Insulin Therapy in the Inpatient and Outpatient Setting

Agustin Busta, MD
Assistant Professor Albert Einstein College of Medicine

Association of DM with total life expectancy and life expectancy with and without cardiovascular disease

Women with diabetes had more than double the risk of developing cardiovascular disease and, 2.2 times higher risk of dying among those with CVD, compared with nondiabetic women, Diabetic men, compared with non-diabetic men, had more than double the risk of developing CVD and a 1.7 times higher risk of dying once CVD was present.

Among those age 50 and older, diabetic men lived an average of 7.5 years less than men without diabetes, and diabetes reduced women's life expectancy by an average of 8.2 years. Life expectancy free of cardiovascular disease was reduced by 7.8 years in men and 8.4 years in women with diabetes.

OH Franco, et al. Arch Intern Med. 2007;167:1145-1151.

Associations of Diabetes Mellitus with Total Life Expectancy and Life Expectancy with and without Cardiovascular Disease

Diabetic men and women 50y and older lived on average 7.5 & 8.2 years less than their nondiabetic equivalents
OH Franco, et al. Arch Intern Med. 2007;167:1145-1151.

Glycemia & Macrovascular Disease in Non-Diabetic Subjects

Coronary Artery Disease
8 7

men women

Adjusted RR (95% CI)

6 5 4 3 2 1 0 <5 %

5 % -5.4 % 5.5 % -5.9 % 6 % -6.4 % 6.5 % -6.9 %

>7 %

Known diabetes

Hb A1c

Khaw KT, et al Ann Intern Med. 2004; 141: 413-420

UKPDS Post-trial monitoring

Enrollment and Outcomes

Holman R et al. N Engl J Med 2008;359:1577-1589

UKPDS 10 yr Follow-Up Studyinsulin/sulfonylurea group

Differences in A1C between intensive & standard glycemic control treatment groups were lost after one year Relative risk reductions at 10 yr in intensive insulin/sulfonylurea group:
9% for any diabetes end point (P=0.04) 24% microvascular disease (P=0.001) 15% myocardial infarction (P=0.01) 13% death from any cause (P=0.007)
N Engl J Med 2008; 359

UKPDS 10 yr Follow-Up StudyMetformin group

Differences in A1C between intensive & standard glycemic control treatment groups were lost after one year Relative risk reductions at 10 yr in intensive metformin group:
21% for any diabetes end point (P=0.01) 33% myocardial infarction (P=0.005) 21% death from any cause (P=0.002)

N Engl J Med 2008; 359

DCCT- EDIC
Post ad-hoc analysis shows a decreased of macrovascular complications on patients who received intensive insulin therapy in the DCCT trial.

Epidemiology of Diabetes Interventions and Complications Study (EDIC) Observational study DCCT participants (type 1 diabetes) Looked at risk factors for long-term complications

DCCT/EDIC N Engl J Med 2005: 353:2643-2653.

DCCT-EDIC: Long-term Risk of Macrovascular Complications

Any Cardiovascular Outcome 12%
Conventional Intensive

0.12
Cumulative Incidence

42% risk reduction P = 0.02

Conventional

Hemoglobin A1C

0.10 0.08 0.06 0.04 0.02 0.00

0 2 4 6 8 10 12 14 16 18 20 Years Since Entry*
Intensive

10%

8%

6%

P < 0.001

P < 0.001

P = 0.61

DCCT
End of Randomized Treatment

EDIC Year 1

EDIC Year 7

*Diabetes Control and Complications Trial (DCCT) ended and Epidemiology of Diabetes Interventions and Complications (EDIC) began in year 10 (1993). Mean follow-up: 17 years.
DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569. Copyright 2002 American Medical Association. All rights reserved. | Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Copyright 2005 Massachusetts Medical Society. All rights reserved.

Key points of recent findings:

Intensive glucose control in newly diagnosed type 1 or type 2 diabetes has benefits during intensive therapy AND a legacy effect for later micro- and macrovascular benefits Optimal glucose management should start as early as possible & continue as long as possible While the A1C goal for the general population is <7%, treatment must be individualized.
N Engl J Med 2008; 359

Regression of atherosclerosis in patients with type 2 diabetes drug naive

Esposito K, On a study using OAD on 175 drug nave patients with type 2 diabetes, resulted in a regression of carotid-intima media thickness after controlling postprandial glucose

Cont r olling Post pr a ndia l H y pe r glyce m ia Le a ds t o Re gr e ssion of gly ce Ca r ot id At he r oscle r osis in Pa t ie nt s W it h Type 2 D ia be t e s Me llit u s
Re p ag lin id e Gly b u r id e
Post pr a n dial Pe a k

