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Ameer MZ, Rehman AU, Amjad Z, Khan S, Ameer F, Shirwany HAK, Hyder SA, Mohsin A, Haiy AU, Akhtar KH, Rehman AU. Cardiovascular outcomes with SGLT-2 inhibitors in individuals with diabetes and co-existing atrial fibrillation: A systematic review and meta-analysis. Int J Cardiol 2025; 426:133083. [PMID: 39993659 DOI: 10.1016/j.ijcard.2025.133083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/01/2025] [Accepted: 02/18/2025] [Indexed: 02/26/2025]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and atrial fibrillation. Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) have demonstrated benefit in reducing T2DM-related morbidity and mortality, but their effects in individuals with concomitant T2DM and atrial fibrillation remain unclear. This meta-analysis is the first to evaluate impact of SGLT-2i in this patient population. METHODS PubMed/MEDLINE, Cochrane Library, and reference lists of the included articles were systematically searched. Results were pooled using a random-effects model and outcomes were reported as risk ratios (RR) with 95 % confidence intervals (CIs). Meta-regression analyses based on baseline patient characteristics were conducted to assess potential sources of heterogeneity. RESULTS Seven retrospective cohort studies and one randomized controlled trial corresponding to 37,229 patients were included, of whom 13,030 received SGLT-2i and 24,199 received other oral anti-diabetic drugs. Follow-up ranged from 2 to 5 years. SGLT-2i use was associated with decreased risk of all-cause mortality (RR = 0.37; 95 % CI: 0.28-0.50), heart failure (RR = 0.66; 95 % CI: 0.53-0.83), stroke (RR = 0.76; 95 % CI: 0.66-0.88), and cardiovascular mortality (RR = 0.57; 95 % CI: 0.44-0.74). No significant difference was observed for myocardial infarction (RR = 0.94; 95 % CI: 0.78-1.12). Results were largely consistent across shorter (<3 years) and longer (≥3 years) follow-up durations. Meta-regression demonstrated no significant associations with baseline patient characteristics (age, gender, prior MI, or prior stroke). CONCLUSION SGLT-2i reduced all-cause mortality, heart failure, stroke, and cardiovascular mortality in individuals with T2DM and atrial fibrillation. Large-scale, randomized controlled trials are warranted to confirm these findings.
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Affiliation(s)
| | - Aqeeb Ur Rehman
- Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Zunaira Amjad
- Services Institute of Medical Sciences, Lahore, Pakistan
| | - Shajia Khan
- Rawalpindi Medical University, Rawalpindi, Pakistan
| | | | - Hamid A K Shirwany
- Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Syed Anas Hyder
- Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Aleenah Mohsin
- Rhode Island Hospital, Brown University, Providence, RI, USA
| | - Ata Ul Haiy
- Department of Internal Medicine, UHS Wilson Medical Center, Johnson City, NY, USA
| | - Khawaja Hassan Akhtar
- Department of Cardiovascular Medicine, University of Oklahoma Health Sciences Center, OK, USA
| | - Afzal Ur Rehman
- Department of Cardiology, UHS Heart and Vascular Institute, Johnson City, NY, USA
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Bellemare M, Bourcier L, Iglesies‐Grau J, Boulet J, O'Meara E, Bouabdallaoui N. Mechanisms of diabetic cardiomyopathy: Focus on inflammation. Diabetes Obes Metab 2025; 27:2326-2338. [PMID: 39930551 PMCID: PMC11964996 DOI: 10.1111/dom.16242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/23/2025] [Accepted: 01/25/2025] [Indexed: 04/04/2025]
Abstract
PURPOSE OF REVIEW Type 2 diabetes (T2D) significantly increases the risk of heart failure (HF), either through the progression of coronary artery disease (CAD) or through direct myocardial alterations, termed diabetic cardiomyopathy. This review examines key pathophysiological mechanisms underlying diabetic cardiomyopathy, focusing on the role of inflammation. It also addresses diagnostic and therapeutic approaches to mitigate myocardial damage in T2D. RECENT FINDINGS Chronic low-grade inflammation is considered as a major contributor to diabetic cardiomyopathy. T2D-related factors, including hyperglycemia and insulin resistance, activate inflammatory pathways that worsen myocardial dysfunction. Despite advances in understanding these mechanisms, no therapies specifically targeting the cardiac changes in T2D have been identified. SUMMARY While significant advances have been made in elucidating the inflammatory mechanisms contributing to diabetic cardiomyopathy, therapeutic advancements remain limited, potentially due to an incomplete understanding of regulatory pathways. A comprehensive investigation into the specific roles of immune cells and inflammatory mediators in diabetic cardiomyopathy is essential for identifying novel therapeutic targets. Expanding our knowledge of these molecular mechanisms has the potential to facilitate the development of innovative therapeutic strategies, thereby improving clinical outcomes in patients with T2D.
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Affiliation(s)
- Myriam Bellemare
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
| | - Liane Bourcier
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
| | - Josep Iglesies‐Grau
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
| | - Jacinthe Boulet
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
| | - Eileen O'Meara
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
| | - Nadia Bouabdallaoui
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
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El-Gazar RA, Zarif B, Ali AA, William MM, Abbassi MM, Sabry NA. Immediate and short-term outcomes of in-hospital canagliflozin initiation in acute heart failure: Results from the CANA-AHF randomized clinical trial. Heart Lung 2025; 72:65-73. [PMID: 40184701 DOI: 10.1016/j.hrtlng.2025.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 03/14/2025] [Accepted: 03/20/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Early initiation of empagliflozin, a sodium-glucose cotransporter 2 inhibitor, in acute heart failure (AHF) patients increases urine output, reduces hospital stays, and enhances quality of life post-hospital discharge. OBJECTIVES This trial aims to investigate the effectiveness and safety of early canagliflozin initiation compared to empagliflozin in hospitalized AHF patients with volume overload. METHODS This was a multicenter, prospective, open-labeled, randomized equivalence trial. AHF diabetic and non-diabetic patients were randomized within 24 h from hospital admission to either receive 100 mg canagliflozin or 10 mg empagliflozin in addition to the standardized protocol for an intravenous loop diuretic. The primary outcome was the median of daily diuresis during the hospitalization period. RESULTS Hospitalized AHF patients were enrolled (71 patients per group). The median daily diuresis during the hospitalization period was 4200 ml in the canagliflozin group, which was statistically equivalent to empagliflozin (4117 ml) with a difference of 83 ml, which falls within the predefined equivalence margin (±10) % of the median of daily diuresis of empagliflozin; Δ = ±411.7 mL), confirming equivalence via bootstrap TSOT p < 0.001. No difference was observed in diuretic response, dyspnea score, orthodema congestion score or length of hospital stay. The NT-proBNP level at day 30 post-discharge and the change in KCCQ-TSS from baseline to day 90 were statistically comparable between both groups, without differences in safety event incidence. CONCLUSION Canagliflozin could be a part of usual care for hospitalized AHF patients and an alternative to empagliflozin without safety concerns.
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Affiliation(s)
- Rabab A El-Gazar
- Department of Clinical Pharmacy, October 6 University, Giza, Egypt.
| | - Bassem Zarif
- Cardiology department, National heart institute, Giza, Egypt.
| | - Ahmed Ali Ali
- Cardiology department, National heart institute, Giza, Egypt.
| | | | - Maggie M Abbassi
- Department of Clinical Pharmacy, Cairo University, Cairo, Egypt.
| | - Nirmeen A Sabry
- Department of Clinical Pharmacy, Cairo University, Cairo, Egypt.
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Shenouda W, Thomas D, Nabi O, Zachariah S. Assessment of Gliflozins prescribing pattern in a United Arab Emirates tertiary-level care hospital. Front Pharmacol 2025; 16:1529528. [PMID: 40235535 PMCID: PMC11996670 DOI: 10.3389/fphar.2025.1529528] [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] [Received: 11/17/2024] [Accepted: 03/14/2025] [Indexed: 04/17/2025] Open
Abstract
Background Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitors, known as Gliflozins, have demonstrated efficacy in managing type 2 diabetes mellitus (T2DM) and providing cardiovascular and renal benefits. Given the prevalence of diabetes, heart failure (HF), and chronic kidney disease (CKD) in the UAE, there is a need to evaluate the prescribing patterns of Gliflozins in these population. The objective of this study was to explore the relationship between Gliflozins use for patients who were admitted to the hospital at least once from 2021 to 2023 and different clinical factors. Methods A retrospective medication review was conducted from 2021 to 2023 at tertiary-level care hospital in Ajman, UAE. Data were collected on prescribed Gliflozins, patient demographic information, BMI, HbA1c levels, and comorbidities (HF, CKD). Chi-square tests and binary logistic regression were used to explore associations between Gliflozin use and clinical factors. Results Out of the 255 patients' data collected, Gliflozin use was significantly associated with obesity (p = 0.002), higher HbA1c levels (p < 0.001), and comorbidities, particularly HF (61.5% of HF patients) and CKD. The use of Gliflozins increased each year. Patients with HF were 8.03 times more likely to use Gliflozins, and those with diabetes were 6.86 times more likely, underscoring the multidimensional role of these medications. Conclusion Gliflozin prescribing patterns in the UAE reflect global trends, with increased use among patients with diabetes, HF, and CKD. Further research is recommended to explore factors influencing prescription practices and optimize Gliflozin therapy if gliflozins use considerably increase in new diagnosis of diabetes and CKD even in mild conditions.
