PPT_MAFLD Update Sun Pharma FOR PRESENTATION.pptx

METABOLIC ASSOCIATED FATTY LIVER DISEASE

1. Metabolic Associated Fatty Liver Disease

2. History Jurgen Ludwig (1980) – First coined the term NASH

3. Introduction Metabolic associated fatty liver disease (MAFLD) (formerly known as non-alcoholic fatty liver disease (NAFLD)) MAFLD - prevalence rising to alarming levels, placing an enormous burden on individuals and health care systems

4. Introduction

5. Introduction Simple steatosis is unlikely to lead to liver related complications NASH may lead to increased fibrosis and cirrhosis, and its complications

6. Introduction MAFLD — frequently associated with raised liver function test The difficulty lies in trying to decide whether raised liver functions tests (LFTs) due to Simple steatosis NASH without fibrosis NASH with severe fibrosis or cirrhosis, or Another cause of hepatitis altogether.

7. Epidemiology

8. Prevalence of NAFLD in general population in Asia pacific region Name of the country Japan China Korea India Indonesia Malasiya Singapore Percentage of NAFLD in adult 9- 30% 5- 18% 18% 5- 28% 30% 17% 5%

9. NAFLD disease burden in Asia The prevalence increases in men throughout life (pink bars), but in women (green bars) the prevalence does not increase until the fifth decade, after which it rises steeply

10. Disease burden – NAFLD in India Epidemiological studies – Prevalence of NAFLD in around 9% to 32% of general population in India with higher prevalence in those with overweight or obesity and those with diabetes or prediabetes Clinicopathological studies NAFLD is an important cause of unexpected rise in hepatic transaminases, cryptogenic cirrhosis, and cryptogenic HCC in Indian patients Indian J Gastroenterol (2010) 29:217–225, Tropical gastroenterology. 2005;26:1-3.

11. NAFLD in rural India Prevalence of NAFLD rural sector from Maharashtra (India): 28.1% Trop gastroenterol 2015 jan-mar;36(1) 25-30

12. NAFLD: Magnitude of the problem Insulin resistance Central obesity Dyslipidaemia Hypertension

13. Characteristics of patients with NAFLD NIDDM: non insulin dependant diabetes mellitus

14. Definition and diagnosis of MAFLD NAFLD – Diagnosis of exclusion rather than one of inclusion Highly heterogeneous Negatively influence in clinical decision making

15. APASL approved a more appropriate nomenclature for the disease "Metabolic associated fatty liver disease" or MAFLD

16. Diagnosis The diagnosis of MAFLD is based on – The detection of liver steatosis (liver histology, non-invasive biomarkers or imaging) together with the presence of at least one of three criteria – Overweight (BMI: 23.044.g kg/m 2 ) or obesity (BMI >25.0 kg/m 2 ) according Asian criteria - Type 2 diabetes mellitus (T2DM) or Presence of two or more features of metabolic syndrome ( MSy )

17. Metabolic syndrome ( MSy ) Waist circumference 102/88 cm in Caucasian men and women (or ≥90/80 cm in Asian men and women) Blood pressure ≥ 130/85 mmHg or on specific drug treatment Plasma triglyceride ≥ 150 mg/dl or specific drug treatment Plasma HDL-cholesterol < 40 mg/d for men or < 50 mg/dl for women or specific drug treatment Prediabetes (i.e., fasting glucose level 100 to 125 mg/dl or 5.6 to 6.9 mmol /L or 2 hour post-load glucose levels 140-199 mg/dl or 7.8 to 11.0 mmol /L or HbA1C 5.7% to 6.4%

18. Natural history of MAFLD

19. Natural history of MAFLD Simple steatosis appears to be a relatively benign condition Cardiovascular disease (CVD) followed by liver failure and cancer are the main causes of death in MAFLD When MAFLD occurs in the presence of other features of the metabolic syndrome ( MSy ) mortality risen The risk of developing cirrhosis is higher in the presence of NASH

20. Natural history of MAFLD NASH is more likely in the presence of the following features Type 2 diabetes mellitus (T2DM) Obesity (BMI'30 kg/m2) Serum aminotransferases (ALT or AST) rnore than two times the upper limit of normal Age more than 50 years NASH cirrhosis probably accounts for the vast majority of what was previously described as 'cryptogenic cirrhosis' Hepatocellular carcinoma has also been reported in NASH without cirrhosis, particularly in association with the metabolic syndrome

