RichardS.Beaser,MDMedicalDirector,ProfessionalEducation

JoslinDiabetesCenterAssociateProfessorofMedicine

HarvardMedicalSchool

AdvancingtoInsulinReplacementTherapy:When,Why,andHow?

Update in Internal Medicine - 2016December 5, 2016

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KeyMessages– InsulinTherapy• Insulinisahighlyeffectivediabetestreatment• Individualizetreatmentgoalsandregimens

– Considerpathophysiology,self-care,andsafety• Usepatternassessmenttoadjustdosingandadvance

therapy• TotreatType2Diabetes,considertheadvancement

sequencerecommendedbynationally-recognizedguidelinesfrombasalalonetobasal-bolusinsulintherapy

• Recognizeandaddresspatient,provider,andpractice-levelbarrierstoinsulintherapy

• Sometreatmentservicesshouldbeprovidedinthepractice,othersobtainedbyconsultation

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American Diabetes Association. Diabetes Care. 2016;39(suppl 1):S39-S46. Garber AJ, Abrahamson MA, Barzilay JI, et al. Endocrine Practice 2016;22:84-113.

A1C is “gold standard” measure of diabetes control over previous 2–3 months

AggressiveControlofDiabetes:GoalsofTreatment

ADA AACEA1C (%) < 7 ≤ 6.5Preprandial glucose (mg/dL) 80–130 < 1102-hour postprandial glucose (mg/dL)

< 180 < 140

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KeyParametersReflectingGlycemicControl

• A1C

• Preprandialglucoselevels

• Fasting

• Sequentiallythroughtheday

• Postprandialglucoselevels

• Absolutelevel

• Levelrelativetopre-prandial

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IndividualizingA1CTargetsforPeoplewithT2DM

ADA, EASD Position Statement. Diabetes Care 2015;38;1364-1379

Most Intensive Less Intensive Least Intensive

LifeExpectancy

DiseaseDuration

ImportantComorbiditiesFew/Mild Severe

RiskfromHypoglycemiaandotheradversedrugeffects

Low HighModerate

8.0%6.0% 7.0%

EstablishedVascularComplications

Few/Mild SevereAbsent

Long Short

Absent

Newly Diagnosed Long-Standing Notusuallymodifiable

Patientattitude/expectedtreatmenteffortHighly Motivated, Adherent, Excellent Self-Care Capacities

Less motivated, Non-adherent, Poor Self-Care Capacities,

ResourcesandSupportSystemReadily available Limited

Potentiallymodifiable

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PhysiologicInsulinSecretion:24-hourProfile

Insulin(µU/mL)

50250 Basal insulin

Breakfast Lunch Dinner

150

Time of day

Glucose(mg/dL)

100500

7 8 9 10 11 12 1 2 3 4 5 6 7 8 9AM PM

Basal glucose

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RelativeContributionofFPGandPPGtoOverallHyperglycemiaDependingonA1CQuintiles

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

n=58 n=58 n=58 n=58n=58

0

20

40

60

80

100

<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2

Postprandial glucose Fasting glucose

Con

trib

utio

n (%

)

A1C (%) Quintiles

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WhentoConsiderInsulininapersonwithType2Diabetes

• Whenacombinationofnon-insulinantidiabetesmedicationsareunabletoachieveA1Ctarget

• Highfastingorpostprandialglycemia

• Unacceptablesideeffectsofothermedications

• Advancedhepaticorrenaldisease

• Specialconsiderations(steroids,infection,pregnancy)

• Hyperglycemiainahospitalizedpatient

• “Severely”uncontrolleddiabetes*

Nathan DM, et al. Diabetes Care. 2009; volume 32,193-203. Inzucchi SE, et al. Diabetes Care.2012;35(6):1364-1379. ADA Diabetes Care. 2015:38(Suppl 1):S41-S48.

* Random Glucose > 300 mg/dL, A1C > 10%, Ketonuria, Symptomatic polyuria/polydipsia, weight loss

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Type2DiabetesandNeedforInsulinP

atie

nts

Req

uirin

g In

sulin

(%)

UKPDS: at 6 years, more than 50% of patients (newly diagnosed at start of study) need insulin to reach target (FPG ≤6.0 mmol/L)

20

40

60

0

10

30

50

1 2 3 4 5 6

Wright A, et al. Diabetes Care. 2002;25:330-336.

