Target Therapies for NASH/NAFLD: From the Molecular Aspect to the Pharmacological and Surgical Alternatives

Finotti, Michele; Romano, Maurizio; Auricchio, Pasquale; Scopelliti, Michele; Brizzolari, Marco; Grossi, Ugo; Piccino, Marco; Benvenuti, Stefano; Morana, Giovanni; Cillo, U.; Zanus, Giacomo

doi:10.3390/jpm11060499

Cited by 9 publications

(6 citation statements)

References 152 publications

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“…Unfortunately, there are very limited treatment options for NAFLD therapy [19]. The recommended first-line treatment includes dietary and lifestyle modification.…”

Section: Therapeutic Drug Candidates For the Treatment Of Nafldmentioning

confidence: 99%

Pharmaceutical Strategies to Make Better Drugs for Nonalcoholic Fatty Liver Disease Therapy

Amatya¹,

Lee²,

Min³

et al. 2023

Preprint

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Nonalcoholic fatty liver disease (NAFLD) has become globally prevalent and is the leading cause of chronic liver disease. Although NAFLD is reversible in the early stage without medical intervention, the condition could be sequentially worsened to nonalcoholic steatohepatitis (NASH) and, in the end, cirrhosis and hepatic cancer. The progression of NAFLD is related to various factors such as genetics, pre-disposed metabolic disorders, and immunologic factors. Because of the complexity of the disease, the treatment options are very limited, and, unfortunately, there is yet no clinically available drug. Thankfully, to date, there have been accumulating research efforts and, as a result, different classes of potent drug candidates have been discovered. Besides, there have also been various attempts to explore pharmaceutical strategies to make the drug candidates to be better drugs. In this review, we provided a brief overview of the drug candidates that have undergone clinical trials. In the latter part, the strategies for developing better drugs are discussed.

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“…Unfortunately, there are very limited treatment options for NAFLD therapy [19]. The recommended first-line treatment includes dietary and lifestyle modification.…”

Section: Therapeutic Drug Candidates For the Treatment Of Nafldmentioning

confidence: 99%

Pharmaceutical Strategies to Make Better Drugs for Nonalcoholic Fatty Liver Disease Therapy

Amatya¹,

Lee²,

Min³

et al. 2023

Preprint

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“…Although there is an increasing need for effective treatments for NAFLD and NASH, until very recently, no specific on-label treatment had been approved or recommended ( 60 ). Furthermore, treating patients with both type 2 diabetes and NAFLD or NASH is complex and challenging because of the various comorbidities that frequently exist in these patients ( 61 ), and data from clinical trials of antidiabetic treatment typically lack high-quality and clinically relevant endpoints related to liver histology. Of note, saroglitazar, a dual PPARα/γ agonist, was approved in India in March 2020 for the treatment of NASH.…”

Section: Disease Managementmentioning

confidence: 99%

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Concurrent Type 2 Diabetes Mellitus and Non-Alcoholic Steatohepatitis: A Review of the Evidence

Yabiku

2021

Front. Endocrinol.

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Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and more than half of individuals diagnosed with type 2 diabetes concurrently present with NAFLD. There is a bidirectional pathological relationship between the two conditions, whereby NAFLD increases the risk of type 2 diabetes, and type 2 diabetes contributes to and accelerates the progression of NAFLD. Furthermore, over 30% of patients with NAFLD progress to non-alcoholic liver steatohepatitis (NASH), which then increases the risk of cirrhosis and hepatocellular carcinoma. Despite its high prevalence and the potential clinical implications, the underlying pathogenesis of NAFLD has yet to be fully elucidated, and there is no consensus regarding standard diagnosis and treatment for either NALFD or NASH. As patients with both NASH and type 2 diabetes have impaired hepatic function owing to chronic inflammation and the resulting structural changes caused by hepatic fat accumulation, they face reduced options for antidiabetic treatment. SGLT-2 inhibitors inhibit glucose reabsorption in the proximal tubule, with increased excretion of glucose in urine and decreased glucose levels in plasma, and their glycemia-lowering effect is insulin-independent. Several other beneficial effects have been reported for SGLT-2 inhibitors, including reduced risks of cardiovascular and renal diseases, improved blood pressure control, body weight reduction, and reductions in liver fat content. Experimental studies in mouse models have suggested that SGLT-2 inhibitors may have beneficial modulatory effects on NAFLD/NASH. Several trials in patients with type 2 diabetes have also suggested that these drugs may be useful in treating both type 2 diabetes and NAFLD or NASH. However, further research is needed to identify the mechanisms by which SGLT-2 inhibitors affect fatty liver and steatohepatitis. In this state-of-the-art review, we explore the literature on the efficacy of SGLT-2 inhibitors in patients with type 2 diabetes and NASH, and present arguments for and against the use of SGLT-2 inhibitors in this patient population.

