1
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Yoo TT, Baek IH, Stoletniy L, Hilliard A, Sakr A, Doycheva D. Impact of sodium-glucose transport protein-2 (SGLT2) inhibitors on the inflammasome pathway in acute myocardial infarction in type 2 diabetes mellitus: a comprehensive review. Cardiovasc Diabetol 2025; 24:227. [PMID: 40420176 PMCID: PMC12105141 DOI: 10.1186/s12933-025-02777-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Accepted: 05/06/2025] [Indexed: 05/28/2025] Open
Abstract
Sodium-glucose transport protein-2 (SGLT2) inhibitors, initially developed for glycemic control in type 2 diabetes mellitus (T2DM), have emerged as potential cardioprotective agents, reducing cardiovascular mortality and improving heart failure outcomes. Recent evidence suggests that SGLT2 inhibitors exert anti-inflammatory effects, particularly through modulating the inflammasome pathway. This review explores the role of the inflammasome in acute myocardial infarction (AMI) in T2DM and discusses the mechanisms by which SGLT2 inhibitors influence this pathway. We evaluate current studies on the impact of SGLT2 inhibitors on key inflammatory mediators, particularly the NLRP3 inflammasome, and discuss their potential therapeutic implications for reducing inflammation and myocardial injury in patients with T2DM experiencing AMI. In summary, the key novelties in this review lie in its focused mechanistic approach on the inflammasome pathway, its integration of diabetes and cardiovascular research, and its potential to influence future therapeutic strategies for AMI in T2DM patients. It offers a novel angle by tying together molecular mechanisms of inflammation with clinical implications in a specific patient population that faces high cardiovascular risk.
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Affiliation(s)
- Thomas T Yoo
- Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA
| | - In Hae Baek
- Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA
| | - Liset Stoletniy
- Division of Cardiology, School of Medicine, Loma Linda University, 11234 Anderson St, Loma Linda, CA, 92354, USA
- Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA
| | - Anthony Hilliard
- Division of Cardiology, School of Medicine, Loma Linda University, 11234 Anderson St, Loma Linda, CA, 92354, USA
- Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA
| | - Antoine Sakr
- Division of Cardiology, School of Medicine, Loma Linda University, 11234 Anderson St, Loma Linda, CA, 92354, USA
- Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA
| | - Desislava Doycheva
- Division of Cardiology, School of Medicine, Loma Linda University, 11234 Anderson St, Loma Linda, CA, 92354, USA.
- Department of Physiology and Pharmacology, Loma Linda University, 11175 Campus St, Loma Linda, CA, 92354, USA.
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2
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González Campos E, Grover Páez F, Ramos Becerra CG, Balleza Alejandri LR, Suárez Rico DO, Cardona Muñoz EG, Pascoe González S, Ramos Zavala MG, Beltrán Ramírez A, García Galindo JJ, Cardona Müller D. Empagliflozin Leads to Faster Improvement in Arterial Stiffness Compared to Dapagliflozin: A Double-Blind Clinical. Life (Basel) 2025; 15:802. [PMID: 40430228 PMCID: PMC12113407 DOI: 10.3390/life15050802] [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: 03/19/2025] [Revised: 04/22/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
(1) Background: Arterial stiffness, often measured by carotid-femoral pulse wave velocity (cf-PWV), is crucial in cardiovascular disease. Dapagliflozin has shown rapid effects on arterial stiffness, but there is limited evidence of empagliflozin's acute effects, especially in type 2 diabetes (T2D) patients. This study evaluated the acute effects of empagliflozin and dapagliflozin on arterial stiffness and blood pressure (BP). (2) Methods: A one-week double-blind randomized trial involved 30 T2D patients on stable metformin therapy. Participants received empagliflozin (25 mg/day), dapagliflozin (10 mg/day), or a placebo. Arterial stiffness was assessed via cf-PWV, and BP was measured with an automated sphygmomanometer. (3) Results: Both SGLT2 inhibitors significantly reduced cf-PWV compared to the placebo after one week (p < 0.05), with dapagliflozin showing a more pronounced effect. No significant differences were observed in BP changes. (4) Conclusion: Short-term treatment with SGLT2 inhibitors acutely reduces arterial stiffness in T2D patients, with empagliflozin demonstrating a stronger effect, supporting the potential vascular benefits of SGLT2 inhibitors beyond glucose control.
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Affiliation(s)
- Erick González Campos
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (E.G.C.); (C.G.R.B.); (L.R.B.A.); (D.O.S.R.); (E.G.C.M.); (S.P.G.); (A.B.R.); (J.J.G.G.); (D.C.M.)
| | - Fernando Grover Páez
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (E.G.C.); (C.G.R.B.); (L.R.B.A.); (D.O.S.R.); (E.G.C.M.); (S.P.G.); (A.B.R.); (J.J.G.G.); (D.C.M.)
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Carlos Gerardo Ramos Becerra
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (E.G.C.); (C.G.R.B.); (L.R.B.A.); (D.O.S.R.); (E.G.C.M.); (S.P.G.); (A.B.R.); (J.J.G.G.); (D.C.M.)
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Luis Ricardo Balleza Alejandri
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (E.G.C.); (C.G.R.B.); (L.R.B.A.); (D.O.S.R.); (E.G.C.M.); (S.P.G.); (A.B.R.); (J.J.G.G.); (D.C.M.)
| | - Daniel Osmar Suárez Rico
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (E.G.C.); (C.G.R.B.); (L.R.B.A.); (D.O.S.R.); (E.G.C.M.); (S.P.G.); (A.B.R.); (J.J.G.G.); (D.C.M.)
| | - Ernesto Germán Cardona Muñoz
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (E.G.C.); (C.G.R.B.); (L.R.B.A.); (D.O.S.R.); (E.G.C.M.); (S.P.G.); (A.B.R.); (J.J.G.G.); (D.C.M.)
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Sara Pascoe González
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (E.G.C.); (C.G.R.B.); (L.R.B.A.); (D.O.S.R.); (E.G.C.M.); (S.P.G.); (A.B.R.); (J.J.G.G.); (D.C.M.)
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - María Guadalupe Ramos Zavala
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (E.G.C.); (C.G.R.B.); (L.R.B.A.); (D.O.S.R.); (E.G.C.M.); (S.P.G.); (A.B.R.); (J.J.G.G.); (D.C.M.)
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Alberto Beltrán Ramírez
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (E.G.C.); (C.G.R.B.); (L.R.B.A.); (D.O.S.R.); (E.G.C.M.); (S.P.G.); (A.B.R.); (J.J.G.G.); (D.C.M.)
| | - Jesús Jonathan García Galindo
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (E.G.C.); (C.G.R.B.); (L.R.B.A.); (D.O.S.R.); (E.G.C.M.); (S.P.G.); (A.B.R.); (J.J.G.G.); (D.C.M.)
| | - David Cardona Müller
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (E.G.C.); (C.G.R.B.); (L.R.B.A.); (D.O.S.R.); (E.G.C.M.); (S.P.G.); (A.B.R.); (J.J.G.G.); (D.C.M.)
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
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3
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Yalçın N, Aktaş S, Uyar S, Koca N. Impact of SGLT2 Inhibitors on Cardiovascular Risk Scores, Metabolic Parameters, and Laboratory Profiles in Type 2 Diabetes. Life (Basel) 2025; 15:722. [PMID: 40430150 PMCID: PMC12112772 DOI: 10.3390/life15050722] [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: 03/26/2025] [Revised: 04/17/2025] [Accepted: 04/20/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Cardiovascular disease (CVD) is a leading cause of mortality in Type 2 diabetes mellitus (T2DM). Sodium-glucose co-transporter 2 (SGLT2) inhibitors are known to provide cardioprotective effects, but their influence on validated cardiovascular risk models remains underexplored. This study assessed the impact of SGLT2 inhibitors on cardiovascular risk scores, metabolic parameters, and laboratory profiles over six months. Methods: This study was conducted on 152 T2DM patients initiating SGLT2 inhibitors. Cardiovascular risk was evaluated using the SCORE2-DM model at baseline and after six months. Generalized Estimating Equation (GEE) analysis assessed temporal risk stratification changes. Metabolic parameters and laboratory profiles were analyzed using repeated-measures ANOVA. Results: Cardiovascular risk scores decreased significantly, i.e., from 21.68 to 17.43 (p < 0.001). Systolic and diastolic blood pressure were reduced by 9.21 mmHg and 6.16 mmHg, respectively (p < 0.001). BMI declined by 1.27 kg/m2 (p < 0.001), and HbA1c decreased by 1.38% (p < 0.001). Triglyceride levels dropped by 22.91 mg/dL (p < 0.001), while renal parameters remained stable. The GEE analysis confirmed significant shifts to lower cardiovascular risk categories (β = -0.777, p < 0.001), with comparable efficacy between empagliflozin and dapagliflozin (p = 0.922). Conclusions: SGLT2 inhibitor therapy significantly reduces cardiovascular risk and improves metabolic and laboratory parameters in T2DM patients. These findings highlight the importance of integrating SGLT2 inhibitors into comprehensive cardiometabolic management strategies.
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Affiliation(s)
- Nazif Yalçın
- Department of Internal Medicine, Bursa Faculty of Medicine, University of Health Sciences, Bursa City Training and Research Hospital, Bursa 16009, Türkiye;
| | - Selman Aktaş
- Department of Biostatistics, Hamidiye Faculty of Medicine, University of Health Sciences, Istanbul 34396, Türkiye;
| | - Seyit Uyar
- Department of Internal Medicine, University of Health Sciences, Antalya Training & Research Hospital, Antalya 07058, Türkiye;
| | - Nizameddin Koca
- Department of Internal Medicine, Bursa Faculty of Medicine, University of Health Sciences, Bursa City Training and Research Hospital, Bursa 16009, Türkiye;
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Pulipati VP, Zilbermint M, Patel SB. Response to Letter to the Editor on the 2025 AACE Clinical Practice Guideline on Pharmacologic Management of Adults With Dyslipidemia. Endocr Pract 2025:S1530-891X(25)00127-2. [PMID: 40268088 DOI: 10.1016/j.eprac.2025.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 04/25/2025]
Affiliation(s)
| | - Mihail Zilbermint
- Division of Hospital Medicine, Johns Hopkins Community Physicians, Johns Hopkins Medicine, Baltimore, Maryland; Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland; Suburban Hospital, Department of Medicine, Bethesda, Maryland
| | - Shailendra B Patel
- Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, Ohio
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5
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Lu F, Li E, Gao Y, Zhang Y, Kong L, Yang X. Dapagliflozin modulates hepatic lipid metabolism through the proprotein convertase subtilisin/kexin type 9/low density lipoprotein receptor pathway. Diabetes Obes Metab 2025; 27:2096-2109. [PMID: 39831337 DOI: 10.1111/dom.16202] [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: 09/23/2024] [Revised: 01/06/2025] [Accepted: 01/07/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND Proprotein convertase subtilisin/kexin type 9 (PCSK9) is mainly secreted by the liver, and plays a crucial role in lipid metabolism disorder. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) can regulate lipid metabolism through various pathways, including reducing visceral fat accumulation, modulating serum lipoprotein levels and alleviating hepatic steatosis. However, the specific regulatory mechanisms remain unclear. METHODS We built a model of glucose and lipid metabolism disorder in vivo and in vitro, and explored the regulatory mechanism of dapagliflozin in regulating liver lipid metabolism. RESULTS We found that the SGLT2i dapagliflozin significantly reduced serum levels of PCSK9, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) in high-fat diet (HFD)-fed mice, while also improving hepatic steatosis. In vitro studies confirmed that dapagliflozin increased LDL receptor (LDLR) expression in HepG2 cells, enhancing their ability to uptake LDL-C. CONCLUSIONS Further mechanistic studies revealed that the hepatocyte nuclear factor-1-alpha (HNF1α)/PCSK9/LDLR signalling pathway may be involved in dapagliflozin's regulation of lipid metabolism homeostasis.
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Affiliation(s)
- Fengyuan Lu
- The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - En Li
- The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Yifeng Gao
- The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Yan Zhang
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lijuan Kong
- The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Xiaoyu Yang
- The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
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6
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Xu M, Lv D, Wei H, Li Z, Jin S, Liu Q, Zhang Y, Liu Y. Effects of antidiabetic agents on lipid metabolism of skeletal muscle: A narrative review. Diabetes Obes Metab 2025; 27:1693-1707. [PMID: 39807619 DOI: 10.1111/dom.16189] [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: 09/27/2024] [Revised: 12/17/2024] [Accepted: 12/26/2024] [Indexed: 01/16/2025]
Abstract
Metabolic syndrome-related diseases frequently involve disturbances in skeletal muscle lipid metabolism. The accumulation of lipid metabolites, lipid-induced mitochondrial stress in skeletal muscle cells, as well as the inflammation of adjacent adipose tissue, are associated with the development of insulin resistance and metabolic dysfunction. Consequently, when antidiabetic medications are used to treat various chronic conditions related to hyperglycaemia, the impact on skeletal muscle lipid metabolism should not be overlooked. However, current research has predominantly focused on muscle mass rather than skeletal muscle lipid metabolism and its interplay with glucose metabolism. In this review, we summarised the latest research on the effects of antidiabetic drugs and certain natural compounds with antidiabetic activity on skeletal muscle lipid metabolism, focusing on data from preclinical to clinical studies. Given the widespread use of antidiabetic drugs, a better understanding of their effects on skeletal muscle lipid metabolism merits further attention in future research.
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Affiliation(s)
- Ming Xu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Dongqing Lv
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Hongxia Wei
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Zhe Li
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Shuqing Jin
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Qinhao Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Yi Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
- Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, China
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
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Kumar N, Kumar B, Ashique S, Yasmin S, Venkatesan K, Islam A, Ghosh S, Sahu A, Bhui U, Ansari MY. A critical review on SGLT2 inhibitors for diabetes mellitus, renal health, and cardiovascular conditions. Diabetes Res Clin Pract 2025; 221:112050. [PMID: 39965722 DOI: 10.1016/j.diabres.2025.112050] [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: 12/31/2024] [Revised: 02/03/2025] [Accepted: 02/11/2025] [Indexed: 02/20/2025]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally formulated to reduce blood glucose levels in individuals with diabetes. Recent clinical trials indicate that this compound can be repurposed for other critical conditions. A literature search was performed on PubMed, Scopus, Embase, ProQuest, and Google Scholar, utilizing key terms such as SGLT2i, diabetes, and oxidative stress. SGLT2i has significant beneficial effects not only in cardiovascular disease but also in renal dysfunction. SGLT2i therapy can mitigate critical cardiovascular complications like heart attacks, strokes, mortality rates, and hospitalization duration, as well as delay the necessity for dialysis irrespective of diabetic condition. Evidence supports potential advantages of SGLT2 inhibitors for individuals with renal problems and heart failure, regardless of diabetes status. In addition to diabetic mellitus, this analysis explores the latest updates on SGLT2i and the therapeutic advantages it offers in many renal and cardiovascular diseases (CVDs).
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Affiliation(s)
- Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh 201204, India
| | - Bimlesh Kumar
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Sumel Ashique
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India.
| | - Sabina Yasmin
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Kumar Venkatesan
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Anas Islam
- Faculty of Pharmacy, Integral University, Lucknow 226026, Uttar Pradesh, India
| | - Suman Ghosh
- Division of Pharmaceutical Chemistry, Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Road, Kolkata, West Bengal 700114, India
| | - Anwesha Sahu
- Division of Pharmacology, Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
| | - Utpal Bhui
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Mohammad Yousuf Ansari
- MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana 133207, India; Ibne Seena College of Pharmacy, Azmi Vidya Nagri Anjhi Shahabad, Hardoi, Uttar Pradesh (U.P.) 241124, India.
