A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

Abstract

There is a close link between steatohepatitis (NASH) and Type 2 diabetes (T2DM). Recently, the American Diabetes Association (ADA) recommended screening for NASH and advanced fibrosis in patients with diabetes and hepatic steatosis or elevated plasma alanine aminotransferase (ALT). This is because as many as ~30% to 40% may have NASH and ~10% to 15% advanced fibrosis. The role of hyperglycemia and the natural history of NASH in diabetes remain poorly understood, as well as which diagnostic algorithm or interventions are most cost‐effective. There is significant clinical inertia and most patients today are still not receiving adequate lifestyle intervention or pharmacological treatment with diabetes agents known to be effective against NASH. Lifestyle intervention improves steatohepatitis in proportion to the magnitude of weight loss, but this trend is not as consistent for regression of fibrosis. This limited success supports the need for concomitant pharmacological therapy. Pioglitazone has been shown to consistently induce resolution of NASH in both patients with or without diabetes in a total of 498 participants in five randomized controlled trials (RCTs), but with modest effects on liver fibrosis. Proof‐of‐concept studies suggest a potential role for GLP‐1RAs and SGLT2 inhibitors. Combination therapy is on the horizon. Treating diabetes and NASH with a combination of pioglitazone, GLP‐1RAs or SGLT2i, could be a cost‐effective strategy to treat both diseases while reducing their high cardiovascular risk. Future combination therapies will likely combine existing diabetes agents with novel NASH‐spechfic drugs under development. This review highlights current knowledge gaps and proposes future directions for the treatment of NASH in diabetes.

Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials

“…A recent Bayesian network meta-analysis of randomized controlled trials (RCTs) and non-randomized intervention studies of individuals with biopsy-proven NASH showed that pioglitazone and bariatric surgery are the two most effective treatment options for NASH, thereby supporting the notion that weight loss and improvement in hepatic insulin resistance are promising approaches for the treatment of this metabolic liver disease [19]. However, although it has been demonstrated that long-term use of pioglitazone in adults with biopsy-proven NASH has beneficial effects on the histological resolution of NASH, this drug may have some side-effects, such as moderate weight gain, peripheral oedema and risk of distal bone fractures (especially in postmenopausal women) [12,20,21].…”

Non-alcoholic fatty liver disease

“…107 In addition, multimorbidity and polypharmacy are common in patients with type 2 diabetes and NAFLD, highlighting a need for multidisciplinary management to address their complex health-care needs. 108 In secondary care diabetes clinics, the prevalence of advanced fibrosis among patients with NAFLD is 10-20%, [109][110][111][112] which is two to four times higher than in primary care. There is increasing recognition that an assessment of NAFLD and liver fibrosis needs to be incorporated into the routine care of patients with type 2 diabetes.…”

“…There is increasing recognition that an assessment of NAFLD and liver fibrosis needs to be incorporated into the routine care of patients with type 2 diabetes. 109 As a result, the American Diabetes Association now recommends that "Patients with type 2 diabetes and elevated liver enzymes (alanine aminotransferase) or fatty liver on ultrasound should be evaluated for the presence of non-alcoholic steatohepatitis and liver fibrosis." 113 However, alanine aminotransferase mea surements are notoriously inaccurate and are within the normal range in most people with type 2 diabetes and NAFLD; thus with this strategy, many patients with clinically significant liver disease will not be diagnosed.…”

Hígado graso no alcohólico: certezas e incertidumbres de una epidemia silenciosa

“…En síntesis, los resultados obtenidos con medicacio-nes aprobadas para el uso en pacientes con DM2 abre la interesante posibilidad del tratamiento con "múltiple propósito", en donde se controle con un agente la glucemia y el perfil cardiometabólico, mientras se trata la EHNA. 123,124 Se necesitan estudios a largo plazo para evaluar el impacto en la historia natural y la mortalidad hepática y extrahepática en esta población. Por último, es importante recordar que las guías de la AASLD 4 apoyan el uso de las estatinas en pacientes con EHNA, dado su alto riesgo cardiovascular, aún con transaminasas moderadamente elevadas, pero esto requiere un monitoreo clínico adecuado.…”