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Créditos fotografia de capa: Dialysis Technician Salary Ana Carolina Queijo Fernandes Impact of Laboratory Standards on the Accuracy of Blood Glucose Meters and Its Clinical Effect on Insulin Dosing. Dissertação apresentada à Universidade de Coimbra para cumprimento dos requisitos necessários à obtenção do grau de Mestre em Engenharia Biomédica Orientador(es): Prof. Dr. Miguel Morgado (Universidade de Coimbra, Coimbra, Portugal) Dr. Jochen Sieber (Sanofi, Frankfurt, Germany.) Coimbra, 2016

Impact of Laboratory Standards on the Accuracy of Blood ......Dr. Jochen Sieber (Sanofi, Frankfurt, Germany.) Coimbra, 2016 i Este trabalho foi desenvolvido em colaboração com: Sanofi

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Page 1: Impact of Laboratory Standards on the Accuracy of Blood ......Dr. Jochen Sieber (Sanofi, Frankfurt, Germany.) Coimbra, 2016 i Este trabalho foi desenvolvido em colaboração com: Sanofi

Créditosfotografiadecapa:DialysisTechnicianSalary

AnaCarolinaQueijoFernandes

ImpactofLaboratoryStandardsontheAccuracyofBloodGlucoseMetersandItsClinicalEffecton

InsulinDosing.

DissertaçãoapresentadaàUniversidadedeCoimbraparacumprimento dos requisitos necessários à obtenção dograudeMestreemEngenhariaBiomédica

Orientador(es):Prof.Dr.MiguelMorgado(UniversidadedeCoimbra,Coimbra,Portugal)Dr.JochenSieber(Sanofi,Frankfurt,Germany.)

Coimbra,2016

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Estetrabalhofoidesenvolvidoemcolaboraçãocom:

Sanofi

InstitutfürDiabetes-Technologie(IDT)

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Estacópiadateseéfornecidanacondiçãodequequemaconsultareconhecequeosdireitos de autor são pertença do autor da tese e que nenhuma citação ouinformaçãoobtidaapartirdelapodeserpublicadasemareferênciaapropriada.Thiscopyofthethesishasbeensuppliedonconditionthatanyonewhoconsultsitisunderstood to recognize that its copyright rests with its author and that noquotation from the thesis and no information derived from it may be publishedwithoutproperacknowledgement.

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Acknowledgments

I am sincerely grateful for the opportunity provided by Sanofi, instigated bytherelentlessDr.GaborBoka.

Iwould like to thankDr. FrankFlacke forwelcomingme since the first day,andprovidingknowledgebeyondmyacademicwork.TomysupervisorDr. JochenSieber for valuable insights on diabetes mellitus and Dr. Alexandra Beer for hermentoring, not only did she give technical knowledge but also very muchappreciatedguiding.ToDr.Freckmannforkindlyprovidingthedata for thisworkandDr.Pleus forpatientlyansweringallmyquestions.A special thankyou tomysupervisorProfessorMorgadoforreviewingthiswork.

Thankyou tomy friendsat Sanofi forgreat conversationsduring lunchbreakandmakingiteasierbeingawayfromhome.

TomybrotherforbeingthedrivingforcetofinishthisworkandtoKatiforthemoralsupport.

Aosmeuspaispeloapoioincondicional

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Abstract

Diabetes Mellitus is characterized by inexistent or insufficient insulinproduction, with consequent hypoglycemia. To overcome this deficiency patientsneedtoadministerexogenousinsulintocoverhighbloodglucoselevels.Asaresulttheamountofdruginjectedisdependentonbloodglucoseconcentration,measuredbypatientswithhandheldbloodglucosemeters.Thesedevices,however,canhavedifferent accuracy depending on various properties and also the laboratorystandardusedtocalibratethem.Therefore itwas firstmadeareviewofBGMs, itstechnology,history,regulatoryrequirements,qualityrequirementsandlimitations,suchas,userhandlingandtechnicalerrors.

Secondly, and since it isnot clearwhat is the impacton insulindosewhenmeasuring glucose with BGMs performing and calibrated in a different way, thequantitativeeffectofthesedifferencesoncorrectinsulindosingwasinvestigated.

With that purpose, insulin doses based on results for each BGM and tworeferencemethodswerecalculatedandcompared.Aseparateanalysiswasmadeforlow,normalandhighbloodglucosetodistinguishmeterswithbetterperformancesineachlevel.

The basis of this work was an accuracy study where 10 meters werecompared with two enzymatic methods following ISO standards. Accuracycompliance to ISO:15197:2013 criteria for the evaluated meters was alsosummarized.

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Resumo

Adiabetesmellituséumadoençacaracterizadapelainexistenteouinsuficienteproduçãode insulina, comconsequentehiperglicemia.Demodoaultrapassarestalimitação,osdoentesnecessitamdeadministrarinsulinaparacobrirníveiselevadosdeglicemia.Assim,aquantidadedeinsulinaadministradadependedaconcentraçãodeglicosenosangue,queémedidacomaparelhosportáteischamadosmedidoresdeglicose no sangue. Estes dispositivos, no entanto, possuem valores diferentes deexactidãoresultadodediferençastecnológicasequímicase,também,doaparelhodecalibração.Primeiro, para perceber o funcionamento dosmedidores de glicose, foi feita umarevisãodahistória,tecnologiaregulamentação,requisitosdequalidadeelimitações,taiscomo,errostécnicosedoutilizador.

Seguidamente, foi investigado as diferenças no doseamento de insulinabaseado em valores adquiridos com dispositivos com tecnologias e desempenhosdiferentes. Para isso, doses de insulina foram calculadas e comparadas utilizandovaloresdeglicosenosanguemedidoscom10dispositivosdiferentesedoismétodoslaboratoriaisdereferência.Umaoutraanálisefoifeitademodoaperceberquaisosmedidorescommelhordesempenhoemváriosníveisdeglicemia.

Este trabalho é fundamentado num estudo laboratorial que analisou aexactidão de 10 medidores de glicose utilizando dois métodos laboratoriais dereferência. O estudo referido seguiu os procedimentos referidos na normainternacionalISO15197.

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TableofContentsAcknowledgments....................................................................................................................vAbstract.....................................................................................................................................viiResumo ...................................................................................................................................... ixTableofContents.................................................................................................................... xi1 Introduction ....................................................................................................................... 11.1 Diabetesmellitus....................................................................................................................11.1.1 Insulintherapy ................................................................................................................................. 2

1.2 Guidelinesandrecommendationsondiabetesdiagnosisandmanagement.....51.3 Selfmonitoringofbloodglucose(SMBG).................................................................... 111.3.1 History................................................................................................................................................111.3.2 Technologyandchemistry ........................................................................................................121.3.3 Requirements..................................................................................................................................181.3.4 ImportanceofAccuracy..............................................................................................................20

2 IntroductiontotheProblem.......................................................................................293 Methods .............................................................................................................................334 Results ................................................................................................................................395 DiscussionandConclusion..........................................................................................415.1 Significanceofthisstudy................................................................................................... 415.2 Methodology.......................................................................................................................... 415.3 Summaryofresults ............................................................................................................. 425.4 Limitationsofthestudy..................................................................................................... 435.5 FutureOutlook ..................................................................................................................... 44

References ...............................................................................................................................47Appendix ..................................................................................................................................51

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1 Introduction

1.1 Diabetesmellitus

Diabetes Mellitus is a chronic disease that affects millions of peopleworldwide. According to the World Health Organization’s (WHO) “Global StatusReport on Noncommunicable Diseases” of 2014, the prevalence of diabetes wasestimatedtobe9%inpeopleolderthan18.Thesamereportsays1.5milliondeathsin2012wererelatedtodiabetes[1].By2040,theInternationalDiabetesFederation(IDF)predicts642millionpeoplewilllivewiththisdisease[2].

Definitionandclassification

It is a metabolic disorder characterized by chronic hyperglycemia due toinsufficient or inexistent insulin production by pancreatic β-cells in the islets ofLangerhansoranacquiredresistancetothehormone’seffect.

Etiologicallydiabetescanbeclassifiedintwomajorcategories,calledtype1and type 2 diabetes [3]. Further clinical cases are gestational diabetes and otherspecifictypes.

Type 1 diabetes is caused by cellular-mediated autoimmune β-celldestructioninpancreaticislets.Asaresultinsulinisnotproducedandpatientsmustrelyonexogenousinsulinadministrationtosurvive[3]. It isfrequentlydetectedinearlyteens.

On the contrary, type 2 characterized by “adult-onset” (age≥45), though inrecent years increasing number of children have been diagnosed [4], is stronglyassociatedwithobesity (about70 to80%ofdiabeticpatients areobese), lifestyleandgeneticpredisposition[5].

Insulinactioninitstargettissuescanbeimpairedduetoobesity.Therefore,today’selevatedrateofobesity(15%ofwomenand11%ofmenolderthan18areobese), has increased theprevalence of diabetes type2. Globally, 90%of diabetic

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patientsaretype2[1].Althoughinearlystagesofdiseaseoverallinsulinproductionisnormal,thereisadelayinitsreleaseanditisrelativelylowtotissuessensitivity.This factor puts stress in pancreatic cells that have to compensate by producingmore insulin. Over time, due to insulin resistance, there is progressive β-celldysfunctionandlowerinsulinavailability.Thusinthefirststagesitcanbemanagedwith healthy diet and regular exercise but, inmost cases, insulin therapywill berequired in later stages [6]. However, patients’ unwillingness to change lifestylehabits leads to an accelerated decline in patients’ health and needing insulinadministration, even earlier. Increasingly sedentary lifestyle is indicated as oneofthereasons for thegrowingnumberofnewtype2diabetesdiagnoses[1].Coupledwith diabetes onset at a younger age, it is possible that the number of insulindependanttype2patientswillgrow.

