A "gliptinek" helye a 2-es típusú diabetes kezelésében Prof. Dr. Jermendy György egyetemi tanár, osztályvezető főorvos Bajcsy-Zs. Kórház, III. sz. Belgyógyászati Osztály, Budapest

Az incterinek hatása Glucose IV per os mmol/L 10 500 Az inzulin szekréció 70%-a az incretin hatásnak köszönhető Insulin pmol/L 1000 500 “Incretin”

GIP és GLP-1 antihiperglycaemiás A DPP-4-gátlás fokozza a biológiailag aktív GLP-1 és GIP plazmaszintjét Táplálék DPP-4-gátló DPP-4 enzim GIP és GLP-1 intesztinális felszabadulása After its release from L cells in the distal gut (ileum and the colon), GLP-1 is rapidly degraded by the enzyme DPP-4.1,2 DPP-4 is located in sites such as intestinal and renal brush borders as well as on the capillary surfaces and in a soluble form in plasma.3 DPP-4 cleaves two N-terminal amino acid residues from GLP-1 (7–36).4-6 The N-terminally truncated peptide GLP-1 (9–36) has no insulinotropic activity.3 Like GLP-1, GIP (1–42) is degraded by DPP-4 after its release into the circulation, resulting in formation of an N-terminally truncated form of the peptide GIP (3–42).4 An in vivo study showed that DPP-4 converted more than half of infused GLP-1 and GIP into their truncated metabolites within approximately two minutes of infusion.2 DPP-4 inhibition has been shown to prevent the rapid degradation of the incretins GLP-1 and GIP to their cleaved forms, thus prolonging the survival of GLP-1 and GIP forms which retain activity within the pancreatic islet cells.4,7,8 GIP (1-42) GLP-1 (7-36) GIP (3-42) GLP-1 (9-36) (inaktívak) Gyors lebomlás (percek alatt) GIP és GLP-1 antihiperglycaemiás hatásai Deacon CF et al Diabetes 1995;44:1126–1131; Kieffer TJ et al Endocrinology 1995;136:3585–3596; Ahrén B Curr Diab Rep 2003;3:365–372; Deacon CF et al J Clin Endocrinol Metab 1995;80:952–957; Weber AE J Med Chem 2004;47:4135–4141. References 1. Deacon CF, Nauck MA, Toft-Nielsen M et al. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 1995;44:1126–1131. 2. Kieffer TJ, McIntosh CHS, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 1995;136:3585–3596. 3. Vilsbøll T, Krarup T, Deacon CF et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001;50:609–613. 4. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372. 5. Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 1995;80:952–957. Weber AE. Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J Med Chem 2004;47:4135–4141. Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs 2003;12:87–100. Pospisilik JA, Stafford SG, Demuth H-U et al. Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats. Diabetes 2002;51:943–950.

A DPP-4 enzim a GLP-1-t gyorsan lebontja 7 37 9 T½=1–2 perc (IV) MCR=5–10 L/perc MCR=metabolic clearance rate. Vilsbøll T et al. J Clin Endocrinol Metab. 2003;88:220–224.

Dipeptidyl Peptidase 4 (DPP-4) Dipeptidyl peptidase 4 (DPP-4) is a membrane-bound serine protease of the prolyl oligopeptidase enzyme family.1 DPP-4 exists in two forms. In its membrane-bound form, it is widely expressed on cells in most tissues.2 In its soluble, circulating form, DPP-4 is found in the blood, saliva, urine, and synovial fluid.1,2 DPP-4 modulates the biological activity of several peptide hormones, chemokines, and neuropeptides by specifically cleaving from the N-terminus after a proline or alanine.3 The slide shows the structure of the extracellular region of DPP-4. The catalytic (active) site is located in a small pocket within a large cavity formed between the alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain. Residues from both domains participate in inhibitor binding. The structure of the active site reveals why most natural DPP-4 substrates are short peptides (<80 amino acids) such as GLP-1 and GIP: only elongated peptides or unfolded or partly unfolded protein fragments can reach the site.2,3 The enzymatic activity of DPP-4 on incretins, especially GLP-1, suggests a pharmacologic role for DPP-4 inhibitors in the treatment of patients with type 2 diabetes.1,2 C C N N Sejtmembrán Cytosol A DPP-4 az oligopeptidáz enzimcsaládba tartozó szerin-proteáz, megjelenési formái: Membránhoz kötött (expresszált forma) Szolubilis Adapted from Evans DM IDrugs 2002;5:577–585; Drucker DJ Expert Opin Investig Drugs 2003;12:87–100; Rasmussen HB et al Nat Struct Biol 2003;10:19–25. References Evans DM. Dipeptidyl peptidase IV inhibitors. IDrugs 2002;5:577–585. Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs 2003;12:87–100. Rasmussen HB, Branner S, Wiberg FC et al. Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat Struct Biol 2003;10:19–25.

