Metabolic changes induced by dapagliflozin, an SGLT2 inhibitor, in Japanese patients with type 2 diabetes treated by oral anti-diabetic agents: A randomized, clinical trial

Horibe, Kayo; Morino, Katsutaro; Miyazawa, Itsuko; Tanaka‐Mizuno, Sachiko; Kondo, Keiko; Sato, Daisuke; Ohashi, Nobuhide; Ida, Shogo; Yanagimachi, Tsuyoshi; Yoshimura, Masahiro; Itoh, Ryuta; Murata, Kiyoshi; Arima, Hisatomi; Fujita, Yukihiro; Ugi, Satoshi; Maegawa, Hiroshi

doi:10.1016/j.diabres.2022.109781

Cited by 19 publications

(19 citation statements)

References 44 publications

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“…The characteristics of the 18 included studies published between 2013 and 2022 are shown in Table 1 [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. The articles involved 1430 participants (726 SGLT-2 inhibitors participants…”

Section: Basic Characteristics and Quality Assessmentmentioning

confidence: 99%

Effect of SGLT-2 inhibitors on body composition in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials

et al. 2022

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Objective Type 2 diabetes mellitus(T2DM) is closely related to sarcopenic obesity(SO). Body composition measurement including body weight, body mass index, waist circumference, percentage body fat, fat mass, muscle mass, visceral adipose tissue and subcutaneus adipose tissue, plays a key role in evaluating T2DM and SO. The weight reduction effect of sodium-glucose cotransporter 2(SGLT-2) inhibitors has been demonstrated. However, there are warnings that SGLT-2 inhibitors should be used with caution because they may increase the risk of sarcopenia. The effect of SGLT-2 inhibitors on body composition in T2DM is inconclusive. In this work, a meta-analysis of randomized controlled trials was conducted to evaluate the effect of SGLT-2 inhibitors on body composition in T2DM. Methods PubMed, the Cochrane Library, EMbase and Web of Science databases were searched by computer. All statistical analyses were carried out with Review Manager version 5. 3. Results were compared by weight mean difference(WMD), with 95% confidence intervals(CI) for continuous outcomes. A random effects model was applied regardless of heterogeneity. The I2 statistic was applied to evaluate the heterogeneity of studies. Publication bias was assessed using Funnel plots. Results 18 studies with 1430 participants were eligible for the meta-analysis. SGLT-2 inhibitors significantly reduced body weight(WMD:-2. 73kg, 95%CI: -3. 32 to -2. 13, p<0. 00001), body mass index(WMD:-1. 13kg/m2, 95%CI: -1. 77 to -0. 50, p = 0. 0005), waist circumference(WMD:-2. 20cm, 95%CI: -3. 81 to -0. 58, p = 0. 008), visceral fat area(MD:-14. 79cm2, 95%CI: -24. 65 to -4. 93, p = 0. 003), subcutaneous fat area(WMD:-23. 27cm2, 95% CI:-46. 44 to -0. 11, P = 0. 05), fat mass(WMD:-1. 16kg, 95%CI: -2. 01 to -0. 31, p = 0. 008), percentage body fat(WMD:-1. 50%, 95%CI:-2. 12 to -0. 87, P<0. 00001), lean mass(WMD:-0. 76kg, 95%CI:-1. 53 to 0. 01, P = 0. 05) and skeletal muscle mass(WMD:-1. 01kg, 95%CI:-1. 91 to -0. 11, P = 0. 03). Conclusion SGLT-2 inhibitors improve body composition in T2DM including body weight, body mass index, waist circumference, visceral fat area, subcutaneous fat area, percentage body fat and fat mass reduction, but cause adverse effects of reducing muscle mass. Therefore, until more evidence is obtained to support that SGLT-2 inhibitors increase the risk of sarcopenia, not only the benefit on body composition, but also the adverse effect of the reduction in muscle mass by SGLT-2 inhibitors in T2DM should be considered.

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Section: Basic Characteristics and Quality Assessmentmentioning

confidence: 99%

Effect of SGLT-2 inhibitors on body composition in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials

et al. 2022

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“…Asparagine has been correlated with homeostatic model assessment for insulin resistance in diabetes patients 20 , and a previous metabolomic study found that elevation of its level in the serum of the population has an inverse relationship with the progression of diabetes risk 21 , 22 . It has been previously identified that there was a positive correlation between the change in body weight and the concentration of amino acids, including asparagine, in patients with diabetes mellitus treated with dapagliflozin compared with a control group using serum metabolomic analysis 23 . It has been shown that the relief of mitochondrial stress through inhibiting the electron transport chain has prevented tumor growth by lowering intracellular asparagine 24 .…”