260 220

Post pr a n dial Pe a k

Carotid Intima-Media Thickness (mm)

* P = 0 .0 1

0 .0 0 1

0.0 1

Glucose (mg/dL)

180 140 100 260 220 180 140

P 0 .0 0 1 P 0 .0 1

* *

Before After

Before After

100
0 60 120 0 Minutes 60 120

Before

After

Before
G l y b u r

After
i d e

Repaglinide

C- II M T Regr e ssion Associa t ed W it h PPG, II L- 6 ,, and CRP C- M T Re gr ession Associat e d W it h PPG, L- 6 and CRP LC-IMT = carotid intima-media thickness; PPG = postprandial glucose; IL-6 = interleukin 6; CRP = C-reactive protein
Esposito K, et al. Circulat ion. 2004;110:214219
Slid e Sou r ce Lipids Online Slide Library www.lipidsonline.org

Natural History of Type 2 Diabetes

Years from diagnosis

-10

-5

10

15

Onset

Diagnosis

Insulin resistance Insulin secretion

Postprandial glucose Fasting glucose

Pre-diabetes

Microvascular complications Macrovascular complications Type 2 diabetes

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. NEJM. 2002;347:1342-1349

UKPDS-DM Pancreas
Is a continue state of beta cell function impairment that will lead to an state of complete pancreas exhaustation and lead to pancreatic insulin secretion unsuffiency. Pancreas exhaustion rapidly occurred at rate of 24 % year, and in 10 years majority of patient needs insulin Majority of T2dm will fail to maintain targets withA1c with OAD because pancreas run out of insulin

Glycemic Control Declines Over Time With Traditional Monotherapy

Patients with A1C <7% (%)

50 40 30 20 10 0

44% 34% 13%

Patients with A1C <7% (%)

50 40 30 20 10 0

50% 34% 24%

3 years

6 years

9 years

3 years

6 years

9 years

Adequately controlled and treated with metformin*

Adequately controlled and treated with sulfonylureas

*Overweight drug-nave patients. Normal weight and overweight drug-nave patients

Turner RC, et al. JAMA. 1999;281:2005-2012.

NHANES III(1988-94) vs NHANES(1999-2000)

Insulin Use Remains Constant NHANES III(1988-94) vs NHANES(1999-2000)

60 50 40 30 20 10 0
Diet/Ex Orals Orals + Ins Insulin Only

Constant: 27% of patients treated with insulin

NHANES III NHANES 1999-2000

Between NHANES III and NHANES 1999-2000, percentage of patients treated with drug therapy increased 7.2% Percentage of patients treated with insulin remained constant at ~27%
Adapted from Koro et al, Diabetes Care. 2004; 27(1):17-20

Estimated Cost of Diabetes in U.S.

Total: $174 billion Direct Medical Cost: $116 billion Indirect Cost: $58 billion

NIDDK, National Diabetes Statistics 2007. www.diabetes.niddk.nih.gov/dm/pubs/statistics

Recent Clinical Trial Findings:

Intensive glucose control in type 2 diabetes: lowers risk of new or worsening microvascular complications (ADVANCE) was associated with increased mortality in patients with longstanding DM and known CVD (ACCORD) increases risk of severe hypoglycemia (ADVANCE, ACCORD and VADT)

ACCORD: N Engl J Med 2008; 358(24):2545-59. ADVANCE: N Engl J Med 2008; 358 (24): 2560-72. VADT: J Diabetes Complications 2003; 17 (6): 314-22

AVAILABLE INSULIN PREPARATIONS

Product (Manufacturer) Rapid Acting (Onset 15-30 min, duration hrs 3-4) Insulin Analog Aspart - Novolog (Novo Nordisk) Lispro - Humalog (Lilly) Glulisine Apidra (Aventis) Short Acting (Onset 0.5-1 hr, duration hrs 5-7)* Human Insulin Novolin R (Rugular) (Novo Nordisk) Humulin R (Regular) (Lilly) Purified Insulin Regular Iletin II (Lilly) Human** Human** Analog** Analog** Form Product (Manufacturer) Analog Mix Humalog 75/25 Mix Novolog Mix 70/30 (combination of fast and intermediate acting insulin with action similar to that of Humalog 75/25 mix) Insulin for Special Use Buffered Insulin (for pumps) Humulin BR Refills for Novolin Pen Novolin R PenFill Novolin N PenFill Novolin 70/30 PenFill Novolog Mix 70/30 PenFill Prefilled Pens Novolin R Novolin N Novolin 70/30 Novolog Novolog Mix 70/30 Humalog Humalog Mix 75/25 Humalog Mix 50/50 Humulin N Apidra Form Analog** Analog**

