An Introduction To Insulin Therapy

Insulin 101
premixed
T1DM
T2DM
titration
An Introduction to
Insulin Therapy in
st
the 21 Century
glycemic control
A1C levels
March 10, 2012

Houston, Texas
Education Partner
Basal-bolus
hypog
Session 3: Insulin 101:

An Introduction to Insulin Therapy in the 21st Century
Learning Objectives
1.
2.
3.
4.
Calculate appropriate insulin doses for initiating basal and basal-prandial insulin regimens in T2DM.
Demonstrate best practices in insulin injection and self-monitoring of blood glucose (SMBG) techniques to improve
treatment adherence and potentially impact patient outcomes.
Apply pattern recognition to SMBG data to appropriately titrate insulin doses and adjust insulin regimens to specific patient
needs.
Summarize the efficacy and safety findings from clinical trials of investigational insulins and the combination of incretinbased therapies with insulin.
Faculty
Debbie Hinnen, ARNP, BC-ADM, FAAN
Director of Education Services
Mid-America Diabetes Associates
Wichita, Kansas
Ms Hinnen has been a diabetes educator for over 30 years. A clinical nurse specialist and director of education services, she
currently works with a multidisciplinary team at Mid-America Diabetes Associates, which provides diabetes care and education.
The cornerstone of their program is a 3-day comprehensive self-management course that serves nearly 1000 people with diabetes
per year.
Ms Hinnen is involved extensively with the American Association of Diabetes Educators (AADE) and previously served as their
national president and chair of the foundation. She was awarded the AADEs prestigious Distinguished Service Award in the
summer of 2001. Ms Hinnen has also served on the national board of directors of the American Diabetes Association and as one
of the editors for the journal Diabetes Spectrum. Ms Hinnen holds faculty positions with the pharmacy department at the University
of Kansas, and with the graduate nursing department and the physician assistant program, both at Wichita State University. She
was inducted as a fellow into both the American Academy of Nursing in 2003 and the AADE in 2010.
Etie Moghissi, MD, FACP, FACE
Clinical Associate Professor
University of California, Los Angeles
Los Angeles, California
Dr Moghissi is a clinical associate professor of medicine at the University of California, Los Angeles, and has a private practice in
Marina del Rey, California. As a native of Shiraz, Iran, she earned her medical degree from Pahlavi University School of Medicine
in Shiraz. She completed an internal medicine residency at St. Lukes-Roosevelt Hospital at Columbia University in New York
City and a fellowship in endocrinology at the University of Southern California in Los Angeles. She is board certified by the
American Board of Internal Medicine and the American Board of Endocrinology.
Dr Moghissi coauthored the 2011 American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for Developing a
Diabetes Mellitus Comprehensive Care Plan and currently serves as the chair of the American Association of Clinical Endocrinologists
(AACEs) Diabetes Resource Center Task Force. She chaired and was the lead author of the 2009 AACE/American Diabetes
Association (ADA) Consensus Statement on Inpatient Glycemic Control. Dr Moghissi was also cochair of the AACE Inpatient Diabetes
Consensus Conference and Position Statement (2004) and the AACE/ADA Inpatient Diabetes Call to Action Consensus Conference and
Position Statement (2006). In 2007, she led the effort to create the AACE Inpatient Glycemic Control Resource Center on AACEs
website. Her efforts have been instrumental in driving a major shift in optimizing the care of hospitalized patients with diabetes.
Session 3
Dr Moghissi is the president-elect of the AACE and past president of its California chapter. Her areas of interest include direct
patient care and teaching in the field of diabetes, and she has lectured extensively on these topics on both the national and
international levels.
Javier Morales, MD
Vice President
Principal Trials Investigator
Advanced Internal Medicine Group, PC
New Hyde Park, New York
Dr Morales is in private practice with the Advanced Internal Medicine Group in New Hyde Park, New York. After graduating
from the University of Medicine and Dentistry of New Jersey, he completed residencies at Memorial Sloan-Kettering Cancer
Center and North Shore University Hospital, where he served as chief medical resident. Dr Morales serves on multiple
committees at St. Francis Hospital in Roslyn, New York. In addition to authoring several publications, he has served as principal
investigator for several different studies and clinical trials. He is active in the educational sector and has been a presenter at many
Pri-Med symposia. He also serves as a clinical instructor for several nurse practitioner, physician assistant, and internal medicine
residency programs at North Shore University Hospital and Winthrop University Hospital. Dr Morales is an avid musician and
percussionist, and he is fluent in Spanish, Italian, and Portuguese.
Faculty Financial Disclosure Statements

The presenting faculty report the following:
Debbie Hinnen, ARNP, BC-ADM, FAAN, receives honoraria from Abbott Laboratories, Amylin Pharmaceuticals, Inc, Aventis
Pharmaceuticals, Boehringer Ingelheim, Intuity Medical, Inc, Janssen Pharmaceuticals, Inc, Eli Lilly and Company, Pamlab, LLC,
and F. Hoffmann-La Roche Ltd.
Etie Moghissi, MD, FACP, FACE, receives honoraria as a consultant from Amylin Pharmaceuticals, Inc, Eli Lilly and Company,
and Novo Nordisk. Dr Moghissi also receives honoraria as a member of a speakers bureau for AstraZeneca, Boehringer
Ingelheim, Bristol-Myers Squibb, and Novo Nordisk.
Javier Morales, MD, receives honoraria from Eli Lilly and Company, Novo Nordisk, and Warner Chilcott.
Education Partner Financial Disclosure Statement
The content collaborators at the Institute for Medical and Nursing Education, Inc., report the following:
Amy Carbonara, Director of Program Development, has no financial relationships to disclose.
Robin Devine, DO, Medical Writer, has no financial relationships to disclose.
Angela McIntosh, PhD, Scientific Director, has no financial relationships to disclose.
Marge Tamas, Editorial Manager, has no financial relationships to disclose.
Steve Weinman, RN, Executive Director, has no financial relationships to disclose.
Acronym List
Acronym
A1C
AACE
AADE
ACE
ADA
AE
ASP
B
BBT
BG
Bi-ASP
BID
BMI
CGM
CKD
Definition
glycosylated hemoglobin A1C
American Association of Clinical
Endocrinologists
American Association of Diabetes
Educators
American College of Endocrinology
American Diabetes Association
adverse event
insulin aspart
breakfast
basal bolus therapy
blood glucose
biphasic aspart
twice daily
body mass index
continuous glucose monitoring
chronic kidney disease
Acronym
CSII
CVD
D
DEG
DET
DPP-4
EPM
EXN
FBG
FPG
FPG LL
FPG UL
GLAR
GLP-1
GLU
HS
IFG
Definition
continuous subcutaneous insulin
infusion
cardiovascular disease
dinner
insulin degludec
insulin detemir
dipeptidyl peptidase-4
events/patient-month
exenatide
fasting blood glucose
fasting plasma glucose
fasting plasma glucose lower limit
fasting plasma glucose upper limit
insulin glargine
glucagon-like peptide-1
insulin glulisine
at bedtime
impaired fasting glucose
Session 3
Acronym
IGT
ILPS
ITT
L
LIRA
LIS
LM 50/50
LM 75/25
LY
MDI
MET
NA
NDA
NPH
NPL
OADs
OD
PBO
PCP
Definition
impaired glucose tolerance
insulin lispro protamine suspension
intention-to-treat
lunch
liraglutide
insulin lispro
insulin lispro protamine (50%)/insulin
lispro (50%)
insulin lispro protamine (75%)/insulin
lispro (25%)
pegylated insulin lispro
multiple daily injections
metformin
not applicable
New Drug Application
neutral protamine Hagedorn
insulin lispro protamine suspension
oral antidiabetes agents
once daily
placebo
primary care physician
Acronym
PD
PH20
PIO
PK
PPG
PPG UL
QHS
QOL
R
RA
RHI
SAXA
SC
SITA
SMBG
STeP
SU
T1DM
T2DM
TDD
TZD
U
Definition
pharmacodynamics
recombinant human hyaluronidase
pioglitazone
pharmacokinetics
postprandial glucose
postprandial upper limit
every night at bedtime
quality of life
recombinant
receptor agonist
regular human insulin SAXA
saxagliptin
subcutaneous
sitagliptin
self-monitoring blood glucose
Structured Testing Program
sulfonylurea
type 1 diabetes
type 2 diabetes
total daily dose
thiazolidinedione
unit
Suggested Reading List
American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. Alexandria, VA: American Diabetes
Association, Inc; 2011:1-68.
Freeman JS. Insulin analog therapy: improving the match with physiologic insulin secretion. J Am Osteopath Assoc. 2009;109(1):2636.
Frid A, Hirsch L, Gaspar R, et al. New injection recommendations for patients with diabetes. Diabetes Metab. 2010;36(suppl 2):S3S18.
Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical
Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(suppl 2):1-53.
Hinnen D, Tomky D. In: Mensing C, et al, eds. The Art and Science of Diabetes Self-Management: A Desk Reference for Healthcare
Professionals. Chicago, IL: American Association of Diabetes Educators; 2011:531-576.
Hirsch E, Bergenstal RM, Parkin CG, et al. A real-world approach to insulin therapy in primary care practice. Clin Diabetes.
2005;23(2):78-86.
Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for
the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European
Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203.
Parkin CG, Davidson JA. Value of self-monitoring blood glucose pattern analysis in improving diabetes outcomes. J Diabetes Sci
Technol. 2009;3(3):500-508.
Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American
College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract.
2009;15(6):541-559.
Skyler JS. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. Alexandria, VA: American Diabetes Association,
Inc; 2004:207-223.
Session 3
Drug List
Generic
albiglutide
alogliptin
bromocriptine
colesevelam
dulaglutide
exenatide BID
exenatide QW
glimepiride
glipizide
glyburide
insulin detemir
insulin glargine
linagliptin
liraglutide
lixisenatide
Trade
Syncria; investigational; not FDA approved
Nesina; approved only outside the United States
Cycloset
Welchol
investigational; not FDA approved
Byetta
Bydureon; submitted for FDA approval
Amaryl
Glucotrol
DiaBeta, Glynase, Micronase
Levemir
Lantus
Tradjenta
Victoza
Lyxumia; submitted for approval by the European
Medicines Agency
Fortamet, Glucophage, Glumetza, Riomet
Actos
Avandia
Onglyza
Januvia
Galvus; approved only outside the United States
metformin
pioglitazone
rosiglitazone
saxagliptin
sitagliptin
vildagliptin
Insulin 101:
Basal Insulin Therapy
DebbieHinnen,ARNP,BCADM,CDE,FAAN,FAADE
DirectorofEducationServices
MidAmericaDiabetesAssociates
Wichita,Kansas
Type 2 Diabetes is Progressive
Basicsofinsulintherapy
Currentlyavailablebasalinsulins
Initiatingbasalinsulintherapy
Optimizinginsulininjectiontechniques
Glucose (mg/dL)
Part1:Basalinsulintherapy
350
300
250
200
150
100
50
Relative Amount
Insulin 101: Course Syllabus
250
Prediabetes
(Obesity, IFG, IGT)
Postmeal Glucose
Diabetes
diagnosis
Fasting glucose
Insulin resistance
-cell failure
200
150
100
Insulin level
50
0
15
10
0
Onset
diabetes
10
15
20
25
30
Years
Macrovascular changes
Clinical
features
Microvascular changes
KendallDM,etal.AmJMed.2009;122:S37S50;
KendallDM,etal.AmJManag Care.2001;7(10suppl):S327S343.
Daily Plasma Insulin Profiles:

Normal and Individual With Diabetes
Types of Insulin Therapies
120
BasalPlus
Time
60
40
Time
24h
1000
1400
1800
2200
0200
InsulinEffect
Time
0600
24h
BasalBolus
Premixed/Biphasic
20
0600
InsulinEffect
InsulinEffect
80
InsulinEffect
MeanInsulinLevel(U/mL)
Basal
Control
Diabetic
100
24h
24h
TimeofDay
Bars denote standard error of the mean.
=insulininjection
Polonsky KS, et al. N Engl J Med. 1988;318:1231-1239.
Del Prato S et al, Diabetes Technol Ther, 2012; 14: 175-182;

American Diabetes Association. Practical Insulin: A Handbook for
Prescribing Providers. 3rd ed. 2011:1-68.
Basal Insulin Added to OADs

Improves Glycemic Control
Basal Insulin Therapy in T2DM

CanbeinitiatedatanypointintheT2DMspectrum
24weeknoninferioritytrialof973insulinnaive
T2DMpatientsinadequatelycontrolledonOADs
A1C>7.5%despitetheuseof2or3OADs
A1C>9.0%despitepreviousT2DMpharmacologictherapy
InsulinglargineQD
A1C>9.0%plussymptomsinanewlydiagnosedT2DM
Insulindetemir BID
inA1C,frombaseline,%
Earlyinitiationisassociatedwithimprovedcellfunction
andreducedinsulinresistance
CombinationwithotheragentsincludingOADs,prandial
insulin,andincretinbasedtherapiescanimproveglycemic
control
Similarhypoglycemiarates
(<30%symptomatic)
Weightgainwashigherwith
insulinglargine (+0.77kg;
P <.001)
0
0.5
1
1.5
1.46
Finalinsulindoses(U/day):
Insulinglargine:43.5
Insulindetemir:76.5(P <.001)
1.54
P =.149
Rodbard H, et al. Endocr Pract. 2009;15:541-559;

McFarlane SI. Diabet Med. 2001;18:10-16.
Swinnen S, et al. Diabetes Care. 2010;33:1176-1178.
Currently Available Basal Insulins
NPHInsulin
InsulinGlargine
InsulinDetemir
Human;
intermediateacting
Analogue;
longacting
Analogue;
longacting
24 hours
N/A
N/A
Peak
410hours
Nopronounced
peak
Relatively flat
Effective
Duration
1016hours
Upto24hours
Upto24hours
InsulinType
Onset
Lucidi D, et al. Diabetes Care. 2011;34:1312-1314.

Niswender K, et al. Clin Diabetes. 2009;27:60-68.
Time-Action Profiles Illustrate Variability in

NPH Insulin vs Basal Insulin Analogues
LongactinginsulinanaloguesarepreferredoverNPHinsulin
becausethey:
GIRtoMaintainConstant
BGLevel(mg/kg/min)
Donotexhibitapronouncedpeakinactivity
Havemorepredictabletimeactionprofilesandlesswithin/between
patientvariability
Areassociatedlessnocturnalhypoglycemia
Detemir
NPH
7
6
5
4
3
2
1
0
Subject214
12
16
20
24
7
6
5
4
3
2
1
0
4
12
16
Glargine
Subject215
20
24
7
6
5
4
3
2
1
0
Subject231
12
16
20
24
ElapsedTime(hours)
N = 54 T1DM patients.
Euglycemic glucose clamp study, 4 trials/subject.
Heise T, et al. Diabetes. 2004;53:1614-1620.

Rodbard H, et al. Endocr Pract. 2009;15:541-559.
Current Authoritative Guidelines on

Initiating Basal Insulin Therapy
Insulin Self-Titration Is as Effective and

Safe as Physician-Adjusted Dosing
ADA/AACE/AADE
Initiateat10U/day
Safetyandefficacyhavebeendemonstratedin3trials
AT.LANTUS (glargine)
or
Useweightbasedapproach:0.10.2U/kg/day
PREDICTIVE303(detemir)
MonitorFPG todeterminedosageadjustments
INITIATEPlus(biphasicaspart 70/30)
Anticipatedbenefits
Costsavings
AADE
ADA
TitratetoFPG 70130mg/dL
FPG<70:reducedoseby
4U or10%TDD
FPG>130:increasedose
by24U every3days
Fewerofficevisits
Equivalentorfewerhypoglycemicepisodes
Increasedoseby2U every3days
untilFPGis70to110mg/dL
or
Increaseby1U/dayuntilFPG<
100mg/dL
Greaterpatientsatisfaction(increasedautonomy)
Confirmingbenefits
Patientcenteredoutcomesstudyisinprogress(Di@log)
Nathan DM, et al. Diabetes Care. 2009;32:193-203;

Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53;
Hinnen D, et al. Combating clinical inertia through pattern management and intensifying therapy. In:
Mensing C, et al, eds. The Art and Science of Diabetes Self-Management Desk Reference. 2011:531-576.
Garber AJ. Diabetes Obes Metab. 2009;11(suppl 5):10-13;

Oyer DS, et al. Am J Med. 2009;122:1043-1049;
Roek MG, et al. BMC Fam Pract. 2009;10:40.
AACE and ADA Recommended

Glycemic Targets
Ideal Glycemic Control
A1C
AACE
ADA
6.5%
<7.0%
BloodGlucose(mg/dL)
300
SMBGReadingsa
FastingPlasmaGlucose
70110 mg/dL
70130mg/dL
Preprandial
N/A
Postprandial
70140mg/dLb
<180mg/dLc
N/A
100140mg/dL
Bedtime
b
c
More than half of the readings should fall within this range.
2-hour PPG reading.
1 to 2-hour PPG reading.
200
FPGUL
100
FPGLL
50
mg/dL
Handelsman Y, et al. Endocr Pract. 2011; 17(suppl 2): 1-53;

PPGUL
150
Bothorganizationsrecognizethatmoreorlessstringentgoalsmaybe
appropriateforsomeindividuals
a
250
Before
breakfast
2hafter
breakfast
Before
lunch
2hafter
lunch
Before
dinner
2hafter
dinner
Before
bed
83
111
79
114
82
118
87
ADA standards shown.
American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68.
Accu-Chek Connect: Quick Reference Guide:
http://behavioraldiabetesinstitute.org/studies/downloads/ACCU-CHEK_Quick_Reference_Guide.pdf.
Basal Dose Too High