Insulin is an anabolic hormone that facilitates glucose transport tomusclecells and adipose tissue and, in the form of glycogen, liver storage. In the pre-prandial state insulin levels are low and there is protein and lipid catabolism,formingketonebodies,hepaticgluconeogenesisandglycogenolisisinordertokeepplasma glucose concentration stable and available for the brain and other tissues(suchasredbloodcells).Whenthereisaspikeinglucoseafterameal if insulinisnotsufficientorthereisadecreasedresponsivenesstoitseffect,metabolismisthesameasinfastingwithincreasinghyperglycemia[5].Theseelevatedglucoselevelslead to microvascular complications such as retinopathy, neuropathy, andnephropathy.Eventuallymacrovascularcomplicationsappear,throughtheprocessofatherosclerosis,namelycoronaryarterydisease,peripheralarterialdiseaseandstroke[7].

1.1.1 Insulintherapy

Insulintherapyisessentialwhenthereisinsulindeficiency[8].Insuchcasesdaily insulindosesareadministered. Initialsourcesof insulin forclinicalusewereanimal pancreases (cow; pig) [9]. In 1972 pharmaceutical companies startedproduction of synthetic “human” insulin manufactured using recombinant DNA

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technique [9]. In 1996 FDA approved the first insulin analog [10]. Insulin analogshaveamodifiedaminoacidsequencethatallowsshorter/longeractionprofiles[11].

Insulinisinjectedthroughsubcutaneousinjectionsensuringthatitarrivestothebloodstream.Otherformulations,lesspopular,allowalternativeadministrationroutesthroughinhalers[9].

One type of insulin is not sufficient tomimic insulin secretion of a healthypersonthroughouttheday.Varioustypesofinsulin,accordingtotheiractionprofile,areavailable.Bolusinsulins(rapid-;short-acting)haveapromptonsetofactionandshort duration. They are administered before meals or snacks. Basal insulins(intermediate-,long-acting)havealongeractingprofilelastingtoupto30hours[8].

Rapid-actinginsulinstartsactingwithin15minofinjectionwithpeakafter2handisclearedafter4to6hours.Itisusedforhighglucosecorrectionortocoverglycemicspikessuchasthoseafterameal.Thereforeitisadministeredbeforemealsorsnacks[12].

Short-actinginsulinreachesbloodstreamafter30min,withapeakofactionbetween2to3hours.Itlastfrom3to6hours[12].

Intermediate-acting insulinhasaprofileof actionmoreextendedwithanonsetbetweensecondandfourthhourafterinjection.Itspeakisaroundhour4to12.Itseffectivenesscanlastupto18hours[12].

Long-acting insulin or basal insulin has duration up to 24h (newerformulationscanlastover30h[13])anddoesnothaveadefinedpeakofaction.Itisadministeredintheeveningbeforebedorinthemorningbeforebreakfast,usuallyreachesbloodstreamafter90minutes[12](newformulations’onsetdevelopsoveraperiod of 6h [13]). It is designed to mimic small amounts of insulin secretionthroughoutthedayinresponsetoglucosereleasebytheliverandtolowermorningfastingplasmaglucoselevels.

WHO Expert Committee of Biological Standardization established aninternationalStandardforhumaninsulin.Bydefinition1InternationalUnit(IU) is

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the activity of 0.03846mgof human insulin [14]. Since insulin analogsmaydifferfromhumaninsulintheyarelabeledinunits(U)[15].InsulinUnitsarerelatedtoitsbiological action,which is the blood glucose-lowering activity. Insulin is stored invialswithdifferentconcentrations(numberofinsulinunitsperml;U-100;U-500).Vialswithsmalleramountsarealsoavailable(U-40).

Syringes or insulin pens can be used to inject insulin. Insulin pens arecommonlyusedduetoeasinessofuse.Avarietyofinsulinpensareavailabletodayfor adults and children. Pre-filled pens already come with one vial and are non-reusable after all unitswere administered. Reusable pens can be usedwithmorethan one vial. Pens are graduated to measure insulin in units. Patients have tochoose,inthepen,theintendeddoseinunits,insertthelancetsubcutaneouslyandtheinsulinpenwillinjecttheselecteddose.Typically,insulinpensmeasureinsulinin2,1or0.5Uincrements.

Continuous subcutaneous insulin infusion is another way of deliveringinsulin that closely resemblesphysiological insulin release.Rapid acting insulin iscontinuously being injected in small doses and in response to measured glucose[16].Insulinpumpscandeliverdosesinevensmallerincrementsthaninsulinpens.

Insulin regimens are usually 40%-50% basal insulin and 50%-60% bolusinsulin[8][17].Basalinsulindosesarecalculatedbasedonglucoseconcentrationinthemorning (fasting). Insulin titrationmay followa titration schemeprovidedbytheHCP(HealthCarePractitioners)wherenumberofunitswillincreaseuntilbloodglucosetargetrangeisreached.

Mealtime insulin doses are intended to cover carbohydrate intake and tocorrectforhighbloodsugar.Dosestocovercarbohydrateintakearedeterminedbytheamountofcarbohydrate inthemealandtheamountofcarbohydratedisposedby1Uofinsulin.Oneunitusuallycoversfrom6-30gofcarbohydrates.Thisvaluemaydependontimeofday,exerciseandvaryfrompersontoperson[8].Dosestocorrect for high blood sugar are calculated based on pre-prandial blood glucose,target BG and insulin sensitivity factor (ISF). ISF expresses what glucoseconcentrationdecreaseisachievedbyinjectingoneunitof insulin.Thisparameter

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is,atleastfordiabetespatientswithpumptherapyorintensifiedtherapy,onemajorparameterindiabetestherapy.

Important factors that affect insulin dose and insulin availability are,carbohydratecount;differences in insulinabsorptionandmeasuredbloodglucose[18].Erroreffectswillbeassociatedtoinsulinactionprofile.Anerrorinbolusdosecan represent an immediate emergency (30min)whereas in basal insulin errorswillhaveamorelastingeffect.Animportantcauseofconcernishypoglycemiaandinparticularnocturnal hypoglycemia (related tobasal insulin)hence the fear andreluctanceofmanypatientsinusinginsulinparticularlyinintensifiedregimens.

1.2 Guidelinesandrecommendationsondiabetesdiagnosisandmanagement

Many internationally recognized organizations are committed to diabetesresearch and patient care. The European Association for the Study of Diabetes(EASD), American Diabetes Association (ADA), American Association of ClinicalEndocrinologists(AACE)andInternationalDiabetesFederation(IDF)aresomewithmoreexposure.

To help patients andHCPsmanage diabetes and inform them of the latestdevelopment in treatment they publish in websites and scientific journalsinformation,guidelinesandrecommendationstoimprovequalityofcare.

Recommendationsandguidelinesarewrittenbygroupsofpeopleconsideredspecialists in the field, supported by clinical evidence. They reflect a consensusopinionamongthegroup.Diagnosis,monitoringandtherapeuticactionsindiabetesaresomeofthetopicsdiscussed.

DiagnosisofDiabetesMellitus

Diabetes is diagnosed by testing the presence of hyperglycemia either byplasmaglucosecriteriaorglycatedhemoglobin (HbA1c) criteria.Cut-offvaluesare

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establishedbasedonthresholdsofglycemiaassociatedwithmicrovasculardisease.Testsareperformedwithlaboratorymethodsusingvenoussamples.

Table 1.1 represents parameters and respective cut-off values for diabetesdiagnosis.

Table1.1:DiagnosisofDiabetes.FPG,fastingplasmaglucose;2hPG,2-hourplasmaglucose;OGTT,oralglucosetolerancetest;HbA1c,glycatedhemoglobin;PG,plasmaglucose

Parameter Cut-offValue

FPG ≥126mg/dL(7mmol/l)2-hourPGOGTT ≥200mg/dL(11.1mmol/l)

HbA1c ≥6.5%(48mmol/mol)RandomPG ≥200mg/dL(11.1mmol/l)In the presence of classic hyperglycemia symptoms (polyuria, polydipsia

unexplainedweightloss),asingletestindiabetesrangeisenoughforclassification.If not, the test previously used should be repeated on a different day, except ifrandomPGwasmeasured,inwhichcaseanalternativemethodisrecommended.

HbA1ctestrepresentsthepercentageofglycatedhemoglobininerythrocytesand is ameasure of glycemic control of the past 2 to 3months (average time forerythrocyte turnover).When usingHbA1c to diagnose diabetes it is important totakeintoconsiderationfactorsthatcanleadtomisleadingresults.Suchfactorsareage,ethnicityandmedicalconditions(hemolyticanemias,hemoglobinopathies,irondeficiency).Thistestisnotintendedfordiagnosisinchildren,adolescents,pregnantwomenorwhensuspectedT1DM.Itmustalsobeperformedusingastandardized,validatedassay.

In patients with likely T1DM, confirmation by laboratory test should notdelaytreatmentinitiationinorderforpreventrapiddeterioration.

GlycemicTargets

ADA,IDF,CDA(CanadianDiabetesAssociation)recommendanHbA1ctarget< 7% or less for adult non-pregnant patients. Patients with no significant risk ofhypoglycemia or adverse events can target to < 6,5%. Conversely a less stringent

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goal (≤ 8%) can be set for patients with risk of hypoglycemia, limited lifeexpectancy, advanced micro and macrovascular complications and othercomorbidities. Premeal capillary blood glucose should be targeted between 80-130mg/dLandthepostprandialpeakbelow180mg/dL [8].AACEproposes fastingandpremealbloodglucosebelow110mg/dLand2hpost-prandial<140mg/dL.

