Physiopathology of Diabetes & DiagnosisPhysiopathology of Diabetes & DiagnosisCCContentsContents

Normal physiology of glucose controlNormal physiology of glucose control

Classification of diabetesClassification of diabetes

Type Type 2 2 diabetesdiabetes

Type Type 1 1 diabetesdiabetesypyp

Diagnosis of diabetesDiagnosis of diabetes

١

Insulin and Glucagon Regulate Normal Glucose Insulin and Glucagon Regulate Normal Glucose HomeostasisHomeostasis

GlGlucagon(alpha cell)

Fasting state Fed statePancreas

Fasting state Fed state

Release of gut hormones

Insulin(beta cell)

hormones —Incretins1,2

(GLP-1 & GIP)

Blood glucose

Glucose output Glucose uptake

Blood glucoseLiver MuscleMuscle

Adipose Adipose tissuetissue

٢Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.Adapted from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

Insulin Action in Muscle and Fat CellsInsulin Action in Muscle and Fat CellsMobilization of GLUTMobilization of GLUT44 to the Cell Surfaceto the Cell Surface

I li

Plasma membrane

ob o o G Uob o o G U 44 o e Ce Su ceo e Ce Su ce

Insulin receptor Intracellular

signaling cascades

IntracellularGLUT4 vesicles

Insulin

cascades

GLUT4 vesicle mobilizationto plasma membrane

GLUT4 vesicle integration into plasma

٣

integration into plasma membrane Glucose entry into cell

via GLUT4GLUT4=glucose transporter 4

Classification of Diabetes MellitusClassification of Diabetes Mellitusb E i lb E i lby Etiologyby Etiology

Type 1 β-cell destruction—complete lack of yp β pinsulin

Type 2 β-cell dysfunction and insulin yp β yresistance

Gestational β-cell dysfunction and insulin Gestational β-cell dysfunction and insulin resistance during pregnancy

Oth ifi t G ti d f t f β ll f tiOther specific types • Genetic defects of β-cell function• Exocrine pancreatic diseases

• Endocrinopathies

۴

Endocrinopathies• Drug- or chemical-induced

• Other rare forms

Etiology of Type Etiology of Type 2 2 DiabetesDiabetesImpaired Insulin Secretion and Impaired Insulin Secretion and Insulin ResistanceInsulin Resistancepp

Genes and environment

I i d i liImpaired insulin secretion Insulin resistance+

Impaired glucose tolerancetolerance

۵

Type 2 diabetes

Natural History of TypeNatural History of Type 22 Diabetes ProgressionDiabetes ProgressionNatural History of Type Natural History of Type 22 Diabetes ProgressionDiabetes Progression

Years from 0 5-10 -5 10 15diagnosis

Insulin secretionInsulin resistance

Microvascular

Type 2 diabetes (T2DM)Pre-diabetes

complicationsMacrovascular complications

۶

yp ( )Onset Diagnosis

Pathogenesis of Type Pathogenesis of Type 1 1 DiabetesDiabetesO D fO D fOne DefectOne Defect

No hepatic No muscle/fat

Absentinsulin

secretionpinsulin effect insulin effect

Hyperglycemia

Unrestrainedglucose production

Impaired glucoseclearance

Less glucose entersi h l ti

٧Glycosuria

More glucose entersthe blood

peripheral tissues

Natural History Of “Pre”Natural History Of “Pre”––Type Type 11 DiabetesDiabetes

Putativetrigger

yy ypyp

trigger

Circulating autoantibodies (ICA, GAD65)

Cellular autoimmunityCellular autoimmunityβ-Cell mass 100%

Loss of first-phase insulin response (IVGTT)

Gl i t lClinicalonsetGlucose intolerance

(OGTT)onset—

only 10% ofβ-cells remainremain

“Pre”-diabetes

Geneticpredisposition

Insulitisβ-Cell injury Diabetes

٨

Time

Eisenbarth GS. N Engl J Med. 1986;314:1360-1368

Glucose Tolerance CategoriesGlucose Tolerance Categories

FPG 2-h PPG (OGTT)Plasma glucose 240 Plasma glucose

200

g(mg/dL) Diabetes

Mellitus

240

220

Plasma glucose(mmol/L)

