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      The effect of dapagliflozin treatment on epicardial adipose tissue volume

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          Abstract

          Background

          Glycosuria produced by sodium–glucose co-transporter-2 (SGLT-2) inhibitors is associated with weight loss. SGLT-2 inhibitors reportedly might reduce the occurrence of cardiovascular events. Epicardial adipose tissue (EAT) is a pathogenic fat depot that may be associated with coronary atherosclerosis. The present study evaluated the relationship between an SGLT-2 inhibitor (dapagliflozin) and EAT volume.

          Methods

          In 40 diabetes mellitus patients with coronary artery disease (10 women and 30 men; mean age of all 40 patients was 67.2 ± 5.4 years), EAT volume was compared prospectively between the dapagliflozin treatment group (DG; n = 20) and conventional treatment group (CTG; n = 20) during a 6-month period. EAT was defined as any pixel that had computed tomography attenuation of − 150 to − 30 Hounsfield units within the pericardial sac. Metabolic parameters, including HbA1c, tumor necrotic factor-α (TNF-α), and plasminogen activator inhibitor-1 (PAI-1) levels, were measured at both baseline and 6-months thereafter.

          Results

          There were no significant differences at baseline of EAT volume and HbA1c, PAI-1, and TNF-α levels between the two treatment groups. After a 6-month follow-up, the change in HbA1c levels in the DG decreased significantly from 7.2 to 6.8%, while body weight decreased significantly in the DG compared with the CTG (− 2.9 ± 3.4 vs. 0.2 ± 2.4 kg, p = 0.01). At the 6-month follow-up, serum PAI-1 levels tended to decline in the DG. In addition, the change in the TNF-α level in the DG was significantly greater than that in the CTG (− 0.5 ± 0.7 vs. 0.03 ± 0.3 pg/ml, p = 0.03). Furthermore, EAT volume significantly decreased in the DG at the 6-month follow-up compared with the CTG (− 16.4 ± 8.3 vs. 4.7 ± 8.8 cm 3, p = 0.01). Not only the changes in the EAT volume and body weight, but also those in the EAT volume and TNF-α level, showed significantly positive correlation.

          Conclusion

          Treatment with dapagliflozin might improve systemic metabolic parameters and decrease the EAT volume in diabetes mellitus patients, possibly contributing to risk reduction in cardiovascular events.

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          Most cited references31

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          Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old.

          Obesity, defined by a body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) of 30.0 or more, is associated with an increased risk of death, but the relation between overweight (a BMI of 25.0 to 29.9) and the risk of death has been questioned. We prospectively examined BMI in relation to the risk of death from any cause in 527,265 U.S. men and women in the National Institutes of Health-AARP cohort who were 50 to 71 years old at enrollment in 1995-1996. BMI was calculated from self-reported weight and height. Relative risks and 95 percent confidence intervals were adjusted for age, race or ethnic group, level of education, smoking status, physical activity, and alcohol intake. We also conducted alternative analyses to address potential biases related to preexisting chronic disease and smoking status. During a maximum follow-up of 10 years through 2005, 61,317 participants (42,173 men and 19,144 women) died. Initial analyses showed an increased risk of death for the highest and lowest categories of BMI among both men and women, in all racial or ethnic groups, and at all ages. When the analysis was restricted to healthy people who had never smoked, the risk of death was associated with both overweight and obesity among men and women. In analyses of BMI during midlife (age of 50 years) among those who had never smoked, the associations became stronger, with the risk of death increasing by 20 to 40 percent among overweight persons and by two to at least three times among obese persons; the risk of death among underweight persons was attenuated. Excess body weight during midlife, including overweight, is associated with an increased risk of death. Copyright 2006 Massachusetts Medical Society.
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            Human epicardial adipose tissue is a source of inflammatory mediators.

            Inflammatory mediators that originate in vascular and extravascular tissues promote coronary lesion formation. Adipose tissue may function as an endocrine organ that contributes to an inflammatory burden in patients at risk of cardiovascular complications. In this study, we sought to compare expression of inflammatory mediators in epicardial and subcutaneous adipose stores in patients with critical CAD. Paired samples of epicardial and subcutaneous adipose tissues were harvested at the outset of elective CABG surgery (n=42; age 65+/-10 years). Local expression of chemokine (monocyte chemotactic protein [MCP]-1) and inflammatory cytokines (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) was analyzed by TaqMan real-time reverse transcription-polymerase chain reaction (mRNA) and by ELISA (protein release over 3 hours). Significantly higher levels of IL-1beta, IL-6, MCP-1, and TNF-alpha mRNA and protein were observed in epicardial adipose stores. Proinflammatory properties of epicardial adipose tissue were noted irrespective of clinical variables (diabetes, body mass index, and chronic use of statins or ACE inhibitors/angiotensin II receptor blockers) or plasma concentrations of circulating biomarkers. In a subset of samples (n=11), global gene expression was explored by DNA microarray hybridization and confirmed the presence of a broad inflammatory reaction in epicardial adipose tissue in patients with coronary artery disease. The above findings were paralleled by the presence of inflammatory cell infiltrates in epicardial adipose stores. Epicardial adipose tissue is a source of several inflammatory mediators in high-risk cardiac patients. Plasma inflammatory biomarkers may not adequately reflect local tissue inflammation. Current therapies do not appear to eliminate local inflammatory signals in epicardial adipose tissue.
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              Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.

              Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding. Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components. This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries. Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin. Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk. Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated. At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, -2.08 kg [95% confidence interval (CI)=-2.84 to -1.31; P<0.0001]; waist circumference, -1.52 cm (95% CI=-2.74 to -0.31; P=0.0143); FM, -1.48 kg (95% CI=-2.22 to -0.74; P=0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI=15.5 to 36.7; P<0.0001); VAT, -258.4 cm3 (95% CI=-448.1 to -68.6; nominal P=0.0084); SAT, -184.9 cm3 (95% CI=-359.7 to -10.1; nominal P=0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%. Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.
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                Author and article information

                Contributors
                +81-258-33-3111 , kirotaro19731013@yahoo.co.jp
                yoshifusa.aizawa@gmail.com
                shosho.yuasa@gmail.com
                shoohei.kishi@gmail.com
                koichi.fusee@gmail.com
                ta-sato320@tatikawa.or.jp
                chahomametah@yahoo.co.jp
                hitoshi.kitazawadesu@yahoo.co.jp
                tamatama19731013@yahoo.co.jp
                ma-sato106@tatikawa.or.jp
                kirotaro19731013@i.softbank.jp
                Journal
                Cardiovasc Diabetol
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central (London )
                1475-2840
                4 January 2018
                4 January 2018
                2018
                : 17
                : 6
                Affiliations
                ISNI 0000 0004 0531 5386, GRID grid.416822.b, Cardiology, , Tachikawa General Hospital, ; 561-1 Jyojyomachi Aza Yauchi, Nagaoka, Japan
                Article
                658
                10.1186/s12933-017-0658-8
                5753537
                29301516
                cd455b2e-2a52-4e87-a1ef-6b274e691b11
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 20 September 2017
                : 29 December 2017
                Categories
                Original Investigation
                Custom metadata
                © The Author(s) 2018

                Endocrinology & Diabetes
                sglt-2 inhibitor,epicardial adipose tissue,diabetes mellitus
                Endocrinology & Diabetes
                sglt-2 inhibitor, epicardial adipose tissue, diabetes mellitus

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