21. Risk factors for MAFLD Major risk factor- Overweight/obesity Type 2 diabetes mellitus Dyslipidemia Hypertension Dietary factors: high-calorie diets rich in saturated fats and cholesterol, soft drinks high in fructose, highly processed foods Sedentary lifestyle or sedentary occupation, low level of physical activity

22. Risk factors for MAFLD Recommendations Population who are at risk of developing MAFLD such as patients with overweight or obesity, T2DM and metabolic syndrome should be screened by ultrasonography (primary diagnostic tool) Patients with MAFLD should be assessed for metabolic syndrome and be treated accordingly

23. MAFLD and other liver disease MAFLD - No longer a diagnosis of exclusion Based on the presence of metabolic dysfunction MAFLD — May coexist with other liver diseases such as Alcoholic liver disease (ALD) Chronic hepatitis B virus infection (CHS) Chronic hepatitis C virus infection (CHC) — genotype 3, primary biliary cholangitis primary hemochromatosis Less frequent alternative causes of fatty liver should be diagnosed, e.g ., long-term use of steatogenic medications or Wilson disease.

24. MAFLD and other liver disease Recommendations MAFLD frequently does coexist with other liver diseases Treatment of MAFLD and other concomitant liver diseases should be given as per the recommendations for each of the diseases

25. Evaluation of MAFLD High risk population for MAFLD such as obese, T2DM and MSy should be assessed by ultrasonography of HBS (primary diagnostic tool) Patients with MAFLD should be evaluated by ALT AST AST/ALT ratio and Platelet count If the baseline investigations are normal, it should be repeated at intervals of 6 months to 1 year

26. Evaluation of MAFLD Risk of advanced fibrosis assessment can be done by non-invasive tests (NITS). Available NITS of fibrosis in Bangladesh are simple fibrosis scores and transient elastography (TE). Simple fibrosis scores – Aspartate aminotransferase (AST)-to-platelet ratio index (APRI) Fibrosis-4 index (FIB-4) NAFLD fibrosis score (NFS)

27. Evaluation of MAFLD Risk of advanced fibrosis assessment can be done by non-invasive tests (NITs) Available NITs of fibrosis are simple fibrosis scores and transient elastography (TE) Simple fibrosis scores: Aspartate aminotransferase (AST)-to-platelet ratio index (APRI) Fibrosis-4 index (FIB-4) NAFLD fibrosis score (NFS)

28. Management of MAFLD The cornerstone of managing MAFLD: Lifestyle modification Achieving weight control Dietary change structured exercise Reduction in cardiovascular risk factors Smoking Diabetes Hypertension Dyslipidaemia

29. Management of MAFLD Lifestyle changes Gradual Weight loss — (up to 1 kg/week) Reductions in liver fat content Resolution of steatohepatitis Resolution of fibrosis Improve a patients ' quality of life

30. Management of MAFLD Lifestyle changes Gradual weight loss — (up to 1 kg/week) >5% weight loss — Improvement in liver histology ( steatohepatitis ) in 58% >10% weight loss — Improvement of liver histology ( steatohepatitis ) in 90% Improvement in fibrosis stage in 45%

31. Management of MAFLD Lifestyle changes Diet — a hypocaloric diet (500—1000 kcal deficit) No particular dietary approach Low carb, low fat diet Mediterranean type diet may be advised

32. Management of MAFLD

33. Management of MAFLD Lifestyle changes Exercise General adult population, physical activity guidelines recommend- Moderate-intensity exercise for 30 min/day of 5 days/week or Vigorous-intensity exercise for 20 min/day on 3 days/week Resistance exercise on 2—3 days/week Flexibility exercises 2 days/week are also recommended

34. Management of MAFLD Follow up MAFLD patients at GP level Target — Normalization of liver function tests Weight loss Monitor — every 6 months Blood pressure Full blood examination (FBE), LFTs Lipid profile

35. Management of MAFLD When to refer for specialist management Referral for specialist management should be undertaken whenever there is a suspicion of severe disease, whether at initial assessment or at any tirne during monitoring.

