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Type 2 Diabetes Treatment: Novel Therapies GLP-1 Receptor Agonists/Analogs and DPP-4 Inhibitors

Type 2 Diabetes Treatment: Novel Therapies GLP-1 Receptor Agonists/Analogs and DPP-4 Inhibitors. Jaime A. Davidson, MD, FACP, MACE Clinical Professor of Medicine Division of Endocrinology Touchstone Diabetes Center The University of Texas Southwestern Medical Center Dallas, Texas.

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Type 2 Diabetes Treatment: Novel Therapies GLP-1 Receptor Agonists/Analogs and DPP-4 Inhibitors

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  1. Type 2 Diabetes Treatment: Novel Therapies GLP-1 Receptor Agonists/Analogs and DPP-4 Inhibitors Jaime A. Davidson, MD, FACP, MACE Clinical Professor of Medicine Division of Endocrinology Touchstone Diabetes Center The University of Texas Southwestern Medical Center Dallas, Texas

  2. Major Therapeutic Targets in T2DM Sulfonylureas Meglitinides GLP-1 agonists DPP-4 inhibitors Pancreas Liver Beta-celldysfunction Hepatic glucoseoverproduction Muscle and fat Metformin Thiazolidinediones GLP-1 agonists DPP-4 inhibitors Insulinresistance Glucose level Thiazolidinediones Metformin Kidney Gut Glucose reabsorption Glucose absorption Alpha-glucosidase inhibitors GLP-1 agonists SGLT-2 inhibitors Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes mellitus. DeFronzo RA. Ann Intern Med. 1999;131:281-303. Buse JB, et al. In: Williams Textbook of Endocrinology. 10th ed. WB Saunders; 2003:1427-1483.

  3. Limitations of Older Agents for T2DM Abbreviations: CHF, congestive heart failure; GI, gastrointestinal.

  4. Function of Incretins in Healthy Individuals

  5. Role of Incretins in Glucose Homeostasis Ingestion of food Increased glucose uptake by muscles Glucose-dependentIncreased insulin from beta cells (GLP-1 and GIP) Release of gut hormones — incretins GI tract Decreased blood glucose Pancreas Active GLP-1 and GIP Glucose-dependent Decreased glucagon from alpha cells (GLP-1) DPP-4 enzyme Decreased glucose production by liver InactiveGLP-1 InactiveGIP Abbreviations: DPP-4, dipeptidyl peptidase-4; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876-913. Ahrén B. Curr Diab Rep. 2003;2:365-372. Drucker DJ. Diabetes Care. 2003;26:2929-2940. Holst JJ. Diabetes Metab Res Rev. 2002;18:430-441.

  6. Actions of GLP-1 Drucker DJ. Cell Metab. 2006;3:153-165. Grieve DJ, et al. Br J Pharmacol. 2009;157:1340-1351. Orskov C, et al. Endocrinology. 1988;123:2009-2013. Freeman JS. Cleve Clin J Med. 2009;76(suppl 5):S12-S19.

  7. DPP-4 • Transmembrane cell surface aminopeptidaseexpressed in liver, lungs, kidneys, intestines, lymphocytes, and endothelial cells1 • Active extracellular domain also circulates as free soluble DPP-4 in plasma1 • Active site is in a large “pocket”2 • Access limited to substrates with small side chains (eg, proline, alanine)2 • Active site cleaves to proline or alanine from 2nd aminoterminal position, inactivating its substrates1 • Key substrates: GLP-1 and GIP2 • Rapid and efficient metabolism by DPP-4 = short half-lives (~2 minutes for GLP-1)3 1. Drucker DJ, et al. Lancet. 2006;368:1696-1705. 2. Kirby M, et al. Clin Sci (Lond). 2009;118:31-41. 3. Chia CW, et al. Diabetes Metab Syndr Obes. 2009;2:37.

  8. Incretin Dysfunction in T2DM

  9. The Incretin Effect Nauck M, et al. Diabetologia. 1986;29:46-52. • Oral glucose vs IV glucose infusion: differences in insulin secretion • Insulin secretion is significantly higher with oral glucose vs IV glucose infusion (“incretin effect”) • Incretin effect is diminished in T2DM patients • Failure of insulin secretion

  10. Postprandial GLP-1 Levels in IGT and T2DM 2500 1927 2000 1587 1500 P <.001 for T2DM vs NGT GLP-1 AUC Incremental from Basal (pmol/L• 240 min) 907 1000 500 0 NGT IGT T2DM Abbreviations: AUC, area under the curve; IGT, impaired glucose tolerance; NGT, normal glucose tolerance. Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-3723.

