Non-alcoholic Steatohepatitis
Conditions
Keywords
Dapagliflozin, SGLT2 inhibitors, NASH, Efficacy, Safety, Liver biopsy, Pioglitazone, Fatty Liver, NAFLD activity score
Brief summary
Patients with non-alcoholic fatty liver disease (NAFLD) are at increased risk of more aggressive liver disease; non-alcoholic steatohepatitis (NASH) and at a higher risk of death from cirrhosis, hepatocellular carcinoma and cardiovascular diseases. NAFLD is spreading as an epidemic in patients with metabolic syndrome. Its components include obesity, type 2 diabetes mellitus (T2DM) and dyslipidemia. The prevalence of NAFLD is likely to increase resulting in tremendous clinical, social and economic burdens. Unfortunately, there is no approved medication to treat patients with NASH-induced advanced fibrosis. Weight management is the first line of NASH treatment even in non-obese patients with at least 7% reduction of patient's weight. However, NASH patients need pharmacological treatment. Sodium glucose co-transporter (SGLT2) inhibitors demonstrated favorable effects on NAFLD without weight gain as an adverse event proposed by pioglitazone used for the same indication. SGLT2 inhibitors are able to reduce fatty liver content, as assessed by different imaging techniques, and improve biological markers of NAFLD, especially serum liver enzymes, in patients with or without T2DM. In addition, there are emerging data to suggest a mechanism beyond the reduction of body weight and hyperglycemia in patients with or without diabetes. This study aims to evaluate the efficacy and safety of SGLT2 inhibitors in NASH patients in comparison to pioglitazone. This is a randomized prospective parallel study, where all patients presented with NASH to the outpatient clinic in the National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt; will be screened for specific inclusion and exclusion criteria. Diabetic and non-diabetic patients will be randomly assigned to receive one of two treatment modalities. The first arm will be the NASH patients receiving dapagliflozin and the second arm will be the NASH patients receiving pioglitazone for 24 weeks. Each group will have an equal number of diabetic and non-diabetic patients. All patients will be assessed for body composition, serum creatinine level, fasting blood glucose level, HbA1C, markers of insulin resistance (HOMA-IR), complete blood count, serum liver function tests, and NAFLD fibrosis score (NAS). Liver biopsy will be performed at baseline and at the end of the study and the total NAS score will be calculated. All patients will be assessed for any adverse drug reactions, and for their adherence by pill count method. Also, quality of life will be assessed for all patients using previously designed and validated questionnaire called Chronic Liver Disease Questionnaire (CLDQ).
Interventions
DRUGDapagliflozin 10Mg Tab
Dapagliflozin 10 mg, administered orally and to be prescribed for diabetic and non-diabetic patients with NASH for 24 weeks; in comparison to pioglitazone.
Pioglitazone 30 mg, administered orally and to be prescribed for diabetic and non-diabetic patients with NASH for 24 weeks; as an active control and standard of care treatment.
Sponsors
Cairo University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age range 18-65 years. * Liver biopsy confirming NASH within 6 months. * For diabetic patients, the patients should be with stable glycemic control defined as HbA1C \<10%.
Exclusion criteria
* Active viral hepatitis (HBV, HCV). * Child Pugh B or C cirrhosis. * Alcohol consumption in the past six months. * A history of alcoholic liver disease. * Secondary causes of steatohepatitis. * Autoimmune hepatitis. * Celiac disease. * Hemochromatosis or Wilson's disease. * Drug induced liver injury (DILI) or patient with history of taking medication(s) that may cause fatty liver (e.g., tamoxifen, valproic acid, amiodarone, methotrexate, steroids, oral contraceptives). * Obstructive biliary disease. * Serum alanine aminotransferase (ALT) more than 2.5 folds of UNL. * History of serious hypersensitivity to dapagliflozin or pioglitazone or any component of the formulation. * Pregnancy and breastfeeding. * Renal impairment (eGFR \<45 mL/minute/1.73 m2), end-stage renal disease (ESRD), or patients on dialysis. * Having any medical condition that would affect metabolism (i.e., known hyperthyroidism or hypothyroidism). * Hypopituitarism. * Patients with Type 1 diabetes. * Starvation. * Serious medical disease with likely life expectancy less than 5 years. * Participation in other clinical trial in the 30 days before enrollment. * Patients who are unwilling or unable to give informed consent. * Patients on statins. * Heart failure defined as New York Heart Association (NYHA) class III or IV. * Recent initiation or change of antidiabetic drugs that influence liver fat including thiazolidinediones, glucagon like peptide 1 receptor agonists or any SGLT2 inhibitor.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Histological Features (Liver Biopsy) | Baseline and 24th week | Change from baseline of NAFLD Activity Score (NAS) and other histological features. NAS score will be assessed using the NASH Clinical Research Network (NASH CRN) scoring system. NAS score ranges from 0 to 8 and the higher score towards 8 means worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting blood glucose level | Baseline, 3rd, 6th, 12th, 18th and 24th week | Change in fasting blood glucose for patients with T2DM |
| Insulin resistance (HOMA-IR) | Baseline, 12th and 24th week | — |
| Quality of life Questionnaire (quality of life assessment) | Baseline and 24th week | Change in health-related quality of life scores using chronic liver disease questionnaire (CLDQ) |
| Drugs adverse events | Baseline, 3rd, 6th, 12th, 18th and 24th week | Assessment of safety by reporting any adverse events |
| NAFLD fibrosis score | Baseline and 24th week | Change in NAFLD fibrosis score (NFS). The score ranges from \< -1.45 (no significant fibrosis) to \> 0.67 (significant fibrosis). The higher score means worse outcome. |
| Fibrosis Index Based on 4 factors | Baseline and 24th week | Change in Fibrosis Index Based on 4 factors (FIB-4). The score ranges from \< 1.45 (minimal to no fibrosis) to \> 3.4 (advanced fibrosis). The higher score means worse outcome. |
| Fibro-controlled attenuated parameter (fibro CAP) | Baseline and 24th week | Improvement of fibro-controlled attenuated parameter (fibro CAP) |
| Serum Alanine Transaminase level (ALT) | Baseline, 12th and 24th week | Change in ALT serum level as inflammatory markers of NASH |
| Lipid profile | Baseline, 12th and 24th week | Change in serum lipids |
| Glycated hemoglobin (HbA1C) | Baseline, 12th and 24th week | Change in HbA1C level for patients with T2DM |
| Serum Aspartate Aminotransferase level (AST) | Baseline, 12th and 24th week | Change in AST serum level as inflammatory markers of NASH |
| Serum Alkaline Phosphatase level (ALP) | Baseline, 12th and 24th week | Change in ALP serum level as inflammatory markers of NASH |
| Serum Gamma-glutamyl Transferase level (GGT) | Baseline, 12th and 24th week | Change in GGT serum level as inflammatory markers of NASH |
| Serum total and direct bilirubin. | Baseline, 12th and 24th week | Change in levels of serum total and direct bilirubin. |
| Waist circumference | Baseline, 3rd, 6th, 12th, 18th and 24th week | Change in waist circumference |
| Body weight | Baseline, 3rd, 6th, 12th, 18th and 24th week | Change in body weight |
Other
| Measure | Time frame |
|---|---|
| Serum creatinine | Baseline, 3rd, 6th, 12th, 18th and 24th week |
| Estimated glomerular filtration rate (eGFR) | Baseline, 3rd, 6th, 12th, 18th and 24th week |
Countries
Egypt
Outcome results
None listed