Dr Paul Peter

8/11/2019 Dr Paul Peter

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Type2DiabetesAnoverview

DrPaulPeter

ConsultantPhysician

DiabetesandEndocrinology

CountyDurhamandDarlingtonFoundationTrust


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Plan

Theepidemic

Cardiovascularimpactofdiabetes

Insulinresistance/metabolicsyndrome

Currentoptions

Newoptions!!

NICEguidelines


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Amos AF et al. Diabet Med 1997; 14 (Suppl 5): S1S85.

Thesizeoftheproblem

Dia

be

tespreva

lence

(thousands

)

0

500

1000

1500

2000

2500

3000

1995 2000 2010

Type 1

Type 2

3 million by 20103 million by 2010


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0

10

20

30

40

50

No history of MI History of MI7-year

inc

idenceo

fc

ard

iovascu

lar

even

ts

(%)

No history of MI History of MI

Haffner SM et al. N Engl J Med 1998; 339: 229234.

Increasedriskofmyocardialinfarctionin

Type2diabetes

Non-diabetic

Type 2 diabetes

RememberRemember look at a person with Type 2 diabetes as iflook at a person with Type 2 diabetes as if

they have already had an MIthey have already had an MI


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UKPDS:benefitsofcontrollingHbA1c

*p < 0.0001**p = 0.016

Epidemiological extrapolation showing benefit of a 1% reduction in mean HbA1c at 12 years

Risk

reduc

tion

(%)assoc

iatedwit

ha

1%

lower

HbA

1c

-40

-35

-30

-25

-20

-15

-10

-5

0

43%

Amputation or

death due to

peripheral

vascular disease

*

*21%

Any diabetes-

related

endpoint

*

37%

Microvascular

complications

*

14%

Myocardial

infarction

*

19%

Cataract

extraction

16%

**

Heart

failure

Stratton IM et al. BMJ 2000; 321: 405412.


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DiabetesandSugar..??

Oscarminkowski..If hewas

ageusic.!!!

Diabetescare2004.

DiabetesItaint aboutsugar!!


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Glucose

(G)

Carbohydrate

Glucose

DIGESTIVE ENZYMES

Insulin

(I)

I

I

I

I

Insulin resistance

Insulin resistance

Insulin resistance

I

I

I

I

I

I

I

G

G

GG

G

G

G

GI

G

G

G


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Improves hyperglycaemia

to achieve tight glycaemic

control and reduce

microvascular complications

TreatingType2diabetes

Improves

cardiovascular risk factors

TargetTarget

Insulin

resistance

a rootcause of

Type 2

diabetes


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IDFDefinitionofMetabolicSyndrome(April2005)

CentralObesitydefinedbywaistcircumference Plusany2ofthefollowing

RaisedTG

(>1.7mmol/Lorspecifictreatmentforthisabnormality)

ReducedHDLcholesterol (or=85mmHgortreatmentofpreviouslydiagnosedhypertension)

RaisedFastingPlasmaGlucose (>or=5.6mmol/L) or

PreviouslydiagnosedType2Diabetes

Ifglucose>5.6anOGTTisstronglyrecommendedbutisnotnecessary todiagnosemetabolicsyndrome


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EthnicSpecificValuesforWaistCircumference

Country/Ethnic Group Waist Circumference

Male > or = 94 cmsEuropidsFemale > or = 80 cms

Male > or = 90 cmsSouth Asians

Chinese, Malay and Asian-Indian Female > or = 80 cms

Male > or = 85 cmsJapanese

Female > or = 90 cms

Ethnic South & Central

Americans

Use South Asian recommendation until

more specific data are available

Sub-Saharan Africans Use European recommendation until


Eastern Mediterranean &

Middle East (Arab)

populations

Use European recommendation until



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HDLM < 1.0mmol/L

W < 1.3mmol/L

TGs

>1.7 mmol/L

FastingGlucose

> 5.6mmol/L

BP> 130/85 mmHg

IDF Criteria of the Metabolic Syndrome

Waist

M > 94 cm

W > 80 cm

+ 2 out of 4


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Currentoptions


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Pharmacologicaltargets

glucosidase inhibitorsDelayintestinalcarbohydrateabsorption

GlitazonesDecreaseinsulinresistance

SulphonylureaIncreaseinsulinsecretionfrom

pancreaticcells

Biguanide(metformin)Decreases

insulinresistance

DDP4=dipeptidyl peptidase4;GLP1=glucagonlikepeptide1;T2DM=type2diabetesmellitus

AdaptedfromChengAY,Fantus IG.CMAJ.2005;172:213226.

MeglitinidesIncreaseinsulinsecretionfrom

pancreaticcells

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ADA=AmericanDiabetesAssociation;HbA1c=hemoglobinA1c

AdaptedfromUKPDSGroup.Lancet.1998;352:854865.

Glycaemiccontrolworsensovertime

MedianHb

A1c

(%)

0 2 4

0

6

7

8

9

6 8 10TimeFromRandomization(y)

Upperlimitofnormalrange(6.2%)

ADAgoal(7.0%)

Conventional(n=200) Insulin(n=199)

Chlorpropamide (n=129)Glibenclamide (n=148)

Metformin(n=181)

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Cellfunctioncontinuestodecline

T2DM=type2diabetesmellitus

*cellfunctionmeasuredbyhomeostasismodelassessment(HOMA)

AdaptedfromUKPDSGroup.Diabetes.1995;44:12491258.44

0

20

40

60

80

100

5 4 3 2 1 0 1 2 3 4 5 6

Yearssincediagnosis

CellFunction

(%)*

Progressivelossofcellfunction

occurspriortodiagnosis

Metformin(n=159)

Diet(n=110)

Sulphonylurea(n=511)

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ADOPT:weightchangeovertime

*Significantdifferencerosiglitazone vs.othertreatmentgroupswithHochbergadjustment.