11 1

160

180

200DiabetesMellitus IGT

11.1

126 120

140

160

IFG7.0

80

100 NormalNormal

IFG5.5

٩American Diabetes Association. Diabetes Care. 2007;30(suppl 1)

60

Criteria for the Diagnosis of Diabetes MellitusCriteria for the Diagnosis of Diabetes Mellitusgg

• Symptoms of diabetes plus random blood glucose• Symptoms of diabetes plus random blood glucose Symptoms of diabetes plus random blood glucose Symptoms of diabetes plus random blood glucose concentration concentration 1111..11mmol/L (mmol/L (200 200 mg/dL)mg/dL)

orororor• Fasting plasma glucose • Fasting plasma glucose 77..0 0 mmol/L (mmol/L (126 126 mg/dL)mg/dL)

orororor• Two• Two--hour plasma glucose hour plasma glucose 1111..1 1 mmol/L (mmol/L (140 140

mg/dL) during an oral glucose tolerance testmg/dL) during an oral glucose tolerance testccmg/dL) during an oral glucose tolerance testmg/dL) during an oral glucose tolerance testcc

١٠

Diabetes Mellitus Diabetes Mellitus ComplicationsComplicationspp

١١

Acute Complications of DMAcute Complications of DMpp

Diabetic Ketoacidosis (DKA)Diabetic Ketoacidosis (DKA)Diabetic Ketoacidosis (DKA)Diabetic Ketoacidosis (DKA)

Hyperglycemic Hyperosmolar State (HHS)Hyperglycemic Hyperosmolar State (HHS)

Both disorders are associated with absolute or Both disorders are associated with absolute or relative insulin deficiency, volume depletion, relative insulin deficiency, volume depletion,

and acidand acid--base abnormalitiesbase abnormalities

١٢

HyperglycemiaHyperglycemiaTh D fi i F f Di bTh D fi i F f Di bThe Defining Feature of DiabetesThe Defining Feature of Diabetes

Excessivel d ti

Impaired

Hyperglycemia

glucose production glucose clearance

١٣

Tissue injury1

Two Mechanisms of Tissue Injury Two Mechanisms of Tissue Injury b H l ib H l iby Hyperglycemiaby Hyperglycemia

HyperglycemiaGlycationpathway

Sorbitolpathwayp y p y

Sorbitol and fructoseGlycated proteins Advanced glycation Sorbitol and fructose Glycated proteins(eg, A1C)

g yend products (AGEs)

Oxidativeeffects

Osmoticeffects

Altered functionor turnover

Receptor-mediatedcytokine effects

١۴Brownlee M. Metabolism. 2000;49(suppl 1):9-13; Greene DA et al. N Engl J Med.1987;316:599-606; Sheetz MJ, King GL. JAMA. 2002;288:2579-2588

effectseffectsor turnover cytokine effects

Chronic Complications of DMChronic Complications of DM

MicrovascularMicrovascularMicrovascularMicrovascularMacrovascularMacrovascularO hO hOtherOther

GastrointestinalGastrointestinalG i iG i iGenitourinaryGenitourinaryDermatologicDermatologicInfectiousInfectiousInfectiousInfectiousCataractsCataractsGlaucomaGlaucoma

١۵

What are theWhat are theMicrovascular Complications ?Microvascular Complications ?

HyperglycemiaHyperglycemia

Microvascular Complications ?Microvascular Complications ?

Kidney NervesEye

NeuropathyPeripheral

RetinopathyM l d

NephropathyMi lb i i – Peripheral

– AutonomicMacular edema – Microalbuminuria

– Gross albuminuria

Blindness Kidney failure Amputation

١۶Death and/or disability

RetinopathyRetinopathyRetinopathyRetinopathy

Normal retina Proliferative retinopathy

١٧

What are theWhat are theMacrovascular Complications ?Macrovascular Complications ?

Metabolic injury to large vesselsMetabolic injury to large vessels

Macrovascular Complications ?Macrovascular Complications ?

