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El-Ashmawy NE, Al-Ashmawy GM, Kamel AA, Khedr EG. Unlocking the therapeutic potential of canagliflozin in NAFLD: Insights into AMPK/SIRT1-mediated lipophagy. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167666. [PMID: 39837063 DOI: 10.1016/j.bbadis.2025.167666] [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: 11/13/2024] [Revised: 12/23/2024] [Accepted: 01/08/2025] [Indexed: 01/23/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a rising global health problem. The antidiabetic canagliflozin (CANA) has been proposed to ameliorate the metabolic abnormalities in NAFLD. AIM This study aimed to explore the possible anti-NAFLD effects of CANA in rats and HepG2 cells, focusing on AMPK/SIRT1-mediated lipophagy. METHODS Wistar rats were assigned to four groups: control group, NAFLD group, NAFLD+CANA group, and NAFLD+CANA+chloroquine (CQ) group, where CQ served as autophagy inhibitor. HepG2 cells were also divided into four groups: control group, NAFLD group, NAFLD+CANA group, and NAFLD+CANA+compound C (Comp C) group, where Comp C served as AMPK inhibitor. RESULTS The histopathological examination showed that CANA alleviated hepatic and intracellular lipid deposition in rats and HepG2 cells. CANA induced lipophagy by increasing LC3-II levels and lowering both p62 and perilipin 2 levels in rats and HepG2 cells, in addition to decreasing mTOR protein expression in rats' livers. These outcomes were associated with upregulation of the lipophagy regulator Rab7 and downregulation of the ER stress-related protein CHOP. CANA enhanced autophagic engulfment of lipid droplets while decreased ER stress and mitochondrial damage in rats' livers, as demonstrated by TEM. In rats, CANA improved hyperglycemia, hyperinsulinemia, dyslipidemia, and obesity. In HepG2 cells, CANA's effects were linked to increased phosphorylated AMPK level and enhanced SIRT1 level and expression. However, blocking lipophagy in rats and AMPK in HepG2 cells markedly weakened CANA's protective effects against NAFLD. CONCLUSION CANA ameliorated NAFLD via enhancing AMPK/SIRT1-mediated lipophagy, suggesting its potential as a therapeutic intervention for this metabolic disorder.
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Affiliation(s)
- Nahla E El-Ashmawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Egypt; Department of Pharmacology & Biochemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Egypt
| | - Ghada M Al-Ashmawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Egypt; Department of Biochemistry, Faculty of Pharmacy, Alsalam University in Egypt, Egypt
| | - Asmaa A Kamel
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Egypt.
| | - Eman G Khedr
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Egypt
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Massey RJ, Chen Y, Panova-Noeva M, Mattheus M, Siddiqui MK, Schloot NC, Ceriello A, Pearson ER, Dawed AY. BMI variability and cardiovascular outcomes within clinical trial and real-world environments in type 2 diabetes: an IMI2 SOPHIA study. Cardiovasc Diabetol 2024; 23:256. [PMID: 39014446 PMCID: PMC11253469 DOI: 10.1186/s12933-024-02299-8] [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: 03/15/2024] [Accepted: 06/10/2024] [Indexed: 07/18/2024] Open
Abstract
BACKGROUND BMI variability has been associated with increased cardiovascular disease risk in individuals with type 2 diabetes, however comparison between clinical studies and real-world observational evidence has been lacking. Furthermore, it is not known whether BMI variability has an effect independent of HbA1c variability. METHODS We investigated the association between BMI variability and 3P-MACE risk in the Harmony Outcomes trial (n = 9198), and further analysed placebo arms of REWIND (n = 4440) and EMPA-REG OUTCOME (n = 2333) trials, followed by real-world data from the Tayside Bioresource (n = 6980) using Cox regression modelling. BMI variability was determined using average successive variability (ASV), with first major adverse cardiovascular event of non-fatal stroke, non-fatal myocardial infarction, and cardiovascular death (3P-MACE) as the primary outcome. RESULTS After adjusting for cardiovascular risk factors, a + 1 SD increase in BMI variability was associated with increased 3P-MACE risk in Harmony Outcomes (HR 1.12, 95% CI 1.08-1.17, P < 0.001). The most variable quartile of participants experienced an 87% higher risk of 3P-MACE (P < 0.001) relative to the least variable. Similar associations were found in REWIND and Tayside Bioresource. Further analyses in the EMPA-REG OUTCOME trial did not replicate this association. BMI variability's impact on 3P-MACE risk was independent of HbA1c variability. CONCLUSIONS In individuals with type 2 diabetes, increased BMI variability was found to be an independent risk factor for 3P-MACE across cardiovascular outcome trials and real-world datasets. Future research should attempt to establish a causal relationship between BMI variability and cardiovascular outcomes.
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Affiliation(s)
- Robert J Massey
- Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK
| | - Yu Chen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Marina Panova-Noeva
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
- Center for Thrombosis and Haemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Michaela Mattheus
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
| | - Moneeza K Siddiqui
- Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK
- Centre for Primary Care, Wolfson Institute of Population Health, Queen Mary University of London, London, UK
| | | | - Antonio Ceriello
- IRCCS MultiMedica, Via Milanese 300, 20099, Sesto San Giovanni, MI, Italy
| | - Ewan R Pearson
- Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK
| | - Adem Y Dawed
- Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK.
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Odutayo A, Zinman B, Wanner C, Zwiener I, Lund SS, Hantel S, Fitchett D, Udell JA, EMPA-REG OUTCOME Trial Investigators. Effect of Qualifying Atherosclerotic Cardiovascular Disease Diagnosis Proximity on Cardiovascular Risk and Benefit of Empagliflozin in the EMPA-REG OUTCOME Trial. CJC Open 2024; 6:868-875. [PMID: 39026628 PMCID: PMC11252526 DOI: 10.1016/j.cjco.2024.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 01/24/2024] [Indexed: 07/20/2024] Open
Abstract
Background In patients with type 2 diabetes mellitus (T2DM), a history of an ischemic event is associated with increased risk for cardiovascular (CV) disease. Whether patients with T2DM and a recent atherothrombotic diagnosis benefit from early intervention with a sodium-glucose co-transporter 2 inhibitor is unknown. Methods This study is a secondary analysis of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), which compared empagliflozin to placebo in adults with T2DM and atherosclerotic CV disease (ASCVD). Participants were categorized based on the time since their last qualifying ASCVD diagnosis (≤ 1 year vs > 1 year). Qualifying ASCVD diagnoses included ischemic or hemorrhagic stroke, myocardial infarction, coronary artery disease, and peripheral artery disease. The primary outcome was a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Results A total of 6796 participants (n = 4547 empagliflozin, n = 2249 placebo) were included. Median time since the last qualifying ASCVD diagnosis was 3.8 years (quartile 1-quartile 3: 1.5-7.6), and most qualifying diagnoses occurred > 1 year before randomization (≤ 1 year, n = 1214; > 1 year, n = 5582). Empagliflozin reduced the incidence of the primary outcome irrespective of the time since the last qualifying ASCVD diagnosis (≤ 1 year: hazard ratio 0.82, 95% confidence interval: 0.57-1.16; vs > 1 year: hazard ratio 0.85, 95% confidence interval: 0.72-1.00; P for interaction = 0.84). Results were similar for the composite of CV death or hospitalization for heart failure. Conclusions Empagliflozin improved CV outcomes in participants with T2DM, irrespective of the time since the last qualifying ASCVD diagnosis at randomization. Prospective trials are necessary to investigate the use of sodium-glucose co-transporter 2 inhibitors at the time of an acute ASCVD event. Trial Registration EMPA-REG OUTCOME (Clinicaltrials.gov identifier: NCT01131676).
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Affiliation(s)
- Ayodele Odutayo
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Cardiovascular Division, Women’s College Hospital and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Bernard Zinman
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Christoph Wanner
- Department of Internal Medicine I, Nephrology, University Hospital Würzburg, Würzburg, Germany
- Clinical Trial Service Unit, Department of Population Health, University of Oxford, Nuffield, Oxford, UK
| | | | - Søren S. Lund
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
| | - Stefan Hantel
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - David Fitchett
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- St. Michael’s Hospital, Division of Cardiology, Toronto, Ontario, Canada
| | - Jacob A. Udell
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Cardiovascular Division, Women’s College Hospital and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | - EMPA-REG OUTCOME Trial Investigators
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Cardiovascular Division, Women’s College Hospital and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Internal Medicine I, Nephrology, University Hospital Würzburg, Würzburg, Germany
- Clinical Trial Service Unit, Department of Population Health, University of Oxford, Nuffield, Oxford, UK
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
- St. Michael’s Hospital, Division of Cardiology, Toronto, Ontario, Canada
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Nielsen SF, Duus CL, Buus NH, Bech JN, Mose FH. Effects of Empagliflozin in Type 2 Diabetes With and Without Chronic Kidney Disease and Nondiabetic Chronic Kidney Disease: Protocol for 3 Crossover Randomized Controlled Trials (SiRENA Project). JMIR Res Protoc 2024; 13:e56067. [PMID: 38680116 PMCID: PMC11170048 DOI: 10.2196/56067] [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: 01/04/2024] [Revised: 04/25/2024] [Accepted: 04/25/2024] [Indexed: 05/01/2024] Open
Abstract
BACKGROUND Sodium-glucose-cotransporter 2 inhibitors (SGLT2is) have revolutionized the treatment of type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), reducing the risk of cardiovascular and renal end points by up to 40%. The underlying mechanisms are not fully understood. OBJECTIVE The study aims to examine the effects of empagliflozin versus placebo on renal hemodynamics, sodium balance, vascular function, and markers of the innate immune system in patients with DM2, DM2 and CKD, and nondiabetic CKD. METHODS We conducted 3 double-blind, crossover, randomized controlled trials, each with identical study protocols but different study populations. We included patients with DM2 and preserved kidney function (estimated glomerular filtration rate >60 mL/min/1.73 m2), DM2 and CKD, and nondiabetic CKD (both with estimated glomerular filtration rate 20-60 mL/min/1.73 m2). Each participant was randomly assigned to 4 weeks of treatment with either 10 mg of empagliflozin once daily or a matching placebo. After a wash-out period of at least 2 weeks, participants were crossed over to the opposite treatment. End points were measured at the end of each treatment period. The primary end point was renal blood flow measured with 82Rubidium positron emission tomography-computed tomography (82Rb-PET/CT). Secondary end points include glomerular filtration rate measured with 99mTechnetium-diethylene-triamine-pentaacetate (99mTc-DTPA) clearance, vascular function assessed by forearm venous occlusion strain gauge plethysmography, measurements of the nitric oxide (NO) system, water and sodium excretion, body composition measurements, and markers of the complement immune system. RESULTS Recruitment began in April 2021 and was completed in September 2022. Examinations were completed by December 2022. In total, 49 participants completed the project: 16 participants in the DM2 and preserved kidney function study, 17 participants in the DM2 and CKD study, and 16 participants in the nondiabetic CKD study. Data analysis is ongoing. Results are yet to be published. CONCLUSIONS This paper describes the rationale, design, and methods used in a project consisting of 3 double-blind, crossover, randomized controlled trials examining the effects of empagliflozin versus placebo in patients with DM2 with and without CKD and patients with nondiabetic CKD, respectively. TRIAL REGISTRATION EU Clinical Trials Register 2019-004303-12; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004303-12, EU Clinical Trials Register 2019-004447-80; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004447-80, EU Clinical Trials Register 2019-004467-50; https://www.clinicaltrialsregister.eu/ctr-search/search?query=and+2019-004467-50. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/56067.
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Affiliation(s)
- Steffen Flindt Nielsen
- University Clinic in Nephrology and Hypertension, Gødstrup Hospital and Aarhus University, Herning, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Camilla Lundgreen Duus
- University Clinic in Nephrology and Hypertension, Gødstrup Hospital and Aarhus University, Herning, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Niels Henrik Buus
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Jesper Nørgaard Bech
- University Clinic in Nephrology and Hypertension, Gødstrup Hospital and Aarhus University, Herning, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Frank Holden Mose
- University Clinic in Nephrology and Hypertension, Gødstrup Hospital and Aarhus University, Herning, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Natale P, Tunnicliffe DJ, Toyama T, Palmer SC, Saglimbene VM, Ruospo M, Gargano L, Stallone G, Gesualdo L, Strippoli GF. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev 2024; 5:CD015588. [PMID: 38770818 PMCID: PMC11106805 DOI: 10.1002/14651858.cd015588.pub2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
BACKGROUND Diabetes is associated with high risks of premature chronic kidney disease (CKD), cardiovascular diseases, cardiovascular death and impaired quality of life. People with diabetes are more likely to develop kidney impairment, and approximately one in three adults with diabetes have CKD. People with CKD and diabetes experience a substantially higher risk of cardiovascular outcomes. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors have shown potential effects in preventing kidney and cardiovascular outcomes in people with CKD and diabetes. However, new trials are emerging rapidly, and evidence synthesis is essential to summarising cumulative evidence. OBJECTIVES This review aimed to assess the benefits and harms of SGLT2 inhibitors for people with CKD and diabetes. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 17 November 2023 using a search strategy designed by an Information Specialist. Studies in the Register are continually identified through regular searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled studies were eligible if they evaluated SGLT2 inhibitors versus placebo, standard care or other glucose-lowering agents in people with CKD and diabetes. CKD includes all stages (from 1 to 5), including dialysis patients. DATA COLLECTION AND ANALYSIS Two authors independently extracted data and assessed the study risk of bias. Treatment estimates were summarised using random effects meta-analysis and expressed as a risk ratio (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The primary review outcomes were all-cause death, 3-point and 4-point major adverse cardiovascular events (MACE), fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, and kidney failure. MAIN RESULTS Fifty-three studies randomising 65,241 people with CKD and diabetes were included. SGLT2 inhibitors with or without other background treatments were compared to placebo, standard care, sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, or insulin. In the majority of domains, the risks of bias in the included studies were low or unclear. No studies evaluated the treatment in children or in people treated with dialysis. No studies compared SGLT2 inhibitors with glucagon-like peptide-1 receptor agonists or tirzepatide. Compared to placebo, SGLT2 inhibitors decreased the risk of all-cause death (20 studies, 44,397 participants: RR 0.85, 95% CI 0.78 to 0.94; I2 = 0%; high certainty) and cardiovascular death (16 studies, 43,792 participants: RR 0.83, 95% CI 0.74 to 0.93; I2 = 29%; high certainty). Compared to placebo, SGLT2 inhibitors probably make little or no difference to the risk of fatal or nonfatal MI (2 studies, 13,726 participants: RR 0.95, 95% CI 0.80 to 1.14; I2 = 24%; moderate certainty), and fatal or nonfatal stroke (2 studies, 13,726 participants: RR 1.07, 95% CI 0.88 to 1.30; I2 = 0%; moderate certainty). Compared to placebo, SGLT2 inhibitors probably decrease 3-point MACE (7 studies, 38,320 participants: RR 0.89, 95% CI 0.81 to 0.98; I2 = 46%; moderate certainty), and 4-point MACE (4 studies, 23,539 participants: RR 0.82, 95% CI 0.70 to 0.96; I2 = 77%; moderate certainty), and decrease hospital admission due to heart failure (6 studies, 28,339 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 17%; high certainty). Compared to placebo, SGLT2 inhibitors may decrease creatinine clearance (1 study, 132 participants: MD -2.63 mL/min, 95% CI -5.19 to -0.07; low certainty) and probably decrease the doubling of serum creatinine (2 studies, 12,647 participants: RR 0.70, 95% CI 0.56 to 0.89; I2 = 53%; moderate certainty). SGLT2 inhibitors decrease the risk of kidney failure (6 studies, 11,232 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 0%; high certainty), and kidney composite outcomes (generally reported as kidney failure, kidney death with or without ≥ 40% decrease in estimated glomerular filtration rate (eGFR)) (7 studies, 36,380 participants: RR 0.68, 95% CI 0.59 to 0.78; I2 = 25%; high certainty) compared to placebo. Compared to placebo, SGLT2 inhibitors incur less hypoglycaemia (16 studies, 28,322 participants: RR 0.93, 95% CI 0.89 to 0.98; I2 = 0%; high certainty), and hypoglycaemia requiring third-party assistance (14 studies, 26,478 participants: RR 0.75, 95% CI 0.65 to 0.88; I2 = 0%; high certainty), and probably decrease the withdrawal from treatment due to adverse events (15 studies, 16,622 participants: RR 0.94, 95% CI 0.82 to 1.08; I2 = 16%; moderate certainty). The effects of SGLT2 inhibitors on eGFR, amputation and fracture were uncertain. No studies evaluated the effects of treatment on fatigue, life participation, or lactic acidosis. The effects of SGLT2 inhibitors compared to standard care alone, sulfonylurea, DPP-4 inhibitors, or insulin were uncertain. AUTHORS' CONCLUSIONS SGLT2 inhibitors alone or added to standard care decrease all-cause death, cardiovascular death, and kidney failure and probably decrease major cardiovascular events while incurring less hypoglycaemia compared to placebo in people with CKD and diabetes.