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Affiliation(s)
- Wessa Shenouda
- College of Pharmacy, Gulf Medical University, Ajman, United Arab Emirates
| | - Dixon Thomas
- College of Pharmacy, Gulf Medical University, Ajman, United Arab Emirates
| | - Omar Nabi
- Operations, Thumbay University Hospital, Ajman, United Arab Emirates
| | - Seeba Zachariah
- College of Pharmacy, Gulf Medical University, Ajman, United Arab Emirates
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Pham LT, Mangmool S, Parichatikanond W. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Guardians against Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Heart Diseases. ACS Pharmacol Transl Sci 2024; 7:3279-3298. [PMID: 39539254 PMCID: PMC11555527 DOI: 10.1021/acsptsci.4c00240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 09/11/2024] [Accepted: 10/03/2024] [Indexed: 11/16/2024]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.
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Affiliation(s)
- Linh Thi
Truc Pham
- Biopharmaceutical
Sciences Program, Faculty of Pharmacy, Mahidol
University, Bangkok, 10400 Thailand
- Department
of Pharmacology, Faculty of Pharmacy, Mahidol
University, Bangkok, 10400 Thailand
| | - Supachoke Mangmool
- Department
of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang
Mai, 50200 Thailand
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Soares RR, Viggiani LF, Reis Filho JM, Joviano-Santos JV. Cardioprotection of Canagliflozin, Dapagliflozin, and Empagliflozin: Lessons from preclinical studies. Chem Biol Interact 2024; 403:111229. [PMID: 39244185 DOI: 10.1016/j.cbi.2024.111229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/12/2024] [Accepted: 09/04/2024] [Indexed: 09/09/2024]
Abstract
Clinical and preclinical studies have elucidated the favorable effects of Inhibitors of Sodium-Glucose Cotransporter-2 (iSGLT2) in patients and animal models with type 2 diabetes. Notably, these inhibitors have shown significant benefits in reducing hospitalizations and mortality among patients with heart failure. However, despite their incorporation into clinical practice for indications beyond diabetes, the decision-making process regarding their use often lacks a systematic approach. The selection of iSGLT2 remains arbitrary, with only a limited number of studies simultaneously exploring the different classes of them. Currently, no unique guideline establishes their application in both clinical and basic research. This review delves into the prevalent use of iSGLT2 in animal models previously subjected to induced cardiac stress. We have compiled key findings related to cardioprotection across various animal models, encompassing diverse dosages and routes of administration. Beyond their established role in diabetes management, iSGLT2 has demonstrated utility as agents for safeguarding heart health and cardioprotection can be class-dependent among the iSGLT2. These findings may serve as valuable references for other researchers. Preclinical studies play a pivotal role in ensuring the safety of novel compounds or treatments for potential human use. By assessing side effects, toxicity, and optimal dosages, these studies offer a robust foundation for informed decisions, identifying interventions with the highest likelihood of success and minimal risk to patients. The insights gleaned from preclinical studies, which play a crucial role in highlighting areas of knowledge deficiency, can guide the exploration of novel mechanisms and strategies involving iSGLT2.
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Affiliation(s)
- Rayla Rodrigues Soares
- Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Investigações NeuroCardíacas, Ciências Médicas de Minas Gerais (LINC CMMG), Belo Horizonte, Minas Gerais, Brazil
| | - Larissa Freitas Viggiani
- Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Investigações NeuroCardíacas, Ciências Médicas de Minas Gerais (LINC CMMG), Belo Horizonte, Minas Gerais, Brazil
| | - Juliano Moreira Reis Filho
- Post-Graduate Program in Health Sciences, Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Julliane V Joviano-Santos
- Post-Graduate Program in Health Sciences, Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Investigações NeuroCardíacas, Ciências Médicas de Minas Gerais (LINC CMMG), Belo Horizonte, Minas Gerais, Brazil.
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Bonnesen K, Heide-Jørgensen U, Christensen DH, Lash TL, Hennessy S, Matthews A, Pedersen L, Thomsen RW, Schmidt M. Comparative Cardiovascular Effectiveness of Empagliflozin Versus Dapagliflozin in Adults With Treated Type 2 Diabetes: A Target Trial Emulation. Circulation 2024; 150:1401-1411. [PMID: 39206550 DOI: 10.1161/circulationaha.124.068613] [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: 01/02/2024] [Accepted: 07/19/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Empagliflozin and dapagliflozin have proven cardiovascular benefits in people with type 2 diabetes at high cardiovascular risk, but their comparative effectiveness is unknown. METHODS This study used nationwide, population-based Danish health registries to emulate a hypothetical target trial comparing empagliflozin versus dapagliflozin initiation, in addition to standard care, among people with treated type 2 diabetes from 2014 through 2020. The outcome was a composite of myocardial infarction, ischemic stroke, heart failure (HF), or cardiovascular death (major adverse cardiovascular event). Participants were followed until an outcome, emigration, or death occurred; 6 years after initiation; or December 31, 2021, whichever occurred first. Logistic regression was used to compute inverse probability of treatment and censoring weights, controlling for 57 potential confounders. In intention-to-treat analyses, 6-year adjusted risks, risk differences, and risk ratios, considering noncardiovascular death competing events, were estimated. Analyses were stratified by coexisting atherosclerotic cardiovascular disease and HF. A per-protocol design was performed as a secondary analysis. RESULTS There were 36 670 eligible empagliflozin and 20 606 eligible dapagliflozin initiators. In the intention-to-treat analysis, the adjusted 6-year absolute risk of major adverse cardiovascular event was not different between empagliflozin and dapagliflozin initiators (10.0% versus 10.0%; risk difference, 0.0% [95% CI, -0.9% to 1.0%]; risk ratio, 1.00 [95% CI, 0.91 to 1.11]). The findings were consistent in people with atherosclerotic cardiovascular disease (risk difference, -2.3% [95% CI, -8.2% to 3.5%]; risk ratio, 0.92 [95% CI, 0.74 to 1.14]) and without atherosclerotic cardiovascular disease (risk difference, 0.3% [95% CI, -0.6% to 1.2%]; risk ratio, 1.04 [95% CI, 0.93 to 1.16]) and in people with HF (risk difference, 1.1% [95% CI, -6.5% to 8.6%]; risk ratio, 1.04 [95% CI, 0.79 to 1.37]) and without HF (risk difference, -0.1% [95% CI, -1.0% to 0.8%]; risk ratio, 0.99 [95% CI, 0.90 to 1.09]). The 6-year risks of major adverse cardiovascular event were also not different in the per-protocol analysis (9.1% versus 8.8%; risk difference, 0.2% [95% CI, -2.1% to 2.5%]; risk ratio, 1.03 [95% CI, 0.80 to 1.32]). CONCLUSIONS Empagliflozin and dapagliflozin initiators had no differences in 6-year cardiovascular outcomes in adults with treated type 2 diabetes with or without coexisting atherosclerotic cardiovascular disease or HF.
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Affiliation(s)
- Kasper Bonnesen
- Departments of Clinical Epidemiology (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.), Aarhus University Hospital, Denmark
- Department of Clinical Medicine, Aarhus University, Denmark (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.)
| | - Uffe Heide-Jørgensen
- Departments of Clinical Epidemiology (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.), Aarhus University Hospital, Denmark
- Department of Clinical Medicine, Aarhus University, Denmark (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.)
| | - Diana H Christensen
- Departments of Clinical Epidemiology (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.), Aarhus University Hospital, Denmark
- Endocrinology and Internal Medicine (D.H.C.), Aarhus University Hospital, Denmark
- Department of Clinical Medicine, Aarhus University, Denmark (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.)
| | - Timothy L Lash
- Department of Epidemiology, Rollins School of Public Health, Emory University, GA (T.L.L.)
| | - Sean Hennessy
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, PA (S.H.)
| | - Anthony Matthews
- Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Sweden (A.M.)
| | - Lars Pedersen
- Departments of Clinical Epidemiology (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.), Aarhus University Hospital, Denmark
- Department of Clinical Medicine, Aarhus University, Denmark (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.)
| | - Reimar W Thomsen
- Departments of Clinical Epidemiology (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.), Aarhus University Hospital, Denmark
- Department of Clinical Medicine, Aarhus University, Denmark (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.)
| | - Morten Schmidt
- Departments of Clinical Epidemiology (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.), Aarhus University Hospital, Denmark
- Department of Clinical Medicine, Aarhus University, Denmark (K.B., U.H.-J., D.H.C., L.P., R.W.T., M.S.)