36. Current pharmacological developments

37. Obeticholic acid Semi-synthetic bile acid analogue: 6 α- ethyl- chenodeoxycholic acid. Selective FXR agonist UDCA do no any action on FXR Key milestones in the development of obeticholic acid OCA Obeticholic acid

38. OCA: Mechanism of action OCA is 100 times more potent than as compare to natural ligand CDCA ↓ bile acid synthesis ↓ uptake and ↑ excretion of BAs’ in hepatocytes Mediates anti-inflammatory and anti-fibrotic pathways Leads to improvement in cholestasis and subsequent reduction in cellular injury Pharmaceuticals 2018, 11, 104; doi:10.3390/ph11040104

39. ↑ Cholesterol ↓ Bile acids CYP7a1 ↓ Fibrosis ↓ Hepatic triglycerides ↑ Glucose tolerance Multiple mechanisms via ↓ SREPB-1C RXR FXR via ↑ β -oxidation  Inflammation ↓ stellate cell activation via ↑ iNOS ↓ Portal pressure FXR agonist (eg, obeticholic acid) Pharmaceuticals 2018, 11, 104; doi:10.3390/ph11040104 FXR Central to a Multitude of Key Pathways in Animal Models FXR Central to a Multitude of Key Pathways responsible for bile improvement in NASH related fibrosis FGF-19 FGF-19

40. Recent updates from EASL 2020 Conclusion : Treatment with OCA resulted in dose-dependent improvements in MRI)-derived iron-corrected T1 (cT1) mapping and liver fat content measured noninvasively by multiparametric MRI , that may be consistent with histologic improvements in steatohepatitis and fibrosis, as well as in serum based noninvasive markers of steatohepatitis and fibrosis. Conclusion: OCA treatment resulted in early and sustained improvements in experimental non-invasive assessments of fibrosis NASH, consistent with previously reported histologic improvements. Specifically, improvements in FM and FM VCTE are consistent with OCA’s anti-fibrotic effect, while improvements in FAST are consistent with amelioration of key histologic features of NASH, including both inflammation and fibrosis.

41. Recent updates from EASL 2020 Conclusion: OCA treatment elicited durable improvements in transaminases, other non-invasive serum markers of fibrosis, and liver stiffness by VCTE at month 24, suggesting continued improvement beyond the categorical histologic benefit seen at 18 months. Conclusion: Quality of life measured by IWQOL was impaired at baseline and improved in dose-dependent manner across treatment groups. To what extent these results are attributable to weight loss and to dose-dependent beneficial effects of OCA on fibrosis and NASH will be examined at the end of the study. The REGENERATE study remains ongoing and will continue through clinical outcomes for verification and description of clinical benefit

42. Mukul R Jain et al., Pharmacology Research & Perspectives 2015 | Vol. 3 | Iss. 3 | e00136 Saroglitazar Saroglitazar is a novel, non-thiazolidinedione (TZD) and non- fibric acid class chemical entity. It has been designed to act as dual regulator of lipid and glucose homeostasis by activating PPARα and PPAR γ . Recently got approved for treatment non-cirrhotic NASH

43. Elafibranor RESOLVE-IT: Our Pivotal Phase 3 Clinical-Trial in NASH: Elafibranor VS placebo in 1,070 adults with NASH with stage 2 or stage 3 scarring (fibrosis) https://www.fiercebiotech.com/biotech/genfit-s-elafibranor-en-route-to-nash-graveyard-phase-3-flop assessed on 16th September 2020

44. Ursodeoxycholic acid in non-alcoholic steatohepatitis : systematic review 12 RCTs N 1160 UDCA therapy is effective in NASH, especially when combined with other drugs. However, the low quality of these studies and the heterogeneity of their results precluded further meta-analysis Xiang 2013 BMC Gastroenterol Treatment with HD-UDCA was safe, improved aminotransferase levels, serum fibrosis markers, and selected metabolic parameters. Ratziu 2011 J Hepatol

45. 250 non cirrhotic and non diabetic NAFLD patients were randomised Vitamin E 400 mg twice a day (Group A, n = 100) UDCA 300 mg twice a day (Group B, n = 100) Duration = 52 weeks The primary endpoint Normalization of ALT Secondary endpoints The proportion of patients with reduction in ALT Relative reduction in the NAFLD Fibrosis score Symptomatic improvement and tolerability

46. Results Group A (vitamin E) Group B (UDCA) Primary endpoint 14% 19% Reduction in ALT 56% 63% Symptomatic improvement 78% 67% Reduction in the NFS 44% 47% Tolerability 98% 95%

47. CONCLUSION UDCA is as effective as vitamin E in Indian patients when combined with adequate dietary guidance and lifestyle modification. UDCA can be utilized as an alternative to Vitamin E in the treatment of NASH as it has minimal side effects and equal tolerability.

