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Ambrosy AP, Sauer AJ, Patel S, Windsor SL, Borlaug BA, Husain M, Inzucchi SE, Kitzman DW, McGuire DK, Shah SJ, Sharma K, Umpierrez G, Kosiborod MN. Baseline kidney function and the effects of dapagliflozin on health status in heart failure in DEFINE-HF and PRESERVED-HF. ESC Heart Fail 2025; 12:1676-1681. [PMID: 39716939 PMCID: PMC12055384 DOI: 10.1002/ehf2.15184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 11/20/2024] [Indexed: 12/25/2024] Open
Abstract
AIMS Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve health status and outcomes in the setting of heart failure (HF) across the range of ejection fraction (EF). Baseline kidney disease is common in HF, complicates HF management and is strongly linked to worse health status. This study aimed to assess whether the treatment effects of dapagliflozin on health status vary based on estimated glomerular filtration rate (eGFR). METHODS AND RESULTS We conducted a pooled participant-level analysis of two double-blind, randomized trials, DEFINE-HF (n = 236) and PRESERVED-HF (n = 324), which evaluated dapagliflozin versus placebo. Both multicentre studies enrolled adults with HF, New York Heart Association Class II or higher, elevated natriuretic peptides, and an EF < 40% in DEFINE-HF or >45% in PRESERVED-HF. The primary exposure was eGFR. The main outcome was the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 12 weeks. Across both trials, there were 583 (99.3%) participants with a baseline eGFR. The median (25th, 75th) eGFR was 59 (46, 77) mL/min/1.73 m2. Dapagliflozin improved KCCQ-CSS at 12 weeks [placebo-adjusted difference, +5.0 points, 95% confidence interval (CI) 2.6-7.5; P < 0.001], and this was consistent in participants with an eGFR ≥ 60 (+6.0 points, 95% CI 2.4-9.7; P = 0.001) and eGFR < 60 (+4.1 points, 95% CI 0.5-7.7; P = 0.025) (P interaction = 0.46). The benefits of dapagliflozin on KCCQ-CSS remained robust across eGFR when modelled as a continuous variable (P interaction = 0.48). CONCLUSIONS Dapagliflozin led to early and clinically meaningful improvements in health status in HF patients, regardless of EF or baseline eGFR.
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Affiliation(s)
- Andrew P. Ambrosy
- Department of CardiologyKaiser PermanenteSan FranciscoCaliforniaUSA
- Division of ResearchKaiser Permanente Northern CaliforniaOaklandCaliforniaUSA
| | - Andrew J. Sauer
- Saint Luke's Mid America Heart InstituteKansas CityMissouriUSA
- Kansas City School of MedicineUniversity of MissouriKansas CityMissouriUSA
| | - Shachi Patel
- Saint Luke's Mid America Heart InstituteKansas CityMissouriUSA
| | | | - Barry A. Borlaug
- Department of Cardiovascular MedicineMayo ClinicRochesterMinnesotaUSA
| | - Mansoor Husain
- Ted Rogers Centre for Heart Research, Peter Munk Cardiac CentreUniversity of TorontoTorontoCanada
| | | | - Dalane W. Kitzman
- Sections on Cardiovascular Medicine and Geriatrics, Department of Internal MedicineWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Darren K. McGuire
- Southwestern Medical Center and Parkland Health and Hospital SystemUniversity of TexasDallasTexasUSA
| | - Sanjiv J. Shah
- Division of Cardiology, Department of Medicine, and Bluhm Cardiovascular InstituteNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| | - Kavita Sharma
- School of MedicineJohns Hopkins UniversityBaltimoreMarylandUSA
| | | | - Mikhail N. Kosiborod
- Saint Luke's Mid America Heart InstituteKansas CityMissouriUSA
- Kansas City School of MedicineUniversity of MissouriKansas CityMissouriUSA
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Packer M, Zile MR, Kramer CM, Murakami M, Ou Y, Borlaug BA. Interplay of Chronic Kidney Disease and the Effects of Tirzepatide in Patients With Heart Failure, Preserved Ejection Fraction, and Obesity: The SUMMIT Trial. J Am Coll Cardiol 2025; 85:1721-1735. [PMID: 40162940 DOI: 10.1016/j.jacc.2025.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Obesity leads to both heart failure with a preserved ejection fraction (HFpEF) and to chronic kidney disease (CKD); CKD may both influence the clinical course of obesity-related HFpEF; and incretin-based drugs may influence renal function. OBJECTIVES This analysis had dual objectives: 1) to evaluate the influence of CKD on the clinical responses to tirzepatide in patients with obesity-related HFpEF; and 2) to investigate the complexity of tirzepatide-related changes in renal function. For both objectives, we focused on discrepancies between creatinine-based and cystatin C-based estimates of the estimated glomerular filtration rate (eGFR). METHODS The SUMMIT trial randomly