- Department of Cardiology, Gødstrup Regional Hospital, Denmark (M.S.)
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Pan SY, Su EL, Huang CJ, Chuang SY, Chiang CE, Chen CH, Cheng HM. Evaluation of glucose-lowering medications in older people: a comprehensive systematic review and network meta-analysis of randomized controlled trials. Age Ageing 2024; 53:afae175. [PMID: 39137064 DOI: 10.1093/ageing/afae175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/08/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is increasingly being diagnosed in older adults. Our objective is to assess the advantages and potential drawbacks of different glucose-lowering medications in this specific population. METHODS A network meta-analysis was conducted to identify randomized controlled trials that examined patient-centered outcomes in adults aged ≥65 years with T2DM. We searched PubMed, Cochrane CENTRAL, and Embase up to September 23, 2023. Quality of eligible studies were assessed using the Cochrane RoB 2.0 tool. RESULTS A total of 22 trials that involved 41 654 participants were included, incorporating sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, sulfonylureas (SU) and acarbose. Our findings reveal that GLP-1RAs reduce the risk of major adverse cardiovascular events (risk ratio [RR], 0.83; 95% confidence interval [CI], 0.71 to 0.97) and body weight (mean difference [MD], -3.87 kg; 95% CI, -5.54 to -2.21). SGLT2 inhibitors prevent hospitalization for heart failure (RR, 0.66; 95% CI, 0.57 to 0.77), renal composite outcome (RR, 0.69; 95% CI, 0.53 to 0.89), and reduce body weights (MD, -1.85 kg; 95% CI, -2.42 to -1.27). SU treatment increases the risk of any hypoglycaemia (RR, 4.19; 95% CI, 3.52 to 4.99) and severe hypoglycaemia (RR, 7.06; 95% CI, 3.03 to 16.43). GLP-1RAs, SGLT2 inhibitors, metformin, SU and DPP-4 inhibitors are effective in reducing glycaemic parameters. Notably, the number of treatments needed decreases in most cases as age increases. CONCLUSIONS Novel glucose-lowering medications with benefits that outweigh risks should be prioritized for older patients with diabetes.
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Affiliation(s)
- Ssu-Yu Pan
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan
| | - En-Lin Su
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chi-Jung Huang
- Division of Evidence-based Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Yuan Chuang
- Institute of Population Health Science, National Health Research Institute, Miaoli, Taiwan
| | - Chern-En Chiang
- School of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan
- General Clinical Research Centre, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chen-Huan Chen
- School of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan
- Institute of Public Health and Community Medicine Research Centre, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan
| | - Hao-Min Cheng
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Evidence-based Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan
- Institute of Public Health and Community Medicine Research Centre, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan
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Landgraf R, Aberle J, Birkenfeld AL, Gallwitz B, Kellerer M, Klein HH, Müller-Wieland D, Nauck MA, Wiesner T, Siegel E. Therapy of Type 2 Diabetes. Exp Clin Endocrinol Diabetes 2024; 132:340-388. [PMID: 38599610 DOI: 10.1055/a-2166-6755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/12/2024]
Affiliation(s)
| | - Jens Aberle
- Division of Endocrinology and Diabetology, University Obesity Centre Hamburg, University Hospital Hamburg-Eppendorf, Germany
| | | | - Baptist Gallwitz
- Department of Internal Medicine IV, Diabetology, Endocrinology, Nephrology, University Hospital Tübingen, Germany
| | - Monika Kellerer
- Department of Internal Medicine I, Marienhospital, Stuttgart, Germany
| | - Harald H Klein
- MVZ for Diagnostics and Therapy Bochum, Bergstraße 26, 44791 Bochum, Germany
| | - Dirk Müller-Wieland
- Department of Internal Medicine I, Aachen University Hospital RWTH, Aachen, Germany
| | - Michael A Nauck
- Diabetology, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef Hospital, Ruhr University, Bochum, Germany
| | | | - Erhard Siegel
- Department of Internal Medicine - Gastroenterology, Diabetology/Endocrinology and Nutritional Medicine, St. Josefkrankenhaus Heidelberg GmbH, Heidelberg, Germany
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Epperson J, Athar ZM, Arshad M, Chen E. A Review of Sodium-Glucose Cotransporter 2 Inhibitor's Clinical Efficacy in Heart Failure With Preserved Ejection Fraction. Cureus 2024; 16:e57380. [PMID: 38694659 PMCID: PMC11062494 DOI: 10.7759/cureus.57380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2024] [Indexed: 05/04/2024] Open
Abstract
Heart failure (HF) poses a significant healthcare burden, with distinct subtypes based on ventricular function. HF with preserved ejection fraction (HFpEF) presents unique epidemiological and mechanistic features compared to HF with reduced ejection fraction (HFrEF). The pathophysiology of HFpEF is complex and involves multiple factors. Current pharmacological therapies for HFpEF remain suboptimal, with inconsistent mortality outcomes observed despite improvements in symptoms and quality of life. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as promising agents in HF management and hospitalizations, particularly in HFpEF patients. The cardioprotective mechanisms of SGLT2 inhibitors are multifactorial. In this article, we performed a comprehensive review of SGLT2 inhibitor use in HFpEF and discussed the implications in the management of HF.
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Affiliation(s)
- Jacob Epperson
- Internal Medicine, BronxCare Health System, New York, USA
| | | | - Mahnoor Arshad
- Internal Medicine, BronxCare Health System, New York, USA
| | - Edward Chen
- Internal Medicine, BronxCare Health System, New York, USA
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Lyu YS, Hong S, Lee SE, Cho BY, Park CY. Efficacy and safety of enavogliflozin vs. dapagliflozin as add-on therapy in patients with type 2 diabetes mellitus based on renal function: a pooled analysis of two randomized controlled trials. Cardiovasc Diabetol 2024; 23:71. [PMID: 38360626 PMCID: PMC10870449 DOI: 10.1186/s12933-024-02155-9] [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: 01/06/2024] [Accepted: 02/05/2024] [Indexed: 02/17/2024] Open
Abstract
BACKGROUND We assessed the efficacy and safety of enavogliflozin (0.3 mg), a newly developed SGLT-2 inhibitor, in patients with type 2 diabetes mellitus based on kidney function via pooled analysis of two 24-week, randomized, double-blind phase III trials. METHODS Data from 470 patients were included (enavogliflozin: 0.3 mg/day, n = 235; dapagliflozin: 10 mg/day, n = 235). The subjects were classified by mildly reduced (60 ≤ eGFR < 90 mL/min/1.73 m², n = 247) or normal eGFR (≥ 90 mL/min/1.73 m², n = 223). RESULTS In the mildly reduced eGFR group, enavogliflozin significantly reduced the adjusted mean change of HbA1c and fasting plasma glucose levels at week 24 compared to dapagliflozin (- 0.94% vs. -0.77%, P = 0.0196). Enavogliflozin exhibited a more pronounced glucose-lowering effect by HbA1c when combined with dipeptidyl peptidase-4 inhibitors than that observed in their absence. Enavogliflozin showed potent blood glucose-lowering effects regardless of renal function. Conversely, dapagliflozin showed a significant decrease in the glucose-lowering efficacy as the renal function decreased. Enavogliflozin showed a higher urinary glucose excretion rate in both groups. The homeostatic model assessment showed that enavogliflozin markedly decreased the insulin resistance. The blood pressure, weight loss, or homeostasis model assessment of beta-cell function values did not differ significantly between enavogliflozin and dapagliflozin. Adverse events were similar between both drugs. CONCLUSIONS The glucose-lowering efficacy of enavogliflozin is superior to that of dapagliflozin in patients with type 2 diabetes mellitus with mild renal function impairment; this is attributed to its potent urinary glucose excretion-promoting ability. The emergence of new and potent SGLT-2 inhibitors is considered an attractive option for patients with inadequate glycemic control and decreased renal function. TRIAL REGISTRATION Not applicable (pooled analysis).
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Affiliation(s)
- Young Sang Lyu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chosun University Hospital, Gwangju, Republic of Korea
| | - Sangmo Hong
- Division of Endocrinology, Department of Internal Medicine, Hanyang University Guri Hospital, 153 Gyeongchun-ro, Guri, 11923, Korea
| | - Si Eun Lee
- Daewoong Pharmaceutical Co., Ltd, Seoul, Republic of Korea
| | - Bo Young Cho
- Daewoong Pharmaceutical Co., Ltd, Seoul, Republic of Korea
| | - Cheol-Young Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul, 03181, Korea.