300
250
250
BloodGlucose(mg/dL)
BloodGlucose(mg/dL)
Basal Dose Too Low

300
200
PPGUL
150
FPGUL
100
FPGLL
50
0
mg/dL
Before
breakfast
2hafter
breakfast
Before
lunch
2hafter
lunch
Before
dinner
2hafter
dinner
Before
bed
173
204
168
199
174
206
183
200
FPGUL
100
FPGLL
50
0
mg/dL
PPGUL
150
Before
breakfast
2hafter
breakfast
Before
lunch
2hafter
lunch
Before
dinner
2hafter
dinner
Before
bed
52
90
48
90
55
90
65
BloodGlucose(mg/dL)
Basal Dose Too High
300
250
200
150
100
PPGUL
FPGUL
FPGLL
50
0
3:00AM
mg/dL
45
Before 2hafter
breakfast breakfast
213
144
Before
lunch
127
2hafter
lunch
123
Before
dinner
75
2hafter
dinner
110
Before
bed
74
Encouraging Proper Insulin Injection

Technique: Step by Step Instructions
aMay
Pen
Syringe
1. Prime pentocheckforflow(adropof
insulinshouldbevisibleatthetipof
theneedle)
2. Ensuredosingdialissetto0anddial
indoseofinsulintobedelivered
3. InsertneedlequicklyintotheSCtissue
4. Fullydepressthumbbutton
5. Countslowlyto10before
withdrawingtheneedlea
6. Followinginjection,removeneedle
anddiscardproperly
7. Neverleaveneedlesattachedtothe
pen
1. Drawupequivalent amountofairinto
syringeandinjectintovialpriorto
drawingupinsulin
2. Tapbarrelandpushplungerto
removeairbubbles
3. InsertneedlequicklyintotheSCtissue
4. Depressplungerfully
5. Followinginjection,removeneedle
anddiscardproperly
6. Neverusesyringeneedlesmorethan
once
need longer time when using high doses of insulin.
Insulin Injection Sites
Frid A , et al. Diabetes Metab. 2010; 36 (suppl1):S3-S18.

Becton Dickinson Diabetes. Step by step injection guide. 2012;
www.bd.com/us/diabetes.
King et al. Nurs Stand. 2003;17:45-52.
UpperArm
Thigh
Abdomen
Buttocks
Becton Dickinson Diabetes. Step by step injection guide. 2012; www.bd.com/us/diabetes.
Tips for Minimizing Pain

From Insulin Injections
Lipohypertrophy Can Result from

Poor or Improper Site Rotation
Ensureinjectionintosubcutaneoustissue,notintramuscularly
Penetrateskinquickly,butinjectslowly
Allownewlyopenedinsulintocometoroomtemperature
Ifusingalcohol,allowtodrybeforeinjectinginsulin
Heat/coldisnotrecommendedasitcanalterabsorption
Resultsfromthegrowtheffectsofinsulinandinductionoflocalgrowth
factorsduetorepeatedinjection
Useshorterlengthneedles(4,5,or6mm)
Oftenlesspainfultoinjectintoareasoflipohypertrophy BUT
Iflongerneedles(8mm)arebeingused,skinpinchtechnique
shouldbeemployed
absorptionofinsulinisalteredandcanleadtohypo orhyperglycemia
Itisrecommendedthatpatientsdonottoinjectintothesesites
Useanewneedlewitheveryinjection
Prevention:
Repeatedusebluntsneedles
Newneedlesarecoatedwithsiliconelubrication
Rotatesites avoidrepeatedinjectionintothesamearea
Useanewneedlewitheveryinjection
King L, et al. Nurs Stand. 2003;17:45-52;
Wallymahmed ME, et al. Postgrad Med. 2004;80:732-733.
King L, et al. Nurs Stand. 2003;17:45-52;

Frid A, et al. Diabetes Metab. 2010; 36 (suppl1):S3-18.
Needle Size Consideration
Conveniences of Insulin Pen Therapy

Easytouse/store/carry
Discreet
Smallneedlesize
5mmx31G
4mmx32G
3/16
5/32
8mmx31G
12.7mmx29G
5/16
1/2
Usetheshortestneedlepossiblewheninitiatinginsulintherapy
Thereisnomedicalreasontouseaneedlelongerthan8mm
Becton Dickinson Diabetes. Step by step injection guide. 2012; www.bd.com/us/diabetes.
Becton Dickinson Diabetes. BD pen needles fit these pens.
http://www.bd.com/us/diabetes/hcp/main.aspx?cat=3067&id=3156
Frid A, et al. Diabetes Metab. 2010;36(suppl 1):S3-18.
Molife C, et al. Diabetes Technol Ther. 2009;11:529-538.
A Prescribers Checklist For Insulin Therapy
Basal Insulin Therapy: Summary
Insulinprescriptionshouldinclude:
BasalinsulincanbeinitiatedthroughouttheT2DMspectrum
Typeofinsulin
Insulininjectionissimpleandstraightforward
Numberofunits,vials/pens
Frequencyofdosing
Alwaysinjectintosubcutaneoustissue,notmuscle
Besuretorotateinjectionsites
Diagnosiscode
Supplies
Analoguebasalinsulins areoftenpreferredoverhuman
insulins (NPH/regular)becauseoftheirmorephysiologic
profiles
Penneedlesorsyringe/needles
SMBG supplies(lancets,teststrips,
controlsolution,log)
Basalinsulinisgenerallyinitiatedat10U/dayor0.10.2
U/kg/dayandtitratedtoachieveFPG glucosetargets
Insulintitrationinstructions
Needledisposal patientresources
Hypoglycemiatreatmentprotocol
Properinjectiontechniqueshouldbereinforcedperiodically
andinjectionsitesshouldbeexaminedregularly
Glucagonkit(ifpatientisatsignificantriskforhypoglycemia)
Diabeteseducationreferral
Joslin Diabetes Center. Writing Prescriptions for Diabetes Medications and Devices.
http://www.bd.com/us/diabetes/hcp/main.aspx?cat=3065&id=63268. Accessed January 18, 2012.
INSULIN 101:
BASAL-PRANDIAL
INSULIN THERAPY
Part2:Basalprandialinsulintherapy
Indicationsforbasalprandialinsulintherapy
Currentlyavailableprandialinsulins
Initiatingbasalprandialinsulintherapy
JavierMorales,MD
InsulintitrationusingSMBG data
St.FrancisHospital
AdvancedInternalMedicineGroup
NewHydePark,NewYork
When Is Prandial Insulin

Therapy Indicated in T2DM?
Relative Contribution of Postprandial

Hyperglycemia to Overall Glycemic Control
Theindividualisnotmeetingglycemictargetsonbasal
insulin
Postprandialhyperglycemia
ContributiontoDiurnal
Hyperglycemia(%)
100
ElevatedA1CdespitenormalFPG (intheabsenceof
availablePPGreadings)withbasalinsulin
FPG withbasalinsuliniswithintargetedrange,butPPGis
persistentlyabovegoal
Furtherincreasesinbasalinsulinresultinhypoglycemia
Fastinghyperglycemia
80
a,b
60
40
a
a
20
0
<7.3%
Somepatientsmayonlyrequireprandialinsulinwith
theirlargestmeal
7.3%to
8.4%
8.5%to
9.2%
9.3%to
10.2%
>10.2%
A1CQuintile
Therelativecontributionofpostprandialhyperglycemiatooverallhyperglycemia
isgreateratA1Clevelsnear7%.
American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed.
2011:1-68; Skyler JS. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders.
Alexandria, VA: American Diabetes Association, Inc.; 2004:207-223; Holman RR, et al. N Engl J Med.
2007;357(17):1716-1730; Davidson MB, et al. Endocr Pract. 2011;17(3):395-403.
a
b
Significantly different between fasting and postprandial.

Significantly different from all other quintiles.
Monnier L, et al. Diabetes Care. 2003;26:881-885.
Currently Available Short-Acting

Prandial Insulins

Regular
Insulin
Insulin
Lispro
Insulin
Aspart
Insulin
Glulisine
Human;
shortacting
Analogue;
rapidacting
Analogue;
rapidacting
Analogue;
rapidacting
Insulintype
Onset, h
0.51
<0.30.5
<0.25
<0.25
Peak, h
23
0.52.5
0.51.0
11.5
Effective duration,h
36
36.5
35
35
30to45
15to
immediately
after
5to10
15 to+20
Injection:
mealtiming, m
American Diabetes Association. Practical Insulin: A Handbook for Prescribing

Providers. 3rd ed. 2011:1-68.
Introducing Basal-Prandial Insulin

Therapy in Patients With T2DM

BasalBolusInsulin
Premixed/BiphasicInsulin
Insulininjection
InsulinEffect
InsulinEffect
Insulininjection
24h
Time
24h
Time
Prandialinsulincanbegivenwith1,2,orall3mealsoftheday
Hirsch IB, et al. Clin Diabetes. 2005;23(2):78-86; Skyler JS. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus
and Related Disorders. Alexandria, VA: American Diabetes Association, Inc.; 2004:207-223; American
Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68.
Initiating Basal-Prandial Insulin Therapy:

Dosing According to Patient Needs
Basal-Prandial Dose Budget:

Equal Carbohydrate Intake Among Meals
Assumespatientisalreadyusingbasalinsulin
TotalDailyDose(TDD)Insulina =
Basal(50%)+Prandial(50%;dividedamongmeals)
Method1:weightbased
Totaldailydose(TDD)0.51.0U/kg/day
Basaldoseis50%ofTDD
Basal
10U
Dividetheremaining50%across3meals
Assumesconsistentcarbohydratecontentwitheachmeal
30U
Breakfast (100gCHO)
10U
Lunch (100gCHO)
10U
Method2:insulin:carbohydrateratiobased
Dinner (100gCHO)
Initiallyestimateprandialdosesat1.01.5U/10g
carbohydrate
a
Skyler JS. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. 2004:207-223;
Hinnen D, Tomky D. In: Mensing C, et al, eds. The Art and Science of Diabetes Self-Management: A
Desk Reference for Healthcare Professionals. 2011:531-576.
220 lb (100 kg) patient, 0.6 U/kg, 60 U total daily insulin;

assumes 1 unit of insulin covers 10 g carbohydrate and
isocaloric meals.
Basal-Prandial Dose Budget:

Varying Mealtime Carbohydrate Intake
Timing of Prandial Insulin Injections Differs

Between Human and Analogue Insulins In T2DM
RapidActingInsulinGlulisine Effect
RelativetoInjectionMealIntervala
TotalDailyDose(TDD)Insulina =
Basal(50%)+Prandial(50%;dividedamongmeals)
Premeal
5U
Basal
288
252
14
216
180
144
15U
108
Lunch (100gCHO)
Dinner (150gCHO)
72
36
Fasting
Postmeal
16
10
Breakfast (50gCHO)
30U
18
12
10U

220 lb (100 kg) patient, 0.6 U/kg, 60 U total daily insulin.

Postbreakfast Prelunch
Postlunch
Predinner
Background of insulin glargine basal insulin.
Postdinner
Bedtime
Regularhumaninsulin
needstobeinjected3045
minutesbefore meals
Lessconvenientfor
patient
Rapidactinginsulin
analogues(aspart,glulisine,
lispro)canbeinjected015
minutesbefore meals
Insulinlispro andinsulin
glulisine canbesafely
injectedimmediatelyaftera
meal
Ratner R, et al. Diabetes Obes Metab. 2011; 13: 1142-1148; Luijf YM, et al.
Diabetes Care. 2010;33(10):2152-2155; Cobry E, et al. Diabetes Technol Ther.
2010;12(3):173-177; Rassam AG, et al. Diabetes Care. 1999;22(1):133-136;
Providers. 3rd ed. 2011:1-68.
Self-Monitored Blood Glucose Can Improve

Glycemic Control In T2DM Patients

SMBG enablesappropriatemanagementofglycemia
Detecting/avoidinghyperglycemia
Detecting/avoidinghypoglycemia
SMBG frequencyandschedulecanbevariedtomeet
individualneeds
ClinicianreviewofSMBG logsisessential
Helpsassessefficacyandsafetyofantidiabetic regimen
Facilitatesproviderpatientpartnership
Comparing Two Methods of Stepwise

Prandial Insulin Intensification in T2DM
Blood Glucose Monitor Features

Display
Parameter/
Characteristic
Largenumericaldisplay
Backlitdisplayorglowinthe
SimpleSTEP
Basalinsulin titration
darkdisplay
Prandialdoseaddition
Graphingcapability
Size
Compact,medium,orlarge
ExtraSTEP
Basedonaverageof3prebreakfastPGmeasurements
Prandial insulintitration
Every12wks,ifneeded
Tolargestperceived
meal
Basedonpremeal PG
Basedonpostmeal PG
Largememorycapacity
SMBG
AudioreportingofSMBG
results
Participantadjustments?
Computerupload
PG,plasmaglucose;SMBG, selfmonitoringofbloodglucose.
3X4point profiles
Beforeeachmeal
Bedtime
Every12wks,ifneeded
Tomealwithhighest
postmeal PGincrease
3X 6pointprofiles
Beforeeachmeal
2haftereachmeal
Yes
Yes
Meneghini L, et al. Endocr Pract. 2011;17:727-736.
Outcomes for Two Methods of Stepwise

Prandial Insulin Intensification in T2DM
SimpleSTEP (n=150)
ExtraSTEP (n=146)
Hypoglycemia(BG<56mg/dL)
Efficacy
15
BLA1C:8.7%8.9%
A1C(%)
0.5
1.0
1.1
1.5
1.3
2.0
2.5
Wt: 2.7 kg
HypoEventRate(EPY)
0.5
0.0
SMBG Alone May Not Lead

to Improved Glycemic Control
10
ClinicianNeeds
Appropriateglycemic
targets(fasting,
postprandial)
MustreviewSMBG logs
Whentotest
5.98 5.87
Whattheresultsmean
1.39 1.01
2.0 kg
PatientEducationNeeds
Minor
Nocturnal
Whentotakeaction
0.04 0.01
Musttakeactionbasedon
SMBG data
Lackofclinician
review/actionmayrender
SMBG ineffective
Major
3.0
Final insulin doses (U/kg/d): SimpleSTEP, 1.25 0.59; ExtraSTEP, 1.37 0.70.
Hypoglycemia definitions: minor, self-treated; major, assistance required.
Dailey G, et al. Mayo Clin Proc. 2007;82:229-236.

Clar C, et al. Health Technol Assess. 2010;14(12):1-140.
Parkin CG, Davidson JA. J Diabetes Sci Technol. 2009;3(3):500-508.
Farmer AJ, et al. Health Technol Assess. 2009;13(15):iii-iv, ix-xi, 1-50.
Meneghini L, et al. Endocr Pract. 2011;17:727-736.
Pattern Recognition and Principles

of Insulin Dose Adjustment
SMBGPattern
Action
Allreadingsabovetargets
Increasebasaldose
PPGreadingsabovetargets
Add/increaseprandialdose
Hypoglycemia
Decreaseinsulindose
Frequent,unpredictableglycemic
fluctuations
Maybeapumpcandidate
Basal-Prandial Insulin Therapy: Summary

Prandialinsulincanbeinitiatedwithbasalinsulinorwhen
FPGiscontrolledwithbasalinsulinandA1CorPPGlevels
remainhigh
Prandialinsulinisavailableinhumanorsyntheticanalogue
forms
Analogueprandialinsulins areoftenpreferredbecauseoftheirmore
physiologicprofilescomparedwithhumanprandialinsulin
Ifglucoselevelsareoutoftargetat: Adjustthisinsulincomponent:
Postbreakfast/prelunch
Prebreakfast prandial
Postlunch/predinner
Prelunch prandialand/ormorningbasalinsulin
Midafternoon
Morningbasalinsulin
Postdinner/bedtime
Predinner prandial
Earlymorning
Eveningbasalinsulin
Prandialinsulinisinitiatedas50%oftheTDDofinsulinand
dividedamongmealsorwithaninsulin:carbohydrateratio
SMBGplaysanimportantroleindeterminingtheefficacy
andsafetyofapatientsantidiabeticregimen
Hinnen D, Tomky D. In: Mensing C, et al, eds. The Art and Science of Diabetes Self-Management Desk
Reference. 2011;20:531-576.
American Diabetes Association. Practical Insulin. 3rd ed. 2011:1-68.
Elective 1: Overcoming Patient

Barriers to Insulin Therapy
and Pattern Management
INSULIN 101: ELECTIVES
DebbieHinnen,ARNP,BCADM,CDE,FAAN,FAADE
DirectorofEducationServices
MidAmericaDiabetesAssociates
Wichita,Kansas
Insulin Initiation Improves

Quality of Life in T2DM
Barriers to Initiating Insulin Therapy Among

Privately Insured PatientsNew Jersey, 2010
Initiated(n=100)
Educational
Barriers
Didnotinitiate(n=69)
6monthsafterinsulininitiation
Beforeinsulininitiation
a
QOL
Risks/benefits not well

explained
Physical complaints
Inadequate health literacy

Side effects of injection
Social worries
Hypoglycemia
Worries about future
Doubt ability to adjust dose
a
b
Fear of hypoglycemia
Negative social impact
Dietary restrictions
Negative job impact

a
Daily struggles
Too painful
10
20
30
40
50
60
40
60
80
100
QOL Score (Higher Scores Indicate Better QOL)
Patients With T2DMa With Moderate to Extreme Concerns (%)

Statistically significant factors influencing insulin use from a survey of
169 privately insured, insulin-naive patients with poorly controlled
T2DM; P < .05, not adherent vs adherent for all factors shown.
a Percentages of omitted responses not shown.
20
Results from 42 insulin-naive older (mean age 68.4 y) German

adults with T2DM who initiated insulin with a structured diabetes
education program.
a P < .05; b P < .01.
Karter AJ, et al. Diabetes Care. 2010;33(4):733-735.
Facilitating Patient Acceptance of and

Adherence to Insulin Therapy
Braun A, et al. Patient Educ Couns. 2008;73(1):50-59.
But I Really Dont Have Enough Time to