A DPP-4 gátlás szerepe a glukózkontrollban Táplálék  Glucose felvétel és tárolás az izomsejtekben és zsírszövetben Glucose függő Insulin  a beta sejtekben (GLP-1 és GIP) Beta sejtek GI tract Aktív GLP-1 és GIP Incretin bélhormonok felszabadulása Pancreas Slide 12 Role of DPP-4 Inhibition in Improving Glucose Control DPP-4 inhibitors are incretin enhancers that increase the levels of active incretins (ie, GLP-1, GIP),1 which physiologically regulate glucose levels by regulating insulin in a glucose-dependent manner. Other effects of GLP-1 include regulation of glucagon in a glucose-dependent manner.2 After ingestion of food, GIP is released from K cells in the proximal gut (duodenum) and GLP-1 is released from L cells in the distal gut (ileum and colon).3 Under normal circumstances, DPP-4 degrades these incretins to their metabolites after their release into the circulation.4 Because the “incretin effect” is diminished in patients with type 2 diabetes mellitus, inhibition of DPP-4 provides a rational therapeutic strategy for these patients.5 By preventing the rapid degradation of biologically active GLP-1 and GIP, treatment with a DPP-4 inhibitor is designed to preserve the beneficial actions of intact incretins.4,6 These actions include stimulating insulin response in pancreatic beta cells.7 GLP-1 also suppresses glucagon production from pancreatic alpha cells when glucose is elevated.7 The subsequent increase in glucose uptake in muscles8,9 and reduced glucose output from the liver10 result in reduced blood glucose levels.6 Stabil glucose kontroll Alpha sejtek  Glucose kiáramlás a májból a véráramba X DPP-4 enzim  Glucagon alpha sejtekből (GLP-1) Glucose - függő DPP-4 Inhibitor GLP-1 és GIP metabolitok Brubaker PL et al. Endocrinology. 2004;145:2653–2659; Ahrén B. Curr Diab Rep. 2003;3:365–372; Drucker DJ. Expert Opin Investig Drugs. 2003;12:87–100; Zander M et al. Lancet. 2002;359:824–830; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441; Holz GG et al. Curr Med Chem. 2003;10:2471–2483; Creutzfeldt WOC et al. Diabetes Care. 1996;19:580–586; Drucker DJ. Diabetes Care. 2003;26:2929–2940. References: 1. Deacon CF. MK-431 Merck. Curr Opin Investig Drugs. 2005;6:419–426. 2. Weber AE. Dipeptidyl peptidase IV inhibitors for the treatment of diabetes. J Med Chem. 2004;47: 4135–4141. 3. Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology. 2004;145:2653–2659. 4. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 5. Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2003;12:87–100. 6. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26: 2929–2940. 7. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: A parallel-group study. Lancet. 2002;359:824–830. 8. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441. 9. Holz GG, Chepurny OG. Glucagon-like peptide-1 synthetic analogs: New therapeutic agents for use in the treatment of diabetes mellitus. Curr Med Chem. 2003;10:2471–2483. 10. Creutzfeldt WOC, Kleine N, Willms B, et al. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7–36) amide in type I diabetic patients. Diabetes Care. 1996;19:580–586.