Pork

Human** Human** Human** Analog** Human** Human** Human** Analog** Analog** Analog** Analog** Analog** Human** Analog**

Intermediate Acting (Onset 1-4 hrs, duration hrs 18-24)* Human Insulin Novolin N (NPH) (Lilly) Humulin N (NPH) (Lilly) Humulin L (Lente) (Lilly) Purified Insulin NPH Iletin III (Lilly) Long Acting (Onset 4-6 hrs, duration hrs 24-34)* Human Insulin Humulin Ultralente (Lilly) Basal Peakless Insulin Glargine-Lantus (Aventis) Detemir Levemir (Novo Nordisk) Mixed Insulins 70/30 Insulin Novolin 70/30 (Novo Nordisk) Humulin 70/30 (Lilly) Humulin 50/50 (Lilly) Humalog 50/50 Human** Human** Human** Pork

Human**

Analog** Analog**

* Onset and duration are rough estimates. They can vary greatly within the range listed and from person to person ** Human insulin is made by recombinant DNA technology

Human** Human** Human** Analog**

Schematic Time-Activity Curves for Selected Insulin Formulations

McMahon G and Dluhy R. N Engl J Med 2007;357:1759-1761

Physiologic Insulin Secretion: Basal/Bolus Concept

Nutritional (Prandial) Insulin

Insulin (U/mL)

50 25 0
Breakfast

Basal Insulin
Lunch Supper

Suppresses Glucose Production Between Meals & Overnight

150 Glucose (mg/dL) 100 50 0

Nutritional Glucose

The 50/50 Rule

Basal Glucose
7 8 9 1011 12 1 2 3 4 5 6 7 8 9 A.M. P.M.

Time of Day

Normal Daily Plasma Insulin Profile

Nondiabetic Obese Individuals
QU/mL
100 B 80 60 40 20 1200 1800 2400 L D

0600

0800

0600

Time of day
B=breakfast; L=lunch; D=dinner
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

Action Profiles of Insulins

Aspart, glulisine, lispro 45 hours
Plasma insulin levels Regular 68 hours NPH 1216 hours

Detemir ~14 hours

Ultralente 1820 hours

Glargine ~24 hours

2 3 4

5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Hours
Burge MR, Schade DS. Endocrinol Metab Clin North Am. 1997;26:575-598; Barlocco D. Curr Opin Invest Drugs. 2003;4:1240-1244; Danne T et al. Diabetes Care. 2003;26:3087-3092

Treat to Target Study Insulin Glargine vs NPH Insulin Added to Oral Therapy
Study Design

24-wk, multicenter, randomized, parallel, openlabel trial. Compared insulin glargine vs NPH given at HS in type 2 diabetics patients inadequately controlled on 1 or 2 oral agents Insulin dosage adjusted weekly by forced-titration schedule seeking FPG e100 mg/dL Measure achievement of A1C e7% without clinically significant nocturnal hypoglycemia 756 insulin-nave patients,on Glargine =367,on NPH = 389, mean age = 55yr, duration of diabetes = 8-9 yr, baseline A1c= 8.6%, BMI = 32 kg/m2.
Riddle M, Rosenstock J, HOE901/4002 Study Group. Diabetes. 2002;51(suppl 2):A113. Abstract 457-P

Insulin Glargine vs NPH Insulin Added to Oral Therapy

Methods
Forced-Titration Schedule
Start with 10 IU/day bedtime basal insulin dose and adjust weekly
Self-monitored FPG (mg/dL)*
u180 mg/dL u140 but <180 mg/dL u120 but <140 mg/dL >100 but <120 mg/dL

o in insulin dose (IU/day)

8 6 4 2

Treat to target FPG e100 mg/dL

*2 consecutive days with no episodes of severe hypoglycemia or PG 72 mg/dL Small q (24 IU/day/adjustment) in dose allowed when self-monitored PG <56 mg/dL or severe hypoglycemic episode occurs
Riddle M, Rosenstock J, HOE901/4002 Study Group. Diabetes. 2002;51(suppl 2):A113. Abstract 457-P

Insulin Glargine vs NPH Insulin Added to Oral Therapy

Results
ITT Analysis FPG, mg/dL mM A1C, % Final A1C e7% (% patients) Nocturnal hypoglycemia Patients,* % Severe hypoglycemia Patients, %
*P<0.01; P<0.002
Riddle M, Rosenstock J, HOE901/4002 Study Group. Diabetes. 2002;51(suppl 2):A113. Abstract 457-P

Insulin Glargine 117 6.5 6.96 57 40

NPH 120 6.68 6.97 57 49

2.5

2.3

INITIATE Trial
28-weeks, parallel group randomized study comparing the safety and efficacy of biphasic insulin Aspart mix 70/30 bid vs Glargine qd.