Metabolic injury to large vesselsMetabolic injury to large vessels

Heart Brain Extremities

Coronary artery disease Cerebrovascular diseasePeripheral vascular Coronary artery disease– Coronary syndrome– MI– CHF

Cerebrovascular disease– TIA– CVA– Cognitive impairment

Peripheral vascular disease

– Ulceration– Gangrene

١٨

– CHF – Cognitive impairment – Gangrene– Amputation

Macrovascular disease at diagnosis Macrovascular disease at diagnosis in Typein Type 22 diabetesdiabetesin Type in Type 22 diabetesdiabetes

11%%Cerebrovascular

disease 7575% of all deaths in % of all deaths in l ith Tl ith T 22

1818%%Abnormal ECG

people with Type people with Type 2 2 diabetes are due to diabetes are due to

cardiovascular diseasecardiovascular disease

3535%%Hypertension

Absent foot pulses 1313%%

33%%Intermittent l di ti

١٩UKPDS Group. Diabetes Res 1990; 13: 1–11.

claudication

Risk of Microvascular Complications Risk of Microvascular Complications vs.vs. AA11C C in Typein Type 11 DiabetesDiabetes

Results From the DCCT

in Type in Type 11 DiabetesDiabetes

Retinopathy progressionNeuropathy progression

20

15

Relative risk

eu opat y p og ess oMicroalbuminuria progression

15

10

5

051 6 7 8 9 10 11 12

٢٠Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254

A1C (%)

Risk of Microvascular Events Risk of Microvascular Events vs.vs. AA11CCin Typein Type 22 DiabetesDiabetesin Type in Type 22 DiabetesDiabetes

Results From Epidemiologic Analysis of the UKPDS

8

10Hazardratio

6

4 37% change per 1% change in A1C

0

2

٢١

5 6 7 8 9 10A1C (%)

Stratton IM et al. BMJ. 2000;321:405-412

AA11C Predicts Myocardial Infarction C Predicts Myocardial Infarction in Type in Type 2 2 DiabetesDiabetes

UKPDSUKPDSUKPDSUKPDS

4585 Patients Followed for 10 Years*

2.5 2.4

3Relative risk

11.3

1.8 1.92

11

0<6 6 to <7 7 to <8 8 to <9 9 to <10 ≥10

٢٢*Adjusted for age, sex, and duration of diabetesStratton IM et al. BMJ. 2000;321:405-412

A1C (%)

TREATMENTTREATMENT

٢٣

Guidelines: LimitationsGuidelines: LimitationsGuidelines: LimitationsGuidelines: Limitations

D i id li f l iD i id li f l iDespite many current guidelines for glycaemic Despite many current guidelines for glycaemic control there is still a lack of consensus on ‘ideal’ control there is still a lack of consensus on ‘ideal’ target and intervention valuestarget and intervention valuesggIncorporation of guidelines into clinical practice Incorporation of guidelines into clinical practice can be difficultcan be difficult

largelarge--scale studies have shown the need for improved scale studies have shown the need for improved glycaemic control, but many patients fail to reach goals glycaemic control, but many patients fail to reach goals for glycaemic controlfor glycaemic controlg yg ythe complexity of the individual’s characteristics, risk the complexity of the individual’s characteristics, risk factors, needs and personal goals still need to be taken factors, needs and personal goals still need to be taken into accountinto account

٢۴

into account into account

Current guidelines recommend targets Current guidelines recommend targets for HbAfor HbA11c, FPG and PPBG levelsc, FPG and PPBG levels

IDFIDF44AACEAACE33ADAADA11HealthyHealthyGlucose controlGlucose control ADA/ ADA/

<<66..55≤≤66..55<<77..00HbAHbA11cc* (%)* (%)

IDFIDFAACEAACEADAADAHealthyHealthyGlucose controlGlucose control

<<66..0011 <<77..00

EASDEASD55

<<55..6622

(<(<100100))<<66..0 0

(<(<110110))≤≤66..0 0

((≤≤110110))55..00−−77..22

((9090−−130130))FBG, mmol/L FBG, mmol/L (mg/dL)(mg/dL)

33..8989−−77..22 22 ((7070−−130130))

<<77..88****22

(<(<140140))

(( 100100)) (( 110110))((≤≤110110))((9090 130130))(mg/dL)(mg/dL)

<<88..00** ** (<(<145145))

≤≤77..88** ** ((≤≤140140))

<<1010..00** ** (<(<180180))

PPBG, mmol/L PPBG, mmol/L (mg/dL)(mg/dL)