DPP-4 gátlók kifejlesztése GLP-1-et szelektíven bontja a DPP-4 (a molekula N-terminális végén) DPP-4 gátlók: GLP-1 szintje tartósan emelkedik Sitagliptin Vildagliptin további vegyületek kifejlesztés alatt;

Sitagliptin-monoterápia hatása a plazma DPP-4 aktivitásra OGTT 100 Trough DPP-4 inhibition 90 80 ~80% 70 Single doses of sitagliptin 25 mg and 200 mg resulted in rapid and marked inhibition of plasma DPP-4 activity.1 Throughout the 12-hour post-dose period, the 200 mg dose was associated with approximately 95% plasma DPP-4 inhibition, falling to approximately 80% inhibition at 24 hours post dose. The 25 mg dose was associated with peak inhibition of approximately 85%, falling to approximately 50% inhibition at 24 hours post dose.1 60 Inhibition of plasma DPP-4 activity from baseline (%) 50 ~50% 40 30 Sitagliptin 25 mg (n=56) Sitagliptin 200 mg (n=56) Placebo (n=56) 20 10 –10 1 2 4 6 8 10 12 14 16 18 20 22 24 26 Hours post-dose Single-Dose OGTT Study Reference Data on file, MSD ______________________.

Sitagliptin-monoterápia hatása a GLP-1 szintre 20 Sitagliptin 25 mg (n=56) Sitagliptin 200 mg (n=56) Placebo (n=56) 15 Sitagliptin stabilized active GLP-1 levels, increasing active GLP-1 concentrations approximately twofold after OGTT challenge (p<0.001 vs. placebo for both doses of sitagliptin).1 This finding illustrated that DPP-4 inhibition enhanced levels of biologically active incretins. Aktív GLP-1 változás 10 OGTT 5 1 2 3 4 5 6 7 A dózis után eltelt idő (óra) Single-Dose OGTT Study ~2-fold increases with sitagliptin vs. placebo (p<0.001 for both doses) Reference Data on file, MSD ______________________.

Sitagliptin-monoterápia hatása az inzulin felszabadulásra 35 Sitagliptin 25 mg (n=56) Sitagliptin 200 mg (n=56) Placebo (n=56) 30 25 20 Sitagliptin also enhanced insulin response levels after OGTT, increasing plasma insulin levels by approximately 20% (p<0.001 vs. placebo for both doses of sitagliptin).1 Plazma inzulin (µIU/ml) OGTT 15 10 5 1 2 3 4 5 A dózis után eltelt idő (óra) Single-Dose OGTT Study ~20% increases with sitagliptin vs. placebo (p<0.001 for both doses) Reference Data on file, MSD ______________________.

Sitagliptin-monoterápia hatása a glukagon szintre 80 Sitagliptin 25 mg (n=56) Sitagliptin 200 mg (n=56) Placebo (n=56) OGTT 70 Sitagliptin also suppressed glucagon levels after OGTT. Plasma glucagon levels were approximately 7% and 14% lower with sitagliptin 25 mg and 200 mg, respectively, after glucose challenge (p=0.02 vs. placebo for sitagliptin 25 mg and p<0.001 vs. placebo for sitagliptin 200 mg).1 Plazma glukagon (pg/ml) 60 50 1 2 3 4 5 A dózis után eltelt idő (óra) Single-Dose OGTT Study ~7% and 14% decreases with sitagliptin 25 mg and 200 mg, respectively, vs. placebo (p=0.02 for 25 mg, p<0.001 for 200 mg) Reference Data on file, MSD ______________________.

Sitagliptin csökkenti a post-load (OGTT) vércukorértékeket ~22%–26% reductions with sitagliptin vs placebo (p<0.001 for both doses) 320 Sitagliptin 25 mg Sitagliptin 200 mg Placebo 300 Slide 13 280 Single-Dose OGTT Study: Sitagliptin Reduced Glycemic Excursions Post OGTT1 A randomized, double-blind, 3-period crossover study examined the effects of the DPP-4 inhibitor sitagliptin in 58 patients with type 2 diabetes (baseline HbA1c 6.5%–11.7%) who were being treated with diet and exercise only. Patients received a single dose of placebo, sitagliptin 25 mg, or sitagliptin 200 mg. The 3 treatments were separated by 1-week washout periods. After an overnight fast, patients had an oral glucose tolerance test (OGTT) 2 hours after administration of study medication. The primary endpoint was post-OGTT incremental glucose area under the curve (AUC). Other endpoints were DPP-4 activity, active GLP-1 concentrations, and plasma concentrations of insulin, C-peptide, and glucagon. Sitagliptin was shown to reduce the primary endpoint of post-OGTT glucose excursions by 22% to 26%, as measured by post-OGTT glucose incremental AUC (p<0.001 vs placebo for both sitagliptin doses). 260 240 Plasma glucose (mg/dL) 220 OGTT 200 180 160 N=56 140 1 2 3 4 5 6 7 Hour Adapted from data on file, MSD, CSR Protocol 005. Reference: 1. Data on file, MSD, CSR Protocol 005.