Primary end point

A1C reduction

Secondary end points

Proportion of patients achieving A1C <7.0% and 6.5% PPG control Safety, including number of hypoglycemic events (major, minor, nocturnal) and adverse events

Addition of glargine or biphasic aspart mix 70/30 to oral therapy

233 People with Type 2 Diabetes on 1 or 2 Oral Agents
Glycaemic Control
Baseline HbA1c 0.0
-0.5 -1.0

Hypoglycaemia
9.8%

9.7%

4 3.4

P<0.05

-1.5 -2.0 -2.5 -3.0 -2.8% -2.4%

Events/Patient-year (PG e 3.1 mmol/l)

( HbA1c

0.7

P<0.01
Final HbA1c 6.9% 7.4%

Biphasic aspart 70/30.( 66%

A1c 7)

Glargine.

(40% A1C 7)

Raskin P et al. Diabetes Care. 2005;28:260-265

Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes

Study Overview In an open-label trial, patients with type 2 diabetes with a suboptimal glycated hemoglobin level while receiving a maximally tolerated dose of metformin and sulfonylurea were randomly assigned to receive biphasic, prandial, or basal insulin The addition of a single analogue-insulin formulation resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. Regimens of biphasic or prandial insulin had greater efficacy than did the basal regimen but were associated with greater risks of hypoglycemia and weight gain

Primary and Secondary Outcomes at 1 Year

Holman RR et al. N Engl J Med 2007;357:1716-1730

Mean (SE) Percentage Change from Baseline to 1 Year in Glycated Hemoglobin, Fasting Plasma Glucose, Postprandial Glucose, and Body Weight (Panel A) and Mean (+SD) Hypoglycemic-Event Rate (Panel B)

Holman RR et al. N Engl J Med 2007;357:1716-1730

Glycated Hemoglobin Level, Hypoglycemia, and Increase in Body Weight at 1 Year and 3 Years

Roden M. N Engl J Med 2009;361:1801-1803

Evidence-based guideline-derived treatment algorithm

Diagnosis Lifestyle intervention then metformin HbA1c u6.5 % Add sulfonylurea HbA1c u6.5 %
*Alternatively, start thiazolidinedione before sulfonylurea, and sulfonylurea later.

HbA1c u6.5 % Add insulin HbA1c u7.0 % intensify insulin

Add thiazolidinedione* HbA1c u7.5 % Start insulin

Meal-time + basal insulin + metformin thiazolidinedione

IDF. Global Guideline for Type 2 Diabetes. 2005

How should I start insulin therapy for my patients with Type 2 diabetes? According to the IDF Global Guideline for Type 2 Diabetes:
Insulin is the most effective way of reducing hyperglycaemia Insulin can be started as a basal insulin alone or with premix insulin Start insulin when glucose control on maximum tablets >7.5 % (HbA1c) Begin at low dose but titrate up rapidly in first month
IDF. Global Guideline for Type 2 Diabetes. 2005

ADA/EASD Treatment Algorithm for Type 2 Diabetes

DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008

Initiation and adjustment of insulin regimens

Start with bedtime intermediate-acting insulin or bedtime(HS) or morning long-acting insulin (can initiate with 10 U or 0.2 units per kg) Check FBG usually daily and increase dose, typically by 2U every 3 days until fasting levels are in target range(70-130 mg/dL). Can increase dose in larger increments,eg, by 4 U every 3 days, if FBS >180 mg/dL

A1c 7% after 2-3 months ? If hypoglycemia occurs, or FBS< 70 mg/dL, reduce HS dose by 4U, or 10% if dose is > 60U

No

Yes
If FBS in target range(70-130mg/dL),check bg before lunch,dinner, and at HS. Depending on bg results,add second injection as below. Can usually begin with ~ 4 U and ajust by 2 U every 3 days until bg is in range

Continue regimen. Check A1c every 3 months

No

Pre-lunch bg out of range. Add rapidacting insulin at breakfast

Pre-dinner bg out of range. Add NPH insulin at breakfast or rapid acting at lunch

Pre-bed(HS) bg out of range. Add rapid-acting insulin at dinner

A1c 7% after 3 months

Yes
ADA/EASD Consensus Algorithm 2009
Recheck pre-meals bg levels and if out of range, may need to add another injection. If A1c continues to be out of range,check 2-h postprandial levels and adjust preprandial rapid-acting insulin