Even though these recommendations are based on clinical evidence ofimproved outcomes, they represent a guide for glycemic control. Goals should betailoredtoindividualneeds.

ManagingDiabetes-Lifestyleinterventions

Diabetes care must comprise lifestyle changes, some of which are dietmodification, increase inexercise, sufficientamountof sleep, smokecessationandmoderationinalcoholconsumption.

Medicalnutrition therapy isbeneficial forglycemiccontrol inDM.Glycatedhemoglobin can be reduced by 0.3-1% in T1DM and 0.5-2% in T2DM [8][19].Patients should be educated about nutrition therapy at the time of diagnosis.Strategies for meal planning, grocery shopping, healthy food choices should beaddressed.Regardingrelativedistributionofcaloriesacrossmacronutrients, thereisnotoneperfectproportionforeachone.Energysourcesmayrangefrom45-60%carbohydrate,15-20%protein,and20-35%fat.Foodchoicescanbeindividualizedconsidering preference, religion and geographic region with metabolic goals inmind.Emphasis shouldbegiven to foodwithhigh fiber contentand lowglycemicload in detriment of high sugar content.Whole grains, vegetables, fruits, legumesanddairyproductsshouldbethepreferredsourceofcarbohydrates[8].Preferenceto food with high content in polyunsaturated and monounsaturated fatty acidsshouldbegivenwithlimitedintakeofsaturatedfattyacidsandavoidanceoftransfats.

Educationoncarbohydratecountisessentialtopatientswithflexibleinsulinregimens since administered dose will depend on carbohydrate amount. Fixed

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insulinregimensdependonsteadycarbohydrate intake.Patientswillbenefit fromeducationonmealplanningandportioncontrol.

In overweight or obese T2DM patients, weight loss has been shown to bebeneficial to reach glycemic targets and reduce need for pharmacologicinterventions [8]. Lower healthier body weight can be achieved following anutritionallybalanceddiet,reducedenergyintakeandregularexercise[20].

Regular physical activity is associated with increased cardiorespiratoryfitness, improved glycemic control, improved insulin sensitivity, blood pressurereduction, improved lipid profile and maintenance of weight loss [21]. It isrecommendedforpeoplewithdiabetestodomoderate-intensityaerobicexerciseatleast3daysaweek(atleast150mincumulatively)withnomorethan2consecutivedaysbetweenexercisedays[8][21].

Resistance training is also related with improved glycemic control anddecreased insulin resistance. Patients should perform resistance exercise twice aweek[21].

Exercisemayprompthypoglycemiainpatientsusinginsulin.Dosereductionor carbohydrate intake adjustment can prevent dangerously low blood glucose.Blood glucose should be checked before exercise and carbohydrates should beingestedifmeasurementislow(<100mg/dL)

Anotherimportantpartofcareindiabetesiseducationonself-management.It helps peoplewith diabetes tomake informed choices regarding treatment andfacilitateseffectiveself-managementthroughouttheirlife[22].

Pharmacologicaltherapy

T1DMrequiresinsulintherapyimmediatelyatdiagnosis.Patientsshouldbetreatedwithmultipledoseinsulininjections(3ormoreinjectionsperdayofbasalandprandial insulin)orcontinuoussubcutaneous insulin infusion(pumptherapy)[8]. Diabetes Control and Complication Trial established the advantages of

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intensified insulin therapy in reducingmicrovascular complications.Although riskof severe hypoglycemia was approximately three times higher, new developedinsulinanalogsareassociatedwithlowerrateofhypoglycemia[23].

Bolusinsulincomprises50-60%oftotaldailyinsulin(TDI)distributedbythenecessary premeal doses. Doses must account for carbohydrate intake, glycemicindexofeachfoodandmeasuredBG.

WhenlifestyleinterventionsalonecannotmaintainglycemicgoalsadditionaloralpharmacologictherapyisonechoiceforT2DMmanagement.Thereareseveralagentswithdifferentphysiologicaleffects.Theyacttoreduceglycemiclevelmainlyby decreasing hepatic glucose production, elevating insulin sensitivity in targettissuesorimprovinginsulinsecretion[5].

Biguanides (Metformin) are generally the first recommended oral anti-hyperglycemicagent[8][24][25].Theyacttosuppresshepaticglucoseproductionandraiseperipherytissuessensitivitytoinsulin.Ifafterapproximately3months,athighestpossibledose,HbA1ctargetisnotachieved,combinationtherapyshouldbeconsidered with a second oral agent. Subsequently a third agent can be added.Choiceoforal agentneeds tobe individualized consideringpatient characteristics(degree of hypoglycemia, height, comorbidities), agent effects (blood glucoselowering efficacy, effect on height, side effect) and costs to provide best possiblecarewhileminimizingsideeffects[8].

Insulin therapy inT2DM isadvantageousandrecommendedwhenpatientspresent hyperglycemic symptoms and elevated glycemia or high HbA1c or whenothermethods fail to help patients achieve glycemic goals. If insulin is necessarytherapyshouldstartwithbasalinsulinoncedaily.

ADA/EASDguidelinespropose initialbasal insulindoseof10U/dayor0.1-0.2U/Kg/dayandadding10-15%or2-4UtopreviousdoseonceortwiceaweekfordosetitrationwhileBGisabovetarget.Ifglycemiccontrolisnotreachedguidelinesrecommendaddingpreferablyoneoralagent(Glucagon-likepeptide-1,GLP-1)thatstimulatesglucosereleaseorprandialinsulin.

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Several schemes are available for prandial insulin initiation and titration.Initially only one dose before largest meal and if targets are not met addinginjectionsbefore2or3meals[8][17].Adjustmentscanbedonebyadding10-15%previousdoseor1-2U,twoorthreetimesaweekwhilepostprandialglucoseisnotattarget[8][24].

MonitoringDiabetes

Monitoring diabetes is needed to evaluate disease progression andeffectiveness of treatment. Glycemic control may be assessed with two principaltools:SMBGorlaboratorytestsforglycatedhemoglobin.

Glycatedhemoglobinisameasureofaverageglycemiccontrolandshouldbetestedevery3monthsor6ifvaluesareconsistentlyintargetrange.

SMBG is used as an aid to guide and assess interventions and detecthypoglycemia.UnderstandinghowtoperformSMBG,what resultsmeanandwhatare the appropriate actions is essential for optimal use of SMBG. Regularmeasurements give patients immediate feedback about intervention effects(exercise, food, medication) on glycemic control. If performed and recordedregularly helps establish glycemic patterns that can be correlated to therapeuticactions.

Frequent self-testing of blood glucose in insulin dependant patients onintensified insulin therapy is of the upmost importance and has been related toHbA1c reduction. Patients are advised to test BG beforemeals and snacks and attimes after meals, before exercise, at bedtime, when they think BG is low, aftertreating low BG until values normalize and before dangerous/serious tasks likedriving.T2DMpatientstreatedwithoncedailybasalinsulinplusoralagentsshouldtest at least once every day at different times [26]. If patients are on non-insulintherapyormedicalnutrition therapy,SMBG is recommended tocontrol treatmenteffectiveness[8].

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1.3 Selfmonitoringofbloodglucose(SMBG)

The Diabetes Control and Complications Trial showed that tight glycemiccontrol, achieved with intensive insulin therapy, can slow the progression ofmicrovascular complications for type 1 patients [23]. Similarly, another study,conducted by UK Prospective Diabetes Study (UKPDS) Group, reached identicalconclusionsfortype2patients[27].Bothstudiesareatestimonytotheimportanceofintensifiedglycemiccontrolandinsulintherapyforwhichdailyself-monitoringofbloodglucose(SMBG)iskey.

1.3.1 History

Self-monitoringofbloodglucosestartedin1963withthedevelopmentofdrychemistryteststripsDextrostix®(MilesLaboratories,Elkhart,IN,USA;nowpartofBayer),byErnestAdamsandhisresearchteam,whichdisplayedabluecolourwithintensityproportional toglucose concentration. It requiredadropofbloodof50-100µl that had to be wiped after 1 minute. Glucose concentration was thenestimatedcomparingthepaperstrip’scolourtoacolour-concentrationchart[28].In1971, Anton Clemens at Miles Laboratories, patented the first device for self-monitoringofbloodglucose[29].Thedevice,calledAmesReflectanceMeter,usingreflectance photometry was able to detect and quantify reflected light fromDextrostix®teststrips.Thismeter,fortoday’sstandards,wasbulky,heavy(1.2kg)and expensive; however, it was an improvement from visual evaluation of teststrips. Further improvements were made releasing meters easier to handle, lessexpensiveandcapableofstoringdata.

Although Clarke and Lyons proposed the first glucose biosensor in 1962usinganamperometricenzymemethod[30],biosensorswereonlyavailabletoendusersaround1987whenMediSence(Waltham,MA,USA;nowAbbottDiabetesCare,Alameda, CA) launched ExacTech® [31]. It was very innovative in terms ofportability and appearance with two types offered. The customer could choose

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betweenapenandacreditcardsizedmeter.Detectionandquantificationofglucosewasdonethroughanenzymecoupledwithanelectrontransfermolecule.

From then on the market of glucose sensing gradually moved fromphotometrictoelectrochemicaltechnology.

Operator-dependant steps that were potentially error sources were alsominimizedorremoved.Forexample,wipingofteststripsandtimingwasnolongernecessary;samplesizewasreducedwiththeintroductionofcapillarityfilling[28].

It is worth mentioning another generation of glucose meters used forcontinuous invivobloodglucosemonitoring.Theelectrochemical sensor isplacedsubcutaneouslythoughaflexiblecatheterintheformofaneedleoflessthan1mmin diameter [32]. Continuous glucose monitoring (CGM) permits a betterunderstanding of glucose levels’ progression with real-time values every 1 to 5minutes.