Placebo-subtracted change from baseline in HbA1c (%) A sitagliptin jelentősen csökkentette a HbA1c szintet (2-es típusú diabeteszes betegek 12 hétig tartó vizsgálata) Placebo-subtracted change from baseline in HbA1c (%) 5 mg BID (n=125) 12.5 mg BID (n=123) 25 mg BID 50 mg BID (n=124) –1.2 –1.0 –0.8 –0.6 –0.4 –0.2 –0.38* –0.64* –0.66* –0.77* –1.0* Glipizid 5–20 mg Sitagliptin Slide 17 BID Dose-Range Finding Study: Sitagliptin Significantly Reduced HbA1c in a 12-Week Study of Patients With Type 2 Diabetes1 A 12-week, multinational, randomized, double-blind, active-comparator, placebo-controlled, parallel-group, dose-range finding study was conducted to evaluate the efficacy and tolerability of sitagliptin in patients with type 2 diabetes mellitus with inadequate glycemic control, who were either drug naïve or taking a single oral antihyperglycemic medication. After a screening/diet/run-in period of up to 10 weeks, 743 patients 21 to 76 years of age with HbA1c values of 6% to 10% (mean: 7.9%, indicating mild to moderate hyperglycemia) were randomized to receive 1 of the following treatments for 12 weeks: Placebo Sitagliptin 5 mg twice daily (BID) Sitagliptin 12.5 mg BID Sitagliptin 25 mg BID Sitagliptin 50 mg BID Glipizide 5 mg/day up-titrated to 20 mg/day The primary efficacy endpoint was the change from baseline in HbA1c. Tolerability was evaluated by adverse experiences, vital signs, and safety laboratory studies. In the placebo group, HbA1c increased 0.23% from baseline at week 12. As shown by the depiction of placebo-subtracted HbA1c changes from baseline to week 12, all doses of sitagliptin and glipizide significantly reduced HbA1c from baseline (p<0.001 vs placebo). Placebo-subtracted differences in HbA1c ranged (depending on dose) from –0.38% to –0.77% in the sitagliptin groups versus a 1.0% reduction in the glipizide group. *p<0.001 vs placebo. Adapted from Scott RS et al. Poster presented at the 41st Annual Meeting of the European Association for the Study of Diabetes (EASD); September 12–15, 2005; Athens, Greece. Reference: 1. Scott R, Herman G, Zhao P, et al. Twelve-week efficacy and tolerability of MK-0431 (sitagliptin), a dipeptidyl peptidase IV (DPP-IV) inhibitor, in the treatment of type 2 diabetes. Poster presented at the 41st Annual Meeting of the European Association for the Study of Diabetes (EASD); September 12–15, 2005; Athens, Greece.