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Affiliation(s)
- Patrizia Natale
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - David J Tunnicliffe
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Tadashi Toyama
- Department of Nephrology, Kanazawa University, Kanazawa, Japan
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan
| | - Suetonia C Palmer
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | - Valeria M Saglimbene
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Marinella Ruospo
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Letizia Gargano
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Loreto Gesualdo
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Fm Strippoli
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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Khoshnazar SM, Dehghani A, Bagheri F, Pezeshki S, Yousefzadeh G. Type 2 diabetes patients requiring empagliflozin in Southeast of Iran: Frequency and guideline adherence (2022-2023). HIPERTENSION Y RIESGO VASCULAR 2024; 41:87-94. [PMID: 38521624 DOI: 10.1016/j.hipert.2023.10.004] [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: 08/22/2023] [Revised: 10/21/2023] [Accepted: 10/23/2023] [Indexed: 03/25/2024]
Abstract
INTRODUCTION Empagliflozin plays a beneficial role in individuals with type 2 diabetes at high risk of cardiovascular complications. This study aimed to assess the prevalence of individuals with type 2 diabetes who required empagliflozin based on clinical guidelines between the years 2022 and 2023. MATERIAL AND METHODS This study was a descriptive-analytical cross-sectional study conducted on a target population of patients with type 2 diabetes. Patient data, including demographic characteristics, smoking status, hypertension, hyperlipidemia, renal insufficiency, retinopathy, and proteinuria, were collected. The indication for prescribing empagliflozin was determined based on the risk of cardiovascular complications. RESULTS A total of 398 individuals with type 2 diabetes with a mean age of 58.4 years were examined. Overall, 87.4% of the patients had an indication for empagliflozin prescription. The indication for empagliflozin prescription was significantly higher in men, individuals with hyperlipidemia, those over 55 years of age, obese individuals, and smokers. The mean age, body mass index, and triglyceride levels were higher in candidates for empagliflozin prescription. Male candidates for empagliflozin had significantly higher rates of smoking and systolic blood pressure compared to females. CONCLUSIONS The findings of this study demonstrated that a significant percentage of individuals with type 2 diabetes had an indication for empagliflozin prescription based on clinical and laboratory criteria.
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Affiliation(s)
- S M Khoshnazar
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - A Dehghani
- Clinical Research Development Unit, Afzalipour Hospital, Kerman University of Medical Sciences, Kerman, Iran
| | - F Bagheri
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - S Pezeshki
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - G Yousefzadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
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Hadjadj S, Cooper ME, Steubl D, Petrini M, Hantel S, Mattheus M, Wanner C, Thomas MC. Empagliflozin and Rapid Kidney Function Decline Incidence in Type 2 Diabetes: An Exploratory Analysis From the EMPA-REG OUTCOME Trial. Kidney Med 2024; 6:100783. [PMID: 38419787 PMCID: PMC10900108 DOI: 10.1016/j.xkme.2023.100783] [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] [Indexed: 03/02/2024] Open
Abstract
Rationale & Objective Kidney function progressively declines in most patients with type 2 diabetes (T2DM). Many develop progressive chronic kidney disease (CKD), but some experience a more rapid decline, with a greater risk of kidney failure and cardiovascular disease. In EMPA-REG OUTCOME, empagliflozin was associated with slower kidney disease progression. This post hoc analysis evaluated the effect of empagliflozin (pooled doses) on the prevalence of a "rapid decliner" phenotype, defined by an annual estimated glomerular filtration rate (eGFR) decline of >3 mL/min/1.73 m2. Study Design This was an exploratory analysis of EMPA-REG OUTCOME, a large randomized, double-blind, placebo-controlled trial in adults with T2DM, established cardiovascular disease and an eGFR of ≥30 mL/min/1.73 m2. Setting & Participants Analysis was undertaken on 6,967 participants (99.2%) in whom serial eGFR data was available. Interventions Patients were randomized (1:1:1) to empagliflozin 10 mg, 25 mg, or placebo in addition to standard of care. Outcomes Annual change in eGFR over the maintenance phase of treatment (week 4 to last value on treatment) was calculated using linear regression models. Logistic regression analysis was used to investigate differences in rapid decline between the treatment groups. Results Over the study period, a rapid decliner phenotype was observed in 188 (9.5%) participants receiving placebo and 134 (3.4%) receiving empagliflozin. After adjusting for other risk factors, this equated to a two-third reduction in odds (OR, 0.32; 95% CI, 0.25-0.40; P < 0.001) among participants receiving empagliflozin versus placebo. A comparable risk reduction was observed using a threshold of eGFR decline of >5 mL/min/1.73 m2/y (empagliflozin vs placebo, 43 [1.1%] vs 44 [2.2%] participants; OR, 0.47; 95% CI, 0.31-0.72; P < 0.001). Limitations This is a post hoc analysis of a trial undertaken in participants with T2DM and CVD. Generalization of findings to other settings remains to be established. Conclusions Patients receiving empagliflozin were significantly less likely to experience a rapid decline in eGFR over a median of 2.6 years of exposure to the study drug. Funding The Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Trial Registration clinicaltrials.gov ID: NCT01131676.
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Affiliation(s)
- Samy Hadjadj
- Institut du thorax, INSERM, CNRS, Université Nantes, CHU Nantes, Nantes, France
| | - Mark E. Cooper
- Department of Diabetes, Monash University, Melbourne, Australia
| | - Dominik Steubl
- Boehringer Ingelheim International GmbH, Ingelheim, Germany, and Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Michaela Petrini
- Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut
| | - Stefan Hantel
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | | | - Christoph Wanner
- Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
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Murphy DP, Wolfson J, Reule S, Johansen KL, Ishani A, Drawz PE. Kidney Outcomes with Sodium-Glucose Cotransporter-2 Inhibitor Initiation after AKI among Veterans with Diabetic Kidney Disease. KIDNEY360 2024; 5:335-343. [PMID: 38287468 PMCID: PMC11000713 DOI: 10.34067/kid.0000000000000375] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 01/22/2024] [Indexed: 01/31/2024]
Abstract
Key Points Post-AKI sodium–glucose cotransporter-2 inhibitor use was associated with a reduced risk for progression of CKD and for recurrent AKI among veterans with diabetic kidney disease even after accounting for recovery from the index AKI. A minority of Veterans with diabetic kidney disease received a sodium–glucose cotransporter-2 inhibitor after having had AKI during the study period. Background The effect of sodium–glucose cotransporter-2 inhibitor (SGLT2i) on kidney function after AKI is unknown. Methods The study population was drawn from a retrospective cohort of Veterans with diabetes mellitus type 2 (DM2) and proteinuria. The study exposure was time-varying use of SGLT2i after an index AKI hospitalization. The two study outcomes were time to (1 ) a sustained decrease in eGFR over at least 3 months to <60 ml/min per 1.73 m2 and ≥30% below a post-AKI–updated eGFR and (2 ) recurrent hospitalization with AKI. AKI was defined as a rise in serum creatinine concentration to ≥50% above a moving outpatient creatinine baseline. DM2 was defined by ≥2 billing codes related to DM2 before the index AKI; proteinuria was defined by the most recent albuminuria, proteinuria, or urinalysis test. Veterans were required to have a baseline eGFR and an eGFR 3–12 months after the index AKI hospitalization ≥30 ml/min per 1.73 m2. Results Ten thousand thirty-six Veterans met study inclusion criteria. Two thousand seven hundred and ninety-four (28%) received a SGLT2i. Seven hundred and seventy-five (8%) had CKD progression, and 1816 (18%) had recurrent AKI over a median follow-up of 1.8 and 1.7 years, respectively, which began 1 year after the index AKI hospitalization. SGLT2i use was associated with lower risk for CKD progression (adjusted hazard ratio 0.72 [95% confidence interval, 0.57 to 0.91]) and for recurrent AKI (adjusted hazard ratio 0.75 [95% confidence interval, 0.65 to 0.88]). Conclusions SGLT2i use was associated with a lower risk for CKD progression and for recurrent AKI among those with diabetic kidney disease and recent AKI.
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Affiliation(s)
- Daniel P. Murphy
- Department of Medicine, Medical School, University of Minnesota, Minneapolis, Minnesota
| | - Julian Wolfson
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Scott Reule
- Department of Medicine, Medical School, University of Minnesota, Minneapolis, Minnesota
- Section of Nephrology, Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota
| | - Kirsten L. Johansen
- Department of Medicine, Medical School, University of Minnesota, Minneapolis, Minnesota
- Division of Nephrology, Hennepin Healthcare, Minneapolis, Minnesota
- Chronic Disease Research Group, Hennepin Healthcare Research Institute, Minneapolis, Minnesota
| | - Areef Ishani
- Department of Medicine, Medical School, University of Minnesota, Minneapolis, Minnesota
- Section of Nephrology, Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota
| | - Paul E. Drawz
- Department of Medicine, Medical School, University of Minnesota, Minneapolis, Minnesota
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9
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Sohn M, Frias JP, Lim S. Cardiovascular efficacy and safety of antidiabetic agents: A network meta-analysis of randomized controlled trials. Diabetes Obes Metab 2023; 25:3560-3577. [PMID: 37649320 DOI: 10.1111/dom.15251] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/18/2023] [Accepted: 08/03/2023] [Indexed: 09/01/2023]
Abstract
AIM An important characteristic of glucose-lowering therapies (GLTs) is their ability to prevent cardiovascular complications. We aimed to investigate the cardiorenal efficacy and general safety of GLTs. MATERIALS AND METHODS Multicentre, randomized, clinical trials that included over 100 participants comparing antidiabetic agents with a placebo or a different antidiabetic agent and reporting major adverse cardiovascular events (MACEs), or primarily reporting heart failure, were searched in the PubMed, Embase and Cochrane databases. Data were extracted independently for random-effects network meta-analyses to calculate the hazard ratio estimates. RESULTS Forty-three trials that compared nine types of GLTs were included in the present analysis. The risk of three-point MACE was reduced in the presence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and thiazolidinedione therapy compared with the placebo, dipeptidyl peptidase-4 inhibitors, or insulin therapy. GLP-1 RAs were favourable for cardiovascular and renal outcomes. SGLT-2is reduced renal outcomes by ~40%, which was superior to other GLTs. Thiazolidinedione therapy increased the risks of hospitalization for heart failure and had no benefits on mortality. Adverse events leading to drug discontinuation were higher with GLP-1 RAs and thiazolidinediones than placebo. CONCLUSIONS GLP-1 RAs, SGLT-2is and thiazolidinediones reduced three-point MACE compared with other GLTs. Each drug class had unique advantages and disadvantages.
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Affiliation(s)
- Minji Sohn
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Juan P Frias
- National Research Institute, Metro Medical Mall, Los Angeles, California, USA
| | - Soo Lim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
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10
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Kolovos S, Bellanca L, Groyer H, Rosano GM, Solé A, Gaultney J, Linden S. Multinational cost-effectiveness analysis of empagliflozin for heart failure patients with ejection fraction >40. ESC Heart Fail 2023; 10:3385-3397. [PMID: 37670496 PMCID: PMC10682900 DOI: 10.1002/ehf2.14470] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 05/02/2023] [Accepted: 06/21/2023] [Indexed: 09/07/2023] Open
Abstract
AIMS Heart failure is a chronic progressive condition, with considerable burden on patients' quality of life and economic burden for the healthcare systems. Before the approval of empagliflozin, there were no proven effective treatments for patients with heart failure with left ventricular ejection fraction (HF LVEF) > 40%. The aim of this study was to evaluate the cost-effectiveness of empagliflozin + standard of care (SoC) compared with SoC alone for patients with HF LVEF > 40%, from the perspective of the healthcare systems of the United Kingdom (UK), Spain, and France, and to quantify the healthcare costs for these patients. METHODS AND RESULTS A lifetime Markov cohort state-transition model was developed based on discrete health states defined by Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score quartiles to track disease severity. Model inputs relied primarily on the EMPEROR-Preserved trial data or obtained from published literature or country-specific databases, as well as local guidelines for the requirements for the conduct of the economic evaluation of healthcare technologies. The total lifetime cost of receiving SoC per patient was £10 092, €15 765, and €14 958 in the UK, Spain, and France, respectively, which increased by £1407, €1148, and €1485, respectively, with the addition of empagliflozin to the SoC. Empagliflozin + SoC was associated with significantly reduced number of hospitalization for HF or cardiovascular death compared with SoC alone, which was a key driver offsetting its drug acquisition costs. The incremental cost-effectiveness ratio per quality-adjusted life year (QALY) gained was consistently favourable at £14 851, €11 706, and €15 447 in the UK, Spain, and France, respectively. Scenario analysis using the New York Heart Association functional class showed similar results. Probabilistic sensitivity analyses showed more than 50% probability for cost-effectiveness for a willingness-to-pay (WTP) threshold of £/€20 000/QALY for the three countries. CONCLUSIONS Empagliflozin was found to be the first targeted treatment option that is clinically effective and cost-effective for patients with HF LVEF > 40%. Prescribing empagliflozin with SoC to patients with HF LVEF > 40% is expected to improve clinical outcomes and patients' quality of life and substantially below accepted WTP threshold for the healthcare systems in the UK, Spain, and France.
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Affiliation(s)
| | | | | | | | | | | | - Stephan Linden
- Boehringer Ingelheim International GmbHIngelheim am RheinGermany
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11
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Lin HS, Yang CH, Yin TC, Sung PH, Chiang JY, Shao PL, Chen YL, Huang CR, Yip HK, Chen KH. Addition of adipose tissue-derived mesenchymal stem cells improves empagliflozin therapy for alleviating hyperglycemia--induced neuropathy. Am J Transl Res 2023; 15:6264-6285. [PMID: 37969202 PMCID: PMC10641353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 10/11/2023] [Indexed: 11/17/2023]
Abstract
BACKGROUND We examined the impact of adipose-derived mesenchymal stem cell (ADMSC)-facilitated empagliflozin (EMPA) therapy for alleviating hyperglycemic induced neuropathy [i.e., diabetic neuropathy (DN)]. METHODS Study constituted N2a cell culture and rats to be classified into groups 1 (sham-operated-control)/2 (DN)/3 (DN + empagliflozin/20 mg/kg/daily orally for 6 weeks since post-day-7 DN induction)/4 (DN + ADMSCs/1.2 × 106 cells by vein transfusion at time intervals of 1/3/5 weeks after DN induction)/5 (DN + empagliflozin + ADMSCs) and sacrificed by day-42 after DN induction. RESULTS In vitro results showed that, compared to N2a cells, the cellular levels of senescence/DNA-damage and protein expressions of oxidative-stress (OS), apoptotic, autophagic and inflammatory biomarkers were significantly higher in N2a + glucose (25 mM) but were significantly reversed in N2a + glucose + ADMSCs, whereas the cellular levels of mitochondrial cytochrome C and protein levels of anti-oxidants displayed an opposite pattern of OS (all P<0.001). The above-mentioned parameters (i.e., OS/apoptosis/fibrosis/autophagy/DNA-damage) were lowest in N2a cells, highest in N2a + glucose and significantly higher in N2a + glucose + EMPA (50 μM) than in N2a + glucose + EMPA (150 μM) (all P<0.001). By days 7/14/21/28/35/42 after DN induction, the values of thermal paw-withdrawal-latency (TPWL)/mechanical-paw-withdrawal-threshold were highest in group 1 and significantly progressively increased from groups 2/4/3/5 (all P<0.0001). The cellular levels of unmyelinated C- and myelinated A-δ fibers, and protein levels of OS/apoptotic/DNA-damaged/fibrotic/autophagic/inflammatory/pain-facilitated/voltage-gated sodium channel biomarkers in L4-L5 levels of dorsal-root-ganglia exhibited an contradictory manner of TPWL among the groups (all P<0.0001). CONCLUSIONS Combination of EMPA and ADMSC therapy was superior to either alone for improving outcomes of DN.
