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

2. 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

3. Diabetes mellitus:
epidemiologija

4. Diabetes mellitus je bolest čija je pandemija u toku

5. Trend porasta incidence DM

6. Incidenca DM u svetu
Broj ljudi sa DM (u milionima) po regionima za 2003 i 2025 (porast 72%)
Evropa m 44.2m (+16%)
USA/Kanada
25.0m 39.7m (+59%)
Azia 81.8m m (+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.

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

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

9. 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 Accessed 1 April 2007.

10. 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.

12. Komplikacije Diabetes mellitus-a se u velikoj meri mogu sprečiti

13. HbA1c i relativni rizik za mikrovaskularne komplikacije: DCCT20
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:
2. DCCT. N Engl J Med. 1993;329:
3. DCCT. Diabetes. 1995;44:
1. Skyler JS. Diabetic complications: the importance of glucose control. Endocrinol Metab Clin North Am. 1996;25:
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:
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:

14. 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.

15. Diabetes mellitus:
dijagnoza

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

17. Diabetes mellitus:
definicija

18. 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).

19. podela i etiopatogeneza
Diabetes mellitus:
podela i etiopatogeneza

20. 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

21. 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

22. 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

23. 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

24. 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

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

26. REZISTENCIJA NA INSULIN
“ŠTEDLJIVI” GENOTIP
REZISTENCIJA NA INSULIN

27. EVOLUCIJA DIABETES MELLITUS-A tip 250
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

28. Diabetes mellitus:
terapija

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

30. 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

31. 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. 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. Accessed February 9, 2010.

32. TERAPIJA DIABETES MELLITUS-a TIP 2

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

34. 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

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

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

37. HbA1c < 7%
3 meseca ! 37

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

39. Oralni antidijabetici
Terapija dijabetesa
Oralni antidijabetici

40. 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

41. 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

42. 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

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

44. METFORMIN

45. 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

46. UKPDS

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

48. 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

49. 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)

50. 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

51. LEKOVI INKRETISNKOG KONCEPTA

52. 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.

53. 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:
Creutzfeldt. Diabetologia. 1985;28:565.

54. 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:
Drucker. Diabetes Care. 2003;26:2929.

55. 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– PBS, phosphate-buffered saline

56. 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:
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.

57. Liraglutide is a once-daily, human GLP-1 analogue7 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

58. 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

59. 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

60. UMESTO ZAKLJUČKA: Koliko smo uspešni u lečenju dijabetes?
GLIKOREGULACIJA
HbA1c <7% %
KRVNI PRITISAK
TA <130/80 mmHg %
LIPOREGULACIJA
LDL-holesterol < 2.6 mmol/L %
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 Am J Med. 2009;122:
2. American Diabetes Association. Standards of medical care in diabetes—2010. Diabetes Care ;33(suppl 1):S11–S61.