((7070 130130))

<<10 10 (<(<180180))

1 American Diabetes Association Diabetes Care 2006;29(suppl 1):S4–S42

*DCCT aligned; **1–2 hours postprandial

(<(<140140)) (<(<145145))((≤≤140140))(<(<180180))(mg/dL)(mg/dL) (<(<180180))

٢۵

1. American Diabetes Association. Diabetes Care 2006;29(suppl 1):S4 S42.2. American Diabetes Association. Diabetes Care 2006;29(suppl 1):S43–8.3. American Association of Clinical Endocrinologists. Endocr Pract 2002;8(suppl 1):40–82.4. International Diabetes Federation. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation, 2005.

http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf5. Nathan D, et al. Diabetologia 2006;49;1711-21.

Insulin and Glucagon Regulate Normal Glucose Insulin and Glucagon Regulate Normal Glucose HomeostasisHomeostasis

GlGlucagon(alpha cell)

Fasting state Fed statePancreas

Fasting state Fed state

Release of gut hormones

Insulin(beta cell)

hormones —Incretins1,2

(GLP-1 & GIP)

Blood glucose

Glucose output Glucose uptake

Blood glucoseLiver MuscleMuscle

Adipose Adipose tissuetissue

٢۶Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.Adapted from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

Treatment of DiabetesTreatment of DiabetesTreatment of DiabetesTreatment of Diabetes

NonNon--pharmacologicpharmacologicNonNon pharmacologicpharmacologicOral agentsOral agentsI liI liInsulinInsulin

٢٧

NonNon--pharmacologicpharmacologicNonNon pharmacologicpharmacologic

NutritionNutritionNutritionNutritionExerciseExerciseLifLif l Chl ChLifeLife--style Changestyle Change

٢٨

Treatment of T2DM Is Accomplished by Different Agents via Different Modes of Action

I liInsulinInhibitors of gluconeogenesisInhibitors of glucose absorption

Insulin secretagogues

Insulin sensitizers

↑ Insulin ↓ Insulin secretion resistance

↓ Liver/gut glucose delivery

↓ Bl d l↓ Glucose toxicity ↓ Glucose toxicity

٢٩

↓ Blood glucose

Oral AntiOral Anti--Diabetes AgentsDiabetes Agents

OADs

INSULIN SECRETAGOGUES

OTHERS α-Glucosidase Inhibitor

INSULIN SENSITIZERS

acarbose GLUCOBAY (Bayer)

S l h l N S l h lBi id Thi lidi di / Sulphonylureas Non-Sulphonylureas

chlorpropamide DIABENESE (Pfizer)

glibenclamide

repaglinide NOVONORM (Novo)

nateglinide

Biguanides Thiazolidinediones / Glitazone (TZD)

metforminroziglitazone

AVANDIA (GSK) glibenclamide DAONIL (Aventis)

nateglinide STARLIX (Novartis)

gliclazide DIAMICRON (Servier)

metformin GLUCOPHAGE (Merck)

AVANDIA (GSK)

pioglitazone ACTOS (Eli Lilly)

٣٠

glipizide MINIDIAB (Pfizer)

glimepiride AMARYL (Aventis)

How Different Agents Regulate How Different Agents Regulate Hyperglycemia in DiabetesHyperglycemia in Diabetesyp g yyp g y

Pancreatic beta cells

• Sulfonylureas• MeglitinidesStimulate insulin release

MuscleLiver

Amelioration of hyperglycemia

MuscleLiver

• PPARs (TZDs or glitazones)

Gut• PPARs

(TZDs or glitazones)• Biguanides

• Biguanides• InsulinStimulate glucose uptake

• Alpha-glucosidase inhibitorsRetard glucose reflux into circulation

Biguanides• InsulinInhibit glucose production

٣١

PPAR=peroxisome proliferator-activated receptor agonist.

Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, Ma: Blackwell Publishing, 2004; DeFronzo RA. Ann Intern Med. 1999;131:281–303; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia, Pa: Saunders, 2003:1427–1483.Adapted from DeFronzo RA. Ann Intern Med. 1999;131:281–303.

