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1
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Mayyas F, Omeish A. Comparison of the cardioprotective effects of liraglutide, dapagliflozin and their combination in a rat model of diabetes induced by streptozotocin. Life Sci 2025; 375:123721. [PMID: 40389022 DOI: 10.1016/j.lfs.2025.123721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 05/02/2025] [Accepted: 05/16/2025] [Indexed: 05/21/2025]
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists positively affect diabetic cardiac complications. AIM To evaluate and compare the impact of liraglutide, dapagliflozin, and their combination on cardiac biomarkers of inflammation, oxidative stress, and fibrosis in a rat model of streptozotocin (STZ)-induced diabetes. METHODS Adult male Wistar rats were assigned into five groups (15-17 rats/group): control rats, diabetic rats (DM, single 50 mg/kg STZ intraperitoneally (IP)), diabetic rats treated with dapagliflozin (Dapa, 1 mg/kg by oral gavage), diabetic rats treated with liraglutide (Lira), 0.4 mg/kg subcutaneously (SC), and diabetic rats treated with both medications (Dapa+Lira) for 8 weeks. Cardiac biomarkers of inflammation, oxidative stress, and fibrosis were evaluated. RESULTS Dapagliflozin and/or liraglutide treatment lowered glucose levels, mostly in the combination group. Diabetes increased heart/body weight ratio, which was normalized by all treatments. DM increased cardiac inflammatory and oxidant markers, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), endothelin-1 (ET-1), myeloperoxidase (1), plasminogen activator inhibitor-2 (PAI-2), total nitrite, and thiobarbituric acid reactive substances (TBARS). Dapagliflozin normalized inflammatory markers levels, but combination with Lira added no benefit, except for PAI-2. Dapagliflozin normalized total nitrite and TBARS levels. Combining treatments further decreased nitrite and TBARS levels and normalized cardiac SOD activity. Both dapagliflozin and the combination normalized cardiac fibrosis and platelet-derived growth factor-BB (PDGF-BB) levels. CONCLUSION Dapagliflozin reduced cardiac fibrosis, and attenuated oxidative stress, and inflammation more effectively than liraglutide. Combining treatments improved oxidative status. Our findings support using dapagliflozin to prevent cardiovascular diseases more than liraglutide.
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Affiliation(s)
- Fadia Mayyas
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.
| | - Anood Omeish
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.
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2
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Deshmukh NJ, Kalshetti MS, Patil M, Nandanwar M, Sangle GV. Therapeutic Potential of Sotagliflozin in Animal Models of Non-alcoholic Fatty Liver Disease with and without Diabetes. Drug Res (Stuttg) 2025. [PMID: 40228542 DOI: 10.1055/a-2557-8927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025]
Abstract
Sotagliflozin, a dual SGLT1/2 inhibitor, enhances glucagon like peptide-1 (GLP-1) levels and GLP-1 receptor agonists are used to manage non-alcoholic fatty liver disease (NAFLD). Study investigates the effects of sotagliflozin on NAFLD, alone and combined with linagliptin, comparing outcomes in normoglycemic and hyperglycemic animal models.Obese fatty liver disease (FLD) model was induced by high-fat diet (HFD) feeding, while a diabetic non-alcoholic steatohepatitis (NASH) model was developed by administering a single dose of streptozotocin to neonatal mice, followed by HFD feeding post-weaning. At termination of the study, parameters including biochemical markers, inflammatory cytokines, hepatic lipid content, and histopathology were assessed.In NASH mice, sotagliflozin and linagliptin reduced hepatic triglycerides by 60% and 44%, respectively, and cholesterol by 46% and 49%. Their combination further decreased triglycerides by 68.5% and cholesterol by 83.9%. In FLD mice, sotagliflozin and linagliptin reduced triglycerides by 33% and 17%, respectively, and cholesterol by 46% and 21%. Combination treatment offered no benefit, reducing triglycerides by 38% and cholesterol by 27%. Both the treatments improved plasma fibroblast growth factor 21, hepatic interlukin-6, glucose tolerance, steatosis and mitigated fat pad weight, but their combination did not show additional benefit. However, combination treatment demonstrated added benefit in modulating NAFLD activity score, liver enzymes, glycogenated hepatic nuclei, plasma glucose and active GLP-1 levels.Study underscores sotagliflozin's potential to mitigate NAFLD and highlights the benefit of combining it with linagliptin in hyperglycemic NASH model, which showed limited efficacy in normoglycemic FLD mice.
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Affiliation(s)
- Nitin J Deshmukh
- D.S.T.S. Mandal's Collage of Pharmacy, Solapur, Maharashtra, India
- Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India
| | - M S Kalshetti
- D.S.T.S. Mandal's Collage of Pharmacy, Solapur, Maharashtra, India
| | - Mohan Patil
- Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India
- Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Australia
| | - Manohar Nandanwar
- Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India
| | - Ganesh V Sangle
- Wockhardt Research Centre, D4 MIDC, Chikalthana, Aurangabad, Maharashtra, India
- Kashiv BioSciences Private Limited, Ahmedabad, Gujarat
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Yokomizo H, Kawanami D, Sonoda N, Ono Y, Maeda Y, Itoh J, Tohyama T, Hirose M, Watanabe H, Kishimoto J, Ogawa Y, Inoguchi T. Relationship of dietary intake and eating behaviors with glycemic control and body weight under long-term treatment with dapagliflozin: an exploratory prospective study. Diabetol Int 2025; 16:303-315. [PMID: 40166435 PMCID: PMC11954782 DOI: 10.1007/s13340-025-00794-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 01/09/2025] [Indexed: 04/02/2025]
Abstract
Sodium glucose cotransporter-2 (SGLT2) inhibitors improve glycemic control and reduce body weight (BW) in individuals with type 2 diabetes. However, there are still concerns that compensatory hyperphagia may affect their effects. Here, we performed an exploratory prospective study to investigate whether dietary intake and/or eating behaviors affect glycemic control and BW under long-term treatment with dapagliflozin. Fifty-three Japanese individuals with type 2 diabetes received dapagliflozin 5 mg daily for 104 weeks, with frequent assessments of HbA1c, BW, body composition, dietary intake, and eating behaviors. Dietary intake was evaluated using a brief self-administered diet history questionnaire, and eating behavior was evaluated using the Dutch Eating Behavior Questionnaire. The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000019192). At 104 weeks, HbA1c decreased by 0.5% and BW decreased by 2.8 kg (both p < 0.001), with a dominant decrease in body fat mass by 2.2 kg (p < 0.001). No significant change was observed in calorie intake or the proportion of carbohydrates, protein, and fat. The change (∆) in HbA1c was significantly correlated with basal HbA1c, basal triglyceride levels, ∆BMI (body mass index), ∆BFP (body fat percentage), and ∆ferritin levels. The ∆BMI was significantly correlated with only the ∆BFP. Neither the ∆HbA1c nor ∆BMI was significantly correlated with dietary intake, any type of eating behavior, or changes in these parameters during this study. In conclusion, dapagliflozin treatment improved glycemic control and reduced BW without being affected by any changes in dietary intake or eating behavior over 104 weeks. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-025-00794-1.
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Affiliation(s)
- Hisashi Yokomizo
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
- Department of Endocrinology and Diabetes, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
| | - Daiji Kawanami
- Department of Endocrinology and Diabetes, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
| | | | - Yasuhiro Ono
- Department of Internal Medicine, Takagi Hospital, Fukuoka, Japan
| | - Yasutaka Maeda
- MINAMI Diabetes Clinical Research Center, Clinic Masae Minami, Fukuoka, Japan
| | - Jun Itoh
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
| | - Takeshi Tohyama
- Center for Advanced Medical Open Innovation, Kyushu University, Fukuoka, Japan
| | - Masayuki Hirose
- Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
| | - Hiroko Watanabe
- Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
| | - Junji Kishimoto
- Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
| | - Toyoshi Inoguchi
- Fukuoka City Health Promotion Support Center, Fukuoka City Medical Association, Fukuoka, Japan
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Popoviciu MS, Salmen T, Reurean-Pintilei D, Voiculescu V, Pantea Stoian A. SGLT-2i-A Useful Tool for Real-Life Metabolic and Body Weight Control in Type 2 Diabetes Mellitus Patients. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:548. [PMID: 40142359 PMCID: PMC11944101 DOI: 10.3390/medicina61030548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/12/2025] [Accepted: 03/19/2025] [Indexed: 03/28/2025]
Abstract
Background and Objectives: Elevated blood sugar poses an increasingly significant challenge to healthcare systems worldwide. We aimed to assess the efficacy of the SGLT-2i class in achieving metabolic control in patients with T2DM within a real-world standard-of-care regimen. Material and Methods: A prospective analysis was conducted over 6 months including individuals receiving care in an outpatient department, with baseline assessments and follow-ups at 3 and 6 months. Results: A total of 280 patients were assessed, with a mean age of 63.69 ± 9.16, 53.9% of which were males, with a mean DM duration of 9.06 ± 5.64 years, and a DM duration varying from 6 months to 24 years. Discussion: Real-world evidence bridges the gap between guidelines and practice. It emphasizes the need to overcome clinical inertia in order to optimize patient outcomes and contributes to the body of evidence supporting the efficacy of fixed-dose SGLT-2i combinations in managing T2DM and associated comorbidities. Conclusions: We demonstrate the significant clinical and therapeutic impact of SGLT-2i in T2DM patients in a real-world setting. This class of medication not only positively influences glycemic and weight control but also reduces CV risk factors and visceral adiposity.
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Affiliation(s)
| | - Teodor Salmen
- Doctoral School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Delia Reurean-Pintilei
- Department of Medical-Surgical and Complementary Sciences, Faculty of Medicine and Biological Sciences, “Ștefan cel Mare” University, 720229 Suceava, Romania
| | - Vlad Voiculescu
- Dermatology Department, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Anca Pantea Stoian
- Diabetes, Nutrition and Metabolic Diseases Department, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
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Ojaimi RE, Cheisson G, Cosson E, Ichai C, Jacqueminet S, Nicolescu-Catargi B, Ouattara A, Tauveron I, Valensi P, Benhamou D. Recent advances in perioperative care of patients using new antihyperglycaemic drugs and devices dedicated to diabetes. Anaesth Crit Care Pain Med 2025; 44:101468. [PMID: 39743045 DOI: 10.1016/j.accpm.2024.101468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 08/28/2024] [Indexed: 01/04/2025]
Affiliation(s)
- Rami El Ojaimi
- Department of Anaesthesia and Intensive Care Medicine, Hôpital Henri Mondor, AP-HP, 1, rue Gustave Eiffel, 94000, Créteil, France.
| | - Gaëlle Cheisson
- Department of Anaesthesia and Intensive Care Medicine, Hôpital Bicêtre, AP-HP, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France
| | - Emmanuel Cosson
- Department of Endocrinology-Diabetology-Nutrition, Avicenne Hospital, University of Paris 13, Sorbonne Paris Cité, CRNH-IdF, CINFO, AP-HP, Bobigny, France; Recherche en Epidémiologie Nutritionnelle (EREN), Université Sorbonne Paris Nord and Université Paris Cité, INSERM, INRAE, CNAM, Center of Research in Epidemiology and StatisticS (CRESS), Bobigny, France
| | - Carole Ichai
- Department of Intensive Care Medicine, Université Côte d'Azur, Hôpital Pasteur 2, CHU de Nice, 30, voie Romaine, 06001 Nice cedex 1, France
| | - Sophie Jacqueminet
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris (APHP), Diabetology Department, La Pitié Salpêtrière-Charles Foix University Hospital, Institute of Cardiometabolism and Nutrition ICAN, Paris, France
| | - Bogdan Nicolescu-Catargi
- Department of Endocrinology ad Metabolic Diseases, Hôpital Saint-André, Bordeaux University Hospital, 1, rue Jean-Burguet, 33000 Bordeaux, France
| | - Alexandre Ouattara
- CHU Bordeaux, Department of Cardiovascular Anaesthesia and Critical Care, F-33000 Bordeaux, France; Univ. Bordeaux, INSERM, UMR 1034, Biology of Cardiovascular Diseases, F-33600 Pessac, France
| | - Igor Tauveron
- Department of Endocrinology and Diabetology, Clermont Ferrand University Hospital, 58, rue Montalembert, 63000 Clermont-Ferrand, France
| | - Paul Valensi
- Polyclinique d'Aubervilliers, Aubervilliers and Université Paris-Nord, Bobigny, France
| | - Dan Benhamou
- Department of Anaesthesia and Intensive Care Medicine, Hôpital Bicêtre, AP-HP, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France.
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Makri ES, Xanthopoulos K, Pettas S, Goulas A, Mavrommatis-Parasidis P, Makri E, Tsingotjidou A, Cheva A, Ntenti C, Zacharis CK, Ballaouri I, Gerou S, Polyzos SA. Limited preventive effects of empagliflozin against metabolic dysfunction-associated steatotic liver disease in a mouse model of fast food diet. Hormones (Athens) 2024:10.1007/s42000-024-00621-3. [PMID: 39699846 DOI: 10.1007/s42000-024-00621-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024]
Abstract
PURPOSE Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent disease with limited treatment options. The aim of this study was to evaluate the preventive effects of a sodium-glucose co-transporter (SGLT)-2 inhibitor, empagliflozin, on a dietary mouse model of MASLD. METHODS In total, 24 C57BL/6 J mice of both sexes were randomly allocated to three groups, as follows: the fast food diet (FFD) group (eight mice, receiving a high-fat, high-cholesterol, high-fructose diet, FFD), the EMPA group (eight mice, fed a FFD with 10 mg/kg/d empagliflozin), and the chow diet (eight mice, CD) group. The mice were weighed and blood samples were drawn every 4 weeks; after 25 weeks the mice were euthanized, at which point liver tissues were histologically evaluated. RESULTS After 25 weeks, there was no significant difference in body weight between the three groups, whereas liver-to-body weight ratio was greater in the EMPA compared to the CD group (p = 0.002). Hepatic fibrosis was marginally different between the three groups (p = 0.045). Fibrosis stage 1 was present in five mice on FFD (62.5%), in one mouse on EMPA (12.5%), and in one mouse on CD (12.5%). Lipogenic, inflammatory, and fibrogenic genes did not differ between the EMPA and FFD groups. Interestingly, mRNA encoding for SGLT-1 and SGLT-2 was detected in the mouse livers. CONCLUSIONS Empagliflozin treatment in mice on a FFD did not result in any significant effects on morphological, biochemical, or histological features or on expression of hepatic genes associated with MASLD compared to those fed a FFD without empagliflozin. The observed effects on mild hepatic fibrosis warrant validation, possibly via studies of longer duration.
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Affiliation(s)
- Evangelia S Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece.
| | - Konstantinos Xanthopoulos
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Institute of Applied Biosciences, Centre for Research and Technology, Thessaloniki, Greece
| | - Spyros Pettas
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece
| | - Panagiotis Mavrommatis-Parasidis
- Laboratory of Anatomy, Histology & Embryology, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleftheria Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece
| | - Anastasia Tsingotjidou
- Laboratory of Anatomy, Histology & Embryology, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Angeliki Cheva
- Department of Pathology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Charikleia Ntenti
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece
| | - Constantinos K Zacharis
- Laboratory of Pharmaceutical Analysis, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | | | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece
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7
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Matsushita K, Sato C, Bruckert C, Gong D, Amissi S, Hmadeh S, Fakih W, Remila L, Lessinger JM, Auger C, Jesel L, Ohlmann P, Kauffenstein G, Schini-Kerth VB, Morel O. Potential of dapagliflozin to prevent vascular remodeling in the rat carotid artery following balloon injury. Atherosclerosis 2024; 397:117595. [PMID: 38879387 DOI: 10.1016/j.atherosclerosis.2024.117595] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 05/17/2024] [Accepted: 05/21/2024] [Indexed: 09/22/2024]
Abstract
BACKGROUND AND AIMS Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular events independently of glycemic control. However, the possibility that SGLT2 inhibitors improve vascular restenosis is unknown. The aim of this study was to examine whether dapagliflozin could prevent neointima thickening following balloon injury and, if so, to determine the underlying mechanisms. METHODS Saline, dapagliflozin (1.5 mg/kg/day), or losartan (30 mg/kg/day) was administered orally for five weeks to male Wistar rats. Balloon injury of the left carotid artery was performed a week after starting the treatment and rats were sacrificed 4 weeks later. The extent of neointima was assessed by histomorphometric and immunofluorescence staining analyses. Vascular reactivity was assessed on injured and non-injured carotid artery rings, changes of target factors by immunofluorescence, RT-qPCR, and histochemistry. RESULTS Dapagliflozin and losartan treatments reduced neointima thickening by 32 % and 27 %, respectively. Blunted contractile responses to phenylephrine and relaxations to acetylcholine and down-regulation of eNOS were observed in the injured arteries. RT-qPCR investigations indicated an increased in gene expression of inflammatory (IL-1beta, VCAM-1), oxidative (p47phox, p22phox) and fibrotic (TGF-beta1) markers in the injured carotid. While these changes were not affected by dapagliflozin, increased levels of AT1R and NTPDase1 (CD39) and decreased levels of ENPP1 were observed in the restenotic carotid artery of the dapagliflozin group. CONCLUSIONS Dapagliflozin effectively reduced neointimal thickening. The present data suggest that dapagliflozin prevents restenosis through interfering with angiotensin and/or extracellular nucleotides signaling. SGLT2 represents potential new target for limiting vascular restenosis.
