Does Inpatient Diabetes Management Matter? · the NICE-SUGAR study ¾Overall no difference …but...
Transcript of Does Inpatient Diabetes Management Matter? · the NICE-SUGAR study ¾Overall no difference …but...
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Does Inpatient Diabetes Management Matter?
Dale Clayton MHSc, MDDivision of EndocrinologyDalhousie University
April 2, 2011
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Disclosure
• Grants/research support: sanofi-aventis
• Speakers bureau/honoraria: Lilly, Novo Nordisk, sanofi, GSK, AstraZeneca, DCPNS, Canadian Agency for Drugs & Technologies in Health, Canadian Diabetes Association
• Consulting fees: sanofi-aventis, Novo Nordisk, Pfizer
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Outline
• Why is high glucose bad?
–Laboratory research
–Clinical research
• Recommendations
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Link Between High Blood Glucose and Poor Outcomes: Potential Mechanisms
Clement S, et al. Diabetes Care. 2004;27:553–591.
Immune dysfunction
Infection dissemination
Reactive O2 species
Secondary mediators
Transcription factors
Metabolic stress response↑ Stress hormones and peptides
GlucoseInsulin
FFAKetonesLactate
Cellular injury/apoptosisInflammation
Tissue damageAltered tissue/wound repair
AcidosisInfarction/ischemia
Prolonged hospital stayDisability
Death
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Cytokines
• Signal cells and coordinate the immune response (“hormones of the immune system”)
• Can be delivered to the target cell by the systemic circulation or the local environment
• Bind to high-affinity surface receptors
• Can be produced by non-immune cells (fibroblasts, endothelial cells)
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IGT
controlEsposito K, et al. Circulation. 2002;106:2067-2072.
Plasma cytokine concentrations attained during hyperglycemicclamps in 12 IGT (blue) and 20 control (green) subjects
Cytokines during Hyperglycemic Clamp Studies
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*P<0.05 betweengroups
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–10 2 4 6 24 48
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Time (hours)
∆ CRP (mg/L) from baseline
(0–h)ControlInsulin
Anti-inflammatory Effects of Insulin inSTEMI IN NON-DIABETIC PATIENTS
Change in C-reactive Protein
Chaudhuri A, et al. Circulation. 2004;109:849-854.
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Taken Together, These Studies Suggest:
• Insulin and glucose co-modulate inflammation
• Hyperglycemia is pro-inflammatory
• Hyperinsulinemia with euglycemia isanti-inflammatory
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The Implications of Glucose Variability--Why Are Ups and Downs Bad?
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PKC activity at low glucose (5mM), high glucose (20 mM), or alternating low and high.
Glucose Fluctuations May Be Involved in the Development of Vascular Injury in Diabetes
Quagliaro L, et al. Diabetes. 2003;52:2795-2804.
11Risso A, et al. Am J Physiol Endocrinol Metab. 2001;281:E924-E930.
& *
# $
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• Cell death of human umbilical vein endothelial cells
• “Variability in glycemic control may be more deleterious than a constant high concentration of glucose”
Glucose Fluctuations May be Involved in the Pathogenesis of Vascular
Diabetic Complications
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Urin
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8-SO
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mg
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MAGE (mmol glucose/L)
R=0.86, p<0.0001
Monnier L, et al. JAMA. 2006;295:1681-1687.
Correlation Between Urinary 8-iso-PGF2 alpha and MAGE in T2DM
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Hypoglycemia Also Increases Cytokines
Freeman and Adler. Diabetes Care 2008;31:1222-3.
14Brownlee M, et al. JAMA. 2006;295:1707-1708.
So What Is The Significance of the Understanding of Glucose Variability?
• “…it suggests that different therapeutic strategies now in use should be evaluated for their potential to minimize glycemic excursion, as well as their ability to lower A1C.”
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Smoothing out the roller coaster!
The Other Goal of Glucose Controlin the Hospital…
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And What Is the Greatest Single Reason for Oxidative Stress in Most Hospitals?
Sliding Scale Insulin!
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Summary
• Hyperglycemia is pro-inflammatory, pro-oxidative and pro-coagulant– all these mechanisms are known to increase mortality and
morbidity in acutely ill patients
• In experimental models, correction of hyperglycemia reverses all the above abnormalities
• In the presence of euglycemia, insulin may have direct anti-inflammatory, anti-oxidative and anti-coagulant effects
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Summary
• High free fatty acid levels that are associated with insulin resistance and hyperglycemia in acutely ill patients can further increase inflammation and cause endothelial dysfunction
• Fluctuating blood glucose levels are also pro-inflammatory and induce endothelial dysfunction and oxidative stress
• Therefore, the best way to suppress the harmful cellular and molecular mechanisms during acute illness is the maintenance of a stable glycemic control in the physiological range
CLINICAL EVIDENCE FOR GLUCOSE CONTROL IN THE INPATIENT SETTING
~2x
Mor
talit
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Mean Glucose Value (mmol/L)
Krinsley JS. Mayo Clin Proc. 2003;78:1471-1478.