Therapeutic Effects and LimitationsTherapeutic Effects and Limitations

Primary Primary ClassClass

yyEffectEffect LimitationsLimitations

SulfonylureasSulfonylureas HbAHbA11cc Hypoglycemia, weight gainHypoglycemia, weight gain

MeglitinidesMeglitinides PPGPPG Hypoglycemia, weight gainHypoglycemia, weight gainBiguanides (metformin)Biguanides (metformin) HbAHbA11cc GI adverse effects, lactic acidosis GI adverse effects, lactic acidosis

(rare)(rare)( )( )PPARsPPARs HbAHbA11cc Weight gain, edema, anemia, Weight gain, edema, anemia,

potential for liver toxicitypotential for liver toxicityAlphaAlpha glucosidaseglucosidase PPGPPG GI adverse effectsGI adverse effectsAlphaAlpha--glucosidase glucosidase inhibitorsinhibitors

PPGPPG GI adverse effectsGI adverse effects

InsulinInsulin HbAHbA11cc Injectable route, hypoglycemia, Injectable route, hypoglycemia, i h ii h iPPG=postprandial glucose; GI=gastrointestinal

٣٢

weight gainweight gainPPG postprandial glucose; GI gastrointestinal.DeFronzo RA. Ann Intern Med. 1999;131:281–303; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, Ma: Blackwell Publishing, 2004; Holz GG, Chepurny OG. Curr Med Chem. 2003;10:2471–2483; Meneilly GS et al. Diabetes Care. 2003;26:2835–2841; Ahrén B et al. Diabetes Care. 2002;25:869–875; Moller DE. Nature. 2001;414:821–827.

Insulin Deficiency and ResistanceInsulin Deficiency and Resistance

Type Type 2 2 DMDM

Insulin resistanceInsulin resistancee e (%)

(%)

200200

250250

Rel

ativ

eR

elat

ive

Func

tion

(Fu

nctio

n (

100100

150150

1515 2020 2525 303010105500––55––1010

ββ--cellcell failurefailure Insulin levelInsulin levelFF

00

5050

Duration of Diabetes (years)Duration of Diabetes (years)

٣٣Adapted from Bergenstal RM. In: Adapted from Bergenstal RM. In: Endocrinology. Endocrinology. Philadelphia, Pa: W.B. Saunders CoPhiladelphia, Pa: W.B. Saunders Co; ; 20012001::810810--820820. .

The Number of Medications Taken Usually The Number of Medications Taken Usually Increases With Duration of DiseaseIncreases With Duration of Disease

100 Diabetesdiagnosed

Requiring insulin

Monotherapyfailure

ion

(%)

g

Dual-drugMonotherapy

80

ell f

unct

i

Insulin-based

regimens

Multidrugcombination

+/–insulin

Dual-drugregimens60

40

Bet

a-ce

20IGT

00 10 15–25

Approximate time (years)

٣۴

IGT=impaired glucose tolerance.UKPDS 16. Diabetes. 1995;44:1249–1258. Turner RC et al. JAMA. 1999;281:2005–2012; Warren RE. Diabetes Res Clin Pract. 2004;65:S3–S8; Lebovitz HE. Med Clin N Am. 2004;88:847–863.

Oral Monotherapy: Failure Is InevitableOral Monotherapy: Failure Is Inevitable

Failure rates for oral monotherapy in type Failure rates for oral monotherapy in type 2 2 diabetes*diabetes*11,,22

Type Type 2 2 DMDM

StudyStudy 3 3 Years Years 6 6 Years Years 9 9 YearsYearsUKPDS UKPDS 49 49 >>4545%% NSNS >>7575%%(N=(N=40754075))

UKPDS UKPDS 24 24 NSNS 5252%% NSNS(N=(N=458458))

*Failure rates defined as A*Failure rates defined as A11C concentration >C concentration >77% in UKPDS% in UKPDS 4949 and >and >88% in UKPDS% in UKPDS 2424

٣۵11. Turner RC et al. . Turner RC et al. JAMA. JAMA. 19991999;;281281::20052005--20122012..22. UKPDS . UKPDS 2424. . Ann Intern Med. Ann Intern Med. 19981998;;128128::165165--175175..