assigned 731 patients with HFpEF and a body mass index ≥30 kg/m2, who were enriched for participants with CKD. Patients received either placebo or tirzepatide for a median of 104 weeks and were followed for cardiovascular death or worsening heart failure events and for changes in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) after 52 weeks. Because of the confounding produced by obesity and changes in muscle mass, eGFR was assessed at randomization and after 12, 24, and 52 weeks by both creatinine-based and cystatin C-based formulae. RESULTS Patients with CKD (based on creatinine or cystatin C) had greater severity of heart failure, as reflected by: 1) worse functional class, KCCQ-CSS scores, and 6-minute walk distance; 2) higher levels of NT-proBNP and cardiac troponin T; and 3) a 2-fold increase in the risk of worsening heart failure events. CKD did not influence the effect of tirzepatide to reduce the relative risk of major adverse heart failure events and to improve KCCQ-CSS, quality of life, and functional capacity, but the absolute risk reduction in the primary events was numerically greater in patients with CKD. Regarding renal function assessments, baseline eGFR-cystatin C was consistently ≈9 mL/min/1.73 m2 lower than that eGFR-creatinine, with significant individual variance. Furthermore, tirzepatide increased eGFR at 52 weeks, assessed by both creatinine-based and cystatin C-based formulae, but with considerable discordance in individual patients. Tirzepatide produced a decline in eGFR at 12 weeks with eGFR-creatinine (but not eGFR-cystatin C), and it led to an improvement in eGFR at 52 weeks in all patients (when assessed by cystatin C), but only in patients with CKD (when assessed by eGFR-creatinine). CONCLUSIONS The triad of obesity, HFpEF, and CKD identifies patients with considerable functional impairment and an unfavorable prognosis, who nevertheless respond favorably to tirzepatide. Long-term tirzepatide improves renal function (both by cystatin C and creatinine), but the measurement of eGFR in patients with obesity receiving incretin-based drugs is likely to be skewed by the effects of fat and muscle mass (and by changes in body composition) on the synthesis of both cystatin C and creatinine. (A Study of Tirzepatide [LY3298176] in Participants With Heart Failure With Preserved Ejection Fraction [HFpEF] and Obesity: The SUMMIT Trial; NCT04847557).
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Affiliation(s)
- Milton Packer
- Baylor University Medical Center, Dallas Texas, USA; Imperial College, London, United Kingdom.
| | - Michael R Zile
- RHJ Department of Veterans Affairs, Medical Center and Medical University of South Carolina, Charleston, South Carolina, USA
| | - Christopher M Kramer
- Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia, USA
| | | | - Yang Ou
- Eli Lilly & Company, Indianapolis, Indiana, USA
| | - Barry A Borlaug
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Iacovoni A, Navazio A, De Luca L, Gori M, Corda M, Milli M, Iacoviello M, Di Lenarda A, Di Tano G, Marini M, Iorio A, Mortara A, Mureddu GF, Zilio F, Chimenti C, Cipriani MG, Senni M, Bilato C, Di Marco M, Geraci G, Pascale V, Riccio C, Scicchitano P, Tizzani E, Gulizia MM, Nardi F, Gabrielli D, Colivicchi F, Grimaldi M, Oliva F. ANMCO position paper: diagnosis and treatment of heart failure with preserved systolic function. Eur Heart J Suppl 2025; 27:v216-v246. [PMID: 40385467 PMCID: PMC12078774 DOI: 10.1093/eurheartjsupp/suaf070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
Heart failure is the leading cardiovascular cause of hospitalization with an increasing prevalence, especially in older patients. About 50% of patients with heart failure have preserved ventricular function, a form of heart failure that, until a few years ago, was orphaned by pharmacological treatments effective in reducing hospitalization and mortality. New trials, which have tested the use of gliflozins in patients with heart failure with preserved ejection fraction (HFpEF), have for the first time demonstrated their effectiveness in changing the natural history of this insidious and frequent form of heart failure. Therefore, diagnosing those patients early is crucial to provide the best treatment. Moreover, the diagnosis is influenced by the patient's comorbidities, and some HFpEF patients have symptoms common to other rare diseases that, if unrecognized, develop an unfavourable prognosis. This position paper aims to provide the clinician with a useful tool for diagnosing and treating patients with HFpEF, guiding the clinician towards the most appropriate diagnostic and therapeutic pathway.
