New Approaches to Managing Inpatient Hyperglycemia

ACP Meeting MTP Session, April 24th, 2009

Review of Recent Developments

in Context

Greg Maynard MD, MScClinical Professor of Medicine and Chief,

Division of Hospital Medicine,University of California, San Diego

Greg Maynard MD, MScGreg Maynard MD, MSc

Has no relationships with any entity Has no relationships with any entity producing, marketing, re-selling, or producing, marketing, re-selling, or

distributing health care goods or services distributing health care goods or services consumed by, or used on, patients.consumed by, or used on, patients.

Disclosure of Financial RelationshipsDisclosure of Financial Relationships

Outline

• Glycemic Target Controversies

• Transition from Infusion

• Ward Glycemic Control

• Hypoglycemia

• Larger Context

AACE - Consensus Conference Blood Glucose Targets

• Upper Limit Inpatient Glycemic Targets:

– ICU: 110 mg/dl (6.1 mmol/L)

– Non-critical care (limited data)• Pre-prandial: 110 mg/dl (6.1 mM)• Maximum: 180 mg/dL (10 mM)

AACE- Endocrine Practice 10 (1): 77-82, 2004ADA- Diabetes Care 27: 553-591, 2004

The current ADA guideline for pre-prandial plasma glucose is now < 126

mg/dLDiabetes Care 31:S12-S54, 2008 - The language around glycemic targets has softened in the 2008 version of the ADA Standards.

Negative Studies of Infusion Insulin

• Recent negative studies – Glucontrol, VISEP, JAMA Meta-Analysis Vol

300 (8):933-944.

• Caveats– Discontinued early– Poor protocols drove results (viewed as

suboptimal)– Delta Glucose less than desirable– Very high hypoglycemia rates seen in these

studies….3 x hypoglycemia rate seen in U.S.

NICE – SUGARMarch 26, 2009 NEJM Vol 360 (13)

• Open Label RCT, Multinational

• 6104 critically ill patients

• Intensive infusion (81-108 mg/dL) vs “Conventional” control (144 – 180 mg/dL)

• 90 day survival – primary end point

Blood Glucose Values, According to Treatment Group

The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

Probability of Survival

Odds Ratios for Death, According to Treatment Group

The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

NICE - SUGAR

90 day mortality 27.5% vs 24.9%Severe hypoglycemia 6.8% vs 0.5%Glucose control (median) 107 vs 141 mg/dLInsulin infusion 97% vs 69%

No difference – 30 day mortality, ICU days, hospital days, days of mechanical ventilation, days of renal replacement, organ failures

Summary Data from Randomized Clinical Trials of Intensive Insulin Therapy in Critically Ill Patients

Inzucchi S and Siegel M. N Engl J Med 2009;360:1346-1349

Severe Hypoglycemia (< 40 mg / dL) with Different Infusion Protocols

Leuven I (Surgical) 5.1%Leuven 2 (Medical) 19%Glucontrol (Med / Surg) 8.6%VISEP (Medical) 17%Yale (Surgical) 0%Yale (Medical) 4.3%Glucommander (Surgical) 2.6%NICE – SUGAR (Med / Surg) 6.8%

Van Den Berghe G, et al. N Engl J Med. 2001:345:1359; Van Den Berghe G, et al. N Engl J Med. 2006;354:449-461; Brunkhorst et al, N Engl J Med 358:125-39, 2008Goldberg PA, et al. Diabetes Care. 2004;27:461; Goldberg PA, et al. J Cardiothorac Vasc Anes. 2004;18:690; Davidson PC. Diabetes Care. 2005;28:2418.NICE – SUGAR investigators NEJM 2009 360 (13) 1283-1297

UCSD Insulin Infusion200 Med Surg patients

>16,000 values Upper Limit – 150 mg /dL

Mean BG126 Median BG121  below 90 6.1% 91-150 76.6% above 150 17.3% % below 70 < 2% Only 2 patients with any glucose < 40 mg/dL

NICE-SUGAR vs UCSD

NICE - SUGAR UCSD

Target Range

(mg / dL)

80 – 110 90 – 150

Median Glucose 118 121

Severe Hypoglycemia

6.8% < 2%

AACE - Consensus Conference Blood Glucose Targets

• Upper Limit Inpatient Glycemic Targets:

– ICU: 110 mg/dl (6.1 mmol/L)

– Non-critical care (limited data)• Pre-prandial: 110 mg/dl (6.1 mM)• Maximum: 180 mg/dL (10 mM)

AACE- Endocrine Practice 10 (1): 77-82, 2004ADA- Diabetes Care 27: 553-591, 2004

The current ADA guideline for pre-prandial plasma glucose is now < 126

mg/dLDiabetes Care 31:S12-S54, 2008 - The language around glycemic targets has softened in the 2008 version of the ADA Standards.

