Drug Therapy for Type 2 Diabetes

107 Pages·2013·5.095 MB·English

by  Andrew Krentz

DDrurgu gT hTehrearpayp y
forfor
TyTpyep e2 2D Diaibaebteetses
Andrew J. Krentz
Pocket Reference
D T
RUG HERAPY FOR
T 2 D
YPE IABETES
An Adis Pocket Reference
D T
RUG HERAPY FOR
T 2 D
YPE IABETES
An Adis Pocket Reference
Andrew J. Krentz MD, FRCP
Bedfordshire & Hertfordshire
Postgraduate Medical School,
United Kingdom
Editor:LouisaMott
Design:DanBenton
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PrintedintheUK
ISBN13:978-1-908517-64-7
CopyrightªSpringerInternationalPublishingSwitzerland2012.AllRightsReserved.
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practitioner;theclinicaltreatmentsdescribedandrecommendedmaynotbeconsidered
absoluteanduniversalrecommendations.
Theauthors,editorsandpublisherhaveexertedeveryefforttoensurethatdrugselection
anddosagesetforthinthistextareinaccordancewithcurrentrecommendationsand
practiceatthetimeofpublication.However,inviewofongoingresearch,changesin
governmentregulations,andtheconstantflowofinformationrelatingtodrugtherapy
anddrugreactions,thereaderisurgedtocheckthepackageinsertforeachdrugforany
changeinindicationsanddosageandforaddedwarningsandprecautions.Thisis
particularlyimportantwhentherecommendedagentisaneworinfrequentlyemployed
drug.
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CONTENTS
CONTENTS
Preface vii
Chapter1
Type2diabetes:rationaleforpharmacologicaltreatment 1
1.Introduction 1
2.Type2diabetes:aprogressivedisorder 5
3.Pathophysiology 7
4.Safetyofintensiveglucose-loweringstrategiesinhigh-riskpatients 11
5.Therapeuticapproaches 17
6.Guidelinesandtreatmentalgorithms 19
Chapter2
Establishedclassesofglucose-loweringdrugs 27
1.Introduction 27
2.Biguanides 28
3.Sulphonylureas 32
4.Meglitinides 36
5.Thiazolidinediones 38
6.Alpha-glucosidaseinhibitors 47
7.Fixeddosecombinationsoforallyactivedrugs 50
8.Principlesofinsulintherapyintype2diabetes 50
9.Weight-reducingdrugs 59
Chapter3
Recentlyintroducedandemergingclassesof 63
glucose-loweringdrugs
1.Drugsactingontheincretinsystem 63
2.Pathophysiologyoftheincretinsystemintype2diabetes 63
3.Dipeptidylpeptidase4inhibitors 65
4.Glucagon-likepeptide1agonists 71
5.Amylinanalogues 78
6.Bromocriptine 79
7.Drugsindevelopment 80
Chapter4
Theplaceofnewerdrugsintreatmentalgorithms 83
1.Recommendedmanagementoftype2diabetes 83
2.CurrentNICEguidance:oralglucose-loweringdrugs 84
3.NICEguidance:injectableagents 88
4.Nationalandinternationalguidelinescompared 89
Index 97
Dedicated to my family
Preface
Thisbookaimstoprovideanupdateondrugsavailableforthetreatment
oftype2diabetesandwheretheyfitwithincurrenttreatmentalgorithms.
The limited efficacy and tolerability of older drugs has spurred the
developmentofseveralnewclassesoforalandinjectableglucose-lowering
agentswithnovelmodesofaction.Theseadvancesreflectprogressinour
understandingofthepathophysiologyoftype2diabetes.Oldandnewer
drugsareincreasinglybeingusedside-by-side.
Type2diabetesisahighlycomplexandheterogeneousdisorderthat
demands careful consideration of the risk-to-benefit profile of glucose-
lowering drugs. The need for drug treatment to be tailored to the in-
dividualpatientisarecurringthemethroughoutthetext.Thepotentialfor
seriousunwantedeffects,notablyrecentsafetyconcernsabouttheriskof
cardiovascular events, has led to more intense scrutiny of new agents.
Theseriskshavetobebalancedagainsthopesformoreeffectivelong-term
metaboliccontrol,improvedtolerabilityandbetterclinicaloutcomes.The
higher cost of new drugs compared with long-established options is an
important additional consideration for healthcare systems with finite
resources.
