Update - Inpatient Diabetes and Hyperglycemia Review of Recent Developments in Context Greg Maynard MD, MSc UCSD

Update - Inpatient Diabetes and

Hyperglycemia

Review of Recent Developments

in Context

Greg Maynard MD, MScUCSD

Outline

• Background

• Infusion Insulin – Critical Care

• Transition from Infusion

• Clinical Inertia and SC insulin

• Hypoglycemia

• Transition Home – Glitazones

• New Tools / Resources

Inpatient Hyperglycemia and Poor Outcomes- Background

• Robust physiologic rationale

• Consistent dose-response relationship in dozens of observational / epidemiologic studies

• Observations of non-RCT interventions (like Portland protocol, Krinsley) show benefit.

• Influential RCTs showed benefit of tight glycemic control

Intensive Insulin Therapy in

Critically Ill Surgical Patients• Setting: Belgian SICU, University Hospital

• Hypothesis: normalization of blood glucose levels with insulin therapy can improve prognosis of patients with hyperglycemia or insulin resistance

• Design: prospective, RCT• Conventional: insulin when blood glucose > 215

mg/dL• Intensive: insulin when glucose > 110 mg/dL and

maintained at 80–110 mg/dL

van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.

0 20 40 60 80

Prolonged (> 14 d) ICU Stay

Dialysis

Prolonged (>14 d) ventilation

Prolonged (>10 d) antibiotics

Bacteremia

Mortality

Intensive Insulin Therapy in Critically Ill Patients

**

**

**

**

**

**

* P < 0.01* P < 0.01

Van-Den Berge et al, NEJM 345:1359, 2001Van-Den Berge et al, NEJM 345:1359, 2001 Relative Risk reduction (%)Relative Risk reduction (%)

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 levels is 90–

130 mg/dl

Things Get More Complicated

Intensive Insulin Therapy in the Medical ICU

Greet Van den Berghe, M.D., Ph.D., and the Leuven GroupN Engl J Med, Volume 354;5:449-461, February 2, 2006

• RCT of insulin infusion to goal of 80-110 mg/dL vs usual therapy (180-200 mg/dL).

• 1,200 patients randomized• A priori outcome of interest: patients in MICU

for > 3 days• Only 17% were diabetic

Intensive Insulin Therapy in MICU: Hospital Mortality

Van-Den Berge et al, NEJM 354:449-61, 2006

0

5

10

15

20

25

30

35

40

45

%

Conventional treatment

Intensive treatment

Intention to Treat

26.824.2

4037.3

ICU mortality Hospital mortality

Hazard ratio 0.94 (95 CI 0.84 – 1.06)

p: 0.31

p: 0.33

0

10

20

30

40

50

60

%

ICU LOS > 3 Days

38.131.3

52.5

43.0

ICU mortality Hospital mortality

p: 0.05

p: 0.009

MortalityReduction17.9%

MortalityReduction18.1%

Conclusions: MICU study• Intensive insulin therapy significantly

reduced overall morbidity but not mortality.

• Predefined population analysis (ICU > 3 d): – In-house mortality reduced (ARR 9.5%) – ICU mortality reduced (ARR 7.2%) p=.05– Morbidity Reduced

• BUT, More deaths (18.8 vs 26.8%) in patients in ICU < 3 days (NS w/ adjustment)

• More studies needed.

Efforts to Validate The Goals Coming from the Van den

Berghe Trials

• Glucontrol

• VISEP

• NICE-SUGAR

Glucontrol Study (abstract info)

• Mixed population of ICU patients

• N = ~3500, multicenter, Europe

• Target glucose:– 80 – 110 mg/dl vs. 140 – 180 mg/dl

• Endpoint: in-hospital and 28 day mortality

• Start: October 2004

Group AGroup A

(n = 550)(n = 550)Group BGroup B

(n = 551)(n = 551) PP

Age, yrAge, yr 65 (51-74)65 (51-74) 65 (51 – 74)65 (51 – 74) 0.92070.9207

Sex ratio, M/FSex ratio, M/F 352/198352/198 338/213338/213 0.38270.3827

CategoryCategory

Medical Medical

Scheduled SurgeryScheduled Surgery

Emergency SurgeryEmergency Surgery

TraumaTrauma

42.9 %42.9 %

31.3 %31.3 %

18.1 %18.1 %

7.7 %7.7 %

41.2 %41.2 %

32.7 %32.7 %

18.1 %18.1 %

7.9 %7.9 %

0.94370.9437

GLUCONTROGLUCONTROLL

Philippe Devos, MDJean-Charles Preiser MD, PhDUniversity Hospital of Liège - Belgium