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Affiliation(s)
- Attilio Iacovoni
- S.S.D. Chirurgia dei Trapianti e del Trattamento Chirurgico dello Scompenso, Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Piazza OMS 1, Bergamo 24127, Italy
| | - Alessandro Navazio
- S.O.C. Cardiologia Ospedaliera, Presidio Ospedaliero Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia—IRCCS, Reggio Emilia, Italy
| | - Leonardo De Luca
- S.C. Cardiologia, Dipartimento Cardio-Toraco-Vascolare, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Mauro Gori
- U.O.C. Cardiologia 1, Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Marco Corda
- S.C. Cardiologia, Azienda di Rilievo Nazionale e Alta Specializzazione ‘G. Brotzu’, Cagliari, Italy
| | - Massimo Milli
- Cardiologia Firenze 1 (Ospedali S. Maria Nuova e Nuovo San Giovanni di Dio), Azienda USL Toscana Centro, Florence, Italy
| | | | - Andrea Di Lenarda
- S.C. Patologie Cardiovascolari, Dipartimento Specialistico Territoriale, Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI), Trieste, Italy
| | - Giuseppe Di Tano
- U.O. CARDIOLOGIA - UCC, Ospedale Cernusco sul Naviglio, Cernusco sul Naviglio, MI, Italy
| | - Marco Marini
- S.O.S. Terapia Intensiva Cardiologica, S.O.D. Cardiologia-UTIC, Dipartimento di Scienze Cardiovascolari, AOU delle Marche, Ancona, Italy
| | - Annamaria Iorio
- S.S.D. Chirurgia dei Trapianti e del Trattamento Chirurgico dello Scompenso, Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Piazza OMS 1, Bergamo 24127, Italy
| | - Andrea Mortara
- Dipartimento di Cardiologia Clinica, Policlinico di Monza, Monza, Italy
| | - Gian Francesco Mureddu
- U.O.S.D. Cardiologia Riabilitativa, Azienda Ospedaliera San Giovanni Addolorata, Rome, Italy
| | - Filippo Zilio
- U.O. Cardiologia, Ospedale Santa Chiara, Trento, Italy
| | - Cristina Chimenti
- Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Azienda Ospedaliera Policlinico Umberto I, Sapienza Università di Roma, Rome, Italy
| | - Manlio Gianni Cipriani
- Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT)-IRCCS, Palermo, Italy
| | - Michele Senni
- S.S.D. Chirurgia dei Trapianti e del Trattamento Chirurgico dello Scompenso, Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Piazza OMS 1, Bergamo 24127, Italy
| | - Claudio Bilato
- U.O.C. Cardiologia, Ospedali dell’Ovest Vicentino, Azienda ULSS 8 Berica, Vicenza, Italy
| | | | - Giovanna Geraci
- U.O.C. Cardiologia, Presidio Ospedaliero Sant’Antonio Abate, ASP Trapani, Erice, TP, Italy
| | - Vittorio Pascale
- UTIC-Emodinamica e Cardiologia Interventistica, Ospedale Civile Pugliese, Catanzaro, Italy
| | - Carmine Riccio
- U.O.S.D. Follow-up del Paziente Post-Acuto, Dipartimento Cardio-Vascolare, AORN Sant’Anna e San Sebastiano, Caserta, Italy
| | | | - Emanuele Tizzani
- Dipartimento di Cardiologia, Ospedale degli Infermi, Rivoli, TO, Italy
| | - Michele Massimo Gulizia
- U.O.C. Cardiologia, Ospedale Garibaldi-Nesima, Azienda di Rilievo Nazionale e Alta Specializzazione ‘Garibaldi’, Catania, Italy
| | - Federico Nardi
- Dipartimento di Cardiologia, Ospedale Santo Spirito, Casale Monferrato, AL, Italy
| | - Domenico Gabrielli
- U.O.C. Cardiologia, Dipartimento Cardio-Toraco-Vascolare, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
- Fondazione per il Tuo cuore—Heart Care Foundation, Florence, Italy
| | - Furio Colivicchi
- U.O.C. Cardiologia Clinica e Riabilitativa, Presidio Ospedaliero San Filippo Neri—ASL Roma 1, Rome, Italy
| | - Massimo Grimaldi
- U.O.C. Cardiologia-UTIC, Ospedale Miulli, Acquaviva delle Fonti, BA, Italy
| | - Fabrizio Oliva
- Fondazione per il Tuo cuore—Heart Care Foundation, Florence, Italy
- Cardiologia 1-Emodinamica, Dipartimento Cardiotoracovascolare ‘A. De Gasperis’, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), Florence, Italy
