Sodium-glucose Co-transporter 2 Inhibitors Reduce the Abdominal Visceral Fat Area and May Influence the Renal Function in Patients with Type 2 Diabetes

Tosaki, Takahiro; Kawanishi, Hideki; Himeno, Tatsuhito; Kato, Yoshiro; Kondo, Masaki; Toyota, Kaori; Nishida, Takeshi; Shiroma, Megumi; Tsubonaka, Kaori; Asai, Hitomi; Moribe, Miho; Nakaya, Yuki; Nakamura, Jiro

doi:10.2169/internalmedicine.56.7196

Cited by 39 publications

(36 citation statements)

References 24 publications

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“…SGLT2 inhibitors, such as dapagliflozin, have been shown to improve glomerular hyperfiltration and blood pressure [10, 11], as add-ons to their action on blood glucose and glycated hemoglobin levels. The renoprotective effect of dapagliflozin in diabetic patients is still discrepant [13, 17].…”

Section: Discussionmentioning

confidence: 99%

“…Dapagliflozin also improves insulin sensitivity and β-cell functions [8, 9], decreases body weight and lowers systolic blood pressure independently from insulin secretion or action [10]. Clinical data show that dapagliflozin lowers the estimated glomerular filtration rate [11] and then slows the progression of DN. It is also reported that dapagliflozin improves DN not only by lowering blood glucose but also by inhibiting inflammation and oxidative stress in db/db mice [12].…”

Section: Introductionmentioning

confidence: 99%

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Dapagliflozin Aggravates Renal Injury via Promoting Gluconeogenesis in db/db Mice

Jia

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: A sodium-glucose co-transporter-2 inhibitor dapagliflozin is widely used for lowering blood glucose and its usage is limited in type 2 diabetes mellitus patients with moderate renal impairment. As its effect on kidney function is discrepant and complicated, the aim of this study is to determine the effect of dapagliflozin on the progression of diabetic nephropathy and related mechanisms. Methods: Twelve-week-old male C₅₇BL/6 wild-type and db/db mice were treated with vehicle or 1 mg/kg dapagliflozin for 12 weeks. Body weight, blood glucose, insulin tolerance, glucose tolerance, pyruvate tolerance and 24-hour urine were measured every 4 weeks. At 24 weeks of age, renal function was evaluated by blood urea nitrogen level, creatinine clearance, urine output, urinary albumin excretion, Periodic Acid-Schiff staining, Masson’s trichrome staining and electron microscopy. Changes in insulin signaling and gluconeogenic key regulatory enzymes were detected using Western blot analysis. Results: Dapagliflozin did not alleviate but instead aggravated diabetic nephropathy manifesting as increased levels of microalbuminuria, blood urea nitrogen, and glomerular and tubular damage in db/db mice. Despite adequate glycemic control by dapagliflozin, urinary glucose excretion increased after administration before 24 weeks of age and was likely associated with renal impairment. Increased urinary glucose excretion was mainly derived from the disturbance of glucose homeostasis with elevated hepatic and renal gluconeogenesis induced by dapagliflozin. Although it had no effect on insulin sensitivity and glucose tolerance, dapagliflozin further induced the expression of gluconeogenic key rate-limiting enzymes through increasing the expression levels of FoxO1 in the kidney and liver. Conclusion: These experimental results indicate that dapagliflozin aggravates diabetes mellitus-induced kidney injury, mostly through increasing gluconeogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dapagliflozin Aggravates Renal Injury via Promoting Gluconeogenesis in db/db Mice

Jia

Wang

et al. 2018

Cell Physiol Biochem

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“…Canagliflozin is a SGLT2 inhibitor that offers an anti-diabetic effect by increasing urinary glucose excretion equates to a loss of approximately 308-476 calories per day [9]. While initial weight loss may reflect fluid loss due to osmotic diuresis, weight loss by canagliflozin is largely result of reduction of subcutaneous and visceral fat [10,11]. Multiple studies have demonstrated that treatment with canagliflozin result in significant reductions of HbA1c from baseline by -0.58% and -1.03% and in body weight by -3.3% and -4.4% after 52 weeks with 100 and 300 mg, respectively, in patients with diabetes [12].…”

Section: Introductionmentioning

confidence: 99%

Beneficials Effects of Canagliflozin in a Weight-Centered Management in Patients with Type 2 Diabetes Mellitus in Real Practice

