Terapija Diabetes mellitus-a tip 2 26.05.2011. Terapija Diabetes mellitus-a tip 2 prof dr Aleksandar ĐUKIĆ Centar za endokrinologiju, dijabetes i bolesti metabolizma KC Kragujevac

AGENDA Epidemiologija, definicija, podela i etiopatogeneza DM Opšti principi terapija DM tip 2 Algoritam lečenja DM tip 2 Lekovi u fokusu: metformin i preparati inkretinskog koncepta

Diabetes mellitus: epidemiologija

Diabetes mellitus je bolest čija je pandemija u toku

Trend porasta incidence DM

Incidenca DM u svetu Broj ljudi sa DM (u milionima) po regionima za 2003 i 2025 (porast 72%) Evropa 38.2m 44.2m (+16%) USA/Kanada 25.0m 39.7m (+59%) Azia 81.8m 156.1m (+91%) Srednji Istok 18.2m 35.9m (+97%) Global prevalence of type 2 diabetes set to increase by 72% from 189 million in 2003 to 324 million in 2025 Latinska Amerika 10.4m 19.7m (+88%) Australazija 1.1m 1.7m (+59%) Afrika 13.6m 26.9m (+98%) P. Zimmet, International Diabetes Institute Melbourne, 2003.

Prevalencija dijabetesa 2000 - 2025 Dijabetičari (milioni) Svet Razvijene zemlje Zemlje u razvoju King H., Diabetes Care, 1998

Diabetes mellitus nije blaga bolest, posledice za pojedinca i društvo su ogromne

Relativni troškovi zbog DM 120 $104 100 $92 80 $65 Direktni i indirektni troškovi (US$ billion) 60 $44 40 $30 20 Moždani udar Depresija Arthritis Diabetes Maligniteti US podaci 1990–1993 Adapted from www.cdc.gov/diabetes/pubs/costs/index.htm. Accessed 1 April 2007.

Troškovi lečenja DM u Evropi Ambulantno lečenje 18% Lekovi za dijabetes 7% Drugi lekovi 21% Hospitalizacija 55% = € 29 milijardi godišnje Adapted from Jönsson B. Diabetologia 2002; 45:S5–S12.

Komplikacije Diabetes mellitus-a se u velikoj meri mogu sprečiti

HbA1c i relativni rizik za mikrovaskularne komplikacije: DCCT 20 Retinopathy Nephropathy Neuropathy Microalbuminuria 15 13 11 9 Relative Risk 7 5 3 1 6 7 8 9 10 11 12 HbA1c(%) 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. 1. Skyler JS. Diabetic complications: the importance of glucose control. Endocrinol Metab Clin North Am. 1996;25:243-254. 2. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitis. N Engl J Med. 1993;329:977-986. 3. Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposure (HbA1C) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes. 1995;44:968-983.

Redukcija troškova lečenja zavisno od poboljšanja glikoregulacije DM2 1994 1995 1996 1997 –100 –200 –300 –400 Troškovi po pacijentu godišnje (US$) –500 –600 –700 –$685 –800 –$772 –$821 –900 –1000 –$950 Pacienti sa HbA1c smanjenim za  1% tokom 1992 i 1993 Te odrđanim smanjenjem 1994 su shvaćeni kao sa poboljšanom glikoregulacijom (n = 732); svi drugi su klasifikovani kao nepoboljšani (n = 4,012) Adapted from Wagner EH, et al. JAMA 2001; 285:182–189.

Diabetes mellitus: dijagnoza

Normalna tolerancija glikoze “Predijabetes” Povišena glikemija našte (engl. impaired fasting glucose, IFG) Smanjena tolerancija glikoze (engl. impaired glucose tolerance, IGT) Diabetes mellitus

Diabetes mellitus: definicija

DEFINICIJA Diabetes mellitus je stanje hronične hiperglikemije (ali i poremećja metabolizma drugih ugljenih hidrata, masti i proteina), koje nastaje kao posledica apsolutnog i/ili relativnog nedostatka insulina ili nedostatka dejstva insulina. U kasnijem toku bolesti mogu se pojaviti komplikacije na malim krvnim sudovima (mikroangiopatije) i velikim krvnim sudovima (makroangiopatije).

podela i etiopatogeneza Diabetes mellitus: podela i etiopatogeneza

PODELA DIABETES MELLITUS-a (Ministarstvo zdravlja, Republika Srbija) Diabetes mellitus tip 1 Diabetes mellitus tip 2 Kod negojaznih osoba (LADA) Kod gojaznih osoba Drugi specifični tipovi dijabetesa bolesti pankreasa indukovani infekcijama endokrinopatije indukovani lekovima ili hemijskim supstancama abnormalnosti sinteze i sekrecije insulina poremećaji insulinskog receptora genetski sindromi Gestacijski Diabetes mellitus