How should I advance insulin therapy for people with Type 2 diabetes?
Algorithm driven dose titration basal regimen*
Once daily intermediate or long-acting insulin Begin 10 U or 0.2 U/kg, titrate by 2 U every 3 days using pre-breakfast plasma glucose (PG) until in target range (70-130 mg/dL) HbA1c 7.0% after 3 months Check pre- breakfast, lunch, dinner, and bedtime PG Add rapid-acting insulin to the meal with the highest excursion Begin 4 U and adjust by 2 U every 3 days based on PG change Add additional meal-time injections if HbA1c 7.0% after 3 months
*Insulin regimens should be designed taking lifestyle and meal schedule into account; this algorithm provides a basic guideline for initiation and adjustment of insulin. Regimens with once- or twice-daily premixed insulins are also possible. Inhaled insulin dosing in 1 mg ( 3 U) steps. Nathan DM et al. Diabetes Care. 2006;29:1963-1972

Insulin in the Hospital Setting:

Glycemic Control and Improved Outcomes

The Increasing Rate of Diabetes Among Hospitalized Patients

Hospitalizations for Diabetes as a Listed Diagnosis
5

Hospital Discharges (millions)

4 3 2 1 0

48%o

1991 92

93

94

95

96

97

98

99 2000 01

Available at: http://www.cdc.gov/diabetes/statistics/dmany/fig1.htm. Accessed June 15, 2004.

Diabetes in Hospitalized Patients

At least 4 million patients with diagnosed diabetes are admitted to hospitals annually in the United States In 2000, 12.4% of hospital discharges in the United States listed diabetes as a diagnosis

Centers for Disease Control 2004.American Diabetes Association. Diabetes Care. 2005;28(suppl 1):S4-S36. 1- American Diabetes Association. Diabetes Care 2008;31:596-615

Hyperglycemia Is Common in Hospitalized Patients

Non-critically ill medical / surgical: 38% Intensive care units (ICU): 29% 100%
Episodes of glucose >110 mg/dL: 100% Episodes of glucose >200 mg/dL: 31% Mean glucose >145 mg/dL: 39%(prevalence)

Umpierrez G et al. J Clin Endocrinol Metabol. 2002, 87:978-982.. Levetan CS et al. Diabetes Care. 1998;21:246-249.. Krinsley JS. Mayo Clin Proc. 2003;78:1471-1478.. Falciglia M et al. 66th ADA Scientific Meeting, 2006.

Hyperglycemia in Patients Predictor of Poor Outcome

Hyperglycemia occurred in 38% of patients admitted to a community hospital in Atlanta
26% had known history of diabetes 12% had no history of diabetes

Newly discovered hyperglycemia was associated with:

Higher in-hospital mortality rate (16%) compared with patients with a history of diabetes (3%) and patients with normoglycemia (1.7%; both P<.01) Longer hospital stays; higher admission rates to intensive care units (ICUs) Less chance to be discharged to home (required more transitional or nursing home care)
Umpierrez GE et al. J Clin Endocrinol Metab. 2002;87:978982.

Effect of Hyperglycemia on Hospital Mortality

History of Normoglycemia Known diabetes New hyperglycemia

35 30 Mortality (%) 25 20 15 10 5 0 Total Non-ICU ICU

*P<.01 compared with normoglycemia and known diabetes.

* *

Umpierrez GE et al. J Clin Endocrinol Metab. 2002;87:978982.

Hyperglycemia and Pneumonia Outcomes

35 30 25

Admission Glucose (mg/dL)

Patients

20 15 10 5 0
<110 110-<198 198-<250 >250

Mortality

Hospital Complications
N=2471 patients with CAP, Canada

Blood Glucose (mg/dL)

*P<0.05 vs BG<198 mg/dL (11 mmol/L) CAP, community acquired pneumonia McAlister et al. Diabetes Care. 2005;28:810-815.

Hyperglycemia and Mortality in the MICU

N=1826 ICU patients.
45 40

~3x ~2x

~4x

Mortality Rate (%)

35 30 25 20 15 10 5 0 80-99 100-119 120-139

140-159 160-179 180-199

200-249

250-299

>300

Mean Glucose Value (mg/dL)

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

Consequences of Poor Glycemic Control in Hospital Patients

Hyperglycemia, with or without a diagnosis of diabetes, can result in
Increased Mortality Increased Morbidity Admission to the ICU Need for extended care Overall poor outcomes

Umpierrez GE et al. J Clin Endocrinol Metab. 2002;87:978-982. Bolk J et al. Int J Cardiol. 2001;79:207-214. Williams LS et al. Neurology. 2002;59:67-71. Malmberg K, et al. BMJ. 1997;314:1512. Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367. Capes SE et al. Stroke. 2001;32:2426-2432.