AACE - Consensus Conference Blood Glucose Targets

• Upper Limit Inpatient Glycemic Targets:

– ICU: 110 mg/dl (6.1 mmol/L)

– Non-critical care (limited data)• Pre-prandial: 110 mg/dl (6.1 mM)• Maximum: 180 mg/dL (10 mM)

AACE- Endocrine Practice 10 (1): 77-82, 2004ADA- Diabetes Care 27: 553-591, 2004

The current ADA guideline for pre-prandial plasma glucose is now < 126

mg/dLDiabetes Care 31:S12-S54, 2008 - The language around glycemic targets has softened in the 2008 version of the ADA Standards.

RCTs with demonstrating convincing benefit of TGC on general med – surg wards:

? New AACE / ADA Guidelines ?

BAD BADGOOD

Hypoglycemia HyperglycemiaSomewhere in the Middle

<40 70 110 140 170 >200

Transitions

Transition from Infusion InsulinRamos, Childers, Maynard – SHM Abstract

N = 41

UCSD new Transition Protocol

• Need SC insulin when infusion stops?YES-

DM1 DM 2 or A1c ≥ 6 and infusion rate ≥ 1 unit / hourOn high dose steroids and rate ≥ 1 unit / hour

NO-Type 2 DM with infusion rate < 1 unit / hourStress hyperglycemia with HbA1c < 6

Even if high infusion rates

Step by Step

• Stable enough for transition?• Need SC insulin with transition?• Calculate TDD

– If taking in nutrition on infusion:IR x 20 = TDD– If not taking nutrition on infusion, infusion only

serving basal needsIR x 40 = TDD

• Give 40-50% of TDD as basal glargine BEFORE you stop the insulin infusion

Run Chart: Outcome MeasuresGlycemic control 48 hrs post transition with and without

protocol.Glucose averages before and after transition from infusion insulin

75

100

125

150

175

200

225

250

6HR 5HR 4HR 3HR 2HR 1HR 1-6HR

7-12HR

13-18HR

19-24 HR

25-30 HR

31-36 HR

37-42 HR

43-48HR

Avera

ge g

lucose m

g/

dL

Protocol NotUsed

Insulin PerProtocol

No Insulin PerProtocol

Insulin Infusion Day 1 Day 2

Transition Time

Outcome Measures

Severe Hypoglycemia (<40 mg/dL)3 of 114 transitions or 2.6%.

Protocol followed1 of 66 patients or 1.5%

Protocol not followed2 of 48 patients or 4.2%

Methods for Managing Methods for Managing Hospitalized Non-ICU Patients Hospitalized Non-ICU Patients

With DiabetesWith Diabetes

• Basal/bolus therapy (MDI)Basal/bolus therapy (MDI)

– Long-acting and rapid-acting insulinLong-acting and rapid-acting insulin

– NPH and Regular insulinNPH and Regular insulin

• Sliding Scale Short-Acting Insulin Sliding Scale Short-Acting Insulin

Treatment Groups:

Insulin glargine once daily + supplemental insulin glulisine (n=65) N= 130

Sliding scale regular insulin four-times daily (n=65)

Study Type: Prospective, randomized, open-label trial

Patient Population: 130 subjects with DM2 Oral hypoglycemic agents or insulin therapy

Study Sites: Grady Memorial Hospital, AtlantaJackson Memorial Hospital, Miami

Randomized Basal Bolus versus Sliding Scale Regular Insulin Therapy in patients with type 2 Diabetes (RABBIT-2 Trial)

• D/C oral antidiabetic drugs on admission

• Starting total daily dose (TDD): – 0.4 U/kg/d x BG between 140-200 mg/dL– 0.5 U/kg/d x BG between 201-400 mg/dL

• Half of TDD as insulin glargine and half as rapid-acting insulin (lispro, aspart, glulisine)– Insulin glargine - once daily, at the same time/day. – Rapid-acting insulin- three equally divided doses (AC)

Smiley & Umpierrez, Southern Med J, June 2006

(RABBIT-2 Trial) Basal / Bolus arm

Blood Glucose Levels During Isulin Treatment

Days of Therapy

Blo

od

glu

cose

(m

g/d

L)