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12
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Kani R, Watanabe A, Miyamoto Y, Ejiri K, Iwagami M, Takagi H, Slipczuk L, Tsugawa Y, Aikawa T, Kuno T. Comparison of Effectiveness Among Different Sodium-Glucose Cotransoporter-2 Inhibitors According to Underlying Conditions: A Network Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc 2024; 13:e031805. [PMID: 38293914 PMCID: PMC11056162 DOI: 10.1161/jaha.123.031805] [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: 07/16/2023] [Accepted: 12/27/2023] [Indexed: 02/01/2024]
Abstract
BACKGROUND To investigate the individual profile of each SGLT2 (sodium-glucose cotransoporter-2) inhibitor in patients with different backgrounds. METHODS AND RESULTS This study included 21 placebo-controlled randomized controlled trials with a total of 96 196 participants, investigating empagliflozin, ertugliflozin, dapagliflozin, canagliflozin, and sotagliflozin. The primary efficacy end point was the composite of cardiovascular death and hospitalizations for heart failure. The secondary efficacy end points were all-cause death, cardiovascular death, hospitalizations for heart failure, kidney disease progression, and acute kidney injury. We conducted subgroup analyses based on the underlying comorbidities, including diabetes and chronic kidney disease. Safety end points were also assessed among SGLT2 inhibitors in the overall cohort. In the overall cohort, there were no significant differences in the primary efficacy outcome among the SGLT2 inhibitors, while empagliflozin (hazard ratio [HR], 0.70 [95% CI, 0.53-0.92]) and dapagliflozin (HR, 0.73 [95% CI, 0.56-0.96]) were associated with lower risk of acute kidney injury than sotagliflozin. The presence or absence of diabetes did not alter the results. In patients with chronic kidney disease, there were no differences in the efficacy outcomes among SGLT2 inhibitors, while in patients without chronic kidney disease, empagliflozin was associated with lower risk of the primary outcome compared with ertugliflozin (HR, 0.77 [95% CI, 0.60-0.98]). For safety outcomes, no significant differences were observed in amputation, urinary tract infection, genital infection, hypoglycemia, and diabetic ketoacidosis. CONCLUSIONS The differences in reducing cardiovascular and kidney outcomes as well as safety profiles across SGLT2 inhibitors were not consistently significant, although empagliflozin might be preferred in patients without chronic kidney disease. Further investigations are needed to better understand the mechanism and clinical effectiveness of each SGLT2 inhibitor in certain populations.
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Affiliation(s)
- Ryoma Kani
- Postgraduate Education Center, Kameda Medical CenterChibaJapan
| | - Atsuyuki Watanabe
- Department of MedicineIcahn School of Medicine at Mount Sinai, Mount Sinai Beth IsraelNew YorkNY
| | - Yoshihisa Miyamoto
- Division of Nephrology and EndocrinologyThe University of Tokyo HospitalTokyoJapan
| | - Kentaro Ejiri
- Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreMD
| | - Masao Iwagami
- Department of Health Services Research, Institute of MedicineUniversity of TsukubaTsukubaJapan
- Department of Non‐Communicable Disease EpidemiologyLondon School of Hygiene and Tropical MedicineLondonUnited Kingdom
| | - Hisato Takagi
- Department of Cardiovascular SurgeryShizuoka Medical CenterShizuokaJapan
| | - Leandro Slipczuk
- Division of CardiologyMontefiore Medical Center, Albert Einstein College of MedicineNew YorkNY
| | - Yusuke Tsugawa
- Division of General Internal Medicine and Health Services ResearchDavid Geffen School of Medicine at UCLALos AngelesCA
- Department of Health Policy and ManagementUCLA Fielding School of Public HealthLos AngelesCA
| | - Tadao Aikawa
- Department of CardiologyJuntendo University Urayasu HospitalUrayasuJapan
| | - Toshiki Kuno
- Division of CardiologyMontefiore Medical Center, Albert Einstein College of MedicineNew YorkNY
- Division of CardiologyJacobi Medical Center, Albert Einstein College of MedicineNew YorkNY
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13
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Ye Q, Zha K. SGLT2i‑treated heart failure patients with a reduced ejection fraction: A meta‑analysis. Exp Ther Med 2023; 26:548. [PMID: 37928504 PMCID: PMC10623217 DOI: 10.3892/etm.2023.12248] [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: 01/16/2023] [Accepted: 09/15/2023] [Indexed: 11/07/2023] Open
Abstract
The aim of this study was to investigate the effects of SGLT2 inhibitors (SGLT2i) on patients with heart failure (HF) and reduced ejection fraction, with or without diabetes. A systematic review of randomized controlled trials (RCTs) was conducted, comparing SGLT2i to a placebo for HF patients. Relevant studies from PubMed, Web of Science, and EMBASE were searched from inception to July 2021, without any language restrictions. The pooled effect was estimated using the odds ratio (OR) and 95% confidence interval (CI). Depending on the heterogeneity test results, either random effects or fixed effects models were selected to estimate the pooled effects. Sensitivity analysis was conducted by gradually removing each study to evaluate the results' stability. A total of 5 RCT studies were included in the analysis. The fixed-effects model demonstrated that the patients in the SGLT2i group had a lower risk of hospitalization for HF/cardiovascular death (OR=0.72; 95% CI, 0.67-0.78), P<0.0001; I2=0.0%, P=0.966), cardiovascular death (OR=0.84, 95% CI (0.77, 0.93), P<0.0001; I2=0.0%, P=0.633), hospitalization for HF (OR=0.69, 95% CI (0.63, 0.75), P<0.0001; I2=0.0%, P=0.933), and all-cause mortality (OR=0.79, 95% CI (0.71, 0.89), P<0.0001; I2=3.3%, P=0.376) compared to the placebo group. Sensitivity analysis showed that the pooled effect value remained stable within the corresponding range, even after each study was gradually removed. In conclusion, SGLT2i can reduce the risk of HF hospitalization, cardiovascular death, and all-cause mortality in patients with HF and a reduced ejection fraction, regardless of the presence or absence of diabetes.
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Affiliation(s)
- Qiang Ye
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Kelan Zha
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
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Riaz M, Smith SM, Dietrich EA, Winchester DE, Guo J, Park H. Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors among patients with heart failure with preserved ejection fraction. Pharmacotherapy 2023; 43:1024-1031. [PMID: 37459069 DOI: 10.1002/phar.2853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 05/05/2023] [Accepted: 05/15/2023] [Indexed: 07/25/2023]
Abstract
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are recommended by the American Heart Association for management of heart failure with preserved ejection fraction (HFpEF), but little is known about their in-class comparative effectiveness in real-world settings. OBJECTIVES To assess the in-class comparative effectiveness of SGLT2i for preventing HF-related and all-cause hospitalizations among patients with HFpEF. METHODS Using MarketScan® Commercial and Medicare Supplemental research databases (2012-2020), this cohort study included adults with HFpEF treated with SGLT2i. Stabilized inverse probability treatment weighted Cox proportional hazards regression was used to compare HF-related and all-cause hospitalizations in three pairwise comparisons: dapagliflozin versus canagliflozin, empagliflozin versus canagliflozin, and dapagliflozin versus empagliflozin. Subgroup and sensitivity analyses were conducted to assess robustness of the main analysis. RESULTS In total, 3629 SGLT2i users (881 dapagliflozin, 1120 canagliflozin, and 1628 empagliflozin) were included. Compared with canagliflozin, dapagliflozin was associated with decreased risk of HF-related hospitalization (adjusted hazard ratio [aHR], 0.75; 95% confidence interval [CI], 0.56-1.01) and all-cause hospitalization (aHR, 0.84; 95% CI 0.73-0.97). Compared with canagliflozin, empagliflozin was associated with 55% decreased risk of HF-related hospitalization (aHR, 0.45; 95% CI 0.34-0.59) and 18% decreased risk of all-cause hospitalization (aHR, 0.82; 95% CI 0.73-0.93). Compared with empagliflozin, dapagliflozin was associated with 50% increased risk of HF-related hospitalization (aHR, 1.50; 95% CI 1.09-2.07) and a statistically nonsignificant increase in the risk of all-cause hospitalization (aHR, 1.05; 95% CI 0.92-1.20). CONCLUSIONS Compared with canagliflozin or dapagliflozin use, empagliflozin use was associated with decreased risk of HF-related and all-cause hospitalizations. Compared with canagliflozin, dapagliflozin was associated with a reduced risk of HF-related and all-cause hospitalizations.