48. AASLD Recommendations on Bariatric Surgery Foregut bariatric surgery is not contraindicated in otherwise eligible obese individuals with NAFLD or NASH (but without established cirrhosis). (1A) The type, safety and efficacy of foregut bariatric surgery in otherwise eligible obese individuals with established cirrhosis due to NAFLD are not established. (1B)

49. Bariatric surgery 2010

50. Drug Mechanism of Action Study Population Trial Primary Endpoint(s) Cenicriviroc Inhibitor of CCR2/CCR5 NASH with liver fibrosis CENTAUR* [1,2] Improvement in NAS w/o fibrosis worsening Simtuzumab Monoclonal antibody to LOXL2 [3] Liver fibrosis secondary to NASH NCT01672866* [4] Morphometric quantitative collagen change; EFS Aramchol Fatty acid–bile acid conjugate [5] NASH Aramchol_005* [6] Change in liver triglycerides by NMRS Liraglutide GLP-1 analogue Overweight NASH LEAN [7,8] Resolution of NASH w/o fibrosis worsening GR-MD-02 Galectin-3 inhibitor [9] Liver fibrosis and portal hypertension in NASH cirrhosis NASH-CX [10] Improvement in HVPG Emricasan Caspase inhibitor NASH with liver fibrosis ENCORE-NF [11] Improvement in fibrosis w/o NASH worsening 1. Konerman MA, et al. J Hepatol ;[In press]; 2. ClinicalTrials.gov. NCT02855164;. 3. ClinicalTrials.gov. NCT02913105; 4. ClinicalTrials.gov. NCT02854605; 5. ClinicalTrials.gov. NCT02781584. 6. ClinicalTrials.gov. NCT02856555; 7. ClinicalTrials.gov. NCT03248882. Emerging Treatments in NASH

51. Drug(s) Mechanism(s) of Action Study Population Trial Primary Endpoint(s) Selonsertib ASK1 inhibitor NASH with F2-F3 liver fibrosis GS-US-384-1497 [1,2] Safety and tolerability JKB-121 TLR-4 antagonist NASH Pro00062677 [3] Safety and tolerability; change in ALT, hepatic fat; TTP NGM-282 FGF-19 agonist [4] NASH 15-0105 [5] Change in hepatic fat BMS-986036 FGF-21 agonist NASH MB130-045 [6] Safety and tolerability; change in hepatic fat GS-0976 ACC inhibitor NASH GS-US-426-3989 [7] Safety and tolerability GS-9674, GS-0976 FXR agonist (bile acid) ACC inhibitor NAFLD GS-US-384-3914 [8] Safety and tolerability Volixibat ASBT inhibitor NASH NCT02787304 [9] Improvement in NAS w/o fibrosis worsening 1. Konerman MA, et al. J Hepatol ;[In press]; 2. ClinicalTrials.gov. NCT03061721; 3.ClinicalTrials.gov. NCT03008070; 4. ClinicalTrials.gov. NCT01237119; 5. Armstrong MJ, et al. Lancet. 2016;387:679-690. 6. ClinicalTrials.gov. NCT02970942; 7. ClinicalTrials.gov. NCT02442687; 8. ClinicalTrials.gov. NCT02443116; 9. ClinicalTrials.gov. NCT02413372. NCT02912260; 11. ClinicalTrials.gov. NCT02787304. Emerging Treatments in NASH