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Affiliation(s)
- Kensuke Matsushita
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France; Université de Strasbourg, Pôle D'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France
| | - Chisato Sato
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France; Université de Strasbourg, Pôle D'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France
| | - Christophe Bruckert
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France
| | - DalSeong Gong
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France
| | - Said Amissi
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France
| | - Sandy Hmadeh
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France
| | - Walaa Fakih
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France
| | - Lamia Remila
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France
| | - Jean-Marc Lessinger
- CHU de Strasbourg, Laboratoire de Biochimie Clinique et Biologie Moléculaire, 67091, Strasbourg, France
| | - Cyril Auger
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France
| | - Laurence Jesel
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France; Université de Strasbourg, Pôle D'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France
| | - Patrick Ohlmann
- Université de Strasbourg, Pôle D'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France
| | - Gilles Kauffenstein
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France
| | - Valérie B Schini-Kerth
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France
| | - Olivier Morel
- UR 3074, Translational CardioVascular Medicine, Biomedicine Research Centre of Strasbourg, FMTS, Université de Strasbourg, Strasbourg, France; Université de Strasbourg, Pôle D'Activité Médico-Chirurgicale Cardio-Vasculaire, Nouvel Hôpital Civil, Centre Hospitalier Universitaire, Strasbourg, France; Hanoï Medical University, Hanoi, Viet Nam.
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Xu Y, Liang W, Huo J, Zhang T, Feng T, Li M, Zhu Z, Zhou P, Zhu S, Lu Y, Wang L. Effect of dapagliflozin on pulmonary vascular remodeling in rats with chronic hypoxic pulmonary arterial hypertension. J Recept Signal Transduct Res 2024; 44:174-180. [PMID: 39673299 DOI: 10.1080/10799893.2024.2433083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 11/17/2024] [Accepted: 11/18/2024] [Indexed: 12/16/2024]
Abstract
OBJECTIVE To investigate the effects of sodium-glucose co-transporter 2 inhibitor dapagliflozin on pulmonary vascular remodeling in a rat model of chronic hypoxic pulmonary arterial hypertension. METHODS Eighteen female Sprague-Dawley rats were divided into three groups: control (CON), chronic hypoxia (HYP), and chronic hypoxia + dapagliflozin. The HYP and dapagliflozin groups were subjected to hypoxia and received saline or dapagliflozin. The CON group was normoxic and received saline. Body weight and fasting blood glucose were measured, and after 21 days, lung and heart tissues were analyzed for pulmonary artery reconstruction and right ventricular hypertrophy. Western blotting assessed Bax and Bcl-2 protein levels. RESULTS Chronic hypoxia increased pulmonary artery wall thickness and lung fibrosis and caused right ventricular hypertrophy. Dapagliflozin reduced these changes, decreasing artery wall thickness, fibrosis, and hypertrophy while increasing the Bax/Bcl-2 ratio. CONCLUSION Dapagliflozin alleviates chronic hypoxia-induced pulmonary artery wall thickening and lung tissue fibrosis in rats, potentially through proapoptotic effects.
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Affiliation(s)
- Yi Xu
- Central Laboratory of Hospital, Xuzhou Medical University Affiliated Hospital (The First People's Hospital of Lianyungang), Lianyungang, China
- Department of Pharmacy, Xuzhou Medical University Affiliated Hospital (The First People's Hospital of Lianyungang), Lianyungang, China
| | - Wenxue Liang
- Central Laboratory of Hospital, Xuzhou Medical University Affiliated Hospital (The First People's Hospital of Lianyungang), Lianyungang, China
| | - Juan Huo
- Central Laboratory of Hospital, Xuzhou Medical University Affiliated Hospital (The First People's Hospital of Lianyungang), Lianyungang, China
| | - Ting Zhang
- Central Laboratory of Hospital, Xuzhou Medical University Affiliated Hospital (The First People's Hospital of Lianyungang), Lianyungang, China
| | - Tianpu Feng
- Central Laboratory of Hospital, Xuzhou Medical University Affiliated Hospital (The First People's Hospital of Lianyungang), Lianyungang, China
- Department of Pharmacy, Xuzhou Medical University Affiliated Hospital (The First People's Hospital of Lianyungang), Lianyungang, China
| | - Man Li
- Central Laboratory of Hospital, Xuzhou Medical University Affiliated Hospital (The First People's Hospital of Lianyungang), Lianyungang, China
| | - Zhemin Zhu
- Central Laboratory of Hospital, Xuzhou Medical University Affiliated Hospital (The First People's Hospital of Lianyungang), Lianyungang, China
| | - Ping Zhou
- Department of Endocrinology, The Second People's Hospital of Lianyungang, Lianyungang, China
| | - Shasha Zhu
- Department of Endocrinology, Nanjing University of Traditional Chinese Medicine Lianyungang Affiliated Hospital, Lianyungang, China
| | - Yingzhi Lu
- Department of Oncology, The Second People's Hospital of Lianyungang, Lianyungang, China
| | - Lei Wang
- Central Laboratory of Hospital, Xuzhou Medical University Affiliated Hospital (The First People's Hospital of Lianyungang), Lianyungang, China
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Isogawa M, Makino H, Son C, Nishimura K, Hirata T, Kasama S, Miyamoto Y, Noguchi M, Kasahara M, Hosoda K. Comparison of canagliflozin and teneligliptin on energy intake and body weight in Japanese patients with Type 2 diabetes: a subanalysis of the CANTABILE study. BMC Endocr Disord 2024; 24:153. [PMID: 39160513 PMCID: PMC11331643 DOI: 10.1186/s12902-024-01690-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 08/13/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND While the Sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) are widely used for the glycemic control in type 2 diabetes mellitus, the differences in the effects of SGLT2 inhibitors and DPP4 inhibitors on energy intake and diabetes-related indicators are unclear. METHODS This was a subanalysis of the CANTABILE study which compared the effects of canagliflozin and teneligliptin on metabolic factors in Japanese patients with Type 2 diabetes. The changes at 24 weeks from the baseline of the diabetes-related indicators including Hemoglobin A1c (HbA1c), energy intake and body weight were compared between the canagliflozin and teneligliptin groups. RESULTS Seventy-five patients in the canagliflozin group and 70 patients in the teneligliptin group were analyzed. A significant decrease in HbA1c was observed in both groups. In the teneligliptin group, although energy intake was significantly reduced, there was no significant change in body weight. Conversely, in the canagliflozin group, although energy intake tended to increase, body weight significantly decreased. CONCLUSION Canagliflozin and teneligliptin have different effects on the dietary status of patients with Type 2 diabetes. Our result suggests that canagliflozin can manage blood glucose without weight gain, even with increased energy intake.
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Affiliation(s)
- Masahiro Isogawa
- Institute for Clinical and Translational Science, Nara Medical University Hospital, 840 Shijo-Cho, Kashihara, Nara, 634-8522, Japan
| | - Hisashi Makino
- Division of Diabetes and Lipid Metabolism, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan.
| | - Cheol Son
- Department of Diabetes and Endocrinology, Kobe City Nishi-Kobe Medical Center, 5-7-1 Koji-Dai Nishi-Ku, Kobe, Hyogo, 651-2273, Japan
| | - Kunihiro Nishimura
- Department of Preventive Medicine, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan
| | - Takumi Hirata
- Human Care Research Team, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi-Ku, Tokyo, 173-0015, Japan
| | - Shu Kasama
- Center for Clinical Research and Advanced Medicine, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan
| | - Yoshihiro Miyamoto
- Open Innovation Center (OIC), National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan
| | - Michio Noguchi
- Division of Diabetes and Lipid Metabolism, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan
| | - Masato Kasahara
- Institute for Clinical and Translational Science, Nara Medical University Hospital, 840 Shijo-Cho, Kashihara, Nara, 634-8522, Japan
| | - Kiminori Hosoda
- Diabetes Center, Ijinkai Takeda General Hospital, 28-1 Ishidamoriminami-cho, Fushimi-ku, Kyoto, 601-1495, Japan
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10
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Tsukamoto S, Kobayashi K, Toyoda M, Tone A, Kawanami D, Suzuki D, Tsuriya D, Machimura H, Shimura H, Wakui H, Takeda H, Yokomizo H, Takeshita K, Chin K, Kanasaki K, Miyauchi M, Saburi M, Morita M, Yomota M, Kimura M, Hatori N, Nakajima S, Ito S, Murata T, Matsushita T, Furuki T, Hashimoto T, Umezono T, Muta Y, Takashi Y, Tamura K. Effect of preceding drug therapy on the renal and cardiovascular outcomes of combined sodium-glucose cotransporter-2 inhibitor and glucagon-like peptide-1 receptor agonist treatment in patients with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2024; 26:3248-3260. [PMID: 38764356 DOI: 10.1111/dom.15652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/27/2024] [Accepted: 04/28/2024] [Indexed: 05/21/2024]
Abstract
AIM To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 receptor agonist (GLP-1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP-1RA first. METHODS We included 438 patients with CKD (GLP-1RA-first group, n = 223; SGLT2 inhibitor-first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)-matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only. RESULTS Using the PS-matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP-1RA-first group, 10%; SGLT2 inhibitor-first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was 1.83 (95% CI 1.71 to 1.95; p < 0.001). CONCLUSION Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was significant. These results suggest that, in GLP-1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP-1RA treatment may lead to more favourable renal outcomes.
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Affiliation(s)
- Shunichiro Tsukamoto
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kazuo Kobayashi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masao Toyoda
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Atsuhito Tone
- Department of Internal Medicine, Diabetes Center, Okayama Saiseikai General Hospital, Okayama, Japan
| | - Daiji Kawanami
- Department of Endocrinology and Diabetes, Fukuoka University School of Medicine, Fukuoka, Japan
| | | | - Daisuke Tsuriya
- Division of Endocrinology and Metabolism, 2nd Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | | | | | - Hiromichi Wakui
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | | | - Hisashi Yokomizo
- Department of Endocrinology and Diabetes, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Kei Takeshita
- Division of Endocrinology and Metabolism, 2nd Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | | | - Keizo Kanasaki
- Department of Internal Medicine 1, Endocrinology and Metabolism, Shimane University Faculty of Medicine, Izumo, Japan
| | | | - Masuo Saburi
- Department of Diabetology, Endocrinology and Metabolism, Tokyo Medical University Hachioji Medical Center, Hachioji, Japan
| | - Miwa Morita
- Department of Internal Medicine 1, Endocrinology and Metabolism, Shimane University Faculty of Medicine, Izumo, Japan
| | - Miwako Yomota
- Department of Internal Medicine 1, Endocrinology and Metabolism, Shimane University Faculty of Medicine, Izumo, Japan
| | - Moritsugu Kimura
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | | | | | - Shun Ito
- Department of Internal Medicine, Sagamihara Red Cross Hospital, Sagamihara, Japan
| | - Takashi Murata
- Department of Clinical Nutrition, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
- Diabetes Center, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
| | - Takaya Matsushita
- Department of Diabetology, Endocrinology and Metabolism, Tokyo Medical University Hachioji Medical Center, Hachioji, Japan
| | | | - Takuya Hashimoto
- Division of Endocrinology and Metabolism, 2nd Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | | | - Yoshimi Muta
- Department of Endocrinology and Diabetes, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Yuichi Takashi
- Department of Endocrinology and Diabetes, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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11
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Huttasch M, Roden M, Kahl S. Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? Metabolism 2024; 157:155937. [PMID: 38782182 DOI: 10.1016/j.metabol.2024.155937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 04/25/2024] [Accepted: 05/12/2024] [Indexed: 05/25/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) closely associates with obesity and type 2 diabetes. Lifestyle intervention and bariatric surgery aiming at substantial weight loss are cornerstones of MASLD treatment by improving histological outcomes and reducing risks of comorbidities. Originally developed as antihyperglycemic drugs, incretin (co-)agonists and SGLT2 inhibitors also reduce steatosis and cardiorenovascular events. Certain incretin agonists effectively improve histological features of MASLD, but not fibrosis. Of note, beneficial effects on MASLD may not necessarily require weight loss. Despite moderate weight gain, one PPARγ agonist improved adipose tissue and MASLD with certain benefit on fibrosis in post-hoc analyses. Likewise, the first THRβ-agonist was recently provisionally approved because of significant improvements of MASLD and fibrosis. We here discuss liver-related and metabolic effects induced by different MASLD treatments and their association with weight loss. Therefore, we compare results from clinical trials on drugs acting via weight loss (incretin (co)agonists, SGLT2 inhibitors) with those exerting no weight loss (pioglitazone; resmetirom). Furthermore, other drugs in development directly targeting hepatic lipid metabolism (lipogenesis inhibitors, FGF21 analogs) are addressed. Although THRβ-agonism may effectively improve hepatic outcomes, MASLD treatment concepts should consider all cardiometabolic risk factors for effective reduction of morbidity and mortality in the affected people.
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Affiliation(s)
- Maximilian Huttasch
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany.
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Sabine Kahl
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research (DZD), Partner Düsseldorf, München-Neuherberg, Germany.
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12
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Duan HY, Barajas-Martinez H, Antzelevitch C, Hu D. The potential anti-arrhythmic effect of SGLT2 inhibitors. Cardiovasc Diabetol 2024; 23:252. [PMID: 39010053 PMCID: PMC11251349 DOI: 10.1186/s12933-024-02312-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 06/16/2024] [Indexed: 07/17/2024] Open
Abstract
Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) were initially recommended as oral anti-diabetic drugs to treat type 2 diabetes (T2D), by inhibiting SGLT2 in proximal tubule and reduce renal reabsorption of sodium and glucose. While many clinical trials demonstrated the tremendous potential of SGLT2i for cardiovascular diseases. 2022 AHA/ACC/HFSA guideline first emphasized that SGLT2i were the only drug class that can cover the entire management of heart failure (HF) from prevention to treatment. Subsequently, the antiarrhythmic properties of SGLT2i have also attracted attention. Although there are currently no prospective studies specifically on the anti-arrhythmic effects of SGLT2i. We provide clues from clinical and fundamental researches to identify its antiarrhythmic effects, reviewing the evidences and mechanism for the SGLT2i antiarrhythmic effects and establishing a novel paradigm involving intracellular sodium, metabolism and autophagy to investigate the potential mechanisms of SGLT2i in mitigating arrhythmias.
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Affiliation(s)
- Hong-Yi Duan
- Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060, Hubei, China
| | - Hector Barajas-Martinez
- Lankenau Institute for Medical Research, Lankenau Heart Institute, Wynnewood, PA, 19096, USA
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, 19107, USA
| | - Charles Antzelevitch
- Lankenau Institute for Medical Research, Lankenau Heart Institute, Wynnewood, PA, 19096, USA
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, 19107, USA
| | - Dan Hu
- Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei, China.
- Hubei Key Laboratory of Cardiology, Wuhan, 430060, Hubei, China.