N=1826 ICU patients.
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4.4-5.4 5.5-6.5 6.6-7.6 7.7-8.7 8.8-9.8 9.9-10.9 11-13.7 13.8-16.5 >16.50
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Hyperglycemia and Mortalityin the Medical Intensive Care Unit
~4x~3x
Hyperglycemia is Linked to Mortality Regardless of Diabetes Status
*≥ 11 mmol/L
180-day Mortality in Patients Admitted for MI (%)
Rady MY, et al. Mayo Clin Proc. 2005;80:1558-1567.Ainla MIT, et al. Diabet. Med. 2005; 22:1321-1325.
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Admission Hyperglycemia Is Also AssociatedWith Adverse Outcomes in Non-ICU Settings
N = 2471
Non-ICU patients with community-acquired pneumonia
% o
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McAlister FA et al. Diabetes Care. 2005;28:810-815.
*P = .03; †P = .01. ‡ Complications include all in-hospital complications except for abnormalities of glucose.
Mortality
Complications‡
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Admission BG Level
Outcomes Associated WithGlycemic Control in the Hospital
Study Setting Population Clinical Outcome
Furnary, 1999 ICU DM undergoing open heart surgery 65% infection
Furnary, 2003 ICU DM undergoing CABG 57% mortality
Krinsley, 2004 Medical/surgical ICU Mixed, no Cardiac 29% mortality
Malmberg, 1995 CCU Mixed 28% mortalityAfter 1 year
Van den Berghe, 2001* Surgical ICU Mixed, with CABG 42% mortality
Lazar, 2004 OR and ICU CABG and DM 60% A Fib post op survival 2 yr
*RCT, randomized clinical trial.
Kitabchi & Umpierrez. Metabolism. 2008;57:116-120.
Benefits of Tight Glycemic Control: Observational Studies and Early
Intervention Trials
First Large Randomized Controlled Trial:Effect of Intensive Glycemic Control in Critically Ill
Patients--Surgical ICU
1548 patientsAM glucose (mmol/L): 5.66 versus 8.42 intensive vs standardMortality decreased from 8.0% to 4.6% (only in patients with >5 d ICU stayIntervention resulted in decreased multiple-organ failure, sepsis, dialysis, transfusion, and neuropathySevere hypoglycemia (≤ 2.2 mmol/L): 7.0% vs 1.1% intensive vs standard
Intensive Insulin Therapy in CriticallyIll Patients: SICU
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*P < 0.01
Van den Berghe G, et al. N Engl J Med. 2001;345:1359-1367.
Relative Risk Reduction (%)
0 20 40 60 80
Prolonged (>14 d) ICU stay
Dialysis
Prolonged (>14 d) ventilation
Prolonged (>10 d) antibiotics
Bacteremia
Mortality
Trial N Setting Primary Outcome ARR RRR
Odds Ratio(95% CI) P-valueVan den Berghe2006 1200 MICU Hospital
mortality 2.7% 7.0% 0.94* (0.84-1.06) N.S.
HI-52006 240 CCU AMI 6-mo
mortality -1.8%* -30%* NR N.S.
Glucontrol2007 1101 ICU ICU
mortality -1.5% -10% 1.10*(0.84-1.44) N.S.
VISEP2008 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-SUGAR2009 6104 ICU 3-mo
mortality -2.6% -10.6 1.14(1.02-1.28) < 0.05
* not significant
Intensive Glucose Management in RCTsShowing No Benefit
Multicenter-multinational RCT (Australia, New Zealand, and Canada) in 6104 ICU patients, randomized to:
• Intensive, BG target: 4.5 and 6.0 mmol/L (81 - 108 mg/dL), • Conventional, BG target: < 10.0 mmol/L (180 mg/dL)
Primary Outcome: • Death from any cause within 90 days after randomizationMean APACHE II score: ~ 21, Reason for ICU admission: surgery: ~37%, medical: 63%, History of DM: 20% (T1DM: 8%, T2DM: 92%)At randomization: Sepsis: 22%, trauma: 15%, APACHE > 25: 31%
NICE-SUGAR Study
Finfer S, et al. N Engl J Med. 2009;360:1283-1297.