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8
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Emanuelsson F, Jensen J, Omar M, Jürgens M, Kistorp C, Brandt-Jacobsen NH, Møller JE, Schou M, Bechmann LE, Larsen EL, Nordestgaard BG, Benn M. Effect of empagliflozin on plasma lipids and lipoproteins in type 2 diabetes and heart failure - Empire HF and SIMPLE. J Clin Lipidol 2025; 19:276-285. [PMID: 39843293 DOI: 10.1016/j.jacl.2024.12.015] [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: 04/28/2024] [Revised: 12/19/2024] [Accepted: 12/20/2024] [Indexed: 01/24/2025]
Abstract
OBJECTIVE Beyond glucose-lowering, sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardioprotective effects with unclear mechanisms. We examined changes in an extensive panel of plasma lipids, lipoproteins, and apolipoproteins and whether these changes were independent of weight loss, hemoglobin A1c, and hematocrit in patients treated with empagliflozin vs placebo to better understand the observed cardioprotective effects. METHODS Post-hoc analyses of 2 double-blind, placebo-controlled trials, the Empire HF trial including 190 patients with heart failure and reduced ejection fraction and the SIMPLE trial including 90 patients with type 2 diabetes randomized to, respectively, 10 mg and 25 mg empagliflozin daily or placebo for 12 weeks. RESULTS In studies combined, empagliflozin reduced age and sex adjusted body weight by 1.40 kg (SEM: 0.10; P < .001) and hemoglobin A1c by 2.71 mmol/mol (SEM: 0.24; P < .001); and increased hematocrit by 1.9% (SEM: 0.12; P < .001) compared to placebo. No mean changes were seen in concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, small dense LDL cholesterol, very low-density lipoprotein cholesterol, triglyceride rich lipoprotein cholesterol, non-high-density lipoprotein (non-HDL) cholesterol, apolipoprotein B, lipoprotein(a), HDL cholesterol, and triglycerides adjusted for body weight, hemoglobin A1c, and hematocrit with empagliflozin compared to placebo. CONCLUSION Empagliflozin treatment reduced body weight and hemoglobin A1c, and increased hematocrit. No changes were seen in concentrations of lipids and lipoproteins with empagliflozin compared to placebo. This suggests that the cardioprotective effects of SGLT2 inhibitors are independent of lipid and lipoprotein concentrations.
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Affiliation(s)
- Frida Emanuelsson
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Centre of Diagnostic Investigation, Copenhagen, Denmark (Emanuelsson, Bechmann, Larsen, Benn)
| | - Jesper Jensen
- Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark (Jensen, Schou)
| | - Massar Omar
- Department of Cardiology, Odense University Hospital, Odense, Denmark (Omar, Møller); Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark (Omar)
| | - Mikkel Jürgens
- Department of Endocrinology, Copenhagen University Hospital - Rigshospitalet, Centre for Cancer and Organ Diseases, Copenhagen, Denmark (Jürgens, Brandt-Jacobsen)
| | - Caroline Kistorp
- Clinical Institute, University of Southern Denmark, Odense, Denmark (Kistorp, Møller); Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark (Kistorp, Brandt-Jacobsen, Schou, Nordestgaard, Benn)
| | - Niels H Brandt-Jacobsen
- Department of Endocrinology, Copenhagen University Hospital - Rigshospitalet, Centre for Cancer and Organ Diseases, Copenhagen, Denmark (Jürgens, Brandt-Jacobsen); Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark (Kistorp, Brandt-Jacobsen, Schou, Nordestgaard, Benn)
| | - Jacob Eifer Møller
- Department of Cardiology, Odense University Hospital, Odense, Denmark (Omar, Møller); Clinical Institute, University of Southern Denmark, Odense, Denmark (Kistorp, Møller)
| | - Morten Schou
- Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark (Jensen, Schou); Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark (Kistorp, Brandt-Jacobsen, Schou, Nordestgaard, Benn)
| | - Louise Ellegaard Bechmann
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Centre of Diagnostic Investigation, Copenhagen, Denmark (Emanuelsson, Bechmann, Larsen, Benn)
| | - Emil List Larsen
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Centre of Diagnostic Investigation, Copenhagen, Denmark (Emanuelsson, Bechmann, Larsen, Benn)
| | - Børge G Nordestgaard
- Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark (Nordestgaard); Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark (Kistorp, Brandt-Jacobsen, Schou, Nordestgaard, Benn)
| | - Marianne Benn
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Centre of Diagnostic Investigation, Copenhagen, Denmark (Emanuelsson, Bechmann, Larsen, Benn); Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Denmark (Kistorp, Brandt-Jacobsen, Schou, Nordestgaard, Benn).
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Seagle HM, Akerele AT, DeCorte JA, Hellwege JN, Breeyear JH, Kim J, Levin M, Khodurksy S, Bress A, Lee K, Meiler J, Gill D, Lee JS, Heberer K, Miller DR, Reaven P, Chang KM, Lynch JA, Khankari NK, Shuey MM, Edwards TL, Vujkovic M. Genomics-Informed Drug Repurposing Strategy Identifies Novel Therapeutic Targets for Metabolic Dysfunction-Associated Steatotic Liver Disease. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.02.18.25321035. [PMID: 40034783 PMCID: PMC11875238 DOI: 10.1101/2025.02.18.25321035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving treatment of diseases. We employed a cross-disciplinary approach to identify potential treatments for metabolic dysfunction associated steatotic liver disease (MASLD) using humans as a model organism. We identified 212 putative causal genes associated with MASLD using data from a large multi-ancestry genetic association study, of which 158 (74.5%) are novel. From this set we identified 57 genes that encode for druggable protein targets, and where the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. These potential targets were then evaluated for evidence of efficacy using Mendelian randomization, pathway analysis, and protein structural modeling. Using these approaches, we present compelling evidence to suggest activation of FADS1 by icosopent ethyl as well as S1PR2 by fingolimod could be promising therapeutic strategies for MASLD.
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Affiliation(s)
- Hannah M Seagle
- Vanderbilt University Genetics Institute, Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
- Joseph Maxwell Cleland Atlanta VA Medical Center, Atlanta, Georgia, United States of America
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Alexis T Akerele
- Vanderbilt University Genetics Institute, Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
- School of Graduate Studies and Department of Microbiology, Immunology and Physiology, Meharry Medical College, Nashville, Tennessee, United States of America
- Division of Quantitative Science, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Joseph A DeCorte
- Vanderbilt Medical Scientist Training Program, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
- Department of Chemical and Physical Biology, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Jacklyn N Hellwege
- Vanderbilt University Genetics Institute, Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
- VA Tennessee Valley Healthcare System (626), Nashville, Tennessee, United States of America
| | - Joseph H Breeyear
- Biostatistics and Computational Biology Branch, National Institute for Environmental Health Sciences, National Institutes of Health, Durham, North Carolina, United States of America
| | - Jeewoo Kim
- Vanderbilt University Genetics Institute, Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
- Division of Quantitative Science, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
- Vanderbilt Medical Scientist Training Program, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America
| | - Michael Levin
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
- Phoenix VA Health Care System; University of Arizona, Phoenix, Arizona, United States of
| | - Samuel Khodurksy
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
- Phoenix VA Health Care System; University of Arizona, Phoenix, Arizona, United States of
| | - Adam Bress
- Salt Lake City VA Medical Center, Salt Lake City, Utah, United States of America
- University of Utah, School of Medicine, Salt Lake City, Utah, United States of America
| | - Kyung Lee
- Salt Lake City VA Medical Center, Salt Lake City, Utah, United States of America
| | - Jens Meiler
- Department of Chemical and Physical Biology, Vanderbilt University, Nashville, Tennessee, United States of America
- Institute for Drug Discovery, Leipzig University Medical School, Leipzig, Germany
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Jennifer S Lee
- Stanford University, Stanford, California, United States of America
- Palo Alto VA Medical Center, Palo Alto, California, United States of America
| | - Kent Heberer
- Palo Alto VA Medical Center, Palo Alto, California, United States of America
| | - Donald R Miller
- VA Center for Medication Safety, Department of Veterans Affairs, Chicago, Illinois, United States of America
- Center for Population Health, Department of Biomedical and Nutritional Sciences, University of Massachusetts, Lowell, MA, United States of America
| | - Peter Reaven
- Phoenix VA Health Care System; University of Arizona, Phoenix, Arizona, United States of
| | - Kyong-Mi Chang
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
- Corporal Michael J. Crescenz Philadelphia VA Medical Center, Philadelphia, Pennsylvania, United States of America
| | - Julie A Lynch
- Salt Lake City VA Medical Center, Salt Lake City, Utah, United States of America
- University of Utah, School of Medicine, Salt Lake City, Utah, United States of America
| | - Nikhil K Khankari
- Vanderbilt University Genetics Institute, Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Megan M Shuey
- Vanderbilt University Genetics Institute, Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Todd L Edwards
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
- VA Tennessee Valley Healthcare System (626), Nashville, Tennessee, United States of America
| | - Marijana Vujkovic
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
- Corporal Michael J. Crescenz Philadelphia VA Medical Center, Philadelphia, Pennsylvania, United States of America
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10
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Liu K, Cooper ME, Chai Z, Liu F. High-Density Lipoprotein in Patients with Diabetic Kidney Disease: Friend or Foe? Int J Mol Sci 2025; 26:1683. [PMID: 40004147 PMCID: PMC11855193 DOI: 10.3390/ijms26041683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/10/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
High-density lipoprotein (HDL) exhibits multiple metabolic protective functions, such as facilitating cellular cholesterol efflux, antioxidant, anti-inflammatory, anti-apoptotic and anti-thrombotic properties, showing antidiabetic and renoprotective potential. Diabetic kidney disease (DKD) is considered to be associated with high-density lipoprotein cholesterol (HDL-C). The hyperglycemic environment, non-enzymatic glycosylation, carbamylation, oxidative stress and systemic inflammation can cause changes in the quantity and quality of HDL, resulting in reduced HDL levels and abnormal function. Dysfunctional HDL can also have a negative impact on pancreatic β cells and kidney cells, leading to the progression of DKD. Based on these findings, new HDL-related DKD risk predictors have gradually been proposed. Interventions aiming to improve HDL levels and function, such as infusion of recombinant HDL (rHDL) or lipid-poor apolipoprotein A-I (apoA-I), can significantly improve glycemic control and also show renal protective effects. However, recent studies have revealed a U-shaped relationship between HDL-C levels and DKD, and the loss of protective properties of high levels of HDL may be related to changes in composition and the deposition of dysfunctional particles that exacerbate damage. Further research is needed to fully elucidate the complex role of HDL in DKD. Given the important role of HDL in metabolic health, developing HDL-based therapies that augment HDL function, rather than simply increasing its level, is a critical step in managing the development and progression of DKD.
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Affiliation(s)
- Ke Liu
- Department of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China;
- Laboratory of Diabetic Kidney Disease, Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mark E. Cooper
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia;
| | - Zhonglin Chai
- Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia;
| | - Fang Liu
- Department of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China;
- Laboratory of Diabetic Kidney Disease, Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
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11
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Viggiano D, Joshi R, Borriello G, Cacciola G, Gonnella A, Gigliotti A, Nigro M, Gigliotti G. SGLT2 Inhibitors: The First Endothelial-Protector for Diabetic Nephropathy. J Clin Med 2025; 14:1241. [PMID: 40004772 PMCID: PMC11856817 DOI: 10.3390/jcm14041241] [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: 01/06/2025] [Revised: 02/05/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025] Open
Abstract
Sodium-glucose co-transporter type 2 inhibitors (SGLT2i) have emerged as a class of agents relevant for managing diabetic nephropathy and cardiopathy. In a previous report, we noticed that these drugs share, with other drugs with "nephroprotective" effects, the ability to reduce the glomerular filtration rate (GFR), thus suggesting the kidney hemodynamic effect as a proxy for optimal drug dosage. We also noticed that all known nephroprotective drugs exert cardioprotective functions, suggesting the possibility of activities not mediated by the kidney. Finally, we observe that nephroprotective drugs can be grouped according to their effects on hemoglobin levels, thus suggesting their mechanism of action. While the primary mechanism of SGLT2i involves glycosuria and natriuria, growing evidence suggests broader therapeutic effects beyond hemodynamic modulation. Specifically, the evidence that SGLT2 can be expressed in several atypical regions under pathological conditions, supports the possibility that its inhibition has several extratubular effects. Evidence supports the hypothesis that SGLT2i influence mitochondrial function in various cell types affected by diabetes, particularly in the context of diabetic nephropathy. Notably, in SGLT2i-treated patients, the extent of albumin-creatinine ratio (ACR) reduction post-treatment may be correlated with mitochondrial staining intensity in glomerular endothelial cells. This implies that the anti-proteinuric effects of SGLT2i could involve direct actions on glomerular endothelial cell. Our investigation into the role of SGLT2 inhibitors (SGLT2i) in endothelial function suggests that the aberrant expression of SGLT2 in endothelial cells in T2DM would lead to intracellular accumulation of glucose; therefore, SGLT2i are the first type of endothelial protective drugs available today, with potential implications for ageing-related kidney disease. The review reveals two major novel findings: SGLT2 inhibitors are the first known class of endothelial-protective drugs, due to their ability to prevent glucose accumulation in endothelial cells where SGLT2 is aberrantly expressed in Type 2 Diabetes. Additionally, the research demonstrates that SGLT2 inhibitors share a GFR-reducing effect with other nephroprotective drugs, suggesting both a mechanism for optimal drug dosing and potential broader applications in ageing-related kidney disease through their effects on mitochondrial function and glomerular endothelial cells.
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Affiliation(s)
- Davide Viggiano
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Rashmi Joshi
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Gianmarco Borriello
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Giovanna Cacciola
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Annalisa Gonnella
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Andrea Gigliotti
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Michelangelo Nigro
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Giuseppe Gigliotti
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
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12
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Wang Z, Huang L, Han L, Hu X, Dong M, Zhang C, Guo L, Liu S, Liao L. The protective effect of sodium-glucose cotransporter-2 inhibitor on left ventricular global longitudinal strain in patients with type 2 diabetes mellitus according to disease duration. Sci Rep 2025; 15:5111. [PMID: 39934210 PMCID: PMC11814146 DOI: 10.1038/s41598-025-89459-2] [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: 07/25/2024] [Accepted: 02/05/2025] [Indexed: 02/13/2025] Open
Abstract
Our study aimed to elucidate the impact of sodium-glucose cotransporter-2 inhibitor on left ventricular systolic function using global longitudinal strain in type 2 diabetes mellitus patients and to assess its protective effect depending on disease duration. Type 2 diabetes mellitus patients treated at our institute were included. According to whether sodium-glucose cotransporter-2 inhibitor was used in drug treatment, the patients were divided into SGLT2i group and control group, and propensity score matching was performed. For subgroup analysis, patients were further classified based on disease duration (1-5 years, 5-10 years, and 10-20 years). A total of 256 patients with type 2 diabetes mellitus were enrolled. Significantly better global longitudinal strain results were observed at the 6-month follow-up in the SGLT2i group than those of the control group and its baseline (p < 0.001). A significantly lower proportion of subclinical cardiac dysfunction was observed in the SGLT2i group (p < 0.001). Significantly greater global longitudinal strains were observed in the SGLT2i subgroups compared with control subgroups (p all < 0.05). Furthermore, sodium-glucose cotransporter-2 inhibitor use and epicardial adipose tissue thickness change were independently associated with global longitudinal strain change according to multivariate analysis. Sodium-glucose cotransporter-2 inhibitor significantly improved left ventricular function in type 2 diabetes mellitus patients without cardiovascular complications, regardless of disease duration, with more prominent outcomes observed in patients with early-stage disease.