300

250

200

150

100

50

Group A

Blo

od

glu

cose

, m

g/d

l

Group B

p < 0.0001


119 mg/dl

147 mg/dl

Group A(n = 550)

Group B(n = 551) P

ICU death rate, % 16.7 15.2 0.5022

Hospital death rate, % 24.5 20.7 0.1452

Day 28 death rate, % 19.5 16.2 0.1685

Median (IQR)


Hypoglycemia 8.6% vs 4%

VISEP Trial

Brunkhorst et al, N Engl J Med 358:125-39, 2008

VISEP Trial

Study Aim: to evaluate clinical outcome in 600 Study Aim: to evaluate clinical outcome in 600 subjects with sepsis randomized to conventional or subjects with sepsis randomized to conventional or intensive insulin therapy in 18 academic hospitals in intensive insulin therapy in 18 academic hospitals in Germany.Germany.

Primary Outcomes: Mortality (28 days) and morbidity (sequential organ failure dysfunction, SOFA) Safety end-point: hypoglycemia (BG<40 mg/dl)

Conventional Therapy: CII started at BG > 200 mg/dl and Conventional Therapy: CII started at BG > 200 mg/dl and adjusted to maintain a BG 180 - 200 mg/dl. adjusted to maintain a BG 180 - 200 mg/dl. Intensive Therapy group: CII started at BG > 110 mg/dl and Intensive Therapy group: CII started at BG > 110 mg/dl and adjusted to maintain BG 80 -110 mg/dl (Leuven’s protocol)adjusted to maintain BG 80 -110 mg/dl (Leuven’s protocol)


0.160.167.87.8

7.3-8.37.3-8.37.77.7

7.3-8.37.3-8.3SOFA ScoreSOFA Score

0.740.74

0.310.3126%26%

35.4%35.4%24.7%24.7%

39.7%39.7%

Mortality rate, %Mortality rate, %

- 28 days- 28 days

- 90 days- 90 days

PPCITCIT

(n = 290)(n = 290)IITIIT

(n = 247)(n = 247)

< 0.0001< 0.00014.1 %4.1 %17.0 %17.0 %Patients with Patients with hypoglycemia < 40, hypoglycemia < 40, %%


Data from 488 patients:IIT [goal: 80 – 110 mg/dL]: mean BG 112 mg/dl CIT [goal: 180 – 200 mg/dL]: mean BG 151 mg/dl

VISEP Trial-

Delta GlucoseIntervention vs Control

Leuven I 50 mg / dL

VISEP 39 mg / dL

Glucontrol 28 mg / dL

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%

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.

Infusion Protocols – Variable Hypoglycemia RatesStudy Population Target

Glucose (upper limit)

mg / dl

Percent of patients with

severe hypoglycemia

Leuven 1 (a) Surgical 110 7.2% Leuven 2 (b) Medical 110 19%

Glucontrol (c) Medical and Surgical 110 8.6% VISEP (d) Medical 110 17%

Yale (e) Surgical 120 0 Yale (e) Medical 120 1.7%

Krinsley (f) Medical and Surgical 140 2.2% Glucommander (g) Medical and Surgical 120 – 140 2.6% (a) vdB 1 (b) vdb 2 (c) Devos (d) Brunkhorst (e) Goldberg – Diabetes Spectrum (f) Krinsley (g) Davidson

Comparison of Insulin Infusion Protocols in the ICU: Computer-Guided Versus Standard

Column-Based Insulin Regimens Stability of glycemic control, hypoglycemia and hyperglycemia once CII achieved target range

Glucommander (Total # BG tests = 1767)