Carral¹,

Cayón²,

Jiménez³

et al. 2018

Endocrinol Metab Syndr

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Objective: Evaluate the real-world efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus (T2DM), associated to a weight-loss intensive lifestyle intervention program (WLIP), to achieve weight loss greater than 5% at 12 months. Methods:Retrospective review of patients with T2DM included in a WLIP, who were prescribed canagliflozin from June 2015 to December 2016 at four endocrinology clinics in the south of Spain within routine clinical practice context. Changes during 12 months in anthropometric variables, HbA1c, uric acid and adverse events were assessed.Results: 201 patients with T2DM (45.8% women, 60.3 ± 9.4 years old and BMI: 34.9 ± 8.7 kg/m 2 ) were studied. Patients treated with canagliflozin lost an average weight and reduced an average of waist circumference of -4.0 ± 4.2 kg and -3.2 ± 8.4 cm, -5.4 ± 5.7 kg and -4.9 ± 9.9 cm and -5.3 ± 8.0 kg and -7.0 ± 14.6 cm, achieving weight loss greater than 5%: 29.0%, 47.9% and 42.7% of patients at 3, 6 and 12 months, respectively. HbA1c levels were average reduced by -1.2%, -1.3% and -1.3% and 68.8% reached an HbA1c level ≤ 7% at 12 months. 17.9% (36 patients) experienced mild adverse events and canagliflozin treatment was suspended in 23 patients (11.4%). Conclusion:The addition of canagliflozin to the treatment of overweight or obese patients with T2DM, as a complement of a weight-loss intensive lifestyle intervention, was associated with improvement in body weight and glycemic control with relative mild adverse events.

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“…In Japanese patients, SGLT2 inhibitor-associated body fat reduction has been examined only in short-term (≤6 months) studies [2]. Therefore, we investigated long-term effects of SGLT2 inhibitor on body fat and liver function in Japanese patients with obese type2 diabetes (T2D).…”

Section: Introductionmentioning

confidence: 99%

“…Ipragliflozin significantly decreased visceral adipose tissue in 4-week observation in 25 Japanese T2D patients [10]. Visceral fat area was significantly reduced in 6-month observation of 64 diabetic patients [2]. However, obesity is difficult to treat as many subjects regain weight after temporary weight loss [11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Long-Term Effects of Ipragliflozin on Adipose Tissue in Japanese Patients with Obese Type 2 Diabetes

Si¹,

Sekido²,

Ohkubo³

et al. 2017

J Obes Weight Loss Ther

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A long-term effect of ipragliflozin on adipose tissue mass reduction by ipragliflozin in Japanese patients with obese type2 diabetes (mean BMI 35.1 ± 1.1 kg/m 2 ) was investigated. 17 of 20 participants completed this study. Ipragliflozin was administered (50 mg/day) once daily for 12 months. At 0, 3, 6 and 12 months, visceral and subcutaneous adipose tissue area was determined by two different bioelectrical impedance methods, and blood samples for HbA1c, renal function, lipids and liver function obtained, and body weight and blood pressure recorded. The primary endpoint was decrease in body fat mass. Secondary endpoints included changes in body weight and the laboratory data. Visceral fat area (cm 2 , mean ± SD) at 0, 3, 6 and 12 months was 166.0 ± 49.7, 149.7 ± 46.1, 149.7 ± 42.4 and 148.5 ± 40.2, respectively: the value at 3 months was significantly lower than baseline (P=0.027). Subcutaneous fat at the corresponding time points was 359.3 ± 110.5, 316.6± 87.1, 326.8 ± 87.2 and 325.9 ± 90.4, respectively: the values at each post treatment period were significantly less than the baseline (P=0.003, 0.018 and 0.036 for the three points, respectively). Body weight was significantly reduced by 12 months (P=0.045). Serum alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase levels decreased significantly. There was no significant correlation between serum hepatobiliary enzyme levels and γ-body weight or visceral fat. But γ-GTP was correlated with subcutaneous fat (Spearman's P=0.004). During 1 year-interval, ipragliflozin significantly reduced subcutaneous adipose tissue and serum hepatobiliary enzyme levels, and may be useful in patients with obese diabetes.

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Sodium-glucose Co-transporter 2 Inhibitors Reduce the Abdominal Visceral Fat Area and May Influence the Renal Function in Patients with Type 2 Diabetes

Cited by 39 publications

References 24 publications

Dapagliflozin Aggravates Renal Injury via Promoting Gluconeogenesis in db/db Mice

Dapagliflozin Aggravates Renal Injury via Promoting Gluconeogenesis in db/db Mice

Beneficials Effects of Canagliflozin in a Weight-Centered Management in Patients with Type 2 Diabetes Mellitus in Real Practice

Long-Term Effects of Ipragliflozin on Adipose Tissue in Japanese Patients with Obese Type 2 Diabetes

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