Age: ~ 60 years
Gender: ~ 36% female
Diabetes: ~ 20% (BMI ~ 28 kg/m2)
Interval, ICU admission to randomization: 13.4 hrs
Reason for ICU admission:
Operative* ~ 37%
Non-operative† ~ 63%Sepsis: ~ 22%Trauma: ~ 15%
NICE-SUGAR: Baseline Characteristics
† Did not include significant numbers of CCU patients
* Did not include significant numbers of CT surgery patients
Finfer S, et al. N Engl J Med. 2009;360:1283-1297.
Outcome Measure Intensive Group
Conventional Group
Morning BG (mmol/L) 6.5 + 1.4 8.0 + 1.4
Hypoglycemia(≤ 2.2mmol/L)
206/3016 (6.8%)
15/3014(0.5%)
28 Day Mortality (p=0.17) 22.3% 20.8%
90 Day Mortality (p=0.02) 27.5% 24.9%
NICE-SUGAR Study Outcomes
Finfer S, et al. N Engl J Med. 2009;360:1283-1297.
NICE-SUGAR: Intensive vs Conventional Glucose Control in Critically Ill Patients
Kaplan–Meier Estimates For The Probability Of Survival
% HR = 1.11 95 confidence interval:(1.01-1.23)
Finfer S, et al. N Engl J Med. 2009;360:1283-1297.
This large, international, randomized trial found that intensive glucose control did not offer any benefit in
critically ill patients
Blood glucose target of < 10 mmol/L with the achieved target of 8.0 mmol/L resulted in lower (90 day) mortality than did a target of 4.5-6.0 mmol/L
There was increased hypoglycemia with lower glucose targets
Finfer S, et al. N Engl J Med. 2009;360:1283-1297.
NICE SUGAR: Conclusions
1. Specified BG targets & ultimate BG separation(-27 mg/dL) not as distinct as prior trials
2. Treatment target not achieved in the intensive arm
3. Variable methods/sources for BG measurement
4. More steroid therapy in intensive arm
5. More hypoglycemia in intensive arm (15-fold)
6. No explanation of increased mortality in intensive arm(? hypoglycemia)
7. ~ 10% early withdrawals in intensive arm; ‘per-procotol’ (‘completers’) analysis not provided
NICE-SUGAR: Limitations
Results of a recent meta-analysis that included the NICE-SUGAR study Overall no difference
…but surgical patients appear to benefit from tight glycemic control
Griesdale DE, et al. CMAJ. 2009;180:821-827.
Intensive Insulin TherapyAnd Mortality
Hyperglycemia is associated with poor clinical outcomes across many disease states in the
hospital setting
Despite the inconsistencies in the clinical trial results, good glucose management remains important in
hospitalized patients
It is likely that benefits on outcomes can bederived from somewhat higher glucose targets than
previously proposed
More conservative glucose targets would be predicted to result in lower rates of hypoglycemia
Summary of the Clinical Trials
What Should We Take Awayfrom These Trials?
Good glucose control, as opposed to near-normal control, is likely sufficient to improve clinical outcomes in the ICU settingHyperglycemia and hypoglycemia are markers of poor outcome in critically and non-critically ill patientsImportantly, the recent studies do not endorse a laissez-faire attitude toward inpatient hyperglycemia that was prevalent a decade ago
(Reference: Mean BG 100-110 mg/dL)
Mean Glucose & In-Hospital Mortality in 16,871 Patients with Acute MI
Kosiborod M, et al. Circulation 2008:117:1018.
AACE-ADA Consensus Statementon Inpatient Glycemic Control
Endocr Pract. 2009;15:353-69. Diabetes Care. 2009;32:1119-31.
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.
ICU setting:Starting threshold of no higher than 10 mmol/LOnce IV insulin is started, the glucose level should be maintained between 7.7 and 10 mg/dL Lower glucose targets (6.0-7.7 mmol/L) may be appropriate in selected patients Targets <6 mg/dL or >10 mg/dL are not recommended
Recommended7.7-10
Acceptable6.0-7.7
Not recommended<6
Not recommended>10
AACE/ADA Recommended Target Glucose Levels in ICU Patients
Non–ICU setting:Premeal glucose targets <7.7 mmol/L Random BG <10 mmol/LTo avoid hypoglycemia, reassess insulin regimen if BG levels fall below 5.5 mmol/LOccasional patients may be maintained with a glucose range below and/or above these cut-points
Hypoglycemia = BG <3.9 mmol/LSevere hypoglycemia = BG <2.2 mmol/L
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
AACE/ADA Target Glucose Levels in Non–ICU Patients
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ConclusionsHigh glucose promotes inflammation
morbiditymortality
Fluctuations in glucose are bad for the vasculature (NO sliding scale!)
Goals in hospital: 6-10 (? 6-7.7)
Goals at home: 4-7
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Questions?
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