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13
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Murayama T, Hosojima M, Kabasawa H, Tanaka T, Kitamura N, Tanaka M, Kuwahara S, Suzuki Y, Narita I, Saito A. Changes in daily intake of nutrients and foods including confectionery after the initiation of empagliflozin in Japanese patients with type 2 diabetes: a pilot study. BMC Nutr 2024; 10:95. [PMID: 38965589 PMCID: PMC11229015 DOI: 10.1186/s40795-024-00902-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 06/28/2024] [Indexed: 07/06/2024] Open
Abstract
INTRODUCTION It is unclear how dietary intake changes after sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment is started in patients with type 2 diabetes. METHODS We performed a non-controlled, open-label study that enrolled 51 patients with type 2 diabetes. The patients were newly administered empagliflozin, and their dietary habits were examined using a self-administered diet history questionnaire at the beginning of the study and after 24 weeks. We investigated the association of changes in HbA1c and body weight with changes in energy, nutrient, and food group intakes. RESULTS At 24 weeks after the start of the study, HbA1c improved significantly and body weight decreased. In the food group, only the intake of confectionery increased, and there were no significant differences in the association between changes in HbA1c and body weight and changes in energy, nutrient, and food group intakes after 24 weeks. However, a significant negative correlation was found between change in HbA1c after 4 weeks and change in energy intake after 24 weeks, and principal component analysis showed an association between change in HbA1c levels after 4 weeks and change in energy intake and some food group intakes including confectionery after 24 weeks. CONCLUSION In this study, after 24 weeks of treatment with empagliflozin, only intake of confectionery increased. Early assessment by dietitians after initiation of SGLT2i treatment might be important because our data suggested that the reduction in blood glucose levels after the start of empagliflozin was associated with a subsequent increase in energy intake. TRIAL REGISTRATION University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) on September 5, 2016 (registration ID, UMIN000002309|| http://www.umin.ac.jp/ctr/ ).
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Affiliation(s)
- Toshiko Murayama
- Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan
- Department of Health Nutrition, University of Niigata Prefecture Faculty of Human Life Studies, Niigata City, Niigata, Japan
| | - Michihiro Hosojima
- Department of Clinical Nutrition Science, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan.
| | - Hideyuki Kabasawa
- Department of Clinical Nutrition Science, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Takahiro Tanaka
- Clinical and Translational Research Center, Niigata University Medical and Dental Hospital, Niigata City, Niigata, Japan
| | - Nobutaka Kitamura
- Clinical and Translational Research Center, Niigata University Medical and Dental Hospital, Niigata City, Niigata, Japan
| | - Mai Tanaka
- Department of Clinical Nutrition Science, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8510, Japan
| | - Shoji Kuwahara
- Department of Applied Molecular Medicine, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan
- Laboratory of Clinical Nutrition, Department of Nutrition, School of Human Cultures, The University of Shiga Prefecture, Hikone, Shiga, Japan
| | - Yoshiki Suzuki
- Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan
| | - Ichiei Narita
- Division of Clinical Nephrology and Rheumatology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan
| | - Akihiko Saito
- Department of Applied Molecular Medicine, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan
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Cuatrecasas G, De Cabo F, Coves MJ, Patrascioiu I, Aguilar G, Cuatrecasas G, March S, Calbo M, Rossell O, Balfegó M, Benito C, Di Gregorio S, Garcia Lorda P, Muñoz E. Dapagliflozin added to metformin reduces perirenal fat layer in type 2 diabetic patients with obesity. Sci Rep 2024; 14:10832. [PMID: 38734755 PMCID: PMC11088615 DOI: 10.1038/s41598-024-61590-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 05/07/2024] [Indexed: 05/13/2024] Open
Abstract
Sodium-glucose co-transporters type 2 inhibitors (SLGT2i) are highly effective in controlling type 2 diabetes, but reported beneficial cardiovascular effects suggest broader actions on insulin resistance. Weight loss may be initially explained by glycosuria-induced net caloric output and secondary volumetric reduction, but its maintenance could be due to loss of visceral fat mass. Structured ultrasound (US) imaging of abdominal adipose tissue ("eco-obesity") is a recently described methodology used to measure 5 consecutive layers of abdominal fat, not assessable by DEXA or CT scan: superficial subcutaneous (SS), deep subcutaneous (DS), preperitoneal (PP), omental (Om) and right perirenal (RK). PP, Om and RK are predictors of metabolic syndrome (MS) with defined cut-off points. To assess the effect of SLGT2i on every fat depot we enrolled 29 patients with type 2 Diabetes (HbA1c 6.5-9%) and Obesity (IMC > 30 kg/m2) in an open-label, randomized, phase IV trial (EudraCT: 2019-000979-16): the Omendapa trial. Diabetes was diagnosed < 12 months before randomization and all patients were treatment naïve. 14 patients were treated with metformin alone (cohort A) and 15 were treated with metformin + dapaglifozin (cohort B). Anthropometric measures and laboratory tests for glucose, lipid profile, insulin, HOMA, leptin, ultrasensitive-CRP and microalbuminuria (MAL) were done at baseline, 3rd and 6th months. At 6th month, weight loss was -5.5 ± 5.2 kg (5.7% from initial weight) in cohort A and -8.4 ± 4.4 kg (8.6%) in cohort B. Abdominal circumference showed a -2.7 ± 3.1 cm and -5.4 ± 2.5 cm reduction, respectively (p = 0.011). Both Metformin alone (-19.4 ± 20.1 mm; -21.7%) or combined with Dapaglifozin (-20.5 ± 19.4 mm; -21.8%) induced significant Om fat reduction. 13.3% of cohort A patients and 21.4% of cohort's B reached Om thickness below the cut-off for MS criteria. RK fat loss was significantly greater in cohort B group compared to cohort A, at both kidneys. Only in the Met + Dapa group, we observed correlations between Om fat with leptin/CRP/MAL and RK fat with HOMA-IR. US is a useful clinical tool to assess ectopic fat depots. Both Metformin and Dapaglifozin induce fat loss in layers involved with MS but combined treatment is particularly effective in perirenal fat layer reduction. Perirenal fat should be considered as a potential target for cardiovascular dapaglifozin beneficial effects.
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Affiliation(s)
- Guillem Cuatrecasas
- CP Endocrinologia SLP, 08037, Barcelona, Spain.
- Center for Obesity Management EASO, Clinica Sagrada Familia, Barcelona, Spain.
- Facultat Ciencies Salut, Open University Catalonia (UOC), Barcelona, Spain.
| | - Francisco De Cabo
- Ultrasound Department, Institut Guirado for Radiology, Barcelona, Spain
| | - M José Coves
- CP Endocrinologia SLP, 08037, Barcelona, Spain
- Center for Obesity Management EASO, Clinica Sagrada Familia, Barcelona, Spain
| | - Ioana Patrascioiu
- CP Endocrinologia SLP, 08037, Barcelona, Spain
- Center for Obesity Management EASO, Clinica Sagrada Familia, Barcelona, Spain
| | - Gerardo Aguilar
- CP Endocrinologia SLP, 08037, Barcelona, Spain
- Center for Obesity Management EASO, Clinica Sagrada Familia, Barcelona, Spain
| | | | - Sonia March
- CP Endocrinologia SLP, 08037, Barcelona, Spain
- Center for Obesity Management EASO, Clinica Sagrada Familia, Barcelona, Spain
| | - Marta Calbo
- CP Endocrinologia SLP, 08037, Barcelona, Spain
- Center for Obesity Management EASO, Clinica Sagrada Familia, Barcelona, Spain
| | - Olga Rossell
- CP Endocrinologia SLP, 08037, Barcelona, Spain
- Center for Obesity Management EASO, Clinica Sagrada Familia, Barcelona, Spain
| | - Mariona Balfegó
- CP Endocrinologia SLP, 08037, Barcelona, Spain
- Center for Obesity Management EASO, Clinica Sagrada Familia, Barcelona, Spain
| | - Camila Benito
- CP Endocrinologia SLP, 08037, Barcelona, Spain
- Center for Obesity Management EASO, Clinica Sagrada Familia, Barcelona, Spain
| | - Silvana Di Gregorio
- CP Endocrinologia SLP, 08037, Barcelona, Spain
- Center for Obesity Management EASO, Clinica Sagrada Familia, Barcelona, Spain
| | - Pilar Garcia Lorda
- Facultat Ciencies Salut, Open University Catalonia (UOC), Barcelona, Spain
- Cognitive NeuroLab, Barcelona, Spain
| | - Elena Muñoz
- Facultat Ciencies Salut, Open University Catalonia (UOC), Barcelona, Spain
- Cognitive NeuroLab, Barcelona, Spain
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Morace C, Lorello G, Bellone F, Quartarone C, Ruggeri D, Giandalia A, Mandraffino G, Minutoli L, Squadrito G, Russo GT, Marini HR. Ketoacidosis and SGLT2 Inhibitors: A Narrative Review. Metabolites 2024; 14:264. [PMID: 38786741 PMCID: PMC11122992 DOI: 10.3390/metabo14050264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/29/2024] [Accepted: 05/01/2024] [Indexed: 05/25/2024] Open
Abstract
An acute metabolic complication of diabetes mellitus, especially type 1, is diabetic ketoacidosis (DKA), which is due to an increase in blood ketone concentrations. Sodium/glucose co-transporter-2 inhibitor (SGLT2-i) drugs have been associated with the occurrence of a particular type of DKA defined as euglycemic (euDKA), characterized by glycemic levels below 300 mg/dL. A fair number of euDKA cases in SGLT2-i-treated patients have been described, especially in the last few years when there has been a significant increased use of these drugs. This form of euDKA is particularly insidious because of its latent onset, associated with unspecific symptomatology, until it evolves (progressing) to severe systemic forms. In addition, its atypical presentation can delay diagnosis and treatment. However, the risk of euDKA associated with SGLT2-i drugs remains relatively low, but it is essential to promptly diagnose and manage it to prevent its serious life-threatening complications. In this narrative review, we intended to gather current research evidence on SGLT2i-associated euDKA from randomized controlled trials and real-world evidence studies, its diagnostic criteria and precipitating factors.
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Affiliation(s)
- Carmela Morace
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Lipid Clinic and Cardiometabolic Disease Center, University Hospital of Messina, 98124 Messina, Italy
| | - Giuseppe Lorello
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
| | - Federica Bellone
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Lipid Clinic and Cardiometabolic Disease Center, University Hospital of Messina, 98124 Messina, Italy
| | - Cristina Quartarone
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
| | - Domenica Ruggeri
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
| | - Annalisa Giandalia
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
- Department of Human Pathology of Adulthood and Childhood “G. Barresi”, University of Messina, 98125 Messina, Italy
| | - Giuseppe Mandraffino
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Lipid Clinic and Cardiometabolic Disease Center, University Hospital of Messina, 98124 Messina, Italy
| | - Letteria Minutoli
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
| | - Giovanni Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
| | - Giuseppina T. Russo
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
| | - Herbert Ryan Marini
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (C.M.); (F.B.); (G.M.); (L.M.); (G.S.); (G.T.R.)
- Internal Medicine and Diabetology Unit, University Hospital of Messina, 98124 Messina, Italy; (G.L.); (C.Q.); (D.R.); (A.G.)
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16
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Nguyen AT, Amigo Z, McDuffie K, MacQueen VC, Bell LD, Truong LK, Batchi G, McMillin SM. Effects of Empagliflozin-Induced Glycosuria on Weight Gain, Food Intake and Metabolic Indicators in Mice Fed a High-Fat Diet. Endocrinol Diabetes Metab 2024; 7:e00475. [PMID: 38475903 DOI: 10.1002/edm2.475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 12/31/2023] [Accepted: 02/08/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Sodium glucose-linked transporter 2 (SGLT2) inhibitors promote glucose, and therefore calorie, excretion in the urine. Patients taking SGLT2 inhibitors typically experience mild weight loss, but the amount of weight loss falls short of what is expected based on caloric loss. Understanding the mechanisms responsible for this weight loss discrepancy is imperative, as strategies to improve weight loss could markedly improve type 2 diabetes management and overall metabolic health. METHODS Two mouse models of diet-induced obesity were administered the SGLT2 inhibitor empagliflozin in the food for 3 months. Urine glucose excretion, body weight, food intake and activity levels were monitored. In addition, serum hormone measurements were taken, and gene expression analyses were conducted. RESULTS In both mouse models, mice receiving empagliflozin gained the same amount of body weight as their diet-matched controls despite marked glucose loss in the urine. No changes in food intake, serum ghrelin concentrations or activity levels were observed, but serum levels of fibroblast growth factor 21 (FGF21) decreased after treatment. A decrease in the levels of deiodinase 2 (Dio2) was also observed in the white adipose tissue, a primary target tissue of FGF21. CONCLUSION These findings suggest that compensatory metabolic adaptations, other than increased food intake or decreased physical activity, occur in response to SGLT2 inhibitor-induced glycosuria that combats weight loss, and that reductions in FGF21, along with subsequent reductions in peripheral Dio2, may play a role.
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Affiliation(s)
- Anh T Nguyen
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Zachary Amigo
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Kathleen McDuffie
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Victoria C MacQueen
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Lane D Bell
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Lan K Truong
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Gloria Batchi
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Sara M McMillin
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
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17
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Rajeev SP, Roberts CA, Brown E, Sprung VS, Harrold JA, Halford JCG, Stancak A, Boyland EJ, Kemp GJ, Perry J, Howarth E, Jackson R, Wiemken A, Schwab R, Cuthbertson DJ, Wilding JPH. No evidence of compensatory changes in energy balance, despite reductions in body weight and liver fat, during dapagliflozin treatment in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled, cross-over trial (ENERGIZE). Diabetes Obes Metab 2023; 25:3621-3631. [PMID: 37667658 DOI: 10.1111/dom.15257] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/27/2023] [Accepted: 08/06/2023] [Indexed: 09/06/2023]
Abstract
AIM This study assessed the impact of dapagliflozin on food intake, eating behaviour, energy expenditure, magnetic resonance imaging (MRI)-determined brain response to food cues and body composition in patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS Patients were given dapagliflozin 10 mg once daily in a randomized, double-blind, placebo-controlled trial with short-term (1 week) and long-term (12 weeks) cross-over periods. The primary outcome was the difference in test meal food intake between long-term dapagliflozin and placebo treatment. Secondary outcomes included short-term differences in test meal food intake, short- and long-term differences in appetite and eating rate, energy expenditure and functional MRI brain activity in relation to food images. We determined differences in glycated haemoglobin, weight, liver fat (by 1 H magnetic resonance spectroscopy) and subcutaneous/visceral adipose tissue volumes (by MRI). RESULTS In total, 52 patients (43% were women) were randomized; with the analysis of 49 patients: median age 58 years, weight 99.1 kg, body mass index 35 kg/m2 , glycated haemoglobin 49 mmol/mol. Dapagliflozin reduced glycated haemoglobin by 9.7 mmol/mol [95% confidence interval (CI) 3.91-16.27, p = .004], and body weight (-2.84 vs. -0.87 kg) versus placebo. There was no short- or long-term difference in test meal food intake between dapagliflozin and placebo [mean difference 5.7 g (95% CI -127.9 to 139.3, p = .933); 15.8 g (95% CI -147.7 to 116.1, p = .813), respectively] nor in the rate of eating, energy expenditure, appetite, or brain responses to food cues. Liver fat (median reduction -4.7 vs. 1.95%), but not subcutaneous/visceral adipose tissue, decreased significantly with 12 weeks of dapagliflozin. CONCLUSIONS The reduction in body weight and liver fat with dapagliflozin was not associated with compensatory adaptations in food intake or energy expenditure.
