"Although our systematic review...supports the efficacy of PPAR agonists or GLP-1R agonists in improving histological features of non-alcoholic steatohepatitis (NASH), as well as the efficacy of SGLT2 inhibitors in reducing hepatic fat content, we believe that larger phase 3 trials with liver histological endpoints (some of which are ongoing) are needed to consider changes in current guidelines," Dr. Alessandro Mantovani of the University Hospital of Verona told Reuters Health by email.
"Given the multiple pathways implicated in NAFLD pathogenesis, as well as the different mechanisms of actions of each of these three classes of drugs, it would be interesting to study combination therapy - for instance, GLP-1R agonists plus SGLT2 inhibitors," he said. "In addition, given the heterogeneity of NAFLD patients, it is also fundamental to find new strategies for identifying appropriate individuals for a specific combination."
As reported in The Lancet Gastroenterology and Hepatology, Dr. Mantovani and colleagues did a systematic review of randomized controlled trials looking at the efficacy of peroxisome proliferator-activated receptor (PPAR) agonists, glucagon-like peptide-1 receptor (GLP-1R) agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors for treating NAFLD in adults with or without type 2 diabetes.
Twenty-five active- or placebo-controlled trials involving 2,597 individuals (mean age, 52; 53%, men; 62%, type 2 diabetes; mean BMI, 32 kg/m2) were included: eight for PPAR agonists, 10 for GLP-1R agonists, and seven for SGLT2 inhibitors.
Pioglitazone, lanifibranor, and GLP1-R agonists (mostly liraglutide and semaglutide) improved individual histological features of non-alcoholic steatohepatitis (NASH) - i.e., steatosis, ballooning, lobular inflammation - or resolved NASH without worsening fibrosis.
SGLT2 inhibitors (mostly empagliflozin and dapagliflozin) reduced liver fat content.
The authors note, "If these promising results are confirmed in larger phase 3 trials with liver histological endpoints, it is reasonable to suggest that PPAR agonists, GLP-1R agonists, and SGLT2 inhibitors will become important treatment options for individuals with NAFLD or NASH."
Dr. Navinder Jassil, Director of Endocrinology and Diabetes Services at Deborah Heart and Lung Center in Brown Mills, New Jersey, commented in an email to Reuters Health, "We endocrinologists see NAFLD on a daily basis. Our treatment includes reducing weight and making lifestyle changes in hope that this may improve the disease. (We use) PPAR agonists to treat diabetes, but also NAFLD. It's exciting to have this study available, since there are not many pharmacologic options to treat NAFLD."
Nonetheless, he added, "The study had strict inclusion criteria that required trials to have biopsy proven NAFLD or MRI showing disease. Several studies were excluded that may have had patients with NAFLD but were diagnosed by other means. Also, the trials evaluated were smaller scale with short follow-up periods. Although the data are promising, larger scale studies with longer term follow-up perhaps that show improvement in mortality are needed."
Meanwhile, he concluded, "We should continue to use PPAR agonists in NAFLD and consider use of GLP-1R agonists and SGLT2 inhibitors as potential future therapies."
SOURCE: https://bit.ly/3IDjuEr The Lancet Gastroenterology and Hepatology, online January 11, 2022.
By Marilynn Larkin
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