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Ammar A, Edwin SB, Whitney R, Lipari M, Giuliano C. Updates in chronic kidney disease management: A systematic review. Pharmacotherapy 2025; 45:291-306. [PMID: 40152479 DOI: 10.1002/phar.70014] [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: 12/01/2024] [Revised: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 03/29/2025]
Abstract
Chronic kidney disease (CKD) is a significant global health challenge that impacts both patients and the health care system. This systematic review aims to evaluate the efficacy and safety of emerging therapeutic strategies for CKD management, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), finerenone, sacubitril/valsartan, and potassium binders. We conducted searches in databases including PubMed, Scopus, CINAHL Complete, and Web of Science Core Collection to identify experimental and observational studies pertaining to each of these agents. Included studies were those that enrolled adult patients with CKD who evaluated SGLT2i, GLP-1RA, finerenone, sacubitril/valsartan, and potassium binders compared to other medications or placebo and evaluated renal-related outcomes as a primary or secondary outcome. Methodological quality and risk of bias were assessed using the Cochrane Risk of Bias (version 2) tool for experimental studies and ROBINS-I for observational studies. After screening 2135 unique studies, 138 studies were eligible for this review. These studies describe a substantial and growing body of evidence focused on improving the management of CKD beyond renin-angiotensin system inhibitors (RASi), such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). Currently, SGLT2i have demonstrated consistent benefits with large effect sizes in preventing the progression of CKD, solidifying this class as a first-line treatment along with RASi. Subsequent consideration for GLP-1RA, finerenone, and sacubitril/valsartan should be dependent on patient-specific comorbidities, while potassium binders may allow for longer use of RASi.
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Affiliation(s)
- Amina Ammar
- Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, Michigan, USA
- Department of Pharmacy, Henry Ford St. John Hospital, Detroit, Michigan, USA
| | - Stephanie B Edwin
- Department of Pharmacy, Henry Ford St. John Hospital, Detroit, Michigan, USA
| | - Rachel Whitney
- Medical University of South Carolina, Charleston, South Carolina, USA
| | - Melissa Lipari
- Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, Michigan, USA
- Department of Pharmacy, Henry Ford St. John Hospital, Detroit, Michigan, USA
| | - Christopher Giuliano
- Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, Michigan, USA
- Department of Pharmacy, Henry Ford St. John Hospital, Detroit, Michigan, USA
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Kitai T, Kohsaka S, Kato T, Kato E, Sato K, Teramoto K, Yaku H, Akiyama E, Ando M, Izumi C, Ide T, Iwasaki YK, Ohno Y, Okumura T, Ozasa N, Kaji S, Kashimura T, Kitaoka H, Kinugasa Y, Kinugawa S, Toda K, Nagai T, Nakamura M, Hikoso S, Minamisawa M, Wakasa S, Anchi Y, Oishi S, Okada A, Obokata M, Kagiyama N, Kato NP, Kohno T, Sato T, Shiraishi Y, Tamaki Y, Tamura Y, Nagao K, Nagatomo Y, Nakamura N, Nochioka K, Nomura A, Nomura S, Horiuchi Y, Mizuno A, Murai R, Inomata T, Kuwahara K, Sakata Y, Tsutsui H, Kinugawa K. JCS/JHFS 2025 Guideline on Diagnosis and Treatment of Heart Failure. J Card Fail 2025:S1071-9164(25)00100-9. [PMID: 40155256 DOI: 10.1016/j.cardfail.2025.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