Hyperglycemia is a Marker of Poor Outcome

Does control of hyperglycemia is important in improving outcomes?

DIGAMI Study
Diabetes, Insulin Glucose Infusion in Acute Myocardial Infarction (1997)

Acute MI With BG > 200 mg/dl Intensive Insulin Treatment IV Insulin For > 24 Hours Four Insulin Injections/Day For > 3 Months Reduced Risk of Mortality By:
28% Over 3.4 Years 51% in Those Not Previous Diagnosed

Malmberg BMJ 1997;314:1512

Mortality After MI Is Reduced by Insulin Therapy in DIGAMI

Standard treatment (314) IV insulin 48 hours, then 4 injections daily (306)
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 4 5 Follow-Up (y)

All Subjects (N=620)

Risk reduction (28%) P=.011

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0

Low-Risk & Not Previously on Insulin (N=272)

Risk reduction (51%) P=.0004

Follow-Up (y)

MI = myocardial infarction; DIGAMI = Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction. (Short and long term effect of intensive insulin therapy) 44vs33 Malmberg K et al. BMJ. 1997;314:1512-1515.

Intensive Insulin Therapy in Critically Ill Patients: The Leuven SICU Study
Randomized controlled trial: 1548 patients admitted to a surgical ICU, receiving mechanical ventilation. Patients were assigned to receive either:
Conventional therapy: IV insulin only 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 Berghe et al. N Engl J Med. 2001;345:1359-1367.

ICU Survival
1548 Patients (mostly OHS pts.) All with BG >200 mg/dl Randomized into two groups
Maintained on IV insulin Conventional group (BG 180-200) Intensive group (BG 80-110)

Conventional Group had 1.74 X mortality

Van den Berghe et al. N Engl J Med. 2001;345:1359-1367.

Intensive Glycemic Control and Survival in Critically Ill Patients

100 96 100

In-Hospital Survival (%)

Intensive treatment, 4.6% mortality

96
Intensive treatment

Survival in ICU (%)

92
Conventional treatment, 8%

92 88 84 80 0

88 84 80 0
0 20 40 60 80 100 120 140 160

Conventional treatment

42.5% reduction in mortality with intensive treatment; P<.04

34% reduction in mortality with intensive treatment; P<.01

50

100

150

200

250

Days After Admission

Days After Admission

Van den Berghe et al. N Engl J Med. 2001;345:1359-1367.

Benefits of IV Insulin Treatment in Critically ill Hospitalized Patients

Total M ortality 0 -10 Blood I nfection Acute Renal Failure Transfusions Polyneuropathy

Reduction (% )

-20 -30 -40 -50 -60

34% 41% 46% 50%

Intensive Glycemic Control BG = 80-110 mg/dL in ICU BG = 180-200 mg/dL after discharge from ICU
Van den Berghe et al. N Engl J Med. 2001;345:1359-1367.

44%

Improvement in Deep Sternal Wound Infection With Continuous IV Insulin

4 3

CII
Patients with diabetes Nondiabetic patients

DSWI (%)

2 1 0 87 88 89 90 91 92 Year 93 94 95 96 97

Target blood glucose <150 mg/dL. IV = intravenous; CII = continuous insulin infusion; DSWI = deep sternal wound infection. Furnary AP et al. Ann Thorac Surg. 1999;67:352-362. (prospective 2467)

AACE - Consensus Conference Suggested 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 90130 mg/dl
AACE- Endocrine Practice 10 (1): 77-82, 2004; AAE Endocrine Practice February 2006; ADA- Diabetes Care 27: 553-591, 2004

Insulin: The Most Effective Treatment for Inpatient Glycemic Control

Adaptable to increased insulin requirement during acute illness Basal insulin administration can prevent excess gluconeogenesis and ketogenesis Dose can be adapted to various categories of patient nutrition status
IV dextrose Total parenteral nutrition Enteral feeding Nutritional supplements

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

Methods For Managing Hospitalized Patients with Diabetes

IV Insulin Drip
Major Surgery, Cardiovascular procedures,NPO, MI, DKA, Steroids, Gastroparesis, MICU, etc

Subcutaneous insulin injections:

Basal / Bolus Therapy (MDI) when eating Basal / Correction Bolus when NPO

Initiate or continue IV insulin infusion as soon as patient comes out from the OR as follows:
Non-Diabetics
Check Finger Stick (FS) and initiate or adjust insulin infusion as per TIER 1 (Green Wheel) if any BG > 200 mg/dL Check FS and initiate or adjust insulin infusion as follows: If FS > 250 mg/dL bolus with 4 units of regular insulin IV and then follow IV Insulin rate as per weight (below) If FS < 250 mg/dL start as per weight (below) If patient < 70 Kg start as per TIER 1 (Green Wheel) If patient > 70 Kg start as per TIER 2 (Yellow Wheel)