Failure rates defined as AFailure rates defined as A11C concentration >C concentration >77% in UKPDS % in UKPDS 49 49 and >and >88% in UKPDS % in UKPDS 2424..NS, not studied; UKPDS, United Kingdom Prospective Diabetes Study.NS, not studied; UKPDS, United Kingdom Prospective Diabetes Study.

Insulin TherapyInsulin TherapyInsulin TherapyInsulin Therapy

٣۶

Action of InsulinAction of Insulin

Time

٣٧

BreakfastBreakfast LunchLunch SupperSupper

Normal Insulin Secretion: Normal Insulin Secretion: The BasalThe Basal--Bolus Insulin ConceptBolus Insulin Concept

Endogenous InsulinEndogenous Insulin

ffect

ffect

Bolus InsulinBolus InsulinBasal InsulinBasal Insulin

gg

nsul

in E

fns

ulin

Ef

InIn

BB DDLL HSHSTime of AdministrationTime of Administration

٣٨

B, breakfast; L, lunch; D, dinner; HS, bedtime.B, breakfast; L, lunch; D, dinner; HS, bedtime.

Adapted from:Adapted from:11.. Leahy JL. In: Leahy JL, Cefalu WT, eds. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; New York, NY: Marcel Dekker, Inc.; 20022002..22.. Bolli GB et al. Bolli GB et al. Diabetologia. Diabetologia. 19991999;;4242::11511151--11671167..

Comparison of Human Insulins Comparison of Human Insulins and Analoguesand Analogues

Insulin Insulin Onset ofOnset of Peak of Peak of Duration ofDuration ofPreparations Preparations Action Action Action (h)Action (h) Action (h)Action (h)ShortShort--actingactingR l hR l h 3030 6060 ii 22 4 64 6 88

gg

Regular human Regular human 3030--6060 min min 22--4 64 6--88Rapid ActingRapid ActingLispro/Aspart/GlulisineLispro/Aspart/Glulisine 55--15 15 minmin 11--2 2 33--44

IntermediateIntermediate actingactingIntermediateIntermediate--actingactingNPH NPH 11--3 3 hh 55--77 1313--1616LenteLente 11--3 3 hh 44--88 1313--2020

LongLong--actingactingLongLong actingactingGlargineGlargine 11--2 2 hh PeaklessPeakless >>24 24 Ultralente Ultralente 22--4 4 hh 88--14 14 <<2020

Ti f ti f i li i diff t l t diff t ti i thTi f ti f i li i diff t l t diff t ti i th

٣٩

Time course of action of any insulin can vary in different people or at different times in the 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 only be considered general guidelines.same person; thus, time periods indicated here should only be considered general guidelines.

Leahy JL. In: Leahy JL, Cefalu WT, eds. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin TherapInsulin Therapy. New York, NY: Marcel Dekker, Inc.; y. New York, NY: Marcel Dekker, Inc.; 20022002..

Insulin Time Action CurvesInsulin Time Action CurvesEf

fect

Effe

ct Rapid (Lispro, Aspart/Glulisine)Rapid (Lispro, Aspart/Glulisine)

e In

sulin

e

Insu

lin

Intermediate (NPH)Intermediate (NPH)Prolonged Intermediate (Ultralente)Prolonged Intermediate (Ultralente)

Short (Regular)Short (Regular)

Rel

ativ

eR

elat

ive

Long (Glargine, Detemir)Long (Glargine, Detemir)

Prolonged Intermediate (Ultralente)Prolonged Intermediate (Ultralente)

0 2 4 6 8 10 12 14 16 18 20

۴٠

Time (Hours)Time (Hours)

Twice-daily pre-mixed insulins

Breakfast DinnerLunch Snack

Regular insulinNPH insulin

Normal endogenous insulin

Both insulins combined

Breakfast DinnerLunch Snack

s

Risk of hypoglycaemiaRisk of hyperglycaemia

asm

a le

vels

Pla

Time of dayNPH=neutral protamine Hagedorn.

۴١

Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc; 2002:87-112.Bolli GB et al. Diabetologia. 1999;42:1151-1167.