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Affiliation(s)
- Hung-Sheng Lin
- Division of Neurology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan
| | - Chien-Hui Yang
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan
| | - Tsung-Cheng Yin
- Department of Orthopaedic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan
| | - Pei-Hsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan
| | - John Y Chiang
- Department of Computer Science and Engineering, National Sun Yat-Sen UniversityKaohsiung 80424, Taiwan
| | - Pei-Lin Shao
- Department of Nursing, Asia UniversityTaichung 41354, Taiwan
| | - Yi-Ling Chen
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan
| | - Chi-Ruei Huang
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan
- Department of Nursing, Asia UniversityTaichung 41354, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial HospitalKaohsiung 83301, Taiwan
- School of Medicine, College of Medicine, Chang Gung UniversityTaoyuan 333, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial HospitalKaohsiung 83301, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical UniversityTaichung 40402, Taiwan
| | - Kuan-Hung Chen
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan
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12
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Chandrasekar B, Mummidi S, DeMarco VG, Higashi Y. Empagliflozin Reverses Oxidized LDL-Induced RECK Suppression, Cardiotrophin-1 Expression, MMP Activation, and Human Aortic Smooth Muscle Cell Proliferation and Migration. Mediators Inflamm 2023; 2023:6112301. [PMID: 37830075 PMCID: PMC10567511 DOI: 10.1155/2023/6112301] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/04/2023] [Accepted: 09/07/2023] [Indexed: 10/14/2023] Open
Abstract
Persistent oxidative stress and inflammation contribute causally to smooth muscle cell (SMC) proliferation and migration, the characteristic features of vascular proliferative diseases. Oxidatively modified low-density lipoproteins (OxLDL) elevate oxidative stress levels, inflammatory responses, and matrix metallopeptidase (MMP) activation, resulting ultimately in SMC migration, proliferation, and phenotype change. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a membrane-anchored MMP inhibitor. Empagliflozin is an SGLT2 inhibitor and exerts pleiotropic cardiovascular protective effects, including antioxidant and anti-inflammatory effects. Here, we investigated (i) whether OxLDL regulates RECK expression, (ii) whether ectopic expression of RECK reverses OxLDL-induced SMC migration and proliferation, and (iii) whether pretreatment with empagliflozin reverses OxLDL-induced RECK suppression, MMP activation, and SMC migration, proliferation, and differentiation. Indeed, results show that OxLDL at pathophysiological concentration promotes SMC migration and proliferation via NF-κB/miR-30b-dependent RECK suppression. Moreover, OxLDL changed the SMC phenotype to a more pro-inflammatory type, and this effect is blunted by RECK overexpression. Further, treatment with empagliflozin reversed OxLDL-induced miR-30b induction, RECK suppression, MMP activation, SMC migration, proliferation, and proinflammatory phenotype changes. OxLDL-induced cardiotrophin (CT)-1 expression and CT-1 stimulated SMC proliferation and migration in part via leukemia inhibitory factor receptor (LIFR) and glycoprotein 130 (gp130). Ectopic expression of RECK inhibited these effects by physically associating with LIFR and gp130, as evidenced by immunoprecipitation/immunoblotting and double immunofluorescence. Importantly, empagliflozin inhibited CT-1-induced mitogenic and migratory effects. Together, these results suggest the therapeutic potential of sustaining RECK expression or empagliflozin in vascular diseases characterized by SMC proliferation and migration.
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Affiliation(s)
- Bysani Chandrasekar
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA
- Medicine, University of Missouri School of Medicine, Columbia, MO, USA
- Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA
- Dalton Cardiovascular Center, University of Missouri, Columbia, MO, USA
| | - Srinivas Mummidi
- Life Sciences, Texas A&M University-San Antonio, San Antonio, TX, USA
| | - Vincent G. DeMarco
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA
- Medicine, University of Missouri School of Medicine, Columbia, MO, USA
- Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA
| | - Yusuke Higashi
- Medicine/Cardiology, Tulane University School of Medicine, New Orleans, LA, USA
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13
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Khunti K, Almalki M, Chan JCN, Amod A. The Role of Real-World Evidence in Treatment Decision-Making, Regulatory Assessment, and Understanding the Perspectives of People with Type 2 Diabetes: Examples with Gliclazide MR. Diabetes Ther 2023; 14:1609-1625. [PMID: 37603144 PMCID: PMC10499769 DOI: 10.1007/s13300-023-01458-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 07/28/2023] [Indexed: 08/22/2023] Open
Abstract
Real-world evidence (RWE) plays an important role in the management of type 2 diabetes (T2D). It provides data about the effectiveness and safety of an intervention from outside the randomised controlled trial (RCT) setting and allows healthcare professionals (HCPs) to determine if RCT data are applicable to their patients in routine clinical practice. This review provides a discussion of the value of RWE in T2D management in day-to-day clinical practice, with a focus on RWE with sulfonylureas (SUs), and presents two examples of a new generation of international real-world studies in people with T2D managed in routine clinical practice. RWE plays a valuable role in advising HCPs in the day-to-day management of T2D, informing regulatory authorities with regard to pharmacovigilance and post-approval updates, and providing insights with regard to patients' treatment adherence and preference. RWE should be used alongside RCTs to increase HCP awareness and understanding of their patients' perspectives, potentially allowing for improvements in treatment adherence, glycaemic control and health-related quality of life (HRQoL). In addition, real-world studies must be conducted in a way that generates robust RWE by limiting the risks of bias and confounding as much as possible. A growing body of RWE is emerging from Asia. For example, in a preliminary HRQoL analysis of the Joint Asia Diabetes Evaluation (JADE) Register, Asian people with T2D had better HRQoL with gliclazide-based treatment than with other SU agents, despite being older and having more diabetes-related complications.
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Affiliation(s)
- Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, LE5 4PW, UK.
| | - Mussa Almalki
- King Fahad Medical City, Obesity, Endocrine and Metabolism Centre, Riyadh, Saudi Arabia
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Aslam Amod
- Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
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14
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Chen X, Hocher CF, Shen L, Krämer BK, Hocher B. Reno- and cardioprotective molecular mechanisms of SGLT2 inhibitors beyond glycemic control: from bedside to bench. Am J Physiol Cell Physiol 2023; 325:C661-C681. [PMID: 37519230 DOI: 10.1152/ajpcell.00177.2023] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 08/01/2023]
Abstract
Large placebo-controlled clinical trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) delay the deterioration of renal function and reduce cardiovascular events in a glucose-independent manner, thereby ultimately reducing mortality in patients with chronic kidney disease (CKD) and/or heart failure. These existing clinical data stimulated preclinical studies aiming to understand the observed clinical effects. In animal models, it was shown that the beneficial effect of SGLT2i on the tubuloglomerular feedback (TGF) improves glomerular pressure and reduces tubular workload by improving renal hemodynamics, which appears to be dependent on salt intake. High salt intake might blunt the SGLT2i effects on the TGF. Beyond the salt-dependent effects of SGLT2i on renal hemodynamics, SGLT2i inhibited several key aspects of macrophage-mediated renal inflammation and fibrosis, including inhibiting the differentiation of monocytes to macrophages, promoting the polarization of macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype, and suppressing the activation of inflammasomes and major proinflammatory factors. As macrophages are also important cells mediating atherosclerosis and myocardial remodeling after injury, the inhibitory effects of SGLT2i on macrophage differentiation and inflammatory responses may also play a role in stabilizing atherosclerotic plaques and ameliorating myocardial inflammation and fibrosis. Recent studies suggest that SGLT2i may also act directly on the Na+/H+ exchanger and Late-INa in cardiomyocytes thus reducing Na+ and Ca2+ overload-mediated myocardial damage. In addition, the renal-cardioprotective mechanisms of SGLT2i include systemic effects on the sympathetic nervous system, blood volume, salt excretion, and energy metabolism.
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Affiliation(s)
- Xin Chen
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Carl-Friedrich Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Klinik für Innere Medizin, Bundeswehrkrankenhaus Berlin, Berlin, Germany
| | - Linghong Shen
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bernhard K Krämer
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Berthold Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany
- Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
- Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, China
- IMD Institut für Medizinische Diagnostik Berlin-Potsdam GbR, Berlin, Germany
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15
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Verma S, Kosmopoulos A, Bhatt DL, Fitchett D, Ofstad AP, Wanner C, Mattheus M, Zinman B, Lawler PR, Leiter LA. Generalizability of REDUCE-IT eligibility criteria in a large diabetes cardiovascular outcomes trial: A post hoc subgroup analysis of EMPA-REG outcome: Analysis of EMPA-REG OUTCOME using REDUCE-IT criteria. Am J Prev Cardiol 2023; 15:100510. [PMID: 37384110 PMCID: PMC10293663 DOI: 10.1016/j.ajpc.2023.100510] [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: 02/16/2023] [Revised: 05/19/2023] [Accepted: 06/09/2023] [Indexed: 06/30/2023] Open
Abstract
Objectives REDUCE-IT showed that icosapent ethyl (IPE) improved cardiovascular (CV) outcomes in participants with established CV disease (CVD) or type 2 diabetes (T2D) and at least one additional risk factor plus mild-moderate hypertriglyceridemia and reasonably controlled low-density lipoprotein cholesterol (LDL-C). As the generalizability of REDUCE-IT has not been investigated in a T2D population with established CVD, this post hoc analysis investigated how many participants from EMPA-REG OUTCOME, which tested the effects of empagliflozin versus placebo on CV outcomes in participants with T2D and CVD, would have been eligible for IPE treatment, and whether CV outcomes differed based on eligibility for IPE treatment. Methods Participants from EMPA-REG OUTCOME were screened for inclusion using both REDUCE-IT-like criteria (baseline statin therapy, triglycerides 135-499 mg/dL and LDL-C 41-100 mg/dL) and slightly amended FDA indication criteria (triglycerides ≥150 mg/dL). Analyses were conducted to characterize the study population and CV outcomes in participants eligible for IPE versus those not eligible for IPE. Results Of the 7020 participants from EMPA-REG OUTCOME, 1810 (25.8%) fulfilled REDUCE-IT criteria and 3182 (45.3%) fulfilled FDA criteria for IPE treatment. Treatment effects of empagliflozin versus placebo on CV and kidney outcomes and mortality were consistent in participants meeting REDUCE-IT and FDA criteria and those who did not. Conclusions These results indicate that a sizable proportion of patients with diabetes and established CVD, such as those in EMPA-REG OUTCOME, may be eligible for IPE treatment to lower residual CV risk. Treatment benefit with empagliflozin was consistent, regardless of REDUCE-IT or FDA eligibility criteria.
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Affiliation(s)
- Subodh Verma
- Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada
| | - Andrew Kosmopoulos
- Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada
| | - Deepak L. Bhatt
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai Health System, New York City, NY, United States
| | - David Fitchett
- St Michael's Hospital, Division of Cardiology, University of Toronto, Toronto, ON, Canada
| | - Anne Pernille Ofstad
- Boehringer Ingelheim Norway Ks, Asker, Norway
- Oslo Diabetes Research Center, Oslo, Norway
| | | | | | - Bernard Zinman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Patrick R. Lawler
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
| | - Lawrence A. Leiter
- Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, ON, Canada
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16
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Kato S, Kuwatsuka Y, Ando M, Tatematsu Y, Nishibori N, Maruyama S. Rationale and study design of a randomized controlled trial to investigate the renoprotective effect of canagliflozin assessed by test of renal hemodynamics in diabetic kidney disease (the FAGOTTO study). BMC Nephrol 2023; 24:228. [PMID: 37537531 PMCID: PMC10401745 DOI: 10.1186/s12882-023-03277-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 07/20/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are considered to have the potential to maintain renal function by correcting glomerular hypertension in patients with diabetic kidney disease (DKD). The aim of this study is to demonstrate the renoprotective effect of SGLT2i by measuring renal hemodynamics, including glomerular filtration fraction (FF), in type 2 diabetic patients with moderate renal dysfunction. METHODS Renoprotective effect of canagliflozin derived from test of renal hemodynamics in diabetic kidney disease (FAGOTTO) study is a 12-week multicenter, open-label, randomized (1:1), parallel-group trial of type 2 diabetic patients with diabetic kidney disease (30 ≤ estimated glomerular filtration rate [eGFR] ≤ 60 mL/min/1.73 m2). A total of 110 patients are to be randomly allocated to receive once-daily canagliflozin 100 mg or control (standard therapy). FF will be calculated by dividing the measured GFR (mGFR) by the effective renal plasma flow (eRPF). mGFR and eRPF will be measured by the clearance of inulin and para-aminohippuric acid (PAH), respectively. The primary endpoint of this trial is the percentage change in FF after 4 weeks of treatment in the canagliflozin and control groups. DISCUSSION The FAGOTTO study will elucidate the mechanism of the renoprotective action of SGLT2i. The background, rationale, and study design of this trial are presented. To date, > 80 patients have been enrolled in this trial. The study will end in 2025. TRIAL REGISTRATION jRCT (Japan Registry Of Clinical Trials) jRCTs041200069. Date of registration: November 27, 2020.
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Affiliation(s)
- Sawako Kato
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65, Tsuruma-Cho, Showa-Ku, Nagoya, Aichi, 464-8550, Japan.
| | - Yachiyo Kuwatsuka
- Department of Advanced Medicine, Nagoya University Hospital, Aichi, Japan
| | - Masahiko Ando
- Department of Advanced Medicine, Nagoya University Hospital, Aichi, Japan
| | - Yoshitaka Tatematsu
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65, Tsuruma-Cho, Showa-Ku, Nagoya, Aichi, 464-8550, Japan
| | - Nobuhiro Nishibori
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65, Tsuruma-Cho, Showa-Ku, Nagoya, Aichi, 464-8550, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65, Tsuruma-Cho, Showa-Ku, Nagoya, Aichi, 464-8550, Japan
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Frąk W, Hajdys J, Radzioch E, Szlagor M, Młynarska E, Rysz J, Franczyk B. Cardiovascular Diseases: Therapeutic Potential of SGLT-2 Inhibitors. Biomedicines 2023; 11:2085. [PMID: 37509724 PMCID: PMC10377079 DOI: 10.3390/biomedicines11072085] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 06/21/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
Cardiovascular diseases (CVD) are a global health concern, affecting millions of patients worldwide and being the leading cause of global morbidity and mortality, thus creating a major public health concern. Sodium/glucose cotransporter 2 (SGLT2) inhibitors have emerged as a promising class of medications for managing CVD. Initially developed as antihyperglycemic agents for treating type 2 diabetes, these drugs have demonstrated significant cardiovascular benefits beyond glycemic control. In our paper, we discuss the role of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and the relatively recently approved bexagliflozin, the class of SGLT-2 inhibitors, as potential therapeutic targets for cardiovascular diseases. All mentioned SGLT-2 inhibitors have demonstrated significant cardiovascular benefits and renal protection in clinical trials, in patients with or without type 2 diabetes. These novel therapeutic approaches aim to develop more effective treatments that improve patient outcomes and reduce the burden of these conditions. However, the major scientific achievements of recent years and the many new discoveries and mechanisms still require careful attention and additional studies.
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Affiliation(s)
- Weronika Frąk
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Żeromskiego 113, 90-549 Łódź, Poland
| | - Joanna Hajdys
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Żeromskiego 113, 90-549 Łódź, Poland
| | - Ewa Radzioch
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Żeromskiego 113, 90-549 Łódź, Poland
| | - Magdalena Szlagor
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Żeromskiego 113, 90-549 Łódź, Poland
| | - Ewelina Młynarska
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Żeromskiego 113, 90-549 Łódź, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Żeromskiego 113, 90-549 Łódź, Poland
| | - Beata Franczyk
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Żeromskiego 113, 90-549 Łódź, Poland
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18
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Forzano I, Wilson S, Lombardi A, Jankauskas SS, Kansakar U, Mone P, Varzideh F, Santulli G. SGLT2 inhibitors: an evidence-based update on cardiovascular implications. Expert Opin Investig Drugs 2023; 32:839-847. [PMID: 37740906 PMCID: PMC10591907 DOI: 10.1080/13543784.2023.2263354] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/22/2023] [Indexed: 09/25/2023]
Abstract
INTRODUCTION Sodium Glucose co-Transporter 2 (SGLT2) inhibitors (also known as 'gliflozins') represent a cornerstone to treat diabetes mellitus. Moreover, recent randomized clinical trials have demonstrated important cardioprotective effects of gliflozins, independent of the presence of diabetes. Herein, we summarize the recent therapeutic progress in the cardiovascular field obtained with SGLT2 inhibitors. AREA COVERED We critically examine the rationale and results of recent clinical studies examining the effects of SGLT2 inhibitors on cardiovascular outcomes, along with a brief overview of the main ongoing trials that have been designed in order to answer the many pending questions in the field of gliflozins and cardiovascular disease. EXPERT OPINION The favorable results of several clinical trials have broadened the therapeutic scenario for SGLT2 inhibitors, opening, at the same time, new challenges. Additionally, recent preclinical findings have evidenced off-target effects of SGLT2 inhibitors.