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Affiliation(s)
- Munaza Riaz
- Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida, USA
- Lahore College for Women University, Lahore, Pakistan
| | - Steven M Smith
- Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida, USA
- Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Eric A Dietrich
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, USA
| | - David E Winchester
- Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Jingchuan Guo
- Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida, USA
| | - Haesuk Park
- Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida, USA
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15
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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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Malkani NP, Aroda VR. Utilizing type 2 diabetes medications outside glycemic parameters - where are we headed? Curr Opin Endocrinol Diabetes Obes 2023; 30:1-6. [PMID: 36541080 PMCID: PMC9870453 DOI: 10.1097/med.0000000000000787] [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] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Glucose-lowering medications have become strong choices for purposes beyond glucose control in both patients with and without type 2 diabetes. Recent studies have explored the use of specific glucose-lowering therapies in areas such as cardiovascular disease, renal disease, obesity, nonalcoholic fatty liver disease (NAFLD), and Alzheimer's disease, among others. This begs the question if glycemic parameters should be the sole criteria utilized for initiation of diabetes therapeutic agents. RECENT FINDINGS Sodium-glucose co-transporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in particular have demonstrated significant benefits beyond glucose control, with each demonstrating improvement, to various extent, on cardiovascular and renal outcomes, disease-modifying weight loss, progression from prediabetes, and treatment of NAFLD by ameliorating inflammation. SUMMARY Clinical practice guidelines have been updated to reflect the use of these medications to achieve cardiometabolic, renal, and weight goals in addition to glycemic control. The success of glucose-lowering medications in the aforementioned areas have informed the research pursuits in investigating these agents for their anti-inflammatory, neuroprotective, and lipotoxic reduction effects in other diseases entirely.
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Affiliation(s)
- Natasha Prakash Malkani
- Brigham and Women's Hospital Division of Diabetes, Endocrinology, and Hypertension. Boston, Massachusetts, USA
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Forycka J, Hajdys J, Krzemińska J, Wilczopolski P, Wronka M, Młynarska E, Rysz J, Franczyk B. New Insights into the Use of Empagliflozin-A Comprehensive Review. Biomedicines 2022; 10:biomedicines10123294. [PMID: 36552050 PMCID: PMC9775057 DOI: 10.3390/biomedicines10123294] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Empagliflozin is a relatively new drug that, as an inhibitor of the sodium−glucose cotransporter 2 (SGLT2), causes increased urinary glucose excretion and thus contributes to improved glycemic control, better glucose metabolism, reduced glucotoxicity and insulin resistance. Although its original use was to induce a hypoglycemic effect in patients with type 2 diabetes mellitus (T2DM), empagliflozin has also shown a number of other beneficial effects by demonstrating a nephroprotective effect, and it has proven to be a breakthrough in the treatment of heart failure (HF). Empagliflozin has been shown to reduce hospitalizations for HF and the number of deaths from cardiovascular causes. Empagliflozin treatment also reduces the incidence of renal events, including death from renal causes, as well as the risk of end-stage renal failure. Empagliflozin appears to be a fairly well-tolerated and safe drug. In patients with inadequate glycemic control, empagliflozin used in monotherapy or as an adjunct to therapy effectively lowers fasting blood glucose, postprandial blood glucose, average daily glucose levels, glycated hemoglobin A1C (HbA1C) and also leads to significant weight reduction in patients with T2DM. Unfortunately, there are some limitations, e.g., severe hypersensitivity reaction to the drug and a glomerular filtration rate (GFR) < 30 mL/min/1.73 m2. As with any drug, empagliflozin is also characterized by several side effects among which symptomatic hypotension, troublesome genital fungal infections, urinary tract infections and rare ketoacidosis are characteristic.
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Affiliation(s)
- Joanna Forycka
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Joanna Hajdys
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Julia Krzemińska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Piotr Wilczopolski
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Magdalena Wronka
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
- Correspondence: ; Tel.: +48-(042)-639-37-50
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland
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Lakušić N, Sopek Merkaš I, Slišković AM, Cerovec D. Euglycemic diabetic ketoacidosis: A rare but serious side effect of sodium-glucose co-transporter 2 inhibitors. World J Cardiol 2022; 14:561-564. [PMID: 36339887 PMCID: PMC9627354 DOI: 10.4330/wjc.v14.i10.561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 08/29/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023] Open
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an insulin-independent class of oral antihyperglycemic medication and from recently established therapy in chronic heart failure patients. A rare, but potentially life-threatening complication of SGLT2 inhibitor use is euglycemic diabetic ketoacidosis. We described a case of a middle-aged male patient with type 2 diabetes who developed metabolic ketoacidosis after a few days of empagliflozin administration. SGLT2 inhibitor related ketoacidosis presents with euglycemia or only modestly elevated glucose blood concentrations, which causes delayed detection and treatment of ketoacidosis. There are multiple possible risk factors and mechanism that might contribute to the pathogenesis of ketoacidosis. It is implied that SGLT2 inhibitor use and prescription by non-diabetologists (cardiologists, nephrologists, family physicians, etc.) will continue to grow in the future. It is important to inform the general cardiac public about this rare but serious side effect of SGLT2 inhibitors.
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Affiliation(s)
- Nenad Lakušić
- Department of Cardiology, Special Hospital for Medical Rehabilitation Krapinske Toplice, Krapinske Toplice 49217, Croatia
- Department of Clinical Medicine, Faculty of Dental Medicine and Health Osijek, Osijek 31000, Croatia
- Department of Internal Medicine, Family Medicine and History of Medicine, Faculty of Medicine Osijek, Osijek 31000, Croatia
| | - Ivana Sopek Merkaš
- Department of Cardiology, Special Hospital for Medical Rehabilitation Krapinske Toplice, Krapinske Toplice 49217, Croatia.
| | - Ana Marija Slišković
- Department of Cardiology, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Dora Cerovec
- Department of Cardiology, Special Hospital for Medical Rehabilitation Krapinske Toplice, Krapinske Toplice 49217, Croatia
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Gong C, Shen SC, Zhang K, Zhou L, Shen JJ, Zhao JY, Ding SG, Ma LK, Gao H. Association of sodium-glucose cotransporter 2 inhibitors with cardiovascular outcome and safety events: A meta-analysis of randomized controlled clinical trials. Front Cardiovasc Med 2022; 9:926979. [PMID: 36312269 PMCID: PMC9613919 DOI: 10.3389/fcvm.2022.926979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/28/2022] [Indexed: 11/22/2022] Open
Abstract
Background The clinical benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors for preventing and treating cardiovascular events remains controversial. We aimed to study the effect of SGLT2 inhibitors on cardiovascular outcomes and safety events, giving particular attention to the benefits in subgroups of patients with different diseases. Method Randomized controlled trials (RCTs) reporting cardiovascular outcomes following the administration of SGLT2 inhibitors and placebo were included in this study. Cardiovascular outcomes included all-cause death, major adverse cardiovascular events (MACEs), cardiovascular (CV) death, myocardial infarction (MI), stroke, and hospitalization for heart failure (HHF). We also focused on the cardiovascular benefits of SGLT2 inhibitor application in subgroups of patients with different diseases, including type 2 diabetes (T2D), heart failure (HF), high risk of atherosclerotic cardiovascular disease (ACD), diagnosed ACD, and chronic kidney disease (CKD). Safety events associated with SGLT2 inhibitors, including acute kidney injury (AKI), diabetic ketoacidosis (DKA), hypoglycemia, urinary tract infection, thromboembolic event, bone fracture, volume depletion, and amputation, were also reported. Results This meta-analysis included 15 RCTs with 78,212 participants. SGLT2 inhibitors reduced the risk of all-cause death (RR 0.89; 95% CI: 0.85-0.94; I2 = 32%; p < 0.01), CV death (RR 0.87; 95% CI: 0.82-0.93; I2 = 11%; p < 0.01), MACEs (RR 0.89; 95% CI: 0.84-0.94; I2 = 46%; p < 0.01), HHF (RR 0.70; 95% CI: 0.66-0.74; I2 = 0%; p < 0.01), and AKI (RR 0.81; 95% CI: 0.73-0.90; I2 = 0%; p < 0.01) but increased the risk of DKA (RR 2.56; 95% CI: 1.72-3.80; I2 = 0%; p < 0.01). However, no apparent benefit in MI and stroke was observed between the SGLT2 inhibitor and control groups. SGLT2 inhibitors reduced the risk of all-cause death, MACEs, CV death, and HHF in diabetic patients; reduced the risk of all-cause death, MACEs, CV death, MI, and HHF in primary prevention; reduced the risk of all-cause death, CV death, and HHF in patients with ACD and HF; and reduced the risk of MACEs, CV death, and HHF in patients with CKD. Conclusion SGLT2 inhibitors have a positive effect in reducing the risk of all-cause death, CV death, MACE, HHF, and AKI and increasing the risk of DKA. The application of SGLT2 inhibitors in the primary prevention of ACD also has certain clinical benefits in reducing MI. Systematic review registration [https://www.crd.york.ac.uk/prospero/], identifier [CRD42022306490].