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Affiliation(s)
- Surya Panicker Rajeev
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
- Liverpool University Hospitals NHS Foundation Trust, University Hospital Aintree, Liverpool, UK
| | - Carl Alexander Roberts
- Department of Psychology, Institute of Population Health, University of Liverpool, Liverpool, UK
| | - Emily Brown
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
- Liverpool University Hospitals NHS Foundation Trust, University Hospital Aintree, Liverpool, UK
| | - Victoria S Sprung
- Liverpool University Hospitals NHS Foundation Trust, University Hospital Aintree, Liverpool, UK
- Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK
| | - Jo A Harrold
- Department of Psychology, Institute of Population Health, University of Liverpool, Liverpool, UK
| | | | - Andrej Stancak
- Department of Psychology, Institute of Population Health, University of Liverpool, Liverpool, UK
| | - Emma J Boyland
- Department of Psychology, Institute of Population Health, University of Liverpool, Liverpool, UK
| | - Graham J Kemp
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Julie Perry
- Liverpool Clinical Trials Centre (LCTC), University of Liverpool, Liverpool, UK
| | - Elaine Howarth
- Liverpool Clinical Trials Centre (LCTC), University of Liverpool, Liverpool, UK
| | - Richard Jackson
- Liverpool Clinical Trials Centre (LCTC), University of Liverpool, Liverpool, UK
| | - Andrew Wiemken
- Division of Sleep Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Richard Schwab
- Division of Sleep Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Daniel J Cuthbertson
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
- Liverpool University Hospitals NHS Foundation Trust, University Hospital Aintree, Liverpool, UK
| | - John P H Wilding
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
- Liverpool University Hospitals NHS Foundation Trust, University Hospital Aintree, Liverpool, UK
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18
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Ünal İ, Cansız D, Beler M, Sezer Z, Güzel E, Emekli-Alturfan E. Sodium-dependent glucose co-transporter-2 inhibitor empagliflozin exerts neuroprotective effects in rotenone-induced Parkinson's disease model in zebrafish; mechanism involving ketogenesis and autophagy. Brain Res 2023; 1820:148536. [PMID: 37591458 DOI: 10.1016/j.brainres.2023.148536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/26/2023] [Accepted: 08/14/2023] [Indexed: 08/19/2023]
Abstract
Sodium-dependent glucose co-transporter-2 (SGLT2) inhibitor empagliflozin (EMP), is the new class of oral hypoglycemic agent approved as a treatment for Type 2 diabetes. SGLT2 inhibitors may induce ketogenesis through inhibiting the renal reabsorption of glucose. In recent years, positive effects of ketogenic diets on neurodegenerative diseases such as Parkinson's disease (PD) have been reported by improving autophagy. We aimed to evaluate the effects of EMP treatment as a SGLT2 inhibitor that can mimic the effects of ketogenic diet, in rotenone induced PD model in zebrafish focusing on ketogenesis, autophagy, and molecular pathways related with PD progression including oxidative stress and inflammation. Adult zebrafish were exposed to rotenone and EMP for 30 days. Y-Maze task and locomotor analysis were performed. Neurotransmitter levels were determined by liquid chromatography tandem- mass spectrometry (LC-MS/MS). Lipid peroxidation (LPO), nitric oxide (No), alkaline phosphatase, superoxide dismutase, glutathione, glutathione S-transferase (GST), sialic acid, acetylcholinesterase, and the expressions of autophagy, ketogenesis and PD-related genes were determined. Immunohistochemical staining was performed for the microglial marker L-plastin (Lcp1) and tyrosine hydroxylase (Th). EMP treatment improved DOPAC/DA ratio, Y-Maze task, locomotor activity, expressions of Th and Lcp-1, autophagy and inflammation related (mTor, atg5, tnfα, sirt1, il6, tnfα); PD-related (lrrk2, park2, park7, pink1), and ketone metabolism-related genes (slc16a1b, pparag, and pparab), and oxidant-damage in brain in the rotenone group as evidenced by decreased LPO, No, and improved antioxidant molecules. Our results showed benefical effects of EMP as a SGLT2 inhibitor in neurotoxin-induced PD model in zebrafish. We believe our study, will shed light on the mechanism of the effects of SGLT2 inhibitors, ketogenesis and autopahgy in PD.
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Affiliation(s)
- İsmail Ünal
- Marmara University, Institute of Health Sciences, Faculty of Pharmacy, Department of Biochemistry, Istanbul, Turkey
| | - Derya Cansız
- Department Medipol University, Faculty of Medicine, Medical Biochemistry, Istanbul, Turkey
| | - Merih Beler
- Marmara University, Institute of Health Sciences, Faculty of Pharmacy, Department of Biochemistry, Istanbul, Turkey
| | - Zehra Sezer
- Department of Histology and Embryology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul 34098, Turkey
| | - Elif Güzel
- Department of Histology and Embryology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul 34098, Turkey
| | - Ebru Emekli-Alturfan
- Marmara University, Faculty of Dentistry, Department of Basic Medical Sciences, Istanbul, Turkey.
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19
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Nakajima H, Okada H, Yoshimura Y, Tanaka T, Hasegawa G, Mitsuhashi K, Kitagawa N, Okamura T, Hashimoto Y, Senmaru T, Ushigome E, Nakanishi N, Yamazaki M, Hamaguchi M, Fukui M. Younger patients and low c-peptide immunoreactivity index but not nutritional states affect fasting blood ketone levels in Japanese with type 1 diabetes after sodium-glucose cotransporter 2 inhibitor administration. Diabetes Obes Metab 2023; 25:3682-3689. [PMID: 37667649 DOI: 10.1111/dom.15262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/07/2023] [Accepted: 08/14/2023] [Indexed: 09/06/2023]
Abstract
AIM Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are available for individuals with type 1 diabetes, but appropriate use is recommended to prevent ketosis or ketoacidosis. This study aimed to evaluate the risk of ketosis in people with type 1 diabetes, focusing on the relationship between nutritional assessment, glycaemic status, c-peptide immunoreactivity (CPR) index and body composition. MATERIALS AND METHODS In total, 46 Japanese patients with type 1 diabetes were included, and dietary assessment from food photographs and ketone levels were evaluated before and after taking SGLT2is. The effect of diet on morning ketone levels was also investigated. RESULTS All patients had an increase in mean ketone concentrations after taking SGLT2is (before 0.12 ± 0.06 mmol/L, after 0.23 ± 0.16 mmol/L). A significant negative correlation was found between average morning ketone levels and age (r = -0.514, p < .001) and the CPR index (r = -0.523, p = .038) after taking SGLT2is. Using a mixed-effects model based on the results before starting the inhibitors, it was noted that both patient-to-patient and age, or patient-to-patient and capacity of insulin secretion, influenced the ketone levels. Multiple regression analysis showed that factors associated with the risk of increasing ketone levels after taking SGLT2is were younger age (β = -0.504, p = .003) and a low ratio of basal to bolus insulin (β = -0.420, p = .005). CONCLUSIONS When administering SGLT2is to patients with a low CPR index or younger patients with type 1 diabetes, adequate instructions to prevent ketosis should be given.
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Affiliation(s)
- Hanako Nakajima
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Hiroshi Okada
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Yuta Yoshimura
- Department of Endocrinology, Metabolism, and Diabetes, Saiseikai Suita Hospital, Osaka, Japan
| | - Toru Tanaka
- Department of Diabetes and Endocrinology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Goji Hasegawa
- Division of Metabolism and Rheumatology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan
| | - Kazuteru Mitsuhashi
- Department of Diabetes Internal Medicine, Fukuchiyama City Hospital, Kyoto, Japan
| | | | - Takuro Okamura
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Yoshitaka Hashimoto
- Department of Diabetes and Endocrinology, Matsushita Memorial Hospital, Moriguchi, Japan
| | - Takafumi Senmaru
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Emi Ushigome
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Naoko Nakanishi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Masahiro Yamazaki
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Michiaki Fukui
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
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20
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Koutentakis M, Kuciński J, Świeczkowski D, Surma S, Filipiak KJ, Gąsecka A. The Ketogenic Effect of SGLT-2 Inhibitors-Beneficial or Harmful? J Cardiovasc Dev Dis 2023; 10:465. [PMID: 37998523 PMCID: PMC10672595 DOI: 10.3390/jcdd10110465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/09/2023] [Accepted: 11/14/2023] [Indexed: 11/25/2023] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, also called gliflozins or flozins, are a class of drugs that have been increasingly used in the management of type 2 diabetes mellitus (T2DM) due to their glucose-lowering, cardiovascular (CV), and renal positive effects. However, recent studies suggest that SGLT-2 inhibitors might also have a ketogenic effect, increasing ketone body production. While this can be beneficial for some patients, it may also result in several potential unfavorable effects, such as decreased bone mineral density, infections, and ketoacidosis, among others. Due to the intricate and multifaceted impact caused by SGLT-2 inhibitors, this initially anti-diabetic class of medications has been effectively used to treat both patients with chronic kidney disease (CKD) and those with heart failure (HF). Additionally, their therapeutic potential appears to extend beyond the currently investigated conditions. The objective of this review article is to present a thorough summary of the latest research on the mechanism of action of SGLT-2 inhibitors, their ketogenesis, and their potential synergy with the ketogenic diet for managing diabetes. The article particularly discusses the benefits and risks of combining SGLT-2 inhibitors with the ketogenic diet and their clinical applications and compares them with other anti-diabetic agents in terms of ketogenic effects. It also explores future directions regarding the ketogenic effects of SGLT-2 inhibitors.
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Affiliation(s)
- Michail Koutentakis
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland;
| | - Jakub Kuciński
- Central Clinical Hospital, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland;
| | - Damian Świeczkowski
- Department of Toxicology, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdańsk, Poland;
| | - Stanisław Surma
- Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland;
| | - Krzysztof J. Filipiak
- Department of Clinical Sciences, Maria Sklodowska-Curie Medical Academy, 00-001 Warsaw, Poland;
- Department of Hypertensiology, Angiology and Internal Medicine, Poznań University of Medical Sciences, 61-848 Poznań, Poland
| | - Aleksandra Gąsecka
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland;
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21
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Kawakami R, Matsui H, Matsui M, Iso T, Yokoyama T, Ishii H, Kurabayashi M. Empagliflozin induces the transcriptional program for nutrient homeostasis in skeletal muscle in normal mice. Sci Rep 2023; 13:18025. [PMID: 37865720 PMCID: PMC10590450 DOI: 10.1038/s41598-023-45390-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 10/19/2023] [Indexed: 10/23/2023] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve heart failure (HF) outcomes across a range of patient characteristics. A hypothesis that SGLT2i induce metabolic change similar to fasting has recently been proposed to explain their profound clinical benefits. However, it remains unclear whether SGLT2i primarily induce this change in physiological settings. Here, we demonstrate that empagliflozin administration under ad libitum feeding did not cause weight loss but did increase transcripts of the key nutrient sensors, AMP-activated protein kinase and nicotinamide phosphoribosyltransferase, and the master regulator of mitochondrial gene expression, PGC-1α, in quadriceps muscle in healthy mice. Expression of these genes correlated with that of PPARα and PPARδ target genes related to mitochondrial metabolism and oxidative stress response, and also correlated with serum ketone body β-hydroxybutyrate. These results were not observed in the heart. Collectively, this study revealed that empagliflozin activates transcriptional programs critical for sensing and adaptation to nutrient availability intrinsic to skeletal muscle rather than the heart even in normocaloric condition. As activation of PGC-1α is sufficient for metabolic switch from fatigable, glycolytic metabolism toward fatigue-resistant, oxidative mechanism in skeletal muscle myofibers, our findings may partly explain the improvement of exercise tolerance in patients with HF receiving empagliflozin.
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Affiliation(s)
- Ryo Kawakami
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Hiroki Matsui
- Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Gunma, Japan
| | - Miki Matsui
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Tatsuya Iso
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Tomoyuki Yokoyama
- Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Gunma, Japan
| | - Hideki Ishii
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Masahiko Kurabayashi
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
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22
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Al Thani NA, Hasan M, Yalcin HC. Use of Animal Models for Investigating Cardioprotective Roles of SGLT2 Inhibitors. J Cardiovasc Transl Res 2023; 16:975-986. [PMID: 37052784 PMCID: PMC10615955 DOI: 10.1007/s12265-023-10379-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 03/14/2023] [Indexed: 04/14/2023]
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent one type of new-generation type 2 diabetes (T2DM) drug treatment. The mechanism of action of an SGLT2 inhibitor (SGLT2i) in treating T2DM depends on lowering blood glucose levels effectively via increasing the glomerular excretion of glucose. A good number of randomized clinical trials revealed that SGLT2is significantly prevented heart failure (HF) and cardiovascular death in T2DM patients. Despite ongoing clinical trials in HF patients without T2DM, there have been a limited number of translational studies on the cardioprotective properties of SGLT2is. As the cellular mechanism behind the cardiac benefits of SGLT2is is still to be elucidated, animal models are used to better understand the pathways behind the cardioprotective mechanism of SGLT2i. In this review, we summarize the animal models constructed to study the cardioprotective mechanisms of SGLT2is to help deliver a more comprehensive understanding of the in vivo work that has been done in this field and to help select the most optimal animal model to use when studying the different cardioprotective effects of SGLT2is.
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Affiliation(s)
- Najlaa A Al Thani
- Research and Development Department, Barzan Holdings, P. O. Box 7178, Doha, Qatar
| | - Maram Hasan
- Biomedical Research Center, Qatar University, P. O. Box 2713, Doha, Qatar
| | - Huseyin C Yalcin
- Biomedical Research Center, Qatar University, P. O. Box 2713, Doha, Qatar.
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, P. O. Box 2713, Doha, Qatar.
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23
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Tan F, Long X, Du J, Yuan X. RNA-Seq transcriptomic landscape profiling of spontaneously hypertensive rats treated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Biomed Pharmacother 2023; 166:115289. [PMID: 37572641 DOI: 10.1016/j.biopha.2023.115289] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/03/2023] [Accepted: 08/04/2023] [Indexed: 08/14/2023] Open
Abstract
BACKGROUND Sodium-glucose co-transporter-2 inhibitor (SGLT2i) are antihyperglycemic medications that reduce cardiovascular disease (CVD) and improve chronic kidney disease prognosis in patients with diabetes mellitus. The specific impact of SGLT2i treatment on hypertensive individuals, however, remains to be established. This underscores the need for systematic efforts to profile the molecular landscape associated with SGLT2i administration. METHODS We conducted a detailed RNA-sequencing (RNA-Seq)-based exploration of transcriptomic changes in response to empagliflozin in eight different tissues (i.e., atrium, aorta, ventricle, white adipose, brown adipose, kidney, lung, and brain) from a male rat model of spontaneously hypertension. Corresponding computational analyses (i.e., clustering, differentially-expressed genes [DEG], and functional association) were performed to analyze these data. Blood pressure measurements, tissue staining studies and RT-qPCR were performed to validate our in silico findings. RESULTS We discovered that empagliflozin exerted potent transcriptomic effects on various tissues, most notably the kidney, white adipose, and lung in spontaneously hypertension rats (SHR). The functional enrichment of DEGs indicated that empagliflozin may regulate blood pressure, blood glucose and lipid homeostasis in SHR. Consistent with our RNA-Seq findings, immunohistochemistry and qPCR analyses revealed decreased renal expression of mitogen-activated protein kinase 10 (MAPK10) and decreased pulmonary expression of the proinflammatory factors Legumain and cathepsin S (CTSS) at 1 month of empagliflozin administration. Notably, immunofluorescence experiments showed increased expression of the AMP-activated protein kinases Prkaa1 and Prkaa2 in white adipose tissue of SHR following empagliflozin therapy. Furthermore, the transcriptomic signatures of the blood pressure-lowing effect by empagliflozin were experimentally validated in SHR. CONCLUSIONS This study provided an important resource of the effects of empagliflozin on various tissues of SHRs. We identified tissue-specific and tissue-enriched transcriptomic signatures, and uncovered the beneficial effects of empagliflozin on hypertension, weight gain and inflammatory response in validated experiments.
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Affiliation(s)
- Fangyan Tan
- Department of Nephrology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 4000l0, China
| | - Xianglin Long
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400040, China
| | - Jianlin Du
- Department of Cardiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400040, China
| | - Xin Yuan
- Department of Nephrology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 4000l0, China.
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24
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Barreto J, Campos-Staffico AM, Nadruz W, Quinaglia T, Sposito AC. The role of SGLT2i in attenuating residual cardiovascular risk through blood pressure-lowering: mechanistic insights and perspectives. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2023; 4:1243530. [PMID: 37822556 PMCID: PMC10562622 DOI: 10.3389/fcdhc.2023.1243530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/11/2023] [Indexed: 10/13/2023]
Abstract
Sodium glucose cotransporter 2 inhibitors (SGLT2) have been increasingly pursued as a promising target for addressing residual cardiovascular risk. Prior trials demonstrated that SGLT2i not only promotes glucose-lowering, but also improves endothelial dysfunction, adiposity, fluid overload, and insulin sensitivity thus contributing to hemodynamic changes implicated in its cardiorenal benefits. The mechanisms in the effect of SGLT2i on blood pressure and their potential role in preventing cardiovascular events are hereby revised.