HbA1c-csökkenés a kiindulási értékek függvényében Sitagliptin 100 mg naponta 1x kiindulási HbA1c <7% 7% – <8.5% ≥8.5% Reductions in HbA1c in all dose groups were greater in patients with higher HbA1c values at baseline. The slide shows this pattern in the group on sitagliptin 100 mg QD according to the per-protocol analysis of completers without data carried forward (non-LOCF). Patients with baseline HbA1c <7% showed a reduction of 0.3%. A greater reduction (0.64%) was seen in patients with baseline HbA1c values of 7% to <8.5%. The greatest reduction (1.13%) was seen in patients with baseline HbA1c values 8.5%.1 Results from the modified intent-to-treat LOCF analysis showed a similar trend toward greater reductions in HbA1c for patients with higher baseline HbA1c values. In this analysis of patients receiving sitagliptin 100 mg QD, HbA1c reductions were as follows: • Patients with baseline HbA1c <7%: 0.37% reduction • Patients with baseline HbA1c 7% – <8.5%: 0.55% reduction • Patients with baseline HbA1c ≥8.5%: 0.82% reduction –0.2 –0.4 –0.3 HbA1c változás (%) (a kindulási értékekhez viszonyítva) –0.6 –0.64 –0.8 –1.0 –1.13 –1.2 QD vs. BID Dose-Range Finding Study Per-protocol analysis without last observation carried forward Adapted from Herman GA et al. Poster presented at the 65th Annual Scientific Sessions of the American Diabetes Association, San Diego, California, USA, June 10–14, 2005. Reference 1. Herman GA, Hanefeld M, Wu M et al. Effect of MK-431 (sitagliptin), a dipeptidyl peptidase IV (DPP-IV) inhibitor, on glycemic control after 12 weeks in patients with type 2 diabetes. Poster presented at the 65th Annual Scientific Sessions of the American Diabetes Association, San Diego, California, USA, June 10–14, 2005. Poster 541-P.

HbA1c változás (1500 mg metforminhoz adva) (Protokoll szerint kezelt betegek. Bevételi HbA1C-kritérium: 6,5-10%) Kiindulási HbA1C <7% 7 - <8% 8 - <9% ≥9% -.27 -.13 -.53 -.59 -1.13 -1.11 -1.68 -1.76 Sitagliptin 1x100 mg Glipizid 1x5-2x10 mg Nauck, Diabetes, Obesity and Metabolism;9:195-205,2007.

Add-on Therapy to Metformin Study Metformin terápia mellé adott sitagliptin hatása a 24-órás glukózprofilra Period 1 Metformin 1500 mg/day (n=13) Sitagliptin 50 mg BID + metformin 1500 mg/day (n=13) Breakfast Lunch Dinner 240 Dose 1 7:30 Dose 2 18:30 220 The 24-hour WMG at the end of period 2 in patients who received placebo during period 2 and sitagliptin in period 1 was substantially lower than the 24-hour WMG at the end of period 1 in patients who received placebo during period 1. This suggests a substantial “carryover” effect of sitagliptin from period 1 still present after treatment with placebo in period 2. Although this could have occurred because of a change in the natural history of the disease, patients had been on a stable dose of metformin and were to have stable glycemic control during the run-in, hence this explanation seems unlikely. For this reason, results of period 1 are the focus of this slide. As shown, combination therapy with metformin plus sitagliptin produced significantly greater improvements in 24-hour WMG than occurred with placebo plus metformin (–32.8 mg/dl; p<0.001).1 The 24-hour profile of mean glucose at week 4 showed that compared with placebo + metformin, sitagliptin + metformin provided substantially lower premeal glucose concentrations and smaller glucose excursions after all three meals.1 Treatment difference: –32.8 mg/dl (p<0.001)* 200 180 Glucose (mg/dl) 160 140 120 100 8:00 Day 1 13:00 19:00 0:00 Day 2 7:30 Add-on Therapy to Metformin Study *Least-squares mean difference in weighted mean glucose Reference 1. Data on file, MSD ____________.

Proinsulin/Insulin és HOMA-ß változás (1500 mg metforminhoz adva) Proinsulin/Insulin arány Sitagliptin + Metformin Glipizide + Metformin Kiindulási értékek (pmol/L/pmol/L): Sitagliptin = 0.334; Placebo = 0.341 Kiindulási értékek : Sitagliptin = 57.6; Placebo = 57.0

Hypoglycaemia aránya (1500 mg metforminhoz adva) 60 1 hypoglycaemiás epizódon átesett betegek aránya az 52 hét alatt 50 40 32,0% % 30 20 10 4,9% Sitagliptin Glipizid Nauck, Diabetes, Obesity and Metabolism;9:195-205,2007.

