SAVREMENA INZULINSKA TERAPIJA MJESTO I ULOGA INZULINSKIH ANALOGA

DCCT, Diabetes Control and Complications Trial.1. Adapted from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254.2. DCCT. N Engl J Med. 1993;329:977-986.3. DCCT. Diabetes. 1995;44:968-983.Relative RiskHbA1C (%)151311975316789101112HbA1C i relativni rizik za nastanak mikrovaskularnih komplikacija u tipu 1 DM : DCCT studija 20

Odnos HbA1c i komplikacija u tipu 2 DM :UKPDS studija% Incidenca/1000 pacijent-godineUKPDS 35. BMJ 2000;321:405-12Srani infarkt

*Lower extremity amputation or fatal peripheral vascular diseasePercentage reduction in relative risk corresponding to a 1% fall in HbA1c 5045403530252015105021%P < 0.0001Any diabetes-related endpoint21%P < 0.0001Diabetes-related death14%P < 0.0001All cause mortality14%P < 0.0001Myocardial infarction12%P = 0.035Stroke43%P < 0.0001Peripheral vascular disease*37%P < 0.0001Microvascular disease19%P < 0.0001Cataract extractionAdapted from Stratton IM, et al. UKPDS 35. Br Med J 2000; 321:405412.UKPDS: Efekti smanjenja HbA1c za 1% na razvoj komplikacija

Efekat popravljanja glikoregulacije na pojavu kasnih komplikacija

DCCT1 Kumamoto2 UKPDS3 HbA1c 9% vs 7% 9.4% vs 7.1% 7.9% vs 7.0%1. DCCT Research Group. NEJM 1993;329:977-9862.Ohkubo et al.Diab Res ClinPract 1995;28:103-117.3. The UKPDS Group. Lancet 1998; 352:837-853.

Glycemic variable AACE/ACE* IDF Europe** ADA***

HbA1c (%) (DCCT standardized) < 6.5 < 6.5 < 7,0

Blood glucose (mmol/l)Fasting/pre-prandial < 6,1 < 5,5 < 6,7

Post-prandial < 7,8 < 7,5

*American Association of Clinical Endocrinologists/American College of Endocrinology **International Diabetes Federation (European Region)***American Diabetes Association. Diabetes Care 1999; 22(Suppl 1):S1-S114;Ciljevi glikemijske kontrole

Cilj terapije dijabetesa:Kontrola glikozne trijadeHbA1c6.5-7%

FBG 5.5 mmol/l

PPG 7.5mmol/l

Preporueno uvoenje inzulinske terapije: 7,5 -8%Realno uvoenje: 9%

Procjenjuje se da vie od 2/3 pacijenata nema zadovoljavajuu kontrolu.

1. Postii normalne ili skoro normalne glikemije prije i poslije obroka

2. Izbjei este i teke hipoglikemije

3. Izbjei vei porast tjelesne teine

4. Obezbjediti da bolesnik prihvati i sprovodi terapiju

5. Prilagoditi lijeenje dijabetesa ivotnim potrebama oboljelih

Cilj inzulinske terapije:

Sadanji inzulinski preparati i njihove farmakodinamske osobine

Farmakokinetiki profil humanih inzulina

Kratkodjelujui humani regularni inzulin

Poetak dejstva (0.5-1h), max (2-3 h), vrijeme trajanja do 6 h.Limitirajui moment u apsorpciji disocijacija u monomere.Izostanak peak-a djelovanja poslije obroka nemogunost adekvatnog savladavanja PPGUsporena apsorpcija produeno dejstvo = kasna postprandijalna hipoglikemija. Vie vrijednosti inzulinemije izmeu obroka centralno deponovanje masti = inzulinska rezistencija.

Farmakokinetiki profil humanih inzulinaSrednjedugodjelujui humani inzulin - NPH

Nedostatak znaajan porast koncentracije u toku dana do viih vrijednosti inzulinemije od potrebnih - pojava hipoglikemije (esto nou izmeu 3-5h).Zbog duine djelovanja do 20 sati, postoji potreba za primjenom 2 dnevne doze NPH inzulina.