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Affiliation(s)
- Chen Gong
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shi-Chun Shen
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Ke Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Lei Zhou
- Department of Cardiology, Jinshan Hospital of Fudan University, Shanghai, China
| | - Jun-Jie Shen
- Second School of Clinical Medicine of Anhui Medical University, Hefei, China
| | - Jia-Ying Zhao
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Sheng-Gang Ding
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li-kun Ma
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Hui Gao
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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20
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Rastogi T, Girerd N. SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction. Heart Fail Clin 2022; 18:561-577. [DOI: 10.1016/j.hfc.2022.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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Aragón-Herrera A, Otero-Santiago M, Anido-Varela L, Moraña-Fernández S, Campos-Toimil M, García-Caballero T, Barral L, Tarazón E, Roselló-Lletí E, Portolés M, Gualillo O, Moscoso I, Lage R, González-Juanatey JR, Feijóo-Bandín S, Lago F. The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile. Front Pharmacol 2022; 13:827033. [PMID: 35185578 PMCID: PMC8847595 DOI: 10.3389/fphar.2022.827033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/04/2022] [Indexed: 12/22/2022] Open
Abstract
The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.
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Affiliation(s)
- Alana Aragón-Herrera
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain
| | - Manuel Otero-Santiago
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Laura Anido-Varela
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Sandra Moraña-Fernández
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Manuel Campos-Toimil
- Group of Pharmacology of Chronic Diseases (CD Pharma), Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Tomás García-Caballero
- Department of Morphological Sciences, University of Santiago de Compostela and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Luis Barral
- Group of Polymers, Department of Physics and Earth Sciences, University of La Coruña, La Coruña, Spain
| | - Estefanía Tarazón
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain.,Cardiocirculatory Unit, Health Research Institute of La Fe University Hospital, Valencia, Spain
| | - Esther Roselló-Lletí
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain.,Cardiocirculatory Unit, Health Research Institute of La Fe University Hospital, Valencia, Spain
| | - Manuel Portolés
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain.,Cardiocirculatory Unit, Health Research Institute of La Fe University Hospital, Valencia, Spain
| | - Oreste Gualillo
- Laboratory of Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Isabel Moscoso
- Cardiology Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS) and Institute of Biomedical Research of Santiago de Compostela (IDIS-SERGAS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Ricardo Lage
- Cardiology Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS) and Institute of Biomedical Research of Santiago de Compostela (IDIS-SERGAS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - José Ramón González-Juanatey
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain
| | - Sandra Feijóo-Bandín
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain
| | - Francisca Lago
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain
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22
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Qiu M, Ding LL, Zhou HR. Comparative Efficacy of Five SGLT2i on Cardiorenal Events: A Network Meta-analysis Based on Ten CVOTs. Am J Cardiovasc Drugs 2022; 22:69-81. [PMID: 34231123 DOI: 10.1007/s40256-021-00484-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND The relative efficacy of different sodium-glucose transporter 2 inhibitors (SGLT2i) on cardiorenal outcomes is unclear. METHODS We included cardiovascular outcome trials (CVOTs) of SGLT2i. The eight endpoints of interest were major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, cardiovascular death (CVD), CVD or hospitalization for heart failure (HHF), HHF, kidney function progression (KFP), and all-cause death (ACD). We conducted a Bayesian network meta-analysis and calculated the surface under the cumulative ranking curve (SUCRA) probability to rank treatments. RESULTS We included ten CVOTs involving five SGLT2i. Canagliflozin (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.53-0.77), dapagliflozin (HR 0.70; 95% CI 0.62-0.79), empagliflozin (HR 0.68; 95% CI 0.59-0.78), ertugliflozin (HR 0.70; 95% CI 0.54-0.90), and sotagliflozin (HR 0.66; 95% CI 0.56-0.77) versus placebo reduced HHF, whereas none reduced MI and stroke. Empagliflozin reduced CVD or HHF (HR 0.81; 95% CI 0.67-0.99) and KFP (HR 0.65; 95% CI 0.45-0.93), and dapagliflozin reduced KFP (HR 0.69; 95% CI 0.52-0.92), versus ertugliflozin. Canagliflozin had the greatest SUCRA values for the reduction of MACE, stroke, and HHF, whereas empagliflozin had the greatest SUCRA values for the reduction of MI, CVD, CVD or HHF, KFP, and ACD. CONCLUSIONS Canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin versus placebo reduce HHF but none reduces MI and stroke. Canagliflozin is most effective in reducing MACE and HHF, and empagliflozin is most effective in reducing CVD, CVD or HHF, KFP, and ACD. These findings will guide the use of specific SGLT2i in the prevention of different cardiorenal events.
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23
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Siamashvili M, Davis SN. Sodium-glucose cotransporter 2 inhibitors for the management of type 2 diabetes. Expert Opin Pharmacother 2021; 22:2181-2198. [PMID: 34388350 DOI: 10.1080/14656566.2021.1967320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Sodium-glucose cotransporter (SGLT) 2 inhibitors reduce glucose reabsorption in the kidney, increase glucosuria, and improve glycemia. Besides glycemic efficacy, the class also lowers risk of cardiovascular and renal disease. AREAS COVERED The authors describe late phase trials of empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin. Safety and efficacy endpoints in monotherapy, combination therapy, cardiovascular, and renal outcomes trials have been identified and presented. EXPERT OPINION SGLT2 inhibitors appear to be safe and effective agents that improve glycemia when used alone or in combination with any other approved antihyperglycemic medications. Other beneficial effects include reductions in body weight and blood pressure, improvements in renal outcomes, all-cause mortality, cardiovascular mortality, and worsening heart failure.
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Affiliation(s)
- Maka Siamashvili
- School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Stephen N Davis
- School of Medicine, University of Maryland, Baltimore, Maryland, USA
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24
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Abushanab D, Liew D, Marquina C, Al-Badriyeh D, Ademi Z. Cost-Effectiveness of Empagliflozin and Metformin Combination Versus Standard Care as First-Line Therapy in Patients with Type 2 Diabetes Mellitus. Endocr Pract 2021; 28:16-24. [PMID: 34389513 DOI: 10.1016/j.eprac.2021.07.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/23/2021] [Accepted: 07/27/2021] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce cardiovascular events, but are currently not used as first-line therapy. This study was conducted to evaluate the cost-effectiveness of first-line empagliflozin plus metformin versus metformin monotherapy among Australians with type 2 diabetes mellitus (T2DM) and existing cardiovascular disease (CVD). METHODS A Markov model with one-year cycles and a five-year time horizon was constructed to simulate the occurrence of recurrent cardiovascular events among Australians aged 50 to 84 years with T2DM and CVD. Efficacy results were derived from the EMPA-REG OUTCOME trial. Costs and utilities were drawn from published sources. The evaluation adopted both healthcare and societal perspectives, with the latter ascribing the Australian Government's 'value of statistical life year' (VoSLY, AUD 213,000) to each year lived by a person. Future outcomes were discounted at 5% annually. Sensitivity analyses were conducted to enhance robustness of conclusions. RESULTS Compared to metformin monotherapy, first-line empagliflozin plus metformin reduced overall cardiovascular events by 0.82% and overall deaths by 7.72% over five years. There were 0.2 years of life saved (YoLS) per person and 0.16 quality-adjusted life years (QALYs) gained, at a net healthcare cost of AUD 4,408. These equated to incremental cost-effectiveness ratios of AUD 22,076 per YoLS and AUD 28,244 per QALY gained. The gains in VoSLY equated to AUD 42,530 per person, meaning that from a societal perspective, the intervention was cost saving. CONCLUSION First-line empagliflozin plus metformin may represent a cost-effective strategy for the management of T2DM and CVD in Australia.