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Affiliation(s)
- Ziying Wang
- Department of Ultrasound, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Long Huang
- Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Leilei Han
- Department of Cardiology,The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xiangsui Hu
- Department of Ultrasound, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Mingyi Dong
- Department of Gastroenterology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Chunquan Zhang
- Department of Ultrasound, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Liangyun Guo
- Department of Ultrasound, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Shengbo Liu
- GE Healthcare Ultrasound Application Specialist, Nanchang, China
| | - Lingmin Liao
- Department of Ultrasound, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
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13
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Vale C, Lourenço IM, Jordan G, Golovaty I, Torres H, Moin T, Buysschaert M, Neves JS, Bergman M. Early combination therapy with SGLT2i and GLP-1 RA or dual GIP/GLP-1 RA in type 2 diabetes. Diabetes Obes Metab 2025; 27:468-481. [PMID: 39604324 DOI: 10.1111/dom.16077] [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: 08/12/2024] [Revised: 10/31/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-Like peptide-1 receptor agonists (GLP-1 RA) are recommended in people with type 2 diabetes (T2D) for glycaemic control and for people with high cardiovascular risk. However, current guidelines do not specifically address the role of initial early combination therapy with SGLT2i and GLP-1 RA or dual gastric inhibitory polypeptide (GIP)/GLP-1 RA, but rather sequential initiation with either in T2D. This review synthesizes the available evidence on the use of SGLT2i and GLP-1-based therapies for T2D and provides a rationale for their combination. The combination of SGLT2i with GLP-1-based therapies addresses complementary pathophysiological mechanisms and enhances efficacy in achieving target haemoglobin A1C (HbA1c) levels. SGLT2i and GLP-1 RA also have been shown to prevent complications of T2D. While both classes reduce adverse cardiorenal events, SGLT2i has a predominant effect on prevention of kidney dysfunction and heart failure, whereas GLP-1 RA has a more marked effect on the risk of atherosclerotic cardiovascular disease. Both drug classes have favourable safety profiles. Finally, weight loss with combination therapy may have disease-modifying effects that may reverse T2D progression. We propose that the combination of SGLT2i with GLP-1 RA or dual GIP/GLP-1 RA should be considered for most patients with T2D who do not have contraindications.
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Affiliation(s)
- Catarina Vale
- Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Internal Medicine, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Inês Mariana Lourenço
- Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | | | - Ilya Golovaty
- General Medicine Service, VA Puget Sound Health Care System, Seattle, Washington, USA
- Division of General Internal Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Hugo Torres
- David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Tannaz Moin
- David Geffen School of Medicine, University of California, Los Angeles, California, USA
- HSR&D Center for the Study of Healthcare Innovation, Implementation & Policy, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Martin Buysschaert
- Department of Endocrinology and Diabetology, Université Catholique de Louvain, University Clinic Saint-Luc, Brussels, Belgium
| | - João Sérgio Neves
- Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Michael Bergman
- Holman Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine and Population Health, VA New York Harbor Healthcare System, New York University Grossman School of Medicine, New York, New York, USA
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Bril F, Berg G, Barchuk M, Nogueira JP. Practical Approaches to Managing Dyslipidemia in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease. J Lipid Atheroscler 2025; 14:5-29. [PMID: 39911965 PMCID: PMC11791423 DOI: 10.12997/jla.2025.14.1.5] [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: 12/25/2023] [Revised: 02/15/2024] [Accepted: 03/10/2024] [Indexed: 02/07/2025] Open
Abstract
Dyslipidemia is a major risk factor for cardiovascular disease, and its impact may be exacerbated when accompanied by metabolic dysfunction-associated steatotic liver disease (MASLD). The simultaneous management of these conditions poses multiple challenges for healthcare providers. Insulin resistance has been implicated in the pathogenesis of both dyslipidemia and MASLD, necessitating a holistic approach to managing dyslipidemia, glucose levels, body weight, and MASLD. This review explores the intricate pathophysiological relationship between MASLD and dyslipidemia. It also examines current guidance regarding the use of lipid-lowering agents (including statins, ezetimibe, fibrates, omega-3 polyunsaturated fatty acids, and proprotein convertase subtilisin/kexin type 9 inhibitors) as well as glucose-lowering medications (such as pioglitazone, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors) in patients with MASLD, with or without metabolic dysfunction-associated steatohepatitis (MASH), and dyslipidemia. Additionally, the review addresses the potential of emerging drugs to concurrently target both MASLD/MASH and dyslipidemia. Our hope is that a deeper understanding of the mechanisms underlying MASLD and dyslipidemia may assist clinicians in the management of these complex cases.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gabriela Berg
- Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Cátedra de Bioquímica Clínica I, Laboratorio de Lípidos y Aterosclerosis, Universidad de Buenos Aires, Buenos Aires, Argentina
- CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Magali Barchuk
- Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Cátedra de Bioquímica Clínica I, Laboratorio de Lípidos y Aterosclerosis, Universidad de Buenos Aires, Buenos Aires, Argentina
- CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Juan Patricio Nogueira
- Centro de Investigación en Endocrinología, Nutrición y Metabolismo (CIENM), Facultad de Ciencias de la Salud, Universidad Nacional de Formosa, Formosa, Argentina
- Universidad Internacional de las Américas, San José, Costa Rica
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15
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Sundra T, Knowles E, Rendle D, Kelty E, Lester G, Rossi G. Short-term clinical and biochemical responses following treatment with dapagliflozin or ertugliflozin in horses with hyperinsulinemia: A retrospective case series. Domest Anim Endocrinol 2025; 90:106894. [PMID: 39581155 DOI: 10.1016/j.domaniend.2024.106894] [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: 09/19/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024]
Abstract
The metabolic and lipid profiles of horses treated with sodium-glucose cotransporter 2 inhibitors are not well understood. This retrospective study evaluated blood parameters in hyperinsulinemic horses treated with either ertugliflozin (0.05 mg/kg) or dapagliflozin (0.02 mg/kg) orally once daily. Blood samples were collected at baseline (day 0) and after 7 and/or 30 days of treatment. Statistical analyses were conducted using Wilcoxon signed-rank, Mann-Whitney and Spearman's rank correlation tests. Thirty-four horses received dapagliflozin and 24 received ertugliflozin. Significant (p<0.05) within-horse changes between day 0 and day 30 included [median, inter-quartile range (IQR)]: basal serum [Insulin] (uU/ml) reduced 170 (92-280) to 28.7 (14.5-90); [triglycerides] (mmol/l) increased 0.5 (0.3-0.6) to 1.0 (0.6-1.56), [β-hydroxybutyrate] (umol/l) increased 0.22 (0.17-2.7) to 0.30 (0.24-0.35); [total cholesterol] (mmol/l) increased 2.36 (2-2.6) to 2.84 (2.4-3.7); and GGT (IU/ml) increased 21 (16-32) to 25 (18-38). As a percentage of total serum lipids, high-density lipoprotein (HDL) reduced 52.4 % (47.9 %-61.0 %) to 50 % (41 %-54.8 %) and very-low density lipoprotein (VLDL) increased 10.4 % (6.4 %-14.4 %) to 12.3 % (9.9 %-16.8 %) (all p<0.05). Differences between ertugliflozin and dapagliflozin groups were not significant in any of these parameters at days 0, 7 or 30. At day 30, 10/48 (21 %) cases had [triglycerides] > 2.0 mmol/l (maximum = 10.8mmol/l). Day 30 [triglyceride] correlated with day 0: basal insulin (rho=0.47); [triglyceride] (rho=0.42); %VLDL (rho=0.34) day 30: [total cholesterol] (rho=0.67), %HDL (rho=-0.432) and %VLDL (rho=0.708). Our findings suggest that SGLT2 inhibitors induce minor changes in lipid profiles, with occasional cases of marked hypertriglyceridemia, and that dapagliflozin and ertugliflozin exhibit similar biochemical effects.
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Affiliation(s)
- Tania Sundra
- Avon Ridge Equine Veterinary Services, Brigadoon, Western Australia, Australia; School of Veterinary Medicine, Murdoch University, Murdoch, Western Australia, Australia.
| | - Edd Knowles
- The Royal Veterinary College, Hatfield, UK; Bell Equine Veterinary Clinic, Mereworth UK
| | | | - Erin Kelty
- School of Population and Global Health, The University of Western Australia, Crawley, Western Australia, Australia
| | - Guy Lester
- School of Veterinary Medicine, Murdoch University, Murdoch, Western Australia, Australia; Equiimed, Perth, Western Australia, Australia
| | - Gabriele Rossi
- School of Veterinary Medicine, Murdoch University, Murdoch, Western Australia, Australia
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16
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Li J, Li C, Feng X, Wei X. SGLT2 inhibition, blood lipids, and cardiovascular disease: A Mendelian randomization study. ESC Heart Fail 2024; 11:3960-3971. [PMID: 39054757 PMCID: PMC11631244 DOI: 10.1002/ehf2.14987] [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: 03/21/2024] [Revised: 05/22/2024] [Accepted: 07/04/2024] [Indexed: 07/27/2024] Open
Abstract
AIMS We aim to investigate the causal effect of blood lipids mediating sodium-glucose cotransporter 2 (SGLT2) inhibition in cardiovascular disease (CVD) using Mendelian randomization (MR). METHODS AND RESULTS A two-sample two-step MR study was conducted to evaluate the association of SGLT2 inhibition with CVDs and the mediation effects of blood lipids linking SGLT2 inhibition with CVDs. Genetic instruments for SGLT2 inhibition were identified as genetic variants, which were associated with the expression of the SLC5A2 gene and glycated haemoglobin level (HbA1c). SGLT2 inhibition was associated with reduced risk of heart failure (HF) (OR 0.44 [95% CI 0.32-0.61]; P = 6.0 × 10-7), atrial fibrillation (AF) (0.47 [0.37-0.61]; P = 1.81 × 10-8), coronary artery disease (CAD) (0.47 [0.30-0.73]; P = 7.46 × 10-4), myocardial infarction (MI) (0.30 [0.15-0.61]; P = 7.44 × 10-4), any stroke (AS) (0.28 [0.18-0.42]; P = 1.14 × 10-9), and ischaemic stroke (IS) (0.27 [0.17-0.44]; P = 1.97 × 10-7). Our results indicated that the proportion mediated of the mediating effect of total cholesterol was 1.7% (OR 0.99 [95% CI 0.98, 0.99], P = 0.004), 4.7% (0.96 [0.95, 0.98], P = 0.002), and 2.7% (0.97 [0.95, 0.98], P = 0.002) in the association between SGLT2 inhibition and the risk of HF, CAD, and MI, respectively. For low-density lipoprotein cholesterol, the proportion mediated of the mediating effect was 2.2% for HF (OR 0.98 [95% CI 0.98, 0.99], P = 0.003), 8.6% for CAD (0.93 [0.91, 0.95], P = 5.74 × 10-4), and 5.0% for MI (0.95 [0.94, 0.96], P = 6.97 × 10-4). For non-high-density lipoprotein cholesterol, the proportion mediated of the mediating effect was 3.4% for HF (OR 0.98 [95% CI 0.97, 0.98], P = 4.42 × 10-6), 11.8% for CAD (0.92 [0.90, 0.93], P = 7.23 × 10-8), 5.7% for MI (0.94 [0.92, 0.95], P = 8.17 × 10-7), 1.5% for AS (0.98 [0.98, 0.99], P = 0.001), and 1.4% for IS (0.98 [0.98, 0.99], P = 0.004). CONCLUSIONS Our study showed the association of SGLT2 inhibition with the reduced risk of CVDs and blood lipids might mediate this association.
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Affiliation(s)
- Jiangtao Li
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of EducationWuhanChina
- NHC Key Laboratory of Organ TransplantationMinistry of HealthWuhanChina
| | - Chenhe Li
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of EducationWuhanChina
- NHC Key Laboratory of Organ TransplantationMinistry of HealthWuhanChina
| | - Xin Feng
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of EducationWuhanChina
- NHC Key Laboratory of Organ TransplantationMinistry of HealthWuhanChina
| | - Xiang Wei
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of EducationWuhanChina
- NHC Key Laboratory of Organ TransplantationMinistry of HealthWuhanChina
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Katsimardou A, Theofilis P, Vordoni A, Doumas M, Kalaitzidis RG. The Effects of SGLT2 Inhibitors on Blood Pressure and Other Cardiometabolic Risk Factors. Int J Mol Sci 2024; 25:12384. [PMID: 39596449 PMCID: PMC11594301 DOI: 10.3390/ijms252212384] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
Beyond their established hypoglycemic, cardioprotective, and nephroprotective properties, sodium-glucose cotransporters 2 (SGLT2) inhibitors exert other pleiotropic actions on blood pressure levels, body weight, and lipid metabolism. Blood pressure (BP) reduction varies based on the background history, including an effect on systolic, diastolic BP, and 24 h BP measurements. The reduction in body weight between 1 and 2 kg for the first months is caused by a reduction in visceral and subcutaneous fat due to glycosuria and loss of calories. Regarding lipid metabolism, a reduction in triglycerides and an increase in total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) have been reported, although these alterations are small and could provide additional cardiovascular protection. Various pathophysiologic mechanisms have been proposed to explain the above-mentioned pleiotropic actions of SGLT2 inhibitors. Natriuresis, osmotic diuresis, body weight reduction, amelioration of endothelial dysfunction and arterial stiffness, sympathetic tone decrease, and uric acid reduction are among those that have been suggested for BP reduction. Apart from glycosuria and calorie loss, other mechanisms seem to contribute to body weight reduction, such as the beiging of white adipose tissue, while the mechanisms involved in lipid metabolism alterations have not been clearly determined.
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Affiliation(s)
- Alexandra Katsimardou
- 2nd Department of Internal Medicine, 401 General Military Hospital of Athens, 11525 Athens, Greece; (A.K.); (M.D.)
- 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital “Hippokration”, 54642 Thessaloniki, Greece
| | - Panagiotis Theofilis
- Center for Nephrology “G. Papadakis”, General Hospital of Nikaia-Piraeus “Ag. Panteleimon”, 18454 Nikaia, Greece; (P.T.); (A.V.)
| | - Aikaterini Vordoni
- Center for Nephrology “G. Papadakis”, General Hospital of Nikaia-Piraeus “Ag. Panteleimon”, 18454 Nikaia, Greece; (P.T.); (A.V.)
| | - Michael Doumas
- 2nd Department of Internal Medicine, 401 General Military Hospital of Athens, 11525 Athens, Greece; (A.K.); (M.D.)
| | - Rigas G. Kalaitzidis
- Center for Nephrology “G. Papadakis”, General Hospital of Nikaia-Piraeus “Ag. Panteleimon”, 18454 Nikaia, Greece; (P.T.); (A.V.)