Since that first blood glucosemonitor (BGM), technology for blood glucosemeasurement evolved substantially. Todaymeters for self-measurement fit in thepalmofahand,requiresamplesofabout1µLorevensmaller,arefast(5s)andareeasytouserequiringverylittleinputfromtheuser.

1.3.2 Technologyandchemistry

BGMs need to be able to detect glucose from a complex blood sample andconvert its concentration into a measurable signal. Themajority of commerciallyavailable SMBG systems use electrochemistry and have two fundamentalcomponents: a biorecognition agent and a transducer. Bioreconignition is donethroughanenzymespecificforglucoseandaredoxmediatoractsastransductor.

Glucose measurement in BGMs is based on oxidation-reduction reactions.Thereiselectrontransferencefromglucosemoleculesfirsttotheenzyme,thenthemediator and lastly picked up by an electrode. Sowhen glucose is present in thesampleafluxofelectronsisgeneratedproportionaltoglucoseconcentration.Figure1.1 is a schematic representation of reactions happening in a GOD test strip. The

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enzymesandmediatorsarecapableofparticipatinginseveralreactionsbecause,asseeninFigure1.1,aftereachreductionthereisanoxidationtoreturnthemoleculestotheirinitialstate.

Figure1.1:Oxidationandreductionreactions thatoccur ina teststripGODbased.OXandRedrepresent theoxidisedandreducedstaterespectively.Reprintedfrom[33]Copyright2008,AmericanChemicalSociety

Enzymes

They are oxidoreductases that act in the reducing end of glucose, thehydroxyl group, to form gluconolactone. In handheld BGMs those enzymes areglucose oxidase (GOD) or glucose dehydrogenase (GDH) [34]. In laboratoryanalysersHexokinase(HK)isalsousedbutnotGDH.

ThereactioncatalyzedbyGODisdescribedineq.(1.1)

(1.1)

GOD oxidises glucose transferring two electrons to the enzyme cofactor,flavin adenine dinucleotide (FAD) reducing it. Oxygen is the natural acceptor ofelectronsfromGOD,forminghydrogenperoxide(eq.(1.1)).H2O2isanactiveoxidantthatcannonspecificallyoxidizemetabolitesfromthesample,suchasuricacidandbilirubin, causing interferences in the measurement. For that reason, othermoleculesareusedasmediators(eq.(1.3)),butoxygencanstillcompetewiththemforelectrons.WhenusingaGODbasedmeter, sample type, i.e. venous, arterialorcapillary,willrenderdifferentresultsintermsofglucoseconcentrationexactlyduetodifferencesinoxygenpartialpressure.

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SinceGDHisunabletouseO2astheelectronacceptoroxygencontentinthesample no longer interferes with measurement. While GOD only uses FAD ascoenzyme,GDHalsousesnicotineadeninedinucleotide(NAD)ornicotineadeninedinucleotidephosphate(NADP)andpyrroloquinolinequinone(PQQ).Thecofactorplays an important role in enzyme specificity. GDH(PQQ) can react withmaltose,xyloseandgalactose[35].GDH(NAD)reactswithxyloseandGDH(FAD)reactswithmaltose, mannose, galactose and lactose but in very low percentages [36]. Whenusing ameter, health carepractitioners (HCP) or patients shouldbe aware of thepossibleinterferencesandchoosedevicesaccordingly.

Mediators

Mediators are organic or inorganic molecules capable of existing in theoxidizedorreduced form. Inotherwords, theyreact rapidly toacceptanddonateelectrons[36].

Subsequent to glucose oxidation by the enzyme (eq. (1.2)), electrons aretransferred from thecofactor to themediator reducing it (eq.(1.3)).Theenzyme,now in the reduced form, canagain takepart inmore reactionswithglucose.Themediatorcanalsoberegeneratedwhenoxidizedbytheelectrode(eq.(1.4)). It isthis reoxidation that gives the signal current needed to measure glucoseconcentration.

(1.2)

(1.3) (1.4)

As seen in eq. 1 the pairO2/H2O2 can act as amediator.However, in BGMothermoleculesareusedas,forexample,hexacyanoferrateIII/hexacyanoferrateII;Hexaammineruthenium(III) chloride/Hexaammineruthenium(II) chloride [37]. Thelower the redox potential, less interference from other bioactive molecules will

glucose +GOD(ox ) →gluconolactone +GOD(red )

GOD(red ) + 2M(ox ) →GOD(ox ) + 2M(red )

2M(red ) →2M(ox ) + 2e−

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occur [36]. Mediators are chosen according to their redox potential along withsolubilityandrateofdissolution,stabilityinmixtureswithproteins,redoxpotential,availabilityandcost[32].

Teststripdesign

Test strips are small thin multilayered plastic strips where the chemicalcomponents for detecting glucose are housed. Each manufacturer has its ownspecificdesign,butoverallteststripsaremaderoughlyinthesameway.

Twolayersofplasticinthebottomandtopgivesupport.Eachteststriphasatleast2or3electrodes.Usuallythereisaworkingelectrodeandareferenceandauxiliary electrode. Fill detection electrodes can also be present to detect whensufficient amountof sample is introduced.One commonmaterial for electrodes iscarbon ink that is screenprinted on test strips. Reference and auxiliary electrodecanbemadeofothermaterialse.g.screenprintedinkofAg/AgCl.

To start the reaction in the test strip themeter has to apply an electricalpotential to the electrodes.After analyzing the current time responseof the strip,the meter then converts the signal into a glucose concentration shown in thedisplay.

Figure1.2:Squematicviewofteststriplayers;(A)electrodesystem;(B)hydrophobiclayer.Reprintedfrom[33]

SMBGdevices takewhole blood samples tomeasure glucose concentrationbutprovideaglucoseresultthatisplasmaequivalent.Duetodifferencesinglucose

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concentrationbetweensamplesaconversionfactorneedstobeapplied. Insystemaccuracytestingthemostcommonconversionfactorisgivenbyeq(1.5):

(1.5)

Gplasma refers to glucose concentration in plasma and Gwhole_blood glucoseconcentration in whole blood. The value 1.11 is the International Federation ofClinicalChemistry(IFCC)recommendedconversionfactoralthoughthereareotherconversionfactors,someofthemhematocritdependent.

Interferences

The complex enzymatic reaction in BGMs can be altered by a series ofinterferingagents.They canbebrought inby environment factors,manufacturingprocessorbloodsamplecomposition.

AltitudeaffectsmetersperformanceduetodifferencesinO2partialpressure.Asdescribedbefore,O2isthenaturalacceptorofelectronsinGODbasedteststrips.Since the electrode can only pick up electrons from the mediator, glucosemeasurement is compromised by changes in O2 partial pressure. For instance, athighaltitude,wherepO2islower,glucosevalueswillbeincreased[38].

Temperature and humidity change reaction kinetics with differentconsequences for different types of test strip [38]. Furthermore, mediator can bereducedathighertemperatures.Amediatorreducedbytemperaturewill,therefore,leadtoanelevatedsignalnotrelatedwithglucoseconcentration[39].Somemetershave internal thermometers to correct temperature differences. It is necessary,however,toavoidmeasurementswhentemperaturechangesrapidly.

Test stripmanufacturing process can prompt changes in enzyme coverageandteststriplotdifferencesthatbringvariability.Enzymecoverageisproportionaltotheproducedcurrent.Lossofenzymeareawillleadtounderestimationofglucose[38].

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Blood compositionof the sample canalsobring interferences.Mostmetershave a percentage range of hematocrit 20-60%where they canmeasure glucose.Outsidethoseboundaries,valuesarenolongerreliable.Hematocritinterfereswithdiffusionofglucoseinthesampletothesiteofreaction.BGMsmeasureglucoseinwholebloodandarecalibratedtoprovidearesultthat isplasmaequivalent.Sinceerythrocytescontainintracellularglucoseatadifferentconcentrationthanplasma,variationsinhematocritcancauseerrors[38].Somemeterscancompensateforthiseffect. Anemia, certain types of cancer, chronic and end-stage renal disease,malnutritionorspecificdietdeficiencies,rheumatoidarthritis,andotherconditionslower HCT [40]. Patients with underlying conditions ormedication that can alterhematocritshouldnotusehandheldmeterssensitivetohematocrit.

PartialpressureofO2 in the sample, as in atmosphere, also interfereswithmeasurements[41].SincepO2isdifferentinarterial,venousorcapillaryblood,onlycapillarybloodshouldbeusedtomeasurebloodglucoseconcentrationwithSMBGsystems intended for capillary samples. Alternate site testing should only beperformedwhenexplicitlyapprovedinBGMs’labelling.

Certainchemicalsubstancespresentinthebloodsample,eitherendogenousorduetomedicationorpathologies,canhaveacompetitivereactioninthreestepsofthereactiononateststrip.Competingwiththeenzymesubtract(1),competingwiththemediator(2)orcompetingwiththeelectrode(3).

Table1.2:Effectofdifferentsubstancesonglucosereadings1–GOD;2–GDH.Adaptedfrom[38]

Substance Effectonreading Step

O2 Variable 2Uricacid Increase1 3Galactose Increase2 1Xylose Increase2 1

Acetaminophen Decrease1 3L-dopa Variable1 3

Tolazamine Variable1 3Ascorbicacid Variable1 3Icodextrin Increase2 3

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Due torapidchanges inhematocrit,pO2,medicationSMBG isnotapprovedfor patients in critical care or neonatal care. Also when choosing a device HCPshouldtakeintoaccountthemedicationofthepatientandcheckmanufacturerlabelforpossibleinterferences.

Although technical limitations can lower accuracy, user handling is also animportant part in obtaining good results. Some basic steps such as handwashingandcontrol testingarevery importantwhenmeasuringbloodglucosewithBGMS.Thesewillbediscussedlaterin“Importanceofaccuracy”section.

