The effects of sodium-glucose cotransporter 2 inhibitors on hepatocellular carcinoma: From molecular mechanisms to potential clinical implications

Arvanitakis, Konstantinos; Koufakis, Theocharis; Kotsa, Kalliopi

doi:10.1016/j.phrs.2022.106261

Cited by 22 publications

(13 citation statements)

References 89 publications

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“…[ 14 ] SGLT2is are kind of drugs that lowering the blood glucose levels by hastening glycosuria. SGLT2i exert many systematic roles beyond lowering blood glucose, such as hypertension, [ 15 ] hepatocellular carcinoma, [ 16 ] cardiovascular disease, [ 17 ] cognitive function. [ 18 ] Meantime SGLT2i have important roles in aging process.…”

Section: Discussionmentioning

confidence: 99%

The Comparation of Renal Anti‐Senescence Effects and Blood Metabolites between Dapagliflozin and Metformin in Non‐Diabetes Environment

Zeng,

Chen,

Gao

et al. 2023

Advanced Biology

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Delaying kidney senescence process will benefit renal physiologic conditions, and prompt the kidney recovering from different pathological states. The renal anti‐senescence effects of sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) and metformin have been proven in diabetic settings, but the roles of each one and combination of two drugs in natural kidney aging process remain undefined and deserve further research. Senescence‐accelerated mouse prone 8 (SAMP8) were orally administered dapagliflozin, metformin, and a combination of them for 16 weeks. Dapagliflozin exhibits better effects than metformin in lowering senescence related markers, and the combination therapy shows the best results. In vitro experiments demonstrate the same results that the combination of dapagliflozin and metformin can exert a better anti‐senescence effect. Blood metabolites detection in vivo shows dapagliflozin mainly leads to the change of blood metabolites enriched in choline metabolism, and metformin tends to induce change of blood metabolites enriched in purine metabolism. In conclusion, the results suggest dapagliflozin may have a better renal anti‐senescence effect than metformin in non‐diabetes environment, and the combination of the two drugs can strengthen the effect. The two drugs can lead to different blood metabolites alteration, which may lead to different systemic effects.

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Section: Discussionmentioning

confidence: 99%

The Comparation of Renal Anti‐Senescence Effects and Blood Metabolites between Dapagliflozin and Metformin in Non‐Diabetes Environment

Zeng,

Chen,

Gao

et al. 2023

Advanced Biology

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show abstract

“…Canagliflozin inhibits the translocation of β-catenin from the cytoplasm to the cell nucleus and enhances its proteasomal degradation, leading to a reduction in HCC growth [ 133 ]. Canagliflozin inhibits not only SGLT2 but also other glucose transporters such as GLUT1, which is overexpressed in HCC cells.…”

Section: Sglt2 Inhibitors and Cancermentioning

confidence: 99%

Unlocking the Full Potential of SGLT2 Inhibitors: Expanding Applications beyond Glycemic Control

Youssef

Yahya

Popoviciu

et al. 2023

IJMS

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The number of diabetic patients has risen dramatically in recent decades, owing mostly to the rising incidence of type 2 diabetes mellitus (T2DM). Several oral antidiabetic medications are used for the treatment of T2DM including, α-glucosidases inhibitors, biguanides, sulfonylureas, meglitinides, GLP-1 receptor agonists, PPAR-γ agonists, DDP4 inhibitors, and SGLT2 inhibitors. In this review we focus on the possible effects of SGLT2 inhibitors on different body systems. Beyond the diabetic state, SGLT2 inhibitors have revealed a demonstrable ability to ameliorate cardiac remodeling, enhance myocardial function, and lower heart failure mortality. Additionally, SGLT2 inhibitors can modify adipocytes and their production of cytokines, such as adipokines and adiponectin, which enhances insulin sensitivity and delays diabetes onset. On the other hand, SGLT2 inhibitors have been linked to decreased total hip bone mineral deposition and increased hip bone resorption in T2DM patients. More data are needed to evaluate the role of SGLT2 inhibitors on cancer. Finally, the effects of SGLT2 inhibitors on neuroprotection appear to be both direct and indirect, according to scientific investigations utilizing various experimental models. SGLT2 inhibitors improve vascular tone, elasticity, and contractility by reducing oxidative stress, inflammation, insulin signaling pathways, and endothelial cell proliferation. They also improve brain function, synaptic plasticity, acetylcholinesterase activity, and reduce amyloid plaque formation, as well as regulation of the mTOR pathway in the brain, which reduces brain damage and cognitive decline.

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“… 80 , 81 By inhibiting SGLT2 in the kidney, the inhibitors lead to glycosuria, resulting in decreased serum glucose, caloric deficit, and thus weight loss. 82 Researchers have also observed the potential of SGLT2 inhibitors against HCC and other malignancies due to the established correlation between hyperglycemia and HCC. For example, Luo et al 83 reported that canagliflozin (an SGLT2 inhibitor) could decrease HIF-1α protein synthesis via the AKT/mTOR pathway, leading to reduced hypoxia-induced metastasis and angiogenesis in HCC.…”

Section: Potential Preventive Strategiesmentioning

confidence: 99%

“…Many others also demonstrated consistent results of the effects of canagliflozin and other SGLT2 inhibitors on HCC cells. 82 A meta-analysis of multiple randomized controlled trials by Benedetti et al 84 exhibited an overall reduced risk of cancer (not limited to HCC) in users of SGLT2 inhibitors, with a risk ratio of 0.35.…”

Section: Potential Preventive Strategiesmentioning

confidence: 99%

Diabetes and Risk of Hepatocellular Carcinoma in Cirrhosis Patients with Nonalcoholic Fatty Liver Disease

et al. 2022

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Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. NAFLD is a hepatic manifestation of insulin resistance, the core pathophysiology of diabetes. Multiple clinical studies show that diabetes increases the risk of liver disease progression and cirrhosis development in patients with NAFLD. Diabetes has causal associations with many different cancers, including hepatocellular carcinoma (HCC). More recent studies demonstrate that diabetes increases the risk of HCC in patients with underlying NAFLD cirrhosis, confirming the direct hepatocarcinogenic effect of diabetes among cirrhosis patients. Diabetes promotes hepatocarcinogenesis via the activation of inflammatory cascades producing reactive oxygen species and proinflammatory cytokines, leading to genomic instability, cellular proliferation, and inhibition of apoptosis. Given the global increase in the burden of NAFLD and HCC, high-risk patients such as older diabetic individuals should be carefully monitored for HCC development. Future larger studies should explore whether the effect of diabetes on HCC risk in NAFLD cirrhosis is modifiable by the type of antidiabetic medication and the effectiveness of diabetes control.

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The effects of sodium-glucose cotransporter 2 inhibitors on hepatocellular carcinoma: From molecular mechanisms to potential clinical implications

Cited by 22 publications

References 89 publications

The Comparation of Renal Anti‐Senescence Effects and Blood Metabolites between Dapagliflozin and Metformin in Non‐Diabetes Environment

The Comparation of Renal Anti‐Senescence Effects and Blood Metabolites between Dapagliflozin and Metformin in Non‐Diabetes Environment

Unlocking the Full Potential of SGLT2 Inhibitors: Expanding Applications beyond Glycemic Control

Diabetes and Risk of Hepatocellular Carcinoma in Cirrhosis Patients with Nonalcoholic Fatty Liver Disease

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