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Doiron JE, Xia H, Yu X, Nevins AR, LaPenna KB, Sharp TE, Goodchild TT, Allerton TD, Elgazzaz M, Lazartigues E, Shah SJ, Li Z, Lefer DJ. Adjunctive therapy with an oral H 2S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction. Br J Pharmacol 2024; 181:4294-4310. [PMID: 38982742 DOI: 10.1111/bph.16493] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/20/2024] [Accepted: 05/26/2024] [Indexed: 07/11/2024] Open
Abstract
BACKGROUND AND PURPOSE Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S donor in two preclinical models of cardiometabolic HFpEF was investigated. EXPERIMENTAL APPROACH Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H2S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8 weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols. KEY RESULTS SGLT2i treatment improved E/e' ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end-diastolic function (E/e' ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow-up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology. CONCLUSIONS AND IMPLICATIONS SGLT2i monotherapy remediated pathological complications exhibited by two well-established HFpEF models. Adjunctive H2S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow-up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.
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Affiliation(s)
- Jake E Doiron
- Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana, USA
| | - Huijing Xia
- Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana, USA
- Cardiovascular Center of Excellence, LSU Health Sciences Center, New Orleans, Louisiana, USA
| | - Xiaoman Yu
- Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Alexandra R Nevins
- Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Kyle B LaPenna
- Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana, USA
| | - Thomas E Sharp
- Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA
| | - Traci T Goodchild
- Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | | | - Mona Elgazzaz
- Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana, USA
- Cardiovascular Center of Excellence, LSU Health Sciences Center, New Orleans, Louisiana, USA
| | - Eric Lazartigues
- Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, Louisiana, USA
- Cardiovascular Center of Excellence, LSU Health Sciences Center, New Orleans, Louisiana, USA
| | - Sanjiv J Shah
- Feinberg School of Medicine, Northwestern University Medicine, Chicago, Illinois, USA
| | - Zhen Li
- Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - David J Lefer
- Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Niemelä A, Giorgi L, Nouri S, Yurttaş B, Rauniyar K, Jeltsch M, Koivuniemi A. Gliflozins, sucrose and flavonoids are allosteric activators of lecithin-cholesterol acyltransferase. Sci Rep 2024; 14:26085. [PMID: 39478139 PMCID: PMC11525561 DOI: 10.1038/s41598-024-77104-3] [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: 07/24/2024] [Accepted: 10/18/2024] [Indexed: 11/02/2024] Open
Abstract
Lecithin-cholesterol acyltransferase (LCAT) serves as a pivotal enzyme in preserving cholesterol homeostasis via reverse cholesterol transport, a process closely associated with the onset of atherosclerosis. Impaired LCAT function can lead to severe LCAT deficiency disorders for which no pharmacological treatment exists. LCAT-based therapies, such as small molecule positive allosteric modulators (PAMs), against LCAT deficiencies and atherosclerosis hold promise, although their efficacy against atherosclerosis remains challenging. Herein we utilized a quantitative in silico metric to predict the activity of novel PAMs and tested their potencies with in vitro enzymatic assays. As predicted, sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), sucrose and flavonoids activate LCAT. This has intriguing implications for the mechanism of action of gliflozins, which are commonly used in the treatment of type 2 diabetes, and for the endogenous activation of LCAT. Our results underscore the potential of molecular dynamics simulations in rational drug design.
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Affiliation(s)
- Akseli Niemelä
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
| | - Laura Giorgi
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Sirine Nouri
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Betül Yurttaş
- Department of Biotechnology and Bioengineering, Izmir Institute of Technology, Izmir, Turkey
| | - Khushbu Rauniyar
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Michael Jeltsch
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Artturi Koivuniemi
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
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20
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Pradhan S, Kalanski S, Tintut Y, Demer LL. Complex actions of sodium glucose transporter-2 inhibitors on lipids, calcific atherosclerosis, and bone density. Curr Opin Lipidol 2024; 35:253-257. [PMID: 39052539 DOI: 10.1097/mol.0000000000000942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
PURPOSE OF REVIEW Inhibitors of sodium-glucose cotransporter-2 (SGLT2) lower renal glucose reabsorption and, thus, are used to treat patients with type 2 diabetes mellitus. Clinical trials coincidentally showed that SGLT2 inhibitors also benefitted patients with heart failure. This review explores the impact of SGLT2 inhibitors on other aspects of cardiovascular disease and skeletal health. RECENT FINDINGS In some, but not all, clinical and preclinical studies, SGLT2 inhibitors are found to reduce serum levels of free fatty acids and triglycerides. Their effects on total and low-density lipoprotein cholesterol and cardiac function also vary. However, SGLT2 inhibitors reduce lipid accumulation in the liver, kidney, and heart, and alter expression of lipid metabolism genes. Effects on free fatty acid uptake in abdominal fat depots depend on the location of adipose tissue. In male, but not female, mice, SGLT2 inhibitors reduce the atherosclerotic lesions and aortic calcium deposition. With respect to skeletal health, recent literature has reported conflicting associations with the risks of fracture and amputation. SUMMARY Studies suggest that SGLT2 inhibitors reduce tissue lipid accumulation, and in a sex-dependent manner, atherosclerosis and vascular calcification. However, their effects on lipid levels and bone health are complex and remain to be established.
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Affiliation(s)
| | | | - Yin Tintut
- Department of Medicine
- Department of Orthopaedic Surgery
- Department of Physiology
| | - Linda L Demer
- Department of Medicine
- Department of Physiology
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
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21
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Dedemen B, Duman TT, Dedemen MM, Aktas G. Effect of sodium glucose Co-transporter 2 inhibitor use on anthropometric measurements and blood glucose in obese and non-obese type 2 diabetic patients. Clin Nutr ESPEN 2024; 63:515-519. [PMID: 39047870 DOI: 10.1016/j.clnesp.2024.07.016] [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: 05/25/2024] [Revised: 07/01/2024] [Accepted: 07/11/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND Obesity and type 2 diabetes mellitus are closely associated with each other and require careful management. This study aimed to assess the impact of sodium-glucose co-transporter 2 (SGLT2) inhibitors on glycemic control and body composition in diabetic patients, stratified by obesity status. METHODS We enrolled patients diagnosed with type 2 diabetes mellitus, categorized as obese (BMI≥30) or non-obese (BMI<30), from our outpatient clinic. SGLT2 inhibitor therapy was added to their existing treatment regimen without altering dietary habits or exercise routines. Anthropometric measurements and laboratory parameters were compared between baseline and the third month of treatment. RESULTS The study included 40 participants, evenly split between obese and non-obese groups. At the third-month follow-up, significant reductions were observed in BMI, weight, waist and hip circumference, and body fat percentage across both groups (p < 0.001). Conversely, muscle mass percentage significantly increased (p < 0.001). Additionally, there were statistically significant decreases in HbA1c, glucose, CRP, ALT, LDL, and total cholesterol levels from baseline to the third month of treatment (p < 0.001 for HbA1c and glucose; p = 0.009, p = 0.022, p = 0.003, and p = 0.021, respectively, for CRP, ALT, LDL, and total cholesterol). CONCLUSIONS The findings of the present study suggest that SGLT2 inhibitors may offer substantial benefits, particularly in the management of obesity-related type 2 diabetes.
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Affiliation(s)
- Busra Dedemen
- Bolu Abant Izzet Baysal University Faculty of Medicine, Bolu, Turkey
| | | | | | - Gulali Aktas
- Bolu Abant Izzet Baysal University Faculty of Medicine, Bolu, Turkey.
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Kamrul-Hasan ABM, Alam MS, Talukder SK, Hannan MA, Dutta D, Nagendra L, Selim S. Efficacy and Safety of Ertugliflozin Compared to Placebo in Patients With Type 2 Diabetes: An Updated Systematic Review and Meta-Analysis. J Diabetes Res 2024; 2024:5553327. [PMID: 39354951 PMCID: PMC11444800 DOI: 10.1155/2024/5553327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/31/2024] [Accepted: 06/22/2024] [Indexed: 10/03/2024] Open
Abstract
Background: No comprehensive meta-analysis has evaluated the efficacy and safety of ertugliflozin compared to a placebo in patients with Type 2 diabetes (T2D) until now. This meta-analysis fills this gap in knowledge. Methods: A systematic search was carried out in electronic databases to identify randomized controlled trials (RCTs) that included patients with T2D receiving ertugliflozin in the treatment group and placebo in the control group. The change in HbA1c from the baseline values was the primary outcome, whereas changes in plasma glucose and other metabolic parameters and adverse events (AEs), including hypoglycemia, were the secondary outcomes. Results: Seven RCTs involving 7283 subjects met the inclusion criteria. Ertugliflozin outperformed placebo in reducing HbA1c in both 5 mg (MD -0.62%, 95% CI [-0.80, -0.44], p < 0.00001, I 2 = 91%) and 15 mg (MD -0.69%, 95% CI [-0.91, -0.47], p < 0.00001, I 2 = 93%) doses. A higher proportion of patients achieved HbA1c < 7.0% with ertugliflozin than with placebo. Ertugliflozin was also superior to placebo in lowering fasting plasma glucose (FPG), body weight, and systolic and diastolic blood pressure (BP). Ertugliflozin and placebo had comparable AE profiles, including urinary tract infection (UTI) and hypoglycemia, except for the greater risk of genital mycotic infections (GMIs) with ertugliflozin. Ertugliflozin 5 and 15 mg have equivalent efficacy and safety profiles except for greater weight reduction with ertugliflozin 15 mg. Conclusion: Ertugliflozin has a good glycemic efficacy and a reassuring safety profile in managing T2D. Trial Registration: Registration number: CRD42023456450.
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Affiliation(s)
| | | | | | - Mohammad Abdul Hannan
- Department of EndocrinologyNorth East Medical College and Hospital, Sylhet, Bangladesh
| | - Deep Dutta
- Department of EndocrinologyCEDAR Superspeciality Healthcare, Dwarka, New Delhi, India
| | - Lakshmi Nagendra
- Department of EndocrinologyJSS Medical CollegeJSS Academy of Higher Education and Research, Mysore, India
| | - Shahjada Selim
- Department of EndocrinologyBangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
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Yuan F, Zhang T, Jia S, Zhao J, Wan B, Liu G. Fine mapping-based multi-omics analysis interprets the gut-lung axis function of SGLT2 inhibitors. Front Cell Infect Microbiol 2024; 14:1447327. [PMID: 39318474 PMCID: PMC11420167 DOI: 10.3389/fcimb.2024.1447327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/21/2024] [Indexed: 09/26/2024] Open
Abstract
Background Currently, Sodium-glucose cotransporter 2 (SGLT2) inhibitors demonstrate additional effects beyond glucose control on the gut microbiota and circulating metabolites. The gut microbiota and metabolites have been found to be useful in elucidating potential biological mechanisms of pulmonary diseases. Therefore, our study aims to investigate the effects of gut microbiota and metabolites mediating SGLT2 inhibition in 10 pulmonary diseases through Mendelian randomization (MR) research. Methods We conducted a two-sample, two-step MR study to assess the association between SGLT2 inhibition and 10 pulmonary diseases and to investigate the mediating effects of gut microbiota and metabolite. Gene-fine mapping and annotation of mediators by FUMA and Magma analyses were performed, and causal associations of mapped genes with diseases were assessed by muti-omics MR analyses. Possible side effects of SGLT2 inhibition were assessed by PheWAS analysis. Results SGLT2 inhibition was linked to a reduced risk of T2DM, Interstitial lung disease (ILD), Pneumoconiosis, Pulmonary tuberculosis, and Asthma(OR=0.457, 0.054, 0.002, 0.280, 0.706). The family Enterobacteriaceae and order Enterobacteriales were associated with SGLT2 inhibition and ILD(95% CI:0.079-0.138). The family Alcaligenaceae and X-12719 were linked to pneumoconiosis (95% CI: 0.042-0.120, 0.050-0.099). The genus Phascolarctobacterium was connected to pulmonary tuberculosis (95% CI: 0.236-0.703).The degree of unsaturation (Fatty Acids), ratio of docosahexaenoic acid to total fatty acids, and 4-androsten-3beta,17beta-diol disulfate 2, were associated with asthma(95% CI: 0.042-0.119, 0.039-0.101, 0.181-0.473). Furthermore, Fuma and Magma analyses identified target genes for the four diseases, and proteomic MR analysis revealed six overlapping target genes in asthma. PheWAS analysis also highlighted potential side effects of SGLT2 inhibition. Conclusions This comprehensive study strongly supports a multi-omics association between SGLT2 inhibition and reduced risk of interstitial lung disease, tuberculosis, pneumoconiosis, and asthma. Four identified gut microbiota, four metabolites, sixteen metabolic pathways, and six target genes appear to play a potential role in this association. The results of the comprehensive phenome-wide association analysis also identified the full effect of SGLT2 inhibitors.
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Affiliation(s)
- Fengqin Yuan
- Department of Infection Control, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Tianlong Zhang
- Department of Critical Care Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Sixiang Jia
- Department of Cardiology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Jianqiang Zhao
- Department of Cardiology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Binbin Wan
- Department of Immunization Planning, Yiwu Center for Disease Control and Prevention, Yiwu, Zhejiang, China
| | - Gang Liu
- Department of Infection Control, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
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Katsuyama H, Horinaka S, Hakoshima M, Adachi H, Yanai H. Retrospective Longitudinal Observational Study on the Long-Term Effects of Sodium-Glucose Cotransporter-2 Inhibitors on the Development of Metabolic Dysfunction-Associated Steatotic Liver Disease in Type 2 Diabetic Japanese Patients. J Clin Med 2024; 13:4929. [PMID: 39201071 PMCID: PMC11355713 DOI: 10.3390/jcm13164929] [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: 07/17/2024] [Revised: 08/14/2024] [Accepted: 08/20/2024] [Indexed: 09/02/2024] Open
Abstract
Background/Objectives: The health burden of metabolic dysfunction-associated fatty liver disease (MASLD) has been increasing lately. Cardiovascular disease (CVD) is the main cause of death in MASLD patients; therefore, the treatments for MASLD should improve both CV risk factors such as obesity, diabetes, and dyslipidemia, in addition to an improvement in liver function. The evidence on the long-term effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on the progression of MASLD in Asian populations is very limited. Methods: The retrospective longitudinal study was performed by using the medical records at our institute. We picked up patients with type 2 diabetes who had taken SGLT2is for at least 3 years or longer between 1 April 2014 and 31 March 2018. We collected the data on metabolic parameters, including laboratory data and anthropometric parameters, and compared the data before and after the initiation of SGLT2is treatment. Results: During the observation period, 324 patients had taken SGLT2is for 3 years. Three-year SGLT2is treatment significantly reduced body weight, hemoglobin A1c, low-density lipoprotein cholesterol, triglyceride, and non-high-density lipoprotein cholesterol (non-HDL-C). Such favorable changes in serum lipids were remarkable in patients with statins. Furthermore, this treatment significantly improved liver function and the markers for hepatic steatosis and hepatic fibrosis. Conclusions: Considering that the development of CVD determines the prognosis of MASLD patients, long-term SGLT2is treatment may be an ideal therapy for MASLD patients.
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Affiliation(s)
| | | | | | | | - Hidekatsu Yanai
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (H.K.); (S.H.); (M.H.); (H.A.)