FPG = fasting plasma glucoseYears from Randomization

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TypesofInsulin

Time (hours)4 8 16 24

Premixed Analogs:- Insulin lispro mix 75/25, 50/50- Biphasic insulin aspart 70/30

Human insulin 70/30: - Premix NPH/regular

Intermediate-acting insulin: NPH

Long-acting insulin:- Detemir, Glargine

Rapid-acting analogs:- Aspart, Glulisine, Lispro (U-100 or U-200)

Short-acting insulin: Regular (soluble)

Rapid-acting:- Inhaled human insulin

Adapted from Hirsch I. N Engl J Med. 2005;352:174-183.

- Glargine U-300- Degludec U-100 or U-200

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Insulin to provide Basal and Bolus Coverage

§ Basal insulin• Replicates normal “basal” insulin secretion in the fasting

and postabsorptive state which regulates hepatic glucose production and limits lipolysis

• Controls fasting and premeal glucose levels• A good basal insulin should have a low risk of

hypoglycemia§ Bolus insulin

• Replicates acute insulin secretion at mealtimes to both suppress liver glucose production and increase uptake of glucose in peripheral tissues

• Blunts rise in glucose after meals

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13

TDD=TotalDailyDose

Reprinted with permission from American Association of Clinical Endocrinologists © 2016 AACE. Garber, AJ Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 2016. Endocr Pract. 2016;22: 84 – 113.

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DesiredCharacteristicsofReplacementBasalInsulin

• Mimicsnaturalpancreaticbasalinsulinsecretorypattern

• Nodistinctpeakeffect

• Continuedeffectover24hours

• Minimizesriskofnocturnalhypoglycemia

• Administeredoncedailyforoptimalpatientadherence

• Reliableabsorptionpattern

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At least 70% of subjects in each group achieved A1C ≤ 7%Weeks

-2 0 12 24

6.57.07.58.08.59.09.5

10.0

A1C

(%)

+6.2 lb

+2.6 lb*

0

180

183

185

187

190

Average Body

Weight (lb)

Detemir NPH

*P<.001

Hermansen K et al. Diabetes Care. 2006;29:1269-1274.

Weight Gain with Detemir vs NPH

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756 Patients with Type 2 Diabetes on 1 or 2 Oral Agents

PG = plasma glucose

Adapted from Riddle et al. Diabetes Care. 2003;26:3080-86.

NPHGlargine

9.0%

8.5%

8.0%

7.5%

7.0%

6.5%

6.0%

A1C

0 4 8 12 16 20 24

Cum

ulat

ive

Num

ber o

f Eve

nts

(Doc

umen

ted

PG ≤

56 m

g/dL

)

Weeks of Treatment Time (days)

900800

600500

300

1000

700

400

200

0 24 48 72 96 120 168144

Glycemic Control Over Time

Hypoglycemia

Glargine vs NPH in Treat-To-TargetNo Difference in A1C but Reduced Hypoglycemia with Glargine

Hypoglycemia Reduced 42-46%

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Insulin glargineNPH insulin

0

50

100

150

200

250

300

350

20:00 22:00 24:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00

Time

B L D

Basal insulin

20:00

Hypoglycemia by Time of Day

Hyp

ogly

cem

ia E

piso

des

(PG

£72

mg/

dL)

Riddle MC, et al. Diabetes Care. 2003;26:3080-3086.

*P <0.05 (between treatment).PG = plasma-referenced glucose.

*

**

**

*

*

Treat-to-Target Trial: Timing and Frequency of Hypoglycemia

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PharmacodynamicsofGlargineU-300versusU-100

GIR

(mg/

kg-1

min

-1)*

1.5

3.0

00 36

Time (hours)3024126 18

0.5

2.5 U100 0.4 U/kg-1

U300 0.4 U/kg-12.0

1.0

U300 0.6 U/kg-1

U300 0.9 U/kg-1SC Injection

• The U-300 glargine has a flatter more prolonged effect • The time it takes for 50% of the effect of a single injection

• U-100 = 12.1 hours• U-300 = 16.7 hours

GIR = glucose infusion rate.