ETIOPATOGENEZA DIABETES MELLITUS-a Autoimunski insulitis Sindrom rezistencije na insulin-hiperinsulinemije Ostali mehanizmi: smanjeno stvaranje insulina zbog razaranja endokrinog pankreasa infekcije endokrinopatije lekovi i toksini abnormalnosti sinteze i sekrecije insulina abnormalnosti insulinskih receptora genetski sindromi

AUTOIMUNSKI INSULITIS 10-20% Diabetes mellitus tip 1 Mlađi od 35 god Negativna porodična anamneza Burno ispoljavanje (DKA) Doživotna zavisnost od insulina Diabetes mellitus tip 2 (negojaznih osoba, podtip LADA) Stariji od 35 godina Obično nisu gojazni Rani neuspeh terapije OA i brz razvoj insulinske zavisnosti

REZISTENCIJA NA INSULIN 80-90% Diabetes mellitus tip 2 (gojaznih osoba) Obično posle 35 godina Osobe su gojazne Pozitivna porodična anamneza Duži period vremena delotvorni su OA, kasnije razvoj sekundarne zavisnosti od insulina Postoje klinički markeri Metabolčičkog sindroma X

MEHANIZAM NASTANKA REZISTENCIJE NA INSULIN INICIJALNA RI genetski uslovljen poremećaj u transdukciji insulinskog signala mogu biti zahvaćeni svi nivoi transmisije: vezivanje insulina za  subjedinicu tirozin kinazna aktivnost  subjedinice nishodna transdukcija signala (IRS 1 i 2, Synip, GLUT 1 i 4) Dominatano zahvaćeno mišićno i masno tkivo

POREKLO REZISTENCIJE NA INSULIN James Neel izlaže koncept koji najbolje integriše efekte genotipa i faktora okoline: (“thrifty genotype”) model štedljivog genotipa

REZISTENCIJA NA INSULIN “ŠTEDLJIVI” GENOTIP REZISTENCIJA NA INSULIN

EVOLUCIJA DIABETES MELLITUS-A tip 2 50 100 150 200 250 300 350 GLIKEMIJA Postprandijalna Glikemija (mg/dL) Našte Insulinska rezistencija 250 200 Relativna Funkcija (%) 150 Sekrecija insulina 100 50 Prediabetes Dijabetes Kardiovaskularne bolesti Mikrovaskularna bolest Godine -10 -5 5 10 15 20 25 30

Diabetes mellitus: terapija

Zdravstveni tim: lekar, farmaceut, sestra, dijetetičar... Pravilna ishrana Medikamenti Fizička aktivnost LEČENJE DM Samokontrola Edukacija

TESTOVI ZA ISPITIVANJE KVALITETA GLIKOREGULACIJE 7.0% HbA1c Procena dugoročnog kvaliteta glikoregulacije (prosečno kretanje glikemije u protekla 2-3 meseca) PPG Pik glukoze u krvi (glikemija 1,5-2h nakon početka obroka) FPG Bazalna glikemija (glikemija pre obroka) 5.5 mmol/l 7.5 mmol/l