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Affiliation(s)
- Joaquim Barreto
- Laboratory of Atherosclerosis and Vascular Biology, University of Campinas (Unicamp), Campinas, Sao Paulo, Brazil
| | | | - Wilson Nadruz
- Cardiology Division, Clinics Hospital, Unicamp, Campinas, Sao Paulo, Brazil
| | - Thiago Quinaglia
- Massachussets General Hospital, Harvard University, Boston, MA, United States
| | - Andrei C. Sposito
- Laboratory of Atherosclerosis and Vascular Biology, University of Campinas (Unicamp), Campinas, Sao Paulo, Brazil
- Cardiology Division, Clinics Hospital, Unicamp, Campinas, Sao Paulo, Brazil
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Kawade S, Ogiso K, Shayo SC, Obo T, Arimura A, Hashiguchi H, Deguchi T, Nishio Y. Luseogliflozin and caloric intake restriction increase superoxide dismutase 2 expression, promote antioxidative effects, and attenuate aortic endothelial dysfunction in diet-induced obese mice. J Diabetes Investig 2023; 14:548-559. [PMID: 36729938 PMCID: PMC10034951 DOI: 10.1111/jdi.13981] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 01/06/2023] [Accepted: 01/11/2023] [Indexed: 02/03/2023] Open
Abstract
AIMS/INTRODUCTION The mechanisms underlying the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on aortic endothelial dysfunction in diet-induced obesity are not clearly understood. This study investigated whether SGLT2 inhibition by luseogliflozin improved free fatty acid (FFA)-induced endothelial dysfunction in high-fat diet (HFD)-induced obese mice. MATERIALS AND METHODS Mice were fed a control diet or high-fat diet for 8 weeks, and then each diet with or without luseogliflozin was provided for an additional 8 weeks under free or paired feeding. Afterward, the thoracic aortas were removed and utilized for the experiments. RESULTS Luseogliflozin treatment decreased body weight, fasting blood glucose, insulin, and total cholesterol in HFD-fed mice only under paired feeding but not under free feeding. Endothelial-dependent vasodilation under FFA exposure conditions was significantly lower in HFD-fed mice than in control diet-fed mice, and luseogliflozin treatment ameliorated FFA-induced endothelial dysfunction. Reactive oxygen species (ROS) production induced by FFA was significantly increased in HFD-induced obese mice. Luseogliflozin treatment increased the expression of superoxide dismutase 2 (SOD2), an antioxidative molecule, and reduced FFA-induced ROS production in the thoracic aorta. Superoxide dismutase reversed FFA-induced endothelial dysfunction in HFD-fed mice. CONCLUSIONS It was shown that caloric restriction is important for the effect of luseogliflozin on metabolic parameters and endothelial dysfunction. Furthermore, SGLT2 inhibition by luseogliflozin possibly ameliorates FFA-induced endothelial dysfunction by increasing SOD2 expression and decreasing reactive oxygen species production in the thoracic aorta.
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Affiliation(s)
- Shigeru Kawade
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Kazuma Ogiso
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Sigfrid Casmir Shayo
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Takahiko Obo
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Aiko Arimura
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Hiroshi Hashiguchi
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Takahisa Deguchi
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
| | - Yoshihiko Nishio
- Department of Diabetes and Endocrine MedicineKagoshima University Graduate School of Medicine and Dental SciencesKagoshimaJapan
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Huang S, Wu B, He Y, Qiu R, Yang T, Wang S, Lei Y, Li H, Zheng F. Canagliflozin ameliorates the development of NAFLD by preventing NLRP3-mediated pyroptosis through FGF21-ERK1/2 pathway. Hepatol Commun 2023; 7:e0045. [PMID: 36757426 PMCID: PMC9916118 DOI: 10.1097/hc9.0000000000000045] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/05/2022] [Indexed: 02/10/2023] Open
Abstract
Recent studies have suggested that sodium-glucose co-transporter2 inhibitors go beyond their glycemic advantages to ameliorate the development of NAFLD. However, little research has been done on the underlying mechanisms. Here, we took deep insight into the effect of canagliflozin (CANA), one of the sodium-glucose co-transporter2 inhibitor, on the progression of NAFLD, and explored the molecular mechanisms. Our findings showed that CANA-treated ob/ob and diabetic mice developed improved glucose and insulin tolerance, although their body weights were comparable or even increased compared with the controls. The CANA treatment ameliorated hepatic steatosis and lipid accumulation of free fatty acid-treated AML12 cells, accompanied by decreased lipogenic gene expression and increased fatty acid β oxidation-related gene expression. Furthermore, inflammation and fibrosis genes decreased in the livers of CANA-treated ob/ob and diabetic mice mice. FGF21 and its downstream ERK1/2/AMPK signaling decreased, whereas NLRP3-mediated pyroptosis increased in the livers of the ob/ob and diabetic mice mice, which was reversed by the CANA treatment. In addition, blocking FGF21 or ERK1/2 activity antagonized the effects of CANA on NLRP3-mediated pyroptosis in lipopolysaccharide plus nigericin-treated J774A.1 cells. We conclude that CANA treatment alleviated insulin resistance and the progression of NAFLD in ob/ob and diabetic mice mice independent of the body weight change. CANA protected against the progression of NAFLD by inhibiting NLRP3-mediated pyroptosis and enhancing FGF21-ERK1/2 pathway activity in the liver. These findings suggest the therapeutic potential of sodium-glucose co-transporter2 inhibitors in the treatment of NAFLD.
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Affiliation(s)
- Shaohan Huang
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Beibei Wu
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yingzi He
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Ruojun Qiu
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Tian Yang
- Department of Endocrinology, The Affiliated Fourth Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Shuo Wang
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yongzhen Lei
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Hong Li
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Fenping Zheng
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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Neutral effect of SGLT2 inhibitors on lipoprotein metabolism: From clinical evidence to molecular mechanisms. Pharmacol Res 2023; 188:106667. [PMID: 36657502 DOI: 10.1016/j.phrs.2023.106667] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/19/2022] [Accepted: 01/15/2023] [Indexed: 01/18/2023]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective, well-tolerated, and safe glucose-lowering compounds for patients with type 2 diabetes mellitus (T2DM). SGLT2i benefit encompasses protection from heart and kidney failure, independently of the presence of diabetes. In addition, SGLT2i consistently reduce the risk of hospitalization for heart failure and, although with some heterogeneity between specific members of the class, favourably affect the risk of cardiovascular outcomes. The molecular mechanisms underlying the cardiovascular favourable effect are not fully clarified. Studies testing the efficacy of SGLT2i in human cohorts and experimental models of atherosclerotic cardiovascular disease (ASCVD) have reported significant differences in circulating levels and composition of lipoprotein classes. In randomized clinical trials, small but significant increases in low-density lipoprotein cholesterol (LDL-C) levels have been observed, with a still undefined clinical significance; on the other hand, favourable (although modest) effects on high-density lipoprotein cholesterol (HDL-C) and triglycerides have been reported. At the molecular level, glycosuria may promote a starving-like state that ultimately leads to a metabolic improvement through the mobilization of fatty acids from the adipose tissue and their oxidation for the production of ketone bodies. This, however, may also fuel hepatic cholesterol synthesis, thus inhibiting atherogenic lipoprotein uptake from the liver. Long-term studies collecting detailed information on lipid-lowering therapies at baseline and during the trials with SGLT2i, as well as regularly monitoring lipid profiles are warranted to disentangle the potential implications of SGLT2i in modulating lipoprotein-mediated atherosclerotic cardiovascular risk.
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Furuya F, Fujita Y, Matsuo N, Minamino H, Oguri Y, Isomura N, Ikeda K, Takesue K, Li Y, Kondo A, Mano F, Inagaki N. Liver autophagy-induced valine and leucine in plasma reflect the metabolic effect of sodium glucose co-transporter 2 inhibitor dapagliflozin. EBioMedicine 2022; 86:104342. [PMID: 36423374 PMCID: PMC9682354 DOI: 10.1016/j.ebiom.2022.104342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 09/14/2022] [Accepted: 10/19/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Sodium glucose co-transporter 2 (SGLT2) inhibitors are anti-diabetic drugs for type 2 diabetes that lower blood glucose levels and body weight. It is of special interest that SGLT2 inhibitors also improve liver metabolism and fatty liver. Liver is an important organ in regulation of energy metabolism, but the metabolic action of SGLT inhibitors in liver remains unclear. METHODS We investigated the factors associated with the beneficial effects of dapagliflozin, a SGLT2 inhibitor, in the liver after confirming its glucose-lowering and weight loss effects using an obesity and diabetes mouse model. We also performed clinical study of patients with type 2 diabetes to explore candidate biomarkers that reflect the beneficial action of dapagliflozin in the liver. FINDINGS In animal study, dapagliflozin induced autophagy in the liver (LC3-II to LC3-I expression ratio: P < 0·05 vs. control), and valine and leucine levels were increased in plasma (P < 0·01 vs. control) as well as in liver (P < 0·05 vs. control). Thus, increased plasma valine and leucine levels are potential biomarkers for improved liver metabolism. Clinical study found that valine and leucine levels were markedly higher in patients treated with dapagliflozin (valine: P < 0·05 vs. control, leucine: P < 0·01 vs. control) than those not treated after one week intervention. INTERPRETATION Dapagliflozin improves liver metabolism via hepatic autophagy, and plasma valine and leucine levels may reflect its metabolic effect. FUNDING AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS), Japan Agency for Medical Research and Development (AMED), Novo Nordisk Pharma Ltd., and Japan Foundation for Applied Enzymology, and MSD Life Science Foundation International.
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Affiliation(s)
| | - Yoshihito Fujita
- Corresponding author. Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
| | | | | | | | | | | | | | | | | | | | - Nobuya Inagaki
- Corresponding author. Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
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Abiri B, Ramezani Ahmadi A, Ebadinejad A, Hosseinpanah F, Valizadeh M. Effects of sodium-glucose co-transporter-2 inhibitors on anthropometric indices and metabolic markers in overweight/obese individuals without diabetes: a systematic review and meta-analysis. Curr Med Res Opin 2022; 38:1853-1863. [PMID: 35993873 DOI: 10.1080/03007995.2022.2115775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
AIMS To identify the impact of sodium-glucose co-transporter-2 (SGLT2) inhibitors on anthropometric indices and metabolic markers in individuals without diabetes who are overweight/obese. MATERIALS AND METHODS Clinical trials investigating the safety and efficacy of SGLT2 inhibitors in overweight or obese adults were sought in PubMed, Scopus, Google Scholar, and EMBASE databases. The overall intervention effect was estimated using a random-effect meta-analysis. Jadad scale was used to assess the risk of bias. The heterogeneity of the studies was assessed using the Cochran's test (Q test) and I2 Index. Analyses of meta-regression were carried out to identify possible sources of heterogeneity among the trials. The analyses were all conducted using Stata, and p < .05 was set as the statistically significant level. RESULTS Of the five clinical trials that were included in the meta-analysis, five, four, three, and two clinical trials met the eligibility criteria for evaluating the efficacy of SGLT2 inhibitors on the weight, waist circumference (WC) and blood pressure, body mass index (BMI), and lipid and glucose profile, respectively. According to the results, SGLT2 inhibitors lowered BMI (WMD = -0.47 [95% CI: -0.63, -0.31]; p < .001), and WC (WMD = -3.25 [95% CI: -6.36, -0.14]; p = .04), but had no significant influence on blood pressure, lipid, and glucose profile of overweight/obese patients compared to the control groups. CONCLUSION The SGLT2 inhibitors appear to ameliorate some anthropometric and metabolic markers. There is, however, a limited number of studies, and further research is required for a firm conclusion. REGISTRATION CODE IN PROSPERO CRD42022306415.
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Affiliation(s)
- Behnaz Abiri
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Amir Ebadinejad
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farhad Hosseinpanah
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Valizadeh
- Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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ElBaset MA, Salem RS, Ayman F, Ayman N, Shaban N, Afifi SM, Esatbeyoglu T, Abdelaziz M, Elalfy ZS. Effect of Empagliflozin on Thioacetamide-Induced Liver Injury in Rats: Role of AMPK/SIRT-1/HIF-1α Pathway in Halting Liver Fibrosis. Antioxidants (Basel) 2022; 11:2152. [PMID: 36358524 PMCID: PMC9686640 DOI: 10.3390/antiox11112152] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 07/30/2023] Open
Abstract
Hepatic fibrosis causes severe morbidity and death. No viable treatment can repair fibrosis and protect the liver until now. We intended to discover the empagliflozin's (EMPA) hepatoprotective efficacy in thioacetamide (TAA)-induced hepatotoxicity by targeting AMPK/SIRT-1 activity and reducing HIF-1α. Rats were treated orally with EMPA (3 or 6 mg/kg) with TAA (100 mg/kg, IP) thrice weekly for 6 weeks. EMPA in both doses retracted the serum GGT, ALT, AST, ammonia, triglycerides, total cholesterol, and increased serum albumin. At the same time, EMPA (3 or 6 mg/kg) replenished the hepatic content of GSH, ATP, AMP, AMPK, or SIRT-1 and mitigated the hepatic content of MDA, TNF-α, IL-6, NF-κB, or HIF-1α in a dose-dependent manner. Likewise, hepatic photomicrograph stained with hematoxylin and eosin or Masson trichrome stain of EMPA (3 or 6 mg/kg) revealed marked regression of the hepatotoxic effect of TAA with minimal injury. Similarly, in rats given EMPA (3 or 6 mg/kg), the immunohistochemically of hepatic photomicrograph revealed minimal stain of either α-SMA or caspase-3 compared to the TAA group. Therefore, we concluded that EMPA possessed an antifibrotic effect by targeting AMPK/SIRT-1 activity and inhibiting HIF-1α. The present study provided new insight into a novel treatment of liver fibrosis.
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Affiliation(s)
- Marwan A. ElBaset
- Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, 33 El-Bohouth St., Dokki, Cairo P.O. Box 12622, Egypt
| | - Rana S. Salem
- Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Science and Arts, Cairo 12451, Egypt
| | - Fairouz Ayman
- Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Science and Arts, Cairo 12451, Egypt
| | - Nadeen Ayman
- Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Science and Arts, Cairo 12451, Egypt
| | - Nooran Shaban
- Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Science and Arts, Cairo 12451, Egypt
| | - Sherif M. Afifi
- Pharmacognosy Department, Faculty of Pharmacy, University of Sadat City, Sadat City 32897, Egypt
| | - Tuba Esatbeyoglu
- Department of Food Development and Food Quality, Institute of Food Science and Human Nutrition, Gottfried Wilhelm Leibniz University Hannover, Am Kleinen Felde 30, 30167 Hannover, Germany
| | - Mahmoud Abdelaziz
- Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Science and Arts, Cairo 12451, Egypt
| | - Zahraa S. Elalfy
- Pathology Department Medical Research and Clinical Studies Institute, National Research Centre, 33 El-Bohouth St., Dokki, Cairo P.O. Box 12622, Egypt
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Li J, Zhou L, Gong H. New insights and advances of sodium-glucose cotransporter 2 inhibitors in heart failure. Front Cardiovasc Med 2022; 9:903902. [PMID: 36186974 PMCID: PMC9520058 DOI: 10.3389/fcvm.2022.903902] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are newly emerging insulin-independent anti-hyperglycemic agents that work independently of β-cells. Quite a few large-scale clinical trials have proven the cardiovascular protective function of SGLT2is in both diabetic and non-diabetic patients. By searching all relevant terms related to our topics over the previous 3 years, including all the names of agents and their brands in PubMed, here we review the mechanisms underlying the improvement of heart failure. We also discuss the interaction of various mechanisms proposed by diverse works of literature, including corresponding and opposing viewpoints to support each subtopic. The regulation of diuresis, sodium excretion, weight loss, better blood pressure control, stimulation of hematocrit and erythropoietin, metabolism remodeling, protection from structural dysregulation, and other potential mechanisms of SGLT2i contributing to heart failure improvement have all been discussed in this manuscript. Although some remain debatable or even contradictory, those newly emerging agents hold great promise for the future in cardiology-related therapies, and more research needs to be conducted to confirm their functionality, particularly in metabolism, Na+-H+ exchange protein, and myeloid angiogenic cells.
