Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

Takata, Tomoaki; Isomoto, Hajime

doi:10.3390/ijms22094374

Cited by 21 publications

(18 citation statements)

References 72 publications

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“…Currently, there are three oral SGLT2 options approved by the U.S. Food and Drug Administration and European Medicines Agency, recommended for patients with type 2 diabetes mellitus and CKD with eGFR > 30 mL/min/1.72 m 2 . Studies indicated significant improvement in upregulation of angiotensin, reductions of UA, oxidative stress, arterial stiffness, inflammation, and body weight [ 93 ]. Other potential advantages from SGLT2 inhibitors may be reduction of anti-inflammatory, anti-oxidant, and anti-fibrotic markers [ 94 ].…”

Section: Available Treatment Option For Lowering Uric Acidmentioning

confidence: 99%

Uric Acid and Oxidative Stress—Relationship with Cardiovascular, Metabolic, and Renal Impairment

Gherghina

Peride

Ţigliş

et al. 2022

IJMS

136

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Background: The connection between uric acid (UA) and renal impairment is well known due to the urate capacity to precipitate within the tubules or extra-renal system. Emerging studies allege a new hypothesis concerning UA and renal impairment involving a pro-inflammatory status, endothelial dysfunction, and excessive activation of renin–angiotensin–aldosterone system (RAAS). Additionally, hyperuricemia associated with oxidative stress is incriminated in DNA damage, oxidations, inflammatory cytokine production, and even cell apoptosis. There is also increasing evidence regarding the association of hyperuricemia with chronic kidney disease (CKD), cardiovascular disease, and metabolic syndrome or diabetes mellitus. Conclusions: Important aspects need to be clarified regarding hyperuricemia predisposition to oxidative stress and its effects in order to initiate the proper treatment to determine the optimal maintenance of UA level, improving patients’ long-term prognosis and their quality of life.

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Section: Available Treatment Option For Lowering Uric Acidmentioning

confidence: 99%

Uric Acid and Oxidative Stress—Relationship with Cardiovascular, Metabolic, and Renal Impairment

Gherghina

Peride

Ţigliş

et al. 2022

IJMS

136

View full text Add to dashboard Cite

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“…Chino et al revealed that the urinary excretion rate of uric acid strongly correlated with the urinary glucose excretion, demonstrating the relation between SUA and glycosuria [ 86 ]. Raised glucose concentration resulting from SGLT2i administration could also disturb the reabsorption of uric acid in the proximal tubule through GLUT9b [ 87 ]. After removing the studies that were conducted on CKD patients, the SUA reduction was increased, which is consistent with the proposed model for uricosuric effects of SGLT2i by Chino et al [ 86 ].…”

Section: Discussionmentioning

confidence: 99%

Impacts of Sodium/Glucose Cotransporter-2 Inhibitors on Circulating Uric Acid Concentrations: A Systematic Review and Meta-Analysis

Akbari

Rafiee

Sathyapalan

et al. 2022

Journal of Diabetes Research

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Background. Several trials have assessed the antihyperglycemic effects of sodium/glucose cotransporter-2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM). We conducted a quantitative analysis to assess the impact of SGLT2is on serum uric acid (SUA) in patients with T2DM. Methods. Placebo-controlled trials published before 13 August 2021 were identified by searching PubMed, Embase, Web of Science, and Scopus. The intervention group received SGLT2i as monotherapy or add-on treatment, and the control group received a placebo that was replaced with SGLT2i. Clinical trials providing changes in SUA were included. The mean change of SUA, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight were calculated (PROSPERO CRD42021287019). Results. After screening of 1172 papers, 59 papers were included in the systematic review. A total of 55 trials (122 groups) of 7 types of SGLT2i on patients with T2DM were eligible for meta-analysis. All SGLT2is significantly decreased SUA levels compared with the placebo groups: empagliflozin mean difference MD = − 40.98 μmol/L, 95% CI [-47.63, -34.32], dapagliflozin MD = − 35.17 μmol/L, 95% CI [-39.68, -30.66], canagliflozin MD = − 36.27 μmol/L, 95% CI [−41.62, −30.93], luseogliflozin MD = − 24.269 μmol/L, 95% CI [-33.31, -15.22], tofogliflozin MD = − 19.47 μmol/L, 95% CI [−27.40, −11.55], and ipragliflozin MD = − 18.85 μmol/L, 95% CI [−27.20, −10.49]. SGLT2i also decreased FPG, body weight, and HbA1c levels. SUA reduction persisted during long-term treatment with SGLT2i (except for empagliflozin), while the SUA reduction was affected by the duration of diabetes. Conclusions. SGLT2i can be a valid therapeutic strategy for patients with T2DM and comorbid hyperuricemia. Besides reducing FPG, body weight, and HbA1c, SGLT2i can significantly decrease SUA levels compared to placebo (Total MD = − 34.07 μmol/L, 95% CI [-37.00, -31.14]).

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“…Many mechanisms are considered to be the mechanism by which SGLT2 inhibitors prevent and improve heart failure ( Figure 2 ) [ 73 , 74 , 75 , 76 ].…”

Section: What Is An Effective Treatment?mentioning

confidence: 99%

Pathophysiology and Treatment of Diabetic Cardiomyopathy and Heart Failure in Patients with Diabetes Mellitus

Nakamura

Miyoshi

Yoshida

et al. 2022

IJMS

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There is a close relationship between diabetes mellitus and heart failure, and diabetes is an independent risk factor for heart failure. Diabetes and heart failure are linked by not only the complication of ischemic heart disease, but also by metabolic disorders such as glucose toxicity and lipotoxicity based on insulin resistance. Cardiac dysfunction in the absence of coronary artery disease, hypertension, and valvular disease is called diabetic cardiomyopathy. Diabetes-induced hyperglycemia and hyperinsulinemia lead to capillary damage, myocardial fibrosis, and myocardial hypertrophy with mitochondrial dysfunction. Lipotoxicity with extensive fat deposits or lipid droplets is observed on cardiomyocytes. Furthermore, increased oxidative stress and inflammation cause cardiac fibrosis and hypertrophy. Treatment with a sodium glucose cotransporter 2 (SGLT2) inhibitor is currently one of the most effective treatments for heart failure associated with diabetes. However, an effective treatment for lipotoxicity of the myocardium has not yet been established, and the establishment of an effective treatment is needed in the future. This review provides an overview of heart failure in diabetic patients for the clinical practice of clinicians.

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Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors: Renoprotective Mechanisms beyond Glycemic Control

Cited by 21 publications

References 72 publications

Uric Acid and Oxidative Stress—Relationship with Cardiovascular, Metabolic, and Renal Impairment

Uric Acid and Oxidative Stress—Relationship with Cardiovascular, Metabolic, and Renal Impairment

Impacts of Sodium/Glucose Cotransporter-2 Inhibitors on Circulating Uric Acid Concentrations: A Systematic Review and Meta-Analysis

Pathophysiology and Treatment of Diabetic Cardiomyopathy and Heart Failure in Patients with Diabetes Mellitus

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