Exenatid - elmélet és klinikum

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1 Exenatid - elmélet és klinikum
Prof. Dr. Winkler Gábor egyetemi tanár, osztályvezető főorvos Fővárosi Szent János Kórház II. sz. Belosztály, Budapest

2 A vércukorszint szabályozása
140 Étkezés Glukóz Inzulin 120 Glukagon mg% Éhomi és interpr. vércukorszint: bazális inz. elválasztás  HGP 100 160 120 Étkezést követően: mU/mL DISCUSSION Insulin release increases in response to a meal, while glucagon levels are suppressed. These trends normalise as glucose levels return to fasting levels (~2 hours post meal). In normal subjects, glucose is maintained in a relatively narrow range following a meal (~ mg/dL). BACKGROUND Plasma insulin and glucagon were measured in normal subjects without diabetes following a meal. 80 40 Inzulin Glukagon 130 Plazma glukóz -sejt  Nerualis tényezők (?) Incretinek 120 110 pg/mL 100 90 -60 60 120 180 240 Idő (min) Unger RH. N Eng J Med 285 : nyomán Copyright © 1971 Massachusetts Medical Society. All rights reserved. Translated with permission 2006.

3 A vércukorszint szabályozása
140 Étkezés Glukóz Inzulin 120 Glukagon mg% Éhomi és interpr. vércukorszint: bazális inz. elválasztás  HGP 100 160 120 Étkezést követően: mU/mL DISCUSSION Insulin release increases in response to a meal, while glucagon levels are suppressed. These trends normalise as glucose levels return to fasting levels (~2 hours post meal). In normal subjects, glucose is maintained in a relatively narrow range following a meal (~ mg/dL). BACKGROUND Plasma insulin and glucagon were measured in normal subjects without diabetes following a meal. 80 40 Inzulin Glukagon 130 Plazma glukóz -sejt  Nerualis tényezők (?) Incretinek 120 110 pg/mL 100 90 -60 60 120 180 240 Idő (min) Unger RH. N Eng J Med 285 : nyomán Copyright © 1971 Massachusetts Medical Society. All rights reserved. Translated with permission 2006.

4 Serum C-peptid (nmol/l) Plazma vércukor (mmol/l)
Incretin hatás áll az oralis vs. iv. glukóz hatására bekövetkező eltérő inzulin secretio hátterében oralis glukóz iv. glukóz 11 2.0 * 1.5 DISCUSSION Despite the same plasma glucose profiles, there are significant differences in the -cell response to oral versus (vs) intravenous glucose, as measured by C-peptide. BACKGROUND This was a crossover study involving healthy subjects. Six young healthy subjects were given a 25, 50, or 100 g oral glucose load or isoglycaemic intravenous glucose infusions. The 50-g data is shown above. C-peptide may be a better measure of insulin secretion than plasma insulin, because C-peptide levels are not affected by hepatic insulin extraction. This difference in C-peptide levels in response to oral vs intravenous glucose suggests that other factors (incretins), and not merely the direct actions of plasma glucose, affect the insulin secretory response. Incretin hatás 5.5 Serum C-peptid (nmol/l) 1.0 Plazma vércukor (mmol/l) 0.5 0.0 01 02 60 120 180 01 02 60 120 180 Idő (perc) Idő (perc) Átlag ± SE; n = 6; *P .05; = glukóz infusio időtartama Nauck MA, et al: Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 63: Copyright 1986, The Endocrine Society.

5 A prandialis inzulin secretio első fázisa 2-es típusú diabetesben
Egészséges kontrollszemélyek 2DM-es személyek iv. glukóz 120 100 100 80 DISCUSSION In contrast to normal insulin release in response to intravenous glucose, there is essentially no first phase insulin response in subjects with type 2 diabetes. BACKGROUND This slide represents acute insulin response to intravenous glucose (20 g) in weight and gender-matched subjects (with diabetes, n=15; without diabetes, n=18). 80 60 iv. glukóz Inzulin Release (U/mL) 60 Inzulin Release (U/mL) 40 40 20 20 -40 -30 -20 -10 10 20 30 -40 -30 -20 -10 10 20 30 Idő (min) Idő (min) Porte, D: Diabetes 40: Copyright © 1991 American Diabetes Association. From Diabetes, Vol 40, 1991; Reprinted with permission from The American Diabetes Association.

6 A plazma glukagon szint 50 gr-os OGTT során
■ = egészségesek ∆ = enyhe 2DM  = középsúly. 2DM O = súlyos 2DM Dunning, BE et al: Diabetologia 48:

7 A -sejt diszfunkció klinikai következményei
Étkezés utáni (postprandials, pp.) vér-cukorszint emelkedése A hepatikus glukózkibocsátás elégtelen supprimálása Az -sejt diszfunkció elmélyülése A lipolízis elégtelen suppressiója A „célszervek” (izom- és zsírszövet) glu-kóz felvételének károsodása

8 Az -sejt diszfunkció 2 – es típusú diabetesben
Éhomi plasma glukagon szint  Plasma átlagos glukagon tartalom  Hyperglykaemia gluk. suppr. hat.  Inzulin glukagonostatikus hatása  Arginin glukagon secretagog hat.  Hypoglykaemia secr. fok. hatása N Az állapot jellemzője: relatív hyperglukagonaemia