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Affiliation(s)
| | - Scott Wilson
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | - Angela Lombardi
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | | | - Urna Kansakar
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | - Pasquale Mone
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | - Fahimeh Varzideh
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | - Gaetano Santulli
- University of Naples “Federico II”
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
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Severino P, D'Amato A, Prosperi S, Costi B, Angotti D, Birtolo LI, Chimenti C, Lavalle C, Maestrini V, Mancone M, Fedele F. Sodium-glucose cotransporter 2 inhibitors and heart failure: the best timing for the right patient. Heart Fail Rev 2023; 28:709-721. [PMID: 34654997 PMCID: PMC10140096 DOI: 10.1007/s10741-021-10170-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/07/2021] [Indexed: 12/17/2022]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially born as anti-diabetic drugs, have shown many beneficial effects on the cardiovascular system, in particular against heart failure (HF). HF is a complex and multifaceted disease that requires a comprehensive approach. It should not be considered as a simplistic cardiac disease, but a systemic disease that leads to multisystemic organ failure and death. Exploiting their pleiotropic effects, SGLT2i are a very valid tool for HF treatment. Beyond the indication to reduce HF hospitalization and death risk, in patients with diabetes mellitus at high cardiovascular risk or with established cardiovascular event, SGLT2i administration reported beneficial effects regarding the wide spectrum of HF manifestations and stages, independently by diabetes mellitus presence. Recent evidence focuses on HF rehospitalization, cardiac and all-cause death reduction, as well as symptoms and quality of life improvement, in patients with chronic HF or with a recent HF decompensation episode. Given the recent finding about the SGLT2i usefulness in HF patients, further studies are needed to define the best administration timing to maximize the SGLT2i-derived beneficial effects.
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Affiliation(s)
- Paolo Severino
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy.
| | - Andrea D'Amato
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Silvia Prosperi
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Bettina Costi
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Danilo Angotti
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Lucia Ilaria Birtolo
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Cristina Chimenti
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Carlo Lavalle
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Viviana Maestrini
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Massimo Mancone
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
| | - Francesco Fedele
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161, Rome, Italy
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20
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Hoehlschen J, Hofreither D, Tomin T, Birner-Gruenberger R. Redox-driven cardioprotective effects of sodium-glucose co-transporter-2 inhibitors: comparative review. Cardiovasc Diabetol 2023; 22:101. [PMID: 37120524 PMCID: PMC10148992 DOI: 10.1186/s12933-023-01822-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/03/2023] [Indexed: 05/01/2023] Open
Abstract
Sodium-glucose co-transporter-2 inhibitors are used in the treatment of diabetes but are also emerging as cardioprotective agents in heart diseases even in the absence of type 2 diabetes. In this paper, upon providing a short overview of common pathophysiological features of diabetes, we review the clinically reported cardio- and nephroprotective potential of sodium-glucose co-transporter-2 inhibitors currently available on the market, including Dapagliflozin, Canagliflozin, and Empagliflozin. To that end, we summarize findings of clinical trials that have initially drawn attention to the drugs' organ-protective potential, before providing an overview of their proposed mechanism of action. Since we particularly expect that their antioxidative properties will broaden the application of gliflozins from therapeutic to preventive care, special emphasis was put on this aspect.
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Affiliation(s)
- Julia Hoehlschen
- Institute of Chemical Technologies and Analytics, TU Wien, Wien, Austria
| | - Dominik Hofreither
- Institute of Chemical Technologies and Analytics, TU Wien, Wien, Austria
| | - Tamara Tomin
- Institute of Chemical Technologies and Analytics, TU Wien, Wien, Austria.
| | - Ruth Birner-Gruenberger
- Institute of Chemical Technologies and Analytics, TU Wien, Wien, Austria.
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria.
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21
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Salem AM, Harris D, Bray JJH, Obaid DR, Stephens JW, Halcox J. Achievement of the ESC recommendations for secondary prevention of cardiovascular risk factors in high-risk patients with type 2 diabetes: A real-world national cohort analysis. Int J Cardiol 2023; 377:104-111. [PMID: 36764610 DOI: 10.1016/j.ijcard.2023.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 01/31/2023] [Accepted: 02/03/2023] [Indexed: 02/11/2023]
Abstract
AIM To assess compliance with European Society of Cardiology (ESC) secondary prevention recommendations in a nationwide contemporary population with diabetes mellitus (DM) and coronary artery disease. METHOD We conducted a retrospective observational study using linked health data in patients across Wales with DM undergoing percutaneous coronary intervention (2012-2017). The follow-up was for one year. We analysed the clinical characteristics, medications, target levels for HbA1c, low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C) and blood pressure against the ESC prevention guidelines. RESULTS Overall, 3478 patients with diabetes had available data at 1-year post-PCI. Only 43% had HbA1c levels <53 mmol/L, but 81% had blood pressure < 140/80 (current ESC targets). Prescribing frequency of the newer hypoglycaemic agents (glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors) was suboptimal, with a higher rate in patients with HbA1c ≥53 mmol/mol. Only 51% & 27% of the patients had LDL-C levels <1.8 &1.4 mmol/L (2016 & 2019 guidelines recommendations respectively), and 55% & 34% had non-HDL-C levels <2.6 & 2.2 mmol/L (2016 & 2019 guidelines respectively). Of the uncontrolled LDL-C patients, 42% (2016 target) and 35% (2019 target) were prescribed high-intensity statins. Females were more likely to have LDL-C targets above the recommended level. CONCLUSION Achievement of ESC treatment goals in this very-high risk cohort for DM and hyperlipidaemia was far from optimal, with a low prescription rate of the guidelines-recommended therapy. Target goals for hypertension were met more frequently. An up-to-date analysis reflecting the current practice against the most recent guidelines is warranted.
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Affiliation(s)
- Ahmed M Salem
- Cardiology Department, Swansea Bay University Health Board, United Kingdom; Institute of Life Sciences-2, Swansea University Medical School, United Kingdom.
| | - Daniel Harris
- Cardiology Department, Swansea Bay University Health Board, United Kingdom; Institute of Life Sciences-2, Swansea University Medical School, United Kingdom
| | - Jonathan J H Bray
- Institute of Life Sciences-2, Swansea University Medical School, United Kingdom
| | - Daniel R Obaid
- Cardiology Department, Swansea Bay University Health Board, United Kingdom; Institute of Life Sciences-2, Swansea University Medical School, United Kingdom
| | - Jeffrey W Stephens
- Institute of Life Sciences-2, Swansea University Medical School, United Kingdom; Department of Diabetes and Endocrinology, Swansea Bay University Health Board, United Kingdom
| | - Julian Halcox
- Cardiology Department, Swansea Bay University Health Board, United Kingdom; Institute of Life Sciences-2, Swansea University Medical School, United Kingdom
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22
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Liang B, Li R, Zhang P, Gu N. Empagliflozin for Patients with Heart Failure and Type 2 Diabetes Mellitus: Clinical Evidence in Comparison with Other Sodium-Glucose Co-transporter-2 Inhibitors and Potential Mechanism. J Cardiovasc Transl Res 2023; 16:327-340. [PMID: 35969357 DOI: 10.1007/s12265-022-10302-4] [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: 04/02/2022] [Accepted: 08/05/2022] [Indexed: 11/25/2022]
Abstract
Heart failure remains a leading cause of morbidity and mortality globally and has been recognized as a common complication of diabetes, especially type 2 diabetes mellitus. Heart failure occurs in diabetic patients even in the absence of hypertension, coronary heart disease, or valvular heart disease, and is, therefore, a major cardiovascular complication in this vulnerable population. Given the continued rise in the prevalence of type 2 diabetes mellitus worldwide, the burden of heart failure on the healthcare system will continue to increase. Recent evidence demonstrates that empagliflozin, a sodium-glucose co-transporter-2 inhibitor, brings clinical benefit to patients with established heart failure and type 2 diabetes mellitus. Herein, we critically reviewed the clinical evidence of empagliflozin for patients with heart failure and type 2 diabetes mellitus with the comparison with other sodium-glucose co-transporter-2 inhibitors and potential mechanism to provide the optimal and evidence-based management for patients with established heart failure and type 2 diabetes mellitus with the goal to be conducive to the mechanism exploration of empagliflozin to advance a more comprehensive understanding of empagliflozin.
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Affiliation(s)
- Bo Liang
- Nanjing University of Chinese Medicine, Nanjing, China
- Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Rui Li
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Peng Zhang
- Neijiang Health Vocational College, Neijiang, China
| | - Ning Gu
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
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23
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Clinical Study of Metabolic Parameters, Leptin and the SGLT2 Inhibitor Empagliflozin among Patients with Obesity and Type 2 Diabetes. Int J Mol Sci 2023; 24:ijms24054405. [PMID: 36901837 PMCID: PMC10002958 DOI: 10.3390/ijms24054405] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/19/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023] Open
Abstract
Obesity is a major public health problem worldwide, and it is associated with many diseases and abnormalities, most importantly, type 2 diabetes. The visceral adipose tissue produces an immense variety of adipokines. Leptin is the first identified adipokine which plays a crucial role in the regulation of food intake and metabolism. Sodium glucose co-transport 2 inhibitors are potent antihyperglycemic drugs with various beneficial systemic effects. We aimed to investigate the metabolic state and leptin level among patients with obesity and type 2 diabetes mellitus, and the effect of empagliflozin upon these parameters. We recruited 102 patients into our clinical study, then we performed anthropometric, laboratory, and immunoassay tests. Body mass index, body fat, visceral fat, urea nitrogen, creatinine, and leptin levels were significantly lower in the empagliflozin treated group when compared to obese and diabetic patients receiving conventional antidiabetic treatments. Interestingly, leptin was increased not only among obese patients but in type 2 diabetic patients as well. Body mass index, body fat, and visceral fat percentages were lower, and renal function was preserved in patients receiving empagliflozin treatment. In addition to the known beneficial effects of empagliflozin regarding the cardio-metabolic and renal systems, it may also influence leptin resistance.
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24
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Ghetti G, Pradelli L, Papageorgiou G, Karpouzos G, Arikan Y. CELESTIA: Cost-Effectiveness Analysis of Empagliflozin Versus Sitagliptin in Patients with Type 2 Diabetes in Greece. CLINICOECONOMICS AND OUTCOMES RESEARCH 2023; 15:97-109. [PMID: 36825076 PMCID: PMC9942503 DOI: 10.2147/ceor.s400522] [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: 12/06/2022] [Accepted: 02/03/2023] [Indexed: 02/19/2023] Open
Abstract
Purpose Globally, the prevalence of diabetes is on the rise, with the number of affected individuals predicted to cross 700 million by 2045. In Greece, in 2015, almost 700,000 people received prescribed medication for type 2 diabetes. The CELESTIA study aims to assess the cost-effectiveness of empagliflozin compared to branded sitagliptin in type 2 diabetes patients both with and without established cardiovascular disease in Greece from a third payer perspective. Methods The IQVIA Core Diabetes Model was used and analyses were conducted from the Greek healthcare payer perspective. Patients received either empagliflozin or sitagliptin until HbA1c threshold of 8.5% (69 mmol/mol) was exceeded. Subsequently, patients were assumed to intensify to insulin therapy. Baseline cohort characteristics and treatment effects were derived from clinical trial data. Literature data were used for input (utilities, treatment costs and costs of diabetes-related complications costs). A lifetime time horizon (50 years) was applied, and costs and benefits were discounted at an annual rate of 3.5%. Results Over a lifetime horizon, for empagliflozin, the estimated ICER was of €6,587 and €966 per quality-adjusted life years gained versus sitagliptin, in patients without established cardiovascular disease and in patients with established cardiovascular disease, respectively. Probabilistic sensitivity analysis confirmed the robustness of the analysis. Conclusion The analysis demonstrated that for type 2 diabetes patients, empagliflozin is a cost-effective treatment option versus branded sitagliptin in Greece.
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Affiliation(s)
- Gianni Ghetti
- AdRes Health Economics and Outcome Research, Turin, Italy,Correspondence: Gianni Ghetti, AdRes Health Economics and Outcome Research, Via Vittorio Alfieri, 17, Turin, 10121, Italy, Email
| | | | | | | | - Yelda Arikan
- Boehringer Ingelheim, Amsterdam, the Netherlands
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25
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Huttunen R, Sainio A, Hjelt A, Haapanen-Saaristo AM, Määttä J, Rummukainen P, Paatero I, Järveläinen H. Distinctive effects of SGLT2 inhibitors on angiogenesis in zebrafish embryos. Biomed Pharmacother 2022; 156:113882. [DOI: 10.1016/j.biopha.2022.113882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/11/2022] [Accepted: 10/13/2022] [Indexed: 11/29/2022] Open
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Zhang Y, Jiang L, Wang J, Wang T, Chien C, Huang W, Fu X, Xiao Y, Fu Q, Wang S, Zhao J. Network meta-analysis on the effects of finerenone versus SGLT2 inhibitors and GLP-1 receptor agonists on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus and chronic kidney disease. Cardiovasc Diabetol 2022; 21:232. [PMID: 36335326 PMCID: PMC9637313 DOI: 10.1186/s12933-022-01676-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE To evaluate the cardiovascular and renal benefits of finerenone, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagonlike peptide-1 receptor agonists (GLP-1 RA) in patients with Type 2 Diabetes Mellitus (T2DM) and chronic kidney disease (CKD) with network meta-analysis. METHODS Systematic literature searches were conducted of PubMed, Cochrane Library, Web of Science, Medline and Embase covering January 1, 2000 to December 30, 2021. Randomized control trials (RCTs) comparing finerenone, SGLT-2i and GLP-1 RA in diabetics with CKD were selected. We performed a network meta-analysis to compare the two drugs and finerenone indirectly. Results were reported as risk ratio (RR) with corresponding 95% confidence interval (CI). RESULTS 18 RCTs involving 51,496 patients were included. Finerenone reduced the risk of major adverse cardiovascular events (MACE), renal outcome and hospitalization for heart failure (HHF) (RR [95% CI]; 0.88 [0.80-0.97], 0.86 [0.79-0.93], 0.79 [0.67,0.92], respectively). SGLT-2i were associated with reduced risks of MACE (RR [95% CI]; 0.84 [0.78-0.90]), renal outcome (RR [95% CI]; 0.67 [0.60-0.74], HHF (RR [95% CI]; 0.60 [0.53-0.68]), all-cause death (ACD) (RR [95% CI]; 0.89 [0.81-0.91]) and cardiovascular death (CVD) (RR [95% CI]; 0.86 [0.77-0.96]) compared to placebo. GLP-1 RA were associated with a lower risk of MACE (RR [95% CI]; 0.86 [0.78-0.94]). SGLT2i had significant effect in comparison to finerenone (finerenone vs SGLT2i: RR [95% CI]; 1.29 [1.13-1.47], 1.31 [1.07-1.61], respectively) and GLP-1 RA (GLP-1 RA vs SGLT2i: RR [95% CI]; 1.36 [1.16-1.59], 1.49 [1.18-1.89], respectively) in renal outcome and HHF. CONCLUSIONS In patients with T2DM and CKD, SGLT2i, GLP-1 RA and finerenone were comparable in MACE, ACD and CVD. SGLT2i significantly decreased the risk of renal events and HHF compared with finerenone and GLP-1 RA. Among GLP-1 RA, GLP-1 analogues showed significant effect in reducing cardiovascular events compared with exendin-4 analogues.
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Affiliation(s)
- Yaofu Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Section II of Endocrinology & Nephropathy Department of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Li Jiang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Section II of Endocrinology & Nephropathy Department of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Junheng Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Section II of Endocrinology & Nephropathy Department of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Tongxin Wang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chieh Chien
- Department of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland
| | - Weijun Huang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Xiaozhe Fu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Section II of Endocrinology & Nephropathy Department of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yonghua Xiao
- Section II of Endocrinology & Nephropathy Department of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Qiang Fu
- Section II of Endocrinology & Nephropathy Department of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Shidong Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
- Section II of Endocrinology & Nephropathy Department of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, China.
| | - Jinxi Zhao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
- Section II of Endocrinology & Nephropathy Department of Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, China.
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Zhang Y, Wang J, Jiang L, Wang T, Li Z, Fu X, Huang W, Xiao Y, Wang S, Zhao J. Network meta-analysis on the efficacy and safety of finerenone versus SGLT2 inhibitors on reducing new-onset of atrial fibrillation in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetol Metab Syndr 2022; 14:156. [PMID: 36303247 PMCID: PMC9609222 DOI: 10.1186/s13098-022-00929-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 10/18/2022] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE To evaluate the efficacy and safety of finerenone and sodium-glucose cotransporter-2 inhibitors (SGLT2i) on reducing new-onset of atrial fibrillation (AF) in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). METHOD We searched the PubMed, Cochrane Library, Web of Science, Medline and Embase covering January 1, 2000 to April 30, 2022. Randomized control trials comparing finerenone or SGLT2i with placebo in patients with T2DM and CKD were selected. Results were reported as risk ratio (RR) with corresponding 95% confidence interval (CI). RESULTS A total of 10 studies (35,841 patients) were included. Finerenone (RR 0.79, 95% CI 0.62-0.99) was associated with a decreased risk of AF compared with placebo, while SGLT2i were not. SGLT2i were associated with a decreased risk of hospitalization for heart failure (RR 0.78, 95% CI 0.63-0.98) compared with finerenone. They were comparable in AF(RR 0.84, 95% CI 0.48,1.46), major adverse cardiovascular events(MACE) (RR 0.93, 95% CI 0.81,1.06) and nonfatal stroke(RR 0.78, 95% CI 0.58,1.05). They both showed no significant risk of adverse events compared with placebo. CONCLUSION There was no significant difference in the reduction of new-onset of atrial fibrillation between Finerenone and SGLT2i based on the indirect comparisons of currently available clinical studies. The large-sampled head-to-head trials was needed for the more precise conclusion.
