Hermayer - Inpatient Management of Diabetes for pdf€¦ · The Nice‐Sugar Study Investigators. NEJM. 2009; 360: 1283‐1297 Why were the results of the Leuven SICU not reproduced?

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South Carolina ChapterAmerican College of Physicians Scientific

Meeting 2015:Inpatient Management of Diabetes

Kathie L. Hermayer, MD, MS, FACE

Professor of Medicine

Division of Endocrinology, Diabetes and Medical Genetics

Medical University of South Carolina

October 30, 2015

Disclosure Verification for:

Name: Kathie L. Hermayer, MD

The presenter listed above:

___ Does not have any significant financial relationships to disclose

_X_ Has disclosed the following relationships:

NovoNordisk

_X Research Grants __Speakers Bureau Patent holder

__Consultant for fee

__Stock/Ownership Employment Partnership

__Advisory Committee/Board ___Other

_X_ Has disclosed this activity will not include discussion ofunapproved/investigational uses of products or devices

__ Has disclosed this activity will include discussion of unapproved/investigational uses of products or devices

Was this activity Supported by an educational grant or received in‐kind support?

__ Yes Name of Company: _X No

Learning Objectives

1. Recognize the pathophysiological changes of patients with stress hyperglycemia and diabetes in the hospital.

2. Discuss several studies which relate to the implications of hyperglycemia in the hospital regarding critically ill and medical‐surgical patients.

3. Discuss the current blood glucose guidelines for critically ill and medical‐surgical patients in the hospital.

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Hospital Cost of Diabetes in USA

• Total estimated cost of diagnosed diabetes in 2012 is

• $245 billion• $176 billion in direct medical costs• $69 billion in reduced productivity

• Components of medical expenditures

• Hospital inpatient care (43%)• Prescription meds to Rx complications of DM (18%)

• Antidiabetic agents and diabetes supplies (12%)• Physician office visits (9%)• Nursing/residential facility stays (8%)

• 41% increase from previous estimate of $174 billion (in 2007 dollars)

ADA, Diabetes Care. 2013. 36 (4): 1033‐1046.

Stress Hyperglycemia Exacerbates Illness

5

Stress Hormonescortisol, epinephrine Glucose Production

Lipolysis

FFAs

FFAs

+

Glucose Uptake

Glucose Fatty Acids

Hemodynamic

insult

Electrolyte losses

Oxidative stress

Myocardial injury

Hypercoagulability

Altered immunity

Wound healing

Inflammation

Endothelial

function

Illness

Clement S, et al. Diabetes Care. 27:553–591, 2004.

Hyperglycemia and Poor Hospital Outcome

Metabolic stress response

stress hormones and peptides

Glucose

InsulinImmune dysfunction

Infection dissemination

Cellular injury/apoptosisInflammation

Tissue damageAltered tissue wound repair

Prolonged hospital stayDisability / Death

FFA Ketones Lactate

Reactive O2 species

Transcription factors

Secondary mediators


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Insulin Requirements in Health and Illness

0

20

40

60

80

100

120

140

Correction

Nutritional

Prandial

Basal

Relative Proportion of

Insulin Requirement

(%)* *Estimations for illustrative purposes: requirements may vary widely.


Illness-Related

Healthy Sick/Eating Sick/NPO

Critically Ill Patients

Mortality Rate (%

)

Mean Glucose Value (mg/dL)N=1826 ICU patients.Krinsley JS. Mayo Clin Proc. 2003;78:1471‐1478.

0

5

10

15

20

25

30

35

40

45

80‐99 100‐119120‐139140‐159160‐179180‐199200‐249250‐299 >3000

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

9

9.6%

42.5%

Diabetes present 22.4% population

~2x~3x

~4x

Note: modest increase BG after ICU admissionwas associated with substantial increase in hospital mortality

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Reference: Mean BG 100‐110 mg/dL

Reference: Mean BG 100‐110 mg/dL

Kosiborod M, et al. Circulation 2008:117:1018.