Standard (Total # BG tests = 2215)

p-value

# BG tests (%) within target range 1212 (68.6%) 1028 (46.4%) <0.0001

# BG tests (%)

46 (2.6%) 31 (1.4%) 0.005 Hypoglycemia: BG <60 mg/dL # Patients

(%) 20 (42.5%) 18 (35.3%) NS

# BG tests (%)

5 (0.3%) 2 (0.1%) NS Severe Hypoglycemia: BG <40 mg/dL # Patients

(%) 2 (4.3%) 2 (3.9%) NS

# BG tests (%)

14 (0.8%) 65 (2.9%) <0.0001 Hyperglycemia: BG >200 mg/dL # Patients

(%) 5 (10.6%) 15 (29.4%) 0.02

CHRISTOPHER A. NEWTON, DAWN SMILEY, PAUL DAVIDSON, BRUCE BODE, DENNIS STEED, SOL JACOBS, ABBAS E. KITABCHI, FRANKIE STENTZ, ANGEL TEMPONI, PATRICK MULLIGAN,GUILLERMOE. UMPIERREZ, Atlanta, GA, Memphis, TN 2008 ADA Abstract

Summary Recent Insulin Infusion Studies

• Recent negative studies – Glucontrol, VISEP

• Caveats– Used Leuven protocol (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 – SUGAR out soon

Infusion Insulin Take Home Points

• Surgical Populations easier

• Protocols vary greatly

• Automated protocols promising

• Need to monitor control and hypoglycemia

• < 5% of patients w/ glucose < 40 mg / dL is a reasonable goal

• Optimal glycemic target debatable

• Different targets for different groups?

• Where are you at?

“The days if ignoring blood sugar levels or tolerating marked hyperglycemia in the ICU (which was common place) are over.”

Malhotra, NEJM 354:516, 2006

Transitions

Transition from Infusion InsulinRamos, Childers, Maynard – SHM Abstract

N = 41

http://shm2008riv.abstractcentral.com/user_images/shm2008riv/1402/458104/DC3x3.jpg

Nurse Mandated Transition from IV insulin to SC Basal Bolus

InsulinCriteria for Transition:• History of diabetes• HbA1c >6%

Methodology:• Glargine SC given at HS POD #1 if able to

eat• IV insulin discontinued at noon POD#2 post

am meal insulin

Davidson, Bode et al, May 2008 JDST pub pending

0

50

100

150

200

250

4/14/0612:00

4/15/060:00

4/15/0612:00

4/16/060:00

4/16/0612:00

4/17/060:00

Bloo

d G

luco

se (m

g/dl

)

0 12 24 36 48 60

hours

SubQ Basal-Bolus

Glucommander

Managed by Anesthesiology

in Operating Room

Transition to SubQ

40

60

80

100

120

140

160

180

200

220

0 8 16 24 32 40 48 56 64 72

Las

t G

M

Lu

nch

Din

ne

r

Bed

tim

e

3:0

0A

M

Bre

akfa

st

Lu

nch

Din

ne

r

Bed

tim

e

3:0

0A

M

Bre

akfa

st

Lu

nch

Din

ne

r

Bed

tim

e

3:0

0A

M

Bre

akfa

st

Blo

od

Glu

cose

(m

g/d

l)

Hours after IV insulin

Transition from Glucommander to Basal-Bolus InsulinGlargine and Aspart

Basal: Multiplier * 500; CIR: 0.5 / Multiplier; Correction Factor: 1.7 / Multiplier

n=209

Davidson, Bode et al, May 2008 JDST pub pending

Transition from infusion insulinTake Home Points

• Transition is opportunity for failure

• Protocols can / should address this

• Insulin multiplier method safe / effective

• Comparisons of transition methods needed

• Patients with stress hyperglycemia do OK without transition to basal - bolus regimen

More Evidence for Clinical Inertia

• Retrospective Analysis• Teaching hospital (200 bed; metro. Phoenix)• LOS 3 or more days; non-ICU• 2,916 / 7,361 discharges with DM or HG

diagnosis• Average age 69 yrs; 90% white• ALOS 5.7 days

Cook CB, et al JHM 2007; 2:203-211

Not much movement….