Shiramoto M et al. Diab Obes Metab. 2015;17:254-260.

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U-300InsulinGlargine

• U-300insulinglargineoffersasmallerdepotsurfacearealeadingtoareducedrateofabsorption

• Providesaflatterandprolongedpharmacokineticandpharmacodynamic profilesandmoreconsistency

• Half-lifeis~23hours

• Associatedwithlesshypoglycemiaespeciallynocturnalhypoglycemia

• Onlyavailableinpens– 300U/mL,1.5mL– Maxdosepershotis80unitswithcurrentpen

Garber AJ. Diabetes Obesity Metab 2014;16:483-491. Owens DR, et al. Diabetes Metab Res Rev. 2014;30(2):104-19. Steinstraesser A, et al. Diabetes Obes Metab. 2014;16:873-876. http://www.australianprescriber.com/magazine/19/3/76/8. Accessed September 4, 2015

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ComparisonofGlargineU-300toGlargineU-100

• SimilarreductioninA1C&FPG

• Lessnocturnalhypoglycemia

• Likelyneed15%higherdose

Ritzel R, et al. Diabetes, Obesity and Metabolism 2015;17:859-867

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PharmacodynamicsofDegludec

Josse RG and Woo V. Diabetes Obes Metab. 2013;15(12):1077-1084. Garber AJ. Diabetes Obesity Metab 2014; 16:483-491. Heise et al. Diabetes Obes Metab 2012;14:944–50

Glu

cose

Low

erin

g Ef

fect

on D

ay 6

(mg/

kg/m

in)

2

6

00 24

Time since Injection (hours)201684 12

4

1

3

5Ideg 0.4 U/kg

Ideg 0.8 U/kgIdeg 0.6 U/kg6

► desB30 insulin acylated (16-c fatty acid chain) at LysB29

► Half-life is ~25.4 hours, duration > 42 h

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VariabilityofEffectVariabilityineffectsofaninsulincancauseunexplainablevariationsinglucosecontrol

fromdaytoday

Insulin Within Subject Variability(CV% of AUC GIR)

NPH 68Glargine U-100 48 – 99Detemir 27Glargine U-300 34.8Degludec 20

Adapted from: Rossetti P, et al. Diabetes Obes Metab, 2014;16:695-706; Becker RHA, et al. Diabetes ObesMetab, 2015;17:261-7

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§ Basal plus GLP-1 agonistOR

§ Switch to a premixed insulin analog– Divide dose in half and give twice daily (before

breakfast and dinner)§ OR§ Basal Plus

– Basal insulin plus a short-acting insulin analogue before the largest meal of the day

OR§ Switch to basal-bolus regimen

InsulinTitration:Optionswhencontrolisnotadequateusingonedailyinjectionofbasalinsulin

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‒1.7

‒1.0

-2.0

-1.5

-1.0

-0.5

0.0

A1CCh

ange(%

)

GLAR+EXNBID GLAR+PBO

Outcome PBO EXENATIDEBID

P-Value

Δ FPG(mg/dL)a ‒27 ‒29 .63

Δ Insulindose(U/d)b 20 13 .03

Δ Weight (kg) 1.0 ‒1.8 <.001

Hypoglycemiac(events/patient-y) 1.2 1.4 0.49

DiscontinuationduetoAEs(%ofpatients)

1 9 <.01

Adapted from Buse JB et al. Ann Intern Med. 2011;154:103-112.

P < .001

EXN BID or PBO Added to GLAR30-week trial (N = 259)

Exenatide BID Added to Insulin Glargine

24

a Baseline FPG: 149 and 142 mg/dL for PBO and EXN BID groups, respectively.

b Baseline insulin: 47.4 and 49.5 U/d for PBO and EXN BID groups, respectively.

c 1 reported event of major hypoglycemia (PBO group).

