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Non-alcoholic fatty liver disease (NAFLD) is becoming the most prevalent liver disease in the world.
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
The strong link between NAFLD and type 2 diabetes
The strong link between NAFLD and type 2 diabetesExisting evidence shows that there is a two-way interaction between NAFLD or NASH and type 2 diabetes
On the other hand, the accumulation of liver fat is associated with decreased insulin sensitivity.
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
▲The role of insulin resistance in NAFLD (picture source: reference [1])
In recent years, some scholars have proposed the use of "metabolic-associated fatty liver disease" (metabolic-associated fatty liver disease) to describe a wider population of fatty liver disease than NAFLD
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
The effect of anti-diabetic drugs in the treatment of NAFLD
The effect of anti-diabetic drugs in the treatment of NAFLDAt present, a variety of anti-diabetic drugs have been used to treat NAFLD and NASH in preclinical and clinical studies
▲The effect of anti-diabetic drugs in the treatment of NAFLD (ALT: alanine aminotransferase; AST: aspartate aminotransferase; DNL: de novo lipogenesis; data source: reference [1], drawing by WuXi AppTec's content team)
GLP1 modulator
GLP1 is an endogenous hormone secreted by the intestinal tract.
In clinical trials, exenatide, liraglutide and semaglutide have shown efficacy in reducing liver lipid levels, liver transaminase and inflammation markers
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
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
▲The proportion of other diseases in NAFLD patients (picture source: reference [1])
Thiazolidinediones
Thiazolidinedione drugs can stimulate the secretion of adipokines, increase insulin sensitivity, promote the storage of triglycerides in adipose tissue, and inhibit fat lysis, which leads to a decrease in the level of free fatty acids in the blood and lower liver fat.
In addition, thiazolidinedione drugs can also directly inhibit the activation and fibrosis of hepatic stellate cells in the rat model
Among the approved thiazolidinediones, pioglitazone has a relatively small ability to activate PPARγ and has relatively few adverse reactions
▲Pioglitazone molecular structure (picture source: PubChem)
SGLT2 inhibitor
SGLT2 is a sodium-dependent glucose transporter expressed mainly in the kidney, and it is mainly responsible for the reabsorption of glucose
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
.
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
.
Therefore, the improvement in liver lipid levels may be due to weight loss and improved metabolic indicators
.
The review authors pointed out that whether SGLT2 inhibitors can improve the histological characteristics of the liver in the treatment of NASH patients still needs to be evaluated by clinical trials
.
Conclusion
ConclusionThe review authors stated that due to the close connection between NAFLD and type 2 diabetes, many drugs used to treat hyperglycemia have achieved positive results in improving NASH biomarkers
.
In addition to hypoglycemic drugs, a variety of research therapies targeting lipid metabolism have also achieved a certain degree of effect
.
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 primary cause of death in patients with NAFLD and NASH Reason
.
Reference materials:
[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