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Minimally Invasive Surgery Symposium Gut Hormones and the Medical Management of Diabesity Donna H. Ryan, MD Pennington Biomedical Research Center Baton.

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Presentation on theme: "Minimally Invasive Surgery Symposium Gut Hormones and the Medical Management of Diabesity Donna H. Ryan, MD Pennington Biomedical Research Center Baton."— Presentation transcript:

1 Minimally Invasive Surgery Symposium Gut Hormones and the Medical Management of Diabesity Donna H. Ryan, MD Pennington Biomedical Research Center Baton Rouge, LA

2 Outline  Physiologic abnormalities in T2DM  Incretins in normal physiology and T2DM  Therapeutic approaches targeting incretins

3 β-Cell mass in Type 2 diabetes Obese Lean -50% -63% Butler et al. Diabetes ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus

4 Excessive hepatic glucose production in Type 2 diabetes Plasma glucose concentration Fasting & postprandial hyperglycaemia Insulin; IR Glucagon Hepatic glucose output IR=insulin resistance

5 Outline  Physiologic abnormalities in T2DM  Incretins in normal physiology and T2DM  Therapeutic approaches targeting incretins

6 What is the Incretin Effect? Time Insulin (pM) Glucose (mM) IV Glucose Oral Incretin effect The amplification of insulin secretion caused by gut hormones. In healthy subjects ~ 70 % less insulin is secreted with an OGTT compared to IVGTT.

7 Postprandial GLP-1 levels are decreased in people with IGT and Type 2 diabetes Toft-Nielsen et al. J Clin Endocrinol Metab Time (min) GLP-1 (pmol/l) * * * * * * * * Meal NGT T2DM IGT *P<0.05 T2DM vs NGT IGT=impaired glucose tolerance; NGT=normal glucose tolerance

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10 Glucagon like peptide  Produced by L cells in proximal and distal gut  Stimulates glucose dependent insulin release  Reduces gastric emptying  Reduces body weight  Inhibits glucagon secretion in glucose dependent manner  Enhances B cell proliferation and survival Glucose-dependent insulinotropic polypeptide  Produced by K cells in duodenum  Stimulates glucose dependent insulin release  Minimal effect on gastric emptying  No effect on body weight  Stimulates glucagon secretion  ? Enhances B cell proliferation and survival What are the Incretin Hormones? GLP-1 and GIP

11 Incretin Function in T2DM  Secretion of GLP-1 impaired  Beta Cell sensitivity to GLP-1 decreased  Secretion of GIP slightly impaired  Effect of GIP abolished or grossly impaired

12 Normalisation of diurnal plasma glucose concentrations by continuous IV GLP-1 infusion (1.2 pmol/kg/min) Rachman et al. Diabetologia T2DM T2DM + GLP-1 Controls Glucose (mmol/l) 16 Clock time (hours) BreakfastLunchSnack

13 Nauck MA et al. Diabetologia. 1993;36: Data are mean±SE; *P<0.05 Placebo GLP-1 Glucose-Dependent Actions of GLP-1 in Patients With Type 2 Diabetes Insulin (pmol/L) * * * * * * * * GLP-1/PBO infusion Time (min) Glucagon (pmol/L) Time (min) * * * * GLP-1/PBO infusion * Glucose (mmol/L) GLP-1/PBO infusion * * * * * * Time (min) Restores Islet-Cell Physiology

14 GLP-1 Inhibits Human Islet Cell Apoptosis and Preserves Islet Morphology Day 1 GLP-1 treated cells Control Day 3 Day 5 Islets treated with GLP-1 are able to maintain their integrity for a longer period of time. Farilla L et al. Endocrinology. 2003;144(12):5149−5158. Permission required.

15 Restoration of Pancreatic Islet Beta Cells by Restoring GLP-1 Levels Diabetic mice Diabetic mice + DPP-4 Inhibitor Lean control mice Green: Insulin-producing β-cell Red: Glucagon-producing α-cell Adapted from Zhang BB et al. Poster presentation at the 64th Scientific Session of the ADA, Orlando, Florida, USA, June Diabetic mice received 10 weeks of treatment with MK-0431 analog. DPP-4 = Dipeptidyl peptidase-4