  11. 2 Strategies for GLP-1 Enhancement GLP-1 analogs DPP-4 inhibitors • Chemically modified GLP-1, not susceptible to DPP-4 metabolism • Longer half-lives • FDA approved: exenatide BID and qwk and liraglutide • Investigational • Albiglutide • Lixisenatide • Dulaglutide • Subcutaneous injection Drucker DJ, et al. Lancet. 2006;368:1696-1705. Gallwitz B. Pediatr Nephrol. 2010;25:1207-1217. ClinicalTrials.gov. 2013. Accessed 12/11/13 at: http://www.clinicaltrials.gov. • Block DPP-4 so that it blunts breakdown of GLP-1 • Raise endogenous GLP-1 levels; should also raise GIP • FDA approved: alogliptin, linagliptin, saxagliptin, and sitagliptin • Vildagliptin (approved outside United States) • Oral administration

  12. DPP-4 Inhibitors MOA Meal Intestinal GLP-1 release Intestinal GIP release ActiveGLP-1 ActiveGIP DPP-4inhibitor DPP-4inhibitor • Incretin effects • Augments glucose-dependentinsulin secretion • Inhibits glucagon secretion and hepatic glucose production • Improves hyperglycemia DPP-4 DPP-4 Inactive GLP-1 Inactive GIP Selective inhibition of DPP-4 increases plasma GLP-1 levels, resulting in reduction in glycemia 12

  13. DPP-4 Inhibition Improves ActiveGLP-1 Levels Single-Dose OGTT Study Abbreviation: OGTT, oral glucose tolerance test. Herman GA, et al. J Clin Endocrinol Metab. 2006;91:4612-4619. • 3 arms (N = 58) • Placebo • Sitagliptin 25 mg • Sitagliptin 200 mg • Increase in active GLP-1 with sitagliptin compared with placebo • Placebo: active GLP-1 increases to ~7 pM at 2−3 h • Sitagliptin: active GLP-1 increases to ~15−20 pM and remains higher than placebo for ~6 h

  14. Linagliptin PharmacodynamicsEffect on GLP-1 and Glucagon • Change from baseline in glucagon AUEC0–2h: • Linagliptin: -17.4 pg/h/L • Placebo: 1.3 pg/h/L • P = .0452 • Change from baseline in intact GLP-1 AUEC0–2h: • Linagliptin: 18.5 pmol/h/L • Placebo: 0.4 pmol/h/L • P <.0001 Statistically significant differences in postprandial intact GLP-1 (increased) and glucagon (decreased) vs placebo after 4 weeks of treatment in T2DM patients Rauch T, et al. Diabetes Ther. 2012;3:10.

  15. Therapeutic Effect of GLP-1 in T2DM 10 patients with unsatisfactory control of T2DM received infusions of GLP-1 or placebo GLP-1 significantly increased GLP-1 significantly reduced Fasting plasma glucose (normal levels reached in all patients) Pancreatic glucagon secretion (-1418 pmol x 1-1 x min) Plasma nonesterified fatty acids (-26.3 mmol x 1-1 x min) • Insulin (17.4 nmol x 1-1 x min)* • C-peptide (228 nmol x 1-1 x min)* *Decreased again after plasma glucose normalized. Nauck MA, et al. Diabetologia. 1993;36:741-744.

  16. GLP-1 Receptor Agonists and DPP-4 Inhibitors Effects on HbA1c, Glucose, and Insulin Levels

  17. Exenatide Has Beneficial Effects on FPG and Insulin in T2DM N = 13 Mean FPG (mg/dL) Peak Mean Incremental Serum Insulin (µU/mL) Abbreviation: FPG, fasting plasma glucose. Kolterman OG, et al. J Clin Endocrinol Metab.2003;88:3082-3089.

  18. Exenatide Has Beneficial Effects on Postprandial Glucose and Glucagon in T2DM N = 24. Kolterman OG, et al. JClin Endocrinol Metab.2003;88:3082-3089.