ADA, AACE, and IDF Guidelines: Treatment Goals for HbA1c, FPG, and PPG Parameter ADA1 Goal AACE/ACE2,3 Goal IDF4 Goal FPG, mg/dL (mmol/L) 70–130 (3.9–7.2) <110 (<6.1) <100 (<5.5) PPG, mg/dL (mmol/L) <180 (<10) <140 (<7.8) HbA1c, % <7 ≤6.5 <6.5 ADA, AACE, and IDF Guidelines: Treatment Goals for HbA1c, FPG, and PPG The table presents guidelines from the American Diabetes Association (ADA), the American Association of Clinical Endocrinologists (AACE), and the Internation Diabetes Federation (IDF).1–4 The ADA suggests that the goal of treatment in the management of diabetes should be an HbA1c value <7%.1 The AACE recommends an HbA1c goal of ≤6.5% and the IDF recommends an HbA1c of <6.5%.2–4 Lowering HbA1c to below or around 7% has been shown to reduce microvascular and neuropathic complications of type 1 and type 2 diabetes. Therefore, for microvascular disease prevention, the HbA1c goal for non-pregnant adults in general is <7%.1 The general goal of <7% appears reasonable for many adults for macrovascular risk reduction. Therefore, for selected individual patients, providers might reasonably suggest even lower HbA1c goals than the general goal of <7%, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant CVD. Conversely, less-stringent HbA1c goals than the general goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, and extensive co-morbid conditions and those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose lowering agents including insulin.1 The AACE suggests that the primary goal should be achieving an HbA1c of 6.5%, but this goal must be customized for the individual patient, with consideration of numerous factors such as comorbid conditions, duration of diabetes, history of hypoglycemia, hypoglycemia unawareness, patient education, motivation, adherence, age, limited life expectancy, and use of other medications.3 The ADA target of FPG levels between 70 and 130 mg/dL (3.9–7.2 mmol/L) is based on the estimate of the range of average glucose values that would be associated with low risk of hypoglycemia and HbA1c <7%.1 The ADA also recommends reducing peak PPG values to <180 mg/dL (<10 mmol/L).1 The AACE recommends reducing FPG levels to <110 mg/dL (<6.1 mmol/L) and PPG levels to <140 mg/dL (<7.8 mmol/L), while the IDF recommends reducing FPG levels to <100 mg/dL (<5.5 mmol/L) and PPG levels to <140 mg/dL (<7.8 mmol/L).2,4 Purpose To provide a reminder of current guidelines for patients with type 2 diabetes. Takeaway Reducing all 3 parameters (HbA1c, fasting plasma glucose [FPG], and postprandial glucose [PPG]) is important for glycemic control; patient goals should be individualized as appropriate. ADA: The general goal of < 7% appears reasonable for many adults with diabetes. Less stringent HbA1c goals may be appropriate for other patients especially those with a history of hypoglycemia. AACE: Achieving an HbA1c of 6.5% is recommended as the primary goal, but this goal must be customized for the individual patient, with consideration of numerous factors, especially hypoglycemia. AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology; ADA=American Diabetes Association; FPG=fasting plasma glucose; PPG=postprandial glucose. aReference to a non-diabetic range of 4.0% to 6.0% using a DCCT-based assay. 1. ADA. Diabetes Care. 2010;33(suppl 1):S11–S61. 2. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13:(suppl 1)3–68. 3. Rodbard HW et al. Endocr Pract. 2009;15(6):540–59. 4. International Diabetes Federation. www.idf.org/webdata/docs/Guideline_PMG.pdf. Accessed February 9, 2010. References American Diabetes Association. Standards of medical care in diabetes—2010. Diabetes Care. 2010;33(suppl 1):S11–S61. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Management of Diabetes Mellitus. Endocr Pract. 2007;13(suppl 1):3–68. Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15(6):540–59. International Diabetes Federation. Guidelines for Management of Postmeal Glucose.2007:1–32. www.idf.org/webdata/docs/Guideline_PMG.pdf. Accessed February 9, 2010.

TERAPIJA DIABETES MELLITUS-a TIP 2

nemanifestan manifestan Klinički Klinički nemanifestan manifestan DM tip 2 DM tip 2 Predijabetes Nasleđe Faktori rizika FOKUS AKTIVNOSTI KASNA KLINIČKA DIJAGNOZA NEPREPO- ZNAVANJE FAKTORA RIZIKA KLINIČKI PRAVOVREMENA, ALI PATOFIZIOLOŠKI KASNA DIJAGNOZA

KLJUČNI PROBLEMI Nedovoljna posvećenost faktorima rizika za DM tip 2 Kasna dijagnoza i zanemarivanje progresivne prirode DM tip 2 Nedovoljno agresivna kontrola bolesti sporo kretanje kroz terapijski algoritam strah i pacijenta i lekara novih terapijskih modaliteta Nedovoljna samokontrola previše često donošenje terapijskih odluka samo na osnovu glikemije našte nedovoljno često određivanje postprandijalnih glikemija i HbA1c

Usaglašeni algoritam za započinjanje i usklađivanje terapije Američke dijabetes asocijacije (ADA) i Evropske asocijacije za proučavanje dijabetesa (EASD)

Extrapolation of the time of deterioration of beta-cell dysfunction 100 80 50% 60 Beta-cell function (%) 40 20 –12 –10 –8 –6 –4 –2 0 2 4 6 Years from diagnosis Adapted from UKPDS 16. Diabetes 1995;44:1249–1258 36

HbA1c < 7% 3 meseca ! 37

Ključni patofiziološki procesi u Diabetes mellitus-u tip 2 INSULINSKA REZISTENCIJA DISFUNKCIJA BETA ĆELIJA HIPERGLIKEMIJA