16 Restoration of Pancreatic Islet Beta Cells by Restoring GLP-1 Levels Diabetic mice Diabetic mice + DPP-4 Inhibitor Lean control mice Green: Insulin-producing β-cell Red: Glucagon-producing α-cell Adapted from Zhang BB et al. Poster presentation at the 64th Scientific Session of the ADA, Orlando, Florida, USA, June Diabetic mice received 10 weeks of treatment with MK-0431 analog. DPP-4 = Dipeptidyl peptidase-4

17 Decreased hepatic glucose output Increased peripheral glucose uptake GI tract Pancreas Incretins Regulate Glucose Homeostasis Through Effects on Islets  Glucagon α in glucose- dependent way from α cells (GLP-1) α cells  Insulin in glucose-dependent way from β cells (GLP-1 and GIP) β cells Ingestion of food Adapted from Brubaker PL, Drucker DJ. Endocrinology. 2004;145: ;Zander M et al. Lancet. 2002;359: ; Ahrén B. Curr Diab Rep. 2003;3: ; Buse JB et al. In Larsen PR et al, eds.: Williams Textbook of Endocrinology. 10th ed. Philadelphia, PA: Saunders; 2003: Inactive GLP-1 (9-36) and GIP (3-42) ↓ GLUCAGON INSULIN DPP-4 inhibitor X  Blood glucose control Release of incretin gut hormones Active GLP-1 and GIP Blood glucose control GLP-1 agonist

18 Outline  Physiologic abnormalities in T2DM  Incretins in normal physiology and T2DM  Therapeutic approaches targeting incretins

19 GLP-1 enhancement Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol GLP-1 secretion is impaired in Type 2 diabetes Natural GLP-1 has extremely short half-life Add GLP-1 analogues with longer half-life: exenatide liraglutide Injectables Block DPP-4, the enzyme that degrades GLP-1: sitagliptin vildagliptin saxagliptin Oral agents

20 GLP-1 Receptor Agonists – February 2010 CompanyCompoundStatus of developmentFormulation Eli Lilly/AmylinByetta (exenatide)LaunchedTwice-daily Novo NordiskVictoza (liraglutide)Approved 1/25/10Once-daily Eli Lilly/Amylinexenatide LARPhase III/Expected 2010Once-weekly Sanofi-aventislixisenatide (AVE0010)Phase III/Expected 2011Once-daily GlaxoSmithKlineSyncria (albiglutide)Phase III/Expected 2011Once-weekly Roche/Ipsentaspoglutide (R1583)Phase IIb-III/Expected 2011Once-weekly Eli LillyLY Phase II/IIIOnce-weekly ConjuChemCJC-1134Phase IIOnce-weekly Eli Lilly LY Phase IIOnce-weekly Sanofi-aventisAVE0010(ZP10)Phase IIOnce-weekly Novo Nordisk NN9535 Phase IIOnce-weekly

21 DPP-4 Inhibitors – February 2010 CompanyCompoundStatus of development MerckJanuvia (sitagliptin, MK-0431)Launched 2006 NovartisGalvus (vildagliptin, LAF-237)Launched EU 2008 BMS/AstraZenecaOnglyza (saxagliptin)Launched August 2009 Takedaalogliptin (SYR-322)Filed US 2008 Boehringer-IngelheimOndero (BI-1356)Phase III Phenomix/Forest Lab.dutogliptin (PHX1149) Phase III Glenmarkmelogliptin (GRC 8200) Phase IIb Mitsubishi Tanabe Pharma TA-6666 Phase II Mitsubishi Tanabe Pharma MP-513 Phase II Amgen/Servier AMG 222/ALS Phase II PfizerPF Phase II TakedaSYR-472Phase II Abbott LaboratoriesABT-279Phase II

22 Incretin mimetics and DPP-4 inhibitors: major differences Properties/effectIncretin mimeticsDPP-4 inhibitors Mechanism of stimulation of insulin secretion exclusively through GLP-1 effect YesUnknown Restitution of insulin secretion (2 phases)Yes (exenatide)Yes HypoglycaemiaNo Maintained counter-regulation by glucagon in hypoglycaemia YesNot tested Inhibition of gastric emptyingYesMarginal Effect on body weightWeight lossWeight neutral Side effectsNauseaNone observed AdministrationSubcutaneousOral Gallwitz. Eur Endocr Dis. 2006

