2024-09-05 Journal-finalGLP-1 obesity .pptx

GLP-1 obesity

1. 報告者 : R3 韓逸宏 指導老師：曾逸豪醫師 2024/09/05

2. Tirzepatide MOUNJARO  ( T irzepatide ) mown-JAHR-OH FDA Approval date: May 13, 2022 for DM control Zepbound ( Tirzepatide ) FDA Approved:  November 8, 2023 for Weight Loss (Obesity/Overweight)

3. Tirzepatide MOUNJARO  ( T irzepatide ) mown-JAHR-OH FDA Approval date: May 13, 2022 for DM control Zepbound ( Tirzepatide ) FDA Approved:  November 8, 2023 for Weight Loss (Obesity/Overweight) Indication for MASH? Metabolic-dysfunction associated steatohepatitis ， 代謝功能障礙相關脂肪性肝炎

4. Study Overview 1 st end point: MASH resolution without worsening of fibrosis 2nd end points: Fibrosis stage ( Decrease ) without worsening of MASH QW for 52 weeks MASH with fibrosis Placebo Tirzepatide 5 mg 10mg 15mg Metabolic dysfunction-associated steatohepatitis Phase 2 trial

5. Introduction: MASH (Metabolic dysfunction–associated steatohepatitis), progressive , with fat accumulation , hepatic inflammation , and hepatocyte injury ( histo : ballooning), with or without fibrosis.

6. Clinical Gastroenterology and Hepatology  DOI: (10.1016/j.cgh.2024.01.032) Adiposity CV risk Liver-related events Introduction: MASH , associated with CV disease. Liver fibrosis , it conveys a higher risk of liver-related complications and death.

7. Introduction: MASH is increasing globally with obesity and type 2 DM. In 2019, MASH was 2 nd indication for liver transplantation and the most rapidly increasing indication . Beneficial of weight reduction are well documented. > 10%: Higher resolution of MASH and liver fibrosis In phase 2 trials, GLP-1 receptor agonists shown the resolution of MASH but not for regression of fibrosis . Tirzepatide , QW, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor dual agonist , shown weight reduction in type 2 DM, obesity, or both . Investigate the efficacy and safety of Tirzepatide in MASH with moderate or severe fibrosis.

8. Tirzepatide mechanism of action at target organs GIP-R GLP-1/ GIP Dual-Agonist Tirzepatide Metabolism Open 16 (2022) 100220 GLP-1R

9. MASH with fibrosis Methods: Phase 2 International Double-blind Randomized SYNERGY-NASH trial Key inclusion criteria: 18-80 yrs , BMI:27-50 MASH (Biopsy) Fibrosis stage: F2,F3 NAFLD score: ≥ 4 (0-8) Key exclusion criteria: C LD other than MASH Cirrhosis Already on GLP-1

10. Fibrosis stage: Int. J. Mol. Sci.   2020 ,  21 (11), 4039

11. NAFLD activity score (NAS) : ( 脂肪變性 ) ( 肝小夜發炎 ) ( 肝細胞氣球狀變性 )

12. 1 st end point: MASH resolution without worsening of fibrosis 2nd end points: Fibrosis stage ( Decrease ) without worsening of MASH QW for 52 weeks Biopsy at 52 weeks MASH with fibrosis n= 190 Placebo Tirzepatide 5mg n=47 10mg n=47 15mg n=48 Methods: Phase 2 International Double-blind Randomized 10 countries SYNERGY-NASH trial Key inclusion criteria: 18-80 yrs MASH (Biopsy) Fibrosis stage: F2,F3 NAFLD score: ≥ 4 (0-8) Key exclusion criteria: C LD other than MASH Cirrhosis Already on GLP-1 n=48

13. Method: Dose Escalation Escalation ( 劑量上調 ) Maintenance ( 劑量維持 )

14. Results : Demographic and Clinical Baseline

15. Results : Demographic and Clinical Baseline

16. Liver stiffness

17. Fibrosis-4 Index

18. The NIS4 scores  range from 0 to 1  and are calculated by combining the results of four individual biomarker assays [ miR34a-5p, α2- macroglobulin (A2M), YKL-40 and HbA1c] each of which contributes to the test's ability to detect liver inflammation and/or fibrosis. NIS4 score

19. Enhanced liver fibrosis score Assess the degree of liver fibrosis 透明質酸（ Hyaluronic Acid, HA ） 組織抑制基質金屬蛋白酶抑制劑 1 （ Tissue Inhibitor of Metalloproteinases 1, TIMP-1 ） 氨基末端前膠原 III 型前肽（ Amino-terminal Propeptide of Type III Procollagen, PIIINP ） ELF score = 2.494 + 0.846*ln(HA) + 0.735*ln(PIIINP) + 0.391*ln(TIMP-1) .