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Affiliation(s)
- Yaofu Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Junheng Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Li Jiang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Tongxin Wang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhuang Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaozhe Fu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Weijun Huang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yonghua Xiao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Shidong Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
| | - Jinxi Zhao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
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Forst T, Mathieu C, Giorgino F, Wheeler DC, Papanas N, Schmieder RE, Halabi A, Schnell O, Streckbein M, Tuttle KR. New strategies to improve clinical outcomes for diabetic kidney disease. BMC Med 2022; 20:337. [PMID: 36210442 PMCID: PMC9548386 DOI: 10.1186/s12916-022-02539-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 08/23/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. MAIN BODY This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. CONCLUSION With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes.
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Affiliation(s)
- Thomas Forst
- Clinical Research Services, Mannheim GmbH, Grenadierstrasse 1, D-68167, Mannheim, Germany.
| | - Chantal Mathieu
- Department of Endocrinology, UZ Gasthuisberg, Katholieke Universiteit, Leuven, Belgium
| | - Francesco Giorgino
- Department of Emergency and Organ Transplantation Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - David C Wheeler
- Department of Renal Medicine, University College London, London, UK
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Roland E Schmieder
- Department of Nephrology and Hypertension, University Hospital Erlangen, Erlangen, Germany
| | | | | | - Marina Streckbein
- Clinical Research Services, Mannheim GmbH, Grenadierstrasse 1, D-68167, Mannheim, Germany
| | - Katherine R Tuttle
- Division of Nephrology, Institute of Translational Health Sciences, University of Washington, Seattle, WA, USA
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Gliozzi M, Macrì R, Coppoletta AR, Musolino V, Carresi C, Scicchitano M, Bosco F, Guarnieri L, Cardamone A, Ruga S, Scarano F, Nucera S, Mollace R, Bava I, Caminiti R, Serra M, Maiuolo J, Palma E, Mollace V. From Diabetes Care to Heart Failure Management: A Potential Therapeutic Approach Combining SGLT2 Inhibitors and Plant Extracts. Nutrients 2022; 14:nu14183737. [PMID: 36145112 PMCID: PMC9504067 DOI: 10.3390/nu14183737] [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: 05/09/2022] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 11/30/2022] Open
Abstract
Diabetes is a complex chronic disease, and among the affected patients, cardiovascular disease (CVD)is the most common cause of death. Consequently, the evidence for the cardiovascular benefit of glycaemic control may reduce long-term CVD rates. Over the years, multiple pharmacological approaches aimed at controlling blood glucose levels were unable to significantly reduce diabetes-related cardiovascular events. In this view, a therapeutic strategy combining SGLT2 inhibitors and plant extracts might represent a promising solution. Indeed, countering the main cardiometabolic risk factor using plant extracts could potentiate the cardioprotective action of SGLT2 inhibitors. This review highlights the main molecular mechanisms underlying these beneficial effects that could contribute to the better management of diabetic patients.
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Affiliation(s)
- Micaela Gliozzi
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Roberta Macrì
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Anna Rita Coppoletta
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Vincenzo Musolino
- Pharmaceutical Biology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
- Correspondence: (V.M.); (C.C.); Tel./Fax: +39-0961-3694301 (V.M. & C.C.)
| | - Cristina Carresi
- Veterinary Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
- Correspondence: (V.M.); (C.C.); Tel./Fax: +39-0961-3694301 (V.M. & C.C.)
| | - Miriam Scicchitano
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Francesca Bosco
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Lorenza Guarnieri
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Antonio Cardamone
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Stefano Ruga
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Federica Scarano
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Saverio Nucera
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Rocco Mollace
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Irene Bava
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Rosamaria Caminiti
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Maria Serra
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Jessica Maiuolo
- Pharmaceutical Biology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Ernesto Palma
- Veterinary Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Vincenzo Mollace
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
- Renato Dulbecco Institute, Lamezia Terme, 88046 Catanzaro, Italy
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Lv K, Ying H, Hu G, Hu J, Jian Q, Zhang F. Integrated multi-omics reveals the activated retinal microglia with intracellular metabolic reprogramming contributes to inflammation in STZ-induced early diabetic retinopathy. Front Immunol 2022; 13:942768. [PMID: 36119084 PMCID: PMC9479211 DOI: 10.3389/fimmu.2022.942768] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/08/2022] [Indexed: 12/14/2022] Open
Abstract
Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness among working-age people. Inflammation is recognized as a critical driver of the DR process. However, the main retina-specific cell type producing pro-inflammatory cytokines and its mechanism underlying DR are still unclear. Here, we used single-cell sequencing to identify microglia with metabolic pathway alterations that were the main source of IL-1β in STZ-induced DR mice. To profile the full extent of local metabolic shifts in activated microglia and to reveal the metabolic microenvironment contributing to immune mechanisms, we performed integrated metabolomics, lipidomics, and RNA profiling analyses in microglia cell line samples representative of the DR microenvironment. The results showed that activated microglia with IL-1β increase exhibited a metabolic bias favoring glycolysis, purine metabolism, and triacylglycerol synthesis, but less Tricarboxylic acid (TCA). In addition, some of these especially glycolysis was necessary to facilitate their pro-inflammation. These findings suggest that activated microglia with intracellular metabolic reprogramming in retina may contribute to pro-inflammation in the early DR.
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Affiliation(s)
- Kangjia Lv
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Ying
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guangyi Hu
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Hu
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qizhi Jian
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fang Zhang
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Fang Zhang,
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31
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Tao LC, Wang TT, Zheng L, Hua F, Li JJ. The Role of Mitochondrial Biogenesis Dysfunction in Diabetic Cardiomyopathy. Biomol Ther (Seoul) 2022; 30:399-408. [PMID: 35410981 PMCID: PMC9424338 DOI: 10.4062/biomolther.2021.192] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/28/2022] [Accepted: 02/22/2022] [Indexed: 11/26/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is described as abnormalities of myocardial structure and function in diabetic patients without other well-established cardiovascular factors. Although multiple pathological mechanisms involving in this unique myocardial disorder, mitochondrial dysfunction may play an important role in its development of DCM. Recently, considerable progresses have suggested that mitochondrial biogenesis is a tightly controlled process initiating mitochondrial generation and maintaining mitochondrial function, appears to be associated with DCM. Nonetheless, an outlook on the mechanisms and clinical relevance of dysfunction in mitochondrial biogenesis among patients with DCM is not completely understood. In this review, hence, we will summarize the role of mitochondrial biogenesis dysfunction in the development of DCM, especially the molecular underlying mechanism concerning the signaling pathways beyond the stimulation and inhibition of mitochondrial biogenesis. Additionally, the evaluations and potential therapeutic strategies regarding mitochondrial biogenesis dysfunction in DCM is also presented.
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Affiliation(s)
- Li-Chan Tao
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Ting-ting Wang
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Lu Zheng
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Fei Hua
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Jian-Jun Li
- State Key Laboratory of Cardiovascular Diseases, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
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Thirumathyam R, Richter EA, Goetze JP, Fenger M, Van Hall G, Dixen U, Holst JJ, Madsbad S, Vejlstrup N, Madsen PL, Jørgensen NB. Investigating the roles of hyperglycaemia, hyperinsulinaemia and elevated free fatty acids in cardiac function in patients with type 2 diabetes via treatment with insulin compared with empagliflozin: protocol for the HyperCarD2 randomised, crossover trial. BMJ Open 2022; 12:e054100. [PMID: 35953245 PMCID: PMC9379482 DOI: 10.1136/bmjopen-2021-054100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
INTRODUCTION Type 2 diabetes (T2D) is characterised by elevated plasma glucose, free fatty acid (FFA) and insulin concentrations, and this metabolic profile is linked to diabetic cardiomyopathy, a diastolic dysfunction at first and increased cardiovascular disease (CVD) risk. Shifting cardiac metabolism towards glucose utilisation has been suggested to improve cardiovascular function and CVD risk, but insulin treatment increases overall glucose oxidation and lowers lipid oxidation, without reducing CVD risk, whereas SGLT2 inhibitors (SGLT2i) increase FFA, ketone body concentrations and lipid oxidation, while decreasing insulin concentrations and CVD risk. The aim of the present study is to elucidate the importance of different metabolic profiles obtained during treatment with a SGLT2i versus insulin for myocardial function in patients with T2D. METHODS AND ANALYSES Randomised, crossover study, where 20 patients with T2D and body mass index>28 kg/m2 receive 25 mg empagliflozin daily or NPH insulin two times per day first for 5 weeks followed by a 3-week washout before crossing over to the remaining treatment. Insulin treatment is titrated to achieve similar glycaemic control as with empagliflozin. In those randomised to insulin first, glycaemia during an initial empagliflozin run-in period prior to randomisation serves as target glucose. Metabolic and cardiac evaluation is performed before and at the end of each treatment period.The primary endpoint is change (treatment-washout) in left ventricular peak filling rate, as assessed by cardiac MRI with and without acute lowering of plasma FFAs with acipimox. Secondary and explorative endpoints are changes in left atrial passive emptying fraction, left ventricular ejection fraction, central blood volume and metabolic parameters. ETHICS AND DISSEMINATION This study is approved by the Danish Medicines Agency (ref. nr.: 2017061587), the Danish Data Protection Agency (ref. nr.: AHH-2017-093) and the Capital Region Ethics Committee (ref. nr.: H-17018846). The trial will be conducted in accordance with ICH-GCP guidelines and the Declaration of Helsinki and all participants will provide oral and written informed consent. Our results, regardless of outcome, will be published in relevant scientific journals and we also will seek to disseminate results through presentations at scientific meetings. TRIAL REGISTRATION NUMBER EudraCT: 2017-002101.
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Affiliation(s)
| | - Erik Arne Richter
- Department of Nutrition, Exercise and Sports, Section of Molecular Physiology, Faculty of Science, University of Copenhagen, Kobenhavn, Denmark
| | - Jens Peter Goetze
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Kobenhavn, Denmark
| | - Mogens Fenger
- Department of Clinical Biochemistry, Hvidovre Hospital, Hvidovre, Denmark
| | - Gerrit Van Hall
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Kobenhavn, Denmark
- Clinical Metabolomics Core Facility, Clinical Biochemistry, Rigshospitalet, Kobenhavn, Denmark
| | - Ulrik Dixen
- Department of Cardiology, Hvidovre University Hospital, Hvidovre, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Kobenhavn, Denmark
- NovoNordisk Center for Basic Metabolic Research, University of Copenhagen, Kobenhavn, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
| | - Niels Vejlstrup
- Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
| | - Per Lav Madsen
- Department of Cardiology, Herlev Hospital, Herlev, Denmark
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Miyamoto S, Heerspink HJL, de Zeeuw D, Toyoda M, Suzuki D, Hatanaka T, Nakamura T, Kamei S, Murao S, Hida K, Ando S, Akai H, Takahashi Y, Koya D, Kitada M, Sugano H, Nunoue T, Nakamura A, Sasaki M, Nakatou T, Fujimoto K, Kawanami D, Wada T, Miyatake N, Yoshida M, Shikata K, the CANPIONE study Investigators. Rationale, design and baseline characteristics of the effect of canagliflozin in patients with type 2 diabetes and microalbuminuria in the Japanese population: The CANPIONE study. Diabetes Obes Metab 2022; 24:1429-1438. [PMID: 35491532 PMCID: PMC9545385 DOI: 10.1111/dom.14731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 04/08/2022] [Accepted: 04/26/2022] [Indexed: 11/28/2022]
Abstract
AIM To evaluate the effect of canagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, on albuminuria and the decline of estimated glomerular filtration rate (eGFR) in participants with type 2 diabetes and microalbuminuria. METHODS The CANPIONE study is a multicentre, randomized, parallel-group and open-labelled study consisting of a unique 24-week preintervention period, during which the rate of eGFR decline before intervention is estimated, followed by a 52-week intervention and a 4-week washout period. Participants with a geometric mean urinary albumin-to-creatinine ratio (UACR) of 50 and higher and less than 300 mg/g in two consecutive first-morning voids at two different time points, and an eGFR of 45 ml/min/1.73m2 or higher, are randomly assigned to receive canagliflozin 100 mg daily or to continue guideline-recommended treatment, except for SGLT2 inhibitors. The first primary outcome is the change in UACR, and the second primary outcome is the change in eGFR slope. RESULTS A total of 258 participants were screened and 98 were randomized at 21 sites in Japan from August 2018 to May 2021. The mean baseline age was 61.4 years and 25.8% were female. The mean HbA1c was 7.9%, mean eGFR was 74.1 ml/min/1.73m2 and median UACR was 104.2 mg/g. CONCLUSIONS The CANPIONE study will determine whether the SGLT2 inhibitor canagliflozin can reduce albuminuria and slow eGFR decline in participants with type 2 diabetes and microalbuminuria.
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Affiliation(s)
- Satoshi Miyamoto
- Center for Innovative Clinical MedicineOkayama University HospitalOkayamaJapan
| | - Hiddo J. L. Heerspink
- Department of Clinical Pharmacy and PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Dick de Zeeuw
- Department of Clinical Pharmacy and PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Masao Toyoda
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal MedicineTokai University School of MedicineIseharaJapan
| | | | - Takashi Hatanaka
- Department of Diabetes and EndocrinologyNational Hospital Organization Fukuyama Medical CenterFukuyamaJapan
| | - Tohru Nakamura
- Diabetes Internal MedicineSumitomo Besshi HospitalNihamaJapan
| | - Shinji Kamei
- Department of Diabetic MedicineKurashiki Central HospitalKurashikiJapan
| | - Satoshi Murao
- Department of Diabetes and EndocrinologyTakamatsu HospitalTakamatsuJapan
| | - Kazuyuki Hida
- Department of Diabetology and MetabolismNational Hospital Organization Okayama Medical CenterOkayamaJapan
| | - Shinichiro Ando
- Department of Internal Medicine Diabetic CenterOkayama City HospitalOkayamaJapan
| | - Hiroaki Akai
- Division of Diabetes and Metabolism, Faculty of MedicineTohoku Medical and Pharmaceutical UniversitySendaiJapan
| | | | - Daisuke Koya
- Department of Diabetology and EndocrinologyKanazawa Medical UniversityUchinadaJapan
- Division of Anticipatory Molecular Food Science and Technology, Medical Research InstituteKanazawa Medical UniversityUchinadaJapan
- Omi Medical CenterKusatsuJapan
| | - Munehiro Kitada
- Department of Diabetology and EndocrinologyKanazawa Medical UniversityUchinadaJapan
- Division of Anticipatory Molecular Food Science and Technology, Medical Research InstituteKanazawa Medical UniversityUchinadaJapan
| | - Hisashi Sugano
- Department of Diabetes and EndocrinologyKochi Health Sciences CenterKochiJapan
| | | | | | - Motofumi Sasaki
- Department of Diabetes and EndocrinologyMatsue City HospitalMatsueJapan
| | | | - Kei Fujimoto
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal MedicineThe Jikei University Kashiwa HospitalKashiwaJapan
| | - Daiji Kawanami
- Department of Endocrinology and Diabetes MellitusFukuoka University School of MedicineFukuokaJapan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Graduate School of Medical SciencesKanazawa UniversityKanazawaJapan
| | - Nobuyuki Miyatake
- Department of Hygiene, Faculty of MedicineKagawa UniversityMikiKagawaJapan
| | - Michihiro Yoshida
- Center for Innovative Clinical MedicineOkayama University HospitalOkayamaJapan
| | - Kenichi Shikata
- Center for Innovative Clinical MedicineOkayama University HospitalOkayamaJapan
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Zügner E, Yang HC, Kotzbeck P, Boulgaropoulos B, Sourij H, Hagvall S, Elmore CS, Esterline R, Moosmang S, Oscarsson J, Pieber TR, Peng XR, Magnes C. Differential In Vitro Effects of SGLT2 Inhibitors on Mitochondrial Oxidative Phosphorylation, Glucose Uptake and Cell Metabolism. Int J Mol Sci 2022; 23:ijms23147966. [PMID: 35887308 PMCID: PMC9319636 DOI: 10.3390/ijms23147966] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 07/07/2022] [Accepted: 07/09/2022] [Indexed: 02/04/2023] Open
Abstract
(1) The cardio-reno-metabolic benefits of the SGLT2 inhibitors canagliflozin (cana), dapagliflozin (dapa), ertugliflozin (ertu), and empagliflozin (empa) have been demonstrated, but it remains unclear whether they exert different off-target effects influencing clinical profiles. (2) We aimed to investigate the effects of SGLT2 inhibitors on mitochondrial function, cellular glucose-uptake (GU), and metabolic pathways in human-umbilical-vein endothelial cells (HUVECs). (3) At 100 µM (supra-pharmacological concentration), cana decreased ECAR by 45% and inhibited GU (IC5o: 14 µM). At 100 µM and 10 µM (pharmacological concentration), cana increased the ADP/ATP ratio, whereas dapa and ertu (3, 10 µM, about 10× the pharmacological concentration) showed no effect. Cana (100 µM) decreased the oxygen consumption rate (OCR) by 60%, while dapa decreased it by 7%, and ertu and empa (all 100 µM) had no significant effect. Cana (100 µM) inhibited GLUT1, but did not significantly affect GLUTs’ expression levels. Cana (100 µM) treatment reduced glycolysis, elevated the amino acids supplying the tricarboxylic-acid cycle, and significantly increased purine/pyrimidine-pathway metabolites, in contrast to dapa (3 µM) and ertu (10 µM). (4) The results confirmed cana´s inhibition of mitochondrial activity and GU at supra-pharmacological and pharmacological concentrations, whereas the dapa, ertu, and empa did not show effects even at supra-pharmacological concentrations. At supra-pharmacological concentrations, cana (but not dapa or ertu) affected multiple cellular pathways and inhibited GLUT1.