23 Exendin-4 Chen & Drucker, J Biol Chem 1997 Gly His Val Ala Glu Gly Glu Gly Leu ThrPheThr Phe Ser Lys Ser Asp Leu GlnMet Leu Lys Glu Arg Asn Ile TrpGly Pro Ser Gly Pro Ala Pro Ser Pro H 2 N- His Ala Glu Gly Glu ThrPheThr Phe Ser Asp Val TyrLeu Val Gln Lys Arg Ile TrpAla Gly Glu C-16 fatty acid (palmitoyl) Based on human GLP-1 (7-37) 97% homologous with GLP-1 Resistant to DPP-4 Full agonist at the GLP-1 receptor Non-covalent binding to albumin, self- association, slow release from injection site gives prolonged survival time – t½ 12 hr after sc injection From saliva of the Gila Monster 53% homologous with GLP-1 Insensitive to DPP-4 Full agonist at the GLP-1 receptor Metabolically stable – t½ 4-5 hr after sc injection Liraglutide Knudsen et al, J Med Chem 2000 Conserved Substituted Additional (relative to human GLP )

24 Exenatide Lowers Postprandial Glucose Large Phase 3 Clinical Studies – Combined (Evaluable) Placebo BID (N = 44) Exenatide 5 mcg BID (N = 42) Exenatide 10 mcg BID (N = 52) Time (min) Prior to Treatment Glucose (mg/dL) Placebo Meal Mean (SE); Evaluable meal tolerance test cohorts Data on file, Amylin Pharmaceuticals, Inc. Week 30 Glucose (mg/dL) Exenatide or Placebo Meal -30

25 N=217; mean (-SE); P< from baseline to 30 weeks and baseline to 3 years. Klonoff DC et al. Curr Med Res Opin. 2007;24: Exenatide Sustained A1C Reduction: 3-Year Completers Time (weeks) Baseline A1C 8.2% Placebo-controlledOpen-label uncontrolled -1.1 ± 0.1% % achieving A1C ≤7% A1C (%) -1.0 ± 0.1% 46% 54%

26 Changes in body weight over time with exenatide Mean weight change (kg ± SEM) Time (week) Placebo-Controlled Trials Placebo  10-μg exenatide bd 5 μg bd  10-μg exenatide bd 10 μg bd  10-μg exenatide bd Open-Label Extension (All subjects: 10 μg bd) N=92; completer cohort; 82-week data; weight change was a secondary endpoint. Baseline weight: placebo=98 kg, 5 μg=98 kg, 10 μg=100 kg. Ratner et al. Diabetes Obes Metab. 2006; Data on file, Amylin Pharmaceuticals, Inc.

27 >4-8>8-12>12-16>16-20>20-24>24-28>28 Time (week) % Incidence of nausea Intent-to-treat 30-week data; N=1446 Data on file, Amylin Pharmaceuticals, Inc Incidence of nausea with exenatide in large phase 3 clinical studies Placebo 5-μg exenatide bd 10-μg exenatide bd Dose increased from 5 μg to 10 μg at week 4

28 26 Week LEAD-6 Trial of Liraglutide vs Exenatide  Liraglutide is GLP-1 analog with a single amino acid substitution and a fatty acid to slow absorption – 97% homology  Half life 13 h. Dose 1.8 mg/d  Exenatide has 57% homology  Liraglutide lowered HgbA1, FPG and HOMA-B more than exenatide.  Weight loss about 2 kg Buse J Lancet 2009;May 23

29 Comparison of Liraglutide and Exenatide in the LEAD-6 Study Buse J et al Lancet 2009; Inadequately controlled T2D were treated with exenatide (n=231) 10 mg/d or liraglutide (n- 233) 1.8 mg/d for 26 weeks. Liraglutide reduced HbA1c and fasting glucose more than exenatide

30 24 Week Study of Liraglutide in Obesity  20 week multi-center clinical trial with 564 obese subjects randomized to placebo, orlistat or 4 doses of liraglutide  75 subjects had prediabetes  Screening and 2 week run-in prior to randomization followed by 20 weeks of therapy

31 Effect of Liraglutide and Orlistat on Body Weight Finer N Diabetes 2009;

32 Time will tell…  Liraglutide is once daily, exenatide is twice daily, with once weekly due soon.  Both liraglutide and exenatide are associated with nausea, vomiting and diarrhea.  Will liraglutide have the side effect of pancreatitis that is seen with exenatide?