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Tewari J, Qidwai KA, Rana A, Tewari A, Tewari V, Maheshwari A. Safety and Efficacy of Remogliflozin in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Cureus 2024; 16:e66145. [PMID: 39233944 PMCID: PMC11372186 DOI: 10.7759/cureus.66145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2024] [Indexed: 09/06/2024] Open
Abstract
Remogliflozin is a novel SGLT-2 inhibitor used for the management of Type 2 Diabetes Mellitus (T2DM). Since its introduction medical literature is scarce on its quantitative effects. We performed this meta-analysis to ascertain its safety and efficacy in the treatment of T2DM. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Handbook, six studies involving 1,605 participants were analyzed. Our analysis found comparable reductions in glycated hemoglobin (HbA1c) by remogliflozin in comparison to the comparators. It was found to be inferior to other anti-diabetic drugs in decreasing fasting plasma glucose and post-prandial glucose. A significant reduction was obtained in body weight and a significant increase was also found in high-density lipoprotein cholesterol (HDL-C) levels. Remogliflozin did not significantly increase the risk for total adverse events, severe adverse events, or hypoglycemic episodes. The results were accompanied by high heterogeneity, which necessitates conducting high-quality randomized control trials for more robust evidence synthesis. Overall Remogliflozin can be considered a safe drug with beneficial effects on body weight and HDL-C levels for the treatment of people with T2DM.
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Affiliation(s)
- Jay Tewari
- Internal Medicine, King George's Medical University, Lucknow, IND
| | | | - Anadika Rana
- Internal Medicine, King George's Medical University, Lucknow, IND
| | - Ajoy Tewari
- Internal Medicine, Hind Institute of Medical Sciences, Lucknow, IND
- Diabetes and Endocrinology, Jai Clinic and Diabetes Care Center, Lucknow, IND
| | - Vineeta Tewari
- Anatomy, Era's Lucknow Medical College and Hospital, Lucknow, IND
| | - Anuj Maheshwari
- Medicine, Hind Institute of Medical Sciences, Lucknow, IND
- Medicine, Shri Hari Kamal Diabetes and Heart Research Clinic, Lucknow, IND
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Lv Q, Yang Y, Lv Y, Wu Q, Hou X, Li L, Ye X, Yang C, Wang S. Effect of different hypoglycemic drugs and insulin on the risk of new-onset atrial fibrillation in people with diabetes: a network meta-analysis. Eur J Med Res 2024; 29:399. [PMID: 39085898 PMCID: PMC11290211 DOI: 10.1186/s40001-024-01954-w] [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: 04/08/2024] [Accepted: 06/26/2024] [Indexed: 08/02/2024] Open
Abstract
OBJECTIVE Diabetes is considered a significant risk factor for the development of atrial fibrillation/flutter (AF/AFL). However, there is still insufficient evidence to determine the varying effects of different hypoglycemic drugs (HDs) on the incidence of new-onset AF/AFL in diabetic patients. To address this gap, we conducted a network meta-analysis to investigate whether various HDs have different effects on the risk of new-onset AF/AFL compared with insulin. METHOD We conducted a comprehensive search in PubMed, EMBASE, Cochrane Library, and Web of Science to identify all clinical trials investigating the association between various HDs or insulin and incident AF/AFL up until April 1, 2024. Bayesian random-effects model was used for network meta-analysis, and the results were expressed as relative risk (RR) and 95% confidence interval (CI). RESULT After searching 2070 articles, a total of 12 studies (2,349,683 patients) were included in the network meta-analysis. The treatment regimen comprised insulin and 8 HDs hypoglycemic drugs, which are sodium-dependent glucose transporters 2 inhibitor (SGLT2i), glucagon-like peptide 1 receptor agonist (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), metformin (Met), sulfonylureas (SU), non-sulfonylureas (nSU), thiazolidinedione (TZD) and α-glycosidase inhibitors (AGI). The use of SGLT2i [RR 0.23, 95%CI (0.11, 0.49)], GLP-1RA [RR 0.28, 95%CI (0.13, 0.57)], and DPP4i [RR 0.34, 95%CI (0.17, 0.67)] demonstrated significant efficacy in reducing the incidence of new-onset AF/AFL when compared to insulin. When HDs were compared in pairs, SGLT2i is more effective than Met [RR 0.35, 95% CI (0.19, 0.62)], SU (RR 0.27, 95% CI (0.14, 0.51)], nSU [RR 0.28, 95% CI (0.08, 0.95)], TZD [RR 0.34, 95% CI (0.17, 0.7)], GLP-1RA is more effective Met [RR 0.42, 95% CI (0.25, 0.71)], SU (RR 0.33, 95% CI (0.18, 0.6)], TZD [RR 0.41, 95% CI (0.21, 0.82)], while Met[RR 1.98, 95% CI (1.23, 3.23)], SU [RR 2.54, 95% CI (1.46, 4.43)], TZD [RR 2.01, 95% CI (1.05, 3.79)] was not as effective as DPP4i. CONCLUSION SGLT-2i, GLP-1RA, and DPP4i showed a superior efficacy in reducing the risk of new-onset AF/AFL compared to insulin therapy.
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Affiliation(s)
- Qianyu Lv
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Yingtian Yang
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Yanfei Lv
- Fudan University, Shanghai, 200433, China
| | - Qian Wu
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Xinzheng Hou
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Lanlan Li
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Xuejiao Ye
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Chenyan Yang
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Shihan Wang
- Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, 100053, China.
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Sohn M, Nam S, Nauck MA, Lim S. Long-term comparison of renal and metabolic outcomes after sodium-glucose co-transporter 2 inhibitor or glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes. BMC Med 2024; 22:273. [PMID: 38956548 PMCID: PMC11218058 DOI: 10.1186/s12916-024-03483-z] [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: 11/13/2023] [Accepted: 06/13/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND Renal outcomes in patients with type 2 diabetes following treatment with sodium-glucose co-transporter-2 inhibitors (SGLT2is) or glucagon-like peptide-1 receptor agonists (GLP1RAs) have not been directly compared. This study compared the impact of SGLT2i and GLP1RA therapy on renal function and metabolic parameters. METHODS Patients with type 2 diabetes who initiated SGLT2i or GLP1RA therapy in a tertiary hospital between January 2009 and August 2023 were included to assess composite renal outcomes, such as a 40% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease, renal death, or new-onset macroalbuminuria. Alterations in blood pressure, glucose regulation parameters, lipid profile, and anthropometric parameters, including body fat and muscle masses, were examined over 4-years. RESULTS A total of 2,112 patients were enrolled using a one-to-three propensity-score matching approach (528 patients for GLP1RAs, 1,584 patients for SGLT2i). SGLT2i treatment was favoured over GLP1RA treatment, though not significantly, for composite renal outcomes (hazard ratio [HR], 0.63; p = 0.097). SGLT2i therapy preserved renal function effectively than GLP1RAs (decrease in eGFR, ≥ 40%; HR, 0.46; p = 0.023), with improving albuminuria regression (HR, 1.72; p = 0.036). SGLT2i therapy decreased blood pressure and body weight to a greater extent. However, more patients attained HbA1c levels < 7.0% with GLP1RAs than with SGLT2is (40.6% vs 31.4%; p < 0.001). GLP1RA therapy enhanced β-cell function and decreased LDL-cholesterol levels below baseline values. CONCLUSIONS SGLT2is were superior for preserving renal function and reducing body weight, whereas GLP1RAs were better for managing glucose dysregulation and dyslipidaemia.
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Affiliation(s)
- Minji Sohn
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-City, 13620, South Korea
| | - Seoungyeon Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-City, 13620, South Korea
| | - Michael A Nauck
- Section Diabetes, Endocrinology, Metabolism, Medical Department I Katholisches Klinikum Bochum gGmbH, St. Josef Hospital Ruhr-University Bochum, Bochum, Germany
| | - Soo Lim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-City, 13620, South Korea.
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Bechmann LE, Emanuelsson F, Nordestgaard BG, Benn M. SGLT2-inhibition increases total, LDL, and HDL cholesterol and lowers triglycerides: Meta-analyses of 60 randomized trials, overall and by dose, ethnicity, and drug type. Atherosclerosis 2024; 394:117236. [PMID: 37582673 DOI: 10.1016/j.atherosclerosis.2023.117236] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 08/17/2023]
Abstract
BACKGROUND AND AIMS Sodium glucose co-transporter 2 (SGLT2)-inhibitors were developed as glucose-lowering drugs. Surprisingly, SGLT2-inhibitors also reduced risk of cardiovascular disease. The impact of SGLT2-inhibitors on lipids and lipoproteins is unclear, but an effect might contribute to the observed lower cardiovascular risk. We conducted a meta-analysis to examine this, overall and by dose, ethnicity, and drug type. METHODS PubMed, EMBASE and Web of Science were searched for randomized controlled trials examining all available SGLT2-inhibitors. Studies with available lipid measurements were included. Quantitative data synthesis was performed using random and fixed effects models. RESULTS We identified 60 randomized trials, including 147,130 individuals. Overall, using random effects models, SGLT2-inhibitor treatment increased total cholesterol by 0.09 mmol/L (95% CI: 0.06, 0.13), low-density lipoprotein (LDL) cholesterol by 0.08 mmol/L (0.05, 0.10), and high-density lipoprotein (HDL) cholesterol by 0.06 mmol/L (0.05, 0.07), while it reduced triglycerides by 0.10 mmol/L (0.06, 0.14). Fixed effects estimates were similar but with smaller effect sizes for HDL cholesterol and triglycerides. For higher SGLT2-inhibitor doses, there was a nominally higher non-significant effect on lipids and lipoproteins. In Asian compared to non-Asian populations, a slightly larger increase in HDL cholesterol and a decrease in triglycerides were observed, but with similar results for total and LDL cholesterol. Treatment effects on lipids and lipoproteins were generally robust across different SGLT2-inhibitor drugs. CONCLUSION In meta-analyses, SGLT2-inhibition increased total, LDL, and HDL cholesterol and decreased triglycerides. Effect sizes varied slightly by drug dose and ethnicity but were generally robust by drug type.
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Affiliation(s)
- Louise E Bechmann
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, 9 Blegdamsvej, DK-2100, Copenhagen, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, 3B Blegdamsvej, DK-2200, Copenhagen, Denmark; Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev Gentofte, Borgmester Ib Juuls Vej 73, DK-2730, Herlev, Denmark
| | - Frida Emanuelsson
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, 9 Blegdamsvej, DK-2100, Copenhagen, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, 3B Blegdamsvej, DK-2200, Copenhagen, Denmark
| | - Børge G Nordestgaard
- Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, 3B Blegdamsvej, DK-2200, Copenhagen, Denmark; Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev Gentofte, Borgmester Ib Juuls Vej 73, DK-2730, Herlev, Denmark
| | - Marianne Benn
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, 9 Blegdamsvej, DK-2100, Copenhagen, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, 3B Blegdamsvej, DK-2200, Copenhagen, Denmark.
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Dardano A, Bianchi C, Garofolo M, Del Prato S. The current landscape for diabetes treatment: Preventing diabetes-associated CV risk. Atherosclerosis 2024; 394:117560. [PMID: 38688748 DOI: 10.1016/j.atherosclerosis.2024.117560] [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: 02/15/2024] [Revised: 04/11/2024] [Accepted: 04/18/2024] [Indexed: 05/02/2024]
Abstract
Despite the risk of atherosclerosis has progressively declined over the past few decades, subjects with type 2 diabetes mellitus (T2DM) continue to experience substantial excess of atherosclerotic cardiovascular disease (ASCVD)-related events. Therefore, there is urgent need to treat ASCVD disease in T2DM earlier, more intensively, and with greater precision. Many factors concur to increase the risk of atherosclerosis, and multifactorial intervention remains the basis for effective prevention or reduction of atherosclerotic events. The role of anti-hyperglycemic medications in reducing the risk of ASCVD in subjects with T2DM has evolved over the past few years. Multiple cardiovascular outcome trials (CVOTs) with new and emerging glucose-lowering agents, namely SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RA), have demonstrated significant reductions of major cardiovascular events and additional benefits. This robust evidence has changed the landscape for managing people with T2DM. In addition to glycemic and ancillary extra-glycemic properties, SGLT2i and GLP1-RA might exert favorable effects on subclinical and clinical atherosclerosis. Therefore, the objective of this review is to discuss the available evidence supporting anti-atherosclerotic properties of SGLT2i and GLP1-RA, with a quick nod to sotagliflozin and tirzepatide.
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Affiliation(s)
- Angela Dardano
- Department of Clinical and Experimental Medicine, University of Pisa, Italy; Section of Diabetes and Metabolic Diseases, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Cristina Bianchi
- Section of Diabetes and Metabolic Diseases, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Monia Garofolo
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Stefano Del Prato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy.
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Pitsiava S, Dimakopoulos G, Tsimihodimos V, Kotsa K, Koufakis T. Association between clinical and laboratory factors and response to sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes: a retrospective observational study. Expert Opin Pharmacother 2024; 25:1095-1104. [PMID: 38822807 DOI: 10.1080/14656566.2024.2364054] [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: 04/04/2024] [Accepted: 05/31/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND This study aimed to investigate the association between clinical and laboratory parameters and response to therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2D). RESEARCH DESIGN AND METHODS We retrospectively analyzed the medical records of people with T2D in whom SGLT2i was started. Clinical and laboratory parameters were recorded before, 3 and 6 months after starting treatment. Specific criteria were applied to classify participants into good and poor responders in terms of weight loss (primary outcome) and glycemic control (secondary outcome), separately. RESULTS Fifty individuals (64% men) with a mean age of 65.8 ± 8.5 years were included in the analysis. 86% and 64% of the participants were classified into good response categories for glycemic control and weight loss, respectively. Good responders in terms of glycemic control had lower high-density lipoprotein cholesterol levels at baseline compared to poor responders (43.3 vs 57.4 mg/dl, p = 0.044). In the logistic regression analysis, a higher baseline weight was associated with a better response to therapy in terms of weight loss (p = 0.04). CONCLUSIONS Our findings suggest that specific clinical and laboratory parameters are associated with response to SGLT2i treatment and can contribute to a more personalized approach to T2D care.
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Affiliation(s)
- Sofia Pitsiava
- School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgios Dimakopoulos
- BIOSTATS, Epirus Science and Technology Park Campus of the University of Ioannina, Ioannina, Greece
| | - Vasilis Tsimihodimos
- Department of Internal Medicine, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Theocharis Koufakis
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Velidakis N, Stachteas P, Gkougkoudi E, Papadopoulos C, Kadoglou NPE. Classical and Novel Lipid-Lowering Therapies for Diabetic Patients with Established Coronary Artery Disease or High Risk of Coronary Artery Disease-A Narrative Clinical Review. Pharmaceuticals (Basel) 2024; 17:568. [PMID: 38794138 PMCID: PMC11124492 DOI: 10.3390/ph17050568] [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: 03/19/2024] [Revised: 04/19/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Diabetic atherosclerosis is a complex process that is characterized by diffuse and unstable lesions increasing 2-4-fold the risk of adverse cardiovascular (CV) events. Diabetic dyslipidemia has a predominant role in coronary artery disease (CAD) and has been the target of classical and emerging pharmaceutical agents with established or promising CV benefits. The aim of the present narrative review was to summarize the effects of classical and novel lipid-lowering pharmaceutical agents on lipid profile and CV outcomes in diabetic patients with established CAD or high risk of CAD. Statins remain the first-line treatment for all diabetic patients since they considerably ameliorate lipid parameters and non-lipid CV risk factors, leading to reduced CV morbidity and mortality. Complementary to statins, ezetimibe exerts lipid-lowering properties with modest but significant reductions in major adverse cardiovascular events (MACEs) and CV mortality. PCSK9 inhibitors considerably reduce LDL-C levels and lower MACEs in diabetic patients. On the other hand, fibrates may confer a very modest decline in MACE incidence, while the CV impact of omega-3 fatty acids is promising but remains questionable. Bempedoic acid and inclisiran have a potential therapeutic role in the management of diabetic dyslipidemia, but this is still not adequately documented. Given the heightened CV risk among individuals with diabetes, more decisive results would be of great importance in the utility of all these drugs.