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Affiliation(s)
- Elmar Zügner
- Institute for Biomedicine and Health Sciences (HEALTH), Joanneum Research Forschungsgesellschaft m.b.H, Neue Stiftingtalstrasse 2, 8010 Graz, Austria; (E.Z.); (B.B.); (T.R.P.)
| | - Hsiu-Chiung Yang
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden; (H.-C.Y.); (S.H.); (S.M.)
| | - Petra Kotzbeck
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; (P.K.); (H.S.)
- Cooperative Centre for Regenerative Medicine (COREMED), Joanneum Research Forschungsgesellschaft m.b.H, Neue Stiftingtalstrasse 2, 8010 Graz, Austria
- Research Unit for Tissue Regeneration, Repair and Reconstruction, Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria
| | - Beate Boulgaropoulos
- Institute for Biomedicine and Health Sciences (HEALTH), Joanneum Research Forschungsgesellschaft m.b.H, Neue Stiftingtalstrasse 2, 8010 Graz, Austria; (E.Z.); (B.B.); (T.R.P.)
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; (P.K.); (H.S.)
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; (P.K.); (H.S.)
| | - Sepideh Hagvall
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden; (H.-C.Y.); (S.H.); (S.M.)
| | | | - Russell Esterline
- Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA; (R.E.); (J.O.)
| | - Sven Moosmang
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden; (H.-C.Y.); (S.H.); (S.M.)
| | - Jan Oscarsson
- Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD 20878, USA; (R.E.); (J.O.)
| | - Thomas R. Pieber
- Institute for Biomedicine and Health Sciences (HEALTH), Joanneum Research Forschungsgesellschaft m.b.H, Neue Stiftingtalstrasse 2, 8010 Graz, Austria; (E.Z.); (B.B.); (T.R.P.)
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; (P.K.); (H.S.)
| | - Xiao-Rong Peng
- Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden; (H.-C.Y.); (S.H.); (S.M.)
- Correspondence: (X.-R.P.); (C.M.)
| | - Christoph Magnes
- Institute for Biomedicine and Health Sciences (HEALTH), Joanneum Research Forschungsgesellschaft m.b.H, Neue Stiftingtalstrasse 2, 8010 Graz, Austria; (E.Z.); (B.B.); (T.R.P.)
- Correspondence: (X.-R.P.); (C.M.)
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Liang B, Gu N. Empagliflozin in the treatment of heart failure and type 2 diabetes mellitus: Evidence from several large clinical trials. Int J Med Sci 2022; 19:1118-1121. [PMID: 35919809 PMCID: PMC9339419 DOI: 10.7150/ijms.72772] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 06/07/2022] [Indexed: 11/06/2022] Open
Abstract
Heart failure coexists with type 2 diabetes mellitus, which seriously affects the clinical treatment and prognosis. At present, the treatment for patients with established heart failure and type 2 diabetes mellitus is usually combined with two treatment strategies for heart failure and type 2 diabetes mellitus. Recently, increasing studies showed that empagliflozin, a sodium-glucose co-transporter-2 inhibitor, has a positive effect on the treatment of patients with established heart failure and type 2 diabetes mellitus. Here, we summarize the latest and current understanding of the management for patients with established heart failure and type 2 diabetes mellitus and further present contemporary treatment options, sodium-glucose co-transporter-2 inhibitor, for these particular populations.
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Affiliation(s)
- Bo Liang
- Nanjing University of Chinese Medicine, Nanjing, China
- Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ning Gu
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
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Anker SD, Sander LE, Fitchett DH, Zinman B, Pernille Ofstad A, Wanner C, Vedin O, Lauer S, Verma S, Yaggi HK, Inzucchi SE. Empagliflozin in patients with type 2 diabetes mellitus and chronic obstructive pulmonary disease. Diabetes Res Clin Pract 2022; 186:109837. [PMID: 35314257 DOI: 10.1016/j.diabres.2022.109837] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/16/2022] [Accepted: 03/16/2022] [Indexed: 02/07/2023]
Abstract
AIMS Type 2 diabetes mellitus (T2DM) and chronic obstructive pulmonary disease (COPD) often co-exist, yielding increased risk of cardiovascular (CV) complications including heart failure (HF). We assessed risk of cardiorenal outcomes, mortality and safety in patients with versus without COPD in the EMPA-REG OUTCOME trial. METHODS Patients (n = 7,020) with T2DM and CV disease (CVD) were treated with empagliflozin (10 mg or 25 mg) or placebo. Cox regression was used to assess COPD subgroup (placebo only) associations with, and treatment effects of empagliflozin versus placebo on first hospitalization for HF (HHF), CV death, all-cause mortality, incident/worsening nephropathy, and all-cause hospitalization. RESULTS At baseline, patients with COPD (n = 707) had more HF and used insulin more frequently than those without COPD. During follow-up in the placebo group, those with baseline COPD had increased risk of HHF (HR 2.15 [95% CI 1.32, 3.49]), HHF/CV death (1.60 [1.10, 2.33]), incident/worsening nephropathy (1.68 [1.26, 2.24]), all-cause hospitalization (1.44 [1.19, 1.74]) and all-cause death (1.60 [1.09, 2.35]) compared to those without COPD. Empagliflozin consistently reduced all clinical outcomes, irrespective of COPD status (interaction p-values 0.14 to 0.96), with a confirmed safety profile. CONCLUSIONS In patients with T2DM and CVD, COPD increased the risk of mortality and cardiorenal outcomes, including HF. Empagliflozin consistently reduced these outcomes versus placebo regardless of COPD, suggesting that empagliflozin's benefits in patients with T2DM and CVD are not mitigated by the presence of COPD.
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Affiliation(s)
- Stefan D Anker
- Department of Cardiology (CVK); and Berlin Institute of Health Center for Regenerative Therapies (BCRT); German Centre for Cardiovascular Research (DZHK) partner site, Berlin, Germany, Charité Universitätsmedizin Berlin, Berlin, Germany; Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland.
| | - Leif-Erik Sander
- Department of Infectious Diseases and Respiratory Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - David H Fitchett
- St Michael's Hospital, Division of Cardiology, University of Toronto, Toronto, ON, Canada
| | - Bernard Zinman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | | | | | - Ola Vedin
- Boehringer Ingelheim AB, Stockholm, Sweden
| | - Sabine Lauer
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
| | - Subodh Verma
- St Michael's Hospital, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada
| | - Henry K Yaggi
- Section of Pulmonary, Critical Care & Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
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Ehlers LH, Lamotte M, Ramos MC, Sandgaard S, Holmgaard P, Kristensen MM, Ejskjaer N. The Cost-Effectiveness of Subcutaneous Semaglutide Versus Empagliflozin in Type 2 Diabetes Uncontrolled on Metformin Alone in Denmark. Diabetes Ther 2022; 13:489-503. [PMID: 35187628 PMCID: PMC8934846 DOI: 10.1007/s13300-022-01221-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 02/02/2022] [Indexed: 11/25/2022] Open
Abstract
INTRODUCTION International and Danish guidelines recommend the use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors already in second line in the management of type 2 diabetes (T2D). The objective of this study was to evaluate the long-term cost-effectiveness (CE) of subcutaneous (SC) semaglutide (GLP-1 RA) versus empagliflozin (SGLT-2 inhibitor) in individuals with T2D uncontrolled on metformin alone from a Danish payer's perspective. METHODS Cost-effectiveness analyses (CEA) were conducted from a Danish payer's perspective, using the IQVIA Core Diabetes model (CDM 9.5), with a time horizon of 50 years and an annual discount of 4% on costs and effects. Patients received either SC semaglutide or empagliflozin, in addition to metformin, until HbA1c threshold of 7.5% (58 mmol/mol) was reached, following which treatment intensification with insulin glargine in addition to empagliflozin or SC semaglutide plus metformin was considered. Baseline cohort characteristics and treatment effects were sourced from a published CEA. Utilities and cost of diabetes-related complications were also obtained from published sources. Treatment costs were derived from Danish official sources. Scenario analyses were also performed to test the accuracy of the base case results. RESULTS Individuals with T2D on SC semaglutide plus metformin gained 0.065 life-years (LYs) and 0.130 quality-adjusted LYs (QALYs), respectively, at an incremental cost of DKK 96,923 (€ 13,031) compared to empagliflozin plus metformin, resulting in an incremental cost-effectiveness ratio (ICER) of DKK 745,561(€ 100,239) per QALY gained. The probabilistic sensitivity analysis (PSA) results showed that the SC semaglutide plus metformin was cost-effective in 19% of simulations assuming a willingness-to-pay (WTP) threshold of DKK 357,100 (€ 48,011)/QALY gained. Duration of therapy with SC semaglutide seems the key driver of results. CONCLUSION The current analyses suggest that SC semaglutide plus metformin is not cost-effective compared to empagliflozin plus metformin from a Danish payer's perspective.
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Affiliation(s)
- Lars H Ehlers
- Department of Clinical Medicine, Aalborg University, Ålborg, Denmark
| | - Mark Lamotte
- IQVIA Global IQVIA, Da Vincilaan 7, 1930, Zaventem, Belgium.
| | | | | | - Pia Holmgaard
- Boehringer Ingelheim Denmark A/S, Copenhagen, Denmark
| | | | - Niels Ejskjaer
- Department of Clinical Medicine, Aalborg University, Ålborg, Denmark
- Steno Diabetes Centre North Denmark, Aalborg University Hospital, Ålborg, Denmark
- Department of Endocrinology, Aalborg University Hospital, Ålborg, Denmark
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Sodium-Glucose Cotransporter-2 Inhibitors: Heart Failure and Renal Protection Indications. J Nurse Pract 2022. [DOI: 10.1016/j.nurpra.2021.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Raju A, Pimple P, Stafkey-Mailey D, Farrelly E, Shetty S. Healthcare Costs and Resource Utilization Associated with the Use of Empagliflozin Versus Other Antihyperglycemic Agents Among Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease: A Real-World Retrospective Cohort Analysis. Diabetes Ther 2022; 13:25-42. [PMID: 34727356 PMCID: PMC8776959 DOI: 10.1007/s13300-021-01173-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 10/08/2021] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION Empagliflozin has demonstrated lower rates of cardiovascular outcomes vs. standard of care among patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). However, the impact of empagliflozin compared to other branded antihyperglycemic agents (AHAs) on total cost of care has yet to be quantified. METHODS AND RESULTS This retrospective cohort study evaluated the impact of empagliflozin (n = 441) on costs and healthcare resource utilization (HCRU) vs. other branded AHAs (n = 13,122) among patients with T2DM and CVD, using the IQVIA PharMetrics® Plus Claims Database (1 August 2013-31 December 2017). Date of the first prescription (index date) for empagliflozin or other branded AHAs was used to classify patients into study cohorts. All-cause costs and HCRU were computed on a per patient per month (PPPM) basis and compared across study cohorts using outcome-appropriate statistical models. Overall, the empagliflozin cohort was younger and had a lower comorbidity burden. After covariate adjustment, the total all-cause costs (mean difference - $412 PPPM; 95% CI - $593, - $214) were significantly lower for the empagliflozin cohort. These cost differences were mainly driven by lower all-cause medical costs (mean difference - $400 PPPM; 95% CI - $577, - $196). For HCRU, the mean adjusted all-cause visits in the physician office and other outpatient settings were lower with empagliflozin vs. other branded AHAs (p < 0.001). CONCLUSIONS This study demonstrated that the all-cause healthcare costs and HCRU were significantly lower for patients with T2DM and CVD who initiated empagliflozin vs. other branded AHAs. Along with the positive clinical evidence base of empagliflozin, these results can guide healthcare decision makers during therapy selection.
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Affiliation(s)
| | - Pratik Pimple
- Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT USA
| | | | | | - Sharash Shetty
- Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT USA
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Ruggenenti P, Kraus BJ, Inzucchi SE, Zinman B, Hantel S, Mattheus M, von Eynatten M, Remuzzi G, Koitka-Weber A, Wanner C. Nephrotic-range proteinuria in type 2 diabetes: Effects of empagliflozin on kidney disease progression and clinical outcomes. EClinicalMedicine 2022; 43:101240. [PMID: 35005582 PMCID: PMC8718931 DOI: 10.1016/j.eclinm.2021.101240] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 11/16/2021] [Accepted: 11/24/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Diabetic kidney disease with nephrotic-range proteinuria (NRP) is commonly associated with rapid kidney function loss, increased cardiovascular risk, and premature mortality. We explored the effect of empagliflozin in patients with type 2 diabetes and cardiovascular disease, complicated by presence of this major risk factor for progressive kidney disease, in a post-hoc analysis of data from the EMPA-REG OUTCOME trial (NCT01131676). METHODS Cox proportional hazards models were used to investigate the risk of cardiovascular and kidney outcomes in participants with and without NRP, defined by urine albumin-to-creatinine ratio (UACR) ≥2200 mg/g at baseline. Annual loss of eGFR during chronic treatment (eGFR slopes) and hypothetical time to projected end-stage kidney disease (ESKD), conditioning upon linearity of eGFR change over time if a patient did not decease before projected ESKD, were calculated using a random-intercept random-coefficient model. Safety was described based on investigator-reported adverse events. FINDINGS 112 participants (pooled empagliflozin, n = 70; placebo, n = 42; median on-treatment follow-up of 1·9 years on placebo compared with 2·3 years on empagliflozin) presented with NRP at baseline; eGFR and UACR were balanced between treatments. Empagliflozin benefits on cardiovascular death, hospitalisation for heart failure, or kidney outcomes, were consistent in participants with and without NRP (pinteraction >0·1). Treatment effects of empagliflozin on adjusted annual mean eGFR slope were more pronounced in participants with NRP versus those without (pinteraction 0·005). Empagliflozin was estimated to double the median hypothetical time to projected ESKD in participants with NRP. The overall safety profile of empagliflozin was comparable between participants with and without NRP at baseline. INTERPRETATION Our data suggests that empagliflozin might slow kidney function loss and delay the estimated onset of projected ESKD in patients with type 2 diabetes and cardiovascular disease complicated by NRP.
