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Update - Inpatient Diabetes and Hyperglycemia. Review of Recent Developments in Context Greg Maynard MD, MSc UCSD. Outline. Background Infusion Insulin – Critical Care Transition from Infusion Clinical Inertia and SC insulin Hypoglycemia Transition Home – Glitazones

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update inpatient diabetes and hyperglycemia

Update - Inpatient Diabetes and Hyperglycemia

Review of Recent


in Context

Greg Maynard MD, MSc


  • 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
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
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.


Intensive Insulin Therapy in Critically Ill Patients







* P < 0.01

Relative Risk reduction (%)

Van-Den Berge et al, NEJM 345:1359, 2001

aace consensus conference blood glucose targets
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)

The current ADA guideline for pre-prandial plasma glucose levels is 90–130 mg/dl

AACE- Endocrine Practice 10 (1): 77-82, 2004

ADA- Diabetes Care 27: 553-591, 2004


Intensive Insulin Therapy in the Medical ICU

Greet Van den Berghe, M.D., Ph.D., and the Leuven Group

N 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

ICU LOS > 3 Days

p: 0.009

p: 0.05







ICU mortality

Hospital mortality







Intensive Insulin Therapy in MICU: Hospital Mortality

Conventional treatment

Intensive treatment

Intention to Treat

p: 0.33

p: 0.31





ICU mortality

Hospital mortality

Hazard ratio 0.94 (95 CI 0.84 – 1.06)

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

conclusions micu study
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
Efforts to Validate The Goals Coming from the Van den Berghe Trials
  • Glucontrol
glucontrol study abstract info
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 A

(n = 550)

Group B

(n = 551)


Age, yr

65 (51-74)

65 (51 – 74)


Sex ratio, M/F






Scheduled Surgery

Emergency Surgery


42.9 %

31.3 %

18.1 %

7.7 %

41.2 %

32.7 %

18.1 %

7.9 %


Philippe Devos, MD

Jean-Charles Preiser MD, PhD

University Hospital of Liège - Belgium




p < 0.0001



Blood glucose, mg/dl

147 mg/dl


119 mg/dl



Group A

Group B



Hypoglycemia 8.6% vs 4%

Median (IQR)



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



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

Conventional Therapy: CII started at BG > 200 mg/dl and adjusted to maintain a BG 180 - 200 mg/dl.

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

Primary Outcomes:

Mortality (28 days) and morbidity (sequential organ failure dysfunction, SOFA)

Safety end-point: hypoglycemia (BG<40 mg/dl)

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



(n = 247)


(n = 290)


Mortality rate, %

- 28 days

- 90 days







< 0.0001

Patients with hypoglycemia < 40, %

17.0 %

4.1 %

SOFA Score






VISEP Trial-

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

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

delta glucose intervention vs control
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
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, 2008

Goldberg 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.

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


summary recent insulin infusion studies
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
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

nurse mandated transition from iv insulin to sc basal bolus insulin
Nurse Mandated Transition from IV insulin to SC Basal Bolus Insulin

Criteria for Transition:

  • History of diabetes
  • HbA1c >6%


  • 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


Transition to SubQ

Managed by Anesthesiology in Operating Room

SubQ Basal-Bolus


0 12 24 36 48 60



Transition from Glucommander to Basal-Bolus Insulin

Glargine and Aspart

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


Blood Glucose (mg/dl)

Hours after IV insulin







Last GM










Davidson, Bode et al, May 2008 JDST pub pending

transition from infusion insulin take home points
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
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 JHM2007; 2:203-211

not much movement
Not much movement….

First 24 hrs


Last 24 hrs

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

insulin dosing
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

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

  • 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

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

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

Study Type: Prospective, randomized, open-label trial

Patient Population: 130 subjects with DM2

Oral hypoglycemic agents or insulin therapy

Study Sites: Grady Memorial Hospital, Atlanta

Jackson Memorial Hospital, Miami


(RABBIT-2 Trial) Basal / Bolus arm

  • 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


Mean Blood Glucose Levels During Insulin Therapy




* p<0.01

¶ p<0.05

Day 3: P=0.06

Umpierrez, Diabetes Care 30: 2007


Blood Glucose Levels in Patients Who Failed SSRI:

Transition to Basal Bolus Insulin

P: 0.02


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

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

Umpierrez, Diabetes Care 30: 2007

improving glycemic control in medical inpatients a pilot study
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

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

Baseline Protocol p

Basal insulin 49% 64% 0.05

Nutritional insulin 0% 13% <0.001

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

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

a win win situation 5 530 patients with dm or hyperglycemia and 7 poc glucose readings tp3 tp1
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 in hospitalized patients treated with antihyperglycemic agents
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
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

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

precipitating factors
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 none

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

antihyperglycemic rxs 48 hrs prior to hypoglycemia
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%

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

hypoglycemia follow up
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
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


Timing mean BG range

24 hrs prior hypo 137.5 + 57.0 63-287

Time D50 Rx 52.1+ 9.3 31-68

Changes in DM Rx % Endo agrees

Insulin 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

non critical care sc insulin and hypoglycemia take home points
Non-critical care SC Insulin and Hypoglycemia: Take Home Points

Suboptimal response to hyper- and hypo- glycemia 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.
factors used for selecting discharge therapy for patients with known diabetes
Factors Used for Selecting Discharge Therapy for Patients with Known Diabetes
  • 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 $$$$
adjusting home regimen using hba1c
Adjusting home regimen using HbA1c

Restart home regimen

New contraindication to therapy

HgbA1c <7





STEP 1:Lifestyle intervention and Metformin

Add Sulfonylurea

-least expensive

Add basal insulin

-Most effective

Add Glitazone

-no hypoglycemia

HgbA1c 7-8:

STEP UP therapy if needed

HgbA1c 8-9:

Add Insulin

Add Glitazone or sulfonylurea

Intensify insulin

HgbA1c >9 Intensive Insulin + Metformin +/- Glitazone

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

nissen s meta analysis of rosiglitazone
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 in1999. DREAM and ADOPT were also included.

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


Rosiglitazone & Cardiovascular Risk

*all-cause death, OR=1.18 (0.89-1.55, P=0.24)

† IGT/IFG patients

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)


Rosiglitazone & Cardiovascular Risk

*all-cause death, OR=1.18 (0.89-1.55, P=0.24)

† IGT/IFG patients

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)

nissen meta analysis of rosiglitazone overall rates of mi and cv death
Nissen Meta-analysis of Rosiglitazone:Overall Rates of MI and CV Death

Myocardial infarction


Cardiovascular death






Odds Ratio



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


Limitations 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

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


JAMA 2007;298:1189-1195

September 12, 2007


Center for Drug Evaluation and Research

Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee

July 30, 2007


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

“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 releases accord and advance
Dueling Press ReleasesACCORD and ADVANCE


10,251 patients with risk factors and DM

Intensive control arm to A1c < 6 257 deaths

A1c target 7 – 7.9 203 deaths

Trial halted, press release sent out


11,000 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
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
inpatient dm resources
Inpatient DM Resources




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 SetsAhmann 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