New mechanisms in glucose control

74 Pages·2011·1.05 MB·English

by  A H Barnett, Jenny Grice

New Mechanisms
in Glucose
Control
Anthony H. Barnett
BSc, MD, FRCP
ProfessorofMedicine
BirminghamHeartlandsHospital
UniversityofBirminghamand
HeartofEnglandNationalHealthServiceFoundationTrust
Birmingham,UK
Jenny Grice
BSc (Hons)
MedicalWriter
LePrioldy,BieuzylesEaux,France
A John Wiley & Sons, Ltd., Publication
Thiseditionfirstpublished2011,(cid:2)C AnthonyH.BarnettandJennyGrice
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Contents
Preface v
Chapter1 EpidemiologyandPathogenesisofType2Diabetes 1
Thecurrentprevalenceofdiabetes 1
Factorsdrivingthetype2diabetesepidemic 2
Pathogenesisoftype2diabetes 4
References 5
Chapter2 OverviewofCurrentDiabetesManagement 7
Recommendedtargetsforglycaemiccontrol 7
Prosandconsofexistingnon-insulinantidiabetes
therapies 9
Whyarenewdrugsneededforthetreatmentoftype2
diabetes? 13
References 14
Chapter3 TheIncretinSystem 17
References 18
Chapter4 TheIncretinMimetics 20
Exenatide 20
Liraglutide 25
Placeintherapyoftheincretinmimetics 29
References 30
Chapter5 DipeptidylPeptidase-4Inhibitors 33
Mechanismofaction 33
DPP-4inhibitorclinicalefficacy 34
Vildagliptin 35
Saxagliptin 39
DPP-4inhibitorsafetyandtolerability 41
iii
iv Contents
DPP-4inhibitoradvantagesanddisadvantages 41
DPP-4inhibitorcurrentindications 42
PlaceintherapyoftheDPP-4inhibitors 43
References 43
Chapter6 Sodium-glucoseCotransporter-2Inhibitors 46
Dapagliflozin 47
Safetyandtolerability 49
SGLT-2inhibitoradvantagesanddisadvantages 50
References 50
Chapter7 PipelineDiabetesTherapies 51
Taspoglutide 51
Linagliptin 51
Bileacidreceptoragonists 52
Glucokinaseactivators 53
Sirtuins 53
Sodium-glucosecotransporter-1inhibitors 53
Sodium-glucosecotransporter-2antisenseinhibitors 54
Glucose-dependentinsulinotropicpolypeptideagonists
andantagonists 54
Glucagonreceptorantagonists 54
References 55
Chapter8 BariatricSurgeryfortheTreatmentofType2Diabetes 56
Potentialmechanismsofdiabetesresolutionafter
bariatricsurgery 56
Efficacyofbariatricsurgeryforthetreatmentoftype2
diabetes 57
Considerations 58
References 59
Chapter9 OrganizationofDiabetesCare 60
Managingdiabetesinprimarycare 60
Deliveryofdiabetescareclosertohome 61
Structuredpatienteducationprogrammes 62
References 62
Index 65
Preface
Whilstinsulinwasfirstisolatedin1921andproducedcommerciallyby1923,
it was not until the mid 1950s that oral agents for type 2 diabetes came to
themarket,firstsulphonylureasandthenthefirstbiguanide.Wethenwaited
another30yearsforthefirstalpha-glucosidaseinhibitor,butsincethenthere
hasbeenaveritableexplosionininterestfornewdrugsinthediabetesmarket
withanumbernowcommerciallyavailable.
It is clear that the traditional agents remain important therapies, but they
have their downside from the point of view of tolerability/side-effect prob-
lems. Moreover, they appear not to influence the natural history of the dis-
ease. The latter is an important issue given the progressive nature of type 2
diabetesandtheneedtoachievegoodglycaemiccontroltoreducetheriskof
devastatinglong-termvascularcomplications.
Inthepastfewdecadesarevolutioninourapproachtotreatingtype2di-
abetes has occurred following the recognition that the disease is caused by
multipledefects.Arangeofnewtreatmentsarenowavailablewithdiffering
mechanismsofaction,andmanymoreareinthepipeline,whichwillallowus
totargetthismultifactorialdiseasemoreeffectivelythaneverbefore.
The increasing requirement in the UK to move much of diabetes practice
intothecommunityrequiresamuchmoredetailedknowledgeofthecondi-
tionbyGPsandpracticenurses.Inthisbespokebook,theauthorsaimtoshow
hownewmechanismsofglucosecontrolandadvancesintreatmentsarising
fromthiscanbetranslatedintoprimarycare.Thebookwillcovertheepidemi-
ology and pathogenesis of type 2 diabetes as well as provide an overview
of current diabetes management including the pros and cons of traditional
therapies. This will be followed by an in-depth discussion of the incretin
system and the new drugs based on this approach – the incretin mimetics
(glucagon-likepeptide-1(GLP-1)agonists)anddipeptidylpeptidase-4(DPP-
4)inhibitors.Theauthorswillalsoreviewotherdrugclassesindevelopment
aswellasdiscussingtheoftenobservedresolutionoftype2diabetesthatoc-
cursafterweight-losssurgery.Finally,theywillconsidereffectiveapproaches
fordiabetescarewithinthatarena.
v
vi Preface