Mean Glucose & In‐Hospital MortalityIn 16,871 Patients with Acute MI

Mean Glucose & In‐Hospital MortalityIn 16,871 Patients with Acute MI

Intensive Insulin Therapy in Critically Ill Surgical Patients: The Leuven Study

Randomized controlled trial: 1,548 pts admitted to a surgical ICU. Pts were assigned to receive either:

• Conventional therapy: IV insulin if BG > 215 mg/dL•Target BG levels: 180‐200 mg/dL

•Mean daily BG: 153 mg/dL

• Intensive therapy: IV insulin if BG > 110 mg/dL

•Target BG levels : 80‐110 mg/dL

•Mean daily BG: 103 mg/dL

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

0 50

Prolonged (> 14 d) ICU Stay

Dialysis

Prolonged (>14 d) ventilation

Prolonged (>10 d) antibiotics

Bacteremia

Mortality 42%

41%

Intensive Insulin Therapy in Critically Ill Patients

*

*

*

*

*

*

* P < 0.01

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

46

36%

38%

28%

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Survival Increased due to IIT (including

non diabetic patients) for Patients with a BG goal

of 80‐110 mg/dL who remained in ICU > 5 days

Van den Berghe. NEJM. 2001; 345: 1359‐1367

ICU Hospital floor

IIT reduced in‐hospital mortality by 34%

Intensive Insulin Therapy: Normoglycemia in Intensive Care Evaluation‐Survival Using Glucose Algorithm Regulation (NICE‐SUGAR) 2009

• Randomized, controlled trial in Australia, New Zealand, Canada, US

• 6104 adult medical and surgical patients admitted to the ICU

• Intensive– IV insulin started if BS > 108: goal 81‐108• Conventional– IV insulin started only if BS > 180: goal 144‐180

• 20% of patients were diabetic

• Primary endpoint: all‐cause 90‐day mortality

The NICE‐SUGAR Study Investigators. NEJM. 2009;360:1283‐97

Intensive Insulin Therapy: NICE‐SUGAR (2009)

• Intensive group• Actual glucose: 115 +/‐ 18 mg/dL

• Patients with BS < 40: 6.8%

• Conventional group• Actual glucose: 144 +/‐ 23 mg/dL

• Patients with BS < 40: 0.5%

The Nice‐Sugar Study Investigators. NEJM. 2009; 360: 1283‐1297

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Mortality:Intensive: n=829 (27.5%)Conventional: n=751 (24.9%)P=0.03


• Discussion:• “In this large, international, randomized trial, we found that

intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg/dL or less resulted in lower mortality than did a target of 81 to 108 mg/dL.”


Why were the results of the Leuven SICU not reproduced?

• Single center vs multicenter studies

• Variability in duration of hyperglycemia before the start of the insulin protocol

• Variability in the type of insulin protocol

• Parenteral hyperalimentation the rule in Leuven study and enteral nutrition the rule in NICE SUGAR

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Pooled Meta‐analysis of 26 trials:Relative Risk of Death with Intensive Insulin Therapy

Griesdale DE, et al. CMAJ. 2009;180:821‐827.

The pooled relativerisk of death with IIT was 0.93 comparedwith conventional therapy(95% CI 0.83‐1.04).

Griesdale DE, et al. CMAJ. 2009;180:821‐827.

Severe Hypoglycemia in ICU Is More Likely With Intensive Insulin Therapy Than Conventional Glycemic Control: A Meta‐analysis

Overall severe hypoglycemia

RR 5.99(4.47‐8.03)

14 trials

Summary of Most Current Professional Societies’ Guidelines for Glycemic Control

Qaseem A., et. Al. Am. J. Med. Quality. 2014. 29 (2): 95‐98.Evans AS, et. Al. Minerva Endocrinologica. 2014; 39: 261‐273Standards Medical Care. Diabetes Care. 2015. 38 (Suppl 1): S80‐S85.

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Point of Care Testing Blood Glucose in Critical Illness

Factors to Consider When Using Devices in ICU Glucose Measurement

• Accuracy

• Speed of results

• Cost per test

• Sample volumes

Huong, T, et al. Journal of Diabetes Science and Technology. 2013 7(2): 489‐499. Hermayer, et. Al. Current Diabetes Reports, 2015; 15:10

Arterial, Capillary or Venous Blood

• Arterial blood has higher glucose levels compared with venous• 5‐10 mg/dL higher than capillary and venous concentrations

Huong, T, et al. Journal of Diabetes Science and Technology. 2013 7(2): 489‐499. Hermayer, et. Al. Current Diabetes Reports, 2015; 15:10

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Patient Conditions that Increase Risk of Errors

• CKD results in greater risk of hypoglycemia and anemia

• Hct <20% (may falsely raise BG in POC BG meters that do not detect Hct)

• End‐stage liver disease and malnutrition add to glycemic instability

• Sepsis heightens risk of hypoglycemia

Hermayer, Loftley, Reddy, Narla, Epps, Zhu. Current Diabetes Reports. 2015; 15:10.www.nursingcriticalcare.com. 2015. Accessed 6/30/15.