Insulin Treatment RegimensInsulin Treatment RegimensOAD + Basal

7 13 19 22 37 13 19 22 3

OAD + Bolus

7 13 19 22 37 13 19 22 3

7 13 19 22 37 13 19 22 3

Premix

7 13 19 22 37 13 19 22 3

7 13 19

Mischinsulin 25/75

22 37 13 19

Mischinsulin 25/75

22 3

Premix

7 13 19

Mischinsulin 25/75

22 37 13 19

Mischinsulin 25/75

22 3

Basal + Bolus

7 13 19 22 37 13 19 22 37 13 19 22 37 13 19 22 3

Basal insulins: The choicesBasal insulins: The choices

Generic nameGeneric name Brand nameBrand nameGeneric nameGeneric name Brand nameBrand name

Insulin analoguesInsulin analogues

Insulin glargineInsulin glargine LantusLantus®®Insulin glargineInsulin glargine LantusLantus

Insulin detemirInsulin detemir LevemirLevemir®®

NPH [Neutral Protamine Hagedorn]NPH [Neutral Protamine Hagedorn] InsulatardInsulatard®® NovolinNovolin®® NNNPH [Neutral Protamine Hagedorn] NPH [Neutral Protamine Hagedorn] insulininsulin

InsulatardInsulatard , Novolin, Novolin N, N, ProtaphaneProtaphane®®

Human insulinHuman insulin

Lente insulin Lente insulin (zinc suspension)(zinc suspension)

Iletin Lente, Insulin Lente PorkIletin Lente, Insulin Lente Pork(Humulin(Humulin®® L*, NovolinL*, Novolin®® L*)L*)

Ul l i liUl l i li (H li(H li ®® U* Ul dU* Ul d®®*)*)Ultralente insulin Ultralente insulin ((extended zinc suspension) extended zinc suspension)

(Humulin(Humulin®® U*, UltratardU*, Ultratard®®*)*)

۴٣*Discontinued

Basal InsulinBasal Insulin

Long acting (e.g. glargine)Long acting (e.g. glargine) Intermediate acting (e.g. NPH, Intermediate acting (e.g. NPH, lente)lente)

-- Provides optimal basal insulinProvides optimal basal insulin

lente)lente)

-- Less optimal as a basal insulin, Less optimal as a basal insulin, Provides optimal basal insulin Provides optimal basal insulin coverage with a once daily coverage with a once daily dosingdosing

ppbecause it doesn’t have a flat because it doesn’t have a flat insulin release profileinsulin release profile

-- Lower risk of hypoglycemiaLower risk of hypoglycemia -- More hypoglycemic episodesMore hypoglycemic episodes

-- Flat release profile Flat release profile

۴۴

Prandial insulinPrandial insulin –– promotes total flexibility in promotes total flexibility in meal timingmeal timing

Ultra short/rapid acting insulin Ultra short/rapid acting insulin analogues (lispro)analogues (lispro)

Short acting insulin (regular insulin)Short acting insulin (regular insulin)

-- Rapid onset of actionRapid onset of action

F d h iF d h i

-- Less optimal profile as compared Less optimal profile as compared to rapid acting analoguesto rapid acting analogues

F h d h lF h d h l-- Forms monomers and thus is Forms monomers and thus is absorbed rapidlyabsorbed rapidly

D ti f ti l t fD ti f ti l t f 44

-- Forms hexamers and has slower Forms hexamers and has slower absorptionabsorption

S t i d d ti f tiS t i d d ti f ti-- Duration of action lasts for Duration of action lasts for 44hours regardless of the dose hours regardless of the dose givengiven

-- Sustained duration of action may Sustained duration of action may lead to postlead to post--prandial hypoglycemiaprandial hypoglycemia

-- Less hypoglycemiaLess hypoglycemia

۴۵

Limitations of Intermediate Insulins: NPHLimitations of Intermediate Insulins: NPH

Does not mimick basal insulin profileDoes not mimick basal insulin profile11,,22

Variable absorptionVariable absorptionVariable absorptionVariable absorptionPronounced peakPronounced peak1313--1616––hour durationhour duration1313 1616 hour duration hour duration Requires twiceRequires twice--daily administration to provide daily administration to provide 2424--hour basal hour basal insulin coverageinsulin coverage

Fear of hypoglycaemiaFear of hypoglycaemia33

Major factor limiting insulin adjustmentsMajor factor limiting insulin adjustmentsMajor factor limiting insulin adjustmentsMajor factor limiting insulin adjustments

1. Chan JL et al. Mayo Clin Proc. 2003;78:459-467.

۴۶

1. Chan JL et al. Mayo Clin Proc. 2003;78:459 467.2. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker,

Inc.; 2002.3. Bergenstal RM et al. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia,

Pa: WB Saunders Co.; 2001:821-835.

