;30:2181-6.
Myocardial energy production: Rationale for
addition of glucose to insulin regimens
Myocyte
FFA
Glucose
Acyl-CoA
Pyruvate
β-oxidation
Acetyl-CoA
• O2 requirement of glucose
pathway is lower than FFA
pathway
• During ischemia, oxidized FFA
levels rise, blunting the glucose
pathway
• Provision of high-dose glucose
during acute ischemia may
improve efficiency of
myocardial energy production
Energy for contraction
Stanley WC et al. Physiol Rev. 2005;85:1093-1129.
CREATE-ECLA Trial Group Investigators. JAMA. 2005;293:437-46.
GIK clinical development: 1965-2005
1965-1987: Multiple small trials
N = 1932 (pooled)
Mortality* ↓28% (pooled data)
1995: DIGAMI 1
N = 620
Mortality* 18%
2005: DIGAMI 2
N = 1253
Mortality neutral
*In-hospital
CREATE-ECLA Trial Group Investigators. JAMA. 2005.
Fath-Ordoubadi F et al. Circulation. 1997.
Malmberg K et al. J Am Coll Cardiol. 1995.
Malmberg K et al. Eur Heart J. 2005.
2005: CREATE-ECLA
N = 20,201
Mortality neutral
Early and late effects of GIK infusion
CREATE-ECLA/OASIS-6 pooled data, N = 22,943 with acute STEMI
Events (%)
Death (days)
Favors
GIK
Favors
control
P
GIK
Control
9.7
6.2
3.7
9.3
5.5
4.0
0.33
0.03
0.20
Heart failure (days)
0-30
0-3
4-30
16.5
12.9
2.4
16.7
12.0
3.1
0.82
0.07
0.10
Death or
heart failure (days)
0-30
0-3
4-30
20.3
15.8
4.1
20.4
14.5
5.0
>0.99
0.02
0.004
0-30
0-3
4-30
0.5
1.0
2.0
Hazard ratio (95% CI)
Diaz R et al. JAMA. 2007;298:2399-405.
Possible explanations for early effect of GIK
in AMI
• Infusion-related
– Hyperglycemia
– Hyperkalemia
– Fluid overload
• Delayed delivery of GIK
Diaz R et al. JAMA. 2007;298:2399-405.
Nesto RW, Lago RM. Circulation. 2008;117:990-2.
CREATE-ECLA re-analysis: Observed vs
estimated 30-day mortality
14
12.2
12
10
9.7
9.9
10
30-day 8
mortality
6
(%)
4
2
0
Control
Observed
GIK
Estimated
Chaudhuri A et al. Diabetes Care. 2007;30:3026-8.
Modified GIK regimen blunts FFA rise and
suppresses pro-MMP-1
N = 32 with STEMI. GIK = 10% dextrose, 40 mmol KCl at 60 mL/hour,
titrated to maintain glucose from 80-200 mg/dL, insulin at 2.5 U/hour.
FFA
Pro-MMP-1
2.0
100
1.8
1.6
*
*†
80
§
mmol/L
1.4
% of
baseline
1.2
§
60
‡
40
1.0
§
‡
‡
‡
20
0.8
0
0
0
2
4
6
24
48
0
2
4
6
24
48
Time (hours)
Control
Insulin
*P = 0.0082 vs baseline, †P = 0.0009 between groups
‡P ≤ 0.0055 vs baseline, §P ≤ 0.005 vs baseline
Chaudhuri A et al. Am J Cardiol. 2007;100:1614-8.
HI-5: Study design
Hyperglycemia: Intensive Insulin Infusion In Infarction
N = 240 with AMI and admission BG >140 mg/dL
Intensive insulin infusion therapy
Insulin 2U/h +
5% dextrose @ 80 mL/h
Target BG 72-180 mg/dL
Conventional therapy
Remain on usual diabetes therapy*
Primary outcomes:
All-cause mortality during hospitalization and at 3 and 6 months
*Metformin temporarily discontinued, sc insulin permitted
Cheung NW et al. Diabetes Care. 2006;29:765-70.
HI-5: Treatment effects on glucose level and
morbidity/mortality
Insulin/dextrose
Conventional
P
150
162
NS
4.8
7.1
7.9
3.5
4.4
6.1
NS
NS
NS
Inpatient cardiac failure (%)
12.7
22.8
0.04
3-month reinfarction (%)
2.4
6.1
0.05
Mean BG (mg/dL)
Mortality (%)
Inpatient
3-month
6-month
Mean admission BG 198 mg/dL
Mean time to insulin/dextrose 13.2 hours
Cheung NW et al. Diabetes Care. 2006;29:765-70.
