Sodium–glucose cotransporter 2 (SGLT-2) inhibitors: a new antidiabetic drug class

Silva, Paula Nogueira da; Conceição, Raissa Alves da; Maia, Rodolfo do Couto; Barbosa, Maria Letícia de Castro

doi:10.1039/c8md00183a

Cited by 15 publications

(16 citation statements)

References 43 publications

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“…The underlying mechanism of SGLT2i causing EDKA is multifactorial and shown in Figure 2 [16][17][18][19]. SGLT2i on kidney enhance glucose excretion and causes the reabsorption of ketone bodies.…”

Section: Pathophysiologymentioning

confidence: 99%

Euglycemic Diabetic Ketoacidosis and Sodium-Glucose Cotransporter-2 Inhibitors: A Focused Review of Pathophysiology, Risk Factors, and Triggers

Somagutta¹,

Agadi²,

Hange³

et al. 2021

Cureus

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Diabetic ketoacidosis (DKA) is an acute and significant life-threatening complication of diabetes. The association of sodium-glucose cotransporter-2 inhibitors (SGLT2i) with euglycemic diabetic ketoacidosis (EDKA) has been well reported. This literature review was conducted to understand the mechanism of EDKA and identify the potential risk factors and precipitants for patients taking SGLT2i. After reviewing the published literature between 2010 and 2020, 32 articles are included in the final review. The underlying mechanism is mainly enhanced lipolysis and ketone body reabsorption. SGLT2i also stimulates pancreatic alpha cells and inhibits beta cells, causing an imbalance in glucagon/insulin levels, further contributing to lipolysis and ketogenesis. Most patients were diagnosed with blood glucose less than 200 mg/dL, blood pH <7.3, increased anion gap, increased blood, or urine ketones. Perioperative fasting, pancreatic etiology, low carbohydrate or ketogenic diet, obesity, and malignancy are identified precipitants in this review. As normoglycemia can conceal the underlying acidosis, physicians should be cognizant of the EDKA diagnosis and initiate prompt treatment. Patient education on risk factors and triggers is recommended to avoid future events.

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Section: Pathophysiologymentioning

confidence: 99%

Euglycemic Diabetic Ketoacidosis and Sodium-Glucose Cotransporter-2 Inhibitors: A Focused Review of Pathophysiology, Risk Factors, and Triggers

Somagutta¹,

Agadi²,

Hange³

et al. 2021

Cureus

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“…The glucose‐lowering effects of SGLT2 inhibition are independent of insulin secretion, and SGLT2 inhibitors have a relatively low possibility of hypoglycaemia. Furthermore, the excretion of urinary glucose may provide many additional advantages by increasing the calorie loss . After optimization and screening many derivatives based on previously reported SAR, SU‐011 was identified as a highly potent SGLT2 inhibitor with 1137‐fold selectivity against SGLT1.…”

Section: Discussionmentioning

confidence: 99%

“…Many SGLT2 inhibitors have been reported, and several candidates have been approved as antidiabetic drugs, such as dapagliflozin and canagliflozin . Moreover, many preclinical candidates are under development as well .…”

Section: Introductionmentioning

confidence: 99%

A novel SGLT2 inhibitor, SU-011, improves glycaemic control in rodents without the risk of hypoglycaemia and weight gain

Huang

Dai

et al. 2019

Journal of Pharmacy and Pharmacology

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Objective To evaluate the pharmacological characteristics of SU-011, a novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor. Methods The in vitro activities of SU-011 were investigated in cell-based assays. The urinary glucose excretion, glucose tolerance and the risk of hypoglycaemia were evaluated in mice. Moreover, the dose-response relationship and chronic pharmacological studies of SU-011 were assessed in streptozotocin (STZ)-induced diabetic model, a STZ-treated model with impaired insulin secretion. Key findings SU-011 is a potential SGLT2 inhibitor with 5.6 nM inhibitory activity for SGLT2 and 1137-fold selectivity for SGLT1. In healthy mice, SU-011 improves the tolerance to a glucose load and promotes the urinary glucose excretion. Besides, SU-011 (10 mg/kg) still exhibited less risk of hypoglycaemia. During chronic treatment, SU-011 exhibited sustained glucose-lowering effect without the side effect of weight gain in STZ-induced diabetic mice. The levels of non-fasting and fasting plasma glucose, glycosylated haemoglobin, food and water intake were significantly decreased in SU-011-treated group. Moreover, SU-011 decreases the plasma levels of interleukin-1b, tumour necrosis factor-a and C-reactive protein even better than that of dapagliflozin. Conclusions All of these results indicated that SU-011 may be effective for the management of diabetes.

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“…Since phlorizin was first isolated from the root of an apple tree in 1,835, more than a dozen SGLT inhibitors have been developed ( 134 ). Due to the significant reduction of CV risk with empagliflozin, dapagliflozin, and canagliflozin in patients with T2DM, these benefits were once considered as class effects of SGLT2 inhibitors ( 135 ).…”

Section: Sglt2 Inhibitorsmentioning

confidence: 99%

“…The differences in selectivity of SGLT2 inhibitors for SGLT2 vs. SGLT1 are summarized in Table 1 ( 134 , 137 , 138 ), which may be the main factor leading to their different pharmacological profiles and clinical effects. For example, several SGLT2 inhibitors such as empagliflozin, dapagliflozin, canagliflozin, tofogliflozin showed to alleviate arterial stiffness ( 41 – 43 , 139 ), while luseogliflozin and ipragliflozin did not demostrate the similar beneficial effect ( 46 , 140 ).…”

Section: Sglt2 Inhibitorsmentioning

confidence: 99%

Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure

Zeng

Zhou

Liu

et al. 2021

Front. Cardiovasc. Med.

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Heart failure (HF) is a common complication or late-stage manifestation of various heart diseases. Numerous risk factors and underlying causes may contribute to the occurrence and progression of HF. The pathophysiological mechanisms of HF are very complicated. Despite accumulating advances in treatment for HF during recent decades, it remains an intractable clinical syndrome with poor outcomes, significantly reducing the quality of life and expectancy of patients, and imposing a heavy economic burden on society and families. Although initially classified as antidiabetic agents, sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated reduced the prevalence of hospitalization for HF, cardiovascular death, and all-cause death in several large-scale randomized controlled clinical trials. These beneficial effects of SGLT-2 inhibitors can be attributed to multiple hemodynamic, inflammatory and metabolic mechanisms, not only reducing the serum glucose level. SGLT2 inhibitors have been used increasingly in treatment for patients with HF with reduced ejection fraction due to their surprising performance in improving the prognosis. In addition, their roles and mechanisms in patients with HF with preserved ejection fraction or acute HF have also attracted attention. In this review article, we discuss the possible mechanisms and applications of SGLT2 inhibitors in HF.

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Sodium–glucose cotransporter 2 (SGLT-2) inhibitors: a new antidiabetic drug class

Cited by 15 publications

References 43 publications

Euglycemic Diabetic Ketoacidosis and Sodium-Glucose Cotransporter-2 Inhibitors: A Focused Review of Pathophysiology, Risk Factors, and Triggers

Euglycemic Diabetic Ketoacidosis and Sodium-Glucose Cotransporter-2 Inhibitors: A Focused Review of Pathophysiology, Risk Factors, and Triggers

A novel SGLT2 inhibitor, SU-011, improves glycaemic control in rodents without the risk of hypoglycaemia and weight gain

Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure

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