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Comparison of GLP-1 RA’s vs. Prandial Insulin when used with Basal Insulin

1. Mathieu et al. Diabetes Obes Metab. 2014;16:636-44.2. Diamant et al. Diabetes Care. 2014;37:2763-73.

3. Rosenstock et al. Diabetes Care. 2014;37:2317-254. Eli Lilly and Co. Trulicity (dulaglutide) prescribing information.

http://pi.lilly.com/us/trulicity-uspi.pdf.5. US FDA. Drugs@FDA.

http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.

Outcome: LIRA vs. ASPART1 EXEN BID vs. LISPRO2 ALBIG vs. LISPRO3

Δ Weight, kg −2.8* 0.9 −2.5 2.1* −0.7* 0.8

Hypoglycemiad 1.0* 8.2 2.1 5.0 0.9 2.3Nausea, % LIRA > ASP, first 2 wks 2.9 0 11 1Basal Insulin used Degludec Glargine GlargineDuration / n 26 weeks /177 30 weeks / 637 26 weeks / 566

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

EXENATIDE BID2, bLIRAGLUTIDE QD1, a ALBIGLUTIDE QW3, cASPART QD1, a LISPRO TID2,3, b, c

∆ A

1C, %

P = .0024

Noninferior

Noninferior

a Added to DEG (26 wk; N = 177)b Added to GLAR (30 wk; N = 637). c Added to GLAR (26 wk; N = 566).d Rates of severe hypoglycemia were low across groups

* P < .05.

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AddingGLP-1-RAvs.bolusinsulintooptimizedbasalinsulinRxprogramforType2diabetes

Diamant M et al Diabetes Care 2014;37:2763-2773

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CombinationBasalInsulin– GLP-1RAFixedRatioFormulations

-1.9 -1.8-1.4

-1.6-1.3

-2

-2

-1

-1

0

Δ A

1C, %

-0.5 -1.0

1.6 d0.5 e

-3.0 d-4

-2

0

2

Δ B

W, K

G

a Not US FDA approved.b 26-week open-label, treat-to-target RCT; N = 1663 (insulin naïve). c 24-week open-label, treat-to-target RCT; N = 323 (insulin naïve). d P < .001 vs DEG-LIRA;e P < .001 vs GLAR-LIXI.

1. Gough et al. Lancet Diabetes Endocrinol. 2014;2:885-893.2. Rosenstock et al. Diabetologia. 2014;57(suppl 1) [abstract 241].3. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.

Current GLP-1 RAs should not be mixed with or injected adjacent to insulin3

LIRA1,bDEG-LIRA1,a,b GLAR2,cDEG1,b GLAR-LIXI2,a,c

Ø ≤ 3 severe hypoglycemic episodes per groupØ Lower rate of hypoglycemia for LIRA vs DEG or DEG-LIRA (overall and nocturnal)1

Ø Lower rate of hypoglycemia for GLAR-LIXI than for GLAR (overall)2,e

Noninferior to DEG; Superior to LIRA

d

Superior to GLAR

A1C < 7%, %: 81 60d 65d 84 80

DEG=Degludec;Lira=liraglutideGLAR=GlargineLixi=Lixisenatide

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RoleforPremixedInsulin• Advantages

– Easy(nomixing,singleproduct,pensavail.)– Coversinsulinrequirementsthroughmostofday

• Disadvantages– Notphysiologic

– LessFlexible:requiresconsistentmeal/exercisepattern,andcannottitrateindividualinsulinsunlesscustommixedinsulinisused

– ↑Nocturnalhypoglycemia(presupperNPH)

– ↑Fastinghyperglycemia(presupperNPHwearsoff)

– HigherA1C(realisticgoalof≤8%)

Janka HU et al. Diabetes Care. 2005;28:254-259. Fritsche et al. Diab Obes Metab. 2010;12(2):115-123. ADA, EASD Position Statement. Diabetes Care 2012;35;1364-1379.

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The1–2–3Study:AchievementofHbA1cTargetsWithPremixedInsulinAnalogTherapy

Garber AJ, et al. Diabetes Obes Metab. 2006;8(1):58-66.