20. Pro-C3

21. Results : Demographic and Clinical Baseline

22. Results : Primary End Point after 52 Week (P<0.001)

23. Results : Secondary End Point after 52 Week

24. Results : Change in Liver-Enzyme Levels over Time. (ALT) (AST)

25. Results : Adverse effects GI

26. QW for 52 weeks MASH with fibrosis n= 190 Placebo Tirzepatide 5mg 10mg 15mg Summary: Phase 2 International Double-blind Randomized 10 countries SYNERGY-NASH trial Key inclusion criteria: 18-80 yrs MASH (Biopsy) Fibrosis stage: F2,F3 NAFLD score: ≥ 4 (0-8) Key exclusion criteria: C LD other than MASH Cirrhosis Already on GLP-1

27. Efficacy of Tirzepatide : - Demonstrated significant efficacy in resolving MASH and improving fibrosis compared to placebo . - Higher doses correlated with better outcomes , suggesting a dose-response relationship . Safety Profile: - Common adverse events were gastrointestinal in nature (e.g., nausea, diarrhea). - Most adverse events were mild to moderate . - No new safety concerns were identified compared to previous trials in patients with diabetes or obesity. Discussion I : Efficacy and Safety

28. Clinical Implications: - Tirzepatide could be a promising therapeutic option for patients with MASH and liver fibrosis, especially in the absence of effective treatments. - Potential to reduce liver-related complications and improve patient outcomes . Future Research: - Larger, long-term trials for liver-related morbidity and mortality . - Further investigation into optimal dosing, long-term safety , and potential combination therapies . Discussion II : Implications and Future Directions

29. QW for 52 weeks MASH with fibrosis n= 190 Placebo Tirzepatide 5mg 10mg 15mg Conclusion: Phase 2 International Double-blind Randomized 10 countries SYNERGY-NASH trial Key inclusion criteria: 18-80 yrs MASH (Biopsy) Fibrosis stage: F2,F3 NAFLD score: ≥ 4 (0-8) Key exclusion criteria: C LD other than MASH Cirrhosis Already on GLP-1 More effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of T irzepatide for the treatment of MASH.

30. Thank you~~

31. Conclusions In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH.

32. Figure 5: Chemical shift–encoded (CSE) MRI enables simultaneous estimation of both liver fat and iron deposition. Fat-corrected R2* (R2* = 1/T2*) mapping is a natural byproduct of multi-echo CSE acquisitions used for R2*-corrected proton density fat fraction (PDFF) mapping. Shown are representative MRI scans in three patients with various fat and iron levels throughout the liver. Starekova J. Published Online: September 21, 2021 https://doi.org/10.1148/radiol.2021204288 MRI-PDFF Magnetic Resonance Imaging (Proton Density Fat Fraction) N on-invasive, quantitative biomarker to assess liver fat content

33. Fibrosis stage: Clinical and Experimental Medicine (2023) 23:273–285

34. The Emerging Role of Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis   Layla A. Abushamat, Pir Ahmad Shah, Robert H. Eckel, Stephen A. Harrison, Diana Barb   Clinical Gastroenterology and Hepatology   DOI: 10.1016/j.cgh.2024.01.032 Copyright © 2024 AGA Institute Terms and Conditions

35. Clinical Gastroenterology and Hepatology  DOI: (10.1016/j.cgh.2024.01.032)

36. Figure 1 Clinical Gastroenterology and Hepatology  DOI: (10.1016/j.cgh.2024.01.032) Copyright © 2024 AGA Institute Terms and Conditions

37. Figure 2 Clinical Gastroenterology and Hepatology  DOI: (10.1016/j.cgh.2024.01.032) Copyright © 2024 AGA Institute Terms and Conditions

38. Figure 3 Clinical Gastroenterology and Hepatology  DOI: (10.1016/j.cgh.2024.01.032) Copyright © 2024 AGA Institute Terms and Conditions

39. Figure 4 Clinical Gastroenterology and Hepatology  DOI: (10.1016/j.cgh.2024.01.032) Copyright © 2024 AGA Institute Terms and Conditions

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43. Weight loss with the obesity pharmacotherapies pipeline in people without diabetes. Int J Obes  (2024). https:// doi.org /10.1038/s41366-024-01473-y

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55. Original Article Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis with Liver Fibrosis Rohit Loomba, M.D., Mark L. Hartman, M.D., Eric J. Lawitz, M.D., Raj Vuppalanchi, M.D., Jérôme Boursier, M.D., Ph.D., Elisabetta Bugianesi, M.D., Ph.D., Masato Yoneda, M.D., Ph.D., Cynthia Behling, M.D., Ph.D., Oscar W. Cummings, M.D., Yuanyuan Tang, Ph.D., Bram Brouwers, Ph.D., Deborah A. Robins, M.S., Amir Nikooie, Ph.D., Mathijs C. Bunck, M.D., Ph.D., Axel Haupt, M.D., Ph.D., Arun J. Sanyal, M.D., for the SYNERGY-NASH Investigators N Engl J Med Volume 391(4):299-310 July 25, 2024

56. Study Overview In this phase 2 trial in patients with metabolic dysfunction–associated steatohepatitis and moderate or severe fibrosis, tirzepatide was more effective than placebo with respect to resolution of MASH without worsening of fibrosis.

57. Loomba R et al. N Engl J Med2024;391:299-310

58. Primary and Key Secondary End Points. Loomba R et al. N Engl J Med2024;391:299-310

59. Mean Liver-Enzyme Levels over Time. Loomba R et al. N Engl J Med2024;391:299-310

60. Demographic and Clinical Characteristics of the Participants at Baseline. Loomba R et al. N Engl J Med2024;391:299-310

61. Changes from Baseline to Week 52 in Selected Liver End Points. Loomba R et al. N Engl J Med2024;391:299-310

62. Adverse Events. Loomba R et al. N Engl J Med2024;391:299-310