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Affiliation(s)
- Juexing Li
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lei Zhou
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hui Gong
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
- Department of Internal Medicine, Shanghai Medical College, Fudan University, Shanghai, China
- *Correspondence: Hui Gong
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Pruett JE, Everman SJ, Hoang NH, Salau F, Taylor LC, Edwards KS, Hosler JP, Huffman AM, Romero DG, Yanes Cardozo LL. Mitochondrial function and oxidative stress in white adipose tissue in a rat model of PCOS: effect of SGLT2 inhibition. Biol Sex Differ 2022; 13:45. [PMID: 35986388 PMCID: PMC9389812 DOI: 10.1186/s13293-022-00455-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 08/03/2022] [Indexed: 11/18/2022] Open
Abstract
Background Polycystic ovary syndrome (PCOS), characterized by androgen excess and ovulatory dysfunction, is associated with a high prevalence of obesity and insulin resistance (IR) in women. We demonstrated that sodium–glucose cotransporter-2 inhibitor (SGLT2i) administration decreases fat mass without affecting IR in the PCOS model. In male models of IR, administration of SGLT2i decreases oxidative stress and improves mitochondrial function in white adipose tissue (WAT). Therefore, we hypothesized that SGLT2i reduces adiposity via improvement in mitochondrial function and oxidative stress in WAT in PCOS model. Methods Four-week-old female rats were treated with dihydrotestosterone for 90 days (PCOS model), and SGLT2i (empagliflozin) was co-administered during the last 3 weeks. Body composition was measured before and after SGLT2i treatment by EchoMRI. Subcutaneous (SAT) and visceral (VAT) WAT were collected for histological and molecular studies at the end of the study. Results PCOS model had an increase in food intake, body weight, body mass index, and fat mass/lean mass ratio compared to the control group. SGLT2i lowered fat mass/lean ratio in PCOS. Glucosuria was observed in both groups, but had a larger magnitude in controls. The net glucose balance was similar in both SGLT2i-treated groups. The PCOS SAT had a higher frequency of small adipocytes and a lower frequency of large adipocytes. In SAT of controls, SGLT2i increased frequencies of small and medium adipocytes while decreasing the frequency of large adipocytes, and this effect was blunted in PCOS. In VAT, PCOS had a lower frequency of small adipocytes while SGLT2i increased the frequency of small adipocytes in PCOS. PCOS model had decreased mitochondrial content in SAT and VAT without impacting oxidative stress in WAT or the circulation. SGLT2i did not modify mitochondrial function or oxidative stress in WAT in both treated groups. Conclusions Hyperandrogenemia in PCOS causes expansion of WAT, which is associated with decreases in mitochondrial content and function in SAT and VAT. SGLT2i increases the frequency of small adipocytes in VAT only without affecting mitochondrial dysfunction, oxidative stress, or IR in the PCOS model. SGLT2i decreases adiposity independently of adipose mitochondrial and oxidative stress mechanisms in the PCOS model. Supplementary Information The online version contains supplementary material available at 10.1186/s13293-022-00455-x.
Androgen excess in PCOS model is associated with decreased markers of mitochondrial content in both subcutaneous and visceral white adipose tissue. Androgen excess in PCOS model is associated with increased frequency of small adipocytes in subcutaneous white adipose tissue while decreasing frequency of small adipocytes in visceral white adipose tissue. SGLT2 inhibition did not modify markers of mitochondrial content or oxidative stress in either subcutaneous or visceral white adipose tissue in PCOS model. SGLT2 inhibition increased frequency of small adipocytes in both subcutaneous and visceral white adipose tissue in control rats; however, SGLT2 inhibition only increased frequency of small adipocytes in visceral white adipose tissue in PCOS model.
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van Ruiten CC, Veltman DJ, Wijdeveld M, ten Kulve JS, Kramer MHH, Nieuwdorp M, IJzerman RG. Combination therapy with exenatide decreases the dapagliflozin-induced changes in brain responses to anticipation and consumption of palatable food in patients with type 2 diabetes: A randomized controlled trial. Diabetes Obes Metab 2022; 24:1588-1597. [PMID: 35491524 PMCID: PMC9546212 DOI: 10.1111/dom.14732] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 04/12/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022]
Abstract
AIMS Sodium-glucose cotransporter-2 inhibitors induce less weight loss than expected. This may be explained by sodium-glucose cotransporter-2 inhibitor-induced alterations in central reward- and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists reduce appetite and body weight because of direct and indirect effects on the brain. We investigated the separate and combined effects of dapagliflozin and exenatide on the brain in response to the anticipation and consumption of food in people with obesity and type 2 diabetes. MATERIALS AND METHODS As part of a larger study, this was a 16 week, double-blind, randomized, placebo-controlled trial. Subjects with obesity and type 2 diabetes were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice-daily 10 μg with dapagliflozin-matched placebo, dapagliflozin plus exenatide, or double placebo. Using functional magnetic resonance imaging, the effects of treatments on brain responses to the anticipation of food and food receipt were assessed after 10 days and 16 weeks. RESULTS After 10 days, dapagliflozin increased activation in right amygdala and right caudate nucleus in response to the anticipation of food, and tended to decrease activation in right amygdala in response to actual food receipt. After 16 weeks, no changes in brain activation were observed with dapagliflozin. Dapagliflozin plus exenatide reduced activation in right caudate nucleus and amygdala to the anticipation of food, and decreased activation in the right amygdala in response to food receipt after 16 weeks. CONCLUSIONS The dapagliflozin-induced changes in brain activation may contribute to the discrepancy between observed and expected weight loss with dapagliflozin. Exenatide blunted the dapagliflozin-induced changes in brain activation, which may contribute to the additional weight loss with combined treatment.
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Affiliation(s)
- Charlotte C. van Ruiten
- Diabetes Center, Department of Internal MedicineAmsterdam University Medical Center, Location VU University Medical CenterAmsterdamThe Netherlands
| | - Dick J. Veltman
- Department of PsychiatryAmsterdam University Medical Center, Location VU University Medical CenterAmsterdamThe Netherlands
| | - Madelief Wijdeveld
- Diabetes Center, Department of Internal MedicineAmsterdam University Medical Center, Location VU University Medical CenterAmsterdamThe Netherlands
| | - Jennifer S ten Kulve
- Diabetes Center, Department of Internal MedicineAmsterdam University Medical Center, Location VU University Medical CenterAmsterdamThe Netherlands
- Department of Vascular MedicineAmsterdam University Medical Center, Location AMCAmsterdamThe Netherlands
| | - Mark H. H. Kramer
- Diabetes Center, Department of Internal MedicineAmsterdam University Medical Center, Location VU University Medical CenterAmsterdamThe Netherlands
| | - Max Nieuwdorp
- Diabetes Center, Department of Internal MedicineAmsterdam University Medical Center, Location VU University Medical CenterAmsterdamThe Netherlands
- Department of Vascular MedicineAmsterdam University Medical Center, Location AMCAmsterdamThe Netherlands
| | - Richard G. IJzerman
- Diabetes Center, Department of Internal MedicineAmsterdam University Medical Center, Location VU University Medical CenterAmsterdamThe Netherlands
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Sargeant JA, King JA, Yates T, Redman EL, Bodicoat DH, Chatterjee S, Edwardson CL, Gray LJ, Poulin B, Waheed G, Waller HL, Webb DR, Willis SA, Wilding JPH, Khunti K, Stensel DJ, Davies MJ. The effects of empagliflozin, dietary energy restriction, or both on appetite-regulatory gut peptides in individuals with type 2 diabetes and overweight or obesity: The SEESAW randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 2022; 24:1509-1521. [PMID: 35441435 PMCID: PMC9541107 DOI: 10.1111/dom.14721] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 04/07/2022] [Accepted: 04/18/2022] [Indexed: 11/28/2022]
Abstract
AIM To assess the impact of the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin (25 mg once-daily), dietary energy restriction, or both combined, on circulating appetite-regulatory peptides in people with type 2 diabetes (T2D) and overweight or obesity. MATERIALS AND METHODS In a double-blind, placebo-controlled trial, 68 adults (aged 30-75 years) with T2D (drug naïve or on metformin monotherapy; HbA1c 6.0%-10.0% [42-86 mmol/mol]) and body mass index of 25 kg/m2 or higher were randomized to (a) placebo only, (b) placebo plus diet, (c) empagliflozin only or (d) empagliflozin plus diet for 24 weeks. Dietary energy restriction matched the estimated energy deficit elicited by SGLT2 inhibitor therapy through urinary glucose excretion (~360 kcal/day). The primary outcome was change in postprandial circulating total peptide-YY (PYY) during a 3-hour mixed-meal tolerance test from baseline to 24 weeks. Postprandial total glucagon-like peptide-1 (GLP-1), acylated ghrelin and subjective appetite perceptions formed secondary outcomes, along with other key components of energy balance. RESULTS The mean weight loss in each group at 24 weeks was 0.44, 1.91, 2.22 and 5.74 kg, respectively. The change from baseline to 24 weeks in postprandial total PYY was similar between experimental groups and placebo only (mean difference [95% CI]: -8.6 [-28.6 to 11.4], 13.4 [-6.1 to 33.0] and 1.0 [-18.0 to 19.9] pg/ml in placebo-plus diet, empagliflozin-only and empagliflozin-plus-diet groups, respectively [all P ≥ .18]). Similarly, there was no consistent pattern of difference between groups for postprandial total GLP-1, acylated ghrelin and subjective appetite perceptions. CONCLUSIONS In people with T2D and overweight or obesity, changes in postprandial appetite-regulatory gut peptides may not underpin the less than predicted weight loss observed with empagliflozin therapy. CLINICAL TRIALS REGISTRATION NCT02798744, www. CLINICALTRIALS gov; 2015-001594-40, www.EudraCT.ema.europa.eu; ISRCTN82062639, www.ISRCTN.org.
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Affiliation(s)
- Jack A. Sargeant
- Diabetes Research CentreUniversity of LeicesterLeicesterUK
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
| | - James A. King
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
- School of Sport, Exercise and Health SciencesLoughborough UniversityLeicestershireUK
| | - Thomas Yates
- Diabetes Research CentreUniversity of LeicesterLeicesterUK
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
| | - Emma L. Redman
- Diabetes Research CentreUniversity of LeicesterLeicesterUK
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
- Leicester Diabetes CentreUniversity Hospitals of Leicester NHS TrustLeicesterUK
| | | | | | - Charlotte L. Edwardson
- Diabetes Research CentreUniversity of LeicesterLeicesterUK
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
| | - Laura J. Gray
- Department of Health SciencesUniversity of LeicesterLeicesterUK
| | - Benoit Poulin
- Diabetes Research CentreUniversity of LeicesterLeicesterUK
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
| | - Ghazala Waheed
- Diabetes Research CentreUniversity of LeicesterLeicesterUK
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
| | - Helen L. Waller
- Diabetes Research CentreUniversity of LeicesterLeicesterUK
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
| | - David R. Webb
- Diabetes Research CentreUniversity of LeicesterLeicesterUK
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
- Leicester Diabetes CentreUniversity Hospitals of Leicester NHS TrustLeicesterUK
| | - Scott A. Willis
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
- School of Sport, Exercise and Health SciencesLoughborough UniversityLeicestershireUK
| | - John P. H. Wilding
- Department of Cardiovascular and Metabolic MedicineUniversity of LiverpoolLiverpoolUK
| | - Kamlesh Khunti
- Diabetes Research CentreUniversity of LeicesterLeicesterUK
- Leicester Diabetes CentreUniversity Hospitals of Leicester NHS TrustLeicesterUK
- NIHR Applied Research Collaboration East MidlandsLeicesterUK
| | - David J. Stensel
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
- School of Sport, Exercise and Health SciencesLoughborough UniversityLeicestershireUK
- Faculty of Sport SciencesWaseda UniversityTokorozawaJapan
| | - Melanie J. Davies
- Diabetes Research CentreUniversity of LeicesterLeicesterUK
- National Institute for Health Research (NIHR) Leicester Biomedical Research CentreLeicesterUK
- Leicester Diabetes CentreUniversity Hospitals of Leicester NHS TrustLeicesterUK
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Singh AK, Singh R. Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes. World J Cardiol 2022; 14:329-342. [PMID: 35979179 PMCID: PMC9258221 DOI: 10.4330/wjc.v14.i6.329] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 03/17/2022] [Accepted: 05/21/2022] [Indexed: 02/06/2023] Open
Abstract
Both GLP-1 receptor agonists (GLP-1RA) and SGLT-2 inhibitors (SGLT-2I) are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure (SBP) modestly. Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c, body weight, and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects. Since several agents from each class of these drugs have shown an improvement in cardiovascular (CV) and renal outcomes in their respective cardiovascular outcome trials (CVOT), combination therapy is theoretically expected to have additional CV and renal benefits. In this comprehensive opinion review, we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone, although body weight lowering was nearly additive and the SBP lowering was more than additive. Our additional meta-analysis of CV outcomes with GLP-1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone, against placebo. Interestingly, a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials. Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.
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Affiliation(s)
- Awadhesh Kumar Singh
- Department of Diabetes and Endocrinology, G.D Hospital and Diabetes Institute, Kolkata 700013, India.
| | - Ritu Singh
- Department of Reproductive Endocrinology, G.D Hospital and Diabetes Institute, Kolkata 700013, India
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Rhee B, Mahbubur RM, Jin C, Choi JS, Lim HW, Huh W, Park JS, Han J, Kim S, Lee Y, Park J. Evaluation of safety and anti-obesity effects of DWP16001 in naturally obese dogs. BMC Vet Res 2022; 18:237. [PMID: 35733159 PMCID: PMC9214997 DOI: 10.1186/s12917-022-03324-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 05/26/2022] [Indexed: 11/12/2022] Open
Abstract
Background The aim of this study was to investigate the anti-obesity effects of DWP16001, a sodium-glucose cotransporter-2 (SGLT2 inhibitor), in naturally obese dogs. A total of 20 dogs were divided into four equal groups: one obese control (OC group), and three treated groups; DWP0.2 group, DWP0.5 group, and DWP1 group. OC group fed with food for maintenance and treated groups were fed with food for maintenance with 0.2 mg/kg DWP16001, 0.5 mg/kg DWP16001 and 1 mg/kg DWP16001, respectively. The food for maintenance was provided to dogs as 2 RER (Resting energy requirement) in kcal and DWP16001-supplemented food was administered once a day for 8 weeks. Results Body condition score, body weight, and fat thickness were significantly reduced (P < 0.05) in the DWP0.2 group compared with the OC group, respectively without affecting the food consumption. At the 10th week the food consumption rate was 101.35 ± 2.56, 166.59 ± 4.72, 98.47 ± 1.44 and 123.15 ± 2.45% compared with initial food consumption rate. Body fat percentage, chest and waist circumference, blood glucose, and insulin were reduced compared to OC group but not significantly different from those of the OC group during experimental period. Serum alanine aminotransferase, alkaline phosphatase, creatine phosphokinase, and creatinine were significantly reduced in DWP0.2 group on 8 weeks. Serum cholesterol and triglycerides were reduced but not significantly. No specific adverse effects were observed throughout the experiment, and hematological parameters were unchanged. The results indicate that DWP16001 was not harmful to the dogs in our study and might have anti-obesity effects in naturally obese dogs. Conclusions The above results and discussion suggest that DWP16001 is safe and might have anti-obesity effects in naturally obese dogs.
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Affiliation(s)
- Beomseok Rhee
- KNOTUS Co., Ltd., Research Center, Incheon, Republic of Korea.,Department of Veterinary Medical Imaging, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | | | - Changfan Jin
- KNOTUS Co., Ltd., Research Center, Incheon, Republic of Korea.,Department of Veterinary Medical Imaging, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Ji-Soo Choi
- Daewoong Pharmaceutical Co., Ltd., Yongin, Republic of Korea
| | - Hyun-Woo Lim
- Daewoong Pharmaceutical Co., Ltd., Yongin, Republic of Korea
| | - Wan Huh
- Daewoong Pharmaceutical Co., Ltd., Yongin, Republic of Korea
| | - Joon Seok Park
- Daewoong Pharmaceutical Co., Ltd., Yongin, Republic of Korea
| | - Jumi Han
- Daewoong Pharmaceutical Co., Ltd., Yongin, Republic of Korea
| | - Sokho Kim
- KNOTUS Co., Ltd., Research Center, Incheon, Republic of Korea
| | - Youngwon Lee
- Department of Veterinary Medical Imaging, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Jinho Park
- Department of Veterinary Internal Medicine, College of Veterinary Medicine, Jeonbuk National University, Iksan, Republic of Korea.