Inzulinski analozi Kratko-djelujuiNovoRapid FlexPen - inzulin aspart Kombinovano dejstvoNovoMix 30 FlexPen - bifazni aspart inzulin

Dugo-djelujuiLevemir- inzulin detemir

Farmakokinetiki profil inzulinskih analoga

Kratkodjelujui inzulinski analozi analozi sa povoljnim efektom na PPG: brza absorpcijaPeak dejstva koincidira sa peak-om absorpcije ugljenih hidrataBazalni inzulinski analozi: Sporija i stabilna absorpcija Produeno djelovanjeMali varijabilitet dejstva

Kratkodjelujui inzulinski analoziInsulin aspart (NovoRapid)Karakteristike: max dejstva unutar 1 h, ukupno trajanje 4 h Hipoglikemijski potencijal isti ili vei od humanog regularnog inzulina.Slian efekat kod svih bolesnikaNeimunogen, hemijski stabilan i pogodan za mijeanje sa drugim inzulinima ili analozima

Struktura inzulina aspart

Insulin (mU/l)VrijemeObrociNormalan nivo slobodnog inzulina (srednje vrijednosti)Kratkodjelujui inzulin + NPHDoruakRuakVeeraIntenzivirana konvencionalna insulinska terapijahumani inzulini vs analoziModifikovano prema Polonsky et al. 1988Kratkodjelujui analozi + NPH

Efekat inzulina aspart na glikemije u dnevnom profilu u T1 DM: bazal-bolusni reim doruakPPGruakPPGveeraPPGRaskin et al. Diabetes Care 2000;23:583-8n = 884

Primjena inzulina aspart: Smanjenje ozbiljnih nonih hipoglikemija kod bolesnika u T1 DM za 72%72%** p < 0.005n = 155Heller et al. Diabetes 2001;50(2):A137

Bifazni aspart inzulinNovoMix 30/70 apsorpcijski profilInzulinski analozi s kombinovanim dejstvom

Imitiranje fizioloke sekrecije inzulina bifaznim inzulinskim analogom Fizioloki inzulinski profil - bazalna komponenta - postprandijalni porastFizioloki inzulinski profil

Boehm B et al. Diabet Med 2002;19(5):393399*Blood glucose (mmol/l)*0Pre-1012Post-86NovoMix 30Premixed human inzulin 30/70*p < 0.05**LunchPre-Post-BreakfastPre-Post-DinnerBedtime0200 hPopravljanje PPG poslije 3 mjeseca lijeenja bifaznim inzulinskim analogomn= 294 type 1 and type 2 patients

Smanjenje teih hipoglikemija poslije 3 mjesecaBroj epozoda hipoglikemije051015202530354045NovoMix 30BHI 3042 dogaaja20 dogaaja50% smanjenja relativnog rizikaBoehm B et al. Diabet Med 2002;19(5):393399(n = 138)(n = 153)

INITIATE: vie pacijenata lijeenih sa inzulinom NovoMix 30 nego sa glargine inzulinom dostie ciljni HbA1cRaskin P et al. Diabetes Care 2005;28:260-5

If HbA1c>6.5%, go to BID, d/c secretagoguesPre-breakfast & dinner for 16 weeksAdd 3 U at breakfast and titrate BIDPhase 2End of StudyHbA1c 6.5%Studija 1-2-3 :NovoMix 30 1X, 2X ili 3X dnevnoGarber et al. Diabetes Obes Metab 2006;8:5866.

Baseline HbA1C was 8.6%Studija 1-2-3: kumulativni procenat pacijenata koji su postigli ciljni HbA1cJain et al. Diabetes 2005;54(Suppl 1):A69

HbA1C 6.5 (AACE, IDF goal)HbA1C < 7% (ADA goal)OD21%41%BID52%70%TID60%77%

Studija 1-2-3: Slino niska uestalost hipoglikemija u svim fazama Nema korelacije izmeu hipoglikemija i broja injekcija Jain et al. Diabetes 2005;54(Suppl 1):A69

Faza 1 ODFaza 2 BIDFaza 3 TIDUestalosttekih hipoglikemija0.130.150.13Uestalost minornih hipoglikemija152212Teke none hipoglikemije000

Inzulinski analog dugog djelovanjaLevemir - inzulin detemir

Faza III klinikih studija sa inzulinom Levemir

Glikemija natate u svim prikazanim fazama III studija koje porede inzulin detemir sa NPH inzulinomSMFBG/SMFPG (mmol/l)Insulin detemir NPH insulin *p

Analozi vs. humani inzulini:bazal-bolusna terapijaBefore breakfast*Mean blood glucose (mmol/l)1110980790 min after breakfastBefore lunch90 min after lunchBefore dinner90 min after dinnerBedtime03:00Overall, *p < 0.001

Smanjen rizik hipoglikemija sa inzulinom Levemir u bazal-bolusnoj terapijiHbA1c1086420Relative risk18%39%16%50%Baseline****Between-group difference, p< 0.05Kolendorf et al. Diabetes 2004;53(Suppl. 2):A130.