Section: Discussionmentioning

confidence: 99%

Metabolomic profiling in kidney cells treated with a sodium glucose-cotransporter 2 inhibitor

Seo

Lee

et al. 2023

Sci Rep

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We aimed to determine the metabolomic profile of kidney cells under high glucose conditions and following sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment. Targeted metabolomics using the Absolute IDQ-p180 kit was applied to quantify metabolites in kidney cells stimulated with high glucose (25 and 50 mM) and treated with SGLT2 inhibitor, dapagliflozin (2 µM). Primary cultured human tubular epithelial cells and podocytes were used to identify the metabolomic profile in high glucose conditions following dapagliflozin treatment. The levels of asparagine, PC ae C34:1, and PC ae C36:2 were elevated in tubular epithelial cells stimulated with 50 mM glucose and were significantly decreased after 2 µM dapagliflozin treatment. The level of PC aa C32:0 was significantly decreased after 50 mM glucose treatment compared with the control, and its level was significantly increased after dapagliflozin treatment in podocytes. The metabolism of glutathione, asparagine and proline was significantly changed in tubular epithelial cells under high-glucose stimulation. And the pathway analysis showed that aminoacyl-tRNA biosynthesis, arginine and proline metabolism, glutathione metabolism, valine, leucine and isoleucine biosynthesis, phenylalanine, tyrosine, and tryptophan biosynthesis, beta-alanine metabolism, phenylalanine metabolism, arginine biosynthesis, alanine, aspartate and glutamate metabolism, glycine, serine and threonine metabolism were altered in tubular epithelial cells after dapagliflozin treatment following 50 mM glucose compared to those treated with 50 mM glucose.

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“…Although the primary action of SGLT2i involves inhibition of SGLT2 expressed on proximal tubule cells, these drugs exhibit pleiotropic effects, which include reductions in body weight, blood pressure, intra-glomerular pressure, hyperuricemia, inflammation and oxidative stress, inhibition of the sympathetic nervous system, and improvements in erythropoiesis, cardiac energy metabolism and vascular function ( 91 – 93 ). The reduction in body weight is at least partly explained by a reduction in fat mass ( 94 , 95 ). SGLT2i also reduce epicardial fat that releases pro-inflammatory mediators ( 96 , 97 ).…”

Section: Discussionmentioning

confidence: 99%

Evolution of sodium-glucose co-transporter 2 inhibitors from a glucose-lowering drug to a pivotal therapeutic agent for cardio-renal-metabolic syndrome

et al. 2023

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Cardio-renal-metabolic (CRM) syndrome, which involves type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and heart failure (HF), is a serious healthcare issue globally, with high morbidity and mortality. The disorders that comprise CRM syndrome are independent can mutually affect and accelerate the exacerbation of each other, thereby substantially increasing the risk of mortality and impairing quality of life. To manage CRM syndrome by preventing vicious interactions among individual disorders, a holistic treatment approach that can simultaneously address multiple disorders underpinning CRM syndrome is of great importance. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) lower blood glucose levels by inhibiting glucose reabsorption in the renal proximal tubule and were first indicated for the treatment of T2DM. Several cardiovascular outcome trials have demonstrated that SGLT2i not only lower blood glucose but also reduce the risk of hospitalization for HF and worsening renal function in patients with T2DM. Results have also suggested that the observed cardiorenal benefits of SGLT2i may be independent of their blood glucose-lowering effects. Several randomized controlled trials subsequently assessed the efficacy and safety of SGLT2i in patients without T2DM, and revealed considerable benefits of SGLT2i treatment against HF and CKD, regardless of the presence of T2DM. Thus, SGLT2i have become an essential therapeutic option to prevent the onset, slow the progression, and improve the prognosis of CRM syndrome. This review assesses the evolution of SGLT2i from a glucose-lowering drug to a therapeutic agent for CRM syndrome by evaluating epoch-making clinical studies, including randomized control trials and real-world studies.

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Metabolic changes induced by dapagliflozin, an SGLT2 inhibitor, in Japanese patients with type 2 diabetes treated by oral anti-diabetic agents: A randomized, clinical trial

Cited by 19 publications

References 44 publications

Effect of SGLT-2 inhibitors on body composition in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials

Effect of SGLT-2 inhibitors on body composition in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials

Metabolomic profiling in kidney cells treated with a sodium glucose-cotransporter 2 inhibitor

Evolution of sodium-glucose co-transporter 2 inhibitors from a glucose-lowering drug to a pivotal therapeutic agent for cardio-renal-metabolic syndrome

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