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Affiliation(s)
- Nikolaos Velidakis
- Medical School, University of Cyprus, 2029 Nicosia, Cyprus; (N.V.); (E.G.)
| | - Panagiotis Stachteas
- Third Department of Cardiology, Aristotle University of Thessaloniki, General Hospital “Hippokration”, 541 24 Thessaloniki, Greece; (P.S.); (C.P.)
| | | | - Christodoulos Papadopoulos
- Third Department of Cardiology, Aristotle University of Thessaloniki, General Hospital “Hippokration”, 541 24 Thessaloniki, Greece; (P.S.); (C.P.)
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Bonilha I, Gomes ÉIL, Carmo HRP, Breder I, Barreto J, Breder J, Munhoz DB, Carvalho LSF, Quinaglia T, Kimura-Medorima ST, Gossi CM, Zimetti F, Nadruz W, Zanotti I, Sposito AC. Effect of Empagliflozin with or without the Addition of Evolocumab on HDL Subspecies in Individuals with Type 2 Diabetes Mellitus: A Post Hoc Analysis of the EXCEED-BHS3 Trial. Int J Mol Sci 2024; 25:4108. [PMID: 38612917 PMCID: PMC11012560 DOI: 10.3390/ijms25074108] [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: 02/16/2024] [Revised: 04/03/2024] [Accepted: 04/04/2024] [Indexed: 04/14/2024] Open
Abstract
Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This post hoc prespecified analysis of the EXCEED-BHS3 trial compared the effects of a 16-week therapy with empagliflozin (E) alone or in combination with evolocumab (EE) on the lipid profile and cholesterol content in HDL subspecies in individuals with T2D divided equally into two groups of 55 patients. Both treatments modestly increased HDL-C. The cholesterol content in HDL subspecies 2a (7.3%), 3a (7.2%) and 3c (15%) increased from baseline in the E group, while the EE group presented an increase from baseline in 3a (9.3%), 3b (16%) and 3c (25%). The increase in HDL 3b and 3c was higher in the EE group when compared to the E group (p < 0.05). No significant interactive association was observed between changes in hematocrit and HDL-C levels after treatment. Over a 16-week period, empagliflozin with or without the addition of evolocumab led to a modest but significant increase in HDL-C. The rise in smaller-sized HDL particles was heterogeneous amongst the treatment combinations.
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Affiliation(s)
- Isabella Bonilha
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
| | - Érica Ivana Lázaro Gomes
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
| | - Helison R. P. Carmo
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
| | - Ikaro Breder
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
| | - Joaquim Barreto
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
| | - Jessica Breder
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
| | - Daniel B. Munhoz
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
- Cardiovascular Center Aalst, OLV Clinic, 9300 Aalst, Belgium
| | - Luiz Sergio F. Carvalho
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
| | - Thiago Quinaglia
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
| | - Sheila T. Kimura-Medorima
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
| | - Camila Moreira Gossi
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
| | - Francesca Zimetti
- Department of Food and Drug, University of Parma, 43124 Parma, Italy; (F.Z.); (I.Z.)
| | - Wilson Nadruz
- Division of Cardiology, State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil;
| | - Ilaria Zanotti
- Department of Food and Drug, University of Parma, 43124 Parma, Italy; (F.Z.); (I.Z.)
| | - Andrei C. Sposito
- Laboratory of Vascular Biology and Atherosclerosis (Aterolab), State University of Campinas (Unicamp), Sao Paulo 13083-887, Brazil; (I.B.); (É.I.L.G.); (H.R.P.C.); (I.B.); (J.B.); (J.B.); (D.B.M.); (L.S.F.C.); (T.Q.); (S.T.K.-M.); (C.M.G.)
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Xie L, Han J, Cheng Z, Liu D, Liu J, Xu C, Sun W, Li Q, Bian F, Zhang W, Chen J, Zhu Q, Thurber TK, Lock JP, Zhang B. Efficacy and safety of bexagliflozin compared with dapagliflozin as an adjunct to metformin in Chinese patients with type 2 diabetes mellitus: A 24-week, randomized, double-blind, active-controlled, phase 3 trial. J Diabetes 2024; 16:e13526. [PMID: 38584148 PMCID: PMC10999497 DOI: 10.1111/1753-0407.13526] [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: 06/21/2023] [Revised: 12/12/2023] [Accepted: 12/21/2023] [Indexed: 04/09/2024] Open
Abstract
BACKGROUND Bexagliflozin and dapagliflozin are sodium-glucose cotransporter-2 (SGLT2) inhibitors. No direct comparison of SGLT2 inhibitors in a randomized controlled trial has been reported to date. METHODS This was a multicenter, randomized, double-blind, active-controlled trial comparing bexagliflozin to dapagliflozin for the treatment of type 2 diabetes mellitus in adults with disease inadequately controlled by metformin. Subjects (n = 406) were randomized to receive bexagliflozin (20 mg) or dapagliflozin (10 mg) plus metformin. The primary endpoint was noninferiority of bexagliflozin to dapagliflozin for the change in glycated hemoglobin (HbA1c) from baseline to week 24. Secondary endpoints included intergroup differences in fasting plasma glucose (FPG), 2-h-postprandial glucose (PPG), body weight, and systolic blood pressure (SBP) from baseline to week 24. The trial also evaluated the safety profiles. RESULTS The model-adjusted mean change from baseline to week 24 HbA1c was -1.08% for bexagliflozin and -1.10% for dapagliflozin. The intergroup difference of 0.03% (95% confidence interval [CI] -0.14% to 0.19%) was below the prespecified margin of 0.4%, confirming the noninferiority of bexagliflozin. The changes from baseline in FPG, PPG, body weight, and SBP were -1.95 mmol/L, -3.24 mmol/L, -2.52 kg, and -6.4 mm Hg in the bexagliflozin arm and -1.87 mmol/L, -3.07 mmol/L, -2.22 kg, and -6.3 mm Hg in the dapagliflozin arm. Adverse events were experienced in 62.6% and 65.0% and serious adverse events affected 4.4% and 3.5% of subjects in the bexagliflozin and dapagliflozin arm, respectively. CONCLUSIONS Bexagliflozin showed nearly identical effects and a similar safety profile to dapagliflozin when used in Chinese patients on metformin.
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Affiliation(s)
| | - Jie Han
- Hebei PetroChina Central HospitalLangfangChina
| | - Zhifeng Cheng
- Fourth Hospital of Harbin Medical UniversityHarbinChina
| | - Dexue Liu
- The First Affiliated Hospital of Nanyang Medical CollegeNanyangChina
| | - Jie Liu
- Henan University of Science and Technology Affiliated First HospitalLuoyangChina
| | | | - Wenli Sun
- Yueyang People's HospitalYueyangChina
| | - Qingju Li
- The Second Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Fang Bian
- Cangzhou People's HospitalCangzhouChina
| | - Wei Zhang
- Newsoara Biopharma Co., LtdShanghaiChina
| | - Jinyu Chen
- Newsoara Biopharma Co., LtdShanghaiChina
| | - Qian Zhu
- Newsoara Biopharma Co., LtdShanghaiChina
| | | | | | - Bo Zhang
- China‐Japan Friendship HospitalBeijingChina
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Akbari A, Hadizadeh S, Heidary L. Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Intima-Media Thickness: Systematic Review and Meta-Analysis. J Diabetes Res 2024; 2024:3212795. [PMID: 38529046 PMCID: PMC10963118 DOI: 10.1155/2024/3212795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 02/08/2024] [Accepted: 02/23/2024] [Indexed: 03/27/2024] Open
Abstract
Background Beyond glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been proposed to reduce the risk of cardiovascular events. The aim of the present systematic review and meta-analysis is to demonstrate the effects of GLP-1 RA and SGLT2is on intima-media thickness (IMT). Methods PubMed, EMBASE, Web of Science, SCOPUS, and Google Scholar databases were searched from inception to September 9, 2023. All interventional and observational studies that provided data on the effects of GLP-1 RAs or SGLT2is on IMT were included. Critical appraisal was performed using the Joanna Briggs Institute checklists. IMT changes (preintervention and postintervention) were pooled and meta-analyzed using a random-effects model. Subgroup analyses were based on type of medication (GLP-1 RA: liraglutide and exenatide; SGLT2i: empagliflozin, ipragliflozin, tofogliflozin, and dapagliflozin), randomized clinical trials (RCTs), and diabetic patients. Results The literature search yielded 708 related articles after duplicates were removed. Eighteen studies examined the effects of GLP-1 RA, and eleven examined the effects of SGLT2i. GLP-1 RA and SGLT2i significantly decreased IMT (MD = -0.123, 95% CI (-0.170, -0.076), P < 0.0001, I2 = 98% and MD = -0.048, 95% CI (-0.092, -0.004), P = 0.031, I2 = 95%, respectively). Metaregression showed that IMT change correlated with baseline IMT, whereas it did not correlate with gender, duration of diabetes, and duration of treatment. Conclusions Treatment with GLP-1 RA and SGLT2i can lower IMT in diabetic patients, and GLP-1 RA may be more effective than SGLT2i.
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Affiliation(s)
- Abolfazl Akbari
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Research Center for Advanced Technologies in Cardiovascular Medicine, Cardiovascular Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Shiva Hadizadeh
- Research Center for Advanced Technologies in Cardiovascular Medicine, Cardiovascular Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Women Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leida Heidary
- Laboratory of Medical Genetics, ART and Stem Cell Research Centre (ACECR), Tabriz, Iran
- Nahal Infertility Center, Tabriz, Iran
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Islam L, Jose D, Alkhalifah M, Blaibel D, Chandrabalan V, Pappachan JM. Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus: A real-world experience. World J Diabetes 2024; 15:463-474. [PMID: 38591092 PMCID: PMC10999032 DOI: 10.4239/wjd.v15.i3.463] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/02/2024] [Accepted: 02/18/2024] [Indexed: 03/15/2024] Open
Abstract
BACKGROUND Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are a class of drugs with modest antidiabetic efficacy, weight loss effect, and cardiovascular benefits as proven by multiple randomised controlled trials (RCTs). However, real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse. AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data. METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs (dapagliflozin, canagliflozin, and empagliflozin) used for treating patients with type 2 diabetes mellitus. Data on the reduction of glycated hemoglobin (HbA1c), body weight, blood pressure (BP), urine albumin creatinine ratio (ACR), and adverse effects were recorded retrospectively. RESULTS Data from 467 patients with a median age of 64 (14.8) years, 294 (62.96%) males and 375 (80.5%) Caucasians were analysed. Median diabetes duration was 16.0 (9.0) years, and the duration of SGLT-2i use was 3.6 (2.1) years. SGLT-2i molecules used were dapagliflozin 10 mg (n = 227; 48.6%), canagliflozin 300 mg (n = 160; 34.3%), and empagliflozin 25 mg (n = 80; 17.1). Baseline median (interquartile range) HbA1c in mmol/mol were: dapagliflozin - 78.0 (25.3), canagliflozin - 80.0 (25.5), and empagliflozin - 75.0 (23.5) respectively. The respective median HbA1c reduction at 12 months and the latest review (just prior to the study) were: 66.5 (22.8) & 69.0 (24.0), 67.0 (16.3) & 66.0 (28.0), and 67.0 (22.5) & 66.5 (25.8) respectively (P < 0.001 for all comparisons from baseline). Significant improvements in body weight (in kilograms) from baseline to study end were noticed with dapagliflozin - 101 (29.5) to 92.2 (25.6), and canagliflozin 100 (28.3) to 95.3 (27.5) only. Significant reductions in median systolic and diastolic BP, from 144 (21) mmHg to 139 (23) mmHg; (P = 0.015), and from 82 (16) mmHg to 78 (19) mmHg; (P < 0.001) respectively were also observed. A significant reduction of microalbuminuria was observed with canagliflozin only [ACR 14.6 (42.6) at baseline to 8.9 (23.7) at the study end; P = 0.043]. Adverse effects of SGLT-2i were as follows: genital thrush and urinary infection - 20 (8.8%) & 17 (7.5%) with dapagliflozin; 9 (5.6%) & 5 (3.13%) with canagliflozin; and 4 (5%) & 4 (5%) with empagliflozin. Diabetic ketoacidosis was observed in 4 (1.8%) with dapagliflozin and 1 (0.63%) with canagliflozin. CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c, body weight, and better than those reported in RCTs, with low side effect profiles. A review of large-scale real-world data is needed to inform better clinical practice decision making.
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Affiliation(s)
- Lubna Islam
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
| | - Dhanya Jose
- Department of Community Medicine, Goa Medical College, Goa 403202, India
| | - Mohammed Alkhalifah
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Department of Family Medicine, King Faisal Specialist Hospital, Riyadh 11564, Saudi Arabia
| | - Dania Blaibel
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
| | - Vishnu Chandrabalan
- Department of Data Science, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, All Saints Building, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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Yang Q, Deng L, Feng C, Wen J. Comparing the effects of empagliflozin and liraglutide on lipid metabolism and intestinal microflora in diabetic mice. PeerJ 2024; 12:e17055. [PMID: 38500527 PMCID: PMC10946396 DOI: 10.7717/peerj.17055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 02/14/2024] [Indexed: 03/20/2024] Open
Abstract
Background and Objectives Recent studies have shown that the imbalance of intestinal flora is related to the occurrence and progression of diabetic nephropathy (DN) and can affect lipid metabolism. Sodium-dependent glucose transporters 2 (SGLT2) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist are commonly used hypoglycemic drugs and have excellent renal safety. The purpose of this study was to compare the protective effects of empagliflozin and liraglutide on kidneys, lipid metabolism, and intestinal microbiota in diabetic mice. Methods We established a mouse model of type two diabetes by feeding rats a high-fat diet (HFD) followed by an intraperitoneal injection of STZ. The mice were randomly divided into groups: normal control (NC), diabetic model (DM), liraglutide treatment (LirT), empagliflozin treatment (EmpT), and liraglutide combined with empagliflozin treatment (Emp&LirT) groups. Blood glucose, lipids, creatinine, and uric acid, as well as urinary nitrogen and albumin levels were measured. The renal tissues were subjected to HE, PAS and Masson's staining. These parameters were used to evaluate renal function and histopathological changes in mice. Mice feces were also collected for 16sRNA sequencing to analyze the composition of the intestinal flora. Results All the indexes related to renal function were significantly improved after treatment with drugs. With respect to lipid metabolism, both drugs significantly decreased the serum triglyceride levels in diabetic mice, but the effect of liraglutide on reducing serum cholesterol was better than that of empagliflozin. However, empagliflozin had a better effect on the reduction of low-density lipoproteins (LDL). The two drugs had different effects on intestinal flora. At the phylum level, empagliflozin significantly reduced the ratio of Firmicutes to Bacteroidota, but no effect was seen with liraglutide. At the genus level, both of them decreased the number of Helicobacter and increased the number of Lactobacillus. Empagliflozin also significantly increased the abundance of Muribaculaceae, Muribaculum, Olsenella, and Odoribacter, while liraglutide significantly increased that of Ruminococcus. Conclusion Liraglutide and empagliflozin were both able to improve diabetes-related renal injury. However, the ability of empagliflozin to reduce LDL was better compared to liraglutide. In addition, their effects on the intestine bacterial flora were significantly different.