  19. Exenatide at 3 Years of Therapy Provides Sustained Effects on HbA1c • 217 patients randomized to placebo, 5 µg exenatide, or 10 µg exenatide during prior 30-week placebo-controlled studies were transitioned to open-label exenatide treatment • All patients had a minimum of 3 years of exenatide exposure for this analysis • By week 12, exenatide reduced HbA1c by 1.1% • Reduction in HbA1c was sustained throughout 156 weeks of treatment • Change from baseline to week 156 = -1.0% (95% CI, -1.1 to -0.8); P <.0001 • 46% of patients achieved HbA1c ≤7%; 30% achieved HbA1c ≤6.5% Klonoff DC, et al. Curr Med Res Opin. 2008:24:275-286.

  20. Liraglutide 1-Year Monotherapy Reduces FPG and PPG .0223 Abbreviations: FPG, fasting plasma glucose; PPG, postprandial glucose. Garber A, et al. Lancet. 2009;373:473-481.

  21. Liraglutide 1-Year Monotherapy Improves Glycemic Control • 52-week phase III study in 746 T2DM patients previously on diet and exercise or oral antidiabetic monotherapy • Baseline HbA1c was 8.3%–8.4% in all groups Glimepiride (n = 248) Liraglutide 1.2 mg (n = 251) Liraglutide 1.8 mg (n = 246) Δ HbA1c (%) P = .0014 P = .0046 P <.0001 Garber A, et al. Lancet. 2009;373:473-481.

  22. Effects of Liraglutide and Glimepiride Monotherapy on HbA1c Over 2 Years 0 -0.4 -0.5 Liraglutide 1.8 mg† HbA1c Change (%) -0.7 Glimepiride -1 -1* -1.4* -1.5 ≥3 y Disease duration: <3 y (n = 55) (n = 42) (n = 60) • % achieving HbA1c <7% • 58% with liraglutide* • 37% with glimepiride • Weight change • -2.7 kg with liraglutide* • 1.1 kg with glimepiride (n = 54) *P <.05 vs glimepiride; † 73% completed 2-year extension. Garber AJ, et al. Diabetes. 2009;58(suppl 1):162-OR.

  23. Effects of Exenatide qwk vs Exenatide BID on Glycemic Control 8.3% Baseline HbA1c: 8.3% 0 -10 -20 FPG Change (mg/dL) -25 -30 -40 -41* -50 Exenatide 10 mcg BID (n = 147) Exenatide 2.0 mg qwk (n = 148) 0 -0.5 HbA1c Change (%) -1 -1.5 -1.5 -2 -1.9* Similar cumulative incidences of nausea Exenatide BID, 35% of patients; Exenatide qwk, 26% of patients Similar weight loss Approximately 4 kg in both groups Similar rates of minor hypoglycemia Exenatide BID, 6.1% of patients; Exenatide qwk, 5.4% of patients 100 77* 80 61 60 HbA1c < 7.0% (% of Patients) 40 20 0 Approximately 90% of patients completed 30 weeks of treatment. *P <.05 vs exenatide BID. Drucker DJ, et al. Lancet. 2008;372:1240-1250.

  24. Exenatide qwk Delivered Powerful HbA1c Reductions Baseline HbA1c: 8.5% 8.4% Exenatide qwk (n = 129) Exenatide BID (n = 123) Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310.

  25. Improvements in HbA1c with Exenatide qwk Were Sustained at 1 Year DURATION-2 Open-Label Extension Completer Analysis Primary Endpoint: Change in HbA1c (%) 0.0 Blinded period1* (N = 326) Open-label period2† (N = 249) -0.5 -1.0 n = 130 -1.5 n = 119 -2.0 0 4 6 10 14 18 22 26 26 30 34 40 46 52 Time (wk) Sitagliptin Exenatide qwk *ITT population. †52-week evaluable population. LS mean (SE). 1. Bergenstal RM, et al. Lancet. 2010;376:431-439. 2. Wysham C, et al. Diabet Med. 2011;28:705-714.

  26. Exenatide qwk Percent to Goal Compared to Sitagliptin or Pioglitazone • Diet and exercise background *P <.001 vs sitagliptin. 1. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 2. Bergenstal RM, et al. Lancet. 2010;376:431-439. • Metformin background • A significantly greater percentage of patients achieved HbA1c <7.0% and HbA1c ≤6.5% with exenatide qwk than with sitagliptin (P <.0001) or pioglitazone (P <.05)2

  27. Overview of GLP-1 Receptor Agonist Safety Data • Meta-analysis • Predominantly exenatide and liraglutide • n = 5429 receiving GLP-1 receptor agonists • n = 3053 receiving active comparators or placebo * Odds ratio based on analysis of exenatide bid trials. † Severe hypoglycemia reported for 19 patients in exenatide BID trials and 1 patient in liraglutide trials. Abbreviation: SU, sulfonylurea. Monami M, et al. Eur J Endocrinol. 2009;160:909-917.