1.3.3 Requirements

IntheEuropeanUnion(EU)BGMsforself-testingareregulatedbydirective98/79/EConinvitrodiagnostic(IVD)medicaldevices.IVDsareaspecificcategoryof medical devices “intended by the manufacturer to be used in vitro for theexaminationof specimens, includingbloodand tissuedonations,derived from thehuman body, solely or principally for the purpose of providing information:concerning a physiological or pathological state; (…) or to monitor therapeuticmeasures.”[42].BGMsareclassifiedasmoderateriskdevices(listB,AnnexII).

Demonstration of compliance with essential requirements described indirective98/79/ECwill allowapplicationof CE (ConformitéEuropéene)Mark andfreemarketing inEU.Notifiedbodiesareapartof theapprovalprocess forBGMS.Theseindependentthirdpartiesevaluatethequalityofdocumentationprovidedbythemanufacturerandcanaskforadditionalinformation.

Thedirectivedoesnotdescribespecific technical factors. Instead, itdefinesbroad essential requirements for any IVD regarding safety for all users. MoredetailedtechnicalevaluationsaredescribedinEuropeanharmonizedstandards(e.g.ISO13485-QualityManagementSystems).

The InternationalOrganization forStandardization(ISO) isan internationalbodythatspecifiesstandardstoensuresafetyandqualityofproductsandservices.

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Performance requirements regardingsystemaccuracyofBGMs for self-testingarespecifiedinISO15197.Thisstandardwasrevisedin2013.

AnalyticalSystemaccuracy

Previousminimumsystemaccuracywasdefinedas:95%ofvaluesshouldbewithin either ±15mg/dL at glucose concentration <75mg/dL orwithin ±20% atglucoseconcentrations≥75mg/dL.Therewasnorestraintregardingoutliers(5%ofresultscouldfallanywhere).

Minimumsystemaccuracycriteriaarenowdefinedas:

“95%ofmeasuredglucosevaluesshallfallwithineither:

• ±0,83 mmol/l (±15 mg/dL) of the average measured values of thereference measurement procedure at glucose concentrations < 5,55mmol/l(<100mg/dL)or

• ±15%atglucoseconcentrations≥5,55mmol/l(≥100mg/dL).”[43]

Glucose concentration cutoff from absolute value to percentagewas raisedfrom75mg/dLto100mg/dL.This,however,doesnotmeanarelaxingincriteria.Figure1.3evidencesthatnewcriteriaaremorestringentforvalueslargerthan75mg/dL.Forvaluesbelow75mg/dL,existingaccuracyrequirementsaremaintained.

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Figure1.3:Differenceplotwithsystemaccuracylimits.AccordingtoISO15197:2003(fullline)atleast95%ofresultsshallbewithin±15mg/dLatBGconcentrations<100mg/dLandwithin20%atBGconcentrations≥100mg/dL.The2013revision(dotedline)stipulatesthatat least95%ofresultsshallbewithin±15mg/dLatBGconcentrations<75mg/dLandwithin±20%atBGconcentrations≥75mg/dL).

Therevisedstandardadoptsarisk-basedapproachwiththeConsensusErrorGrid(CEG)forT1DM.Whereasbeforetherewerenorequirementsfor5%ofresults,now 99% of measured values are required to fall within zones A and B of CEG(explainedinnextsection).

1.3.4 Importanceofaccuracy

Measurement variability in BGM can be related to numerous factorsintroducedsincethemanufacturingprocesstothetimeofuserhandling.Ingeneral,sources of interferences can be related to the monitoring system, as describedearlier, calibration process or user errors [44]. All three can be present andcontributetothefinalsystemaccuracy.

BGMSystemaccuracycriteriaandproceduresforitsassessmentaredefinedby the International Organization for Standardization in ISO 15197. Thestandardizationoftheseproceduresisimportanttodefineminimumrequirements

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and to have comparability between laboratory studies. These studies determinesystem accuracy and demonstrate meter’s compliance to the internationalstandards,whichismandatoryforCEmarking.Butregularandindependentstudiesare also important to ensure constant adherence of BGMS to internationalstandards. However, such studies are not compulsory and there is no EU-wideindependent institution that evaluates BGMS quality. Manufacturers themselvesgenerally do these studies. But variability between test strip batches may affectmeasurementquality [45]. Individual test strip lots fromEUmarketedBGMShavebeenreportedtonotfulfilminimumsystemaccuracycriteria[46][47].

It is important to point out that an analytically accurate meter does notassureoptimalperformanceindailyuse.User’shandlingproficiencyisabigpartofthe measurement. In a standardized laboratory study, performed by trainedpersonnel,wherethereisacontrolledenvironmentsetforoptimalperformanceandwhere interferences can be reduced to a minimum, analytical accuracy can beevaluated exclusively. However, these conditions do not reflect patients’ dailymeasurements where sampling conditions and device handling may influencemeasurement results. Figure 1.4 summarizes conditions in daily life that mayinfluencesystemaccuracy.

Usererrors

Amongthemostfrequentusererrorsarefailingtocleansitebeforedrawingthesampleandincorrectteststripandmeterhandling[48].

An unclean hand containing traces of glucose-containing products cansubstantially increase glucose concentration values [49] [50]. More so withmicrosamplemeterssincesmallamountsofcontaminatingsubstanceshavegreaterinfluencewhensamplevolumeissmaller[38].Inastudywheresubjects’fingershadbeen exposed to fruit previous tomeasurement showed that for 88%of subjects’valuesweremorethan10%highercomparedtocontrolmeasurementusingthefistdropofblood.Usingtheseconddropofblood improvedresults.However,11%ofpatientsstillobtainedvalues10%higherthancontrol[51].Onlywashinghandswith

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soap and water and drying them provided satisfactory results. Traces of othersubstances, forexamplehydrogenperoxide, found inhandsanitizersandascorbicacid,foundinfruit,mayactasareducingagentsandaffectmeasurementsaswell.

IncorrectteststriphandlingTeststripsduetotheircomplexenzymaticreactionareaverysensitivepart

of BGM. Its lifetime is about 2 years when stored in appropriate humidity andtemperature conditions, as per manufacturer recommendations, for optimalperformance [38]. A study comparing performance between test strips of openversus closed vials in different conditions of humidity, temperature and lightexposure concluded that test strips fromopen vials deteriorated faster than teststrips in closed vials. Even test strips from closed vials stored incorrectly underdirectlightorhighhumiditydidnotremain“analyticallystable”lasting28ofthe50study days [39]. Patients should be aware of and respect manufacturer’s storagerecommendations.

Figure1.4:Sourcesoferrorinroutinebloodglucosetesting.Reprintedfrom[53].

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Mechanicalstressappliedtotheteststripandteststripreusehavealsobeenreported as commonmistakes patientsmake [52][53]. The later is, inmost cases,owedtoteststripcost.

Incorrectmeterhandling

When performing the measurement some aspects need to be taken inconsideration. Sample evaporation, with consequent elevation of glucose, andcontactwith oxygen can alter sample composition. Correct sample application onthe test stripandswiftmeasurement reduce thoseerrors.These simplemeasurescanbeimprovedwithtrainingandmakeobtainingreliableresultseasier.

Alternatesitetestingfromforearm,palm,thighandearlobeisavailablewithsomemeters.Theseoptionsaredescribedtobelesspainfulandsomoreappealingfor frequent testing.Howeverdue todifferences in skinblood flow,bloodglucoseresults can have a lag time especially during rapid glucose excursions delayinghyper-orhypoglycemiadetection[54].

Adding up meter’s technical limitations and user errors can make adifference in the final result. It is both important to have an analytically accuratesystemandcorrectmeasurementtechnique.

To minimize user error SMBG manufacturers must provide clear labelingwith instructions for use, understandable to patients, so that goodmeasurementscanbeobtainedwithoutfurthertraining.Evidentlypatientsshouldtakethetimetoreadthemcarefullyandadheretothem.AtthetimeoffirstSMBGcontacttrainingshouldalsobeprovidedby theHCPwhoshouldalsobe familiarwith instructionsfor use. Another strategy, adopted bymanufacturers, is to reduce the number ofoperator-dependantineachmeasurementand,consequently,diminishingmistakeslikelihood.Forexamplewhen test stripcodingwasabsent,user relatederrorwaslowercomparedwithmetersthatstillemployedthattechnology[55].

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When using blood glucose meters patients should be aware of itsperformance under different environmental conditions, know meters’ limits,technical limitations and possible interferences. Knowing these users can takemeasurestomitigateerrorsandmakeaconsciousinterpretationoftheresultsgivenby themeter.Frequent testingwithcontrolsolutioncanhelpestablish ifdevice isperformingcorrectly.

At home a patient has to rely on values given by BGM systems to make

appropriate therapeutic decisions. Blood glucose values,measuredwith handheldBGMs,areasourceof information tooptimizeglycemiccontrolandpreventacutechroniccomplicationsofdiabetes.Inmanagingdiabetesthemeasuredvalueistakenasthe“true”glucoseconcentrationandtreatmentdecisionsaremadebasedonthatsupposition.Preprandial glycemia for example is akeyvalue to calculateprandialinsulin dose. This dosewill determine postprandial glycemic excursions and overtimeglobalmetaboliccontrol[56].