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“…20 Although preclinical data with steroidal MRAs and a small clinical study with spironolactone have suggested potential benefits in patients with NAFLD, 21 further studies are needed for conclusive evidence in humans. 22 Data available within the current literature regarding the relationship between non-steroidal MRAs, CKD and liver abnormalities are limited. However, a recent phase II clinical trial investigating the effect of apararenone in patients with non-alcoholic steatohepatitis found reductions in serum alanine transaminase (ALT) and fibrosis markers, and improvements in liver fibrosis score, compared with placebo.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, eplerenone therapy has been associated with a low rate of serum aminotransferase elevations, markers of liver injury that are typically mild and transient 20 . Although preclinical data with steroidal MRAs and a small clinical study with spironolactone have suggested potential benefits in patients with NAFLD, 21 further studies are needed for conclusive evidence in humans 22 . Data available within the current literature regarding the relationship between non‐steroidal MRAs, CKD and liver abnormalities are limited.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of finerenone in patients with type 2 diabetes, chronic kidney disease and altered markers of liver steatosis and fibrosis: A FIDELITY subgroup analysis

Perakakis,

Bornstein,

Birkenfeld

et al. 2023

Diabetes Obesity Metabolism

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AimInvestigating the effect of finerenone on liver function, cardiovascular and kidney composite outcomes in patients with chronic kidney disease and type 2 diabetes, stratified by their risk of liver steatosis, inflammation and fibrosis.Materials and MethodsPost hoc analysis stratified patients (N = 13 026) by liver fibrosis and enzymes: high risk of steatosis (hepatic steatosis index >36); elevated transaminases [alanine transaminase (ALT) >33 (males) and >25 IU/L (females)]; and fibrosis‐4 (FIB‐4) index scores >3.25, >2.67 and >1.30. Liver enzymes were assessed by changes in ALT, aspartate aminotransferase and gamma‐glutamyl transferase. Composite kidney outcome was defined as onset of kidney failure, sustained estimated glomerular filtration rate decline ≥57% from baseline over ≥4 weeks or kidney death. Composite cardiovascular outcome was defined as cardiovascular death, non‐fatal myocardial infarction, non‐fatal stroke or hospitalization for heart failure.ResultsALT, aspartate aminotransferase and gamma‐glutamyl transferase levels were consistent between treatment groups and remained stable throughout. Finerenone consistently reduced the risk of composite kidney outcome, irrespective of altered liver tests. Higher FIB‐4 score was associated with higher incidence rates of composite cardiovascular outcome. Finerenone reduced the risk of composite cardiovascular outcome versus placebo in FIB‐4 subgroups by 52% (>3.25), 39% (>2.67) and 24% (>1.30) (p values for interaction = .01, .13 and .03, respectively).ConclusionsFinerenone has neutral effects on liver parameters in patients with chronic kidney disease and type 2 diabetes. Finerenone showed robust and consistent kidney benefits in patients with altered liver tests, and profound cardiovascular benefits even in patients with higher FIB‐4 scores who were at high risk of developing cardiovascular complications.

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Target Therapies for NASH/NAFLD: From the Molecular Aspect to the Pharmacological and Surgical Alternatives

Cited by 9 publications

References 152 publications

Pharmaceutical Strategies to Make Better Drugs for Nonalcoholic Fatty Liver Disease Therapy

Pharmaceutical Strategies to Make Better Drugs for Nonalcoholic Fatty Liver Disease Therapy

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Concurrent Type 2 Diabetes Mellitus and Non-Alcoholic Steatohepatitis: A Review of the Evidence

Efficacy of finerenone in patients with type 2 diabetes, chronic kidney disease and altered markers of liver steatosis and fibrosis: A FIDELITY subgroup analysis

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