First 24 hrs

Last 24 hrs

Stay

Cook CB, et al. J Hosp Med 2007; 2: 203-211

Insulin dosing

Δ insulin dose from first to last 24hr period• 54% (n=1680) increased (avg 17 units)• 39% decreased (avg 12 units)• 7% no change

Heterogeneous patterns of change within tertiles

Increase in dose with rising hyperglycemia

1st tertile 41% on more insulin by d/c

3rd tertile 65% on more insulin; 31% less by d/c


Conclusions

• Glycemic control poor

• Suboptimal use of insulin even when sustained hyperglycemia present (clinical inertia)

• Education should focus on importance of inpatient BG control and provide guidelines on how and when to change hyperglycemia therapy


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

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

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

¶¶

¶¶


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


Improving Glycemic Control in Medical Inpatients: A Pilot

Study

• Implement SC Insulin Protocol on Med Service n = 89

• Monitor acceptance and effect on hypoglycemia, insulin use, glycemic control

• Compare to prior observational study n = 91

Trujillo et al with JL Schnipper JHM 3:1 55-64

Results

• Resident acceptance poor - 56%• Reluctant to start and adjust

Baseline Protocol p Basal insulin 49% 64% 0.05Nutritional insulin 0% 13% <0.001Any hypoglycemia 7% 13% 0.20

ns

Glycemic control not significantly improved

If you build it, will they come?

Effect of Structured Insulin Orders and an Insulin Management Algorithm

• 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?

• Outcomes– Insulin Use Patterns– Glycemic Control – Hypoglycemia

Maynard et al, JHM publication pending 2008

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

0.73 (0.66 - 0.81)

RR Hypoglycemic Patient-Day 0.68 (0.59 – 0.80)

RR Hypoglycemic Patient-Stay

0.77 (0.64 – 0.92)

Maynard et al, JHM publication pending 2008

Hypoglycemia

Hypoglycemia in Hospitalized Patients Treated with Antihyperglycemic Agents

• Setting: 675 bed university hospital

• 2,174 monitored patients received glucose lowering agents in 3 months

• 206 (9.5%) had one or more BG < 60 within 48 hrs of Rx with antihyperglycemic agent

• 484 hypoglycemic events (44% more than one event) 29% in DM 1 23% in ICU 72% in those Rxd with insulin alone

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

Hypoglycemic severity

• 20 (4%) with hypoglycemia-related adverse event; mean BG was 43mg/dl

• 10 (2%) serious with seizure or LOC

• 464 episodes with no adverse event; mean BG 50.9 mg/dl


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)

Antihyperglycemic Rxs 48 hrs prior to hypoglycemia

Episodes on insulin Rx 78% (362/484)If on insulin - SSI alone 10.5% (38/362) SSI plus drip or basal 45.0% (163/362) Insulin with no SSI 44.5% (161/362)

Orals alone 10.9% (Glyburide 19.1%, p<.01)Insulin alone 10.0%Orals plus insulin 7.9%


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)


Provider Response to Insulin-Induced Hypoglycemia in Hospitalized

Patients

• To evaluate changes in treatment after hypoglycemia

• Retrospective data analysis of those treated with D50 for hypoglycemia; assessed by 2 diabetes specialists

• 52 subjects

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

Results

Timing mean BG range24 hrs prior hypo 137.5 + 57.0 63-287Time D50 Rx 52.1+ 9.3 31-68

Changes in DM Rx % Endo agreesInsulin held for hypo 100 100%Change in insulin Rx 40 52%No change in Rx 52 32%

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

UCSD- Hypoglycemia Study

Patients with glu < 60 mg / dL 65

< 40 mg / dL 8

% Any mismatch 49.2

% with Documentation 71%

Harm documented 2

minutes until next glucose 127 mean (med 60)

minutes until nl glu 259 mean (med 180)

Cases n = 65 Controls n = 65

Age 58 56

Male 42% 60%

Hillcrest 72% 86%

DM 1 9.2% 4.6%

Liver Dz 4.6% 13.9%

Kidney Dz 35.4% 16.9%

CHF 38.5% 15.4%

Low / Lean BMI 48% 25%

Prior Hypoglycemia 51% 8%

Mismatch 49% 32%

Non-critical care SC Insulin and Hypoglycemia: Take Home

PointsSuboptimal response to hyper- and hypoglycemia

is the rule– Nurses and physicians

• Opportunities for prevention of hypoglycemia often missed

• 2% of monitored inpatients - LOC / seizures • Need more studies / prevention• SC insulin protocols promoting basal / bolus

regimens can achieve improved control safely ---hypoglycemia can even be reduced.