52. Title: Risk Factors Assessment and Incidence of Metabolic Syndrome in a Tertiary Care Hospital in Odisha . Authors – Gopal Krishna Mishra, Dr. Sanghamitra Dash, Dr. Harischandra Mishra Affiliation – Life Institute Of Gastroenterology and Gynecology, Nayabazar, Cuttack – 753004 isha . VELLORE ENDOCRINOLOGY INTERNATIONAL CONGRESS 2025 [JAN 10-11, 2025] Metabolic Syndrome (MetS) is a clustering of specific risk factors, namely:- Central obesity - Raised blood pressure - Impaired fasting glucose - Raised triglycerides Low levels of high-density lipoprotein-cholesterol (HDL-C). MetS increasing cardiovascular risk, is also associated with diabetes, chronic kidney disease and many more. Background The National Cholesterol Education Program (NCEP) Adult Treatment Panel III The (ATP III) guidelines also define metabolic syndrome as the presence of three or more of the following risk factors:  Waist circumference greater than >102 cm for men or >88 cm for women Elevated triglycerides (greater than or equal to 150 mg/dl) Low HDL cholesterol (less than 40 mg/dl for men or less than 50 mg/dl for women) Hypertension (greater than or equal to 130/85 mmHg) Impaired fasting glucose (greater than or equal to 100 mg/dl)

53. This study aims to determine the prevalence of metabolic syndrome in individuals with varying waist circumferences (WC) and investigate its associations with age, sex, body mass index (BMI), body surface area (BSA), total cholesterol (TC), low density lipoprotein (LDL), very low-density lipoprotein (VLDL), glycated hemoglobin (HbA1c), homeostatic model assessment for Insulin resistance (HOMA-IR), and C-reactive protein (CRP). Aims and Objectives This cross-sectional study included 68 participants attending a comprehensive health checkup clinic at a tertiary care hospital in Cuttack, Odisha, India. Anthropometric measurements (waist circumference, weight, and height), blood pressure, blood sugar levels, and fasting lipid profiles were collected. The NCEP ATP III criteria were used to diagnose metabolic syndrome. Materials and Methods

54. Parameters Metabolic Syndrome (N=68) P- value Present (N=35) Absent (N=33) Sex Male 13 14 0.6 Female 22 19 Age (years) <50 29 29 0.5 >50 6 4 BMI <25 11 27 0.001* 25-29.5 17 2 >30 7 4 WC High 34 9 0.001* Normal 1 24 BSA <1.7 19 22 0.3 >1.7 16 11 Table: Clinical and Biochemical Characteristics of Patients with and without Metabolic Syndrome

55. Parameters Metabolic Syndrome (N=68) P- value Present (N=35) Absent (N=33) TG (mg/Dl) >=150 31 27 0.4 <150 4 6 TC (mg/Dl) <200 20 19 0.9 >200 15 14 HDL (mg/Dl) <40 10 0.001* >40 25 33 LDL (mg/ dL ) <100 16 14 0.7 >100 19 19 VLDL (mg/ dL ) <30 4 13 0.008* >30 31 20 FBS (mg/ dL ) <100 8 0.002* >100 35 25 HBA1C (%) <5.7 21 24 0.2 >5.7 14 9 HOMA IR ≥1.9 35 17 0.001* <1.9 16 CRP (mg/ dL ) <10 32 30 0.9 >10 3 3 Hypertension >Stage 1 12 1 0.0008* < Stage 1 23 34

56. The prevalence of metabolic syndrome among the total cases was 51.4%. Females exhibited a higher prevalence (62%) compared to males (37.1%), with the highest prevalence observed in the age group below 50 years. BMI >25, high waist circumference, decreased HDL (<40 (mg/ dL ), elevated VLDL, fasting blood sugar exceeding 100 mg/ dL , HOMA-IR values of 1.9 or higher, and hypertension exceeding stage I were significantly associated with metabolic syndrome (p-value < 0.05). These parameters were significantly more prevalent in females compared to males. Results “ Life Simple 7” defined by the American Heart Association as 7 risk factors that people can improve through lifestyle changes to help achieve ideal cardiovascular health and greatly improve the individual conditions that make up metabolic syndrome . . 1. Manage Blood Pressure 2. Control Cholesterol 3. Reduce Blood Sugar 4. Get Active 5. Eat Better 6. Lose Weight 7. Stop Smoking Message

57. The observed prevalence of metabolic syndrome in this hospital-based study population may represent a higher-than-average occurrence due to the inherent selection bias of a hospital setting. This highlights the need for larger, population-based studies to accurately estimate the true prevalence of metabolic syndrome in the general population. Furthermore, aggressive lifestyle modification interventions are crucial for preventing the metabolic complications associated with this syndrome. Conclusions