P1:SFK/UKS P2:SFK/UKS QC:SFK/UKS T1:SFK Color:4C BLBK368-FM BLBK368-Barnett February1,2011 13:10 Trim:229mmX152mm 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 i P1:SFK/UKS P2:SFK/UKS QC:SFK/UKS T1:SFK Color:4C BLBK368-FM BLBK368-Barnett February1,2011 13:10 Trim:229mmX152mm Thiseditionfirstpublished2011,(cid:2)C AnthonyH.BarnettandJennyGrice BlackwellPublishingwasacquiredbyJohnWiley&SonsinFebruary2007.Blackwell’s publishingprogramhasbeenmergedwithWiley’sglobalScientific,TechnicalandMedical businesstoformWiley-Blackwell. 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Setin9.5/12ptPalatinobyAptara(cid:2)R Inc.,NewDelhi,India 1 2011 ii P1:SFK/UKS P2:SFK/UKS QC:SFK/UKS T1:SFK Color:4C BLBK368-FM BLBK368-Barnett February1,2011 13:10 Trim:229mmX152mm 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 P1:SFK/UKS P2:SFK/UKS QC:SFK/UKS T1:SFK Color:4C BLBK368-FM BLBK368-Barnett February1,2011 13:10 Trim:229mmX152mm 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 P1:SFK/UKS P2:SFK/UKS QC:SFK/UKS T1:SFK Color:4C BLBK368-FM BLBK368-Barnett February1,2011 13:10 Trim:229mmX152mm 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 P1:SFK/UKS P2:SFK/UKS QC:SFK/UKS T1:SFK Color:4C BLBK368-FM BLBK368-Barnett February1,2011 13:10 Trim:229mmX152mm 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 P1:SFK/UKS P2:SFK Color:4C BLBK368-01 BLBK368-Barnett January31,2011 13:35 Trim:229mmX152mm 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 P1:SFK/UKS P2:SFK Color:4C BLBK368-01 BLBK368-Barnett January31,2011 13:35 Trim:229mmX152mm 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. P1:SFK/UKS P2:SFK Color:4C BLBK368-01 BLBK368-Barnett January31,2011 13:35 Trim:229mmX152mm EpidemiologyandPathogenesisofType2Diabetes 3 7.5 78 7.0 Diabetes 77 %) 6.5 Mean body weight 76 Me Diabetesprevalence ( 565...005 7754 an weight (kg ) 4.5 73 4.0 72 1990 1992 1994 1996 1998 2000 Year Figure1.1 Thegrowingepidemicoftype2diabetesinrelationtoobesity(Mokdadetal.,2000). DatafromDiabetesCare2000;23:1278–1283,Copyright2000AmericanDiabetesAssociation. worryingfindinggiventhattheriskofcomplicationsincreaseswithduration ofdisease. Overweightandobesity More and more of the world’s population is being exposed to the dietary habitsandsedentarylifestylesofthedevelopednations.Theincreaseincalo- rieintake,mainlyderivedfromcarbohydratesandanimalfat,withadecrease inphysicalactivity,hasledtoexcessiveobesityandincreasingresistancetoin- sulinaction.Type2diabetesisstronglyassociatedwithoverweightandobe- sity (Figure 1.1) (Mokdad et al., 2000), and a high proportion of people with type2diabetesareoverweightorobeseatthetimeofdiagnosis,whichmay reachupto80%insomepopulations(Hedleyetal.,2004). In the UK, rates of obesity have dramatically increased in the past two decades. The ongoing Health Survey for England highlights the increasing trend. In 1993, 13% of men and 16% of women were estimated to be obese (bodymassindex(BMI)>30kg/m2)(DoH,1994).Justoveradecadelaterthe proportionofmenandwomenclassedasobesehadincreasedto24%forboth sexes(DoH,2004).TheForesightreport‘TacklingObesities:FutureChoices’, whichwascommissionedbytheUKGovernment,hasestimatedthatifnoac- tionistaken,60%ofmen,50%ofwomenand25%ofunder-20yearoldswill beobeseby2050basedoncurrenttrends(Foresight,2007). Socioeconomicclass Theprevalenceofdiabetesappearstobehigheramongstlowsocioeconomic groups,witha36%higherprevalencenotedamongstmenlivinginthemost deprivedareasofEnglandandWalescomparedwiththoselivinginthemost affluent areas. For women the prevalence amongst those living in the most deprivedareasis80%higherthanamongstthoselivingintheleastdeprived parts. Interestingly, the reverse situation is found in developing countries P1:SFK/UKS P2:SFK Color:4C BLBK368-01 BLBK368-Barnett January31,2011 13:35 Trim:229mmX152mm 4 Chapter1 (Mohan et al., 2001).The tendency for the increased prevalence of type 2 di- abetestobeconcentratedinlowersocioeconomicgroupsindevelopedcoun- tries and higher socioeconomic groups in developing countries probably re- flectstheadoptionofahealthierlifestylebybettereducatedpeopleindevel- opedcountries,whileitisgenerallytheaffluentindevelopingcountrieswho enjoyahighcalorieintakeandlowlevelofphysicalactivity. Ethnicity Certain ethnic minorities (e.g. individuals originating from the Indian sub- continent,PimaIndians,MexicanAmericans,andAfricanAmericans)appear tohaveanincreasedsusceptibilitytodevelopinsulinresistancewhenmeet- ingcertainenvironmentalfactorsincludingobesityandasedentarylifestyle and are more prone to type 2 diabetesthan Caucasians (Barnett et al., 2006). Thesepopulationsmayhaveanincreasedgeneticsusceptibilitytolaydown intra-abdominalfat,particularlywhenencounteringaWesternstyleofliving. IntheUK,theriskoftype2diabetesisincreasedfour-tosixfoldinSouth AsianscomparedwithCaucasians(Barnettetal.,2006).Theageatpresenta- tion is also significantly younger (UKPDS, 1994). As duration of diabetes is oneofthestrongestriskfactorsforcomplications,thisplacesthispopulation atparticularrisk. Pathogenesis of type 2 diabetes Type2diabetesischaracterizedbythreemaindefects:peripheralinsulinre- sistance(decreasedglucoseuptakeinmuscle,fatandtheliver),excesshepatic glucoseoutput,andapancreaticbeta-cellinsulin-secretorydeficit.Thedevel- opmentoftheconditionisagradualprocess,however,andinmostindivid- uals, insulin resistance is the first defect to occur (Haffner et al., 2000). Both genetic and environmental factors play a role in the pathogenesis of type 2 diabetes,butoneofthemostcommoncausesofinsulinresistanceisobesity, particularlyabdominalobesity. Insulin resistance precedes abnormalities in insulin secretion by several years because pancreatic beta cells are initially able to compensate for in- sulinresistancebyincreasinginsulinsecretionsufficientlytomaintainnormal blood glucose levels. Eventually, the beta cells become exhausted, however, andcannolongerproduceenoughinsulin. Followingameal,insulinisproducedintwophases.First-phaseinsulinse- cretionisreleasedrapidlyafterameal,anditisthisresponsethatislostvery early in type 2 diabetes. When the first-phase insulin response fails, plasma glucose levels rise sharply after a meal producing postprandial hypergly- caemia. Initially, this precipitates an increased stimulation of second-phase insulinrelease,buteventuallythistoowillbebluntedandfastinghypergly- caemiawillalsoresult. The results of the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that beta-cell function is already reduced at the time of