9 Az incretin hatás csökkent 2-es típusú diabetesben
iv. glukóz Oralis glukóz Kontroll személyek 2-es típusú diabeteszes személyek 80 80 DISCUSSION The -cell secretory response to glucose ingestion, as measured by increases in plasma insulin, was reduced in patients with diabetes. Patients with diabetes exhibited a greater -cell secretory response than control subjects, as indicated by higher insulin secretion levels, during the 180-minute course of intravenous glucose infusion. BACKGROUND Differences in insulin response to oral and intravenous glucose administration, which are attributed to factors other than glucose itself, describe the incretin effect; the incretin effect appears to be reduced in patients with type 2 diabetes. measured insulin and C-peptide responses to a 50-g oral glucose load and an isoglycaemic intravenous infusion. Additionally, an attempt was made to correlate incretin effects to GIP responses. Insulin measurements are shown here. Plasma insulin responses were studied for 14 patients This study with type 2 diabetes and 8 metabolically healthy control subjects. 60 60 Se inzulin (mU/l) 40 40 * * 20 20 30 60 90 120 150 180 30 60 90 120 150 180 Idő (perc) Idő (perc) *P ≤.05 az oralis bevitel azonos időpontjához viszonyítva Nauck, MA, et al: Diabetologia 29: Reprinted with permission from Springer-Verlag © 1986.

10 A GLP-1 és a GIP ma ismert fontosabb élettani tulajdonságai I.
Termelődés helye A vékonybél L-sejtjei (dominálóan az alsó vékonybélszakaszban) A vékonybél K-sejtjei (dominálóan a felső vékonybélszakaszban) Metabolizmus DPP-IV (80% perceken belül lebomlik, a keringő mennyiség alig 20%-a az intakt forma) DPP-IV (50% perceken belül lebomlik, a keringő mennyiség 40-50%-a az intakt forma) Féléletideje Kb. 2 min Kb. 7 min Inaktív metabolitok eliminációja vese vese Inaktív metabolitok féléletideje 5 min 17 min Az anyagcserehatások helye -sejt: inzulinelválasztás  - exocytosis  - de novo szintézis  - „glukóz szenzor” elemek génjeinek expressz  -sejt: glukagon elvál  Gyomor: motilitas  Kp. idegrendszer : - jóllakottság-érzet  - táplálékfelvétel  -sejt: inzulinelválasztás  - exocytosis  - de novo szintézis  Adipocyta

11 fontosabb élettani tulajdonságai II.
A GLP-1 és a GIP ma ismert fontosabb élettani tulajdonságai II. GLP-1 GIP Az inzulintermelés serkentése - a glukóz indukálta inzulinszek- réció serkentése - az inzulin gén expressziójának erősítése - az inzulin bioszintézis vala - mennyi fázisának serkentése - in vitro vizsgálatokban és ál- latmodellekben a -sejt tömeg növelése, a sejtproliferáció serkentése és az apotosis gát- lása révén a glukóz indukálta inzulinszek- réció serkentése az inzulin gén expressziójának erősítése az inzulin bioszintézis vala - mennyi fázisának serkentése in vitro vizsgálatokban és ál – latmodellekben a b-sejt tömeg növelése, a sejtproliferáció serkentése és az apotosis gát- lása révén Cukorbetegségben inzulin secretagog hatás 2-es típ. diabetesben is megtartott - vérszintje (elválasztása)  inzulin secretagog hatás  elválasztása 1-es és 2-es típusú diabetesben meg- tartott

12 A GLP-1 inzulin secretagog hatása glukóz-dependens (2DM-ben is)
Placebo (PBO) GLP-1 n = 10; Átl ± SEM; *P <.05; GLP-1: iv. infusio 1,2 pmol/kg/min 4 órán át PBO PBO PBO GLP-1 GLP-1 GLP-1 270 300 DISCUSSION A continuous infusion of GLP-1 resulted in significant decrease in plasma glucose over a 4-hour period, compared to placebo. Compared to placebo, GLP-1 initially enhanced insulin secretion, but as plasma glucose approached normal concentrations, insulin secretion subsided despite the continuing GLP-1 infusion – demonstrating glucose-dependent insulin secretion. GLP-1 suppresses glucagon concentrations in the presence of hyperglycaemia. However, glucagon levels return to baseline as plasma glucose approaches normal, despite continued infusion of GLP-1, demonstrating that GLP-1 does not suppress glucagon during euglycaemia or hypoglycaemia. Glucose dependency is demonstrated by a return of plasma insulin and glucagon to pretreatment concentrations as plasma glucose approaches the normal range. BACKGROUND This study involved subjects with type 2 diabetes (n=10) – all on diet + a sulphonylurea (SFU) and some on metformin or acarbose. All antidiabetic medications were withheld at the start of the study. Intravenous GLP-1 (7-36 amide) was infused for 4 hours at 1.2 pmol/kg/min. 20  * 180 200  Glukóz (mg/dl) Inzulin (pmol/l) * * Glukagon (pmol/l) 10 * * * * * 90 100 * * * * * -30 60 120 180 240 -30 60 120 180 240 -30 60 120 180 240 Idő (min) Idő(min) Idő (min) . Nauck, MA, et al: Diabetologia 36: Reprinted with permission from Springer-Verlag © 1993.