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Salerno N, Ielapi J, Cersosimo A, Leo I, Di Costanzo A, Armentaro G, De Rosa S, Sciacqua A, Sorrentino S, Torella D. Early hemodynamic impact of SGLT2 inhibitors in overweight cardiometabolic heart failure: beyond fluid offloading to vascular adaptation- a preliminary report. Cardiovasc Diabetol 2025; 24:141. [PMID: 40140861 PMCID: PMC11948974 DOI: 10.1186/s12933-025-02699-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 03/20/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Heart failure (HF) is increasingly recognized as a heterogeneous cardiometabolic disorder, often in the context of overweight/obesity independently from diabetes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce HF hospitalizations and cardiovascular mortality across ejection fraction (EF) categories, yet their early hemodynamic effects in cardiometabolic HF, and with preserved ejection fraction (HFpEF) in particular, remain underexplored. METHODS A prospective, single-center study included 20 consecutive HF patients receiving SGLT2i alongside optimized therapy. Transthoracic echocardiography and non-invasive bioimpedance assessments (NICaS system) were performed at baseline and after 4 weeks. RESULTS The median patient age was 75 years [58-84], with 14 patients (70%) being overweight/obese, and only 4 patients with diabetes. The majority (65%) had HF with preserved EF (HFpEF), 25% with mildly reduced EF (HFmrEF), and 10% with reduced EF (HFrEF). At a median follow-up of 33 days [30-68], significant reductions were observed in body weight (67.65 kg [46-99.20] to 65.50 kg [46.30-97], p = 0.027) and systolic blood pressure (130 mmHg [100-150] to 116.50 mmHg [100-141], p = 0.015). Hemodynamic assessments revealed a significant decrease in total peripheral resistance index (TPRi, 3616.50 dynes·sec·cm3 [1600-5024] to 3098.50 dynes·sec·cm3 [1608-4684], p = 0.002). The left atrial volume index decreased significantly (42.84 ml/m² [27-69.40] to 41.15 ml/m² [26-62.60], p < 0.001); a significant decrease in peak tricuspid regurgitation velocity [2.52 m/Sect. (1.30-3.20]), vs. 2.21 m/Sect. (1.44-2.92), p = 0.023] and in pulmonary artery systolic pressure (PASP) [31.0 mmHg (15.0-40.0) vs. 25.50 mmHg (15.0-38.0-), p = 0.010] was observed. Patients with HFrEF or HFmrEF showed significant reduction in total body water (66.33 [51.45-74.45] vs. 58.68 [55.13-66.50]), while HFpEF patients (overweight/obese, n = 11, 79%) had a significant reduction in TPRi (3681 dynes·sec·cm3 [1600-5024] vs. 3085 dynes·sec·cm3 [1608-4684] p = 0.005). CONCLUSIONS Early hemodynamic responses to SGLT2i may differ across HF subtypes. In overweight patients with cardiometabolic HFpEF, our preliminary findings suggest an association with reduced vascular resistance, while in HFrEF/HFmrEF, the primary benefit appears to be volume unloading. However, the vascular effects of SGLT2i remain uncertain, and given the small sample size, these results should be interpreted as hypothesis-generating. Our findings also highlight the potential role of non-invasive hemodynamic monitoring in guiding therapy in HF.
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Affiliation(s)
- Nadia Salerno
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100, Catanzaro, Italy
| | - Jessica Ielapi
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100, Catanzaro, Italy
| | - Angelica Cersosimo
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100, Catanzaro, Italy
| | - Isabella Leo
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100, Catanzaro, Italy
| | - Assunta Di Costanzo
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100, Catanzaro, Italy
| | - Giuseppe Armentaro
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100, Catanzaro, Italy
| | - Salvatore De Rosa
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100, Catanzaro, Italy
| | - Angela Sciacqua
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100, Catanzaro, Italy
| | - Sabato Sorrentino
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100, Catanzaro, Italy.
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100, Catanzaro, Italy.