Inferences and Limitations of POC Devices: Clinical

• Interference from endogenous substances• Triglycerides, bilirubin, uric acid

• Conditions: Dehydration, hypoxia, DKA/HHS, hypotension, shock, capillary hypo‐perfusion, heart failure, finger edema

• Hematocrit outside range: ~ <10% or > 60%

• Interference from other sugars: maltose‐containing infusions• Glucose dehydrogenase pyrroloquinoline quinone (GDH‐PQQ) reagents

Hermayer, Loftley, Reddy, Narla, Epps, Zhu. Current Diabetes Reports. 2015; 15:10.www.nursingcriticalcare.com. 2015. Accessed 6/30/15.

Point of Care Devices

• International Organization for Standardization guideline (ISO 15197, 2003)

• BG > 75 mg/dL, 95% need to be within + 20% of the “reference” value (lab analyzed BG)

• BG < 75 mg/dL, 95% need to be within + 15 mg/dL• 1 out of 20 tests may have poor accuracy

• meter will be approved

Huong, T, et al. Journal of Diabetes Science and Technology. 2013 7(2): 489‐499. Hermayer, et. Al. Current Diabetes Reports, 2015; 15:10www.nursingcriticalcare.com. 2015. Accessed 6/30/15

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Point of Care Devices

• International Organization for Standardization guideline: 2014 FDA Draft• BG > 70 mg/dL, 99% need to be within + 10% of the “reference” value (lab analyzed BG)

• The other 1% must not exceed + 20%

• BG < 70 mg/dL, 99% need to be within + 7 mg/dL• The other 1% cannot exceed + 15 mg/dL

www.nursingcriticalcare.com. 2015. Accessed 6/30/15.

FDA Draft Recommendations for Hospital POC BG Meters

www.nursingcriticalcare.com. 2015. Accessed 6/30/15.

Wired vs Wireless POC Glucose Meters

Hermayer, Loftley, Reddy, Narla, Epps, Zhu. Current Diabetes Reports. 2015; 15:10.

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Non‐Critically Ill Patient Population

Glycemic Targets in Non‐Critical Care Setting

1. Premeal BG target of <140 mg/dl (7.8 mmol/L) and random BG <180 mg/dl (10 mmol/L) for the majority of patients.

2. Glycemic targets be modified according to clinical status.

• ‐ Patients with terminal illness, a higher target range

(BG <180‐200 mg/dl) may be reasonable.

3. For avoidance of hypoglycemia, diabetic therapy be reassessed when BG<100 mg/dl (5.5 mmol/L).

Umpierrez et al. J Clin Endocrinol Metabol. 97(1):16‐38, 2012

American College of Physicians recommended a BG target < 200 mg/dl (11.1 mmol/L), Ann Intern Med. 2012

Use of Oral Diabetes Agents in Hospitalized Patients

• 3 primary categories of oral agents:• Secretagogues: sulfonylureas and meglitinides

• Long action and predisposition to hypoglycemia

• Biguanides• Lactic acidosis (rare), however hospitalized pts at risk for hypoxia, hypoperfusion and renal insufficieny

• Side effects: nausea, diarrhea and decreased appetite

• Thiazolidinediones• Increase intravascular volume, concern for CHF and hemodynamic changes

• OHA have significant limitations for inpatient use

• OHA provide little flexibility for titration • Insulin when used properly may have many advantages in the hospital setting

Clement et al. Diabetes Care. 2004; 27: 553‐591

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DPP‐4 Therapy in Hospitalized Patients

Study Type: Multicenter, prospective, open‐label randomized clinical trial

Patient Population: Patients with T2D admitted to general medicine and surgery services at 3 hospitals: Emory University, Grady, and University of Michigan

Treatment Groups* Group 1. Sitagliptin once daily (n=30)Group 2. Sitagliptin plus glargine insulin once daily (n=30) Group 3. Basal bolus regimen with glargine once daily

and lispro before meals (n=30)

* All groups received supplemental doses of lispro for BG > 140 mg/dl before meals

Umpierrez et al. Diabetes Care. 2013 Nov;36(11):3430-5.

Randomization

Mean Daily BG During Treatment

Umpierrez et al. Diabetes Care. 2013 Nov;36(11):3430‐5.

Mean BG before Meals and at Bedtime during Treatment

Data is mean ± SE

P=0.22 P=0.15 P=0.52 P=0.57

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Randomization Blood Glucose (<180 mg/dl and >180 mg/dl) and Mean Daily Glucose

Concentration

Mean Daily Blood Glucose (mg/dL)

p= 0.91

p= 0.08


Conclusions

• Treatment with sitagliptin alone or in combination with basal insulin is safe and effective for the management of hyperglycemia in general medicine and surgery patients with T2DM.