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van Ruiten CC, Veltman DJ, Schrantee A, van Bloemendaal L, Barkhof F, Kramer MHH, Nieuwdorp M, IJzerman RG. Effects of Dapagliflozin and Combination Therapy With Exenatide on Food-Cue Induced Brain Activation in Patients With Type 2 Diabetes. J Clin Endocrinol Metab 2022; 107:e2590-e2599. [PMID: 35134184 PMCID: PMC9113812 DOI: 10.1210/clinem/dgac043] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Indexed: 12/13/2022]
Abstract
CONTEXT Sodium-glucose cotransporter-2 inhibitors (SGLT2i) cause less weight loss than expected based on urinary calorie excretion. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists are associated with reduced appetite and body weight, mediated by direct and indirect central nervous system (CNS) effects. OBJECTIVE We investigated the separate and combined effects of dapagliflozin and exenatide on the CNS in participants with obesity and type 2 diabetes. METHODS This was a 16-week, double-blind, randomized, placebo-controlled trial. Obese participants with type 2 diabetes (n = 64, age 63.5 ± 0.9 years, BMI 31.7 ± 0.6 kg/m2) were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice daily 10 µg with dapagliflozin-matched placebo, dapagliflozin and exenatide, or double placebo. Using functional MRI, the effects of treatments on CNS responses to viewing food pictures were assessed after 10 days and 16 weeks of treatment. RESULTS After 10 days, dapagliflozin increased, whereas exenatide decreased CNS activation in the left putamen. Combination therapy had no effect on responses to food pictures. After 16 weeks, no changes in CNS activation were observed with dapagliflozin, but CNS activation was reduced with dapagliflozin-exenatide in right amygdala. CONCLUSION The early increase in CNS activation with dapagliflozin may contribute to the discrepancy between observed and expected weight loss. In combination therapy, exenatide blunted the increased CNS activation observed with dapagliflozin. These findings provide further insights into the weight-lowering mechanisms of SGLT2i and GLP-1 receptor agonists.
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Affiliation(s)
- Charlotte C van Ruiten
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, location VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Dick J Veltman
- Department of Psychiatry, Amsterdam University Medical Center, location VU University Medical Center, 1081 HJ Amsterdam, The Netherlands
| | - Anouk Schrantee
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, location Academic Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Liselotte van Bloemendaal
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, location VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Frederik Barkhof
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, location VU University Medical Center, 1081 BT Amsterdam, The Netherlands
| | - Mark H H Kramer
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, location VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Max Nieuwdorp
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, location VU University Medical Center, 1081 HV Amsterdam, The Netherlands
- Department of Vascular Medicine, Amsterdam University Medical Center, Location AMC, 1105 AZ Amsterdam, The Netherlands
| | - Richard G IJzerman
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, location VU University Medical Center, 1081 HV Amsterdam, The Netherlands
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Sato D, Nakamura T, Amarume J, Yano M, Umehara Y, Nishina A, Tsutsumi K, Feng Z, Kusunoki M. Effects of dapagliflozin on adipose and liver fatty acid composition and mRNA expression involved in lipid metabolism in high-fat-fed rats. Endocr Metab Immune Disord Drug Targets 2022; 22:944-953. [PMID: 35255800 DOI: 10.2174/1871530322666220307153618] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/23/2021] [Accepted: 01/25/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND SGLT2 inhibitor enhances not only glucose excretion but also fatty acid utilization. Those facts suggest that SGLT2 inhibitor affects fat accumulation and lipid storage. OBJECTIVE In the present study, we evaluated the effects of dapagliflozin on fatty acid composition and gene expression involved in fatty acid metabolism in rat adipose and liver tissues. METHODS We administered 1 mg/kg/day dapagliflozin for 7 weeks to male high-fat-fed rats (DAPA group), and then weights and 22 fatty acid contents in the epididymal (EPI), mesenteric (MES), retroperitoneal (RET) and subcutaneous (SUB) adipose tissues, and the liver were compared with vehicle-administered control group. RESULTS In the EPI, RET, and SUB in the DAPA group, contents of several fatty acids were lower (P<0.05) than those in the control group while no significant difference was detected in tissue weight. In the MES, not only tissue weight but also wide variety of fatty acid contents including saturated, monounsaturated, and polyunsaturated fatty acids were lower (P<0.05). As for the liver tissue, no significant difference was observed in fatty acid contents between the groups. mRNA expression of Srebp1c in EPI was significantly higher (P<0.05) in the DAPA group than in the control group, while Scd1 expression in the liver was lower (P<0.01). CONCLUSION These results suggest that dapagliflozin might suppress lipid accumulation especially in the MES, and could reduce contents of fatty acids not in the liver but in adipose tissues in high-fat-fed rats. In addition, dapagliflozin could influence mRNA expression involved in lipogenesis in the EPI and liver.
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Affiliation(s)
- Daisuke Sato
- Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University (4-3-16 Johnan, Yonezawa 992-8510, Japan)
| | - Takao Nakamura
- Department of Biomedical Information Engineering, Graduate School of Medical Science, Yamagata University (2-2-2 Iida-nishi, Yamagata 990-9585, Japan)
| | - Jota Amarume
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University (4-3-16 Johnan, Yonezawa 992-8510, Japan)
| | - Mizuna Yano
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University (4-3-16 Johnan, Yonezawa 992-8510, Japan)
| | - Yuta Umehara
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University (4-3-16 Johnan, Yonezawa 992-8510, Japan)
| | - Atsuyoshi Nishina
- Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University (1-8-14 Kandasurugadai, Chiyoda-ku, 101-8308, Japan)
| | - Kazuhiko Tsutsumi
- Okinaka Memorial Institute for Medical Research (2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan)
| | - Zhonggang Feng
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University (4-3-16 Johnan, Yonezawa 992-8510, Japan)
| | - Masataka Kusunoki
- Research Center of Health, Physical Fitness and Sports, Nagoya University (Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan)
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van Ruiten CC, Veltman DJ, Nieuwdorp M, IJzerman RG. Brain Activation in Response to Low-Calorie Food Pictures: An Explorative Analysis of a Randomized Trial With Dapagliflozin and Exenatide. Front Endocrinol (Lausanne) 2022; 13:863592. [PMID: 35600575 PMCID: PMC9114766 DOI: 10.3389/fendo.2022.863592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/31/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND AND AIM Sodium-glucose cotransporter-2 inhibitors (SGLT2i) induce less weight loss than expected. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, contributing to increased appetite and food intake. This hyperphagia may be specific to high-calorie foods. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are associated with lower preferences for high-calorie foods, and with decreased activation in areas regulating satiety and reward in response to high-calorie food pictures, which may reflect this lower preference for energy-dense foods. To optimize treatment, we need a better understanding of how intake is controlled, and how [(un)healthy] food choices are made. The aim of the study was to investigate the effects of dapagliflozin, exenatide, and their combination on brain activation in response to low-calorie food pictures. METHODS We performed an exploratory analysis of a larger, 16-week, double-blind, randomized, placebo-controlled trial. Sixty-eight subjects with obesity and type 2 diabetes were randomized to dapagliflozin, exenatide, dapagliflozin plus exenatide, or double placebo. Using functional MRI, the effects of treatments on brain responses to low-calorie food pictures were assessed after 10 days and 16 weeks. RESULTS Dapagliflozin versus placebo decreased activity in response to low-calorie food pictures, in the caudate nucleus, insula, and amygdala after 10 days, and in the insula after 16 weeks. Exenatide versus placebo increased activation in the putamen in response to low-calorie food pictures after 10 days, but not after 16 weeks. Dapagliflozin plus exenatide versus placebo had no effect on brain responses, but after 10 days dapagliflozin plus exenatide versus dapagliflozin increased activity in the insula and amygdala in response to low-calorie food pictures. CONCLUSION Dapagliflozin decreased activation in response to low-calorie food pictures, which may reflect a specific decreased preference for low-calorie foods, in combination with the previously found increased activation in response to high-calorie foods, which may reflect a specific preference for high-calorie foods, and may hamper SGLT2i-induced weight loss. Exenatide treatment increased activation in response to low-calorie foods. Combination treatment may lead to more favorable brain responses to low-calorie food cues, as we observed that the dapagliflozin-induced decreased response to low-calorie food pictures had disappeared.
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Affiliation(s)
- Charlotte C. van Ruiten
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, Vrije University Medical Center (VUmc), Amsterdam, Netherlands
- *Correspondence: Charlotte C. van Ruiten,
| | - Dick J. Veltman
- Department of Psychiatry, Amsterdam University Medical Center, Vrije University Medical Center (VUmc), Amsterdam, Netherlands
| | - Max Nieuwdorp
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, Vrije University Medical Center (VUmc), Amsterdam, Netherlands
- Department of Vascular Medicine, Amsterdam University Medical Center (AMC), Amsterdam, Netherlands
| | - Richard G. IJzerman
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Center, Vrije University Medical Center (VUmc), Amsterdam, Netherlands
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Sato D, Nakamura T, Amarume J, Yano M, Nishina A, Feng Z, Kusunoki M. Effects of dapagliflozin on peripheral sympathetic nerve activity in standard chow- and high-fat-fed rats after a glucose load. J Pharmacol Sci 2022; 148:86-92. [PMID: 34924134 DOI: 10.1016/j.jphs.2021.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/21/2021] [Accepted: 09/27/2021] [Indexed: 12/31/2022] Open
Abstract
To clarify the effects of long-term administration of SGLT2 inhibitor, a hypoglycemic agent, on basal sympathetic nerve activity (SNA) and on SNA under development of insulin resistance, we measured peripheral SNA in response to a glucose load in standard chow- (SCF) and high-fat-fed (HFF) rats treated with or without dapagliflozin for 7 weeks. We conducted an intravenous glucose administration (IVGA), and evaluated SNA microneurographically recorded in the unilateral sciatic nerve. Dapagliflozin did not affect the steady state action potential (AP) rate just before the IVGA (baseline) in both the SCF and HFF rats. After the IVGA, in the SCF rats, the AP rate in dapagliflozin-treated group transiently decreased within 20 min after the IVGA, and was significantly lower (P < 0.05) than non-treated group for 60 min. In the HFF rats, no significant difference was seen in the AP rate between dapagliflozin-treated and non-treated groups. The rate in the dapagliflozin-treated group after the IVGA was significantly lower (P < 0.05) than the baseline whereas such difference was not found in the non-treated group. In conclusion, dapagliflozin attenuate SNA in response to glucose load, and that the SNA response is different between standard chow-fed- and high-fat-fed rats.
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Affiliation(s)
- Daisuke Sato
- Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Johnan, Yonezawa 992-8510, Japan.
| | - Takao Nakamura
- Department of Biomedical Information Engineering, Graduate School of Medical Science, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
| | - Jota Amarume
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Johnan, Yonezawa 992-8510, Japan
| | - Mizuna Yano
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Johnan, Yonezawa 992-8510, Japan
| | - Atsuyoshi Nishina
- Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University, 1-8-14 Kandasurugadai, Chiyoda-ku, 101-8308, Japan
| | - Zhonggang Feng
- Department of Bio-Systems Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Johnan, Yonezawa 992-8510, Japan
| | - Masataka Kusunoki
- Research Center of Health, Physical Fitness and Sports, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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Cho YK, Kim YJ, Jung CH. Effect of Sodium-Glucose Cotransporter 2 Inhibitors on Weight Reduction in Overweight and Obese Populations without Diabetes: A Systematic Review and a Meta-Analysis. J Obes Metab Syndr 2021; 30:336-344. [PMID: 34897070 PMCID: PMC8735829 DOI: 10.7570/jomes21061] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND We aimed to evaluate the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors for managing obesity in non-diabetic overweight or obese patients. METHODS For purposes of this study, PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched through May 2021. Randomized controlled trials published in English that compared SGLT2 inhibitors with placebo in overweight and obese patients without diabetes were included in the primary analysis. The random effects standardized mean difference ±95% confidence interval (95% CI) was calculated as the effect size. RESULTS Five randomized controlled trials were included to evaluate body weight change, four trials to assess body mass index (BMI), and three trials to assess waist circumference were included. Results showed that the mean body weight loss on SGLT2 inhibitors in obese patients without diabetes was -1.62 kg (95% CI, -2.38 to -0.85 kg) when compared with placebo. Treatment with SGLT2 inhibitors was also associated with a greater reduction in BMI than placebo (weighted mean difference, -0.47 kg/m2; 95% CI, -0.62 to -0.31 kg/m2). The mean reduction in waist circumference with SGLT2 inhibitors versus placebo was 1.29 cm (95% CI, -2.62 to 0.04 cm), which was not statistically significant. There were no significant changes in fat mass, blood pressure, low-density lipoprotein cholesterol or high-density lipoprotein cholesterol with SGLT2 inhibitor treatment. CONCLUSION A meta-analysis demonstrated that although the weight lowering effect was mild, SGLT2 inhibitors significantly reduced body weight in obese patients without diabetes.
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Affiliation(s)
- Yun Kyung Cho
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
| | - Ye-Jee Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang Hee Jung
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Asan Diabetes Center, Asan Medical Center, Seoul, Korea
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Kusunoki M, Hisano F, Wakazono N, Tsutsumi K, Oshida Y, Miyata T. Effect of Treatment With Sodium-Glucose Cotransporter 2 Inhibitor on the Initiation of Continuous Positive Airway Pressure Therapy in Type 2 Diabetic Patients With Obstructive Sleep Apnea Syndrome. J Clin Med Res 2021; 13:497-501. [PMID: 34925660 PMCID: PMC8670768 DOI: 10.14740/jocmr4626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 11/09/2021] [Indexed: 11/11/2022] Open
Abstract
Background Obese patients with type 2 diabetes mellitus often develop obstructive sleep apnea syndrome (OSAS). In this study, continuous positive airway pressure (CPAP) was initiated in Japanese patients with type 2 diabetes mellitus who developed OSAS during treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the effect of the SGLT2 inhibitor therapy on the patients was investigated. Methods The study was conducted in outpatients with type 2 diabetes mellitus with serum hemoglobin A1c (HbA1c) values of ≥ 6.5% who developed OSAS. The patients were divided into two groups according to whether they were receiving treatment with an SGLT2 inhibitor or with other oral hypoglycemic agents: the SGLT2 inhibitor group (n = 9) and non-SGLT2 inhibitor group (n = 7). The patients in the former group were under treatment with one of the following three SGLT2 inhibitors: luseogliflozin (2.5 mg/day), dapagliflozin (5 mg/day) and empagliflozin (10 mg/day). The patients took the drugs once daily, before or after breakfast. The patients were initiated on CPAP therapy for OSAS, and their weight, body mass index (BMI), serum HbA1c level, lipid profile, liver function parameters, serum uric acid, and apnea-hypopnea index (AHI) measured before the initiation of CPAP therapy (baseline) were compared with the values measured 3 months after the start of CPAP therapy. Results The AHI decreased significantly after 3 months of CPAP therapy, as compared to that at the baseline, in both the SGLT2 inhibitor and non-SGLT2 inhibitor groups. There was no significant change in the serum HbA1c value after 3 months of CPAP therapy as compared to that at the baseline in either group. The body weight and BMI increased significantly after 3 months of CPAP therapy in the SGLT2 inhibitor group, but not in the non-SGLT2 inhibitor group. Conclusion The body weight and BMI increased significantly after 3 months of CPAP therapy initiated for OSAS in the type 2 diabetic patients who were receiving SGLT2 inhibitor therapy. Thus, when CPAP therapy is adopted for an obese diabetic patient with OSAS, it should be borne in mind that the body weight may increase if the patient is receiving SGLT2 inhibitor treatment.
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Affiliation(s)
- Masataka Kusunoki
- Department of Diabetes, Motor Function and Metabolism, Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan
| | - Fumiya Hisano
- Graduate School of Medicine, Department of Integrated Health Sciences, Nagoya University, Nagoya, Japan
| | - Naomi Wakazono
- Department of Diabetes, Motor Function and Metabolism, Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya, Japan
| | | | | | - Tetsuro Miyata
- Office of Medical Education, School of Medicine, International University of Health and Welfare, Chiba, Japan
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Lund SS, Sattar N, Salsali A, Neubacher D, Ginsberg HN. Potential contribution of haemoconcentration to changes in lipid variables with empagliflozin in patients with type 2 diabetes: A post hoc analysis of pooled data from four phase 3 randomized clinical trials. Diabetes Obes Metab 2021; 23:2763-2774. [PMID: 34463415 PMCID: PMC9290508 DOI: 10.1111/dom.14534] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/10/2021] [Accepted: 08/24/2021] [Indexed: 01/24/2023]
Abstract
AIM To examine the association between changes in lipids and markers of haemoconcentration (haematocrit and serum albumin) with empagliflozin, a sodium-glucose co-transporter-2 inhibitor, in patients with type 2 diabetes (T2D) using pooled data from four phase 3 randomized trials. MATERIALS AND METHODS Patients with T2D received placebo (n = 825), empagliflozin 10 mg (n = 830) or 25 mg (n = 822) for 24 weeks. In post hoc mediation analyses, we assessed total changes in LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein (Apo) B, and Apo A-I, and changes in these variables associated with, and independent of, changes in haematocrit and serum albumin at week 24 using ANCOVA models. RESULTS Empagliflozin versus placebo increased serum LDL-cholesterol, HDL-cholesterol, and Apo A-I, decreased triglycerides (empagliflozin 10 mg only), and (non-significantly) increased Apo B. Empagliflozin modestly increased haematocrit and serum albumin. In mediation analyses, haematocrit changes (increases) with empagliflozin were associated with significant changes (increases) in all lipid variables, including Apo B. Except for triglycerides (non-significant), similar lipid variable associations were observed with serum albumin changes. Haematocrit- and serum albumin-independent changes in lipids with empagliflozin were significant for HDL-cholesterol (increases), mostly significant for triglycerides (decreases), and less so for other lipid fractions. CONCLUSION Haematocrit and serum albumin increases were associated with increases in lipid fractions with empagliflozin. Empagliflozin-associated changes in serum lipids, particularly LDL-cholesterol increases, may be partly attributable to haemoconcentration resulting from increased urinary volume and subsequent volume contraction.