33 Sitagliptin improves both fasting and post-meal glucose in monotherapy vs placebo *Least-squares (LS) mean difference from placebo after 24 weeks Aschner et al. Diabetes Care Fasting Glucose Plasma glucose (mmol/l) Time (weeks) Placebo (n=247) Sitagliptin 100 mg (n=234)  FPG* = -1.0 mmol/l (P<0.001) Post-meal Glucose Time (minutes) Plasma glucose (mmol/l)  in 2-hr PPG* = -2.6 mmol/l (P<0.001) Placebo (n=204)Sitagliptin (n=201) Baseline 24 weeks Baseline 24 weeks

34 Difference in 24-hour mean glucose: -1.8 mmol/l (-32.8 mg/dl), P<0.001 Brazg et al. Diabetes Obes Metab Sitagliptin added to metformin improves 24-hour glucose profile in Type 2 diabetes Glucose (mmol/l) 8:00 Day 1 13:0019:00 0:00 Day 2 7: Dose 1 7:30 Dose 2 18:30 BreakfastLunchDinner Placebo + metformin (n=13) Sitagliptin 50 mg bd + metformin (n=15) Time

35 Sitagliptin once daily lowers HbA 1c when added to metformin or pioglitazone *Placebo-subtracted difference in LS means Charbonnel et al. Diabetes Care. 2006; Rosenstock et al. Clin Ther  in HbA 1c vs Pbo* = -0.65% (P<0.001)  in HbA 1c vs Pbo* = % (P<0.001) Placebo (n=224) Sitagliptin 100 mg (n=453) Add-on to Pioglitazone Study Placebo (n=174) Sitagliptin 100 mg (n=163) Time (weeks) HbA 1c (%) Add-on to Metformin Study Time (weeks) HbA 1c (%)

36 Safety and tolerability profile: once-daily sitagliptin vs glipizide  between groups = –2.5 kg (P<0.001) Change in body weight Time (weeks) Body weight (kg) Sitagliptin 100 mg (n=382) Glipizide (n=411) 4.9% 32% Hypoglycaemia P<0.001 Week 52 Incidence (%) Glipizide (n=584) Sitagliptin 100 mg (n=588) Stein. ADA Late-breaking clinical presentation; Nauck et al. Diabetes Obes Metab. 2007

37 Adapted from Herman, et al. J Clin End Met. 2006; 91:4612. Study Drug OGTT Sitagliptin 200 mg (n=54) Sitagliptin 25 mg (n=55) Placebo (n=55) Active GLP-1 (pM/L) Plasma Levels of Active GLP-1 After Sitagliptin Administration Time (h) 7

38 Sitagliptin Once Daily Shows Similar Glycemic Efficacy to Glipizide When Added to Metformin Sitagliptin 100 mg qd (n=382) Glipizide (n=411) Mean Change in HbA 1c Mean change from baseline (for both groups)*: % Time (weeks) *per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysis Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205

39 Hypoglycemia Week 52 Incidence (%) Glipizide (n=584) Sitagliptin 100 mg (n=588) Sitagliptin Once Daily Shows Better Safety and Tolerability Profile Compared to Glipizide (52 Weeks) p<0.001 Sitagliptin 100 mg qd (n=382) Glipizide (n=411)  between groups = –2.5 kg (p<0.001) 32% 4.9% Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205 Change in Body Weight Time (weeks) Body weight (kg)

40 DPP IV inhibitors – the down side  DPP IV is important in the immune system regulation.  DPP IV has been reported to be a tumor suppressor  Rare reports of Stevens-Johnsons Syndrome with sitagliptin

41 Mean HbA 1c of patients HbA 1c, % OAD monotherapy Diet and exercise OAD combination OAD up-titration OAD plus multiple daily insulin injections OAD plus basal insulin Traditional stepwise approach Earlier Use of Combination Therapy may Improve Treatment of Diabetes Early combination approach Duration of Diabetes Time OAD=oral anti-hyperglycaemic drug. Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355 and Campbell IW. Br J Cardiol. 2000;7:625–631.

42 Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications for clinical practice, 771–789, © 1999, with permission from Elsevier. Development and Progression of Type 2 Diabetes and Related Complications* *Conceptual representation. Insulin level Insulin resistance Hepatic glucose production Postprandial glucose glucose Fasting plasma glucose Beta-cell function Progression of Type 2 Diabetes Mellitus Impaired Glucose Tolerance Diabetes Diagnosis Frank Diabetes 4–7 years Development of Macrovascular Complications Development of Microvascular Complications *

43 Thank you


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