Subj

ects

(C

umul

ativ

e %

)

ITT population* (n = 100)Mean baseline A1C level: 8.6%

≤6.5%(AACE)

<7.0%(ADA)

*All patients enrolled in the trial.

21

4152

7060

77

0

20

40

60

80

100

QD

BID

TID

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30Raskin P, Allen E, Hollander P, et al. Diabetes Care. 2005;28(2):260-265.

Change in A1C Level From Baseline to Study End

9.8%

6.9%7.4%

5

6

7

8

9

Insulin Glargine + OADs

Biphasic Insulin Aspart 70/30

P < 0.01

A1C

Lev

el (

%)

–2.4% –2.8%

10

9.7%

BaselineEndpoint

0.7

3.4

0

1

2

3

4

Episo

des p

er P

atie

nt Y

ear

P < 0.05

Insulin Glargine + OADs

Biphasic Insulin Aspart 70/30

Total units = 51.3 � 26.7 with glargine plus OADs vs. 78.5 � 39.5 with premixed insulinOAD = Oral antihypertlycemic agent

Documented Hypoglycemic Episodes (<56 mg/dL)

INITIATE: Basal Analog vs Premixed Analog

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Description of Event (Adjusted Rate)

Insulin Glargine/Insulin Glulisine-3(Events/Patient-

Year; n=194)

Insulin Glargine/Insulin Glulisine-1 (Events/Patient-

Year; n=194)

Premixed Insulin Aspart 70/30

(Events/Patient-Year; n=194)

SMBG < 70 mg/dL (with symptoms) 7.23 (0.99)a 7.11 (0.99)a 12.23 (1.68)

SMBG < 50 mg/dL (with symptoms) 0.89 (0.15)b 0.83 (0.15)b 1.91 (0.31)

SMBG < 36 mg/dL 0.15 (0.03) 0.10 (0.03)a 0.23 (0.05)Severe hypoglycemiac 0.17 (0.05) 0.10 (0.03) 0.17 (0.05)

Serious hypoglycemiad N/A N/A N/A

Rate of Hypoglycemic Event Occurrence

Insulin glargine/insulin glulisine-3 and insulin glargine/insulin glulisine-1 groups had lower hypoglycemic event rates than premixed insulin aspart 70/30 groupaP<0.01 vs premixed insulin aspart 70/30 bP£0.001 vs premixed insulin aspart 70/30cHypoglycemic events requiring assistance and either BG <36 mg/dL or prompt response to

countermeasuresdHypoglycemia with coma/loss of consciousness or seizure/convulsion.N/A = not applicable; SMBG = self-monitored blood glucose.

Riddle et al. ADA Scientific Sessions 2011.

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Comparison of Insulin Degludec/Insulin Aspartand Biphasic Insulin Aspart 30 in Uncontrolled, Insulin-Treated Type 2 Diabetes

Fulcher, GR, et al. Diabetes Care 2014:37:2084

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Clinical Features of Rapid-Acting Analogues: Aspart, Glulisine, and Lispro

§ Administration immediately prior to meals§ Faster onset of action matches timing of

carbohydrate absorption § Limits postprandial hyperglycemic peaks§ Shorter duration of activity

• Reduced risk of late postprandial hypoglycemia• Frequently can have late postprandial hyperglycemia

§ Glulisine can be given after meals if needed *

6-27

* Garg S et al. American Diabetes Association 64th Scientific Sessions; June 4-8, 2004; Orlando, FL; Abstract 530-P.

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FewerNocturnalHypoglycemicEventsinPatientsTreatedwithAspart vsRegularHumanInsulin

Aspart0

Regular Human Insulin

0.5

1.0

1.5

2.0

2.5

3.0

72%

P=0.001

Maj

or N

octu

rnal

Hyp

ogly

cem

ic

Even

ts p

er P

atie

nt-Y

ear

Adapted from Heller SR et al. Diabet Med. 2004;21:769-775.