Transition out of the Hospital

• Control at home and admission HbA1C

• Home regimen prior to admission• Admission reason: Hypoglycemia, Acute MI,

Related to hyperglycemia (DKA, HHS, etc.)• Physical limitations• New co-morbidities that may limit prior oral therapy• Hypoglycemia risk factors• Treatment goals (I.e. hospice)• Frequency of self monitoring • Financial $$$$

Factors Used for Selecting Discharge Therapy for Patients with Known Diabetes

Adjusting home regimen using HbA1c

HgbA1c <7

STEP 1:Lifestyle intervention and Metformin

HgbA1c >9 Intensive Insulin + Metformin +/- Glitazone

HgbA1c 7-8: Add basal insulin

-Most effective

Add Sulfonylurea

-least expensive

Add Glitazone

-no hypoglycemia

HgbA1c 8-9: Intensify insulin Add Insulin Add Glitazone or sulfonylurea

New contraindication to therapy

ST

EP

UP

th

e ra p

y i f

ne e

de d

No

NoYes

Yes

Restart home regimen

Adapted from “Management of Hyperglycemia in Type 2 Diabetes: A consensus Algorithm for the initiation and Adjustment of Therapy”. Diabetes Care Aug 2006 + 2007 AACE inpatient glycemic control resouce room

Published on-line May 21, 2007

Nissen’s Meta-analysis of Rosiglitazone

• Meta-analysis of 42 trials• Inclusion criteria:

– Duration >24 weeks– Randomized control group– Outcome data for myocardial infarction (MI) or death from

cardiovascular (CV) causes

• A total of 15,560 patients were randomly assigned to receive rosiglitazone and 12,283 patients received a comparator

• The studies used included 5 studies submitted to the Food and Drug Administration’s approval hearing for rosiglitazone in 1999. DREAM and ADOPT were also included.

Nissen SE, Wolski K. N Engl J Med. 2007;356:2457-2471.

Nissen SE & Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Deeath from Cardiovascular Causes. N Engl J Med 2007; 356 (www.nejm.org, accessed 5/21/07)

† IGT/IFG patients *all-cause death, OR=1.18 (0.89-1.55, P=0.24)

Rosiglitazone & Cardiovascular Risk

Study

(N=42) Rosiglitazone Control

OR

(95% CI)

P

MI

Small trials 44 / 10,280 (0.43%) 22 / 6105 (0.36%) 1.45 (0.88-2.39) 0.15

DREAM* 15 / 2635 (0.57%) 9 / 2634 (0.34%) 1.65 (0.74-3.68) 0.22

ADOPT 27 / 1456 (1.85%) 41 / 2895 (1.44%) 1.33 (0.80-2.21) 0.27

Overall 1.43 (1.03-1.98) 0.03

CV Death*

Small trials 25 / 6557 (0.38%) 7 / 3700 (0.19%) 2.40 (1.17-4.91) 0.02

DREAM† 12 / 2365 (0.51%) 10 / 2634 (0.38%) 1.20 (0.52-2.78) 0.67

ADOPT 2 / 1456 (0.14%) 5 / 2854 (0.18%) 0.80 (0.17-3.86) 0.78

Overall 1.64 (0.98-2.74) 0.06

http://www.nejm.org/

Nissen SE & Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Deeath from Cardiovascular Causes. N Engl J Med 2007; 356 (www.nejm.org, accessed 5/21/07)

† IGT/IFG patients *all-cause death, OR=1.18 (0.89-1.55, P=0.24)

Study

(N=42) Rosiglitazone Control

OR

(95% CI)

P

MI

Small trials 44 / 10,280 (0.43%) 22 / 6105 (0.36%) 1.45 (0.88-2.39) 0.15

DREAM* 15 / 2635 (0.57%) 9 / 2634 (0.34%) 1.65 (0.74-3.68) 0.22

ADOPT 27 / 1456 (1.85%) 41 / 2895 (1.44%) 1.33 (0.80-2.21) 0.27

Overall 86 / 14,371 (0.60%) 72 / 11,634 (0.62%) 1.43 (1.03-1.98) 0.03

CV Death*

Small trials 25 / 6557 (0.38%) 7 / 3700 (0.19%) 2.40 (1.17-4.91) 0.02

DREAM† 12 / 2365 (0.51%) 10 / 2634 (0.38%) 1.20 (0.52-2.78) 0.67

ADOPT 2 / 1456 (0.14%) 5 / 2854 (0.18%) 0.80 (0.17-3.86) 0.78

Overall 39 / 10,378 (0.38%) 22 / 9188 (0.24%) 1.64 (0.98-2.74) 0.06

Rosiglitazone & Cardiovascular Risk

http://www.nejm.org/

3.02.0

Odds Ratio

1.0 1.5

1.64†

1.43*

Nissen SE, Wolski K. N Engl J Med. 2007;356:2457-2471.