  28. Current DPP-4 Inhibitors Sitagliptin Saxagliptin Vildagliptin (approved outside United States) Alogliptin Linagliptin

  29. Comparative Efficacies of DPP-4s Placebo-corrected change from baseline in HbA1c - Monotherapy Saxagliptin3 5 mg 5 mg 7%-10% 8.0% Sitagliptin4 100 mg 100 mg 8.0% 8.0% Vildagliptin5 50 mg BID 50 mg 8.6% 8.4% Alogliptin1 12.5 mg 25 mg 7.9% 7.9% Linagliptin2 5 mg 5 mg 8.1% 8.0% -0.1 -0.2 -0.3 -0.4 ΔHbA1c (%) -0.4 -0.5 -0.5 -0.6 -0.56 -0.59 -0.6 -0.6 -0.6 -0.7 -0.7 -0.7 -0.8 -0.8 -0.9 -1.0 The current DPP-4s have comparative efficacy -1.1 -1.2 • DeFronzo R, et al. Diabetes Care2008;31:2315-2317. 2. Linagliptin Prescribing Information. 3. Saxagliptin Prescribing • Information. 4. Sitagliptin Prescribing Information. 5. Vildagliptin Summary of Product Characteristics.

  30. Alogliptin Phase III Trials: HbA1c Change from Baseline After 26 Weeks Alogliptin monotherapy1 Add-on therapy LS Mean Change HbA1c from Baseline (%) Baseline HbA1c: 8.0% Abbreviations: MET, metformin; PIO, pioglitazone; SU, sulfonylurea. *P <.001 vs control. 1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315-2317. 2. Pratley RE, et al. Diabetes ObesMetab. 2009;11:167-176. 3. Nauck MA, et al. Int J ClinPract. 2009;63:46-55. 4. Pratley RE, et al. Curr Med Res Opin. 2009;25:2361-2371. 5. Rosenstock J, et al. Diabetes ObesMetab. 2009;11:1145-1152.

  31. Linagliptin Significantly Reduced HbA1c After 24 Weeks in Patients on a Stable Insulin Dose Baseline HbA1c (%): 8.29 8.31 Full analysis set (last observation carried forward). Change-from-baseline HbA1c at Week 24 is the primary endpoint. *Model includes treatment, baseline HbA1c, renal function, concomitant OADs. †Sensitivity analyses (FAS OC and PPS) revealed similar results. Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

  32. HbA1c Reduction with Linagliptin in Elderly Patients Over 75 Years • In a prespecified subgroup analysis, there was no significant interaction according to patient age group (P = .1000) • The study had a high proportion of elderly patients • 65−74 years: 26.1% linagliptin, 28.7% placebo • ≥75 years: 5.5% linagliptin, 6.5% placebo Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

  33. Linagliptin Reduced HbA1c After 24 Weeks (Primary Endpoint) and Maintained it in a 52-Week Free Insulin Titration Period Stable insulin dose Baseline to week 24 Free insulin dose starting at week 24 • The difference in HbA1c reduction between linagliptin and placebo was maintained during a 52-week free insulin titration period starting at week 24 (out to week 76) Full analysis set (last observation carried forward). *Model includes treatment, baseline HbA1c, renal function, concomitant OADs. Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

  34. Linagliptin Significantly Reduced FPG After 24 Weeks and Maintained it in 28-Week Free Insulin Titration Period Stable insulin dose baseline to week 24 Free insulin dose starting at week 24 Full analysis set (observed case set). Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

  35. Insulin Dose Stabilized in 1st 24 Weeks and Increased in Both Groups in 2nd 28-Week Free-Titration Period, but With Greater Extent in Placebo Group Stable insulin dose Baseline to week 24 Free insulin dose starting at week 24 Full analysis set, original analysis. Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