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de la Peña A et al. Clin Pharmacol Drug Dev 2016;5:69-75

ConcentratedInsulinLispro U-200vsU-100

Time From Dose (h)

Insulin Lispro 100 Units/mlInsulin Lispro 200 Units/ml

Gluc

ose

Infu

sion

Rat

e (m

g/m

in)

(Mean± SEData)

PharmacodynamicsofLispro U-100&U-200arecomparable

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Afrezza Package insert; Santos Cavaiola T, Edelman S. Clin Ther. 2014;36:1275-1289

RSS = Rapid-acting analogGIR = Glucose infusion rate

InhaledInsulin

§ Technosphere insulin (TI) marketed as Afrezza, recently FDA approved

§ Indicated for adults with type 1 or 2 diabetes, in combination with long-acting insulin.

§ “Ultra-rapid-acting” insulin: Onset 12-15 minutes, peak 60 minutes, duration 2.5 – 3 hr

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InhaledInsulin:LimitationsandContraindicationsLimitations:

§ Inhaledinsulinisnotasubstituteforlong-actinginsulin.

§ Notrecommendedforthetreatmentofdiabeticketoacidosis

§ Notrecommendedinpatientswhosmokeorwhohavestoppedsmokinginlast6months.

Contraindications:§ Duringepisodesofhypoglycemia

§ InpatientswhohavechroniclungdiseasesuchasCOPDorasthma

www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm390865.pdf

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• Consideraddingprandial(mealtime)insulininabout3–6monthsif:– A1Ciselevated– Significantpostprandialglucoseexcursionsoccur(>180mg/dL)

– Therearesignificantdropsinglucosebetweenmealsorovernightasthebasalinsulindoseisincreased

– Likelyneededifthetotaldailyinsulindoseexceeds0.5Units/kg/day.

ADA, EASD Position Statement. Diabetes Care 2015;38;1364-1379

AddingBolusInsulin

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Based on: Nathan DM, et al. Diabetes Care. 2009;32:193-203. ADA, EASD Position Statement. Diabetes Care 2015;38;140-149.AACE/ACE Comprehensive Diabetes Management Algorithm, Endocr Pract. 2015;21(No. 4)

AddingBolusInsulin§ Add prandial insulin before meal with largest

glucose excursion (>180 mg/dl) or the meal with the largest CHO content.

§ Other meals can be covered subsequently. § Alternatively start with coverage of all three meals

at once.§ TDD: 0.3 – 0.5 U/kg; 50/50 basal/prandial§ Antihyperglycemic medications:

§ Generally, stop insulin secretagogues (SU, DPP-4 inhibitors, glinides)

§ Reduce or stop TZD’sTDD=TotaldailydoseSU=Sulfonlyurea

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Do you add injection at the largest meal or the one with the highest postprandial elevation?• Overall reduction in HbA1C of 1.2% was achieved with

the addition of prandial insulin.• Greatest HbA1C reductions were achieved with the first

and second bolus injections.• Glycemic improvement comparable in both groups.• Number of hypoglycemic episodes increased with

increasing number of prandial injections.• Basal-bolus treatment can be introduced in a more

patient-friendly approach, using simple stepwise addition of prandial insulin.

STEPwise Study

Meneghini, et al. Endocr Pract. 2011;17:727-736

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Adding Prandial Insulin to Basal Therapy Further Improves HbA1C

Davies M et al Diabetes Obes Metab. 2008 May;10(5):387-99.

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

DecreaseinA1C

(%)

Glargine± OHA(n=534)

Glargine± OHA+ODPrandial(n=534)

Glargine± OHA+BDPrandial(n=178)

Glargine± OHA+>BDPrandial(n=193)

*p<0.001forbaselinetoendpointchange:OHA=oralantihyperglycemic agent;OD=oncedaily;BD=twicedaily

-1.74*

-1.35*

-1.21*

-1.39*

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PhysiologicInsulinRegimenswithbasalinsulinplusrapid-actinginsulindosingbeforeeachmeal§ Checking blood glucose 4 to 6 times a day § CHO counting or consistent CHO Intake§ Premeal insulin dosing by algorithmic scale

or, preferably, carbohydrate counting § Surveillance and risk for hypoglycemia § Record keeping: “Monitoring” rather than

just “checking”

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*Treat with food first, retest, then use algorithmic dose.