Explain All of This To My Patients
Educatepatientsfromthebeginningofthediseaseprocess
about
Strategiestohelpyoucommunicatethiscriticalinformation
withlimitedtime:
Utilizethediabetesteamtodeliver/reinforceyourmessages
TheprogressivenatureofT2DM
Nursingassistantscansafelyteachinsulinuseandtitration
Diabeteseducatorsandcomprehensiveeducationcanhelpwith
Thecomplicationsassociatedwithpoorglycemiccontrol
Theshort andlongtermeffectsofimprovedglycemiccontrol
initiationandtitrationofinsulin,hypoglycemiaawareness,and
glucagonuse
Avoidthreateningpatientswithinsulintherapy
Considergroupvisits
Useasimpleinsulinregimentostart
Often,820patientscanbeseenatgroupvisits
Reimbursedbythirdpartypayors
Allowpatientstoparticipateintheirinsulindosetitration
Developorobtaincomprehensivehandoutsforpatientsand
reinforceeducationinsmallamountsateachvisit
Patientswhoreceiveeducationabouttheirglycemicgoals
aremorelikelytoacceptinsulintherapy
Providers. 3rd ed. 2011:1-68; Cobble M, et al. J Fam Pract. 2009; 58(suppl 11): S7-14.
Unger J, et al. Diabetes Metab Obes. 2011;4:253-261.
Structured SMBG Reduces A1C in T2DM:

STeP Trial Dose Adjustment
PATTERN MANAGEMENT
7pointBGprofilescollected
over3days
AACE/ACEtitrationandgoals
recommended
DatausedbypatientAND
provider
Basaldoseadjustment
Initiateat10units/dayat
bedtime
or12unitsevery23
daysuntilFBG goalsmet
Patternmanagementpriorities:
1. Hypoglycemia
2. Fasting/preprandial
hyperglycemia
3. Postprandialhyperglycemia
Abnormalityoccurringon2of3
daysatthesametimeofday
mustbeaddressed
Prandialdoseadjustment
Initiateat5units/meal
or23unitsevery23
daysuntilgoalsmet,
consideringboth2hPBG
andpreprandial BG
Polonsky W, et al. BMC Family Practice. 2010;11:37.

Rodbard HW, et al. Endocr Pract. 2009;15(6):541-559.
Priority 1 Correct Hypoglycemia
Priority 2 Fix the Fastings ( > 110 mg/dL)
Priority3 PostprandialHyperglycemia
7/24
7/25
7/26
PATTERN MANAGEMENT
CASES
10
Fix the Fasting
Hypoglycemia
Date
Fasting
5/12/2010
141
5/14/2010
5/16/2010
51
98
6/6/2010
6/8/2010
81
43
156
146
102
Beforedinner
Afterdinner
79
86
Bedtime
94
133
142
92
115
89
162
93
6/1/2010
6/3/2010
151
101
77
5/28/2010
5/30/2010
Afterlunch
82
109
72
88
5/23/2010
5/26/2010
Beforelunch
68
96
5/18/2010
5/21/2010
Afterbreakfast
65
76
89
163
123
116
183
87
100
162
68
67
82
122
109
84
73
87
212
74
108
72
75
Postprandial Hyperglycemia
Elective 2:
Premixed/Biphasic Insulin Therapy
JavierMorales,MD
St.FrancisHospital
AdvancedInternalMedicineGroup
NewHydePark,NewYork
Insulin Added to Any Combination of OADs

Improves Glycemic Control in Insulin-Nave
Patients With T2DM (DURABLE Study)
Premixed/Biphasic Insulin Regimens

Combinationof2differenttypesofinsulin,usuallyupto2
injections/day
11
Lispro 75/25 (n = 1045)
Glargine (n = 1046)
10
A1C (%)
ForpatientswithT1DMorT2DM
Requiresconsistentmealtimesandcarbohydratecounting
MayormaynotcausemoreweightgainthanBBT
MayresultinpoorerglycemiccontrolthanBBT
ForpatientswithT2DMtransitioningfrombasalonlyregimens
9.1
9.0
7.2
7.3
8
7
6
Premixed/biphasicinsulindoesnotguarantee reducedA1C
Mayincreaseriskofhypoglycemia
Baseline
Maycausemoreweightgain
Week 24
OADskeptatbaselinedose(s)throughoutthestudy
A1Cgoalsweremaintainedamedianof16.8monthswith
lispro 75/25and14.4monthswithglargine (P =.04)
Roach P, et al. Clin Ther. 1999;21:523-534.

Garber AJ, et al. Diabetes Obes Metab. 2006;8:58-66.
Tanaka M, Ishii H. J Diabetes Complications. 2011;25:83-89.
Sharplin P, et al. Cardiovasc Diabetol. 2009;8:9.
Miser WF, et al. Clin Ther. 2010;32:896-908.
Holman RR, et al. N Engl J Med. 2009;361:1736-1747.
11
P < .0001 vs baseline.
Buse JB, et al. Diabetes Care. 2009;32:1007-1013.

Buse JB, et al. Diabetes Care. 2011;34:249-255.
Comparison of Biphasic and Basal

Bolus Therapy: PREFER Study
Randomized Population
A1C = 9.7 1.5% 9.8 1.4%
n=
117
116
Baseline
A1C > 8.5%
Baseline
A1C 8.5%
89
28
99
Detemir-aspart
17
Patients Meeting
Target (%)
0
0.4
Change in A1C (%)
0.8
1.2
1.6
2.0
2.4
70
60
50
40
30
20
10
0
Biphasic aspart 70/30
60
50
A1C 7%
2.8
4.4
4.8
1.21
1.42
1.69
P =.0129
Minorhypoglycemiaoccurredin31%ofpatientsinthedetemiraspart
groupand28%inthebiphasicaspart group
Weightgainwassimilarinbothgroups(2.4kgvs 2.1kg)
4.0
P < .01; b P < .05, biphasic vs glargine.

All oral drugs except MET PIO discontinued at baseline;
patients were insulin-naive at baseline.
0.75
1
1.5
P =.106
Glargine
3.6
Previously
TreatedWith
BasalInsulin
0.5
Biphasicaspart 70/30
3.2
InsulinNaive
0
MeanA1CReduction
Frombaseline(%)
Premixed Insulin Added to MET PIO Improves

Glycemic Control at 28 Weeks INITIATE Study

Insulin was titrated to fasting, predinner, and postprandial plasma
glucose targets.
Raskin P, et al. Diabetes Care. 2005;28:260-265.
Initiating and Adjusting Premixed/Biphasic

Insulin in T2DM AACE Recommendations,
Expert Consensus, and INITIATE Study
Liebl A, et al. Diabetes Obes Metab. 2009;11:45-52.
Available Premixed/Biphasic Insulins
AACE
Product
Administerat2largestmealstwicedaily
ORadministeratlargestmealoncedaily
Adjustprebreakfast dosebasedonpredinner glucoselevel
Adjustpredinner dosebasedonprebreakfast (fasting)glucoselevel
Onset(h)
Peak(h)
EffectiveDuration (h)
HumanBiphasic Insulin
Hirschetal(2005)
70%NPH/30%regular
Transitioningfromoncedailybasalinsulintotwicedailypremixed/biphasic:
DivideTDDby2tocomputethedoseofeachinjection(beforebreakfastanddinner)
Ifmealsarenotofequalsize,largermealrequiresalargerproportionofinsulin
AdjustdosesaccordingtoSMBGanddiethistory
ReduceTDDby20%ifthereisrecurrenthypoglycemia
0.51
Dual
1016
Analogue BiphasicInsulin
INITIATE
Beginat10units/dayifFPG<180mg/dL
ORbeginat12units/dayifFPG180mg/dL
BeginwithTDDequallydividedbetweenbreakfastanddinner
Administerdoses015minutesbeforemeals
Adjustaccordingtotitrationscheduleshowninbackofprogrambook
Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.
Hirsch IB, et al. Clin Diabetes. 2005;23(2):78-86.
Raskin P, et al. Diabetes Care. 2005;28(2):260-265.
75%NPL/25% lispro
<0.25
Dual
1016
50%NPL/50%lispro
<0.25
Dual
1016
70%aspart protamine/
30% aspart
<0.25
Dual
1518

Points for Consideration When

Using Premixed Insulin
Elective 3:
Insulin Therapy in T1DM
Preparation
Mustberolledand/ortipped(NOTSHAKEN)for20cycles
EtieMoghissi,MD,FACP,FACE
Siteselection
ClinicalAssociateProfessor
UniversityofCalifornia,LosAngeles
LosAngeles,California
Considerationmustbegiventoinjectionsitewhenusingmixes
containingNPH
AMinjectionisbestgivenintheabdomenbecauseofmorerapid
absorption(coverageforbreakfast)
PMinjectionshouldbegiveninthebuttocksorthighbecauseof
slowerabsorption(preventionofnocturnalhypoglycemia)
Frid A, et al. Diabetes Metab. 2010;36(suppl 2):S3-18.
12
Maintaining Physiologic Insulin Delivery :

Basal Bolus
Insulin Therapy Considerations in T1DM

T1DMischaracterizedbyabsoluteinsulindeficiency insulin
administrationisrequiredforpatientsurvival
Correctionor
Supplemental
insulin
Insulin
GlycemicvariabilitytendstobegreaterinpatientswithT1DM
thaninT2DMpatientstreatedwithinsulin
TheoccurrenceofhypoglycemiaisgreaterinT1DMpatientsthan
T2DMpatients
NormalSecretory
PatternofInsulin
T1DMdemandsbasal+multipleprandialinsulininjections/day
Basalinsulin
ExpertsrecommendSMBG measurements3timesdailyin
individualswithT1DM
Breakfast
Lunch
Dinner
Bedtime
American Diabetes Association. Diabetes Care. 35(suppl 1); 2012:S1-53