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Affiliation(s)
- Dina Abushanab
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia; Pharmacy Department, Hamad Medical Corporation, Doha, Qatar
| | - Danny Liew
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Clara Marquina
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
| | | | - Zanfina Ademi
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
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25
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Duan XY, Liu SY, Yin DG. Comparative efficacy of 5 sodium glucose cotransporter 2 inhibitor and 7 glucagon-like peptide 1 receptor agonists interventions on cardiorenal outcomes in type 2 diabetes patients: A network meta-analysis based on cardiovascular or renal outcome trials. Medicine (Baltimore) 2021; 100:e26431. [PMID: 34397684 PMCID: PMC8322563 DOI: 10.1097/md.0000000000026431] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 06/03/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been demonstrated to be able to improve the cardiovascular and renal prognosis in patients with type 2 diabetes (T2D). However, the relative efficacy of various SGLT2 inhibitors and GLP-1 RAs on cardiorenal outcomes is unestablished. METHODS We searched PubMed and Embase for relevant cardiovascular or renal outcome trials (CVOTs). Endpoints of interest were major adverse cardiovascular events (MACE), stroke, myocardial infarction (MI), cardiovascular death (CVD), all-cause death (ACD), kidney function progression (KFP), and hospitalization for heart failure (HHF). Bayesian network meta-analysis was conducted to produce pooled hazard ratio (HR) and 95% confidence interval (CI). We calculated the probability values of surface under the cumulative ranking curve to rank active and placebo interventions. RESULTS Fourteen COVTs were included in analysis. Sotagliflozin (HR 0.76, 95% CI 0.61-0.94), subcutaneous semaglutide, and albiglutide lowered MACE versus lixisenatide among others. Sotagliflozin (HR 0.59, 95% CI 0.40-0.89), canagliflozin, and empagliflozin lowered HHF versus subcutaneous semaglutide among others. Dapagliflozin and empagliflozin lowered KFP versus exenatide among others. Empagliflozin and oral semaglutide lowered CVD versus dapagliflozin among others. Sotagliflozin (HR 0.65, 95% CI 0.47-0.91) and albiglutide lowered MI versus ertugliflozin among others. Sotagliflozin (HR 0.56, 95% CI 0.37-0.85) and subcutaneous semaglutide lowered stroke versus empagliflozin among others. Oral semaglutide and empagliflozin lowered ACD versus subcutaneous semaglutide among others. The maximum surface under the cumulative ranking curve values followed sotagliflozin, subcutaneous semaglutide, and albiglutide in lowering MACE; sotagliflozin, canagliflozin, and empagliflozin in lowering HHF; dapagliflozin and empagliflozin in lowering KFP; empagliflozin and oral semaglutide in lowering CVD; sotagliflozin and albiglutide in lowering MI; sotagliflozin and subcutaneous semaglutide in lowering stroke; and oral semaglutide and empagliflozin in lowering ACD. CONCLUSIONS This updated network meta-analysis reproduced the findings in the first network meta-analysis, and moreover revealed that sotagliflozin was one of the most effective drugs as for lowering MI, stroke, MACE, and HHF, whereas ertugliflozin was not. These findings will provide the according evidence regarding the usage of specific SGLT2 inhibitors and GLP-1 RAs in T2D patients for prevention of specific cardiorenal endpoints.
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Affiliation(s)
- Xue-Yan Duan
- Department of General Medicine, Shenzhen Longhua District Central Hospital, Shenzhen
| | - Shu-Yan Liu
- Department of Endocrinology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Dao-Gen Yin
- Department of General Medicine, Shenzhen Longhua District Central Hospital, Shenzhen
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26
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Gager GM, Gelbenegger G, Jilma B, von Lewinski D, Sourij H, Eyileten C, Filipiak K, Postula M, Siller-Matula JM. Cardiovascular Outcome in Patients Treated With SGLT2 Inhibitors for Heart Failure: A Meta-Analysis. Front Cardiovasc Med 2021; 8:691907. [PMID: 34336954 PMCID: PMC8316592 DOI: 10.3389/fcvm.2021.691907] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/14/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Sodium–glucose co-transporter 2 (SGLT2) inhibitors are an emerging class of glucose-lowering drugs that have become increasingly relevant for the treatment and prevention of heart failure (HF). Therefore, we aimed to investigate various SGLT2 inhibitors in patients with established HF at baseline and focused on the different types of HF. Methods: An extensive search of PubMed and Web of Science until January 2021 was done. Two reviewers, independently and in duplicate, applied the selection criteria. This meta-analysis was conducted according to the PRISMA guidelines. Data were pooled using a random-effects model. Randomized controlled trials (RCTs) of SGLT2 inhibitors vs. a comparator in patients with HF reporting clinical outcomes were included. The primary efficacy outcome was the composite of hospitalization for HF (HHF) or cardiovascular (CV) mortality. All-cause mortality, CV mortality, and HHF were considered as secondary endpoints. Subgroup analyses involving the status of diabetes, type of HF, administered type of SGLT2 inhibitor, sex, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), cause of HF, and concomitant medication were performed. Results: Seventeen RCTs, comprising a total of 20,749 participants, were included (n = 10,848 treated with SGLT2 inhibitors and n = 9,901 treated with a comparator). Treatment with SGLT2 inhibitors in a HF population was associated with a 27% relative risk reduction (RRR) of HHF or CV mortality [risk ratio (RR) = 0.73, 95% CI = 0.68–0.78], 32% RRR of HHF (RR = 0.68, 95% CI = 0.62–074), 18% RRR of CV mortality (RR = 0.82, 95% CI = 0.73–0.91), and 17% RRR of all-cause mortality (RR = 0.83, 95% CI = 0.75–0.91). The effect of SGLT2 inhibitors on the primary endpoint was consistent among the different gliflozines. The effect of SGLT2 inhibitors on the primary endpoint was independent of underlying diabetes mellitus, age, sex, BMI, renal function, and HF type. Conclusions: SGLT2 inhibitors are associated with improved CV outcomes in patients with HF.
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Affiliation(s)
- Gloria M Gager
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.,Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Georg Gelbenegger
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Bernd Jilma
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Dirk von Lewinski
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Harald Sourij
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Krzysztof Filipiak
- First Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Jolanta M Siller-Matula
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.,Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
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27
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Real J, Vlacho B, Ortega E, Vallés JA, Mata-Cases M, Castelblanco E, Wittbrodt ET, Fenici P, Kosiborod M, Mauricio D, Franch-Nadal J. Cardiovascular and mortality benefits of sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes mellitus: CVD-Real Catalonia. Cardiovasc Diabetol 2021; 20:139. [PMID: 34243779 PMCID: PMC8272340 DOI: 10.1186/s12933-021-01323-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/23/2021] [Indexed: 02/06/2023] Open
Abstract
Background Evidence from prospective cardiovascular (CV) outcome trials in type 2 diabetes (T2DM) patients supports the use of sodium–glucose co-transporter-2 inhibitors (SGLT2i) to reduce the risk of CV events. In this study, we compared the risk of several CV outcomes between new users of SGLT2i and other glucose-lowering drugs (oGLDs) in Catalonia, Spain. Methods CVD-REAL Catalonia was a retrospective cohort study using real-world data routinely collected between 2013 and 2016. The cohorts of new users of SGLT2i and oGLDs were matched by propensity score on a 1:1 ratio. We compared the incidence rates and hazard ratio (HR) for all-cause death, hospitalization for heart failure, chronic kidney disease, and modified major adverse CV event (MACE; all-cause mortality, myocardial infarction, or stroke). Results After propensity score matching, 12,917 new users were included in each group. About 27% of users had a previous history of CV disease. In the SGLT2i group, the exposure time was 60% for dapagliflozin, 26% for empagliflozin and 14% for canagliflozin. The use of SGLT2i was associated with a lower risk of heart failure (HR: 0.59; 95% confidence interval [CI] 0.47–0.74; p < 0.001), all-cause death (HR = 0.41; 95% CI 0.31–0.54; p < 0.001), all-cause death or heart failure (HR = 0.55; 95% CI 0.47–0.63; p < 0.001), modified MACE (HR = 0.62; 95% CI 0.52–0.74; p < 0.001), and chronic kidney disease (HR = 0.66; 95% CI 0.54–0.80; p < 0.001). Conclusions In this large, retrospective observational study of patients with T2DM from a Catalonia, initiation of SGLT-2i was associated with lower risk of mortality, as well as heart failure and CKD. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-021-01323-5.
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Affiliation(s)
- Jordi Real
- DAP‑Cat Group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.,CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Bogdan Vlacho
- DAP‑Cat Group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain
| | - Emilio Ortega
- Department of Endocrinology and Nutrition, Institut d'Investigacions Biomèdiques August Pi i Suñer, Hospital Clinic, Barcelona, Spain.,CIBER of Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Joan Antoni Vallés
- DAP‑Cat Group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.,Drug Area, Gerència d'Atenció Primaria, Institut Català de la Salut, Barcelona, Spain
| | - Manel Mata-Cases
- DAP‑Cat Group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.,CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.,Primary Health Care Center La Mina, Gerència d'Àmbit d'Atenció Primària Barcelona Ciutat, Institut Català de la Salut, Sant Adrià de Besòs, Spain
| | - Esmeralda Castelblanco
- DAP‑Cat Group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.,CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | | | - Peter Fenici
- Cardiovascular Renal Metabolisms, BioPharmaceuticals Global Medical, AstraZeneca, Cambridge, UK
| | - Mikhail Kosiborod
- Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO, USA
| | - Dídac Mauricio
- DAP‑Cat Group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain. .,CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. .,Department of Endocrinology and Nutrition, Hospital Universitari de la Santa Creu i Sant Pau, Autonomous Universtity of Barcelona, Sant Quintí, 89, 08041, Barcelona, Spain. .,Departament of Medicine, University of Vic-Central University of Catalonia, Vic, Barcelona, Spain.
| | - Josep Franch-Nadal
- DAP‑Cat Group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain. .,CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. .,Primary Health Care Center Raval Sud, Gerència d'Atenció Primaria, Institut Català de la Salut, Av. Drassanes, 17-21, 08001, Barcelona, Spain.
