Effect on Non-Alcoholic Fatty Liver Disease With Advanced Fibrosis in Patients With Type 2 Diabetes Mellitus on Treatment With Gastric Inhibitory Polypeptide / Glucagon Like Peptide-1 Analogue (Tirzpatide)

Background:

Over the past few decades Non-Alcoholic Fatty liver disease (NAFLD) related non-alcoholic steatohepatitis (NASH) cirrhosis has overtaken all other causes of liver cirrhosis in the developed world, secondary to the rising epidemic of obesity and type 2 Diabetes mellitus. The prevalence of NAFL is estimated at 30% in developed work and nearly one fifth of them NFALD will progress to NASH, 20% of which will develop liver cirrhosis subsequently leading to liver failure and hepatocellular carcinoma (HCC). Annual medical costs directly attributed to NAFLD exceed €35 billion in top European countries (United Kingdom, France, Germany, and Italy) and over $100 billion in the United States, while cost of this in unknown in Middle East. Non-alcoholic fatty liver disease (NAFLD) is defined as fatty infiltration of the liver not related to alcohol excess or other usual causes of hepatic steatosis (e.g. viral or autoimmune hepatitis or secondary to medications) and includes a spectrum ranging from steatosis, steatohepatitis, and fibrosis to cirrhosis; it is now the most common cause of chronic liver disease worldwide. Although most patients with NAFLD may not progress to advanced fibrosis or cirrhosis, due to the high prevalence the number of patients develop cirrhosis is still high and is now a leading indication for liver transplantation in Europe. Global prevalence data for NAFLD suggest that the, Midlle East region has one of the highest prevalence rate of up to 32%.Type 2 diabetes mellitus (T2DM) is an important risk factor for non-alcoholic fatty liver disease (NAFLD) with recent metanalysis showing that the global prevalence of NAFLD among patients with T2DM to be around 55.5% with no specific available data for Emirati population with respects to NAFLD in T2DM patients. Obesity is another well-known risk factor and there is high prevalence of NAFLD in obese patients, with up to 65% of people with grade I-II obesity (BMI = 30-39.9 kg/m2) and in 85% of patients with grade III obesity (BMI = 40-59 kg/m2) having NAFLD.

United Arab Emirates (UAE) has one of the highest prevalence of type 2 Diabetes Mellitus in the world with 16.4% of adult population diagnosed with this condition as per International Diabetes federation. UAE also has the highest prevalence of obesity, doubled from 1989 to 2017, currently ranking among the top 40 countries in the world with estimated prevalence rate of 31.7%, using body mass index (BMI) cut-off of 30 kg/m2. This rate will be substantially higher if newer definition of ethnicity specific BMI cut off for obesity (i.e. > 25 kg/m2 being obese) is used, which is more relevant for Asian population. The presence of both these conditions means UAE is likely to have very high prevalence of NAFLD in patients having both diabetes and obesity.

The gold standard test for identifying NALFD and Non-alcoholic steatohepatitis (NASH) is a liver biopsy. However, liver biopsy is an invasive procedure and is associated with complications. A non-invasive method using Vibration-controlled transient elastography (VCTE) utilizing FibroScan provides a liver stiffness measurement (LSM) expressed in kilopascals (kPa) which correlate with fibrosis advanced stages like F3 (bridging fibrosis) with LSM of 9.9-13.9 KPa and F4 (advanced scarring or cirrhosis) quite well and has emerged as an alternative to invasive liver biopsy. Other non-invasive tools used to detect the presence of advanced fibrosis in NAFLD include clinical/biochemical scoring systems like NAFLD fibrosis score (NFS) and FIB-4 index, aspartate aminotransferase (AST) to platelet ratio index (APRI), Enhanced Liver Fibrosis panel, Hepascore; and imaging techniques like VCTE or magnetic resonance elastography(MRE). The NFS is based on six clinical/biochemical variables including age, presence of impaired fasting glucose or Diabetes, Body Mass Index (BMI), platelet count, albumin and AST/ALT (alanine aminotransferase) ratio. A recent large meta-analysis, showed that NFS had an area under the receiver operating curve (AUROC) of 0.85 for predicting advanced fibrosis stages like F3 (bridging fibrosis) and F4 (advanced scarring or cirrhosis) with a score of 0.676 or more having 67% sensitivity and 97% specificity to identify the presence of advanced fibrosis. A recent study that compared various risk scores and elastography (including MRE and VCTE) versus liver histology to identify NAFLD fibrosis showed that NFS were better than other indices such as BARD, APRI, and AST/ALT ratio; and found to be as good as MRE and and FIB-4 for predicting advanced fibrosis in patients with biopsy-proven NAFLD. Recent guidelines therefore recommend NFS as a clinically useful tool for identifying patients with NAFLD with a higher likelihood of having advanced fibrosis (F3 or F4).

Currently various treatments have been used for NALFD. The current guidelines from American Association for study of liver diseases suggests that Pioglitazone can improve histological appearance in patient with type 2 Diabetes Mellitus and NASH while Vitamin E may offer benefit in non-diabetic population, while GLP-1 Analgoues like liraglutide could be beneficial however there is not enough evidence for it to be used routinely for patients with NASH.