Kato T, et al. Diabetes Res Clin Pract. 2010 Dec;90(3):e64-66.
Greven WL, et al. Diabetes Technol Ther. 2010 Sep;12(9):695-699.
Marre M, et al. Diabetes Metab. 2009 Dec;35(6):469-75.
Hirsch IB. N Engl J Med. 2005;352:174183.
Calculating Insulin Dose for

Adult Patient With T1DM
Insulin Options for T1DM
Obtainpatientweightinkg
Calculatetotaldailydose(TDD)
as0.20.4U/kg/daya
Basal
Analogues
Prandial (Nutritional)
Analogues
Insulinglargine
Insulindetemir
Insulin aspart
Insulinglulisine
Insulinlispro
Human
Human
NPH
Regular
Choosethedosingschedule
Give50%ofTDDasbasalinsulin
Give50%ofTDDasbolus(premeal )insulin
Adjustaccordingtoresultsof
BGmonitoring
a

Prescribing Providers. 3rd ed. 2011:1-68
Silverstein J, et al. Diabetes care. 2005; 28: 186-212.
Hirsch I. Am Fam Physician. 1999;60:2355-2356.
Dose may vary depending on whether patient is a

child or adult and on patients clinical situation.

Prescribing Providers. 3rd ed. 2011:1-68
Efficacy and Safety in T1DM:

Basal Insulin Analogues vs NPH
EfficacyorSafety
Parameter
WeightedMean
Difference(95%CI)
Interpretation
Treatment
A1C
0.08 (0.12to0.04)a
Favorsanalogues
Fastingplasmaglucose
0.63(0.86to0.40)a
Favorsanalogues
Fastingbloodglucose
0.86(1.00to0.72)a
Favorsanalogues
Weightgain
0.67(0.87to0.45)a
Favorsanalogues
Hypoglycemia
OddsRatio(95%CI)
Interpretation
Any
Efficacy and Safety in T1DM:

Rapid Insulin Analogues vs RHI
0.93(0.8 to1.08)
Equivalent
Severe
0.73(0.61 to0.87)a
Favorsanalogues
Nocturnal
0.70(0.63 to0.79)a
Favorsanalogues
a P < .05.
Results based on 23 studies in adults with T1DM, 3872 on basal
insulin analogues, 2915 on NPH insulin.
Trials
(N)
AdultsWith
T1D(N)
ChangeinA1C
%(95%CI)
Interpretation
Aspart
3035
0.13(0.20to0.07)a
Favorsanalogue
Lispro
22
6021
0.09(0.16to0.02)a
Favorsanalogue
SevereHypoglycemia
RelativeRiskRatio
%(95%CI)
Interpretation
Treatment
Trials AdultsWith
(N)
T1D(N)
Aspart
1814
0.83(0.65to1.04)
Equivalent
Lispro
10
4502
0.80(0.67to0.96)a
Favorsanalogue
a P < .05.
Glulisine was not licensed in Canada during
the period covered by the analysis.
Vardi M, et al. Cochrane Database Syst Rev. 2008;(3):CD006297.
13
Singh SR, et al. CMAJ. 2009;180(4):385-397.
Analogues Are Associated With Lower

Hypoglycemia Rates Than Human Insulins for
the Same Degree of Control in T1DM
Upto40%ofT1DMpatientsintheUSutilizecontinuoussubcutaneous
insulininfusion(CSII)1,2
CSII usesrapidactinginsulintodeliverbothbasalandbolustherapy1
3500
16
Lispro
14
NPHinsulin
RHI
Insulinglargine
RateofHypoglycemia
(Events/100PatientYears)
FrequencyofMildHypoglycemia
(Episodes/PatientMonth)
Insulin Pump Therapy
12
10
8
6
4
AdvantagesofpumptherapyinT1DMinclude:1,2,3,4,5
3000
2500
2000
CSII canbepairedwithcontinuousglucosemonitoring(CGM):4,5
Toprovidemorefrequentglucosereadings
Toreducetheincidenceofhypoglycemia
1500
2
0
CGM doesnotreplaceSMBG3
1000
5.5
6.0
6.5
7.0
7.5
Improvedglycemiccontrol
Areductioninhypoglycemia
Improvedqualityoflife
Reducedfrequencyofdiabeticketoacidosis
6.0
8.0
7.0
A1C(%)
8.0
9.0
10.0
A1C(%)
1. Handelsman Y, et al. Endocr. Pract. 2011;17(suppl 2):1-53; 2. Pickup J, et al. Int J Clin Pract. 2011;65:16-19
3. Hinnen D, Tomky D. In: Mensing C, et al, eds. The Art and Science of Diabetes Self-Management: A Desk
Reference for Healthcare Professionals. 2011:531-576; 4. Blevins T, et al. Endocr Pract. 2010;16:730-745;
5. Klonoff D et al. J Clin Endocrinol Metab. 2011;96:2968-2979
Lalli C, et al. Diabetes Care. 1999;22(3):468-477.

Mullins P, et al. Clin Ther. 2007;29(8):1607-1619.
Prerequisites for CSII
Insulin in T1DM: Summary
Motivatedtoimproveglycemiccontrol
Intellectuallyandphysicallyabletomanageinsulin
pumptherapy
SimilarlytoT2DM,insulinanaloguesarepreferredinthe
treatmentofT1DMduetotheirmorephysiologicprofile
ExperiencewithfrequentSMBG
Thetimeactionprofilesofinsulins maydifferinindividuals
withT1DMcomparedtoT2DM
Fluentincarbohydratecountingandinsulincorrection
InsulintherapyconsiderationsdifferforpatientswithT1DM
andpatientswithT2DM
Insulinpumptherapycancontributetoimprovedglycemic
controlandlesshypoglycemiainT1DM
Willingnesstocommunicatewiththediabetesteam
Insulinpumptherapyrequiresamotivated,compliant
patientwillingtocommunicatewiththediabetesteam
Handelsman Y, et al. Endocr. Pract. 2011;17(suppl 2):1-53.
Insulin 201: New Insulin Combinations

and Investigational Insulins*
NewInsulinCombinations
Insulin+DPP4inhibitors
Insulin+GLP1receptoragonists
EtieMoghissi,MD,FACP,FACE
InvestigationalInsulins
ClinicalAssociateProfessor
UniversityofCalifornia,LosAngeles
LosAngeles,California
Limitationsofcurrentinsulins andfutureneeds
Investigationalbasalinsulins
Investigationalprandialinsulins
* Some of the agents and/or combinations to be discussed are not US FDA-approved at this time.
14
DPP-4 inhibitors as Add-On Therapy to Insulin:

Glycemic Efficacy
US FDA-Approval Status for DPP-4

Inhibitor Combinations
Approvedforuseincombinationwithinsulin1
Saxagliptin
Approvedforuseincombinationwithinsulin1
Notapprovedforuseincombinationwithinsulin1
Linagliptin
Clinical trialsinprogress2
0.0
0.2
0.4
0.6
0.6
0.8
P <.001
MeanA1C from BL (%)
Sitagliptin
INSb +SAXA(n=304)
INSb +PBO(n=151)
24weektrial
0.0
Approval StatusforCombinationwithInsulin
MeanA1Cfrom BL (%)
Agent
INSa +SITA(n=322)
INSa +PBO(n=319)
1.0
a
1. US FDA. Drugs@FDA Web site. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/.

2. US National Institutes of Health. http://www.clinicaltrials.gov/ct2/home.

Hypoglycemia
10
5
0
52weektrial
INSb +SAXA(n=304)
INSb +PBO(n=151)
24weektrial
1.0
15
1.0
0.8
0.6
0.4
0.2
52weektrial
0.8
0.6
0.5
0.4
0.2
0.1
0.1
0.0
0.0
Long- or intermediate-acting (73-74%), premixed (26-27%);

mean BL dose = 44-74 U/d MET.
b Premixed (57%), intermediate acting (19%), long acting (18%);
mean BL dose = 30 150 U/d MET.
0.8
Difference=0.4
(95%CI,0.6to0.2)
Vilsboll T, et al. Diabetes Obes Metab. 2010;12:167-177.

