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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

7

6

5

4

3

2

1

0

–10 2 4 6 24 48

*

*

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.

& *

# $

*

• 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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1200

1000

800

600

400

200

00 1.1 2.2 3.3 4.4 5.5 6.6 7.7 8.8

Urin

ary

8-SO

-PG

F2 a

lpha

Exc

retio

n R

ates

(pg/

mg

crea

tinin

e)

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

y R

ate

(%)

Mean Glucose Value (mmol/L)

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

N=1826 ICU patients.

0

5

10

15

20

25

30

35

40

45

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

5

10

15

20

25

30

35

40

45

0

5

10

15

20

25

30

35

40

45

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.

*

*

Admission Hyperglycemia Is Also AssociatedWith Adverse Outcomes in Non-ICU Settings

N = 2471

Non-ICU patients with community-acquired pneumonia

% o

f P

atie

nts

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‡

*

*

†

†

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

*

*

*

*

*

*

*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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