13 GLP-1 a szénhidrát-anyagcsere szabályozásában
A pp. inzulinelválasztás serkentése Glukagon secretio supprimálása Gyomorürülés lassítása -sejt replikáció elősegítése Teltségérzet fokozása

14 A GLP -1 experimentálisan igazolt, nonmetabolikus hatásai
Kardiovaszkuláris hatások (?) - endothelvédő hatás - kísérletes körülmények között a postischae- miás keringés javítása (Nyström, T et al.: Am J Physiol Endocrinol Metab 287: E1209-E1215. 2004.) - direkt vasorelaxáns hatás (Nyström, T et al.: Regul pept 125: ) - a systolés pumpafunkció javítása postischae- miás viszonyok között (Nikolaidis, LA et al.: Circulation 109: )

15 A GLP-1 hatás farmakológiai erősítésének lehetőségei
Az élettani GLP-1 hatás erősítése (incretin enhancers) - gliptinek (sita- Januvia, vilda- Gal- vus Farmakológiai GLP-1 hatás érvényesít. - GLP-1 analógok (liraglutid) - GLP-1 receptor agonisták: exenatid  szintetikus exendin-4  Byetta

16 Gila Monster (Heloderma suspectum)

17 Exendin-4 és GLP-1 Exendin-4 aminosav összetéte-
le hasonlít a h-GLP1-hez (53%) Exendin-4 és a GLP-1 teljesen különböző génekből származ-nak a Gila monster-ben. Exendin-4 és a GLP-1 egyaránt kötődik a pancreas GLP-1 re-ceptoraihoz in vitro. Aminosav szekvencia: GLP-1 receptor iránti kötés affinitás: 100 80 60 Percent of Maximum Binding 40 20 GLP-1 Exendin-4 Zero -11 -10 -9 -8 -7 -6 Peptide Concentration (log molar) Eng J, et al: J Biol Chem 267: Chen, YQE, Drucker, DJ: J Biol Chem 272: Data on file, Amylin Pharmaceuticals, Inc.

18 Az exendin - 4 (exenatid, AC 2993) főbb hatástani jellemzői
*39 aminosavból épül fel Rendelkezik a GLP-1 szénhidrát-anyagcserét érintő hatásaival *Nem gátolja a gyomornedv termelést *Nem befolyásolja a vagus működést *Eliminatiója kizárólag renalis *Felezési ideje sc. beadás esetén ~ 2-6 óra (125 – 373 min) * Az élettani GLP-1 hatástól eltérő tulajdonság

19 Pivotalis exenatid –”amigo”– vizsgálatok: vizsgálati alapstruktúra
Randomizált, hármas-vak, placebo-kontrollos, multicentri- kus vizsgálat Exenatid vagy placebo hozzáadása a maximalis hatékony metformin (MET) és/vagy SU dózishoz 2 DM-es betegeken DISCUSSION: 4-week placebo lead-in Both exenatide arms began with 5 µg exenatide for 4 weeks, to minimize nausea Subsequently one arm had exenatide increased to 10 µg BID for 26 weeks, while the other arm remained at 5 µg Placebo groups were combined for analyses STUDY BACKGROUND: Could terminate if: HbA1c up 1.5% from baseline or HbA1c >11.5% at Week 18 or 24 or Fasting glucose >240 mg/dL (lab test), or fasting glucose >260 mg/dL (finger stick) for 2+ weeks 112 – 30-week triple-blind, phase 3 study; patients with type 2 diabetes randomized to placebo or 5 or 10 µg exenatide BID w/MET, ITT n=336 113 – 30-week triple-blind, phase 3 study; patients with type 2 diabetes randomized to placebo or 5 or 10 µg exenatide BID w/SFU, ITT n=377 115 – 30-week triple-blind, phase 3 study; patients with type 2 diabetes randomized to placebo or 5 or 10 µg exenatide BID w/MET and SFU, ITT n=734 Exenatid 5 µg BID Exenatid 5 µg BID Exenatid 10 µg BID Szűrés Placebo bevezetés Placebo 0.02 mL Placebo 0.02 mL Placebo 0.04 mL -4 4 12 24 30 Idő (hét) Buse, J, et al.: Diabetes Care 27: ; Kendall, DM, et al: Diabetes Care 28: ; DeFronzo, RA, et al: Diabetes Care 27:

20 112-es vizsgálat: a HbA1c változása a vizsgálat során
Placebo 5 µg exenatid 10 µg exenatid 5 10 15 20 25 30 6.5 7.0 7.5 8.0 8.5 9.0 +0.1% -0.4% -0.8% DISCUSSION: Study effect: 0.2% to 0.3% decrease in HbA1c during 4-week placebo lead-in Both exenatide arms received 5 µg exenatide for 4 weeks to minimize nausea After Week 4, the dose in one exenatide arm was increased to 10 µg exenatide BID for 26 weeks and the other remained at 5 µg BID By Week 6, significant (P <0.0005) reductions from baseline (pairwise comparison to placebo) in HbA1c in both 5 and 10 µg arms were achieved and sustained for 30 weeks These data show a dose-dependent response (P=0.0053) in reduction of HbA1c STUDY BACKGROUND: 112 – 30-week triple-blind, phase 3 study; patients with type 2 diabetes randomized to placebo or 5 or 10 µg exenatide BID w/MET, ITT n=336 Átlag (±SE) HbA1c (%) Placebo bevez. Szűrés Idő (hét) ITT population, n=336 (Placebo, n=113; 5 µg exenatide, n=110; 10 µg exenatide, n=113); P < reductions from baseline (pairwise comparison to placebo) in both exenatide arms for Weeks 6 to 30 DeFronzo, RA, et al: Diabetes Care 27:

21 A kívánt A1C értéket elérő
112-es vizsg.: HbA1C 7% célértéket elérő betegek aránya a vizsgálat 30. hetében Placebo 5 µg exenatid 10 µg exenatid 50 * * 40 46% * A kívánt A1C értéket elérő személyek száma 30 32% 20 10 13% A kiindulási HbA1c >7% értékkel rendelkezők száma: n=234 (Placebo, n=77; 5 µg exenatid, n=79; 10 µg exenatid, n= 84) *P <0.01, **P <0.0001 DeFronzo, RA, et al: Diabetes Care 27:

22 Az éhomi vércukorszint átlagos (±SE) változása
112-es vizsgálat: az éhomi vércukorszint változása, az ITT populációra számítva Placebo 5 µg exenatid 10 µg exenatid -20 -10 10 20 * ** 14 mg/dl DISCUSSION: Reductions in FPG were significant Exenatide reductions in HbA1c may reflect the importance of postprandial control on HbA1c STUDY BACKGROUND: 112 – 30-week triple-blind, phase 3 study; patients with type 2 diabetes randomized to placebo or 5 or 10 µg exenatide BID w/MET, ITT n=336 Az éhomi vércukorszint átlagos (±SE) változása (mg/dl) -7 mg/dl -10 mg/dl ITT populatio, n=336 (Placebo, n=113; 5 µg exenatid, n=110; 10 µg exenatid, n=113) *P <0.005, **P <0.0005 DeFronzo, RA, et al: Diabetes Care 27:

23 112 – es vizsgálat: a testsúly változása, ITT betegszám
Placebo 5 µg exenatid 10 µg exenatid 5 10 15 20 25 30 -4 -3 -2 -1 1 * ** -0.3 kg DISCUSSION: No special weight loss programs, exercise programs, or standardized diets were used in the study Progressive, dose-dependent reduction in weight was seen in exenatide-treated patients A study effect was evident in the placebo population STUDY BACKGROUND: 112 – 30-week triple-blind, phase 3 study; patients with type 2 diabetes randomized to placebo or 5 or 10 µg exenatide BID w/MET, ITT n=336 Testsúlyváltozás átlag (±SE) (kg) -1.6 kg -2.8 kg Idő (hét) ITT populatio, n=336 (Placebo, n=113; 5 µg exenatid, n=110; 10 µg exenatid, n=113) * P ≤0.05 ** P ≤ DeFronzo, RA, et al: Diabetes Care 27:

24 A proinzulin / inzulin hányados változása
112-es vizsg.: a proinzulin / inzulin arány változása a kiindulási értékhez képest Placebo 5 µg exenatid 10 µg exenatid -0.3 -0.2 -0.1 0.0 0.1 * -0.03 -0.17 DISCUSSION: The fasting proinsulin-to-insulin ratio is a marker of beta-cell function. A decrease in this ratio is suggestive of an improvement in beta-cell function From baseline to Week 30, proinsulin-to-insulin ratios were reduced ‑0.03% for 5 μg and -0.17% (P<0.001) for 10 μg compared with placebo STUDY BACKGROUND: 112 – 30-week triple-blind, phase 3 study; patients with type 2 diabetes randomized to placebo or 5 or 10 µg exenatide BID w/MET, ITT n=336 A proinzulin / inzulin hányados változása átlag (± SE) ITT populatio, N=336 (Placebo, n=113; 5 µg exenatid, n=110; 10 µg exenatid, n=113); *P <0.001 DeFronzo, RA, et al: Diabetes Care 27:

25 A 82 hetes nyílt követés interim adatai
A vizsgálat felépítése: Placebo-kontrollos klinicai vizsgálat Nyílt kontrollálatlan kiterjesztés DISCUSSION: All subjects continued any preexisting treatment regimens of MET and SFU. All subjects who elected to continue in the open-label extension were given 5 g exenatide for the first 4 weeks of the open-label extension (overall, Weeks 30 to 34), after which they received 10 g exenatide. Endpoints: HbA1c, body weight, and safety Exenatid 5 µg (0.02 ml) BID Exenatid 5 µg (0.02 ml) BID Bevezető szak 0.02 ml BID Placebo (PBO) Szűrés Exenatid 10 µg (0.04 ml) BID Exenatid 5 µg (0.02 ml) BID Exenatid 10 µg (0.04 ml) BID PBO 0.02 ml BID PBO 0.02 or 0.04 mL BID -4 4 30 34 82 Idő (hét)