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Feng Q, Wu M, Mai Z. Emerging horizons: clinical applications and multifaceted benefits of SGLT-2 inhibitors beyond diabetes. Front Cardiovasc Med 2025; 12:1482918. [PMID: 40182430 PMCID: PMC11965600 DOI: 10.3389/fcvm.2025.1482918] [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: 01/19/2025] [Accepted: 03/10/2025] [Indexed: 04/05/2025] Open
Abstract
SGLT-2 inhibitors, initially developed for type 2 diabetes, demonstrate profound cardiorenal and metabolic benefits. This review synthesizes evidence from clinical trials and mechanistic studies to elucidate their roles in cardiovascular diseases, chronic kidney disease, and non-alcoholic fatty liver disease. Key findings include a notable reduction in cardiovascular death/heart failure hospitalization, a marked decrease in heart failure hospitalization risk, and significant improvements in renal and hepatic outcomes. Emerging mechanisms, such as autophagy induction, ketone utilization, and anti-inflammatory effects, underpin these benefits. Ongoing trials explore their potential in non-diabetic populations, positioning SGLT-2 inhibitors as transformative agents in multisystem disease management.
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Affiliation(s)
- Qing Feng
- Department of Cardiology, Kaiping Central Hospital, Kaiping, China
| | - Miaoqiong Wu
- Department of Endocrinology, Kaiping Central Hospital, Kaiping, China
| | - Zizhao Mai
- School of Stomatology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Julián MT, Codina P, Lupón J, Zamora E, Pérez-Montes de Oca A, Domingo M, Santiago-Vacas E, Borrellas A, Ruiz-Cueto M, González-Gallego C, Troya M, Romero-González GA, Alonso N, Bayes-Genis A. Long-term trajectory of estimated glomerular filtration rate in ambulatory patients with type 2 diabetes and heart failure: clinical insights and prognostic implications. Cardiovasc Diabetol 2025; 24:104. [PMID: 40045364 PMCID: PMC11884049 DOI: 10.1186/s12933-025-02632-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 02/05/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND Although previous studies have evaluated renal function decline in patients with heart failure (HF), there is limited evidence on long-term renal trajectories, especially in patients with concomitant HF and type 2 diabetes (T2D). This study aims to provide a detailed analysis of renal function decline over an extended follow-up period in a well-characterized cohort of patients with HF and T2D. METHODS This is a post hoc subanalysis of a prospective registry involving ambulatory patients with HF and T2D referred to a specialized HF clinic. The estimated glomerular filtration rate (eGFR) was assessed at baseline and during scheduled follow-up visits every three months using the Chronic Kidney Disease Epidemiology Collaboration formula. Loess curves were plotted for predefined subgroups, and multivariable longitudinal Cox regression analyses were performed to evaluate the associations between eGFR trajectories and all-cause mortality. RESULTS A total of 1,114 patients with HF and T2D were included, with a mean age of 69.3 ± 10.3 years, and 68.2% were men. In total, 10,830 scheduled creatinine measurements were analysed, with a mean of 15.8 ± 9.4 measurements per patient. A significant progressive decline in the eGFR was observed, with an average annual rate of - 2.05 (95% CI - 2.11 to - 1.95, p < 0.001) ml/min/1.73 m2. Subgroup analysis indicated that older age, nonischaemic HF aetiology, HFpEF or HFmrEF, poor glycaemic control, and higher baseline eGFRs were associated with a more pronounced decline in renal function. Furthermore, a decrease in the eGFR was independently associated with an increased risk of all-cause mortality. CONCLUSIONS This study offers novel insights into long-term renal function trajectories in patients with HF and T2D and identifies key clinical factors associated with accelerated renal decline. Future research is warranted to validate these results in larger, more diverse cohorts and to explore potential therapeutic interventions.