Rapid-Acting InsulinBLOOD GLUCOSE BREAKFAST LUNCH SUPPER BED

0 – 70* — — —71 – 100 3 6 9

101 – 150 4 7 10151 – 200 5 8 12201 – 250 6 9 13251 – 300 7 10 14301 – 400 8 11 15OVER 400 9 12 16

Basal Insulin 20

An option for determining premeal insulin doses if carbohydrate counting is not possible

*Treat with food first, retest, then use algorithmic dose.

Sample Insulin Adjustment Algorithm: Premeal Rapid-Acting and Bedtime Basal Insulin

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CarbohydrateCounting,MatchingandPostprandialControl

• Twofactorsprimarilygovernthedoseofpremealinsulin:– Gramsofcarbohydrate– Correctiondosesifpremealhyperglycemiaispresent

• Twocalculationsareusefulforinitialdosing:– Carbohydratecoverage:Totaldailyinsulindose(TDD)dividedinto500givestheapproximatenumberofcarbgramsthat1unitofrapidactinginsulinwill“cover.”

– Correctiondose:DividetheTDDinto1500.Usuallyinitiallytargetaglucoseof120mg/dL

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CarbohydrateCounting,MatchingandPostprandialControl:Example

Ø Calculatingacarbohydrate(CHO)countinginsulindosingprogramforatotaldailyinsulindoseof50units:

– Basalinsulin:25unitsdailyatbedtime– PremealcoveragebasedonCHOintake:

§ Totaldailyinsulindose(TDD)=50units§ 500/50=10§ Give1unitofpremealrapid-actinginsulinforevery10gramsofcarbohydratetobeconsumed.

– Correctiondose:§ 1500/50=30§ Giveanextraunitofrapid-actingpremealinsulinforevery30pointsabove120mg/dL

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Simple Algorithm vs Carbohydrate Counting For Mealtime Insulin Adjustment

Insulin dose (U/kg/d) Simple Algorithm: 1.9 Carb Counting: 1.7 P < 0.0002

A1C

%8.5

8.0

7.5

7.0

6.5

6.0Baseline 2 6 12 18 24

8.167.94

7.40

6.88 6.76 6.70

6.546.646.79

7.30

7.868.16

Simple Algorithm Group

Carb-Count Group

Bergenstal R, Johnson M, Powers MA et al. Diabetes Care. 2008;31:1305-1310.

Weight gain (kg): Simple Algorithm: 3.6 Carb Counting: 2.4 P = 0.06

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GlucoseMonitoring• Nooneshouldperformasingleglucosetestunlessheorsheknowswhattodowiththeresult!

• Thereisadifferencebetweenglucosechecking(testing)andglucosemonitoring

• Individualizemonitoringschedule

• Record-keepingisofcrucialimportancetothemonitoringprocess

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B L S HS B

Insu

lin E

ffect

Meals

External Insulin Pump Using Rapid Acting Insulin

Insulin Bolus Doses

Insulin Basal

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SuggestedSequenceforAssessmentofGlycemicPatterns

• Fastingvalue• Generalpremeal andbedtimevaluesand

trendsthroughouttheday• Postprandialvalues– absolutelevels• Relativechange,pre- topostprandial

glycemiclevels

à Also,continuallymonitornocturnalglycemia

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12:00 am 6:00 am 12:00 6:00 pm 12:00 am

Glu

cose

(mg/

dL)

400

300

200

100

0

Glucose measurement

Insulinbolus

TargetRange

Fingerstick Blood Glucoses (Type 1)

ContinuousGlucoseMonitoringProvidesaMoreComprehensivePictureofthePatterns

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CGM Software Report

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Factors Influencing Therapeutic ChoicesØ Medical needs and treatment goals

• A1C level and distance from target• Postprandial glycemia

Ø SafetyØ Need for flexibility in treatment programØ Patient issues with respect to insulin use

• Intellect and judgment• Psychosocial and cultural considerations• Physical capabilities and limitations• Other medical conditions and issues

relating to use of other non-insulin medications

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Adapted from Funnell MM. Clinical Diabetes. 2007;25(1):36-38.