  36. Safety Profile of Linagliptin Compared with Placebo After 52 Weeks • The overall risk of adverse events (AEs) with linagliptin (n = 631) vs placebo (n = 630): • Patients with any AEs • 78.4% with linagliptin vs 81.4% with placebo • Patients with investigator-defined drug-related AEs • 18.7% with linagliptin vs 22.2% with placebo • Patients with AEs leading to discontinuation of trial drug • 3.3% with linagliptin vs 4.4% with placebo • Patients with serious AEs • 13.8% with linagliptin vs 13.2% with placebo Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

  37. Linagliptin, When Added to Insulin, and Its Association with the Risk of Hypoglycemia Week 24 Week 52 Improved glycemic control with linagliptin added to insulin does not appear to increase the risk of hypoglycemia Treated set (all patients who were treated with at least 1 dose of study medication). Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

  38. Linagliptin Shows Rates of Hypoglycemia Similar to PlaceboThe Majority of Hypoglycemia is Nonsevere Investigator-defined hypoglycemia AEs at week 24 by category All HypoglycemiaAEs DocumentedSymptomatic(≤72 mg/dL) DocumentedSymptomatic(<54 mg/dL) Severe Placebo Linagliptin Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881.

  39. Study Summary: Linagliptin as Add-On to Insulin Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875-3881. Efficacy and safety of linagliptin as add-on therapy to insulin in type 2 diabetes • Linagliptin significantly reduced HbA1c after 24 weeks in patients on a stable insulin dose (placebo-corrected reduction after 24 weeks -0.65%) • The efficacy of linagliptin was reliable in different prespecified subgroups, such as • Elderly patients age ≥75 years • Different categories of renal function • HbA1c reductions were maintained over 52 weeks • Linagliptin significantly reduced fasting plasma glucose after 24 weeks and maintained it in 28-week free insulin titration period • Linagliptin has a safety profile comparable to placebo • Incidence of hypoglycemia with linagliptin was comparable to placebo

  40. 50 mg QD 100 mg QD 0 –0.2 –0.4 Placebo-Subtracted Δ in HbA1c(%) from Baseline to Week 12 –0.6 –0.8 –1.0 –1.2 –1.15 –1.18 Both Sitagliptin and Saxagliptin Produced Greatest Reductions in HbA1c in Patients with High Baseline HbA1c Open-Label Saxagliptin in 66 Patientswith Baseline HbA1c >10% to ≤12% Sitagliptin-Treated Subgroup with Baseline HbA1c >9% 10 mg QD 0 –0.2 –0.4 –0.6 –0.8 –1.0 Δ HbA1c from Baseline to Week 24 (%) –1.2 –1.4 –1.6 –1.8 –1.87 –2.0 Hanefeld M, et al. Curr Med Res Opin. 2007;23:1329-1339. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411

  41. Incretin-Based Therapy Improves Glycemic Control When Used in Combination Abbreviation: TZD, thiazolidinedione. *Added to thiazolidinedione plus metformin. 1. Bergenstal RM, et al. Lancet. 2010;376:431-439. 2. DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100. 3. DeFronzo RA, et al. Diabetes Care. 2010;33:951-957. 4. Buse JB, et al. Diabetes Care. 2004;27:2628-2635. 5. Buse JB, et al. Lancet. 2009;374:39-47. 6. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 7. Marre M, et al. Diabet Med. 2009;26:268-278. 8. Pratley R, et al. ADA 2012. Abstract 1158-P. 9. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55. 10. Pratley RE, et al. Curr Med Res Opin. 2009;25:2361-2371. 11. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176. 12. Haak T, et al. Diabetes Obes Metab. 2012;14:565-574. 13. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 14. Gomis R, et al. Diabetes Obes Metab. 2011;13:653-661. 15. Lewin AJ, et al. Clin Ther. 2012;34:1909-1919.e15. 16. Williams-Herman D, et al. Curr Med Res Opin. 2009;25:569-583. 17. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 18. Nauck M, et al. Diabetes Care. 2009;32:84-90. 19. Derosa G, et al. Metabolism. 2010;59:887-895. 20. Rosenstock J, et al. Clin Ther. 2006;28:1556-1568. 21. Hermansen K, et al. Diabetes Obes Metab. 2007;9:733-745. 22. Jadzinsky M, et al. Diabetes Obes Metab. 2009;11:611-622. 23. DeFronzo RA, et al. Diabetes Care. 2009;32:1649-1655. 24. Hollander P, et al. J Clin Endocrinol Metab. 2009;94:4810-4819. 25. Chacra AR, et al. Int J Clin Pract. 2009;63:1395-1406.