100

120

140

160

180

200

220

240

Admit 1 2 3 4 5 6 7 8 9 10

SSRI

Lantus + glulisine

Mean Blood Glucose Levels During Insulin Therapy

* p<0.01¶ p<0.05

¶* * *

¶ ¶ ¶

Day 3: P=0.06

Umpierrez, Diabetes Care 30: 2007

Basal–Bolus Insulin Regimen in Basal–Bolus Insulin Regimen in Noncritically Ill Patients Noncritically Ill Patients

Days of Therapy

0 1 2 3 4 5 6 7 8 9 10 11 12

Blo

od G

luco

se (

mg/

dL)

100

120

140

160

180

200

220

240

260

280

300

SSRILantus plus Glulisine

Admit 1 2 3 4 1 2 3 4 5 6 7

Blood Glucose Levels in Patients Who Failed SSRI:Transition to Basal Bolus Insulin

Failure was defined as 3 consecutive BG values > 240 mg/dL during SSRI

¶

P: NS P: 0.02

¶¶

¶¶

Umpierrez, Diabetes Care 30: 2007

RABBIT 2

• Improved glycemic control with basal / bolus insulin regimen compared to SSRI

• Subset that failed with SSRI controlled with basal / bolus

• No difference in hypoglycemia – (3% of patients in each arm)

Umpierrez, Diabetes Care 30: 2007

Effect of Structured Insulin Orders and an Insulin Management Algorithm -

UCSD• 400 bed academic center• All adult monitored stays on Med / Surg wards

with dx of DM or Documented Hyperglycemia n = 9,314 > 7 readings n = 5,530

• What is effect of implementing a structured insulin order set?

• What is the incremental effect of an insulin management protocol?– Insulin Use Patterns– Glycemic Control – Hypoglycemia

Maynard et al, JHM January 2009; 4: 3-15

The Use of Basal Insulin Increases(sliding scale only regimens decline)

Percent Sliding Scale Insulin Only

0

10

20

30

40

50

60

70

80

Per

cent

10/20/03

New Order Set

01/20/04

CPOE - TH

72% of 477 insulin regimens SSI only in May-Oct 2003 vs 26% of 499 in Mar-Aug 2004

% of 9,314 Patient-Stays with Uncontrolled Hyperglycemia

A Win / Win Situation5,530 patients with DM or Hyperglycemia and > 7

POC Glucose readings TP3:TP1

RR Uncontrolled Patient-Day

0.77 (0.74 - 0.80)

RR Uncontrolled Patient-Stay (70% controlled vs 60%)

0.73 (0.66 - 0.81)

RR Hypoglycemic Patient-Day (prevents 208 / year)

0.68 (0.59 – 0.80)

RR Hypoglycemic Patient-Stay

0.77 (0.64 – 0.92)

Maynard et al, JHM January 2009; 4: 3-15

Methods for Managing Methods for Managing Hospitalized Non-ICU Patients Hospitalized Non-ICU Patients

With DiabetesWith Diabetes

• Basal/bolus therapy (MDI)Basal/bolus therapy (MDI)

– Long-acting and rapid-acting insulinLong-acting and rapid-acting insulin

– NPH and Regular insulinNPH and Regular insulin

• Sliding Scale Short-Acting Insulin Sliding Scale Short-Acting Insulin

Blo

od

glu

co

se

(mg

/dL

)

Duration of Therapy (days)

Detemir + NovologNPH + Regular

DEAN-Trial

Basal/bolus regimen: Detemir was given once daily and Novolog before meals.NPH/regular regimen: NPH and Regular insulin were given twice daily, 2/3 A.M., 1/3 P.M.

Data are ± SEM

HypoglycemiaHypoglycemia

• Detemir/Aspart Group:Detemir/Aspart Group:– 22 patients (32.8%) had ≥ 1 BG < 60 mg/dL22 patients (32.8%) had ≥ 1 BG < 60 mg/dL– 3 patients (4.5%) had a < 40 mg/dL (0.2%)3 patients (4.5%) had a < 40 mg/dL (0.2%)

• NPH/Regular Group:NPH/Regular Group:– 16 patients (25.4%) had ≥ 1 BG < 60 mg/dL 16 patients (25.4%) had ≥ 1 BG < 60 mg/dL – 1 patient (1.6%) had a BG < 40 mg/dL1 patient (1.6%) had a BG < 40 mg/dL

ADA, 68th Scientific Sessions, 2008; JCEM, in press

RABBIT-2 vs. DEAN Trials

Days of Insulin therapy

Blo

od

Glu

co

se

(m

g/d

L)