Diabetics

Finger Stick (FS) Monitoring

FS Q 1 hour If no change in BG range for two (2) consecutive measurements move-up a tier within the same range If at goal for three (3) consecutive FS can change FS to Q2 hours, and if again at goal for three (3) consecutive measurements can change to FS Q 4 hours Resume monitoring FS Q 1 hour if:
Significant change in clinical condition Initiation or cessation of corticosteroids and / or vasopressors Initiation or cessation of hemodialysis

Initiation, cessation, or change in nutritional support

DIABETES / HYPERGLYCEMIA DISCHARGE SUMMARY Date: Mr./ Ms. Diabetes Mellitus Type 1 Diabetes Mellitus Type 2 Post-Operative Hyperglycemia Who underwent: Coronary Artery Bypass Grafting Cardiac Valve Surgery Other Post-operatively treatment : Novolog ( Aspart ) Lantus

( Glargine ) Oral antihyperglycemic medication(s) Diet-control only

Important data: HgA1c Serum creatinine Weight Your patients Diabetes/Hyperglycemia discharge plan is as follows: Life style improvement- diet-control only Oral antihyperglycemic medication(s) Glucophage (Metformin) Prandin (Repaglinide) Januvia (DPP-IV Inh ) Sulfonylureas: Other Insulin(s) _____ AST/ALT

_____ _____ _____

Ejection Fraction _____ %

LDL-c

_____

Lantus _____ units at _____, daily Novolog/Humalog at meals Other

Diabetes follow up appointment :

Dr. Gouller #420-3917 Dr..Busta #420-4198 Dr... #420-

Endo Clinic (212) 420- 4412

Date :

Location : Fierman Hall. 317East 17th street 7 Floor.

Recommendations:
1) HgA1c goal of 7% or lower 2) You may also refer your patient to the Friedman Diabetes Institute for diabetes education.Friedman Diabetes Israel Medical Center317 East 17th Street, 8th Floor New York, NY 10003 www.frie

Comparison of Human Insulins and Analogues

Insulin Preparations Lispro/Aspart/Glulisine Regular human Human NPH Detemir Insulin Glargine Onset of Action 10 - 15 min 30 - 60 min 1-2h 2-4h 2-4h Peak (h) 1-2 2-4 4-8 flat/ 6-8 * flat Duration of Action (h) 3-6 6-8 12 - 16 14-20 * 18-24

Time course of action of any insulin can vary in different people or at different times in the same person; thus, time periods indicated here should be considered general guidelines only. * Dose dependent
1. Mudaliar S et al. Endocrinol Metab Clin North Am. 2001;30:935-982.; 2. Endotext.com

Insulin Order
There are 6 options (order sets) for the initial insulin orders:
1. 2. 3. 4. 5. 6. Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients eating Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients NPO Patients with type 2 diabetes previously on oral agents- insulinnave patients - eating Patients with type 2 diabetes previously on oral agents, insulin-nave patients NPO Patients with newly diagnosed hyperglycemia - patient eating Patients with newly diagnosed hyperglycemia - patient NPO

Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients eating
Order HgbA1C Order hypoglycemia management nest Use Prior Total Daily Dose (TDD) of insulin, whenever possible, if patient was well controlled. If dose is not known or unable to assess control, TDD should be weight-based. TDD (0.4 u/kg)should be split as follows:
Basal: 50% of TDD : Lantus dose should be calculated as 50% of 0.4units/kg (0.2 units/kg) and given immediately upon arrival to the floor. Prandial: Novolog should be calculated as 15% of 0.4units/Kg given before each meal (TID AC) Correction/Supplemental Insulin Scale: Standard (or Low, Medium or High Dose according to risk of hypo or hyperglycemia). Correction Scale is given before meals and is added to Prandial dose. HS Correction Scale may be ordered but separately.

Reassess TDD in 24 hours.

Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients eating
Approximate dose for a 70 kg patient 0.4 u/kg x 70 kg= 28 units a) Lantus 15 units SC Q 24hr (Q HS) b) Novolog 5 units SC Q AC before Breakfast, before Lunch and Before Dinner c) Correction/Supplement Insulin (Novolog) Scale before meals TID AC (Pick Standard, Low Dose, Medium Dose or High Dose)

Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients NPO
Order HgbA1C Order hypoglycemia management nest Use Prior Total Daily Dose (TDD) of insulin, whenever possible, if patient was well controlled. If dose is not known or unable to assess control, TDD should be weight-based. TDD should be split as follows:
Basal: 50% of TDD : Lantus dose should be calculated as 50% of 0.4 units/kg (0.2 units/kg) and given immediately upon arrival on the unit. Prandial: None Correction/Supplemental Insulin Scale: Standard Scale should be given q4-6 hours

All Patients will need to be on D5 1/2NS @ 75-100ml/hr. Reassess TDD in 24 hours.

Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients NPO Approximate dose for a 70 kg patient : 0.4 u/kg x 70 kg = 28 units a) Lantus 15 units SC Q 24hr (Q HS) b) Correction/Supplement Insulin (Novolog) scale (Standard) Q 4h c) D5 1/2NS at 100 cc/hr

Patients with type 2 diabetes previously on oral agents, insulin-nave - patients eating
Order HgbA1C Order hypoglycemia management nest Total Daily Dose (TDD) (0.3u/kg)of insulin should be weightbased; insulin should be dosed as follows:
Basal: 50% of TDD: Lantus dose should be calculated as 50% of 0.3 units/kg (0.15 units/kg) and given immediately upon arrival on the unit. Prandial: Novolog should be calculated as 15% of 0.3 units/kg and given before each meal (TID AC). Correction/Supplemental Insulin Scale: Standard (or Low, Medium or High Dose according to risk of hypo or hyperglycemia). Correction Scale is given before meals and is added to Prandial dose. HS Correction Scale may be ordered but separately.

Reassess TDD in 24 hours.

Patients with type 2 diabetes previously on oral agents- insulin-nave patients - eating
Approximate dose for a 70 kg patient: 0.3 u/kg x 70 kg = 21 units a) Lantus 10 units SC Q 24hr (Q HS) b) Novolog 3 units SC Q AC before Breakfast, before Lunch and Before Dinner c) Correction/Supplement Insulin (Novolog) Scale before meals TID AC (Pick Standard, Low Dose, Medium Dose or High Dose)

Patients with type 2 diabetes previously on oral agents, insulin-nave - patients NPO
Order HgbA1C Order hypoglycemia management nest Total Daily Dose (TDD) of insulin should be weight-based; insulin should be dosed as follows:
Basal: Lantus dose should be calculated as 0.1 U/kg and given immediately upon arrival to the floor. Prandial: None Correction/Supplemental Insulin Scale: Standard Scale should be given q4-6hours.

Reassess TDD in 24 hours.

Patients with type 2 diabetes previously on oral agents, insulin-nave - patients NPO Approximate: 0.1 u/kg x70 kg = 7 units a) Lantus 7 units SC Q 24hr (Q HS) b) Correction/Supplement Insulin (Novolog) scale (Standard) Q 4h c) D5 1/2NS at 100 cc/hr

Patients with newly diagnosed hyperglycemia patient eating

Order HgbA1C Order hypoglycemia management nest Total Daily Dose (TDD) of insulin should be weight-based; insulin should be dosed as follows:
Basal: 50% of TDD: Lantus dose should be calculated as 50% of 0.3 units/kg and given immediately upon arrival to the floor. Prandial: Novolog should be calculated as 15% of 0.3 units/kg and given before each meal (TID AC). Correction/Supplemental Insulin Scale: Standard (or Low, Medium or High Dose according to risk of hypo or hyperglycemia). Correction Scale is given before meals and is added to Prandial dose. HS Correction Scale may be ordered but separately.

Reassess TDD in 24 hours.

Patients with newly diagnosed hyperglycemia patient eating

Approximate: 0.3u/kg x 70 kg = 21 units a) Lantus 10 units SC Q 24hr (Q HS) b) Novolog 3 units SC Q AC before Breakfast, before Lunch and Before Dinner c) Correction/Supplement Insulin (Novolog) Scale before meals TID AC (Pick Standard, Low Dose, Medium Dose or High Dose)

Patients with newly diagnosed hyperglycemia patient NPO

Order HgbA1C Order hypoglycemia management nest Total Daily Dose (TDD) of insulin should be weight-based; insulin should be dosed as follows:
Basal: None Prandial: None Correction/Supplemental Insulin Scale: Standard Scale should be given q4-6hours.

Reassess TDD in 24 hours.

Patients with newly diagnosed hyperglycemia patient NPO Approximate: Correction/Supplement Insulin (Novolog) scale (Standard) Q 4h

Hypoglycemia
Treatment of Hypoglycemia Patient alert : 15-30 gm of carbs ( 8 onz of juice, 2 crackers=10 carbs , glucose tablets) Non alert patient : 1 amp D50 or 1 mg glucagon IM (repeat q 15 min ) RULE OF THUMB : 15 gm of carbs will increased glucose levels 25-50 mg/dL Do Not Hold Insulin When BG Normal