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Affiliation(s)
- Qiong Yang
- Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Ling Deng
- Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Changmei Feng
- Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
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Omari MB, Naseri S, Hassan AJ. Drug Safety Evaluation of Sodium-Glucose Cotransporter 2 Inhibitors in Diabetic Comorbid Patients by Review of Systemic Extraglycemic Effects. Diabetes Metab Syndr Obes 2024; 17:1131-1141. [PMID: 38465348 PMCID: PMC10924842 DOI: 10.2147/dmso.s448670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 02/28/2024] [Indexed: 03/12/2024] Open
Abstract
Purpose The aim of this study is to evaluate the safety of this drug in diabetic patients with comorbidities of all systems. Method In this review, the beneficial effects of this drug and its mechanism on the disorders of every system of humans in relation to diabetes have been studied, and finally, its adverse effects have also been discussed. The search for relevant information is carried out in the PubMed and Google Scholar databases by using the following terms: diabetes mellitus type 2, SGLT, SGLT2 inhibitors, (SGLT2 inhibitors) AND (Pleiotropic effects). All English-published articles from 2016 to 2023 have been used in this study. It should be noted that a small number of articles published before 2016 have been used in the introduction and general informations. Results Its beneficial effects on improving cardiovascular disease risk factors and reducing adverse events caused by cardiovascular and renal diseases have proven in most large clinical studies that these effects are almost certain. It also has beneficial effects on other human systems such as the respiratory system, the gastrointestinal system, the circulatory system, and the nervous system; more of them are at the level of clinical and pre-clinical trials but have not been proven in large clinical trials or meta-analyses. Conclusion With the exception of a few adverse effects, this drug is considered a good choice and safe for all diabetic patients with comorbidities of all systems.
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Affiliation(s)
- Mohammad Belal Omari
- Department of Endocrinology, Hematology and Rheumatology, Ali Abad Teaching Hospital, Kabul University of Medical Sciences "Abu Ali Ibn Sina", Kabul, Afghanistan
| | - Shafiqullah Naseri
- Cardio-Pulmonary Department, Ali Abad Teaching Hospital, Kabul University of Medical Sciences "Abu Ali Ibn Sina", Kabul, Afghanistan
| | - Abdul Jalil Hassan
- Department of Infectious Disease and Tuberculosis, Ali Abad Teaching Hospital, Kabul University of Medical Sciences "Abu Ali Ibn Sina", Kabul, Afghanistan
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Mone P, Guerra G, Lombardi A, Illario M, Pansini A, Marro A, Frullone S, Taurino A, Sorriento D, Verri V, Iaccarino G, Santulli G. Effects of SGLT2 inhibition via empagliflozin on cognitive and physical impairment in frail diabetic elders with chronic kidney disease. Pharmacol Res 2024; 200:107055. [PMID: 38176528 PMCID: PMC11379121 DOI: 10.1016/j.phrs.2023.107055] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 12/31/2023] [Indexed: 01/06/2024]
Affiliation(s)
- Pasquale Mone
- Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York City, New York, USA; ASL Avellino, Italy; University of Molise, Campobasso, Italy
| | - Germano Guerra
- University of Molise, Campobasso, Italy; International Translational Research and Medical Education (ITME) Consortium, Academic Research Unit, Naples, Italy
| | - Angela Lombardi
- Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York City, New York, USA
| | | | | | | | | | | | - Daniela Sorriento
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy
| | | | | | - Gaetano Santulli
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy; International Translational Research and Medical Education (ITME) Consortium, Academic Research Unit, Naples, Italy; Department of Medicine, Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York City, New York, USA; Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York City, New York 10461, USA.
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Stepanova N. SGLT2 inhibitors in peritoneal dialysis: a promising frontier toward improved patient outcomes. RENAL REPLACEMENT THERAPY 2024; 10:5. [DOI: 10.1186/s41100-024-00523-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 01/14/2024] [Indexed: 01/12/2025] Open
Abstract
AbstractPeritoneal dialysis (PD) stands as an important modality among kidney replacement therapies for end-stage kidney disease, offering patients remarkable flexibility and autonomy. Despite its widespread use, challenges such as glucose-related complications, peritoneal membrane fibrosis, declining renal function, and cardiovascular risks persist, necessitating innovative therapeutic approaches. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, originally developed for treating type 2 diabetes mellitus, have recently shown promise as add-on therapy for patients with diabetic and non-diabetic chronic kidney disease (CKD), even in advanced stages. This review describes the potential role of SGLT2 inhibitors as a breakthrough therapeutic option in PD, emphasizing their ability to address unmet clinical needs and improve patient outcomes. The multiple effects of SGLT2 inhibitors in CKD, including metabolic modulation, antihypertensive, diuretic, anemia-reducing, antioxidant, and antiinflammatory properties, are reviewed in the context of PD challenges. Additionally, the potentially protective influence of SGLT2 inhibitors on the integrity of the peritoneal membrane and the transport of solutes and water in the peritoneum are emphasized. Despite these encouraging results, the paper highlights the potential risks associated with SGLT2 inhibitors in PD and emphasizes the need for cautious and thorough investigation of dosing, long-term safety considerations, and patient-specific factors through comprehensive clinical trials. Looking forward, the review argues for well-designed studies to evaluate the expanded safety profile of SGLT2 inhibitors in PD, with particular attention paid to peritoneal membrane integrity and overall patient outcomes.
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Capece U, Pavanello C, Cinti F, Leccisotti L, Mezza T, Ciccarelli G, Moffa S, Di Giuseppe G, Soldovieri L, Brunetti M, Giordano A, Giaccari A, Calabresi L, Ossoli A. Dapagliflozin-Induced Myocardial Flow Reserve Improvement is not Associated with HDL Ability to Stimulate Endothelial Nitric Oxide Production. Diabetes Ther 2024; 15:257-268. [PMID: 37883003 PMCID: PMC10786750 DOI: 10.1007/s13300-023-01491-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 10/09/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown controversial results in modulating plasma lipids in clinical trials. Most studies found slight increases in high-density lipoprotein (HDL) cholesterol but few have provided evidence on HDL functionality with disappointing results. However, there is broad agreement that these drugs provide cardiovascular protection through several mechanisms. Our group demonstrated that dapagliflozin improves myocardial flow reserve (MFR) in patients with type 2 diabetes (T2D) with coronary artery disease (CAD). The underlying mechanisms are still unknown, although in vitro studies have suggested the involvement of nitric oxide (NO). AIM To investigate changes in HDL-mediated modulation of NO production with dapagliflozin and whether there is an association with MFR. METHODS Sixteen patients with CAD-T2D were enrolled and randomized 1:1 to dapagliflozin or placebo for 4 weeks. Blood samples were collected before and after treatment for each group. The ability of HDL to stimulate NO production in endothelial cells was tested in vitro by incubating human umbilical vein endothelial cells (HUVEC) with apoB-depleted (apoB-D) serum of these patients. The production of NO was assessed by fluorescent assay, and results were expressed as fold versus untreated cells. RESULTS Change in HDL-mediated NO production remained similar in dapagliflozin and placebo group, even after adjustment for confounders. There were no significant correlations between HDL-mediated NO production and MFR either at baseline or after treatment. No changes were found in HDL cholesterol in either group, while low-density lipoprotein cholesterol (LDL cholesterol) significantly decreased compared to baseline only in treatment group (p = 0.043). CONCLUSIONS In patients with T2D-CAD, beneficial effects of dapagliflozin on coronary microcirculation seem to be unrelated to HDL functions. However, HDL capacity to stimulate NO production is not impaired at baseline; thus, the effect of drug treatments would be negligible. To conclude, we can assume that HDL-independent molecular pathways are involved in the improvement of MFR in this population. TRIAL REGISTRATION EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.
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Affiliation(s)
- Umberto Capece
- Dipartimento di Scienze Mediche e Chirurgiche, Centro Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy
| | - Chiara Pavanello
- Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Francesca Cinti
- Dipartimento di Scienze Mediche e Chirurgiche, Centro Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy
| | - Lucia Leccisotti
- Radioterapia Oncologica ed Ematologia, UOC di Medicina Nucleare, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy
| | - Teresa Mezza
- Dipartimento di Scienze Mediche e Chirurgiche, Centro Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gea Ciccarelli
- Dipartimento di Scienze Mediche e Chirurgiche, Centro Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy
| | - Simona Moffa
- Dipartimento di Scienze Mediche e Chirurgiche, Centro Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gianfranco Di Giuseppe
- Dipartimento di Scienze Mediche e Chirurgiche, Centro Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy
| | - Laura Soldovieri
- Dipartimento di Scienze Mediche e Chirurgiche, Centro Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy
| | - Michela Brunetti
- Dipartimento di Scienze Mediche e Chirurgiche, Centro Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessandro Giordano
- Radioterapia Oncologica ed Ematologia, UOC di Medicina Nucleare, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy
| | - Andrea Giaccari
- Dipartimento di Scienze Mediche e Chirurgiche, Centro Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Laura Calabresi
- Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Alice Ossoli
- Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
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Dogan NB, Yasar HY, Kilicaslan B. Cardioprotective Effects of Sodium-Glucose Cotransporter 2 Inhibitors and Their Possible Association With Normalization of the Circadian Index of Heart Rhythm. Tex Heart Inst J 2023; 50:e238196. [PMID: 38083821 PMCID: PMC10751477 DOI: 10.14503/thij-23-8196] [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] [Indexed: 12/18/2023]
Abstract
BACKGROUND Updated recommendations for the treatment of heart failure with reduced ejection fraction (HFrEF) include sodium-glucose cotransporter 2 (SGLT2) inhibitors and other long-established HFrEF therapies. These drugs' mechanisms of action have yet to be fully clarified. OBJECTIVE This study evaluated the effects of SGLT2 inhibitors on the modulation of autonomic function at 1 month beyond conventional HF therapy. METHODS This single-center, observational, prospective study was conducted from January 2020 to December 2022. Patients with type 2 diabetes who had ischemic HFrEF and met the study criteria were considered for SGLT2 inhibitor treatment with empagliflozin or dapagliflozin. Changes in the circadian index were used as the primary outcome to assess the early effects of SGLT2 inhibitors on autonomic function. Changes in functional effort capacity and laboratory findings were also evaluated. Participants' circadian index was measured by a 24-hour rhythm Holter monitoring recorder (BTL-08 Holter H100). A symptom-limited treadmill test assessed patients' effort capacities. Tests were repeated after 1 month of therapy. RESULTS The mean (SD) age of the 151 participants was 56.95 (7.29) years; their mean (SD) left ventricular EF was 35.69% (7.10%), and 95 participants were men (62.9%). From baseline to 1 month, mean (SD) daytime heart rate (80.63 [9.17] vs 77.67 [8.04] beats per minute; P = .004) and nighttime heart rate (76.83 [11.34] vs 73.81 [10.25] beats per minute; P = .03) decreased significantly. Variation in the circadian indexes (mean [SD], 1.04 [0.02] vs 1.10 [0.04]; P < .001) was statistically significant, favoring increased modulation of autonomic function. The increases in exercise duration (mean [SD], 8.88 [3.69] minutes and median [IQR], 8.81 [5.76-12.13] minutes vs 9.72 [3.14] and 9.59 [7.24-12.22] minutes; P = .04) and exercise capacity (mean [SD], 203.38 [65.18] m and median [IQR], 119.22 [149.43-259.15] m vs 335.61 [51.39] and 325.79 [293.59-376.91] m; P < .001] were also significant. CONCLUSION The use of SGLT2 inhibitors during early treatment can favorably affect both autonomic dysfunction and functional effort capacity of patients with type 2 diabetes with ischemic HFrEF.
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Affiliation(s)
- Nazile Bilgin Dogan
- Department of Cardiology, University of Health Sciences Tepecik Training and Research Hospital, Izmir, Turkey
| | - Hamiyet Yilmaz Yasar
- Department of Endocrinology, University of Health Sciences Tepecik Training and Research Hospital, Izmir, Turkey
| | - Baris Kilicaslan
- Department of Cardiology, University of Health Sciences Tepecik Training and Research Hospital, Izmir, Turkey
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Taheri H, Chiti H, Reshadmanesh T, Gohari S, Jalilvand A, Arsang-Jang S, Ismail-Beigi F, Ghanbari S, Dadashi M, Asgari A, Mahjani M, Karbalaee‑Hasani A, Ahangar H. Empagliflozin improves high-sensitive cardiac troponin-I and high-density lipoprotein cholesterol in patients with type 2 diabetes mellitus and coronary artery disease: a post-hoc analysis of EMPA-CARD Trial. J Diabetes Metab Disord 2023; 22:1723-1730. [PMID: 37975102 PMCID: PMC10638116 DOI: 10.1007/s40200-023-01305-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 09/05/2023] [Indexed: 11/19/2023]
Abstract
Background Empagliflozin is a sodium glucose cotransporter-2 (SGLT2) inhibitor that has been suggested to improve cardiac function and vascular recovery. The risk of coronary artery diseases is much higher in diabetic patients and is associated with greater morbidity and mortality. High-sensitivity cardiac troponin-I (hs-cTnI) is an important prognostic biomarker in cardiac diseases. Therefore, this study aimed to investigate the effect of empagliflozin compared to placebo on changes in hs-cTnI and lipid profile after 26 weeks of treatment. Methods This was an ancillary study in a randomized trial of patients with concomitant type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) (The EMPA-CARD study). Patients who were already on standard anti-diabetic/anti-ischemic medications were randomized to receive either placebo or empagliflozin 10 mg/daily. Serum hs-cTnI and lipid profile were measured at baseline and after 26 weeks. Results Of the 95 randomized patients, hs-cTnI and lipid profile were measured for a total of 77 patients. No significant difference was observed regarding the baseline characteristics between the two arms. Compared to placebo, empagliflozin significantly reduced hs-cTnI after 26 weeks (mean difference (MD) of -13.242, 95%CI: -14.151 to -12.333, p < 0.001). In the empagliflozin group, non-significant reductions in total cholesterol, LDL-C, and triglyceride have resulted; however, there was an increase in HDL-C level (MD = 2.40,95%CI:0.16-4.60, p < 0.04). Conclusion Empagliflozin compared to placebo was superior in reducing circulating hs-cTnI that may indicate improvements in cardiomyocytes function in patients with T2DM and CAD. Moreover, empagliflozin had a modest impact on the serum lipid profile biomarkers. Trial registration The original EMPA-CARD study has been registered in Iranian Registry of Clinical Trials. www.IRCT.ir, Identifier: IRCT20190412043247N2. Registration Date: 6/13/2020. Registration timing: prospective.