Resultspositivelybiasedcanpreventpatients fromdetectinghypoglycemiaorleadtotheadministrationofanexcessiveamountofanti-hyperglycemicdrugs.Apatientwhoseglucoseconcentrationisalreadylowcanhaveaseverehypoglycemicepisode if low glycemic levels are undetected. On the other hand, if a meter isnegatively biased hyperglycemia can remain concealed allowing chronicallyelevated BG levels associated with risk of developing diabetes-relatedcomplications.Evenwithinaccuracylimitsresultsmayvarysubstantially.Accordingto revised ISO of 2013 standards the cut-off is ±15 mg/dL for glucose levels of<100mg/dLand±15%forglucoselevelsof≥100mg/dL.Thismeansthataresultof60mg/dL, for example, couldbebetween45mg/dLand75mg/dL. ADA sets analertvalueforhypoglycemiaatplasmaglucoseconcentrationof≤70mg/dL,this,ofcourse, varies between patients and may shift depending on patients’ glucoseconcentrationhistory.FollowingADAhypoglycemiccutoff,theformerresultwouldbeidentifiedashypoglycemicwhereasthelatterwouldn’t.Fearofhypoglycemiaisoneofthemostthreateningfactorsinpatients’perspectiveandabarrierforinsulintherapy adherence [56]. A hypoglycemic event may prompt confusion, loss of

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consciousness and, at the extreme, death. Therefore, it is a concern to accuratelymeasureBGinlowglycemicranges.

On the other side of the scale a value of 400 mg/dL could be reportedbetween340mg/dLand460mg/dLpromptingdifferenttherapeuticdecisions[48].

OnewayofmeasuringtheclinicaleffectofbasingtreatmentdecisionsonBGmeasurements isbyerrorgridanalysis. InthisqualitativeapproachBGMmeasurevalues are comparedwith adesignated comparisonmethodandplottedona griddividedby5zonesaccordingtoclinicaloutcomes(Figure1.5).ZonesrangefromA(no effect on clinical action) to E (Altered clinical action, could have dangerousconsequences). Table 1.3 describes potential clinical actions of errors falling inzonesA,B,C,DandE.Thisassessment reflectsexpertopinionbasedonevidenceavailable previous to 1994 and may be obsolete with new analytical accuracycriteria, insulin types and clinical practice. It is however a good tool to classifyoutlierdatapointsfromBGMaccordingtotheseriousnessofalteredclinicalaction.

Figure1.5:ParkserrorgriddevelopedforT1DM.

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Table1.3:Definitionsoftheerrorgridzones

Risklevel(CEGzone)

Risktodiabeticpatient

A NoeffectonclinicalactionB Alteredclinicalaction–littleornoeffectonclinicaloutcomeC Alteredclinicalaction–likelytoaffectclinicaloutcomeD Alteredclinicalaction–couldhavesignificantmedicalriskE Alteredclinicalaction–couldhavedangerousconsequences

WhenlookingataccuracyoneshouldhaveinmindthepurposeSMBG.SMBGisrecommendedtodetermineinsulindoses,toachieveglycemicgoalsanddetectionofhypoglycemia[57].Howrelevanterrorsareandwhichlevelofaccuracyisneededwilldependonwhatwayvaluesareusedforintherapeuticdecisions.

A diverse population of patients with varied therapeutic regimens anddifferent diabetes types and acuteness uses BGMs. Evidently they have differentneeds in terms of SMBG system accuracy. For patients in insulin therapy earlydetection of hypoglycemia is essential. These patients need especially accuracy inthehypoglycemicrange.Patientsinintensifiedinsulinandinsulinpumptherapyareadvisedtocheckbloodglucosebeforemealsandexercise,atbedtime,sporadicallyposprandially,whenhypoglycemia is suspectedamongothers [8].Accuracyacrossallglucoserangesisexpected.

NotonlytheBGvalueisimportantininsulindosing,alsocarbohydrateintakeestimation,accuracyofinsulinpens,differencesininsulin’smetaboliceffect,amountofinsulinstillactivefrompreviousdosesandsubsequentphysicalexercise.Allthesefactors affect postprandial glycemic excursions. Nevertheless, an error in the firststep, i.e. BG value, will be amplified by possible subsequent errors or variations[56][58].

Calibratingmethodalsoplaysanimportantroleinmetersaccuracy.Thereisnotastandardizedmethodtocalibratemeters.Manufacturersmaychoosethemostconvenientone.Itistypicallybasedoneitherhexokinaseorglucoseoxidase.StudieshaveshowedmethodologicaldifferencesbetweenlaboratorymethodsusingHKand

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GOD of about 8% [59]. This discrepancy yields different results with meterscalibrated with either method. Nevertheless, many BGMS exhibit largermeasurement error than the bias between HK and GOD based methods. ThuslaboratorymethodplaysavitalroleonlyinhighqualityBGMS.

Hematocritwasincludedintheinterferingsubstancestobetested.

New analytical accuracy criteria were motivated by an understanding ofSMBG importance in supporting diabetes management. Lifestyle and therapeuticdecisions are based on BGM values. Many diabetes patients have hypoglycemiaunawareness and SMBG is the only practical means for detecting asymptomatichypoglycemia. Additionally, BGM technology improvements, since publication offirstedition,ensuredthatmanufacturerscouldcomplywithstrictercriteria.

BGMSarecompared to laboratorydevicesbut there isnotoneharmonizedmethod for accuracy evaluation. Typically, laboratory devices are based either onthehexokinaseorglucoseoxidasemethod.

Laboratorydevices forcomparativeaccuracystudies(following ISO15197)needtocomplywithtraceabilityrequirementsestablishedinISO17511.Figure1.6showsoneexampleofatraceabilitychainforglucosemeasurementinbodyfluids.Atraceabilitychainusuallystartswiththedefinitionofameasurementunit,followedbyaprimarymeasurementmethodandaprimarycalibratormaterial.Forglucose,theacceptedprimarymethod is ID-GC/MS(IsotopeDilutionGasChromatography-Mass Spectrometry), but this does not exclude other methods. The primarycalibratormaterialcanbe,forexample,StandardReferenceMaterial917c(glucosepowder)fromtheUS-basedNationalInstituteforStandardsandTechnology(NISTSRM917c)orNISTSRM965b(glucose inhumanserum).Thetraceabilitychain isthencomposedofsecondary(andsuccessive)measurementmethodsandsecondary(andsuccessive)calibratormaterials.

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Figure1.6:Traceabilitychainforthemeasurementofglucoseinbodyfluids.Reprintedfrom[60]

ID-GC/MS is considered the most accurate reference method for glucose.HoweveronlyafewlaboratoriesperformthismethodandmanufacturerscalibrateBGMS to alternative methods that are easier to handle. These methods should,nonetheless,haveID-GC/MSintheirtraceabilitychain.

An internationally recognized reference method would improvecomparabilityofresultsandhelpinterpretperformanceofBGMS.

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2 IntroductiontotheProblem

Severalstudieshavedemonstratedconsiderablevariations inmeasurement

quality between BGM systems. Even amongmarketed systems some studies have

reportedBGMsnotcompliantwithISOsystemaccuracycriteria[61][46].Sincethe

revisionofISO15197in2013,morestringentrequirementswereproposed.Aftera

transitioningperiodof3years,in2016,inordertobemarketedinEU,allsystems

willhavetoprovecompliancetothenewinternationalstandard.

Systemaccuracyof10marketavailableBGMSwasevaluatedinalaboratory

study conducted byDr. Guido Freckmann at the Institut fürDiabetes-Technologie

Forschungs- und Entwicklungsgesellschaft mbH an der Universität Ulm (IDT),

Germany. Following ISO 15197:2013, which allows any method conforming to

establishedtraceabilityrequirementstobeusedforreferencemeasurement,system

accuracy was assessed against two laboratory methods based on Hexokinase or

GlucoseOxidase.

For one system considerable number of values were measured with test

stripsfromtwovials.Elevatedresultsfromcontrolsolutionmeasurementswithtest

strips from these two vials were detected during the study. Manufacturer’s

investigationattributedthis topossiblevialexposuretomoisture.Forthisreason,

even though ten systems were evaluated, only results with respect to 9 systems

weredescribed.

In the study, 7 systems showed compliance with system accuracy

specifications.Morethan95%ofresultswerewithinaccuracylimits,withall3lots

tested, independentof thecomparisonmethodused.Twosystemsdidnot comply

with minimum accuracy requirements irrespective of comparison method used.

Lookingatindividuallotsofthesetwosystems,90%to94%ofresultswerewithin

the established system accuracy limits when evaluated against the manufacturer

comparison method (GOD) and 84% to 99% if compared with the alternative

laboratorymethod(HK).

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Regarding clinical accuracy all systems showed 100% of results within

consensuserrorgridzonesAandB.

Relativebiasofindividuallotstoeachlaboratorymethodwasalsocalculated.

A difference in relative bias between lots of each system bigger than 5% (5.4%;

7.6%)wasfoundin2systems.

Previousstudieshavereporteddifferencesbetweenlaboratorymethods[59].

Yet, few studies have weighted analytical accuracy results against two different

laboratory comparison methods. Now that any traceable laboratory reference

methodcanbeusedincomparisonaccuracystudies, independentofmanufacturer

calibrationmethod, the questionwhether calibrationmethod can have impact on

BGM accuracy is relevant. Variations were observed, in the referred laboratory

study, between results obtained with both laboratory methods. Differences were

reflectedinasystematicmeandifferenceofapproximately3%,indicatingthatthese

differences may have “considerable impact” on results from system accuracy

studies.

ThevariabilityfoundinmarketedBGMsinEuropebringstheissueofclinical

implicationsofusingpoorqualityBGM.

BoydandBruns’simulationmodeloftheuseofBGMtoadjustinsulindoses

weightedinsulindoseerrorsagainstdeviceimprecisionandbias.Variabilityof10%

ledto16%to45%ofincorrectinsulindoses.Toachieve95%correctinsulindoses,

precisionandbiaswouldhavetobelessthan2%.Anothersimulationevaluatedthe

percentageofinsulinerrorswithvariousBGMs,fordifferentdegreesofbias(-1.35%

–4%)andimprecision(CV:4.84%–7%).Insulindoseswhereontargetin64%to

82%ofcases.