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Affiliation(s)
- Piero Ruggenenti
- Department of Renal Medicine, Clinical Research Center for Rare Diseases "Aldo and Cele Daccò", Centro Anna Maria Astori (IRCCS), Science and Technology Park Kilometro Rosso, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Stezzano, 87, Bergamo 24126, Italy
- Unit of Nephrology, Azienda-Socio-Sanitaria-Territoriale, Papa Giovanni XXXIII, Bergamo, Italy
| | - Bettina J. Kraus
- Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
- Comprehensive Heart Failure Centre, University of Würzburg, Würzburg, Germany
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
| | - Silvio E. Inzucchi
- Section of Endocrinology, Yale University School of Medicine, New Haven, CT, USA
| | - Bernard Zinman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and University of Toronto, Toronto, Canada
| | - Stefan Hantel
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | | | - Maximilian von Eynatten
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
- Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Giuseppe Remuzzi
- Department of Renal Medicine, Clinical Research Center for Rare Diseases "Aldo and Cele Daccò", Centro Anna Maria Astori (IRCCS), Science and Technology Park Kilometro Rosso, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Stezzano, 87, Bergamo 24126, Italy
| | - Audrey Koitka-Weber
- Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| | - Christoph Wanner
- Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany
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Nashawi M, Ahmed MS, Amin T, Abualfoul M, Chilton R. Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy. World J Cardiol 2021; 13:676-694. [PMID: 35070111 PMCID: PMC8716977 DOI: 10.4330/wjc.v13.i12.676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/02/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) have been substantiated by multiple clinical trials, resulting in increased interest in the multifarious pathways by which their mechanisms act. The principal effect of SGLT2i (-flozin drugs) can be appreciated in their ability to block the SGLT2 protein within the kidneys, inhibiting glucose reabsorption, and causing an associated osmotic diuresis. This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter. These include aberrant mitochondrial metabolism and oxidative stress burden, endothelial cell dysfunction, pernicious neurohormonal activation, and the development of inimical hemodynamics. Positive outcomes within these domains have been validated with SGLT2i administration. However, by modulating the sodium-glucose cotransporter in the proximal tubule (PT), SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention. Phosphatemia, even at physiologic levels, poses a risk in cardiovascular disease burden, more so in patients with type 2 diabetes mellitus (T2DM). There also exists an association between phosphatemia and renal impairment, the latter hampering cardiovascular function through an array of physiologic roles, such as fluid regulation, hormonal tone, and neuromodulation. Moreover, increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels, also detrimental to homeostatic cardiometabolic function. A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature. Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia, we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease, as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects. Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.
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Affiliation(s)
- Mouhamed Nashawi
- Department of Internal Medicine, Baylor Scott and White All Saints Medical Center, Fort Worth, TX 76132, United States.
| | - Mahmoud S Ahmed
- Division of Medicine-Cardiology, UT Health San Antonio, San Antonio, TX 78229, United States
| | - Toka Amin
- Division of Medicine-Cardiology, UT Health San Antonio, San Antonio, TX 78229, United States
| | - Mujahed Abualfoul
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Dallas, TX 75203, United States
| | - Robert Chilton
- Department of Internal Medicine, Methodist Dallas Medical Center, Dallas, TX 75203, United States
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Vaduganathan M, Inzucchi SE, Sattar N, Fitchett DH, Ofstad AP, Brueckmann M, George JT, Verma S, Mattheus M, Wanner C, Zinman B, Butler J. Effects of empagliflozin on insulin initiation or intensification in patients with type 2 diabetes and cardiovascular disease: Findings from the EMPA-REG OUTCOME trial. Diabetes Obes Metab 2021; 23:2775-2784. [PMID: 34463409 PMCID: PMC9291462 DOI: 10.1111/dom.14535] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/16/2021] [Accepted: 08/26/2021] [Indexed: 01/14/2023]
Abstract
AIM To evaluate the effects of empagliflozin versus placebo on subsequent insulin initiation or dosing changes in a large cardiovascular outcomes trial. MATERIALS AND METHODS In EMPA-REG OUTCOME, 7020 patients with type 2 diabetes and cardiovascular disease received empagliflozin 10 mg, 25 mg, or placebo. Median follow-up was 3.1 years. After 12 weeks of treatment, changes in background antihyperglycaemic therapy were permitted. Among insulin-naïve patients, we assessed the effects of pooled empagliflozin arms versus placebo on time to initiation of insulin. Among insulin-treated patients, we assessed effects on time to an increase or decrease in insulin dose of more than 20%. RESULTS In 3633 (52%) participants not treated with insulin at baseline, empagliflozin reduced new use of insulin versus placebo by 60% (7.1% vs. 16.4%; adjusted HR 0.40 [95% CI 0.32-0.49]; P < .0001). In 3387 (48%) patients using insulin at baseline, empagliflozin reduced the need for a greater than 20% insulin dose increase by 58% (14.4% vs. 29.3%; adjusted HR 0.42 [95% CI 0.36-0.49]; P < .0001) and increased the proportion achieving sustained greater than 20% insulin dose reductions without subsequent increases in HbA1c compared with placebo (9.2% vs. 4.9%; adjusted HR 1.87 [95% CI: 1.39-2.51]; P < .0001). Sensitivity analyses confirmed consistent findings when insulin dose changes of more than 10% or more than 30% were considered. CONCLUSIONS In patients with type 2 diabetes and cardiovascular disease, empagliflozin markedly and durably delays insulin initiation and substantial increases in insulin dose, while facilitating sustained reductions in insulin requirements over time.
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Affiliation(s)
- Muthiah Vaduganathan
- Division of Cardiovascular MedicineBrigham and Womenʼs Hospital, Harvard Medical SchoolBostonMassachusettsUSA
| | - Silvio E. Inzucchi
- Section of Endocrinology, Yale School of MedicineYale UniversityNew HavenConnecticutUSA
| | | | - David H. Fitchett
- Division of Cardiology, St. Michaelʼs HospitalUniversity of TorontoTorontoOntarioCanada
| | | | - Martina Brueckmann
- Boehringer Ingelheim International GmbHIngelheimGermany
- Faculty of Medicine Mannheim at the University of HeidelbergMannheimGermany
| | | | - Subodh Verma
- Division of Cardiac Surgery, St. Michaelʼs HospitalUniversity of TorontoTorontoOntarioCanada
| | | | - Christoph Wanner
- Department of Internal Medicine I, NephrologyUniversity Hospital WürzburgWürzburgGermany
| | - Bernard Zinman
- Lunenfeld‐Tanenbaum Research Institute, Mount Sinai HospitalUniversity of TorontoTorontoOntarioCanada
| | - Javed Butler
- Department of MedicineUniversity of MississippiJacksonMississippiUSA
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Young TK, Li JW, Kang A, Heerspink HJL, Hockham C, Arnott C, Neuen BL, Zoungas S, Mahaffey KW, Perkovic V, de Zeeuw D, Fulcher G, Neal B, Jardine M. Effects of canagliflozin compared with placebo on major adverse cardiovascular and kidney events in patient groups with different baseline levels of HbA 1c, disease duration and treatment intensity: results from the CANVAS Program. Diabetologia 2021; 64:2402-2414. [PMID: 34448033 PMCID: PMC8494676 DOI: 10.1007/s00125-021-05524-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 04/19/2021] [Indexed: 01/14/2023]
Abstract
AIMS/HYPOTHESIS Type 2 diabetes mellitus can manifest over a broad clinical range, although there is no clear consensus on the categorisation of disease complexity. We assessed the effects of canagliflozin, compared with placebo, on cardiovascular and kidney outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program over a range of type 2 diabetes mellitus complexity, defined separately by baseline intensity of treatment, duration of diabetes and glycaemic control. METHODS We performed a post hoc analysis of the effects of canagliflozin on major adverse cardiovascular events (MACE) according to baseline glucose-lowering treatments (0 or 1, 2 or 3+ non-insulin glucose-lowering treatments, or insulin-based treatment), duration of diabetes (<10, 10 to 16, >16 years) and HbA1c (≤53.0 mmol/mol [<7.0%], >53.0 to 58.5 mmol/mol [>7.0% to 7.5%], >58.5 to 63.9 mmol/mol [>7.5 to 8.0%], >63.9 to 69.4 mmol/mol [8.0% to 8.5%], >69.4 to 74.9 mmol/mol [>8.5 to 9.0%] or >74.9 mmol/mol [>9.0%]). We analysed additional secondary endpoints for cardiovascular and kidney outcomes, including a combined kidney outcome of sustained 40% decline in eGFR, end-stage kidney disease or death due to kidney disease. We used Cox regression analyses and compared the constancy of HRs across subgroups by fitting an interaction term (p value for significance <0.05). RESULTS At study initiation, 5095 (50%) CANVAS Program participants were treated with insulin, 2100 (21%) had an HbA1c > 74.9 mmol/mol (9.0%) and the median duration of diabetes was 12.6 years (interquartile interval 8.0-18 years). Canagliflozin reduced MACE (HR 0.86 [95% CI 0.75, 0.97]) with no evidence that the benefit differed between subgroups defined by the number of glucose-lowering treatments, the duration of diabetes or baseline HbA1c (all p-heterogeneity >0.17). Canagliflozin reduced MACE in participants receiving insulin with no evidence that the benefit differed from other participants in the trial (HR 0.85 [95% CI 0.72, 1.00]). Similar results were observed for other cardiovascular outcomes and for the combined kidney outcome (HR for combined kidney outcome 0.60 [95% CI 0.47, 0.77]), with all p-heterogeneity >0.37. CONCLUSIONS/INTERPRETATION In people with type 2 diabetes mellitus at high cardiovascular risk, there was no evidence that cardiovascular and renal protection with canagliflozin differed across subgroups defined by baseline treatment intensity, duration of diabetes or HbA1c.
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Affiliation(s)
- Tamara K Young
- The George Institute for Global Health, UNSW, Sydney, NSW, Australia
| | - Jing-Wei Li
- The George Institute for Global Health, UNSW, Sydney, NSW, Australia
| | - Amy Kang
- The George Institute for Global Health, UNSW, Sydney, NSW, Australia
| | | | - Carinna Hockham
- The George Institute for Global Health, Imperial College London, London, UK.
| | - Clare Arnott
- The George Institute for Global Health, UNSW, Sydney, NSW, Australia.
- University of Sydney, Sydney, NSW, Australia.
| | - Brendon L Neuen
- The George Institute for Global Health, UNSW, Sydney, NSW, Australia
| | - Sophia Zoungas
- The George Institute for Global Health, UNSW, Sydney, NSW, Australia
- Monash University, Melbourne, VIC, Australia
| | - Kenneth W Mahaffey
- Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Vlado Perkovic
- The George Institute for Global Health, UNSW, Sydney, NSW, Australia
| | - Dick de Zeeuw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, the Netherlands
| | | | - Bruce Neal
- The George Institute for Global Health, UNSW, Sydney, NSW, Australia
| | - Meg Jardine
- The George Institute for Global Health, UNSW, Sydney, NSW, Australia
- University of Sydney, Sydney, NSW, Australia
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Kanie T, Mizuno A, Takaoka Y, Suzuki T, Yoneoka D, Nishikawa Y, Tam WWS, Morze J, Rynkiewicz A, Xin Y, Wu O, Providencia R, Kwong JS. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev 2021; 10:CD013650. [PMID: 34693515 PMCID: PMC8812344 DOI: 10.1002/14651858.cd013650.pub2] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cardiovascular disease (CVD) is a leading cause of death globally. Recently, dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) were approved for treating people with type 2 diabetes mellitus. Although metformin remains the first-line pharmacotherapy for people with type 2 diabetes mellitus, a body of evidence has recently emerged indicating that DPP4i, GLP-1RA and SGLT2i may exert positive effects on patients with known CVD. OBJECTIVES To systematically review the available evidence on the benefits and harms of DPP4i, GLP-1RA, and SGLT2i in people with established CVD, using network meta-analysis. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, and the Conference Proceedings Citation Index on 16 July 2020. We also searched clinical trials registers on 22 August 2020. We did not restrict by language or publication status. SELECTION CRITERIA We searched for randomised controlled trials (RCTs) investigating DPP4i, GLP-1RA, or SGLT2i that included participants with established CVD. Outcome measures of interest were CVD mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, all-cause mortality, hospitalisation for heart failure (HF), and safety outcomes. DATA COLLECTION AND ANALYSIS Three review authors independently screened the results of searches to identify eligible studies and extracted study data. We used the GRADE approach to assess the certainty of the evidence. We conducted standard pairwise meta-analyses and network meta-analyses by pooling studies that we assessed to be of substantial homogeneity; subgroup and sensitivity analyses were also pursued to explore how study characteristics and potential effect modifiers could affect the robustness of our review findings. We analysed study data using the odds ratios (ORs) and log odds ratios (LORs) with their respective 95% confidence intervals (CIs) and credible intervals (Crls), where appropriate. We also performed narrative synthesis for included studies that were of substantial heterogeneity and that did not report quantitative data in a usable format, in order to discuss their individual findings and relevance to our review scope. MAIN RESULTS We included 31 studies (287 records), of which we pooled data from 20 studies (129,465 participants) for our meta-analysis. The majority of the included studies were at low risk of bias, using Cochrane's tool for assessing risk of bias. Among the 20 pooled studies, six investigated DPP4i, seven studied GLP-1RA, and the remaining seven trials evaluated SGLT2i. All outcome data described below were reported at the longest follow-up duration. 1. DPP4i versus placebo Our review suggests that DPP4i do not reduce any risk of efficacy outcomes: CVD mortality (OR 1.00, 95% CI 0.91 to 1.09; high-certainty evidence), myocardial infarction (OR 0.97, 95% CI 0.88 to 1.08; high-certainty evidence), stroke (OR 1.00, 95% CI 0.87 to 1.14; high-certainty evidence), and all-cause mortality (OR 1.03, 95% CI 0.96 to 1.11; high-certainty evidence). DPP4i probably do not reduce hospitalisation for HF (OR 0.99, 95% CI 0.80 to 1.23; moderate-certainty evidence). DPP4i may not increase the likelihood of worsening renal function (OR 1.08, 95% CI 0.88 to 1.33; low-certainty evidence) and probably do not increase the risk of bone fracture (OR 1.00, 95% CI 0.83 to 1.19; moderate-certainty evidence) or hypoglycaemia (OR 1.11, 95% CI 0.95 to 1.29; moderate-certainty evidence). They are likely to increase the risk of pancreatitis (OR 1.63, 95% CI 1.12 to 2.37; moderate-certainty evidence). 2. GLP-1RA versus placebo Our findings indicate that GLP-1RA reduce the risk of CV mortality (OR 0.87, 95% CI 0.79 to 0.95; high-certainty evidence), all-cause mortality (OR 0.88, 95% CI 0.82 to 0.95; high-certainty evidence), and stroke (OR 0.87, 95% CI 0.77 to 0.98; high-certainty evidence). GLP-1RA probably do not reduce the risk of myocardial infarction (OR 0.89, 95% CI 0.78 to 1.01; moderate-certainty evidence), and hospitalisation for HF (OR 0.95, 95% CI 0.85 to 1.06; high-certainty evidence). GLP-1RA may reduce the risk of worsening renal function (OR 0.61, 95% CI 0.44 to 0.84; low-certainty evidence), but may have no impact on pancreatitis (OR 0.96, 95% CI 0.68 to 1.35; low-certainty evidence). We are uncertain about the effect of GLP-1RA on hypoglycaemia and bone fractures. 3. SGLT2i versus placebo This review shows that SGLT2i probably reduce the risk of CV mortality (OR 0.82, 95% CI 0.70 to 0.95; moderate-certainty evidence), all-cause mortality (OR 0.84, 95% CI 0.74 to 0.96; moderate-certainty evidence), and reduce the risk of HF hospitalisation (OR 0.65, 95% CI 0.59 to 0.71; high-certainty evidence); they do not reduce the risk of myocardial infarction (OR 0.97, 95% CI 0.84 to 1.12; high-certainty evidence) and probably do not reduce the risk of stroke (OR 1.12, 95% CI 0.92 to 1.36; moderate-certainty evidence). In terms of treatment safety, SGLT2i probably reduce the incidence of worsening renal function (OR 0.59, 95% CI 0.43 to 0.82; moderate-certainty evidence), and probably have no effect on hypoglycaemia (OR 0.90, 95% CI 0.75 to 1.07; moderate-certainty evidence) or bone fracture (OR 1.02, 95% CI 0.88 to 1.18; high-certainty evidence), and may have no impact on pancreatitis (OR 0.85, 95% CI 0.39 to 1.86; low-certainty evidence). 4. Network meta-analysis Because we failed to identify direct comparisons between each class of the agents, findings from our network meta-analysis provided limited novel insights. Almost all findings from our network meta-analysis agree with those from the standard meta-analysis. GLP-1RA may not reduce the risk of stroke compared with placebo (OR 0.87, 95% CrI 0.75 to 1.0; moderate-certainty evidence), which showed similar odds estimates and wider 95% Crl compared with standard pairwise meta-analysis. Indirect estimates also supported comparison across all three classes. SGLT2i was ranked the best for CVD and all-cause mortality. AUTHORS' CONCLUSIONS Findings from both standard and network meta-analyses of moderate- to high-certainty evidence suggest that GLP-1RA and SGLT2i are likely to reduce the risk of CVD mortality and all-cause mortality in people with established CVD; high-certainty evidence demonstrates that treatment with SGLT2i reduce the risk of hospitalisation for HF, while moderate-certainty evidence likely supports the use of GLP-1RA to reduce fatal and non-fatal stroke. Future studies conducted in the non-diabetic CVD population will reveal the mechanisms behind how these agents improve clinical outcomes irrespective of their glucose-lowering effects.