The Ideal Basal InsulinThe Ideal Basal Insulin

1 1 injection daily covers injection daily covers 24 24 hourshoursNo peaksNo peaksL i id f h l iL i id f h l iLow incidence of hypoglycaemiaLow incidence of hypoglycaemiaGood glycaemic controlGood glycaemic controlLess weight gainLess weight gaing gg gSafeSafePredictablePredictableEasy handlingEasy handlingEasy handlingEasy handling

Injection at different sitesInjection at different sitesInjection at different timesInjection at different timesN i i / l l iN i i / l l iNo mixing necessary/clear solutionNo mixing necessary/clear solution

High treatment satisfaction and acceptanceHigh treatment satisfaction and acceptance

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Characteristics of Insulin GlargineCharacteristics of Insulin Glargine

Recombinant human insulin analogueRecombinant human insulin analogue11

Basal (longBasal (long--acting) insulinacting) insulin11

Relatively constant peakless concentration over Relatively constant peakless concentration over 24 24 hourshours11,,22

OnceOnce--daily SC administrationdaily SC administration11

For adult and paediatric (aged For adult and paediatric (aged ≥≥6 6 years) patients with type years) patients with type 1 1 di b t nd d lt ith t pdi b t nd d lt ith t p 22 di b tdi b t 11 22diabetes and adults with type diabetes and adults with type 22 diabetesdiabetes11,,22

Lower risk of hypoglycaemia than with traditional basal insulinsLower risk of hypoglycaemia than with traditional basal insulins11

Flexible dosingFlexible dosing11Flexible dosingFlexible dosing11

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1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002.2. Lantus® receives European approval for pediatric use. Aventis Pharma Web site. Available at:

http://www.aventis.no/nyheter/nyheter/nyheter_lantus_eu_approval_pediatric.shtml. Accessed March 19, 2003.

Diagnosis

ADA/EASD consensus algorithm for type 2 diabetes mellitus (2006)

g

Lifestyle intervention and metformin

HbA1 ≥7%No YesaHbA1c ≥7%No Yes

Add basal insulinc − most effective

Add sulfonylurea − least expensive

Add glitazone −no hypoglycemia

HbA1c ≥7% HbA1c ≥7% HbA1c ≥7%No YesaNo YesaNo Yesa

Add glitazonebIntensify insulinc Add basal insulin Add sulfonylureab

HbA1c ≥7% HbA1c ≥7%No Yesa No Yesa

Add basal or intensify insulinc

Intensive insulin + metformin +/− glitazone

a Check HbA1c every 3 months until HbA1c is <7%, and then at least every 6 months. b Although three oral agents can be used initiation and intensification of insulin therapy

Nathan D, et al. Diabetologia 2006;49:1711−21.

b Although three oral agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and expense.

c See Nathan et al for initiation and adjustment of insulin.

ADA/EASD consensus algorithm ADA/EASD consensus algorithm

for typefor type 22 diabetes mellitusdiabetes mellitus ((20082008))for type for type 2 2 diabetes mellitus diabetes mellitus ((20082008))

Tier 1: well-validated therapies

At diagnosis:Lifestyle + Metformin

Lifestyle + Metformin+ Basal insulin

Lifestyle + Metformin+ Intensive insulin

MetforminLifestyle + Metformin+ Sulfonylureas

STEP 1 STEP 2 STEP 3Tier 2: Less well validated therapies

Lifestyle + Metformin+ PioglitazoneN h p l i

Lifestyle + metformin+ PioglitazoneNo hypoglycaemia

Oedema/CHFBone loss

Lifestyle + metformin+ GLP 1 agonist

+ Pioglitazone+ Sulfonylurea

Lifestyle + metformin+ GLP-1 agonistNo hypoglycaemiaWeight lossNausea/vomiting

+ Pioglitazone+ Basal insulin

Nathan DM, et al. Diabetes Care 2008;31:1–11.