26 HbA1c változás: 82 hetes interim eredmények
Placebo- kontroll Nyílt kiterjesztés 0.5 Kiindulási HbA1c Placebo BID (n = 69) 8.2% 5 mg exenatid BID (n = 69) 8.3% DISCUSSION: Exenatide treatment resulted in sustained mean HbA1c reductions from baseline, with a decrease of -1.0% at 82 weeks. Placebo cohort upon receiving exenatide (at Week 30) showed an immediate decrease of HbA1c similar to that observed with exenatide treatment in the first 30 weeks. The slight upward trend seen for both the placebo and exenatide treatment groups from Weeks 18 to 30 likely represents an initial study effect that disappears over time, and is similar in magnitude to the decrease in HbA1c during the 4-week placebo lead-in period. STUDY BACKGROUND: Interim results from subjects who completed one of the three 30-week pivotal trials (with a background of MET and SFU) and completed an additional 52 weeks of exenatide treatment in the corresponding open-label extension for a total of 82 weeks of treatment (n=205). Subjects are grouped by the treatment to which they were originally randomized in the placebo-controlled trial, with the increase to 10 g in the extension indicated with an arrow: placebo BID (placebo10 g), 5 g BID (5 g 10 g), 10 g BID (10 g 10 g). All subjects were given 5 g exenatide for the first 4 weeks of the open-label extension (overall, Weeks 30 to 34), after which they received 10 g exenatide. 0.0 10 mg exenatid BID (n = 67) 8.5% D HbA1c (%) -0.5 -1.0 ± 0.1% -1.0 -1.0 ± 0.2% -1.0 ± 0.2% -1.5 10 20 30 40 50 60 70 80 90 Idő (hét) Ratner, RE et al: Diab Obes Metab 8: Blonde, L et al : Diab Obes Metab 8: Mean (SE)

27 Testsúly változás: 82 hetes interim eredmények
Placebo- kontroll Nyílt kiterjesztés Kiindulási súly Placebo BID (n = 69) 97.6 kg 5 mg exenatid BID (n = 69) 97.4 kg DISCUSSION: Exenatide treatment resulted in progressive mean weight reductions from baseline, with a decrease of -3.9 to -4.4 kg at 82 weeks. Placebo cohort upon receiving exenatide showed an immediate decrease of weight similar to that observed with exenatide treatment in the first 30 weeks. No diet and/or exercise counseling provided by the protocol. STUDY BACKGROUND: Interim results from subjects who completed one of the three 30-week pivotal trials (with a background of MET and SFU) and completed an additional 52 weeks of exenatide treatment in the corresponding open-label extension for a total of 82 weeks of treatment (n=205). Subjects are grouped by the treatment to which they were originally randomized in the placebo-controlled trial, with the increase to 10 g in the extension indicated with an arrow: placebo BID (placebo10 g), 5 g BID (5 g 10 g), 10 g BID (10 g 10 g) All subjects were given 5 g exenatide for the first 4 weeks of the open-label extension (overall, Weeks 30 to 34), after which they received 10 g exenatide. 10 mg exenatid BID (n = 67) 99.5 kg -1 -2 D Testsúly (kg) -3 -4.0 ± 0.5 kg -4 -3.9 ± 0.6 kg -4.4 ± 0.5 kg -5 10 20 30 40 50 60 70 80 90 Idő (hét) Ratner, RE et al: Diab Obes Metab 8: Mean (SE)

28 Keringési kockázati tényezők alakulása I. : a vérnyomás változása a 82
Keringési kockázati tényezők alakulása I.: a vérnyomás változása a 82. héten testsúly kvartilisek szerinti bontásban Systolés BP Diastolés BP 6 2 4 DISCUSSION: A majority of subjects had both systolic and diastolic blood pressure (BP) improvements When analyzed by quartile, only those subjects in quartile 4 did not have decreased BP These reductions occurred even in the context of relatively low baseline BP (mean = 129/79). STUDY BACKGROUND: Interim results from subjects who completed the 30-week pivotal trials (5 g and 10 g arms, not placebo) and completed an additional 52 weeks of exenatide treatment in the corresponding open-label extensions for a total of 82 weeks of exenatide (n=265). Quartiles consisted of four subgroups with approximately equal number of subjects (n=66-67), with quartile 1 consisting of the 25% of subjects with the greatest weight reductions, quartile 4 consisting of the 25% of subjects with the smallest weight reductions (or weight gains), and quartiles 2 and 3 are for those with the intermediate weight reductions. These same quartiles are used in portraying BP changes. +3.0 0.0 2 D BP (Hgmm ) D BP (Hgmm) -2 -2 -2.6 -3.0 -4.1 -3.3 -4 -4.4 -4.5 -4 -6 -6 I II III IV I II III IV Testsúly kvartilis Testsúly kvartilis Blonde, L et al.: Diab Obes Metab 8: n=265; Mean (SE)