Oralni antidijabetici Terapija dijabetesa Oralni antidijabetici

FARMAKOLOŠKE GRUPE ORALNIH ANTIDIJABETIKA SULFONILUREJA MEGLITINIDI (kratkodelujući insulotropni agensi) BIGVANIDINI PPARγ agonisti (THIAZOLIDINEDIONI) PPARά,γ agonisti (GLITAZARI) INHIBITORI -GLUKOZIDAZE POTENCIRANJE INKRETINSKOG EFEKTA: DPP4 inhibitori, GLP-1 mimetici, GLP-1 analozi

DISFUNKCIJA BETA ĆELIJA BIGVANIDINI INSULINSKA THIAZOLIDINEDIONI SULFONILUREJA MEGLITINIDI DPP-4 inhibitori GLP-1 analozi GLP-1 mimetici INSULINSKA REZISTENCIJA BIGVANIDINI THIAZOLIDINEDIONI PPARάγ agonisti BRZINA APSORPCIJE GLIKOZE INHIBITORI -GLUKOZIDAZE

Sulfonilureja Oralna antihiperglikemijska sredstva Disfunkcija beta-ćelija (insulinska sekrecija) Sulfonilureja I generacija tolbutamid, hlorpropamid, acetoheksamidin, tolazamin II generacija glibenklamid, gliklazid, glipizid, glikvidon III generacija glimepirid Meglitinidi repaglinid, nateglinid

Bigvanidi Oralna antihiperglikemijska sredstva insulinska senzitivnost metformin Tiazolidindioni pioglitazon, roziglitazon Oralna antihiperglikemijska sredstva apsorpcija glukoze Inhibitori alfa glukozidaze akarboza, miglitol

METFORMIN

METFORMIN podaci iz UKPDS-a Lečenje Metforminom, SU ili insulinom ima isti efekat na kvalitet glikoregulacije u DM2 Primena Metformina Smanjuje kardiovaskularni rizik Nema hipoglikemija, ni dobijanja u TM Signifikatno manji ukupni i za DM vezan mortalitet, kao i završne tačke DM

UKPDS

REDUKCIJA KARDIOVASKULARNOG RIZIKA Libby P. Metformin and vascular protection: a cardiologist s view. Diabetes Metab 2003, 29, 6S117-20

METFORMIN plejotropni efekti POBOLJŠAVA Senzitivnost na insulin Fibrinoliza Kapilarni protok Hemoreološka svojstva Postishemični protok SMANJUJE Hipertrigliceridemija Formiranje AGE Umrežavanje fibrina Neovaskularizacija Oksidativni stres SMANJENJE ATEROGENEZE

primene Metformina u osoba sa MAKSIMALIZACIJA primene Metformina u osoba sa DM tip 2 G C Jones, J P Macklin W and D Alexander BMJ 2003;326:4-5 (4 January)

METFORMIN Prva linija farmakoterapije u DM tip 2 Uvesti ga odmah po otkrivanju bolesti Propisivanje svima kojima je indikovan Propisati ga svima koji nemaju kontraindikacije i koji nemju nuspojave Ne prekidati sa njegovom primenom (ni nakon uvođenja insulinske terapije) Postizanje optimalne doze Minimalna doza 1500mg, maksimalna 3000mg, opstimalna 2000mg Postepeno uvođenje (2x250mg) i povećavanje doze u intervalima 5 do 10 dana Lek uzimati za vreme ili nakon obroka

LEKOVI INKRETISNKOG KONCEPTA

Creutzfeldt. Diabetologia. 1985;28:565. Inkretinski efekat Oralno uzeta glukoza dovodi do značajno boljeg insulinskog odgovora nego kada se aplikuje intravenski što ukazuje na prisustvo supstanci unutar gastrointestinalnog trakta koje stimulišu glukozom indukovano oslobadjanje insulina. Creutzfeldt. Diabetologia. 1985;28:565.

In ● cre ● tin Definicija inkretina “GIT faktori koji povećavaju glukozom-stimulisanu insulinsku sekreciju” In ● cre ● tin Intestine Secretion Insulin Major discussion point: INtestine SeCRETion INsulin Creutzfeldt W, Ebert R. New developments in the incretin concept. Diabetologia. 1985;28:565-573. Creutzfeldt. Diabetologia. 1985;28:565.

GLP-1: Intestinalni hormon Sekretuju ga L ćelije intestinalne mukoze nakon obroka Efekti Stimuliše insulinsku sekreciju Suprimira sekreciju glukagona Usporava pražnjenje želuca Povećava osećaj sitosti Povećava masu -ćelija/replikaciju u životinja Brzo se inaktivira proteaznim enzimom dipeptidil peptidaza IV (DPP-IV) Major discussion point: Facts about GLP-1. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929-2940. Drucker. Diabetes Care. 2003;26:2929.