Testsúlyváltozás (1500 mg metforminhoz adva)  A csoportok között = –2.5 kg (p<0.001) 86 88 90 92 94 12 24 38 52 Idő (hét) Testsúly (kg) Sitagliptin 100 mg + Metformin (n=382) Glipizid + metformin (n=411) Nauck, Diabetes, Obesity and Metabolism;9:195-205,2007.

Általánosságban jól tolerálható Nem okoz testsúlynövekedést Összefoglalás: A Sitagliptin biztonságosan alkalmazható 2-es típusú diabetesben Általánosságban jól tolerálható Nem okoz testsúlynövekedést Alacsony a hypoglycaemia előfordulása Slide 25 Summary: Safety Profile of Sitagliptin in Patients With Type 2 Diabetes In clinical trials in patients with type 2 diabetes, sitagliptin was generally well tolerated, with no weight gain and few episodes of hypoglycemia.1-4 Adapted from Herman GA et al. Poster presented at the 40th Annual Meeting of the European Association for the Study of Diabetes (EASD); September 5–9, 2004, Munich, Germany; Scott R et al. Poster presented at the 41st Annual Meeting of the European Association for the Study of Diabetes (EASD); September 12–15, 2005, Athens, Greece; Herman GA et al. Poster presented at the 65th Annual Scientific Sessions of the American Diabetes Association; June 10–14, 2005, San Diego, Calif; Brazg RL et al. Poster presented at the 65th Annual Scientific Sessions of the American Diabetes Association; June 10–14, 2005, San Diego, Calif. References: 1. Herman G, Zhao P-L, Dietrich B, et al. The DPP-IV inhibitor MK-0431 enhances active GLP-1 and reduces glucose following an OGTT in type 2 diabetics. Poster presented at the 40th Annual Meeting of the European Association for the Study of Diabetes (EASD) September 5–9, 2004; Munich, Germany. 2. Scott R, Herman G, Zhao P, et al. Twelve-week efficacy and tolerability of MK-0431 (sitagliptin), a dipeptidyl peptidase IV (DPP-IV) inhibitor, in the treatment of type 2 diabetes. Poster presented at the 41st Annual Meeting of the European Association for the Study of Diabetes (EASD); September 12–15, 2005; Athens, Greece. 3. Herman G, Hanefeld M, Wu M, et al. Effect of MK-0431, a dipeptidyl peptidase IV (DPP-IV) inhibitor, on glycemic control after 12 weeks in patients with type 2 diabetes. In: Abstract Book of the 65th Annual Scientific Sessions of the American Diabetes Association; June 10–14, 2005; San Diego, California. Poster 541-P. 4. Brazg RL, Thomas K, Zhao P, Xu L, Chen X, Stein P. Effect of adding MK-0431 to on-going metformin therapy in type 2 diabetic patients who have inadequate glycemic control on metformin. In: Abstract Book of the 65th Annual Scientific Sessions of the American Diabetes Association; June 10–14, 2005; San Diego, California.

A GLP-1R agonisták vs DPP-4 gátlók GLP-1R agonista DPP-4 gátló Alkalmazása Sc. injekció Per os GLP-1 koncentráció Farmakológiás Fiziológiás Hatásmechanizmus Portalis glucose sensor aktiváció GLP-1 Nem GLP-1 + GIP Igen Insulin szekreció +++ + Glucagon szekréció ++ Gyomorürülés Gátolja +/- Súlycsökkenés Beta-sejt tömeg növekedés Preklinikai vizsgálatokban Hányinger, hányás Potenciális immunogenitás Slide 26 GLP-1R Agonists vs DPP-4 Inhibitors The overlapping and distinct properties of GLP-1R agonists vs DPP-4 inhibitors for the treatment of type 2 diabetes are contrasted in this table. These agents exhibit similar actions on the islet beta cell. GLP-1 also inhibits glucagon secretion. GLP-1 and GIP have contrasting actions on weight loss and gastric emptying.1-4 The side-effect profile is also different, with GLP-1R agonists exhibiting a much greater tendency to produce gastrointestinal side effects.3 References: 1. Riddle MC, Drucker DJ. Emerging therapies mimicking the effect of amylin and glucagon-like peptide 1. Diabetes Care. 2006;29:435–449. 2. Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2003;12:87–100. 3. Nielsen LL. Incretin mimetics and DPP-IV inhibitors for the treatment of type 2 diabetes. Drug Discov Today. 2005;10:703–710. 4. Sinclair EM, Drucker DJ. Glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase IV inhibitors: New therapeutic agents for the treatment of type 2 diabetes. Curr Opin Endocrinol Diabet. 2005;12:146–151.