Umpierrez GE, et. Al. Diabetes Care. 2013. 36: 3430‐3435.

Exenatide for Hyperglycemia in CICU

• Prospective, single‐center, open‐label, nonrandomized pilot study

• 40 patients admitted to the CICU with BG 140‐400 mg/dL

• All patients received IV exenatide as a bolus followed by a fixed dose infusion for up to 48 hours

• Exenatide effectiveness benchmarked to two historical insulin infusion cohorts, one (INT) with BG target 90‐119 mg/dL (n=84) and the other (MOD) with a target of 100‐140 mg/dL (n=71)

Abuannadi M, et. Al., Endocrine Practice. 2013. 19 (1): 81‐90.

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Median Glucose Values over Time

Target glucose levels were 100‐140 mg/dL for both the exenatide and modified control (MOD) arms, and 90‐119 mg/dL for the intensive control group (INT)

Abuannadi M, et. Al. Endocrine Practice. 2013. 19 (1): 81‐90.

Conclusions

• Steady state glucose values were similar between the exenatide(132 mg/dL) and the MOD groups (127 mg/dL), but lower in the INT group (105 mg/dL).

• Median time to steady state was 2.0 hrs in the exenatide group compared to 12.0 hours in the MOD group and 3.0 hours in the INT group.

• No episodes of severe hypoglycemia (<50 mg/dL) occurred in patients who received exenatide.

• Nausea was reported by 16 patients and vomiting by 2 patients.

• Summary: IV exenatide is effective in lowering glucose levels in CICU patients, but its use may be limited by nausea.

Abuannadi M, et. Al. Endocrine Practice. 2013. 19 (1): 81‐90.

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 diet therapy, insulin naive

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)

Umpierrez et al, Diabetes Care. 30:2181–2186, 2007

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Rabbit 2 Trial: Changes in Glucose Levels with Basal‐Bolus vs. Sliding Scale Insulin

Umpierrez GE, et al. Diabetes Care. 2007;30(9):2181‐2186.

Days of Therapy

BG

, mg/

dL

100

120

140

160

180

200

220

240

Admit 1

Sliding‐scale

Basal‐bolus

bP<.05.

aa a

b bb

b

2 3 4 5 6 7 8 9 10

aP<.05.

• Sliding scale regular insulin (SSRI) was given 4 times daily • Basal‐bolus regimen: glargine was given once daily; glulisine was given before meals.

0.4 U/kg/d x BG between 140‐200 mg/dL

0.5 U/kg/d x BG between 201‐400 mg/dL

Basal–Bolus Insulin Regimen inNon‐critically Ill Patients

Rabbit‐2: Conclusion

• Basal/bolus insulin regimen with glargine once daily and glulisine before meals is a better insulin regimen than SSRI in the management of type 2 diabetics in the non‐ICU setting

• SSRI as a single insulin regimen should not be used for the management of patients with type 2 diabetes

Umpierrez et al. Diabetes Care. 30:2181–2186, 2007.

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• Study Type: Multi‐center, prospective, open‐label randomized clinical trial

• Patient Population: Patients with known T2DM admitted to general surgery services

• Study Sites: Grady Memorial Hospital, Veterans Affairs Medical Center and Emory University Hospital, Atlanta, GA

• Treatment Groups:

– Group 1: basal bolus regimen (n=104)

– Group 2: sliding scale regular insulin (n= 107)

Rabbit Surgery (Randomized Study of Basal Bolus Insulin Therapy in the Inpatient Management of Patients with T2DM Undergoing General Surgery):

Research Design and Methods

Umpierrez, et. Al. Rabbit Surgery. Diabetes Care. 2011; 34: 256‐261.

Duration of Treatment (days)

Blo

od G

luco

se (

mg/

dl)

120

140

160

180

200

220

SSRIBasal Bolus

* p: <0.001† p: 0.01ŧ p: 0.02

*

*

††

ŧ

ŧ

Randomi-zation

1 2 3 4 5 6 7 8 9

Glucose Levels During Basal Bolus and SSI Therapy

Postoperative Complications

P=0.003

P=NS

P=0.05 P=0.10

P=0.24

Glargine+Glulisine

Sliding Scale Insulin

Umpierrez et al. Diabetes Care. 34 (2):1–6, 2011.