Nissen Meta-analysis of Rosiglitazone:Overall Rates of MI and CV Death

*P=0.03;†P=0.06.

Myocardial infarction

Cardiovascular death

Limitations of This Meta-AnalysisLimitations of This Meta-Analysis

• No access to actual data – therefore, no time to events calculation, no confirmation of events, no combined analyses (i.e. some subjects may have had both MI and death)

• Of 42 studies, only 11 peer reviewed, 26 never published

• Very small number of events

• Most trials of short duration

• Trials not designed to capture or adjudicate events

Published on-line June 5, 2007

RECORD Trial

N Engl J Med. 2007 Jul 5;357(1):28-38

Summary

http://www.annals.org/

JAMA 2007;298:1189-1195 September 12, 2007

JAMA 2007;298:1180-1188. September 12, 2007

Center for Drug Center for Drug Evaluation and ResearchEvaluation and ResearchJoint Meeting of the Endocrinologic and Metabolic Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Drugs Advisory Committee and the Drug Safety and Risk Management Advisory CommitteeRisk Management Advisory Committee

July 30, 2007July 30, 2007

ConclusionsConclusions

• TZDs are associated with increased CHF

• No evidence of increased death with TZDs

• Unclear whether or not there is any association with myocardial ischemia or other CVD end points

• Meta-analyses are extremely difficult to interpret

“Black Box” Warning

• Thiazolidinediones (TZDs), including ACTOS & Avandia, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of ACTOS & Avandia and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of ACTOS & Avandia must be considered.

• ACTOS & Avandia) are not recommended in patients with symptomatic heart failure. Initiation of ACTOS & Avandia in patients with established NYHA Class III or IV heart failure is contraindicated.

• November 2007: The use of Avandia in patients treated with insulin and nitrates is contraindicated.

Dueling Press ReleasesACCORD and ADVANCE

ACCORD10,251 patients with risk factors and DM

Intensive control arm to A1c < 6 257 deathsA1c target 7 – 7.9 203 deathsTrial halted, press release sent out

ADVANCE11,000 patients with risk factors and DM

Intensive control arm to A1c < 6.5

Press release - not in our study!

Selecting Discharge Therapy Take Home Messages

• Once A1C is >8.5% additional oral agents are unlikely to achieve goals

• Insulin at bedtime with or without oral agents is a good initial strategy

• Cost is heavily dependent on testing • Elderly – hypoglycemia risk• Hypoglycemia risk Glyburide > Glipizide• Glitazones – in spite of imperfect evidence -

be hesitant to start de novo• Tailor glycemic target to individual

Regulatory / Public Reporting

• TJC

• SCIP

• UHC

• AHA

• IHI

Inpatient DM Resources

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

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

www.hospitalmedicine.org

Improving Care of the Hospitalized Patient with Hyperglycemia and Diabetes - from the SHM Glycemic Control Task Force JHM Supplement

The Case for Supporting Inpatient Glycemic Control Programs Now: The Evidence and Beyond Braithwaite et al

Management of Diabetes and Hyperglycemia in the Hospital: A Practical Guide to Subcutaneous Insulin Use in the Non-Critically Ill Adult Patient Wesorick et al

Subcutaneous Insulin Order Sets and Protocols:Effective Design and Implementation Strategies Maynard et al

Designing and Implementing Insulin Infusion Protocols and Order Sets Ahmann et al

Bridge Over Troubled Waters: Safe and Effective Transitions of the Inpatient with Hyperglycemia O’Malley et al

SHM Glycemic Control Task Force Summary: Practical Recommendations for Assessing the Impact of Glycemic Control Efforts. Schnipper et al

Practical Strategies for Developing the Business Case for Hospital Glycemic Control Teams Magee et al

Documents

Update - Inpatient Diabetes and Hyperglycemia Review of Recent Developments in Context Greg Maynard MD, MSc UCSD