Correct glycemic measurement and insulin dosing help achieve glycemic

targetswithsmalleramountofglycemicexcursions.Thiscanbetranslatedinbetter

metaboliccontrolandlessdiabetesrelatedcomplications.SMBGistheprimarytool

toachievetheseaims.Yet,itisagreedthatdifferentpatientgroupsrequiredifferent

levels of BGM accuracy within the clinically relevant BG ranges, hypoglycemia,

euglycemia, and hyperglycemia [62]. Among those patient groups are type 2

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diabetes patients, type 1 diabetes on intensified insulin therapy and patients in

intensivecare.

PatientsfollowinganintensiveinsulinregimenarerecommendedtotestBG

levelsatleast6timesaday[8].BGMaccuracyforthesepatientsisimportantacross

allglucoseconcentrationrangesbutspecificallyinthehypoglycemicrange.Type2

diabetes mellitus patients do not necessarily need accuracy in low ranges. A

distinctionbetweenBGMperformancesisessentialtohelppatientsandHCPchoose

systemsthatwillofferbetterperformance,accordingtoclinicalneed.

There is concern whether BGM performance can be a source of insulin

errors even with meters compliant with accuracy criteria. In addition, a

categorizationofBGMaccordingtoaccuracyinseveralglucoseranges(low,normal

andhigh)isdesirable.Withthatintentinsulin,dosingerrorswerecalculatedbased

ondatafromBGMsmeasurements.

InordertoevaluateBGMSperformanceindifferentglycemiclevels,errors

separatedbyglucoserangeswereconsidered.

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3 Methods

A laboratory study was performed at IDT under principal investigator Dr.

GuidoFreckmannwithtrialregistrynumber(ClinicalTrials.gov):NCT01909687.

Study duration was between 03.07.2013 to 22.10.2013. 164 different

subjects entered the study. Subjects were type 1 or 2 diabetes mellitus or non-

diabetic.Previoustothestudy,eachpatientwascheckedforinterferingsubstances

as well as inclusion and exclusion criteria p.e. pregnancy, lactation period, acute

disease,chronicdisease.

Investigated systems were: Accu-Chek® Aviva, Contour

® XT, FreeStyle

InsuLinx,Contour®nextUSB,BGStar

®,OneTouch

®Verio

®IQ,Accu-Chek

®Performa,

mylifeTMPura

TM,Glucocard

TMG+andMyStar

TMExtra. Itwasused for each system

three test strip lots. All test strips lots and 9 of the investigated systems were

purchasedatpharmacies.MyStarExtra®wasnotfreelyavailableinGermanyandso

itwasobtainedfromthedistributor(Sanofi-AventisDeutschlandGmbH,Germany).

Controlmeasurementsweredoneeachdaytoensuresystemsproperfunctioning.

Twolaboratorymethodswereusedtoperformcomparisonmeasurement:a

glucose oxidase based method (YSI 2300 STAT Plus™ glucose analyzer, YSI

Incorporated, Yellow Springs, OH, USA) and a Hexokinase based method (Cobas

Integra®400plus,RocheInstrumentCenter,Rotkreuz,Switzerland)referredtoas

YSIandCobasrespectively.TraceabilityrequirementsaccordingtoISO17511were

confirmedbythemanufacturers.

Studywasperformedinthreeparts: inthefirstandsecondpart3different

systemsineachpartwereevaluatedchangingtheorderoftheinvestigatedsystems

every 1/3 of subjects. In the third, 4 systemswere assessed. Orderwas changed

every¼ofsubjects.

Temperatureatwhichmeasurementsweremadewas23°C±5°C.Humidity

wasmaintainedbetween37,5%–57,8%. Samplehematocrit had tobebetween

20%-60%andglucoseconcentrationmeasuredwithlaboratorymethodhadtobe

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within systems’ measurement rage 10 mg/dL – 600mg/dL (or according to

manufacturerspecifications).

Procedures specified in international standard ISO 15197:2013 were

followedforsystemaccuracyevaluation.

Procedure

Each patientwas asked towash handswith soap andwater and dry them

beforesamplecollection.Sampleswerecollected fromfingertipcapillariesbyskin

puncture.Individualsamplesweretestedinduplicateforeachsystemlotusingtest

strips from the same vial and two devices. To ensure that test strips from 10

differentvialswereused,vialswerechangedevery10subjects,approximately.

Figure3.1:Testingsequence

Aliquotswere collected fromeach sample immediatelybefore the first and

immediately after the last measurement with up to 4 systems for duplicate

measurementwiththecomparisonmethods.

Samplestabilitywasconfirmedbycheckingthatthedifferencebetweenthe

firstaliquotandsecondwas≤4mg/dLatBGconcentrations≤100mg/dLand≤4%at

BGconcentrations>100mg/dL.

Eachsamplewasallocatedtoabinaccordingtoglucoseconcentrationmean

valuemeasuredwiththerespectivereferencemethodasspecifiedinTable3section

6.3.5ofISO15197anddescribedinTable3.1.

Skin

puncture

1streference

value(both

lab

methods)

System1

bothdevices

System2

bothdevices

System3

bothdevices

2nd

reference

value(both

labmethods

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Table3.1:BloodglucoseconcentrationofsamplesaccordingtoISO15197:2013[1]

Bin#

Percentageofsamples[%]

Glucoseconcentration[mg/dL]

15 ≤50

215 >50–80

320 >80–120

430 >120–200

520 >200–300

615 >300–400

75 >400

Toattainthedefineddistributionofglucoseconcentrationsonlyintherange

<50 mg/dL and >400 mg/dL samples can be adjusted. Sample adjustment was

performed by incubation to allow glycolysis to take place or by glucose

supplementationwithastocksolutionof40%glucosein0,9%NaCl.

At least 100 fresh capillary blood samples were collected and prepared

according to device manufacturer’ instructions. This ensured 200 data points for

eachsystemlotwitchis600datapointsperBGMS.

Insulindoseerror

Insulin doses were calculated based on BGMSmeasurements. A simplified

modelofpre-mealinsulindosewasused.

Beforemealsinsulindosesneedtocovercarbohydrateintakeandcorrectfor

high blood sugar. Insulin dose to cover carbohydrates is calculated taking meal

carbohydratecontentdividedbyinsulin-to-carbohydrateratio.Tocorrectglycemic

levelsdifferencebetweenmeasuredBGandglycemicgloaldividedbytheirInsulin

Sensitivity Factor (ISF) is used. Carbohydrate intake was excluded from the

proposed model in order to relate BGM’s values to insulin doses. Carbohydrate

intakeandcarbohydrateestimationerrorwasconsequentlydismissed.

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True valueof glucose concentration is not accessibledue to inherent error

when using a laboratory method. Results from the manufacturer designated

comparisonmethodwereassumedtrueandinsulindosescalculatedbasedonthose

resultswereconsideredcorrect.

Intendedinsulindoseswerethencalculatedusingthefollowingequation:

(3.1)

BGreference is the blood glucose concentration measured with a

laboratory/reference method; BGgoal is the target value for blood glucose after

insulinadministration;ISFistheinsulinsensitivityfactor.IfwesubstituteBGreference

byBGBGM,bloodglucosemeasuredwithaBGM(eq.2.2),wethenhaveinsulindose

relatedtoBGMvalues,IDBGM.

(3.2)

Thisisconsideredthedoseapatientwouldinject.

ErrorininsulindoseisthenthedifferencebetweenIDreferenceandIDBGM.

(3.3)

Wherethesignaloftheequation,plus(+)orminus(–),translatestooveror

underdosing,respectively.

IDreferenceandIDBGMwereroundedtothenearest0,5IUgiventhattypicalfor

insulinpensmeasurein0,5IUincrements.

IDreference =BGreference − BGgoal

ISF

IDBGM =BGBGM − BGgoal

ISF

Error = IDreference − IDBGM

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For each system and each test trip lot insulin dose errorswere calculated,

takingbothlaboratorymethodsasreference,withtheobjectiveofdeterminingthe

percentageofinsulindoseswithin0,5IUoftheintendeddose.Percentageofinsulin

above1IUand2IUwasalsodetermined.Percentageofunderdosingwascalculated

fordoses2IUormorebelowintendeddose.

It was checked, as well, percentages of target insulin doses, overdose and

underdosebasedonlyonunadulteratedsamples.

Furthermore, dose errors were calculated per glycemic level following

glucose concentration distribution of Table 3.1 to assesswitchmeters performed

better for each glycemic range. In this assessment only the manufacturer

comparisonmethodwasusedtocalculateintendedinsulindoseforeachsystem.

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4 Results

PleaseseeAppendixAthroughE.

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5 DiscussionandConclusion

Theaimofthisthesisworkwastoassesserrorsininsulindosingthatmarket

availableBGMsystemsmightcauseandalsotoinvestigatewhichsystemsmightbe

moreappropriatetotype1ortype2diabetes.

5.1 Significanceofthisstudy

Patients suffering from diabetes and on insulin therapy depend on blood

glucosemonitoringsystemsdaily.Glucoseconcentration is themainparameter to

calculate insulin doses. Patient’s metabolic control is linked with correct insulin

levelinthebloodstreamandthereforewiththecorrectdosageinjected.Themajor

risk of incorrect under dosage is hypoglycemia. This can be a consequence of

incorrectly high BG value. Symptoms of hypoglycemia are confusion, anxiety,

palpitations and others. Severe hypoglycemiamay cause coma and death. Insulin

overdosing,ontheotherhand,preventstheachievementofglycemicgoalsandisan

impedimenttothedelayofmicroandmacrovascularcomplications.Thislimitsthe

years of healthy life. Also the cost in healthcare increases substantially due to

diabetesrelatedcomplications[63]. It is, therefore, inthebest interestofHCPand

patients to achieve balancedmetabolic control. For these reasons, it is important

that BGMsmeasureBG concentration accurately for correct insulin dose and that

patientsusethemappropriately.