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Affiliation(s)
- Takayoshi Kanie
- Department of Cardiology, St. Luke's International Hospital, Tokyo, Japan
| | - Atsushi Mizuno
- Department of Cardiology, St. Luke's International Hospital, Tokyo, Japan
- Penn Medicine Nudge Unit, University of Pennsylvania Philadelphia, Philadelphia, PA, USA
- Leonard Davis Institute for Health Economics, University of Pennsylvania, Philadelphia, PA, USA
- Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Yoshimitsu Takaoka
- Department of Cardiology, St. Luke's International Hospital, Tokyo, Japan
| | - Takahiro Suzuki
- Department of Cardiology, St. Luke's International Hospital, Tokyo, Japan
| | - Daisuke Yoneoka
- Division of Biostatistics and Bioinformatics, Graduate School of Public Health, St. Luke's International University, Tokyo, Japan
| | - Yuri Nishikawa
- Department of Gerontological Nursing and Healthcare Systems Management, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Gerontological Nursing, Kyorin University, Tokyo, Japan
| | - Wilson Wai San Tam
- Alice Lee Center for Nursing Studies, NUS Yong Loo Lin School of Medicine, Singapore, Singapore
| | - Jakub Morze
- Department of Human Nutrition, University of Warmia and Mazury, Olsztyn, Poland
| | - Andrzej Rynkiewicz
- Department of Cardiology and Cardiosurgery, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland
| | - Yiqiao Xin
- Health Economics and Health Technology Assessment (HEHTA), Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Olivia Wu
- Health Economics and Health Technology Assessment (HEHTA), Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Rui Providencia
- Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
| | - Joey Sw Kwong
- Global Health Nursing, Graduate School of Nursing Science, St. Luke's International University, Tokyo, Japan
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Yugueros González A, Kanter J, Sancho A, Gavela E, Solá E, Ávila A, Pallardó LM. Institutional Experience With New Antidiabetic Drugs in Kidney Transplant. Transplant Proc 2021; 53:2678-2680. [PMID: 34615601 DOI: 10.1016/j.transproceed.2021.08.042] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 08/25/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND The recent introduction of new antidiabetic drugs, analogs of glucagon-like peptide-1 (GLP-1) and sodium-glucose cotransporter 2 inhibitors, has shown excellent results in the management of patients with diabetes with chronic kidney disease. However, documented results of these medications in the population that has undergone kidney transplant are sparse. We report our institutional experience with them, including occurrence of side effects and possible interactions with immunosuppressive medications. METHODS A retrospective analysis of 15 patients (10 with diabetes and 5 without diabetes but with obesity) managed with these medications was carried out in the kidney transplant unit of Hospital Doctor Peset during the year 2019. Data acquired at baseline and 3, 6, and 12 months were analyzed. RESULTS The median hemoglobin A1c at baseline was 6.7 (interquartile range [IQR] = 5.8-8.2) and at 12 months it was 6 (IQR = 5.3-8.1, P = .96). The mean weight difference at 12 months was a loss of 7.2 ± 6 kg; median body mass index at baseline was 31.2 kg/m2 (IQR = 29.7-35.5) and 29.5 kg/m2 (IQR = 27.6-31.6, P = .01) at 12 months. In addition to weight loss, a reduction in insulin and oral antidiabetic drug requirements was observed. No significant changes were detected in serum creatinine or proteinuria values and the immunosuppressant levels remained stable. No acute rejection episodes were observed. CONCLUSION Based on our experience, the new antidiabetic drugs are safe, with no significant changes in renal function or immunosuppressant levels or clinically important adverse effects.
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Affiliation(s)
| | - Julia Kanter
- Nephrology Department, Hospital Doctor Peset, Valencia, Spain
| | - Asunción Sancho
- Nephrology Department, Hospital Doctor Peset, Valencia, Spain
| | - Eva Gavela
- Nephrology Department, Hospital Doctor Peset, Valencia, Spain
| | - Eva Solá
- Endocrinology Department, Hospital Doctor Peset, Valencia, Spain
| | - Ana Ávila
- Nephrology Department, Hospital Doctor Peset, Valencia, Spain
| | - Luis M Pallardó
- Nephrology Department, Hospital Doctor Peset, Valencia, Spain
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Johansson I, Dicembrini I, Mannucci E, Cosentino F. Glucose-lowering therapy in patients undergoing percutaneous coronary intervention. EUROINTERVENTION 2021; 17:e618-e630. [PMID: 34596567 PMCID: PMC9724943 DOI: 10.4244/eij-d-20-01250] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/03/2021] [Indexed: 01/08/2023]
Abstract
The number of individuals with diabetes and pre-diabetes is constantly increasing. These conditions are overrepresented in patients undergoing percutaneous coronary intervention and are associated with adverse prognosis. Optimal glycaemic control during an acute coronary syndrome is a relevant factor for the improvement of longer-term outcomes. In addition, the implementation of newer glucose-lowering drugs with proven cardiovascular benefits has a remarkable impact on recurrence of events, hospitalisations for heart failure and mortality. In this narrative review, we outline the current state-of-the art recommendations for glucose-lowering therapy in patients with diabetes undergoing coronary intervention. In addition, we discuss the most recent evidence-based indications for revascularisation in patients with diabetes as well as the targets for glycaemic control post revascularisation. Current treatment goals for concomitant risk factor control are also addressed. Lastly, we acknowledge the presence of knowledge gaps in need of future research.
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Affiliation(s)
- Isabelle Johansson
- Cardiology Unit, Department of Medicine Solna, Karolinska Institute Heart & Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
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Smidt LCA, Visseren FLJ, de Ranitz-Greven WL, Nathoe HM, Kappelle LJ, de Borst GJ, de Valk HW, Westerink J. External applicability of SGLT2 inhibitor cardiovascular outcome trials to patients with type 2 diabetes and cardiovascular disease. Cardiovasc Diabetol 2021; 20:181. [PMID: 34496847 PMCID: PMC8427950 DOI: 10.1186/s12933-021-01373-9] [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: 06/15/2021] [Accepted: 08/28/2021] [Indexed: 11/10/2022] Open
Abstract
Background Recent treatment guidelines support the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and cardiovascular disease based on the results of cardiovascular outcome trials (CVOTs). Applicability of these trials to everyday patients with type 2 diabetes and cardiovascular disease is however unknown. The aim of this study is to assess the external applicability of SGLT2i CVOTs in daily clinical practice type 2 diabetes patients with established cardiovascular disease. Methods Trial in- and exclusion criteria from EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS-CV were applied to 1389 type 2 diabetes patients with cardiovascular disease in the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART). To evaluate the difference in cardiovascular risk (MACE) and all-cause mortality between trial eligible and ineligible patients, age and sex-adjusted Cox-regression analyses were performed. Results After applying trial in- and exclusion criteria, 48% of UCC-SMART patients with type 2 diabetes and cardiovascular disease would have been eligible for DECLARE-TIMI 58, 35% for CANVAS, 29% for EMPA-REG OUTCOME and 21% for VERTIS-CV. Without the eligibility criteria of HbA1c, eligibility was 58–88%. For all trials the observed risk for cardiovascular events and all-cause mortality was similar in eligible and ineligible patients after adjustment for age and gender. Conclusion A large proportion of patients with type 2 diabetes and cardiovascular disease in daily clinical practice would have been eligible for participation in the SGLT2i CVOTs. Trial eligible and ineligible patients have the same risk for MACE and all-cause mortality. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-021-01373-9.
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Affiliation(s)
- Lisanne C A Smidt
- Department of Vascular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Frank L J Visseren
- Department of Vascular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | | | - Hendrik M Nathoe
- Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - L Jaap Kappelle
- Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Gert J de Borst
- Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Harold W de Valk
- Department of Endocrinology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jan Westerink
- Department of Vascular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
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Ramos M, Men P, Wang X, Ustyugova A, Lamotte M. Cost-effectiveness of empagliflozin in patients with type 2 diabetes and established cardiovascular disease in China. COST EFFECTIVENESS AND RESOURCE ALLOCATION 2021; 19:46. [PMID: 34348729 PMCID: PMC8336098 DOI: 10.1186/s12962-021-00299-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 07/19/2021] [Indexed: 01/14/2023] Open
Abstract
Background In several cardiovascular outcome trials (CVOTs), empagliflozin (SGLT-2 inhibitor), sitagliptin (DPP-4 inhibitor) and liraglutide (GLP-1 receptor agonist) + standard of care (SoC) were compared to SoC in patients with type 2 diabetes and established cardiovascular disease (CVD). This study assessed the cost-effectiveness (CE) of empagliflozin + SoC in comparison to sitagliptin + SoC and liraglutide + SoC based on the respective CVOT. Methods The IQVIA Core Diabetes Model (CDM) was calibrated to reproduce the CVOT outcomes. EMPA-REG OUTCOME baseline characteristics and CVOT specific treatment effects on risk factors for cardiovascular disease (HbA1c, BMI, blood pressure, lipids) were applied. Three-year observed cardiovascular events of empagliflozin + SoC versus sitagliptin + SoC and liraglutide + SoC were derived from EMPA-REG OUTCOME and an indirect treatment comparison. Relative risk adjustments to calibrate the CDM were obtained after a trial and error process to match as closely the observed and CDM-predicted outcomes. The drug-specific treatment effects were considered up until HbA1c reached 8.5% and treatment switch occurred. After this switch, the United Kingdom Prospective Diabetes Study 82 risk equations predicted events based on co-existing risk factors and treatment intensification to basal bolus insulin were applied. The analysis was conducted from the perspective of the Chinese healthcare system applying 3% discounting. The time horizon was lifelong. Results Empagliflozin + SoC provides additional Quality Adjusted Life years (QALY + 0.564) for an incremental cost of 42,497RMB (US$6053) compared to sitagliptin + SoC, resulting in an Incremental Cost Utility Ratio of 75,349RMB (US$10,732), thus below the willingness-to-pay threshold of 212,676RMB, corresponding to three times the Gross Domestic Product in China (2019). Compared to liraglutide + SoC, empagliflozin + SoC use leads to 0.211QALY gained and cost savings of 71,427RMB (US$10,173) and is as such dominant. Scenario and probabilistic sensitivity analyses demonstrated the robustness of the results. Conclusion Results suggest that empagliflozin + SoC is cost-effective compared to sitagliptin + SoC and liraglutide + SoC at a willingness-to-pay threshold of 212,676RMB ($30,292)/QALY. Supplementary Information The online version contains supplementary material available at 10.1186/s12962-021-00299-z.
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Affiliation(s)
- Mafalda Ramos
- IQVIA Global HEOR, Lagoas Park, Edifício 3 - Piso 3, 2740-266, Porto Salvo, Portugal.
| | - Peng Men
- Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, China.,Institute for Drug Evaluation, Peking University Health Science Center, Beijing, 100191, China
| | - Xu Wang
- Boehringer Ingelheim, Beijing, China
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Pellicori P, Fitchett D, Kosiborod MN, Ofstad AP, Seman L, Zinman B, Zwiener I, Wanner C, George J, Inzucchi SE, Testani JM, Cleland JG. Use of diuretics and outcomes in patients with type 2 diabetes: findings from the EMPA-REG OUTCOME trial. Eur J Heart Fail 2021; 23:1085-1093. [PMID: 34031968 PMCID: PMC11497224 DOI: 10.1002/ejhf.2220] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 04/30/2021] [Accepted: 05/09/2021] [Indexed: 11/08/2022] Open
Abstract
AIMS Loop diuretics (LD) relieve symptoms and signs of congestion due to heart failure (HF), but many patients prescribed LD do not have such a diagnosis. We studied the relationship between HF diagnosis, use of LD, and outcomes in patients with type 2 diabetes mellitus (T2DM) enrolled in the EMPA-REG OUTCOME trial. METHODS AND RESULTS The relationship between HF diagnosis, use of LD, and outcomes was evaluated in four patient subgroups with T2DM: (i) investigator-reported HF on LD, (ii) investigator-reported HF not on LD, (iii) no HF on LD, and (iv) no HF and not on LD, and we assessed their risk of cardiovascular events. Of 7020 participants, 706 (10%) had a diagnosis of HF at baseline, of whom 334 were prescribed LD. However, 755 (11%) patients who did not have a diagnosis of HF were prescribed LD. Compared to those with neither HF nor prescribed LD (reference group; placebo), those with both HF and receiving LD had the highest rates for all-cause [hazard ratio (HR) (95% confidence interval) 3.19 (2.03-5.01)] and cardiovascular mortality [3.83 [(2.28-6.44)], and HF hospitalizations [9.51 (5.61-16.14)]. Patients without HF but prescribed LD had higher rates for all three outcomes [1.62 (1.10-2.39); 1.97 (1.26-3.08); 3.20 (1.90-5.39)], which were similar to patients with HF who were not receiving LD [1.42 (0.78-2.57); 1.56 (0.78-3.11); 3.00 (1.40-6.40)]. Empagliflozin had similar benefits regardless of subgroup (P for interaction >0.1 for all outcomes). CONCLUSION Patients with T2DM prescribed LD are at greater risk of cardiovascular events even if they are not reported to have HF; this might reflect under-diagnosis. Empagliflozin was similarly effective in all subgroups investigated.
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Affiliation(s)
| | - David Fitchett
- St. Michael's Hospital, Division of CardiologyUniversity of TorontoTorontoCanada
| | | | | | - Leo Seman
- Boehringer Ingelheim Pharmaceuticals IncorporatedRidgefieldCTUSA
| | - Bernard Zinman
- Lunenfeld‐Tanenbaum Research InstituteMount Sinai Hospital, University of TorontoTorontoCanada
| | | | - Christoph Wanner
- Department of MedicineWuerzburg University ClinicWuerzburgGermany
| | - Jyothis George
- Boehringer Ingelheim International GmbH & Co KGIngelheimGermany
| | | | - Jeffrey M. Testani
- Section of Cardiovascular MedicineYale University School of MedicineNew HavenCTUSA
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50
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Correale M, Petroni R, Coiro S, Antohi EL, Monitillo F, Leone M, Triggiani M, Ishihara S, Dungen HD, Sarwar CMS, Memo M, Sabbah HN, Metra M, Butler J, Nodari S. Paradigm shift in heart failure treatment: are cardiologists ready to use gliflozins? Heart Fail Rev 2021; 27:1147-1163. [PMID: 34097173 DOI: 10.1007/s10741-021-10107-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/07/2021] [Indexed: 11/26/2022]
Abstract
Despite recent advances in chronic heart failure (HF) therapy, the prognosis of HF patients remains poor, with high rates of HF rehospitalizations and death in the early months after discharge. This emphasizes the need for incorporating novel HF drugs, beyond the current approach (that of modulating the neurohumoral response). Recently, new antidiabetic oral medications (sodium-glucose cotransporter 2 inhibitors (SGLT2i)) have been shown to improve prognosis in diabetic patients with previous cardiovascular (CV) events or high CV risk profile. Data from DAPA-HF study showed that dapaglifozin is associated with a significant reduction in mortality and HF hospitalization as compared with placebo regardless of diabetes status. Recently, results from EMPEROR-Reduced HF trial were consistent with DAPA-HF trial findings, showing significant beneficial effect associated with empagliflozin use in a high-risk HF population with markedly reduced ejection fraction. Results from the HF with preserved ejection fraction trials using these same agents are eagerly awaited. This review summarizes the evidence for the use of gliflozins in HF treatment.
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Affiliation(s)
- Michele Correale
- Cardiology Department, University Hospital Ospedali Riuniti, Foggia, Italy.
| | - Renata Petroni
- Department of Medicine, Di Lorenzo Clinic, Avezzano, Italy
- Cardiology, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Stefano Coiro
- Cardiology Department, Santa Maria della Misericordia University Hospital, Perugia, Italy
| | - Elena-Laura Antohi
- ICCU, Emergency Institute for Cardiovascular Diseases "C.C. Iliescu", Bucharest, Romania
- The University for Medicine and Pharmacy "Carol Davila", Bucharest, Romania
| | - Francesco Monitillo
- Cardiology, Emergency Cardiology Unit, University Hospital Policlinico Bari, Bari, Italy
| | - Marta Leone
- Cardiology Department, Santissima Annunziata Hospital, Taranto, Italy
| | - Marco Triggiani
- Division of Cardiology, La Memoria" Hospital, Gavardo (Bs), Italy
| | - Shiro Ishihara
- Internal Medicine, Cardiology, and Intensive Care Unit, Nippon Medical School Musashi-Kosugi Hospital, Kawasaky, Japan
| | - Hans-Dirk Dungen
- Department of Internal Medicine-Cardiology, Charite' Universitäts Medizin, Berlin, Germany
| | - Chaudhry M S Sarwar
- Pulse Heart Institute, Spokane, WA, 99204, USA
- Stony Brook University, Stony Brook, NY, 11794, USA
| | - Maurizio Memo
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Hani N Sabbah
- Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Marco Metra
- Cardiology Section, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Javed Butler
- Department of Medicine, University of Mississippi, Jackson, MS, USA
| | - Savina Nodari
- Cardiology Section, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
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