Barnett A, et al. Diabetologia. 2011; 54 (suppl 1):243.
0.8
0.8
INSa +SITA(n=322)
INSa +PBO(n=319)
20
10
0.4
0.6

Effect on Body Weight
BodyWeight(kg)
16
15
ConfirmedHypoglycemia
(%ofPatients)
SymptomaticHypoglycemia
(%ofPatients)
P =.003
20
25
0.4

Premixed (57%), intermediate acting (19%), long acting (18%);
INSb +SAXA(n=304)
INSb +PBO(n=151)
24weektrial
25
0.2
1.0
BodyWeight(kg)
INSa +SITA(n=322)
INSa +PBO(n=319)
52weektrial

b Premixed (57%), intermediate acting (19%), long acting (18%);

US FDA-Approval Status for

Insulin-GLP-1 RA Combinations

Exenatide BID Added to Insulin Glargine

EXN BIDorPBO AddedtoGLAR 30weektrial
GLAR +PBO (n=122)
GLAR +EXN BID(n=137)
Agent
Approval StatusforCombinationwithInsulin
0.0
1.5
Liraglutide
Exenatide QW
A1C(%)
ExenatideBID
Notyetapprovedincombinationwithinsulin
NDAfiledin2011 awaitingresponsefromtheUSFDA2
approvedincombinationwithinsulin1
Notyet
Clinicaltrialsinprogress3
1.0
1.0
1.5
2.0
Weight (kg)
1
0.5
Approvedincombinationwithinsulinglargine1
0.5
0
0.5
1
1.5
1.7
1.8
P < .001
SimilarratesofminorhypoglycemiainEXNBID(25%)andPBO(29%)groups
1. US FDA. Drugs@FDA Web site. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/;
2. Reuters. 2011. http://uk.reuters.com/article/2011/06/28/novonordisk-idUKLDE71F09U20110628;
3. US National Institutes of Health. http://www.clinicaltrials.gov/ct2/home.
More discontinued due to AEs in EXN BID (9%) vs PBO (1%) group (P < .01).
15
Buse JB, et al. Ann Intern Med. 2011;154:103-112.
Does Order of Initiation Matter?

Insulin and Exenatide BID
Insulin Detemir Added to Liraglutide
Studyonorderofaddition
(chartreview,24motreatment)
0.0
TreatmentPeriod
(Weeks052)
0.10
Runin:Weeks12to0
1.8mgLIRA+MET
PatientsnotachievingA1C<7%
randomizedtostudytreatments
0.7
a
1.0
A1CChange(%)
A1CChange(%)
0.01
0.00
0.5
1.0
a
1.5
GLAR addedtoEXN BID(n=30)

EXN BIDaddedtoGLAR (n=106)
0.20
0.30
Weightdecreasedsignificantly(2.5kg)intheEXNBIDaddedtoGLARgroupa
0.50
0.50
WeightremainedunchangedintheGLAR addedtoEXN BIDgroup

0.60
MET+LIRA1.8mgcontrol
(n=161)
MET+LIRA1.8mg+insulindetemir
(n=162)
0.40
2.0
Study+extension:Weeks0to52
26weekstudy+26week
extension
Addedinsulindetemir ornothing
MeanstartingA1C=7.6%
0.10
P < .005 vs baseline.
P <.0001
Levin PA, et al. Endocr Pract [published online ahead of print July 8, 2011]:1-28.
Bain SC, et al. EASD 47th Annual Meeting. 2011;73.
Milestones in Insulin Development
1920
1930
1940
Insulindetemir
approvedinUS
(2005)
Recombinanthuman
insulindeveloped
(1979)
NPHinsulin
developed(1946)
Insulinlisproapproved
inUS(1996)
Synthetichuman
insulindeveloped(1965)
Insulindiscovered(1921)
1950
1960
1970
1980
Inhaledinsulin
developed(2006)
1990
2000
2010
Investigationalbasalinsulins
Insulinpen
developed(1981)
Lente(zinc)insulins
developed(1952)
Insulinaspartand
insulinglargine
approvedinUS(2000)
Firsthumantreatment
withbovineinsulin(1922)
Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed.
Blackwell Science: Malden, MA; 2003:1.1-1.22; Drugs@ FDA;
http://diabetes.webmd.com/news/20071018/pfizer-quits-inhaled-insulin-exubera.
Withdrawn.
Glargine and Detemir Time-Action Profiles

Are Dose-Dependent
Subject231
8 12 16 20 24
ElapsedTime(hours)
InsulinActionProfilesforClinicallyRelevantDosesinPatientsWithT2DMa,b
Subject214
4 8 12 16 20 24
ElapsedTime(hours)
GlucoseinfusionRate
(mg/kg/min)
Glargine
7
6
5
4
3
2
1
0
NPH
BGLevel(mg/kg/min)
BGLevel(mg/kg/min)
BGLevel(mg/kg/min)
Time Action Profile of Basal Insulins

7
6
5
4
3
2
1
0
Detemir
7
6
5
4
3
2
1
0
Subject215
3.0
Detemir(0.4U/kg)
Glargine(0.4U/kg)
2.5
Detemir(0.8U/kg)
Glargine(0.4U/kg)
2.0
1.5
1.0
0.5
0
0
10
12
14
16
18
20
22
24
Time(h)
8 12 16 20 24
ElapsedTime(hours)
a
Euglycemic glucose clamp study, 4 trials/subject.
Insulinglulisine
approvedinUS
(2004)
Insulinpump
developed(1978?)
Protamineandprotamine
zincinsulinsdeveloped(1936)
Heise T, et al. Diabetes. 2004;53:1614-1620.
16
24-h randomized, double-blind, parallel-group comparison

under glucose clamp conditions (N = 27).
1.4 U/kg doses yielded similar pharmacodynamic profiles.
Klein O et al. Diabetes Obes Metab. 2007;9:290-299.

Philis-Tsimikas A et al. Clin Ther. 2006;28:1569-1581.
Are Current Basal Insulins

True 24-Hour Therapies?
Why Do We Need New Insulins?

Characteristics of An Ideal Basal Insulin
Flat,peakless timeactionprofile
Lowvariabilitywithinand
betweenindividuals
Injectiontimeandfrequencyof
insulinglargineinT1DM(n=292)
Morning
21%
Late-Stage Investigational Basal Insulinsa
Evening
43%
Insulin
Administration
Status
Peak
Effective
Duration
Insulin lispro protamine

suspension (ILPS)1-3, b
Once or twice daily
Approved
outside US
3h
24 h
Once daily,
thrice weekly
Filed for
approval
Peakless
> 24 h
Degludec (NN1250)4-6
a
b
Garg S, et al. Diabetes Res Clin Pract. 2004;66:49-56.
None of these insulins are US FDA approved.

Also known as neutral protamine lispro (NPL).
Once-Daily Degludeca vs Once-Daily Glargine in

Insulin Naive Patients With T2DM
Insulin Degludec Time-Action Profile
GlucoseInfusionRate
(mg/kg/min)
Phase2trial
0.8units/kg
0.6units/kg
0.4units/kg
5
4
1. Fogelfeld L, et al. Diabet Med. 2010;27:181-188;

2. Strojek K, et al. Diabetes Obes Metab. 2010;12:916-922;
3. Ocheltree SM, et al. Eur J Endocrinol. 2010;163:217-223;
4. Zinman B, et al. Lancet. 2011;377:924-931;
5. Birkeland KI, et al. Diabetes Care. 2011;34:661-665;
6. Nosek L, et al. ADA 71st Annual Scientific Sessions. 2011: 49-L;.
16weeks
DEG(n=61)vs GLAR
(n=62),allreceivingOADs
BLA1C:8.6% 8.7%
3
2
SimilarA1Cchanges
16
12
20
DEG
15
5
1.1
0
Confirmed
Overall
GLAR:1.5%
24
GLAR
10
0.6
DEG:1.3%
HypoglycemiaRate
(events/pty)
Twice
daily
36%
Longdurationofaction
Lowriskofhypoglycemia
0.1
Nocturnal
Time(h)
a Degludec
is currently not FDA approved.

Groups receiving 6 nmol/U formulations.
Hypoglycemia, severe if assistance was required, confirmed if
plasma glucose < 56 mg/dL or classified as severe.
Nosek L, et al. ADA 71st Annual Scientific Sessions. 2011:49-LB.
Once-Daily Degludeca vs Once-Daily Glargine With

Mealtime Aspart in T2DM: 1-Year Datab
GLAR
50
A1C:1.2%1.3%
PatientsAttainingA1C<7%
a Degludec is currently not FDA approved.

b N = 992; all with mealtime aspart and MET PIO.
Hypoglycemia, plasma glucose < 56 mg/dL or severe per ADA definition.
15
11.1
10
P =.04
1.4 1.8
40
Nocturnal
40
P =NS
43
30
20
10
0
0
Confirmed
Overall
GLAR
P =NS
50
13.6
Patients(%)
P =NS
50
DEG
BLA1C:7.7%
P =.04
HypoglycemiaRate
(events/pty)
Patients(%)
60
50
40
30
20
10
0
Once-Daily Degludeca vs Once-Daily Glargine With

Mealtime Aspart in T1DM: 1-Year Datab
A1C:0.4%0.4%
PatientsAttainingA1C<7%
HypoglycemiaRate
(events/pty)
DEG
BLA1C:8.3%
Zinman B, et al. Lancet. 2011;377:924-931.
50
40
42.5 40.2
30
20
P =.021
4.4 5.9
10
0
Confirmed
Overall
Nocturnal
a Degludec is currently not FDA approved.

b N = 629.
Hypoglycemia, plasma glucose < 56 mg/dL or severe per ADA definition. Russell-Jones D, et al. Diabetologia. 2011;54(suppl 1):1045.
Hollander PA, et al. Diabetologia. 2011;54 (suppl 1):1035.
17
ILPS, Detemir, and Glargine PK/PD in T2DM
GIR(mg/min/kg)
ILPS(0.8U/kg;n=28)
DET(0.8U/kg;n=32)
GLAR(0.8U/kg;n=29)
1
0
0
10
12
14
16
18
20
22
24
Time(hours)
Also known as neutral protamine lispro (NPL).
Hompesch M, et al. Curr Med Res Opin. 2009;25(11):2679-2687.
Pharmacokinetics of Rapid-Acting Analogs

vs Regular Human Insulin
Rapid-acting analog
70
60
50
40
30
20
10
0
60 120 180 240 300 360 420 480
Time (min)
Rapidonset
Quickpeak
Insulin Glulisine
140
80
Shortdurationofaction
Lowriskofhypoglycemia
Investigational Very Rapid-Acting Subcutaneous Insulinsa
120
60
Insulin, IU/mL
Free Serum Insulin, mU/L
80
Why Do We Need New Insulins?