  42. Exenatide qwk HbA1c Reduction Compared with Sitagliptin or Pioglitazone Diet and exercise background1 Metformin background2 Baseline : 8.5% 8.5% 8.5% 8.6% 8.5% 8.5% Exenatide qwk (n = 160) Exenatide qwk (n = 248) LS Mean. ITT population. *P <.001 vs sitagliptin. †P <.0001 vs sitagliptin ‡P <.05 vs pioglitazone. 1. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 2. Bergenstal RM, et al. Lancet. 2010;376:431-439.

  43. Fasting Plasma Glucose Improvement Was Greater with Exenatide qwk and Pioglitazone Diet and exercise background1 Metformin background2 Exenatide qwk (n = 248) Exenatide qwk (n = 160) LS Mean. ITT population. *P <.05 exenatide qwk vs sitagliptin. 1. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258. 2. Bergenstal RM, et al. Lancet. 2010;376:431-439

  44. GLP-1 Receptor Agonists and DPP-4 Inhibitors Effects on Weight

  45. Why Is Weight a Concern? • Most patients with T2DM are overweight/obese • Some currently available therapies cause weight gain • Secretagogues • Glitazones • Insulin

  46. Exenatide Open-Label Extension Study Continuous Loss of Body Weight Baseline 99.3 kg Baseline BMI (kg/m2) <30 Δ Body Weight from Baseline to Week 156 (kg) ΔBody Weight from Baseline (kg) Klonoff DC, et al. Curr Med Res. 2008;24:275-286.

  47. Exenatide qwk Weight Reduction Compared with Sitagliptin or Pioglitazone Diet and exercise background1 Metformin background2 Baseline (kg) : 87.5 88.7 86.1 89 87 88 Exenatide qwk (n = 160) Exenatide qwk (n = 248) *P <.001 vs sitagliptin. †P <.001 vs pioglitazone. ‡P = .002 vs sitagliptin. §P <.0001 vs pioglitazone. 1. Russell-Jones D, et al. Diabetes Care. 2012;35:252-258.2. Bergenstal RM, et al. Lancet. 2010;376:431-439.

  48. Effect of Liraglutide vs Standard Therapy on Body Weight Weight Change from Baseline (kg) *P = .0001 vs glimepiride; †P <.05 vs placebo; ‡P ≤.0001 vs placebo. Abbreviations: SU, sulfonylurea; TZD, thiazolidinedione. 1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Marre M, et al. Diabetic Med. 2009;26:268-278. 4. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 5. Russell-Jones D, et al. Diabetologia.2009;52:2046-2055.

  49. Liraglutide Delayed Gastric Emptying • Comparative trial: liraglutide, glimepiride, placebo in T2DM patients (N = 46) • Gastric emptying was slowed with liraglutide, mainly during the first postprandial hour • Mean estimated acetaminophen AUC0-60 min ratios • 0.62 with liraglutide vs placebo (P <.001) • 0.67 with liraglutide vs glimepiride (P <.001) • Mean estimated percentage of acetaminophen exposure during the first postprandial hour (AUC0-60 min/AUC0-300 min) • 30% less with liraglutide compared with placebo (P <.001) • 29% less with liraglutide compared with glimepiride (P <.001) • Acetominophen Cmax • 20% lower with liraglutide compared with placebo (P ≤.006) • 15% lower with liraglutide compared with glimepiride (P ≤.006) Horowitz M, et al. Diabetes Res Clin Pract. 2012;97:258-266.

  50. Neutral Effect of DPP-4 Inhibitors on Body Weight • Sitagliptin produced statistically significant (P <.05) decreases of 0.5–0.8 kg in body weight from baseline at week 12 at all doses1 • Not significantly different from weight loss seen with placebo (-0.5 kg) • Saxagliptin reduced body weight by -0.1 to -1.2 kg at week 24 compared with baseline2 • Weight loss was -1.4 kg with placebo • In a comparative trial, mean weight loss after 26 weeks was -0.96 kg with sitagliptin vs -3.38 kg with liraglutide 1.8 mg and -2.86 kg with liraglutide 1.2 mg3 • Linagliptin produced no significant difference in body weight from baseline4 • No significant difference in body weight from baseline with placebo 1. Hanefeld M, et al. Curr Res Med Opin. 2007;23:1329-1339. 2. Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267.

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