HI-5: Mortality correlated with mean 24-hour
blood glucose
Mean BG (mg/dL)*
≤144
≥145
Odds ratio (95% CI)
P
Inpatient
0
7
7.2 (0.9-58.9)
0.07
3-month
2
9
4.7 (1.0-22.4)
0.05
6-month
2
11
5.6 (1.2-26.1)
0.03
Mortality (%)
*Median on-treatment BG = 144 mg/dL
Cheung NW et al. Diabetes Care. 2006;29:765-70.
HI-5: Study limitations
• Glucose target in intensive insulin infusion group
not met
• Study underpowered to demonstrate difference in
mortality between groups
• Insulin therapy instituted relatively late (13 hours after
symptom onset)
Cheung NW et al. Diabetes Care. 2006;29:765-70.
Ongoing trials of insulin therapy in ACS
IMMEDIATE
INTENSIVE
Hypothesis
Earlier GIK infusion will
reduce clinical outcomes
Insulin limits hyperglycemia
and has benefits independent
of glucose control
N
15,450
700
Population
Acute chest pain
All ACS
Glucose >140 mg/dL plus
anterior STEMI
Settings
Prehospital (ambulance)
ED
ED
Cath lab
Comparator
Placebo
Standard glycemic care with
sliding-scale insulin
Primary outcomes
30-day and 1-year mortality
MRI-determined infarct size
Opie LH. Circulation. 2008;117:2172-7.
Nesto RW, Lago RM. Circulation. 2008;117:990-2.
ADA: Glycemic targets in hospitalized patients
Noncritically ill
Fasting glucose <126 mg/dL and all random
glucoses <180-200 mg/dL (LOE E)
Critically ill
BG levels should be kept as close to 110 mg/dL as
possible and generally <140 mg/dL (LOE A)
These patients require an intravenous insulin
protocol that has demonstrated efficacy and safety
in achieving the desired glucose range without
increasing risk for severe hypoglycemia (LOE E)
ADA = American Diabetes Association
LOE = level of evidence
ADA. Diabetes Care. 2008;31(suppl 1):S12-S54.
AHA Scientific Statement: In-hospital treatment
of hyperglycemia in ACS
• In patients hospitalized in the non-ICU setting, goal is
plasma glucose <180 mg/dL (LOE C)
– Subcutaneous insulin is most effective method of glucose
control in this setting
• Reasonable to consider in patients admitted to ICU with
plasma glucose >180 mg/dL, regardless of diabetes
history (LOE B)
– Precise goal of treatment has not been defined
– Reasonable goal is 90-140 mg/dL (LOE C)
– IV infusion of insulin is most effective method of glucose control
in this setting
Deedwania P et al. Circulation. 2008;117:1610-9.
Suboptimal glucose control in hospitalized
patients
N = 16,871 patients in 40 US hospitals
Diabetes
50
40
Patients
(%)
40
78%
30
30
20
20
10
10
0
0
<110
110-140 140-170 170-200
No diabetes
50
>200
26%
<110
110-140 140-170 170-200
>200
Mean hospitalization glucose (mg/dL)
Kosiborod M et al. J Am Coll Cardiol. 2007;49:1018-183:283A-284A.
Suggested strategies for improving management
of hyperglycemia in hospitalized patients
• Gather administrative support
• Establish a multidisciplinary steering committee
• Assess current processes of care
– Standardized order sets, insulin-infusion protocols, frequency
of glucose measurement
• Identify metrics for evaluation
• Set realistic goals based on current baseline
• Use validated IV insulin protocols
• Establish performance improvement models
Kelly JL et al. Semin Thorac Cardiovasc Surg. 2006;18:346-58.
ACE/ADA Task Force on Inpatient Diabetes. Diabetes Care. 2006;29:1955-62.
In-hospital therapeutic strategies for insulin:
Summary
• Numerous protocols available to treat hyperglycemia in
hospitalized patients
• No consensus on level of glucose and treatment
• Clinical studies of insulin infusion vs conventional care
in progress
Wilson M et al. Diabetes Care. 2007;30:1005-11.