Characteristics of An Ideal Prandial Insulin
Regular human insulin
Insulin Aspart
Insulin Lispro
40
20
100
60 120 180 240 300 360

Time (min)
Clinical
Trial Phase
Peak
Effective
Duration
Human insulin with

hyaluronidase
With meals
45-120 min
<5h
Analogue insulin with

hyaluronidase
With meals
30-90 min
<5h
80
60
40
20
Administration
Insulin
0
0
60
120 180
240 300 360
Time (min)
US FDA. Drugs@FDA Web site. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.
Hyaluronidase Accelerates Insulin

Pharmacokinetics
Adding Hyaluronidase To Insulin Accelerates

Subcutaneous Insulin Absorption
Hyaluronidase
Naturallyoccurringspacefilling
gellikesubstance
Anaturallyoccurringenzyme
Majorcomponentofnormalsoft
connectivetissuesuchasskin
Temporarilydegradeshyaluronan
andfacilitatespenetrationof
drugsattheinjectionsite
Lispro
Lispro+rHuPH20
RHI
RHI+rHuPH20
1500
Naturalandsynthetic
hyaluronidase formulationsare
available
USFDAapprovedasadjuvantsto
increasethedispersionand
absorptionofinjecteddrugs
250
1250
200
1000
150
750
100
500
50
250
0
Transientlocallyactingpermeation
enhancers
Girish KS, Kemparaju K. Life Sci. 2007;80(21):1921-1943.

Drugs@FDA. Hyaluronidase.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021859s006lbl.pdf.
60
120
180
240
300
Mean( SEM)
ImmunoreactiveInsulin(U/mL)
Hyaluronan
Hompesch M, et al. Diabetes Care. 2011;34(3):666-668.

Buse JB, et al. Diabetes. 2011;60(suppl 1):A19.
www.clincialtrials.gov.
None of these insulins are US FDA approved.
Mean( SEM)
ImmunoreactiveInsulin(pmol/L)
Serum Free Insulin Concentration, mU/L
0
360
Vaughn DE, et al. Diabetes Technol Ther. 2009;11(6):345-352.
18
Twice-Dailya Degludec Plus Aspart vs

Twice-Dailya Biphasic Aspart in T2DM:
Efficacyb and Hypoglycemia at 16 Weeks
Other Investigational Insulinsa
DEG 70%/ASP30%(0.57U/kg)(n=61)
DegludecPlus
Inhaled insulin
Once daily
Peak
Thrice daily
Efficacy(TreattoTargetDesign)
Yes
10-16 min
> 24?
1.0
1.5
2.0
2.5
a None of these insulins or administration

routes are US FDA approved.
BLA1C:8.5%8.6%
0.5
60-120 m
Heise T, et al. Diabetes Care. 2011;34(6):669-674.

Boss AH, et al. Drug Dev Res. 2008;69:138-142.
Rosenstock J, et al. Lancet. 2010;375(9733):2244-2253.
http://www.thepharmaletter.com/file/110488/novo-nordisk-opens-type-1-diabetes-rdcenter-in-seattle.html.
http://seekingalpha.com/article/270094-biotech-some-crl-recipients-to-consider.
http://clinicaltrials.gov.
3.0
Hypoglycemia
15
0.5
0.0
filed for
approval
BIASP 70/30(0.66U/kg)(n=62)
EventRate(EPY)
Administration
Effective
Duration
A1C(%)
Insulin
Clinical
Trial
Phase
1.8
10
P <.05
7.3
5
2.9
1.9
ProportionwithA1C<7%
withouthypoglycemia:
67% 40%
0.4
1.1
0
Confirmed
Hypo
Nocturnal
Severe
Abdominal injections before breakfast and evening meals;

99% used MET 2000 mg/day throughout RCT; DEG 55%/ASP 45% (n
= 59) arm not reported (discontinued agent).
Thrice-Daily Inhaled Prandial Insulin

With Once-Daily Glargine vs Twice-Daily
Biphasic Aspart in T2DM
Vaag A, et al. Diabetes. 2011;60(suppl 1):A313.
Insulin 201: Summary

GLPL1RAsorDPP4inhibitorscombinedwithinsulin
canimproveglycemiccontrol,withweightlossorno
appreciableweightgain,inpatientswithT2DM
52weeknoninferioritytrial
IHP(n=323);9%withdrewduetoAEs(P <.05vs BIASP)
BIASP(n=331);4%withdrewduetoAEs
SimilarA1Cchanges
Investigationalbasalinsulinanalogueshavethe
potentialtoimproveinsulintherapybyproviding
relativelypeakless timeactionprofilesandlowerrates
ofhypoglycemia
IHP:0.59%
BIASP:0.71%
SignificantlyfewerhypoglycemiceventswithIHP
IHP:0.41eventsperpatientmonth
BIASP:0.61eventsperpatientmonth
Prandialinsulins withmorerapidonsetandoffsetthan
currentprandialanaloguesareindevelopment
SignificantlylessweightgainwithIHP(0.9kg)vs BIASP(2.5kg;P =.0002)

MorereportedcoughwithIHP(32%)vs BIASP(4%)
BIASP, biphasic insulin aspart; IHP, inhaled prandial insulin.
Rosenstock J, et al. Lancet. 2010;375:2244-2253
19

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Insulin 101

March 10, 2012

Session 3: Insulin 101:

Faculty Financial Disclosure Statements

Education Partner Financial Disclosure Statement

Suggested Reading List

Type 2 Diabetes is Progressive

Insulin 101: Course Syllabus

Daily Plasma Insulin Profiles:

Types of Insulin Therapies

Polonsky KS, et al. N Engl J Med. 1988;318:1231-1239.

Del Prato S et al, Diabetes Technol Ther, 2012; 14: 175-182;

Basal Insulin Added to OADs

Basal Insulin Therapy in T2DM

Rodbard H, et al. Endocr Pract. 2009;15:541-559;

Swinnen S, et al. Diabetes Care. 2010;33:1176-1178.

Insulin 101: Course Syllabus

Currently Available Basal Insulins

Lucidi D, et al. Diabetes Care. 2011;34:1312-1314.

Time-Action Profiles Illustrate Variability in

Insulin 101: Course Syllabus

Heise T, et al. Diabetes. 2004;53:1614-1620.

Current Authoritative Guidelines on

Insulin Self-Titration Is as Effective and

Nathan DM, et al. Diabetes Care. 2009;32:193-203;

Garber AJ. Diabetes Obes Metab. 2009;11(suppl 5):10-13;

AACE and ADA Recommended

Ideal Glycemic Control

Handelsman Y, et al. Endocr Pract. 2011; 17(suppl 2): 1-53;

ADA standards shown.

Basal Dose Too High

Basal Dose Too Low

ADA standards shown.

ADA standards shown.

Basal Dose Too High

Insulin 101: Course Syllabus

ADA standards shown.

Encouraging Proper Insulin Injection

need longer time when using high doses of insulin.

Insulin Injection Sites

Frid A , et al. Diabetes Metab. 2010; 36 (suppl1):S3-S18.

Becton Dickinson Diabetes. Step by step injection guide. 2012; www.bd.com/us/diabetes.

Tips for Minimizing Pain

Lipohypertrophy Can Result from

King L, et al. Nurs Stand. 2003;17:45-52;

Needle Size Consideration

Conveniences of Insulin Pen Therapy

Molife C, et al. Diabetes Technol Ther. 2009;11:529-538.

A Prescribers Checklist For Insulin Therapy

Basal Insulin Therapy: Summary

Insulin 101: Course Syllabus

When Is Prandial Insulin

Relative Contribution of Postprandial

Significantly different between fasting and postprandial.

Monnier L, et al. Diabetes Care. 2003;26:881-885.

Currently Available Short-Acting

Insulin 101: Course Syllabus

American Diabetes Association. Practical Insulin: A Handbook for Prescribing

Introducing Basal-Prandial Insulin

Insulin 101: Course Syllabus

Initiating Basal-Prandial Insulin Therapy:

Basal-Prandial Dose Budget:

220 lb (100 kg) patient, 0.6 U/kg, 60 U total daily insulin;