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Affiliation(s)
- Søren S. Lund
- Boehringer Ingelheim International GmbHIngelheimGermany
| | | | - Afshin Salsali
- Boehringer Ingelheim Pharmaceuticals, IncRidgefieldConnecticutUSA
| | | | - Henry N. Ginsberg
- Vagelos College of Physicians and Surgeons of Columbia UniversityNew YorkNew YorkUSA
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Young SL, Ryan L, Mullins TP, Flint M, Steane SE, Walton SL, Bielefeldt-Ohmann H, Carter DA, Reichelt ME, Gallo LA. Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload. Front Physiol 2021; 12:738594. [PMID: 34621187 PMCID: PMC8490778 DOI: 10.3389/fphys.2021.738594] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/31/2021] [Indexed: 01/10/2023] Open
Abstract
Selective SGLT2 inhibition reduces the risk of worsening heart failure and cardiovascular death in patients with existing heart failure, irrespective of diabetic status. We aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in normal diet (ND) and high fat diet (HFD) mice with cardiac pressure overload. Five-week-old male C57BL/6J mice were randomized to receive a HFD (60% of calories from fat) or remain on ND for 12 weeks. One week later, transverse aortic constriction (TAC) was employed to induce cardiac pressure-overload (50% increase in right:left carotid pressure versus sham surgery), resulting in left ventricular hypertrophic remodeling and cardiac fibrosis, albeit preserved ejection fraction. At 4 weeks post-TAC, mice were treated for 7 weeks by oral gavage once daily with sotagliflozin (10 mg/kg body weight) or vehicle (0.1% tween 80). In ND mice, treatment with sotagliflozin attenuated cardiac hypertrophy and histological markers of cardiac fibrosis induced by TAC. These benefits were associated with profound diuresis and glucosuria, without shifts toward whole-body fatty acid utilization, increased circulating ketones, nor increased cardiac ketolysis. In HFD mice, sotagliflozin reduced the mildly elevated glucose and insulin levels but did not attenuate cardiac injury induced by TAC. HFD mice had vacuolation of proximal tubular cells, associated with less profound sotagliflozin-induced diuresis and glucosuria, which suggests dampened drug action. We demonstrate the utility of dual SGLT1/2 inhibition in treating cardiac injury induced by pressure overload in normoglycemic mice. Its efficacy in high fat-fed mice with mild hyperglycemia and compromised renal morphology requires further study.
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Affiliation(s)
- Sophia L Young
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia.,Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia
| | - Lydia Ryan
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia.,Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia
| | - Thomas P Mullins
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia.,Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia
| | - Melanie Flint
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Sarah E Steane
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Sarah L Walton
- Cardiovascular Disease Program, Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | | | - David A Carter
- Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
| | - Melissa E Reichelt
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Linda A Gallo
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia.,Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia
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Ando Y, Shigiyama F, Hirose T, Kumashiro N. Simplification of complex insulin regimens using canagliflozin or liraglutide in patients with well-controlled type 2 diabetes: A 24-week randomized controlled trial. J Diabetes Investig 2021; 12:1816-1826. [PMID: 33650779 PMCID: PMC8504902 DOI: 10.1111/jdi.13533] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/15/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
AIMS/INTRODUCTION We investigated the potential use of canagliflozin, in comparison with liraglutide, as an alternative to bolus insulin in patients with well-controlled type 2 diabetes mellitus receiving multiple daily insulin injection therapy. MATERIALS AND METHODS In 40 patients, with glycated hemoglobin (HbA1c) levels <7.5% controlled by multiple daily insulin injection therapy, all bolus insulin was randomly switched to canagliflozin (100 mg/day) or liraglutide (0.3-0.9 mg/day) for 24 weeks. Basal insulin was continued with dose adjustment according to a predefined algorithm. The end-points were the change in the HbA1c level, glycemic variability assessed by continuous glucose monitoring, body mass index, insulin dose, quality of life (QOL) and safety assessments. Factors influencing the changes in QOL were also assessed using a simple regression analysis. RESULTS The change in HbA1c from baseline was comparable between the treatments. Both treatments maintained the HbA1c level to the baseline levels with stable glucose variability and no severe hypoglycemia for 24 weeks, decreased total insulin dose, and significantly increased the QOL score. The change in QOL was significantly associated with injection frequency. CONCLUSIONS For patients with well-controlled type 2 diabetes mellitus, under the support of basal insulin, complex insulin regimens can be simplified by replacing all bolus insulin with once-daily canagliflozin or liraglutide, which improves patients' QOL.
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Affiliation(s)
- Yasuyo Ando
- Division of Diabetes, Metabolism, and EndocrinologyDepartment of MedicineToho University Graduate School of MedicineTokyoJapan
| | - Fumika Shigiyama
- Division of Diabetes, Metabolism, and EndocrinologyDepartment of MedicineToho University Graduate School of MedicineTokyoJapan
| | - Takahisa Hirose
- Division of Diabetes, Metabolism, and EndocrinologyDepartment of MedicineToho University Graduate School of MedicineTokyoJapan
| | - Naoki Kumashiro
- Division of Diabetes, Metabolism, and EndocrinologyDepartment of MedicineToho University Graduate School of MedicineTokyoJapan
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Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress. Int J Mol Sci 2021; 22:ijms221910606. [PMID: 34638943 PMCID: PMC8508693 DOI: 10.3390/ijms221910606] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/26/2021] [Accepted: 09/28/2021] [Indexed: 12/18/2022] Open
Abstract
(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects. Nuclear magnetic resonance (NMR)-based metabolomics; quantitative PCR of relevant genes involved in lipid and glucose metabolism, or senescence; glucose and palmitic acid oxidation in isolated tissues and cell lines of adipocytes and hepatocytes were used. (3) Results: empagliflozin inhibited weight gain and decreased adipose tissue weight, fasting blood glucose, and triglycerides and increased HDL-cholesterol. It also improved insulin sensitivity in white fat. NMR spectroscopy identified higher plasma concentrations of ketone bodies, ketogenic amino acid leucine and decreased levels of pyruvate and alanine. In the liver, adipose tissue and kidney, empagliflozin up-regulated expression of genes involved in gluconeogenesis and down-regulated expression of genes involved in lipogenesis along with reduction of markers of inflammation, oxidative stress and cell senescence. (4) Conclusion: multiple positive effects of empagliflozin, including reduced cell senescence and oxidative stress, could contribute to its long-term cardio- and nephroprotective actions.
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Pabel S, Hamdani N, Luedde M, Sossalla S. SGLT2 Inhibitors and Their Mode of Action in Heart Failure-Has the Mystery Been Unravelled? Curr Heart Fail Rep 2021; 18:315-328. [PMID: 34523061 PMCID: PMC8484236 DOI: 10.1007/s11897-021-00529-8] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/09/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW SGLT2 inhibitors (SGLT2i) are new drugs for patients with heart failure (HF) irrespective of diabetes. However, the mechanisms of SGLT2i in HF remain elusive. This article discusses the current clinical evidence for using SGLT2i in different types of heart failure and provides an overview about the possible underlying mechanisms. RECENT FINDINGS Clinical and basic data strongly support and extend the use of SGLT2i in HF. Improvement of conventional secondary risk factors is unlikely to explain the prognostic benefits of these drugs in HF. However, different multidirectional mechanisms of SGLT2i could improve HF status including volume regulation, cardiorenal mechanisms, metabolic effects, improved cardiac remodelling, direct effects on cardiac contractility and ion-homeostasis, reduction of inflammation and oxidative stress as well as an impact on autophagy and adipokines. Further translational studies are needed to determine the mechanisms of SGLT2i in HF. However, basic and clinical evidence encourage the use of SGLT2i in HFrEF and possibly HFpEF.
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Affiliation(s)
- Steffen Pabel
- Department of Internal Medicine II, University Medical Centre Regensburg, Regensburg, Germany
| | - Nazha Hamdani
- Department of Molecular and Experimental Cardiology and Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Mark Luedde
- Department of Cardiology and Angiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Samuel Sossalla
- Department of Internal Medicine II, University Medical Centre Regensburg, Regensburg, Germany. .,Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Göttingen, Germany.
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Janež A, Fioretto P. SGLT2 Inhibitors and the Clinical Implications of Associated Weight Loss in Type 2 Diabetes: A Narrative Review. Diabetes Ther 2021; 12:2249-2261. [PMID: 34244976 PMCID: PMC8342745 DOI: 10.1007/s13300-021-01104-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/03/2021] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION The obesity epidemic is closely linked to the rising prevalence of type 2 diabetes (T2D). Body weight reduction remains an important challenge in patients with T2D, as it requires changing their overall metabolic control. Of all glucose-lowering therapies, only sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) consistently result in weight improvement. Moreover, the same two classes have important cardiovascular and renal benefits. We summarize the key available information related to the weight loss effect of SGLT2is in T2D, focusing on the unexploited potential of these drugs. METHODS Data on weight change with SGLT2is in patients with T2D were extracted from published cardiovascular outcomes trials (CVOTs). A discussion on patient perspectives about weight change is based on key preclinical and clinical trials, meta-analyses, and reviews and is supplemented by the authors' clinical judgment and research experience in the field. RESULTS SGLT2is have a unique mode of action resulting in caloric loss through glycosuria. The anticipated weight loss with SGLT2is is not reflected in clinical trial results. There is a discrepancy between the magnitude of improvement in glycemic control and the weight loss, cardiovascular, and renal benefits obtained in large clinical trials. CONCLUSION The relationships between the magnitude of weight loss, improvement in glycemic control, and cardiorenal benefits with SGLT2i are still unclear. Potential mechanisms other than simple glycemic efficacy should be revealed and explained. Better weight control may be achieved if adequately intensive lifestyle changes are implemented and monitored in the T2D population treated with SGLT2is.
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Affiliation(s)
- Andrej Janež
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Zaloška Cesta 7, 1000, Ljubljana, Slovenia.
| | - Paola Fioretto
- Department of Medicine, University of Padua, Padua, Italy
- Unit of Medical Clinic 3, Hospital of Padua, Padua, Italy
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Tanaka A, Shimabukuro M, Teragawa H, Okada Y, Takamura T, Taguchi I, Toyoda S, Tomiyama H, Ueda S, Higashi Y, Node K, the EMBLEM Investigators. Comparison of the clinical effect of empagliflozin on glycemic and non-glycemic parameters in Japanese patients with type 2 diabetes and cardiovascular disease treated with or without baseline metformin. Cardiovasc Diabetol 2021; 20:160. [PMID: 34332584 PMCID: PMC8325864 DOI: 10.1186/s12933-021-01352-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 07/21/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The most recent treatment guidelines for type 2 diabetes (T2D) recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors should be considered preferentially in patients with T2D with either a high cardiovascular risk or with cardiovascular disease (CVD), regardless of their diabetes status and prior use of conventional metformin therapy. Whether the therapeutic impact of SGLT2 inhibitors on clinical parameters differs according to the use of metformin therapy however remains unclear. METHODS The study was a post hoc analysis of the EMBLEM trial (UMIN000024502). All participants (n = 105; women 31.4%; mean age 64.8 years) had both T2D and CVD and were randomized to either 24 weeks of empagliflozin 10 mg daily or placebo. Analysis of the data assessed the effect of empagliflozin on changes from baseline to 24 weeks in glycemic and non-glycemic clinical parameters, according to the baseline use of metformin. RESULTS Overall, 53 (50.5%) patients received baseline metformin. In the 52 patients treated with empagliflozin (48.1% with baseline metformin), the decrease in systolic blood pressure from baseline levels was greater in patients receiving metformin, compared to that observed in metformin-naïve patients (group difference - 8.5 [95% confidence interval (CI) - 17.7 to 0.6 mmHg], p = 0.066). Reduction in body mass index (BMI) was significantly greater in patients receiving baseline metformin, relative to nonusers (- 0.54 [95% CI - 1.07 to - 0.01] kg/m2, p = 0.047). The group ratio (baseline metformin users vs. nonusers) of proportional changes in the geometric mean of high-sensitivity Troponin-I (hs-TnI) was 0.74 (95% CI 0.59 to 0.92, p = 0.009). No obvious differences were observed in glycemic parameters (fasting plasma glucose, glycohemoglobin, and glycoalbumin) between the baseline metformin users and nonusers. CONCLUSION Our findings suggest 24 weeks of empagliflozin treatment was associated with an improvement in glycemic control, irrespective of the baseline use of metformin therapy. The effects of empagliflozin on reductions in BMI and hs-TnI were more apparent in patients who received baseline metformin therapy, compared to that observed in metformin-naïve patients. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502.
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Affiliation(s)
- Atsushi Tanaka
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501 Japan
| | - Michio Shimabukuro
- Department of Diabetes, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima, Japan
| | - Hiroki Teragawa
- Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima, Japan
| | - Yosuke Okada
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Isao Taguchi
- Department of Cardiology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
| | - Shigeru Toyoda
- Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Mibu, Japan
| | | | - Shinichiro Ueda
- Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus, Nishihara, Japan
| | - Yukihito Higashi
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501 Japan
| | - the EMBLEM Investigators
- Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501 Japan
- Department of Diabetes, Endocrinology, and Metabolism, Fukushima Medical University, Fukushima, Japan
- Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima, Japan
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
- Department of Cardiology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
- Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Mibu, Japan
- Department of Cardiology, Tokyo Medical University, Tokyo, Japan
- Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus, Nishihara, Japan
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
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McMillin SM, Pham ML, Sherrill CH. Effects of sodium-glucose cotransporter-2 inhibitors on appetite markers in patients with type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis 2021; 31:2507-2511. [PMID: 34167866 DOI: 10.1016/j.numecd.2021.05.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 04/23/2021] [Accepted: 05/05/2021] [Indexed: 12/01/2022]
Abstract
BACKGROUND AND AIMS Glycosuria induced by sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to weight loss and improved diabetes control, but a significant disparity exists between observed and expected weight loss with these medications, hindering clinical effects. This study investigated whether this discrepancy could be explained by compensatory increases in appetite and associated alterations in appetite-regulating hormones. METHODS AND RESULTS This was a prospective single-center observational pilot study. Adults 18-70 years old newly prescribed an SGLT2 inhibitor through usual care were invited to participate. Fasting and postprandial appetite was assessed immediately before, 1 week after, and 12 weeks after SGLT2 inhibitor initiation. Serum samples were collected at corresponding time points to measure ghrelin, leptin, and peptide tyrosine-tyrosine (PYY). Seven patients were included. At 1 and 12 weeks after SGLT2 inhibitor initiation, self-reported appetite did not change significantly and trended toward a decrease in appetite. There were no significant differences in fasting or postprandial ghrelin, leptin, or PYY. CONCLUSION Results suggest the discrepancy between expected and observed weight loss with SGLT2 inhibitors cannot be explained by increases in appetite or changes in appetite-regulating hormones. Further studies are needed to investigate alternative metabolic compensatory mechanisms to optimize weight loss with SGLT2 inhibitor use.
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Affiliation(s)
- Sara M McMillin
- High Point University Fred Wilson School of Pharmacy, One University Parkway, High Point, NC, 27268, USA
| | - Mimi L Pham
- High Point University Fred Wilson School of Pharmacy, One University Parkway, High Point, NC, 27268, USA; Present affiliation: Moses H. Cone Memorial Hospital, 1121 North Church Street, Greensboro, NC, 27407, USA
| | - Christina H Sherrill
- High Point University Fred Wilson School of Pharmacy, One University Parkway, High Point, NC, 27268, USA.
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