A 2-es típusú diabétesz kezelési algoritmusa Diagnózis ADA és EASD közös állásfoglalása (2006) 1 Életmódváltozás + metformin* Nem HbA1c ł 7% Igen a Egészítse ki a kezelést bázisinzulinnal - leghatékonyabb Egészítse ki a kezelést szulfanil-ureával - legkevésbé költséges Egészítse ki a kezelést glitazonnal - nem hypoglikaemizál Nem HbA1c ł 7% Igen a Nem HbA1c ł 7% Igen a Nem HbA1c ł 7% Igen a Intenzifikálja az inzulin kezelést Egészítse ki a kezelést glitazonnal Egészítse ki a kezelést bázisinzulinnal Egészítse ki a kezelést szulfanilureával b b Nem HbA1c ł 7% Igen a Nem HbA1c ł 7% Igen a 1 * a. b. Diabetológia (2006) 49:1718. o. A metformin kezelés során a maximálisan effektív és tolerálható dózist 1-2 hónap alatt kell elérni. Ellenőrizze a HbA1c-t 3 havonta, amíg az <7% és azt követően legalább minden 6 hónapban. Bár három orális antidiabetikum kombinációja alkalmazható, az inzulin terápia elkezdése és intenzifikálása hatékonysága és költsége miatt előnyben részesül. Egészítse ki a terápiát bázisinzulinnal vagy intenzifikálja az inzulin kezelést intenzív inzulin + metformin +/- glitazon (TZD + inzulin kombináció nincs jóváhagyva az EU-ban) ADA: American Diabetes Association; EASD: European Association for the Study of Diabetes Hangsúlyozza az életmódváltozás fontosságát minden vizit során!

DPP-4 gátlók klinikai hatásai Inzulin szekréciót szignifikánsan növelték (korai fázisban is !) Glucagon szekréciót szignifikánsan csökkentették Inzulin bioszintézis minden lépését potenciálták Étvágyat és testsúlyt (kissé) csökkentették Segítik a béta-sejt regenerációt Gátolják a béta-sejtek apoptózisát Béta-sejt neogenezist okoznak (ductális hámsejtekből) Talán megállítják a DM progresszióját

Beta-Cell Function Declines Regardless of Intervention in Type 2 Diabetes Progresszív béta-sejt funkció- csökkenés már a diagnosis felállítása előtt 100 Betegség progresszió 80 Beta-Cell Function Declines Regardless of Intervention in Type 2 Diabetes1 This slide shows results from the UKPDS, which investigated beta-cell function of patients with type 2 diabetes who were still on their initial therapy—metformin, a sulfonylurea, or diet—at 6 years. The trends show that beta-cell function, as measured by the homeostasis model assessment beta-cell function (HOMA-B) declined over time regardless of therapy. Indeed these data can be extrapolated to show that the progressive loss of beta-cell function (dashed line) begins years before the diagnosis of type 2 diabetes mellitus is made. For all patients, beta-cell function was assessed using HOMA-B, a mathematical formula that uses the fasting insulin and glucose measurements to assess the degree of beta-cell function (and insulin resistance) that would account for a given person’s set of fasting insulin and glucose levels. 60 Béta-sejt funkció (%)* 40 Sulfonylurea 20 Diéta Metformin –5 –4 –3 –2 –1 1 2 3 4 5 6 A diagnózis felállításától eltelt idő *A Béta-sejtl funkciót HOMA módszerrel mérték UKPDS 16 Group. Diabetes. 1995;44:1249–1258. Reference: 1. UK Prospective Diabetes Study Group. U.K. Prospective Diabetes Study 16: Overview of 6 years’ therapy of type II diabetes: A progressive disease. Diabetes. 1995;44:1249–1258.

Köszönöm a figyelmet.