Inzulin detemir u svakodnevnoj praksi: PREDICTIVETM

Otvorena, multinacionalna, observaciona studija na >30,000 bolesnika s tipom 1 ili 2 DM

Ukljueno 11 zemalja

Dornhorst A et al. Diabetes 2006; 55 (Suppl. 1): A110 (462-P) Observacione studije inzulinskih analoga u svakodnevnoj praksi

PREDICTIVETM: efikasnost pri zapoinjanju inzulinske terapije inzulinom detemir u tipu 2 DM - HbA1cMean HbA1c (%)n=1799-1.3%p

PREDICTIVETM: broj injekcija inzulina detemir (Levemir) na danProsjena dnevna doza: 22 U18%82%n=2,377, sa T2DM, prethodno bez insulinske terapije

Glavne prednosti inzulinskih analoga u odnosu na humani inzulinBolja predvidljivost i stabilnost farmakokinetikeObezbjeuju fleksibilan i stabilan efekat na glikemiju natate, PPG i HbA1cUestalost hipoglikemija manjaMogu se primjenjivati u svim inzulinskim reimima Dobri efekti u lijeenju oboljelih sa nestabilnim oblikom dijabetesa, (sa estim teim i nonim hipoglikemijama) Observacione studije pokazuju da se poboljanje vrijednosti HbA1c moe bezbjedno postii u svakodnevnoj praksi koritenjem inzulinskih analoga.

The following presentation will provide you with an overview of the MODERN programme toolkit. MODERN MOdern Insulins: Demonstrating The BEnefits FoR Diabetes MaNagement is a Novo Nordisk initiative designed to demonstrate the benefits of modern insulins for diabetes management, as well as for patients. As part of the MODERN programme we have designed for you, a toolkit which provides information about the purpose of MODERN and guidance on how you can maximise existing opportunities to communicate MODERN messages through a number of communication tools. To support the modern insulins brand portfolioAlthough there are clear synergies between our three modern insulin portfolio brands, MODERN will provide us with an umbrella communications strategy to ensure that as brands teams we work together as a portfolio and any communication from each brand, benefits the others because of the common modern insulins messages To prepare the market for the discontinuation of human insulins in line with the COMMIT programme timelineThe COMMIT programme has become a key leadership platform for Novo Nordisk. However, in terms of communication, it is largely a reactive initiative. MODERN is designed to interlock with the COMMIT programme and aims to prepare the market to ensure it is receptive and not hostile to the discontinuation of human insulins in line with Novo Nordisks overall strategyTo demonstrate Novo Nordisks market leadership position in modern insulinsDemonstrating the patient need for modern insulins as a category is the territory of a market leader. By undertaking the MODERN programme, we are reinforcing to the market our ongoing leadership position in diabetesTo establish the positive and understandable language of modern insulins as opposed to current insulin analogue terminologyModern insulins is a term that we have pioneered in an attempt to make the category more understandable to a broad rage of stakeholders. To establish this terminology with the diabetes community, we need to actively communicate it at every opportunityTo complement and interconnect with other Novo Nordisk leadership programmes; Changing Diabetes (including the bus), DAWN, COMMIT, etc.We have worked hard over recent years to distill our efforts into core leadership programmes. MODERN will be mindful of these programmes and their activities, and maximise any opportunities where possibleTo maximise existing modern insulin brand and leadership platform activitiesThe modern insulins brands have a number of excellent communications opportunities coming up over the next year [NOTE TO NN - PLEASE GIVE CURRENT EXAMPLES]. MODERN is intended to work alongside brands to maximise these opportunities for the Novo Nordisk modern insulins brands more broadly*Hyperglycaemia and complications in type 2 diabetes

The UKPDS has proven beyond doubt that intensive glycaemic control is associated with real clinical benefits for patients with type 2 diabetes.The relationship between HbA1C and increased risk of complications is continuous and extends into levels of HbA1C normally considered to lie within the normal range (