5.2 Methodology

ThisworkestablishesarelationshipbetweenBGMperformanceandinsulin

dosingerrorswithtwolaboratorymethods(HKandGOD)asreference.

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Inthisstudy,itwasobtaineddataregardingglucoseconcentrationfrom164

patients.Allpatientswere testedwith10systems twice (twodevicesper system)

and using 3 different test strip lots. At least 100 values per device per lot were

obtained,inconformitywithISOspecifications.Intheend,600differentdatapoints

per BGM system were generated. In addition, samples were measured with two

laboratorymethodstobeusedasreference.

In order to determine the accuracy of devices under study, BGM

measurements were compared with reference values. In the study led by Dr.

Freckman, two systems did not fulfil with ISO 15197: 2013 system accuracy

(OneTouch Verio IQ and GlucoCard G+). Those systems showed less than 95% of

results within stipulated criteria. In fact, GlucoCard G+ did not fulfill system

accuracy criteria with none of the 3 tested lots, irrespective of the laboratory

referencemethodused [64]. ContourNext showed100%of resultswithin system

accuracycriteriairrespectiveofcomparisonmethod.

Insulindoseswerecalculated fromtheoriginal600BGdatapoints. Itwere

alsocalculatedinsulindosesfromtwolaboratoryreferencemethods.Results from

BGMinsulindoseswerethencomparedwithresultsfrombothlaboratorymethods

todetermineinsulindosingerrors

5.3 Summaryofresults

In the present study, it was system 3 that showed on target insulin doses

closesttotherespectivemanufacturerreferencemethod.Bothsystemsthatdidnot

fulfil accuracy criteria were among the ones with lowest percentage of on target

insulinalongwithsystem2.

Overdoseequalorabove2Uwasrelativelylow,notsurpassing5%.Overall

thestudyshowedthatthe10BGMsunderstudygiveBGconcentrationvalueswith

limitedimpactininsulindoses.

ThisstudyrevealeddifferencesininsulindoseerrorwithinBGconcentration

rangesallowingtodistinguishbetweenBGMssuitablefordiabetestype1ortype2.

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It can be argued that type 1 patients need small error across all ranges and

especially in the hypoglycemic range. On the contrary, type 2 patients do not

necessarilyneedthesameinthelowglycemicrange.

System5,system3andsystem7showedinsulindoseerrorsnotsuperiorto

1.5 U across all ranges and 100% of on target insulin doses in the hypoglycemic

range.

Inparticularcases,suchaspatientstreatedwithintensiveinsulintherapyor

insulinpump,moreaccuratemeasuringdevicesareneeded.Inthesegroups,insulin

doseerrorsof1Ucanhaveamorepronouncedimpactthaninotherpatients.Inthis

study,overdoseby1Uormorewasashighas12.5%(YSIreference).

Alsothethresholdof1Uwasstudiedbecauseofthesignificantphysicaland

psychological consequences of hypoglycemia. A benchmark for diabetes therapy

assessment is HbA1c, established by the publication of the Diabetes Control and

Complications (DCCT). The study showed a direct relationship between glycemic

controlandthedevelopmentofmicroandmacrovascularcomplications.Itshowed

aswell that intensively treated patients reachedHbA1c levels faster and vascular

complicationsweredelayed.This,however,camewithhigherrateofhypoglycemic

events.As itwas referredpreviously,new insulin formulationshave lower riskof

hypoglycemia.

When lookingatresults fromunadulteratedsamples,errorsare lower than

comparedwithall samples.This is theconsequenceofexcludingsampleswithBG

concentrationabove400mg/dLwhereingeneralBGMsarelessaccurate.

5.4 Limitationsofthestudy

Thereweresomelimitationsinthedevelopmentofthisstudy,whichshould

be pointed out. These limitations refer to the study methods and to the

simplificationofthedoseerrormodel.Alaboratorystudydoesnotmimiceveryday

conditions inwhichpatientscarryoutthemeasurements.Asdiscussed,usererror

plays a significant part in the quality of results, as do ambient conditions. It is

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nonetheless agreed that errors derived by poor analytical performance will be

propagatedwithsubsequentinterferingfactors.

Another limitation is knowing the exact value of glucose concentration.

Inherent to the measurement of a biological substance is the impossibility of

knowingitstruevalue.Inthisstudy,BGMresultswerecomparedtotwolaboratory

methodsandtherespectiveresultswereassumedasthetruevalue.

Finally,thelastlimitationinthisstudywasthesimplificationoferrormodel.

Insulin dose calculation was based on the equation used by patients to calculate

mealtimeinsulindoses.Thisequationincludesacarbohydratecomponenttocover

carbohydrateintake.ThiscomponentwasdisregardedtolinkBGMperformanceto

insulindose.

In conclusion, accuracy of BGM systems must be guaranteed before it is

availabletocustomersaswellasinpost-marketingstages.HCPandpatientsshould

beinformedabouttechnicalaspectsofBGMsanditsperformanceinordertomake

informedchoices regarding itsuse. Special consideration shouldbegiven in cases

whereBGMisusedtocalculateinsulindosesandifitwillbeusedbytype1ortype2

diabetespatients.

5.5 Futureoutlook

Diabetes is a chronic disease, which requires constant management and is

associated with several complications such as retinopathy, nephropathy,

neuropathyandcardiovasculardisease.Reducedpatientcomplianceorinadequate

treatmentregimesmaycontributetoafasterdeteriorationofpatient’shealth.Upon

diagnosis, patientsmust frequently visit thedoctor in order to reach an adequate

treatmentplan.Periodicappointmentsfollowthisinitialphaseapproximatelyevery

6months.Duringthoseperiods,patients followasetofwrittenrulesgivenbythe

doctortoreachormaintainglycemictargetandmanageglycemiclevels.

Patients with diabetes mellitus are faced with a daily cumbersome routine.

Theymustpayattentiontowhatandhowmuchtoeat,whatdoseofinsulintotake

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and howmuch exercise to practice. Patients need help and information to make

thosedecisions.Butnotonlypatientsstruggle.Physiciansoftenhaveashortamount

of time with each patient and need to analyze all the information that a patient

bringstoconsultsandreevaluatetreatmentifnecessary.Thereisanapparentneed

forclearandaccessibleinformation.

Tools that enable easier contact between patient and HCP can improve

treatmentadjustmentandassistinmakingpromptalterationswhennecessary.

Manyappsareavailablewhichmostlyoffersimplefunctionalities.Themain

benefittousersofsuchappsforregulatingbloodglucoselevelsistheavailabilityof

quickinformationwhichgivespatientsgreaterlevelofautonomy.

One solution comes in the form of software for computers, smartphones or

tablets, capable of receiving and storing patients’ necessary data (carbohydrate

intake, insulindose,FPG,BG,HbA1c)anddocalculationsinordertogivefeedback

on the development of a given parameter or treatment suggestions. Apps for cell

phones have increasingly been promoted for patient use in day-to-day care.

Ultimately, patients are able to make informed lifestyle choices and at the same

time, if treatment is effective, see improvements in metabolic control. The visual

feedback provided by these apps acts as an incentive to behavioral changes. If a

patientisabletoseehisdailyachievementsandthateachstepbringshimcloserto

goal,hewillbemoremotivatedtocontinuetreatment.

Storingdata is not the only important component of these apps. Sharing it

withtherightpartiesalsoplaysasignificantrole inmanagingthepatients’health.

Forexample,HCPshouldhaveaccess toselected information,ensuringbetterand

safer care. Stored and shared data of blood glucose levels, insulin doses,

hypoglycemic events and pertinent graphs can give HCP a fast way to evaluate

treatmentevolutionandeventuallyactremotelyifsomevalueiscauseofconcern.

Likewise,themarketofSMBGhasbeenevolvingtobringnewfunctionalitiesto

the user, in the form of smarter BGMs that can store BG values, calculate insulin

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dosesandstoretimeandamountofpreviousdoses.

It is important to note that these new advances inmanaging diabetes give

freedom to the patient with lessmedical interaction. These tools should be used

withcautioninparticulariftheyaredesignedtogivetreatmentsuggestions,asfor

exampleinsulindoses.HCPsshouldprescribewithcautionandonlytotrainedand

informedpatients.

Regardless of these newer Smartphone applications and the added

functionalities theyprovide, anaccuratemeasurementofbloodglucose is still the

most fundamental piece of information for a proper management of diabetes.

Therefore, BGMs’ system accuracy must be guaranteed to ensure safety for the

patient.

Studies have suggested that SMBG frequency as an important role in

metaboliccontrol(HbA1c)[65][66].Yet it is importanttoemphasizethatSMBGin

itself isnotan intervention. It isa tool toassist treatmentdecisionandultimately

achieve glycemic targets. Quality of measurement is nonetheless linked with

metabolicoutcomes.Qualityofmeasurementdoesnotreferexclusivelytoanalytical

accuracy, but its assurance is important if only to prevent propagation of error if

BGMismishandled.

AlthoughSMBGisparamounttoensureproperinsulindosage,literaturehas

shownthatthereareotherfactorswhichmaycontributetoerrors.Forpatientson

fixed insulin regimens, dose calculation is obviously not necessary. For these

patients,mealplanningwithcomparablecarbohydrateportionsismoreimportant.

Amoreadaptableregimen,however,maybepreferabletosomepatientswhowant

to have choice on type of meal and exercise. In such cases, education on insulin

calculationandcarbohydratecountingisextremelyimportant.

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Appendix

Appendixhasbeenremovedduetoconfidentiality