120

140

160

180

200

220

240

SSRIGlargie + GlulisineDetemir + AspartNph + Regular

Admit 1 2 3 4 5 6 7-10

Umpierrez et al, ADA, 68th Scientific Sessions, 2008; JCEM, in press Umpierrez et al, Diabetes Care 30:2181–2186, 2007

Blood Glucose Concentration During SSRI, NPH-regular, and Basal Bolus Regimen in Medical Patients with Type 2

Diabetes

DEAN Trial

Percent of Glucose values within target (< 140 mg/dl)

RABBIT-2 Trial

% %38%

66%

48%45%

*

* P < 0.01

Umpierrez et al. JCEM, in press Umpierrez et al. Diabetes Care 30:2181–86, 2007

%

25.4

32.8

Rate of Hypoglycemia(# patients with BG < 60 mg/dl)

33

%

DEAN TrialRABBIT-2 Trial

Umpierrez et al. JCEM, in press Umpierrez et al. Diabetes Care 30:2181–86, 2007

Summary – Ward Glycemic Control

• Optimal Glycemic Target Uncertain – My bias: Fasting should likely be < 150 mg/dL– Upper limit of no sugars > 180 mg/dL reasonable

• Basal / Bolus regimens with Glargine / RAA-insulin more effective than sliding scale and present no higher risk of hypoglycemia

• Well executed order sets / protocols can improve glycemic Well executed order sets / protocols can improve glycemic control control and reduceand reduce hypoglycemia. hypoglycemia.

• Detemir/aspart resulted in equivalent glycemic control to a Detemir/aspart resulted in equivalent glycemic control to a split-mixed NPH and regular regimen (but hypoglycemia split-mixed NPH and regular regimen (but hypoglycemia higher than with RABBIT 2 regimen and UCSD regimens) higher than with RABBIT 2 regimen and UCSD regimens)

Hypoglycemia

Precipitating factors

Etiologic factor % of hypo cases

Reduction in enteral intake 40

Insulin adjustment 6.1

Steroid withdrawal 0.4

Unclear 43

“Diverse causes” 10.4

Medication error noneVarghese P, et al. J Hosp Med. 2007; 2:234-240)

Hypoglycemia follow-up

1/3 with documented BG rechecked within 60 minutes

< 50% with documented euglycemia within 2 hours of low

Average time to documented resolution was 4 hrs, 3mins (median 2 hrs, 25mins)

Varghese P, et al. J Hosp Med. 2007; 2:234-240)

Provider Response to Insulin-Induced Hypoglycemia in Hospitalized

Patients

• Case series – 52 patients

• Delays in treatment

• Suboptimal adjustment of regimens common

Garg, et al. J Hosp. Med. 2007; 2:258-260

Iatrogenic Hypoglycemia – Risk Factors, Treatment, and

Prevention• 130 ward inpatients monitored for glucose

• 65 consecutive cases with iatrogenic hypoglycemic day

• Matched 1:1 with controls (monitored, similar hospital day, not hypoglycemic)

• Examine risk factors for hypoglycemia

• Study hypoglycemia treatment and adjustments made to prevent recurrence

Maynard et al, Diabetes Spectrum 2008 Vol 21:4 241-247.

Hypoglycemia – 65 cases

Severe (≤ 40 mg / dL) 11 17%

Nutrition / insulin mismatch 32 49%

Absent documentation 19 29%

Time next value (minutes) 60 (8 – 600)

Time to resolution (minutes) 180 (10 – 1,260)

Temporary harm 2 3%

Hypoglycemic Cases vs Controls

Univariate Unadjusted Statistically Different

Lower weight: 73.4 vs 89.7 Kg

Lower BMI: 26 vs 31

More CKD / ESRD: 35% vs 17%

More CHF: 37% vs 15%

Hypoglycemia: Take Home Points

Suboptimal response to hypoglycemia is the rule– Nurses and physicians!

• Opportunities for prevention often missed.• Make a change after hypoglycemic event. • Mere Existence of a hypoglycemia protocol does

not guarantee good management

• SC insulin protocols promoting basal / bolus regimens can achieve improved control safely ---hypoglycemia can even be reduced.

Society of Hospital MedicineBig Picture Context

• DM / Hyperglycemia very common

• Controversy over exact glycemic target distracts from larger issues

• Chaos and avoidable hyper- and hypo-glycemia are the rule

• Alternatives (SSI, laissez faire) don’t work and can be dangerous

• Standardization / team approach / protocols / order sets / metrics

Inpatient DM Resources

http://www.aace.com/resources/igcrc/

http://www.hospitalmedicine.org/ResourceRoomRedesign/GlycemicControl.cfm

SHM Glycemic Control Mentored Implementation Program

Questions / Comments