Native GLP-1 must be administered continuously to realise full therapeutic potential Intermittent (16 h/day) GLP-1 IV infusion (8 ng/kg/min) (n=8) Continuous (24 h/day) GLP-1 IV infusion (8 ng/kg/min) (n=8) 25 25 20 20 15 15 Plasma glucose (mmol/L) Plasma glucose (mmol/L) 10 10 5 GLP-1 infusion 5 PBS PBS GLP-1 infusion 04 08 12 16 20 00 04 04 08 12 16 20 00 04 Time (h) Time (h) Day 0 Blood glucose profiles: Day 7 55 Adapted from Larsen et al, Diabetes Care 2001;24:1416–21 PBS, phosphate-buffered saline

Farmakološki pristup modulaciji GLP-1 delovanja u dijabetesu Agonisti GLP-1 receptora Mimetici Poseduju fiziološke karakteristike i biološku aktivnost nativnog GLP-1 ali su rezistentni na degradaciju od strane DPP-IV Exenatide (exendin-4) Analozi Produžen polu-život modulacijom rekombinantnog humanog GLP-1 koji je rezistentan na degradaciju od strane DPP-IV Liraglutide DPP-IV inhibitori Vildagliptin, sitagliptin Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929-2940. Dungan K, Buse JB. Glucagon-like peptide 1–based therapies for type 2 diabetes: a focus on exenatide. Clin Diabetes. 2005;23:56-62. Drucker. Diabetes Care. 2003;26:2929. Dungan. Clin Diabetes. 2005;23:56.

Liraglutide is a once-daily, human GLP-1 analogue 7 36 9 Lys His Ala Thr Ser Phe Glu Gly Asp Val Tyr Leu Gln Ile Trp Arg 97% homology to human GLP-1 Improved PK: albumin binding though acylation; self-association Slow absorption from subcutis Resistant to DPP-4 Long plasma half-life (T½=13 h) C-16 fatty acid (palmitoyl) His Ala Thr Ser Phe Glu Gly Asp Val Tyr Leu Gln Lys Ile Trp Arg 7 9 36 Enzymatic degradation by DPP-4 T½=1.5–2.1 min 57 Knudsen et al, J Med Chem 2000;43:1664–9; Degn et al, Diabetes 2004;53:1187–94

Glycaemic control: liraglutide monotherapy markedly reduces HbA1c 0.4 Placebo 0.65 mg/day 1.25 mg/day 1.90 mg/day 0.0 Mean baseline HbA1c = 8.2% Mean baseline HbA1c = 8.1% Mean baseline HbA1c = 8.3% Mean baseline HbA1c = 8.5% 1.7% HbA1c reduction vs. placebo -0.4 Change in HbA1c vs. baseline (%) -0.8 -1.2 -1.6 p<0.0001 p<0.0001 p<0.0001 Plotted data are estimated means from the model corrected for pre-treatment, treatment and baseline as covariate ; p values are vs. placebo 58 Vilsbøll et al, Diabetes Care 2007;30:1608–10

Novi pravci u terapiji DM2 Poboljšanje preparata “inkretinskog koncepta” Novi DDP-IV inhibitori Analozi GLP-1 sa produženim dejstvom Agonisti PPAR-ά,γ (potencijalan simultani efekat na DM i HLP) Osteokalcin Inhibitori Natrijum-glukoznog kotransportera 2 (SGLT-1) u bubrezima

UMESTO ZAKLJUČKA: Koliko smo uspešni u lečenju dijabetes? GLIKOREGULACIJA HbA1c <7% 57.1% KRVNI PRITISAK TA <130/80 mmHg 45.5% LIPOREGULACIJA LDL-holesterol < 2.6 mmol/L 46.5% Samo 12.2% obolelih od dijabetesa uspeva da ostvari sva 3 cilja Local country can adapt to similar local information, if appropriate. Purpose To examine the proportion of individuals who are achieving ADA diabetes management goals. Takeaway There are still many patients who are not yet at goal in either HbA1c, BP, or LDL. NHANES=National Health and Nutrition Examination Survey; 1. Cheung BM, et al. Am J Med. 2009;122(5):443–453. 2. ADA. Diabetes Care. 2010;33(suppl 1):S11–S61. References 1. Cheung BM, Ong KL, Cherny SS, et al. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med. 2009;122:443-453. 2. American Diabetes Association. Standards of medical care in diabetes—2010. Diabetes Care. 2010;33(suppl 1):S11–S61.