Readersaredirectedtotheirnationalclinicalguidanceonuseofthese
new drugs. It should be noted that the product licenses for individual
agents not infrequently differ between countries. New indications and
fixed-dosecombinationscanbeexpectedtoappear.Safetywarningsfrom
regulatoryauthoritiesshouldbeheeded.
AndrewJ.KrentzMD,FRCP
October2012
Acknowledgements
ThanksgotothemanycolleaguesthatIhavehadthepleasureofcollaborating
withovertheyears.IthankDiabetesUKfortheirconstructivecommentson
themanuscript.IamgratefultoLouisaMottandhercolleaguesatSpringer
Healthcarefortheirprofessionalismandforbearance.
Chapter 1
Type 2 diabetes: rationale for
pharmacological treatment
1.Introduction
Itisestimatedthattherearenearly350millionadultswithdiabetes.Type2
diabetesaccountsforover90%ofthisburden.TheInternationalDiabetes
Federation(IDF)estimatesthatdiabetesresultedinalmost4milliondeaths
in 2007. The World Health Organization (WHO) estimates that the
numberofpeopleaffectedworldwidewillgrowtomorethan470million
by2030,themajorityinlowtomiddle-incomecountries.Apowerfuldose
associationexistsbetweenobesityandtheriskofdevelopingtype2diabetes
(Figure1.1).TheWHOestimatesthatmorethan1billionadultsareover
theiridealbodyweight,atleast300millionofthembeingclinicallyobese.
Thepreventionoftype2diabetesisapressingpublichealthissue.Trans-
latingtheresultsofstudiesthathaveshownthatintensivelifestylemeasures
i.e.weightreductionandincreasedlevelsofphysicalactivity,canavertor
postponeprogressiontodiabetesisaformidablechallenge.
DiabetesUK(www.diabetes.org.uk)calculatesthattheproportionof
theUKpopulationwithdiagnoseddiabetesisover4%,i.e.approximately
3 million people, the prevalence showing a strong association with
increasingage.Another850,000ormoremayhaveasyetundiagnosedtype2
diabetes;thisrelectstheofteninsidiousnatureofthedevelopmentoftype2
Figure1.1.Associationbetweenbodymassindexandriskoftype2diabetes.
Men
Women
sk 100 Normal weight Overweight Obese
e ri
ativ 75
el
d r 50
e
st
u
dj 25
a
e-
Ag 0
<22 <23 −23.9 −24.9 −26.9 −28.9 −30.9 −32.9 −34.9 ≥35
23 24 25 27 29 31 33
AdaptedfromChanetal.(1994)andColditzetal.(1995).
A.J.Krentz,DrugTherapyforType2Diabetes,
DOI:10.1007/978-1-908517-77-7_1, 1
(cid:2)SpringerInternationalPublishingSwitzerland2012
AndrewJ.Krentz
diabetes with many years of pre-clinical disease. Casting the net wider,
the number of people in the UK with less marked degrees of impaired
glucose regulation is several fold higher. The adverse metabolic impact
of excess adipose tissue is further modulated by anatomical patterns
of fat accumulation, central or upper body adiposity being most dis-
advantageous.Thegreatmajorityofpeoplewithtype2diabetesfallinto
the categories of overweight or obesity. Type 2 diabetes develops at a
youngerageinmanynon-whiteethnicpopulations,andgenerallyatlower
levelsofadiposity.Theincreasingprevalenceoftype2diabetesinobese
adolescentsandchildreniscausingparticularalarm.Studiessuggestahigh
propensitytoseriouscomplications,suchasprogressiverenaldiseaseand
coronaryheartdiseaseinindividualswithearly-onsettype2diabetes.
Abriefreviewofthepresentationanddiagnosisoftype2diabetesis
presentedinBox1.1andBox1.2.