29 Serum HDL-koleszterin
Keringési kockázati tényezők alakulása II.: a serum triglicerid és HDL-chol. 82. heti változása testsúly kvartilisek szerinti bontásban Serum triglicerid Serum HDL-koleszterin 20 10 -3 +7 8 DISCUSSION: Triglycerides (TG) decreased in the two quartiles of patients that had the greatest weight reductions. High-density lipoprotein (HDL)-C increased in all 4 quartiles, most dramatically in quartile 1. Both HDL and TG changes were clinically significant. STUDY BACKGROUND: Interim results from subjects who completed the 30-week pivotal trials (5 g and 10 g arms, not placebo) and completed an additional 52 weeks of exenatide treatment in the corresponding open label extensions for a total of 82 weeks of exenatide (n=265). Quartiles consisted of four subgroups with approximately equal number of subjects (n=66-67), with quartile 1 consisting of the 25% of subjects with the greatest weight reductions, quartile 4 consisting of the 25% of subjects with the smallest weight reductions (or weight gains), and quartiles 2 and 3 are for those with the intermediate weight reductions. These same quartiles are used in portraying lipid changes. -20 +7.4 6 -40 D (mg/dl) -58 D (mg/dl) -60 4 +3.8 -80 +3.5 -92 +3.0 2 -100 -120 I II III IV I II III IV Testsúly kvartilis Testsúly kvartilis n=265; átlag ± SE Blonde, L et al.: Diab Obes Metab 8:

30 Metformin + sulfanylurea glarginnal, illetve exenatiddal kiegészítve
Hipotézis: az exenatiddal elért glykaemiás kontroll nem rosszabb a glargin hozzáadásával elérhetőnél MET + SU kezelés önmagában nem kielégítő hatása esetén Elsődleges végpont: a HbA1c érték változása Intention-to-treat minta: N = 549 DISCUSSION: Trial was designed to test the hypothesis that the exenatide effect was non-inferior to the insulin glargine effect Based on 95% confidence interval of difference of change in HbHbA1c (exenatide - glargine) HbA1c was measured at screening (Week -4), baseline (Week 0), Week 12, Week 26 (endpoint) and, if possible, at the time of discontinuation for those who dropped out of the study before completion of Week 26. Non-inferiority was concluded if the upper limit of 95% CI was <0.4% Secondary endpoints: proportion of patients achieving HbA1c <7%; body weight; incidence and rate of hypoglycemic events; fasting serum glucose (FSG); 7-point self-monitored blood glucose (SMBG) profile; safety and tolerability; patient-reported health outcomes. Insulin glargine titration was achieved by daily self-monitoring of blood glucose levels by fingerstick, and titrating insulin dose toward a target FPG level of <100mg/dL. This was not required for exenatide patients, since fixed dosing schedule was used. STUDY BACKGROUND: The primary objective of this multi-center, randomized, open-label phase 3 clinical trial was to compare the effects of exenatide and insulin glargine on glycemic control over 26 weeks, as measured by reduction in HbA1c, in patients with type 2 diabetes achieving inadequate glycemic control using combination metformin and sulfonylurea therapy at maximally effective doses. Exenatide (before morning and evening meals) fixed dose of 5 µg twice daily for 4 weeks, escalated to 10 µg twice daily for the remainder of the study. Insulin glargine (at bedtime) initiated at 10 Units/day, fixed dose algorithm to adjust dose, self-titrating in 2-Unit increments every 3 days based on a fasting blood glucose target of 5.6 mmol/L (100 mg/dL). 21.6% of insulin glargine patients, compared with 8.6% of exenatide patients, achieved a fasting glucose of <5.6 mmol/L (100 mg/dL). Metformin and sulfonylurea doses were fixed at pre-study levels, except when patients experienced hypoglycemia, in which case a 50% reduction in sulfonylurea dose was recommended. Patients were 30 to 75 years of age and treated with stable and maximally effective doses of metformin and a sulfonylurea for at least 3 months prior to screening. General inclusion criteria included a screening HbA1c >7.0% to <10.0% and a body mass index (BMI) >25 to <45 kg/m2. -4 -2 2 4 8 12 18 26 Randomizáció Szűrés (HbA1c >7.0% to <10.0%) Inzulin Glargin + (MET+SU) (az inzulinadagot VCéh < 5.6 mmol/l értékhez igazítva naponkénti méréssel) Exenatid 10µg BID + (MET+SU) Exenatid 5µg BID + (MET+SU) A korábbi MET+SU terápia Idő (hét) Heine, RJ et al: Ann Intern Med 143:

31 A HbA1c alakulása a vizsgálatban
Exenatid, 10 mg naponta 2x Glargin inzulin, átl.dózis a kezelés végén = 25.0 U/nap 12 26 0.0 6.5 7.0 7.5 8.0 8.5 DISCUSSION: HbA1c was measured at screening (Week -4), baseline (Week 0), Week 12, Week 26 (endpoint) and, if possible, at the time of discontinuation for those who dropped out of the study before completion of Week 26. Eight patients in each group discontinued without a post-baseline measurement of HbA1c. Thus, the intent-to-treat sample is made up of 275 exenatide and 260 insulin glargine patients. HbA1c was significantly reduced from baseline at Week 26 in both treatment arms (change from baseline to endpoint, exenatide: ± 0.059%, insulin glargine: ± 0.058%). The 95% CI for the difference between treatments (exenatide–insulin glargine) was % to 0.157%. This is within the non-inferiority criteria of the upper limit <0.4%. STUDY BACKGROUND: At endpoint, the average dose of insulin glargine was 25.0 IU/day (n = 244). 21.6% of insulin glargine patients, compared with 8.6% of exenatide patients, achieved a fasting glucose of <5.6 mmol/L (100 mg/dL). The daily insulin dose achieved in the present study is lower when compared to other published large-scale randomized clinical trials of insulin glargine (Riddle et al, Diabetes Care. 2003; Benedetti et al, Horm Metab Res 2003; Fritsche et al, Ann Intern Med 2003; Rosenstock et al, Diabetes Care 2001; Yki-Jarvinen et al, Diabetes Care 2000). However, in the present study, the baseline HbA1c was lower than each of those previous trials, possibly resulting in less insulin required to attain a certain glycemic improvement, and all patients entered this trial already taking two oral agents. The mean reduction in HbA1c in the present trial was within the range of reductions observed in previous insulin glargine trials with comparable study designs (ranging from -0.4 to -1.0% for weeks), except the Treat-to-Target trial (-1.65% at 24 weeks) (Riddle et al, Diabetes Care. 2003). In the Treat-to-Target trial, Riddle et al described a number of factors to explain the magnitude of the HbA1c decrease observed, including an ambitious titration target combined with a protocol for encouraging patient adherence. Although problematic to compare across trials, the Treat-to-Target trial also reported a higher incidence of symptomatic (13.9 events per year) and nocturnal hypoglycemia (4.0 events per year) and slightly greater weight gain (+3.0 kg) than observed in the present trial. Moreover, the mean HbA1c achieved at study endpoint in the Treat-to-Target trial (6.96%) was not greatly different from the mean value achieved in the current study (7.12%), and the proportion of patients achieving HbA1c 7% was 58% (Treat-to-Target) versus 48% (present study). Two recently published trials have demonstrated very favorable results adding insulin glargine to patients receiving metformin and/or combination oral therapy (Janka et al, Diabetes Care, 2005 and Raskin et al, Diabetes Care 2005). However the study designs of these trials included the addition of new sulfonylurea therapy (Janka) or the discontinuation of some oral therapies during a run-in period (Raskin), making a direct comparison of these trial results somewhat difficult to interpret. The insulin glargine titration schedule and approach to encouraging patient adherence in the present trial may have been more reflective of real-world usage; as a result, the data (~1% lowering) may better indicate the broader clinical experience with insulin glargine. Intent-to-treat sample was defined as any randomized patient who had at least one post-baseline measurement of the dependent variable. HbA1c (%) Hét Blonde, L et al.: Diab Obes Metab 8: ITT population; Mean ± SE shown

32 Betegek aránya, akik elérték
A HbA1c változása Exenatid Inzulin glargin 46% 48% 32% 25% 10 20 30 40 50 60 -1.1% -1.5 -1.0 -0.5 0.0 DISCUSSION: Eight patients in each group discontinued without a post-baseline measurement of HbA1c. Thus, the intent-to-treat sample is made up of 275 exenatide and 260 insulin glargine patients. HbA1c was significantly reduced from baseline at Week 26 in both treatment arms (change from baseline to endpoint, exenatide: ± 0.059%, insulin glargine: ± 0.058%). The 95% CI for the difference between treatments (exenatide–insulin glargine) was % to 0.157%. This is within the non-inferiority criteria of the upper limit <0.4%. A similar percentage of patients reached the HbA1c goal of <7% for each treatment. Proportion of patients to <6.5% were 31% for exenatide and 24% for insulin glargine. STUDY BACKGROUND: A meta-analysis of phase 3/3b controlled trials comparing insulin glargine to NPH insulin in 1142 adults with type 2 diabetes, including the Treat-to-Target study, reported an average HbA1c change associated with insulin glargine from a baseline of 8.8 ± 1.1% to 7.8 ± 1.3% (mean ± SD, trial endpoints ranged from weeks). [Rosenstock et al, Diabetes Care, 2005.] The insulin glargine titration schedule and approach to encouraging patient adherence in the present trial may have been more reflective of real-world usage; as a result, the data (~1% lowering) may better indicate the broader clinical experience with insulin glargine. Intent-to-treat sample was defined as any randomized patient who had at least one post-baseline measurement of the dependent variable. For % to HbA1c <7%, ITT comprised patients with HbA1c >7% at baseline, and at least one post-baseline measurement of the dependent variable Betegek aránya, akik elérték a cél HbA1c értéket (%) Change in HbA1c (%) ITT populatio; átlag ± SE HbA1c<7% HbA1c<6.5% Blonde, L et al.: Diab Obes Metab 8:

33 Testsúlyváltozás (fontban)
A testsúly változása Exenatid Glargin inzulin * 2 4 8 12 18 26 -6 -4 -2 6 DISCUSSION: Insulin glargine patients gained weight throughout the trial period, while exenatide was associated with progressive reductions in weight. Mean body weight was significantly different between the two treatments as early as 2 weeks, and this difference persisted throughout the study. Adjusted mean change in body weight at endpoint was -5.1 ± 0.4 lbs for exenatide, +4.0 ± 0.4 lbs for insulin glargine. Mean difference (exenatide - insulin glargine) was -9.0 lbs, 95% CI for the difference -10.1, -7.7 lbs. Baseline body weights were exenatide: 87.5 ± 16.9 kg and insulin glargine: 88.3 ± 17.9 kg. Enhancing insulin secretion in the absence of weight gain is an important aspect of the incretin mimetics, and may represent an important therapeutic advance in the treatment of type 2 diabetes. STUDY BACKGROUND: Intent-to-treat sample was defined as any randomized patient who had at least one post-baseline measurement of the dependent variable. Testsúlyváltozás (fontban) Idő (hét) ITT populatio; Átlag ± SE; * P<0.0001, exenatid vs inzulin glargin azonos időpontban értékelve Blonde, L et al.: Diab Obes Metab 8:

34 Exenatid kezelés potenciális előnyei és korlátai
Előnyök Korlátok  Fix adagban, dózis titrálás  Parenteralis (sc.) bevitel nélkül adható szükségessége  Alkalmazását testsúly csök  Viszonylag gyakori nau- kenés kíséri sea a kezelés elején  Hypoglykaemia kockázata el- hanyagolható  A prandialis inzulin secretio mindkét fázisát serkenti  Glukóz-dependens secretagog természetével előnyösen kom- binálható OAD - kkal

35 Exenatid LAR (Long-Acting Release)
biológiai lebomlású, nyújtott hatást biztosító polymer microsphera szerkezet egyszeri adás után is heteken-hónapokon át mérhető plazma exenatid koncentráció Refs: Bartus 37143Science1998_p1161.pdf Amylin_2993-LAR102_p5.pdf Amylin_2993-LAR_IB_Jan 06_p9 .pdf Ref: Slide Index ARC- L: DISCUSSION POINTS: LAR technology, developed by Alkermes, Inc., uses biodegradable polymeric microspheres to deliver a sustained release of exenatide SLIDE BACKGROUND: The microspheres consist of exenatide embedded in a matrix of poly D,L lactic-co-glycolic acid (PLGA) Hatáskezdet Nyújtott hatás hydratio diffusio degradatio erosio Bartus. RT et al: Science 281:

36 Összefoglalás Az incretinek hatásának megismerése és az incre-tin mimetikum GLP1 receptor agonista exenatid előállítása új lehetőséget jelent a 2DM kezelésében Vércukorcsökkentő hatását komplex módon fejti ki (fokozza a glukóz-dependens inzulin szekréciót, gátolja a glukagon elválasztást, valamint lassítja a gyomorürülést) Normalizálja a pp. inzulinelválasztás károsodott el-ső fázisát Slide Index L: A,B,D,E DISCUSSION POINTS: Amylin Pharmaceuticals and Eli Lilly are developing exenatide (synthetic exendin-4), a peptide having an amino acid sequence identical to that of native active exendin-4. In phase 2 clinical studies, exenatide lowered both postprandial and fasting glucose concentrations. Exenatide and GLP-1 share certain antidiabetic actions. These actions are glucose‑dependent enhancement of insulin secretion, glucose‑dependent suppression of inappropriately high glucagon secretion, slowing of gastric emptying, which may be paradoxically accelerated in people with diabetes,and reduction of food intake. These antidiabetic actions of exenatide, combined with a longer half-life in vivo, result in considerably higher in vivo potency relative to native GLP‑1 and make exenatide an attractive pharmaceutical agent. SLIDE BACKGROUND:

37 Összefoglalás II. Csökkenti az éhomi és –kifejezettebben– a pp. vércukorszintet Alkalmazása során kevéssé kell számolni hypo - glykaemiával, nem okoz súlygyarapodást, sőt, e-lősegítheti a túlsúly mérséklődését Az eddigi tapasztalatok alapján fix adagban, dózis-titrálás nélkül alkalmazható Slide Index L: A,B,D,E DISCUSSION POINTS: Amylin Pharmaceuticals and Eli Lilly are developing exenatide (synthetic exendin-4), a peptide having an amino acid sequence identical to that of native active exendin-4. In phase 2 clinical studies, exenatide lowered both postprandial and fasting glucose concentrations. Exenatide and GLP-1 share certain antidiabetic actions. These actions are glucose‑dependent enhancement of insulin secretion, glucose‑dependent suppression of inappropriately high glucagon secretion, slowing of gastric emptying, which may be paradoxically accelerated in people with diabetes,and reduction of food intake. These antidiabetic actions of exenatide, combined with a longer half-life in vivo, result in considerably higher in vivo potency relative to native GLP‑1 and make exenatide an attractive pharmaceutical agent. SLIDE BACKGROUND:

38 Exenatid + OAD (MET+SU) vs. premix analóg + OAD
Exenatid és premix analóg (MET+SU adása mellett) közel azonos HbA1c értéket és éhomi vércukorszin-tet biztosított a vizsgálat végén Exenatid adásakor: Javult a pp. vércukor kontroll A résztvevők nagyobb hányada érte el a cél HbA1c értéket Progresszív testsúlycsökkenés mutatkozott Premix inzulin adásakor: Kedvezőbben alakult a preprandialis vércukorszint Kevesebb volt a mellékhatások száma Súlygyarapodás volt kimutatható BACKGROUND This 52-week, open-label, noninferiority trial was designed to compare the safety and efficacy of exenatide and premixed insulin Patients failing to reach treatment goals with metformin and a sulphonylurea were randomised to exenatide (n=253; 5μg BID 4 weeks, 10μg thereafter) or premixed insulin (n=248; BID doses titrated for optimal glucose control) The primary endpoint was change in HbA1c at Week 52