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Affiliation(s)
- Homa Taheri
- Department of Cardiology, Mousavi Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Hossein Chiti
- Endocrinology and Metabolism Research Centre, Vali-E-Asr Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Tara Reshadmanesh
- Student Research Center, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Sepehr Gohari
- Student Research Center, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Ahmad Jalilvand
- Department of Pathology, Mousavi Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Shahram Arsang-Jang
- Department of Biostatistics, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Faramarz Ismail-Beigi
- Department of Medicine, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH USA
| | - Samin Ghanbari
- Department of Cardiology, Mousavi Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohsen Dadashi
- Department of Cardiology, Mousavi Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Atieh Asgari
- Department of Cardiology, Mousavi Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mahsa Mahjani
- Endocrine Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Karbalaee‑Hasani
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Hassan Ahangar
- Department of Cardiology, Mousavi Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
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Yanai H, Adachi H, Hakoshima M, Iida S, Katsuyama H. Metabolic-Dysfunction-Associated Steatotic Liver Disease-Its Pathophysiology, Association with Atherosclerosis and Cardiovascular Disease, and Treatments. Int J Mol Sci 2023; 24:15473. [PMID: 37895151 PMCID: PMC10607514 DOI: 10.3390/ijms242015473] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/13/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease that affects more than a quarter of the global population and whose prevalence is increasing worldwide due to the pandemic of obesity. Obesity, impaired glucose metabolism, high blood pressure and atherogenic dyslipidemia are risk factors for MASLD. Therefore, insulin resistance may be closely associated with the development and progression of MASLD. Hepatic entry of increased fatty acids released from adipose tissue, increase in fatty acid synthesis and reduced fatty acid oxidation in the liver and hepatic overproduction of triglyceride-rich lipoproteins may induce the development of MASLD. Since insulin resistance also induces atherosclerosis, the leading cause for death in MASLD patients is cardiovascular disease. Considering that the development of cardiovascular diseases determines the prognosis of MASLD patients, the therapeutic interventions for MASLD should reduce body weight and improve coronary risk factors, in addition to an improving in liver function. Lifestyle modifications, such as improved diet and increased exercise, and surgical interventions, such as bariatric surgery and intragastric balloons, have shown to improve MASLD by reducing body weight. Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to improve coronary risk factors and to suppress the occurrence of cardiovascular diseases. Both SGLT2i and GLP-1 have been reported to improve liver enzymes, hepatic steatosis and fibrosis. We recently reported that the selective peroxisome proliferator-activated receptor-alpha (PPARα) modulator pemafibrate improved liver function. PPARα agonists have multiple anti-atherogenic properties. Here, we consider the pathophysiology of MASLD and the mechanisms of action of such drugs and whether such drugs and the combination therapy of such drugs could be the treatments for MASLD.
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Affiliation(s)
- Hidekatsu Yanai
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine, Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Japan; (H.A.); (M.H.); (S.I.); (H.K.)
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Li J, Yu Y, Sun Y, Yu B, Tan X, Wang B, Lu Y, Wang N. SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study. Cardiovasc Diabetol 2023; 22:278. [PMID: 37848934 PMCID: PMC10583416 DOI: 10.1186/s12933-023-02019-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/09/2023] [Indexed: 10/19/2023] Open
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown promise in reducing the risk of atrial fibrillation (AF). However, the results are controversial and the underlying metabolic mechanism remains unclear. Emerging evidence implied that SGLT2 inhibitors have extra beneficial metabolic effects on circulating metabolites beyond glucose control, which might play a role in reducing the risk of AF. Hence, our study aimed to investigate the effect of circulating metabolites mediating SGLT2 inhibition in AF by Mendelian randomization (MR). METHODS A two-sample and two-step MR study was conducted to evaluate the association of SGLT2 inhibition with AF and the mediation effects of circulating metabolites linking SGLT2 inhibition with AF. Genetic instruments for SGLT2 inhibition were identified as genetic variants, which were both associated with the expression of SLC5A2 gene and glycated hemoglobin level (HbA1c). Positive control analysis on type 2 diabetes mellitus (T2DM) was conducted to validate the selection of genetic instruments. RESULTS Genetically predicted SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of T2DM (odds ratio [OR] = 0.63 [95% CI 0.45, 0.88], P = 0.006) and AF (0.51 [0.27, 0.97], P = 0.039). Among 168 circulating metabolites, two metabolites were both associated with SGLT2 inhibition and AF. The effect of SGLT2 inhibition on AF through the total concentration of lipoprotein particles (0.88 [0.81, 0.96], P = 0.004) and the concentration of HDL particles (0.89 [0.82, 0.97], P = 0.005), with a mediated proportion of 8.03% (95% CI [1.20%, 14.34%], P = 0.010) and 7.59% ([1.09%, 13.34%], P = 0.011) of the total effect, respectively. CONCLUSIONS This study supported the association of SGLT2 inhibition with a reduced risk of AF. The total concentration of lipoprotein particles and particularly the concentration of HDL particles might mediate this association. Further mechanistic and clinical studies research are needed to understand the mediation effects of circulating metabolites especially blood lipids in the association between SGLT2 inhibition and AF.
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Affiliation(s)
- Jiang Li
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuefeng Yu
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Sun
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bowei Yu
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Tan
- School of Public Health, Zhejiang University, Hangzhou, China
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Bin Wang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingli Lu
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ningjian Wang
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Ide S, Maezawa Y, Yokote K. Updates on dyslipidemia in patients with diabetes. J Diabetes Investig 2023; 14:1041-1044. [PMID: 37347218 PMCID: PMC10445203 DOI: 10.1111/jdi.14042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/06/2023] [Accepted: 06/08/2023] [Indexed: 06/23/2023] Open
Affiliation(s)
- Shintaro Ide
- Department of Medicine, Division of Diabetes, Metabolism and EndocrinologyChiba University HospitalChibaJapan
- Department of Endocrinology, Hematology and GerontologyChiba University Graduate School of MedicineChibaJapan
| | - Yoshiro Maezawa
- Department of Medicine, Division of Diabetes, Metabolism and EndocrinologyChiba University HospitalChibaJapan
- Department of Endocrinology, Hematology and GerontologyChiba University Graduate School of MedicineChibaJapan
| | - Koutaro Yokote
- Department of Medicine, Division of Diabetes, Metabolism and EndocrinologyChiba University HospitalChibaJapan
- Department of Endocrinology, Hematology and GerontologyChiba University Graduate School of MedicineChibaJapan
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Banerjee Y, Patti AM, Giglio RV, Ciaccio M, Vichithran S, Faisal S, Stoian AP, Rizvi AA, Rizzo M. The role of atherogenic lipoproteins in diabetes: Molecular aspects and clinical significance. J Diabetes Complications 2023; 37:108517. [PMID: 37329706 DOI: 10.1016/j.jdiacomp.2023.108517] [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: 02/18/2023] [Revised: 05/21/2023] [Accepted: 05/21/2023] [Indexed: 06/19/2023]
Abstract
Dyslipidaemia plays a prominent role in the genesis of atherosclerotic plaque and the increased cardiovascular risk in diabetes. Macrophages readily take up atherogenic lipoproteins, transforming into foam cells and amplifying vascular damage in the presence of endothelial dysfunction. We discuss the importance of distinct lipoprotein subclasses in atherogenic diabetic dyslipidaemia as well as the effects of novel anti-diabetic agents on lipoprotein fractions and ultimately on cardiovascular risk prevention. In patients with diabetes, lipid abnormalities should be aggressively identified and treated in conjunction with therapeutical agents used to prevent cardiovascular disease. The use of drugs that improve diabetic dyslipidaemia plays a prominent role in conferring cardiovascular benefit in individuals with diabetes.
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Affiliation(s)
- Yajnavalka Banerjee
- Department of Basic Sciences, College of Medicine and Health Sciences, Mohammed Bin Rashid University (MBRU), Dubai, United Arab Emirates.
| | - Angelo M Patti
- Internal Medicine Unit, "Vittorio Emanuele II" Hospital, Castelvetrano, Trapani, Italy
| | - Rosaria V Giglio
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine, and Laboratory Medicine, University of Palermo, Palermo, Italy; Department of Laboratory Medicine, University Hospital "P. Giaccone", Palermo, Italy
| | - Marcello Ciaccio
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine, and Laboratory Medicine, University of Palermo, Palermo, Italy; Department of Laboratory Medicine, University Hospital "P. Giaccone", Palermo, Italy
| | - Suhina Vichithran
- Department of Basic Sciences, College of Medicine and Health Sciences, Mohammed Bin Rashid University (MBRU), Dubai, United Arab Emirates
| | - Shemima Faisal
- Department of Basic Sciences, College of Medicine and Health Sciences, Mohammed Bin Rashid University (MBRU), Dubai, United Arab Emirates
| | - Anca Panta Stoian
- Department of Diabetes, Nutrition, and Metabolic Diseases, Carol Davila University of Medicine, Bucharest, Romania; "Prof. Dr.N.C.Paulescu" National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania
| | - Ali Abbas Rizvi
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL, USA
| | - Manfredi Rizzo
- Department of Basic Sciences, College of Medicine and Health Sciences, Mohammed Bin Rashid University (MBRU), Dubai, United Arab Emirates; Department of Diabetes, Nutrition, and Metabolic Diseases, Carol Davila University of Medicine, Bucharest, Romania; "Prof. Dr.N.C.Paulescu" National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania; School of Medicine, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (Promise), University of Palermo, Italy
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Yu D, Shen S, Zhang J, Wang Q. Effect of the Dual Glucose‐Dependent Insulinotropic Peptide/Gulcagon‐like Peptide 1 Receptor Agonist Tirzepatide on Lipid Profile and Waist Circumference: A Systematic Review and Meta‐analysis. Clin Ther 2023; 45:787-796. [PMID: 37455226 DOI: 10.1016/j.clinthera.2023.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 05/28/2023] [Accepted: 06/07/2023] [Indexed: 07/18/2023]
Abstract
PURPOSE Tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide 1 receptor agonist, has been approved by the US Food and Drug Administration for the treatment of type 2 diabetes. The purpose of this meta-analysis is to evaluate the impact of tirzepatide on lipid profile and waist circumference (WC), both of which are risk factors of cardiovascular diseases. METHODS The PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases were systematically searched for articles published from database inception to July 31, 2022. This meta-analysis included 7 randomized controlled trials with a minimum duration of 12 weeks that compared tirzepatide with placebo or other antidiabetic medications. The random-effects model was used to estimate mean differences in lipid profile and WC from baseline. The Cochrane risk-of-bias tool for randomized trials, version 2 was used to assess the outcome's risk of bias. We evaluated the evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. FINDINGS A total of 8 articles from 7 trials with 7151 participants were included. All 3 eligible maintenance doses of tirzepatide (5, 10, and 15 mg once a week) were effective in increasing total cholesterol (TC) (P < 0.05), HDL-C (P < 0.05), VLDL-C (P < 0.01), triglyceride (TG) (P < 0.01), and WC (P < 0.01) changes from baseline compared with control agents including placebo, semaglutide, dulaglutide, and degludec. Although the evidence for VLDL-C and TGs by GRADE were high or moderate, the evidences for TC, HDL-C, and WC were low or moderate. Only 5mg once-weekly tirzepatide (P < 0.05), not 10 or 15 mg, could induce significant alteration in LDL-C before sensitivity analysis. The evidence by GRADE was moderate. IMPLICATIONS Tirzepatide had superiority over placebo or other antidiabetic agents in controlling lipid and WC levels. However, the levels of evidence by GRADE varied greatly across different outcome indicators. Limitations of the study include evaluating secondary outcomes of original trials for the meta-analyses, not assessing the effect of baseline lipid-lowering therapy on lipid levels, and not exploring the bias induced by glycemic improvement and weight loss.
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Affiliation(s)
- Dan Yu
- Department of Endocrinology, Zhejiang Hospital, Hangzhou, China
| | - Shanshan Shen
- Department of Geriatrics, Zhejiang Hospital, Hangzhou, China
| | - Jinghong Zhang
- Department of Endocrinology, Zhejiang Hospital, Hangzhou, China
| | - Qijun Wang
- Department of Endocrinology, Zhejiang Hospital, Hangzhou, China.
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Piccirillo F, Mastroberardino S, Nusca A, Frau L, Guarino L, Napoli N, Ussia GP, Grigioni F. Novel Antidiabetic Agents and Their Effects on Lipid Profile: A Single Shot for Several Cardiovascular Targets. Int J Mol Sci 2023; 24:10164. [PMID: 37373310 PMCID: PMC10299555 DOI: 10.3390/ijms241210164] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/06/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Type-2 diabetes mellitus (DM) represents one of the most important risk factors for cardiovascular diseases (CVD). Hyperglycemia and glycemic variability are not the only determinant of the increased cardiovascular (CV) risk in diabetic patients, as a frequent metabolic disorder associated with DM is dyslipidemia, characterized by hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol levels and a shift towards small dense low-density lipoprotein (LDL) cholesterol. This pathological alteration, also called diabetic dyslipidemia, represents a relevant factor which could promotes atherosclerosis and subsequently an increased CV morbidity and mortality. Recently, the introduction of novel antidiabetic agents, such as sodium glucose transporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), has been associated with a significant improvement in CV outcomes. Beyond their known action on glycemia, their positive effects on the CV system also seems to be related to an ameliorated lipidic profile. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs and their effects on diabetic dyslipidemia, which could explain the provided global benefit to the cardiovascular system.
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Affiliation(s)
- Francesco Piccirillo
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Sara Mastroberardino
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Annunziata Nusca
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Lorenzo Frau
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Lorenzo Guarino
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Nicola Napoli
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Endocrinology and Diabetes Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Gian Paolo Ussia
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
| | - Francesco Grigioni
- Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy; (F.P.); (S.M.); (L.F.); (L.G.); (N.N.); (G.P.U.); (F.G.)
- Research Unit of Cardiovascular Sciences, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128 Roma, Italy
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Moady G, Ben Gal T, Atar S. Sodium-Glucose Co-Transporter 2 Inhibitors in Heart Failure-Current Evidence in Special Populations. Life (Basel) 2023; 13:1256. [PMID: 37374037 PMCID: PMC10301138 DOI: 10.3390/life13061256] [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: 04/20/2023] [Revised: 05/17/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally used for diabetes mellitus, are gaining more popularity for other indications, owing to their positive cardiovascular and renal effects. SGLT2 inhibitors reduce heart failure (HF) hospitalization and improve cardiovascular outcomes in patients with type 2 diabetes. Later, SGLT2 inhibitors were evaluated in patients with HF with reduced ejection fraction (HFREF) and had beneficial effects independent of the presence of diabetes. Recently, reductions in cardiovascular outcomes were also observed in patients with HF with preserved ejection fraction (HFPEF). SGLT2 inhibitors also reduced renal outcomes in patients with chronic kidney disease. Overall, these drugs have an excellent safety profile with a negligible risk of genitourinary tract infections and ketoacidosis. In this review, we discuss the current data on SGLT2 inhibitors in special populations, including patients with acute myocardial infarction, acute HF, right ventricular (RV) failure, left ventricular assist device (LVAD), and type 1 diabetes. We also discuss the potential mechanisms behind the cardiovascular benefits of these medications.
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Affiliation(s)
- Gassan Moady
- Department of Cardiology, Galilee Medical Center, Nahariya 2210001, Israel;
- Azrieli Faculty of Medicine, Bar Ilan University, Safed 5290002, Israel
| | - Tuvia Ben Gal
- Heart Failure Unit, Cardiology Department, Rabin Medical Center, Petah Tikva 4941492, Israel;
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Shaul Atar
- Department of Cardiology, Galilee Medical Center, Nahariya 2210001, Israel;
- Azrieli Faculty of Medicine, Bar Ilan University, Safed 5290002, Israel
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Duell PB, Puri R, Mehta V, Wong ND. Evidence regarding SGLT-2 inhibitors for the management of diabetic dyslipidemia. J Clin Lipidol 2023; 17:422-423. [PMID: 37164839 DOI: 10.1016/j.jacl.2023.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 04/14/2023] [Indexed: 05/12/2023]
Affiliation(s)
- P Barton Duell
- Knight Cardiovascular Institute & Division of Endocrinology Diabetes & Clinical Nutrition, Oregon Health & Science University, Portland, OR, USA.
| | - Raman Puri
- Founder and Chair, Lipid Association of India. Sr. Consultant Cardiologist, Indraprastha Apollo Hospitals, New Delhi, India
| | - Vimal Mehta
- Department of Cardiology, G.B. Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
| | - Nathan D Wong
- Heart Disease Prevention Program, Division of Cardiology, University of California Irvine, Irvine, CA, USA
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