1.1Morbidityandprematuremortality
Estimatesoftheglobaldirectandindirectcostsruntohundredsofbillions
ofdollars.Thelargestcomponentofdirectcostsisincurredfrominpatient
care,muchofwhichreflectstheburdenoflong-termmicrovascularand
macrovascular complications. Occlusive atherothrombotic disease accounts
Box1.1:Presentationandoutlineofdiagnosisoftype2
diabetes
Type2diabetesmaypresentwiththeclassicsymptomsofhyperglycaemia,i.e.
thirst,polyuria,blurredvision,recurrentmucocutaneousinfections,genital
itching,slowwoundhealingandfatigue.Thesesymptomsare,however,often
inconspicuous.Type2diabetesfrequentlyremainsundiagnosedfortenyearsor
morebeforeitisidentifiedduringinvestigationofobesity,aspartofalife
insuranceexamination,cardiovascularriskassessmentorfollowingaserious
vascularevent.Presentationwithadvancedmicrovascularcomplicationsis
uncommon,butsubclinicalorclinicalvasculardamageisoftenpresentat
diagnosis.Bythetimetheyarediagnosed,halfofthepeoplewithtype2diabetes
showsignsofcomplications.Briefly,diagnosisrestsonreliable(i.e.bylaboratory)
measurementofbloodglucose,repeatedifnecessaryparticularlyifthevalueis
borderlineorthepatientisasymptomatic.Arecentadvanceistheuseofglycated
haemoglobintodiagnosediabetes.Prominentosmoticsymptoms,especiallywhen
accompaniedbyrecentunintentionalweightlossorketonuria,pointtomarked
insulindeficiencythatwarrantsconsiderationofearlyinsulintherapy.Evenin
theabsenceofketonuria,anyresponsetooralglucose-loweringagentsislikelyto
beinadequateasaresultofpronouncedinsulindeficiency.Thesituationcanbe
morecomplexinnon-whitepopulationsinwhomketosismaybetransient.
Hyperglycaemicemergencies,i.e.hyperosmolarnon-ketotichyperglycaemiaand
diabeticketoacidosisareuncommonpresentations.
2
Rationaleforpharmacologicaltreatment Chapter1
Box1.2:InternationalDiabetesFederationstandardcare
guidelinesfordiagnosisoftype2diabetes
(cid:2) Eachhealthserviceshoulddecidewhethertohaveaprogrammetodetect
peoplewithundiagnoseddiabetes.Thisdecisionshouldbebasedonthe
prevalenceofundiagnoseddiabetesandontheresourcesavailabletoconduct
thedetectionprogrammeandtreatthosewhoaredetected.
(cid:2) Universalscreeningforundiagnoseddiabetesisnotrecommended.
(cid:2) Detectionprogrammesshouldtargethigh-riskpeopleidentifiedbyan
assessmentofriskfactors.
(cid:2) Detectionprogrammesshouldusethemeasurementofplasmaglucose,
preferablyfasting.Individualsshouldhavearepeatfastingplasmaglucose
measurementorHbA followedbyanoralglucosetolerancetesttoassess
1c
glycaemia.
(cid:2) Fordiagnosis,anoralglucosetolerancetestshouldbeperformedinpeople
withafastingplasmaglucoseof5.6mmol/lorgreaterandlessthan
7.0mmol/l.
(cid:2) Whenarandomplasmaglucoselevelof5.6mmol/lorgreaterandlessthan
11.1mmol/lisdetectedonopportunisticscreening,itshouldberepeated
fasting,oranoralglucosetolerancetestshouldbeperformed.
(cid:2) Diabetesshouldnotbediagnosedonthebasisofasinglelaboratory
measurementintheabsenceofsymptoms.
(cid:2) Peoplewithscreen-detecteddiabetesshouldbeofferedtreatmentandcare.
Note:In2010theAmericanDiabetesAssociationofficiallyendorsedthe
diagnosisofdiabetesusingHbA measurements(www.diabetes.org).
1c
forapproximately70–80%ofdeathsamongpatientswithtype2diabetes.
Coronaryheartdiseaseheadsthelistofcausesofprematuredeath,therisk
beingapproximatelytwotofourfoldhigherinpeoplewithdiabetes.While
thereissomeevidencethatlifeexpectancyhas improvedinrecentyears
diabetes continues to be associated with poorer clinical outcomes. Mor-
talityaftermyocardialinfarctionisapproximatelythreefoldhigherinthe
presenceofdiabetes.Type2diabetesisnowtheleadingcauseofend-stage
renal failure, placing strains on renal replacement services; nephropathy
furtherraisestheriskofmacrovasculardiseaseandprematuredeath.Re-
tinopathy,neuropathyandfootcomplicationscauseconsiderablechronic
disability.
1.2Economicconsiderations
IntheUK,ithasbeenestimatedthatapproximately10%oftheNational
Health Service (NHS) budget is accounted for by diabetes, some
3