CI=confidenceinterval.

KahnSE,etal.NEngl JMed2006;355:24272443.

Treatmentdifference(95%CI)

Rosiglitazonevs.metformin,6.9(6.3to7.4);P


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IFG=impairedfastingglucose;IGT=impairedglucosetolerance;NGT=normalglucosetolerance

AdaptedfromInternationalDiabetesCenter.Type2DiabetesBASICS.Minneapolis,Minn:InternationalDiabetesCenter;2000.

Prediabetes

(IFG/IGT)NGT Diabetes

Insulinresistance

Isletcellfunction

Diagnosis

Treatingtype2diabetes:

Deterioratingisletcellfunctioninthesettingof

insulinresistance/Obesity

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Isletcellfunction..


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Type2diabetesisacombinationofinsulinresistanceandpancreatic

isletdysfunction

Pancreaticisletdysfunction

Inadequate

glucagon

suppression

(cell

dysfunction)

Impairedglucose

dependent

response

Insufficientinsulin

secretion

(cell

dysfunction)

Insulinresistance

(impairedinsulinaction)

Triplitt C et al. Pharmacotherapy 2006:26:360-374

Krentz AJ, Bailey CJ. Drugs 2005:65(3):385-411

SulphonylureasGlitazones

Metformin

Most frequently prescribed OADs either address insulin resistance orelements of pancreatic islet dysfunction

25


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TheIncretin effect

28


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IV=intravenous

AdaptedfromNauck MA,etal.JClin Endocrinol Metab.1986;63:492498.

OralglucosetolerancetestandmatchedIVinfusion

PlasmaGluco

se(mg

/dL)

0

50

100

150

200

30 0 30 60 90 120 150 180 210

Time(Min)

PlasmaInsulin(pmol/L)

0

100

200

300

400

30 0 30 60 90 120 150 180 210

Time(Min)

Proofofagastrointestinalincretin effect:differentresponses

tooralvs.IVglucose

Oral IV

50gGlucose

N=6

29


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LCell

(ileum)

Proglucagon

GLP1[737]

GLP1[736NH2]

KCell

(jejunum)

ProGIP

GIP[142]

GIP=glucosedependentinsulinotropic peptide;GLP1=glucagonlikepeptide1

AdaptedfromDrucker DJ.DiabetesCare.2003;26:29292940.

GLP1andGIParesynthesizedandsecretedfromthegutinresponse

tofoodintake

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GLP1=glucagonlikepeptide1;T2DM=type2diabetesmellitus*P


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GLP 1 effects in humans


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GLP1effectsinhumans

Adapted from 1Nauck MA, et al. Diabetologia 1993;36:741744; 2Larsson H, et al.Acta Physiol Scand 1997;160:413422; 3Nauck MA, etal. Diabetologia 1996;39:15461553; 4Flint A, et al. J Clin Invest 1998;101:515520; 5Zander et al. Lancet 2002;359:824830.

GLP-1 secreted upon

the ingestion of food

1.-cell:cell:

Enhances glucoseEnhances glucose--dependentdependentinsulin secretion in theinsulin secretion in the

pancreaspancreas11

3.Liver:3.Liver:

reduces hepatic glucosereduces hepatic glucose

outputoutput22

2.2.--cell:cell:Suppresses pSuppresses postprandialostprandial

glucagonglucagon secretionsecretion11

4.Stomach:4.Stomach:slows the rate ofslows the rate of

gastric emptyinggastric emptying33

5.Brain:5.Brain:Promotes satiety andPromotes satiety and

reduces appetitereduces appetite4,54,5

Insulin gene

transcription and

synthesis

Decreasing apoptosis,Increasing

replication and Neogenesis


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SoWhatstheproblem??

GLP1 secretion in the intestineDPP4


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htt ://wwhtt ://ww


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GLP1inactive

(>80%ofpool)

Active

GLP1

Meal

DPP4

IntestinalGLP1release

GLP1t=12min

DPP4=dipeptidyl peptidase4;GLP1=glucagonlikepeptide1

AdaptedfromRothenbergP,etal.Diabetes.2000;49(suppl 1):A39.Abstract160OR.AdaptedfromDeaconCF,etal.Diabetes.1995;44:11261131.

33


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ToincreaseGLP1.

Preventdegradation

Createanalogues

Inhibition of DPP 4 increases active


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InhibitionofDPP4increasesactive

GLP1

GLP1inactive

(>80%ofpool)

Active

GLP1

Meal

DPP4

IntestinalGLP1release

GLP1t=12min

DPP4

inhibitor

DPP4=dipeptidyl peptidase4;GLP1=glucagonlikepeptide1

AdaptedfromRothenbergP,etal.Diabetes.2000;49(suppl 1):A39.Abstract160OR.AdaptedfromDeaconCF,etal.Diabetes.1995;44:11261131.

GLIPTIN

33

Gliptins


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Gliptins

Sitagliptin

Vildagliptin

Saxagliptin

DecreaseinHba1cof1%

Weightneutral

Nohypoglycemia

Elderly

Overweight type 2 diabetes

as second / third line


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GLP1analogues

Exenatide

Liraglutide*

Decreaseofhba1c>1% Weightlossof3 6kgs 6months

Decreaseinwaistcircumference Littlehypoglycemia

*submittedformarketingauthorisation

Overweight--- BMI>35??


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NICEguidelines


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DontForget

Diabetesaint justaboutsugar

Treatweight,lipids,BP and.sugar.

Neweragentswithmultiplebenefits

?longtermbenefit


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Questions

Documents

Dr Paul Peter