Aiming at the primary cause of death from non-alcoholic fatty liver, this type of therapy is becoming an emerging research direction.

▎Non-alcoholic fatty liver disease (NAFLD), editor of WuXi AppTec's content team, is becoming the most prevalent liver disease in the world.
It is estimated that a quarter of the world’s population may have NAFLD
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As the disease progresses, NAFLD will develop into non-alcoholic steatohepatitis (NASH)
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Among NASH patients with advanced liver fibrosis, about 22% will develop liver cirrhosis, and 2% of patients with liver cirrhosis will develop hepatocellular carcinoma within 3 years
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Although liver disease caused by NASH is the primary cause of liver transplantation, due to the close connection between NAFLD and type 2 diabetes, most patients with NASH die due to cardiovascular and metabolic diseases rather than liver-related causes
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A review published recently in Nature Reviews Endocrinology stated that therapies targeting type 2 diabetes and cardiovascular metabolic risk factors may become one of the most effective treatments for NAFLD
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The close link between NAFLD and type 2 diabetes has evidence that there is a two-way interaction between NAFLD or NASH and type 2 diabetes
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Type 2 diabetes and obesity are independent risk factors for NAFLD, and improving insulin sensitivity is associated with improvement of NASH histological symptoms and regression of liver fibrosis
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On the other hand, the accumulation of liver fat is associated with decreased insulin sensitivity.
In NASH patients, decreased insulin sensitivity may indicate the occurrence of liver fibrosis
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The accumulation of certain lipids in the liver (such as diacylglycerols or ceramides) can impair insulin signaling in the liver, leading to a pathological increase in liver glucose production
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The increase in transaminase is associated with an increased risk of type 2 diabetes in the future
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NAFLD patients are twice as likely to develop type 2 diabetes
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We already know that the risk of cardiovascular disease (CVD) and chronic kidney disease in diabetic patients will be significantly increased, and the risk of CVD and chronic kidney disease in NAFLD patients will also increase
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▲The role of insulin resistance in NAFLD (picture source: Reference [1]) In recent years, some scholars have proposed that "metabolic-associated fatty liver disease" (metabolic-associated fatty liver disease) is used to describe a wider range of fats than NAFLD Liver disease group
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These patients may carry one or more metabolic risk factors (such as obesity or type 2 diabetes) at the same time as liver steatosis, which may help the cooperation between hepatologists and diabetologists to promote this Understanding of the patient population and treatment development
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Based on the interaction between NAFLD, NASH and type 2 diabetes, targeting insulin sensitivity and hyperglycemia, and adopting a more comprehensive strategy for the treatment of metabolic diseases may bring better treatment results
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The effect of anti-diabetic drugs in the treatment of NAFLD At present, a variety of anti-diabetic drugs have been used to treat NAFLD and NASH in preclinical and clinical studies
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The review authors stated that metformin, the first-line treatment for diabetes, has not yet shown significant benefits in the treatment of patients with NASH, but a modulator that modulates the activity of glucagon-like peptide 1 (GLP1) and a thiazolidinedione drug that improves insulin sensitivity.
) And sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown promising effects
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▲The effect of anti-diabetic drugs in the treatment of NAFLD (ALT: alanine aminotransferase; AST: aspartate aminotransferase; DNL: de novo lipogenesis; data source: reference material [1], drawing by WuXi AppTec's content team) GLP1 regulation The agent GLP1 is an endogenous hormone secreted by the intestinal tract.
By binding to the GLP1 receptor (GLP1R), it directly stimulates the production and secretion of insulin, while inhibiting the secretion of glucagon and reducing food intake
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In clinical trials, exenatide, liraglutide and semaglutide have shown efficacy in reducing liver lipid levels, liver transaminase and inflammation markers
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At the same time, they also reduce glycosylated hemoglobin (HbA1C) levels and patient weight
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Compared with placebo, smeglutide significantly increased the proportion of patients whose symptoms of NASH were eliminated in the phase 2 clinical trial, and did not cause the deterioration of liver fibrosis
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Novo Nordisk is also conducting a number of clinical trials to explore the effect of combining smeglutide with other therapies to treat NASH
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Since the expression level of GLP1 receptors in the liver is very low, the effect of GLP1 modulators on liver endpoints may not be due to a direct effect on the liver, but an overall improvement in the patient's metabolic indicators
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▲Proportion of other diseases in NAFLD patients (picture source: reference [1]) Thiazolidinedione drugs Thiazolidinedione drugs can stimulate the secretion of adipokines, improve insulin sensitivity, and promote triglycerides The storage of esters in adipose tissue inhibits fat lysis, leading to a decrease in the level of free fatty acids in the blood and reducing liver lipid accumulation
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In addition, thiazolidinediones can directly inhibit the activation and fibrosis of hepatic stellate cells in the rat model
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However, thiazolidinediones are also potent agonists of PPARγ
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In human use, it will be limited by PPARγ-driven adverse reactions, including weight gain, increased risk of fractures, and so on
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Among the approved thiazolidinediones, pioglitazone has a relatively small ability to activate PPARγ and has relatively few adverse reactions
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When treating patients with both NASH and type 2 diabetes, pioglitazone improves insulin sensitivity while reducing inflammation and liver cell degeneration, and reducing liver fibrosis compared to the baseline before treatment
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▲Pioglitazone molecular structure (picture source: PubChem) SGLT2 inhibitor SGLT2 is a sodium-dependent glucose transporter expressed mainly in the kidney, which is mainly responsible for the reabsorption of glucose
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SGLT2 inhibitors can cause more glucose to be excreted in the urine, thereby reducing blood sugar levels
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A number of SGLT2 inhibitors have been approved by the FDA to treat patients with type 2 diabetes, and they have also shown the effect of reducing the risk of cardiovascular and chronic kidney disease in patients
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In clinical trials for the treatment of patients with NAFLD and type 2 diabetes, a variety of SGLT2 inhibitors can reduce blood sugar while improving liver lipid levels, reducing liver transaminase levels and liver stiffness
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Similar to GLP1 modulators, SGLT2 inhibitors can cause weight loss, which is closely related to the decrease in liver lipid levels, and SGLT2 is not expressed in the liver
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Therefore, the improvement in liver lipid levels may be due to weight loss and improved metabolic indicators
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The review authors pointed out that whether SGLT2 inhibitors can improve the histological characteristics of the liver in the treatment of patients with NASH still needs to be evaluated by clinical trials
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Image source: 123RF Conclusion The author said that due to the close connection between NAFLD and type 2 diabetes, many drugs used to treat hyperglycemia have achieved positive effects in improving NASH biomarkers
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In addition to hypoglycemic drugs, a variety of research therapies targeting lipid metabolism have also achieved a certain degree of effect
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Taken together, targeted metabolism therapies are attractive in the treatment of NAFLD and NASH because they may reduce the risk of cardiovascular disease and other complications related to type 2 diabetes, which is the leading cause of death in patients with NAFLD and NASH Reason
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Source of title picture: 123RF Reference: [1] Ferguson and Finck, (2021).
Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus.
Nature Reviews Endocrinology, https://doi.
org/10.
1038/s41574-021 -00507-z Note: This article aims to introduce the progress of medical and health research and is not a treatment plan recommendation
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If you need guidance on treatment plans, please go to a regular hospital for treatment
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