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28
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Arbel R, Aboalhasan E, Hammerman A, Azuri J. Usefulness of Sodium-Glucose Cotransporter 2 Inhibitors for Primary Prevention of Heart Failure in Patients With Type 2 Diabetes Mellitus. Am J Cardiol 2021; 150:65-68. [PMID: 34001339 DOI: 10.1016/j.amjcard.2021.03.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 03/18/2021] [Accepted: 03/22/2021] [Indexed: 01/25/2023]
Abstract
The sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin, canagliflozin, and dapagliflozin reduce the risk of heart failure (HF) events in patients with diabetes mellitus (DM) at high risk for HF. Differences in HF outcomes between SGLT2i were demonstrated in a recent-published meta-analysis. Nevertheless, comparative cost-effectiveness analyses of SGLT2i provided for this indication have not been published yet. Therefore, we aimed to provide a preceding economic comparison of the costs required for improving HF outcomes by these three SGLT2i. The primary outcome was the cost needed to treat (CNT) to prevent one event of hospitalization for HF or cardiovascular mortality. CNT is calculated by multiplying the annualized number needed to treat to prevent one event by the annual cost of therapy. Clinical outcome data were extracted from pre-specified cohorts of HF-naïve patients in the pivotal randomized controlled trials (RCTs). Costs of interventions were estimated as 75% of the US National Average Drug Acquisition Cost listing. Sensitivity analysis was performed to mitigate differences between the RCT's populations. We figured the CNT for the primary prevention of HF events in DM patients to be $542,328 ($409,044-$905,412) for empagliflozin, $2,347,488 ($1,066,208-∞) for canagliflozin and $2,128,374 ($1,204,740-$48,140,518) for dapagliflozin. Sensitivity analysis confirmed the cost benefit of empagliflozin. Our findings suggest that between the available SGLT2i, the cost of primary prevention of HF in patients with DM at high risk for HF is lowest with empagliflozin. These findings may help choose an SGLT2i until head-to-head RCTs, and comprehensive cost-effective analyses for this indication are available.
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Affiliation(s)
- Ronen Arbel
- Maximizing Health Outcomes Research Lab, Sapir College, Sderot, Israel.
| | - Enis Aboalhasan
- Maximizing Health Outcomes Research Lab, Sapir College, Sderot, Israel
| | - Ariel Hammerman
- Department of Pharmaceutical Technology Assessment, Clalit Health Services Headquarters, Tel-Aviv, Israel
| | - Joseph Azuri
- Diabetes Clinic, Central District, Maccabi Healthcare Services, Israel; Sackler Faculty of Medicine, Tel Aviv University, Israel
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First-line Treatment with Empagliflozin and Metformin Combination Versus Standard Care for Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease in Qatar. A Cost-Effectiveness Analysis. Curr Probl Cardiol 2021; 47:100852. [PMID: 33992426 DOI: 10.1016/j.cpcardiol.2021.100852] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 12/15/2022]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown to reduce cardiovascular events and mortality in patients with type 2 diabetes mellitus (T2DM), but they are currently not used as first-line therapy in clinical practice. This study sought to evaluate the cost-effectiveness of first-line empagliflozin plus standard care for patients with newly diagnosed T2DM and existing cardiovascular disease (CVD). A decision-analytic Markov model with one-year cycles and a lifetime time horizon was developed from the perspective of the Qatari healthcare system to compare first-line empagliflozin combined with metformin versus metformin monotherapy for patients aged 50 to 79 years with T2DM and existing CVD. Two health states were considered: 'Alive with CVD and T2DM' and 'Dead'. Patients could experience non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure, hospitalization for unstable angina, and cardiovascular or non-cardiovascular death. Model inputs were ascertained from published and publicly available sources in Qatar. Costs and outcomes were discounted at 3% per annum. Sensitivity analyses were conducted to evaluate parameter uncertainty. The model predicted that adding empagliflozin to current standard care led to additional 1.9 years of life saved (YoLS) and 1.5 quality-adjusted life year (QALYs) per person, and an incremental cost of QAR 56,869 (USD 15,619), which equated to an incremental cost-effectiveness ratio of QAR 30,675 (USD 8,425) per YoLS and QAR 39,245 (USD 10,779) per QALY. Sensitivity analyses showed the findings to be robust. First-line empagliflozin combined with metformin appears to be a cost-effective therapeutic option for patients with T2DM and CVD.
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Sukhanov S, Higashi Y, Yoshida T, Mummidi S, Aroor AR, Jeffrey Russell J, Bender SB, DeMarco VG, Chandrasekar B. The SGLT2 inhibitor Empagliflozin attenuates interleukin-17A-induced human aortic smooth muscle cell proliferation and migration by targeting TRAF3IP2/ROS/NLRP3/Caspase-1-dependent IL-1β and IL-18 secretion. Cell Signal 2021; 77:109825. [PMID: 33160017 PMCID: PMC8118186 DOI: 10.1016/j.cellsig.2020.109825] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 02/07/2023]
Abstract
Chronic inflammation and persistent oxidative stress contribute to the development and progression of vascular proliferative diseases. We hypothesized that the proinflammatory cytokine interleukin (IL)-17A induces oxidative stress and amplifies inflammatory signaling in human aortic smooth muscle cells (SMC) via TRAF3IP2-mediated NLRP3/caspase-1-dependent mitogenic and migratory proinflammatory cytokines IL-1β and IL-18. Further, we hypothesized that these maladaptive changes are prevented by empagliflozin (EMPA), an SGLT2 (Sodium/Glucose Cotransporter 2) inhibitor. Supporting our hypotheses, exposure of cultured SMC to IL-17A promoted proliferation and migration via TRAF3IP2, TRAF3IP2-dependent superoxide and hydrogen peroxide production, NLRP3 expression, caspase-1 activation, and IL-1β and IL-18 secretion. Furthermore, NLRP3 knockdown, caspase-1 inhibition, and pretreatment with IL-1β and IL-18 neutralizing antibodies and IL-18BP, each attenuated IL-17A-induced SMC migration and proliferation. Importantly, SMC express SGLT2, and pre-treatment with EMPA attenuated IL-17A/TRAF3IP2-dependent oxidative stress, NLRP3 expression, caspase-1 activation, IL-1β and IL-18 secretion, and SMC proliferation and migration. Importantly, silencing SGLT2 attenuated EMPA-mediated inhibition of IL-17A-induced cytokine secretion and SMC proliferation and migration. EMPA exerted these beneficial antioxidant, anti-inflammatory, anti-mitogenic and anti-migratory effects under normal glucose conditions and without inducing cell death. These results suggest the therapeutic potential of EMPA in vascular proliferative diseases.
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Affiliation(s)
- Sergiy Sukhanov
- Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
| | - Yusuke Higashi
- Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
| | - Tadashi Yoshida
- Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
| | - Srinivas Mummidi
- Department of Human Genetics, South Texas Diabetes and Obesity Institute, The University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, USA.
| | - Annayya R Aroor
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA; Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA.
| | - Jacob Jeffrey Russell
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA; Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA.
| | - Shawn B Bender
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA; Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA; Dalton Cardiovascular Center, University of Missouri, Columbia, MO, USA.
| | - Vincent G DeMarco
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA; Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA; Dalton Cardiovascular Center, University of Missouri, Columbia, MO, USA; Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA.
| | - Bysani Chandrasekar
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA; Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA; Dalton Cardiovascular Center, University of Missouri, Columbia, MO, USA; Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA.
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31
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Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Heart Failure Events in Patients with Type 2 Diabetes Mellitus: A Cost Per Outcome Analysis. Clin Drug Investig 2020; 40:665-669. [PMID: 32449083 DOI: 10.1007/s40261-020-00929-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND OBJECTIVE Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have significant efficacy in reducing the risk of hospitalization for heart failure (hHF) or cardiovascular (CV) mortality in patients with type 2 diabetes mellitus (T2DM). However, there are differences in HF outcomes between the SGLT2i. Therefore, we compared the cost needed to achieve these outcomes between empagliflozin, canagliflozin, and dapagliflozin. METHODS We calculated the cost needed to treat (CNT) in order to prevent one event of hHF or CV mortality, by multiplying the annualized number needed to treat (NNT) to prevent one event, by the annual cost of each therapy. Efficacy estimates were extracted from published randomized controlled trial (RCT) data. A sensitivity analysis was performed to mitigate differences between the RCT populations. Drug costs were extracted from the 2020 US National Average Drug Acquisition Cost listing. RESULTS We figured empagliflozin's CNT to be $664,464 (95% CI $499,872-$1,097,280), $1,535,387 (95% CI $886,074-$3,210,501) for canagliflozin, and $2,693,145 (95% CI $1,639,563-$11,092,206) for dapagliflozin. The sensitivity analysis confirmed the cost advantage of empagliflozin. CONCLUSIONS Our findings suggest that empagliflozin prescribed for preventing CV death or hHF in T2DM patients seems to be cost saving compared to treatment with canagliflozin, and dapagliflozin.
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