* Composite of hospital complications: wound infection, pneumonia, respiratory failure, acute renal failure, and bacteremia.

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DEAN Trial: Changes in Mean Daily Blood Glucose Concentration

BG

, mg/

dL

Duration of Therapy, d

Data are means SEM.

Detemir + aspart

NPH + regular

Basal-bolus regimen: detemir was given once daily; aspart was given before meals.NPH/regular regimen: NPH and regular insulin were given twice daily, two thirds in AM, one third in PM.

Umpierrez GE, et al. J Clin Endocrinol Metab. 2009;94(2):564‐569.

P=NS

100

120

140

160

180

200

220

240

Pre-RxBG

0 1 2 3 4 5 6-10

NPH/Regular BG < 40 mg/dl: 1.6% BG < 60 mg/dl: 25.4%

Detemir/Aspart BG < 40 mg/dl: 4.5% BG < 40 mg/dl: 32.8%

DEAN Trial: Hypoglycemia

Emory University, Atlanta, GAMedical University of South Carolina, Charleston, SCTulane University, New Orleans, LA

Basal Plus Trial:Basal + Correction vs. Basal Bolus

Basal plus supplementsStarting glargine*: 0.25 units/kg Correction with glulisinefor BG >140 mg/dl per sliding scale

Basal Bolus Regimen

Starting TDD*: 0.5 U/kg

Glargine: 0.25 U/kg

Glulisine: 0.25 U/kg before meals

Correction with glulisinefor BG >140 mg/dl per sliding scale

* Reduce TDD to 0.15 U/kg in patients ≥70 yrs and/or serum creatinine ≥ 2.0 mg/dL

* Reduce TDD to 0.3 U/kg in patients ≥70 yrs and/or serum creatinine ≥ 2.0 mg/dL

Umpierrez et al. Diabetes Care. 2013 Aug;36(8): 2169‐74.

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Basal‐PLUS vs Basal Bolus: 375 Medical & Surgical Non‐ICU Patients

Patients treated with diet, oral agents or with low‐dose insulin ≤ 0.4 U/Kg/Day

Basal Plus:glargine once daily0.25 U/kg plus glulisine supplements

Basal Bolus:TDD: 0.5 U/kg/dGlargine 50%glulisine 50%

Umpierrez et al. Diabetes Care. 2013 Aug;36(8): 2169‐74.

A1C < 7%

Re‐start outpatient treatment regimen

(OAD and/or insulin)

A1C 7%‐9%

Re‐start outpatient oral agents and D/C on glargine once daily at 50% of hospital dose

A1C >9%

D/C on basal bolus at same hospital dose.

Alternative: re‐start oral agents and D/C on glargine once daily at 80% of hospital dose

Discharge Insulin Algorithm

Discharge Treatment


6.5

7

7.5

8

8.5

9

HbA1c

8.67±2.5

7.86±1.7

7.26±1.5

Hemoglobin A1c, %

Change in HbA1C after Discharge

Data are mean ±SD* p<0.001 from admission

Admission 4 Weeks 12 Weeks

*

*


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Conclusion

Measurement of HbA1c is a useful tool to assess metabolic control and to design treatment regimen at the time of hospital discharge.

The proposed HbA1c‐based hospital discharge algorithm is an effective and safe regimen for the management of general medicine and surgical patients with T2DM.

This study included frequent contacts not common for all post‐discharge patients, thus future randomized trials are need to confirm the efficacy of the proposed HbA1c based discharge algorithm in general medicine and surgery with type 2 diabetes.

Accessed 9/19/15

MUSC JC‐ADA Certifications

Carbohydrate Counting Diet

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Discharge Planning

• Be proactive! Start early (2‐3 days before)

• What can this patient handle at home, assisted living, rehabilitation, or skilled nursing facilities

• Consider side effects, drug intolerances,

comorbidities, costs

• Rx’s, supplies, appointments

• Medication reconciliation

• “Survival skills”

• Outpatient follow up with primary care provider, endocrinologist or diabetes educator within 1 month of discharge is key for all patients having hyperglycemia in the hospital

ADA. Diabetes Care. Standards of Medical Care in Diabetes. 2015. 38 (1): S83.

Overcoming the Barriers to Optimal GlycemicControl in the Hospital

• Achievable goals

• Teamwork

• Optimal glycemic control

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Thank you

Documents

Hermayer - Inpatient Management of Diabetes for pdf€¦ · The Nice‐Sugar Study Investigators. NEJM. 2009; 360: 1283‐1297 Why were the results of the Leuven SICU not reproduced?