This book is particularly timely given the recent guidelines from the Na-
tional Institute for Health and Clinical Excellence (NICE) on Newer Agents
for Blood Glucose Control in Type 2 Diabetes, and is intended primarily for the
multi-professionaldiabetescareteam.Itshould,however,alsobeofinterest
tohospitalspecialistsintrainingandotherrelevantstaff.Itishopedthatby
increasingawarenessoftheexpandingtherapeuticoptionsfortype2diabetes
andtheirmechanisms,wecanbettertargetthemultitudeofphysiologicalde-
fectsthatcharacterizethediseaseandcustomizetreatmentregimenstofitthe
individualneedsofeachpatient.
AnthonyH.Barnett
Birmingham
CHAPTER 1
1 Epidemiology and Pathogenesis of
Type 2 Diabetes
Throughouttheworldtheincreasingprevalenceofdiabetesisposingsignifi-
cantstrainsonalreadyoverburdenedhealthcaresystems.Type2diabetesac-
countsformostoftheprojectedincrease,whichreflectsnotonlypopulation
growthandthedemographicsofanagingpopulation,butalsotheincreasing
numbersofoverweightandobesepeoplewhoareatincreasedriskofdiabetes.
The current prevalence of diabetes
Latest estimates from the International Diabetes Federation indicate that in
2010theglobalprevalenceofdiabeteswillbe285million,representing6.4%
oftheworld’sadultpopulation,withapredictionthatby2030thenumberof
peoplewithdiabeteswillhaverisento438million(IDF,2009).
InEurope,thereisawidevariationinprevalencebycountry,butthetotal
numberofadultswithdiabetesintheregionisexpectedtoreach55.2million
in 2010, accounting for 8.5% of the adult population (IDF, 2009). Estimates
indicate that at least € 78 billion will be spent on healthcare for diabetes in
theEuropeanRegionin2010,accountingfor28%ofglobalexpenditure(IDF,
2009).
In the United Kingdom (UK), there are now more than 2.6 million people
withdiabetesregisteredwithgeneralpracticesandmorethan5.2millionreg-
isteredasobese(Tables1.1and1.2)(DiabetesUK,2009).Arecentanalysisof
UKdatafromTheHealthImprovementNetwork(THIN)databasehasshown
asharpjumpindiabetesprevalence(Masso´-Gonza´lezetal.,2009).Thestudy
useddataon49999prevalentcasesand42642incidentcases(1256type1di-
abetes,41386type2diabetes)ofdiabetesinUKpatientsaged10to79years
intheTHINdatabase.From1996to2005,prevalenceincreasedfrom2.8%to
4.3%, while the incidence rose from 2.71 per 1000 person-years to 4.42 per
1000person-years.Thestudyalsofoundthattheproportionofpatientsnewly
diagnosed with type 2 diabetes who were obese increased from 46% to 56%
duringthedecade,furtherhighlightingtheimportantrolethatobesityplays
inthetype2diabetesepidemic.
NewMechanismsinGlucoseControl,FirstEdition.AnthonyH.Barnett&JennyGrice.
(cid:2)c 2011AnthonyH.Barnett&JennyGrice.Published2011BlackwellPublishingLtd.
1
2 Chapter1
Table1.1 PrevalenceofdiabetesinpeopleregisteredinUKgeneralpractice
Diabetes
Numberofpeople
withdiabetes Increaseinnumber
registeredwithGP Diabetesprevalence ofpeoplewith
Nation practicesin2009 in2009(%) diabetessince2008
England 2213138 5.1 124803
NorthernIreland 65066 4.5 4244
Wales 146173 4.6 7185
Scotland 209886 3.9 9217
UKtotal 2634263 4.0 145449
Source:DiabetesUK(2009).Reproducedwithpermission.
In the United States (US), recent predictions, which account for trends in
risk factors such as obesity, the natural history of diabetes and the effects of
treatments, suggest that the number of people with diagnosed and undiag-
nosed diabetes will double in the next 25 years from 23.7 million in 2009 to
44.1millionin2034(Huangetal.,2009).Furthermore,theresearcherspredict
thateveniftheprevalenceofobesityremainsstable,diabetesspendingover
thesameperiodwillnearlytripletoUS$336billion.
Factors driving the type 2 diabetes epidemic
Age
The prevalence of type 2 diabetes increases with age and with more people
livingwellintooldagethelikelihoodofdevelopingthediseaseisincreased.
However,increasesinprevalencehavebeenobservedinyoungeragegroups
in association with the rising prevalence of childhood obesity and physical
inactivity(Ehtisham,BarrettandShaw,2000;Fagot-Campagna,2000).Thisisa
Table1.2 PrevalenceofobesityinpeopleregisteredinUKgeneralpractice
Obesity
Numberofpeople Increaseinnumber
registeredas ofpeopleregistered
obesewithGP Obesityprevalence asobesesince
Nation practicesin2009 in2009(%) 2008
England 4389964 9.9 260660
NorthernIreland 165956 11.27 4085
Wales 305923 9.7 5442
Scotland 375649 7.0 22476
UKtotal 5237492 8.1 292663
Source:DiabetesUK(2009).Reproducedwithpermission.