PatientBarrierstoInsulinInitiationØ Needinginsulinrepresentsapersonalfailure

• Describethenaturalprogressionoftype2diabetesandtheinevitabilityoftheneedforinsulin

• Donotuseinsulinasathreat

Ø Insulinisnoteffective• Manypatientsdonotbelieveinsuliniseffective• Matchinsulinusetogoalsthatpatientscansee:Glycemic

patterns,symptoms

Ø Insulincausescomplications• Manypatientssawrelatives/friendsstartinsulininthe

contextofbadeventshappening• Providesupportiveeducation

Ø Impactonlifestyle• Perceivedcauses:Injectionschedule,hypoglycemia• Providesupportiveeducation• Insulinpens

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Adapted from Funnell MM. Clinical Diabetes. 2007;25(1):36-38.

Ø Injectionsarepainful• Perceivethattheyarethesameasinoculationsorotherpainful

injectionexperiences• Comparetoglucosechecking• Demonstrationinjection• Discussneedlesize;useofpens

Ø Fearofhypoglycemia• Observingproblemsinothers• Educationfocusingonadvantagesofnewerinsulins,hypoglycemia

avoidance,appropriategoalsetting

Ø Insulincausesweightgain• Acknowledgethepossibility• Discussstrategiestoavoid:Dietitian,CHOcounting

Ø Cost• Acknowledge/comparecostforinsulinvs.DMMeds• Explorestrategiestoreducecosts

PatientBarrierstoInsulinInitiation

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PhysicianBarrierstoInsulinInitiation

Adapted from Funnell MM. Clinical Diabetes. 2007;25(1):36-38. Derr RL, et al. Diabetes Spectrum. 2007; 20(3):177-185.

Ø Systemsdeficiencies• Recognizingindications,impactoftreatment:EMRreminders• Educationalsupport:Trainofficestaff;identify/developworking

relationshipwithadditionaleducationalresources

Ø Providereducationaboutinsulin• Optimizeyourownknowledgeandskills

Ø Concernabouthypoglycemia• Similarissuestopatients• SetindividualizedgoalsanddesignappropriateRx• Providesupportiveeducation

Ø Weightgain• Usedietitians,physiologicinsulinprograms

Ø Uneaseindealingwithpatientemotions/barriers• Developstrategiesandpracticethem!

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AStepwisePerspectiveonInsulinTreatment

• Abilitytoidentifypeopleforwhominsulinisindicatedanddiscussthisneedwiththem

• Capabilityoridentifiedreferralresourcestooverseeinsulintreatmentinitiationandsupport

• Abilitytoteachinsulinuse:– Techniques– KnowledgeandSkillsforself-management– Spectrumofprograms,frombasaltopumps

• Abilitytoidentifypeopleforwhomthecurrentprogramisinadequateandadvancementoftherapyisindicated

• Troubleshooting• Referralmanagement

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AStepwisePerspectiveonInsulinTreatment

• Abilitytoidentifypeopleforwhominsulinisindicatedanddiscussthisneedwiththem

• Capabilityoridentifiedreferralresourcestooverseeinsulintreatmentinitiationandsupport

• Abilitytoteachinsulinuse:– Techniques– KnowledgeandSkillsforself-management– Spectrumofprograms,frombasaltopumps

• Abilitytoidentifypeopleforwhomthecurrentprogramisinadequateandadvancementoftherapyisindicated

• Troubleshooting• Referralmanagement

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Take-AwayMessages

• Treatmentgoals,programdesign,andmonitoringrecommendationsmustbeindividualized

• Monitoringofglycemicpatternsisakeytooltoguidetherapeuticdecisions

• Basal-bolusregimensrequiremoreinjectionsbutprovidebetterinsulincoverageandglycemiccontrol

• Patient,provider,andpracticesystemsbarrierstoinsulintherapymustberecognizedandaddressed

• Self-assessofficecapabilitiesinthecontextofinsulintreatmentsupport

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“Insulin is a remedy for the wise and not the foolish, be they patients or doctors. Everyone knows it requires brains to live long with diabetes, but to use insulin successfully requires more brains.”

§ Elliott P. Joslin, MD, ScD§ Diabetic Manual, 1959

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