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Affiliation(s)
- Maria Teresa Julián
- Department of Endocrinology and Nutrition and Heart Failure Clinic, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Pau Codina
- Heart Failure Clinic and Cardiology Department, Hospital Germans Trias i Pujol, Badalona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona (UAB), Carretera del Canyet s/n, 08916, Barcelona, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
| | - Josep Lupón
- Heart Failure Clinic and Cardiology Department, Hospital Germans Trias i Pujol, Badalona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona (UAB), Carretera del Canyet s/n, 08916, Barcelona, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
| | - Elisabet Zamora
- Heart Failure Clinic and Cardiology Department, Hospital Germans Trias i Pujol, Badalona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona (UAB), Carretera del Canyet s/n, 08916, Barcelona, Spain
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Mar Domingo
- Heart Failure Clinic and Cardiology Department, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Evelyn Santiago-Vacas
- Heart Failure Clinic and Cardiology Department, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Andrea Borrellas
- Heart Failure Clinic and Cardiology Department, Hospital Germans Trias i Pujol, Badalona, Spain
| | - María Ruiz-Cueto
- Heart Failure Clinic and Cardiology Department, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Carlos González-Gallego
- Department of Endocrinology and Nutrition and Heart Failure Clinic, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Maribel Troya
- Heart Failure Clinic and Nephrology Department, Hospital Germans Trias i Pujol, Badalona, Spain
| | | | - Nuria Alonso
- Department of Endocrinology and Nutrition and Heart Failure Clinic, Hospital Germans Trias i Pujol, Badalona, Spain.
- Department of Medicine, Universitat Autònoma de Barcelona (UAB), Carretera del Canyet s/n, 08916, Barcelona, Spain.
- Center for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
| | - Antoni Bayes-Genis
- Heart Failure Clinic and Cardiology Department, Hospital Germans Trias i Pujol, Badalona, Spain.
- Department of Medicine, Universitat Autònoma de Barcelona (UAB), Carretera del Canyet s/n, 08916, Barcelona, Spain.
- CIBERCV, Instituto de Salud Carlos III, Madrid, Spain.
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Hong D, Hong M, Kim O, Shin H, Bak M, Kim D, Kim J, Hong Choi K, Kyoung Kim E, Myung Lee J, Hoon Yang J, Chang SA, Park SJ, Lee SC, Woo Park S, Choi JO. Efficacy and safety of SGLT2 inhibitors in patients with heart failure according to kidney function: a systematic review and meta-analysis. REVISTA ESPANOLA DE CARDIOLOGIA (ENGLISH ED.) 2025:S1885-5857(25)00080-5. [PMID: 40043944 DOI: 10.1016/j.rec.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/18/2025] [Indexed: 03/23/2025]
Abstract
INTRODUCTION AND OBJECTIVES This study aimed to evaluate the efficacy and safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors throughout the spectrum of kidney function in patients with heart failure (HF). METHODS This meta-analysis included randomized controlled trials comparing SGLT2 inhibitors with placebo in patients with HF stratified by renal function. Literature from inception to June 8, 2024 was searched. The primary outcome was a composite of cardiovascular death or HF events. RESULTS Five trials were identified, comprising 21 204 patients (10 605 in the SGLT2 inhibitor group and 10 599 in the placebo group) who were randomized and followed up for a weighted median duration of 1.8 years. When patients were classified by estimated glomerular filtration rate (eGFR) of 60mL/min/1.73 m2, SGLT2 inhibitors reduced the risk of the primary outcome irrespective of kidney function (RR, 0.81; 95%CI, 0.75-0.87; P<.01 for eGFR <60mL/min/1.73 m2; RR, 0.79; 95%CI, 0.72-0.87; P<.01 for eGFR≥ 60mL/min/1.73 m2; test for subgroup differences P=.75). The beneficial impact of SGLT2 inhibitors was consistently observed when patients were further subclassified by eGFR values of 20-30, 30-45, 45-60, and >60mL/min/1.73 m2 (test for subgroup differences, P=.54). Early eGFR decline showed a differential impact with increased risk only in the placebo subgroup (RR, 1.30; 95%CI, 1.15-1.47; P<.01), but not in the SGLT2 inhibitor subgroup (RR, 0.99; 95%CI, 0.86-1.13; P=.84) (test for subgroup differences, P<.01). CONCLUSIONS SGLT2 inhibitor therapy is safe and effective throughout the spectrum of kidney function and regardless of the initial decline in kidney function in patients with chronic HF. Registered at PROSPERO: CRD42024565218.
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Affiliation(s)
- David Hong
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Minseok Hong
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Onyou Kim
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Heayoung Shin
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Minjung Bak
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Darae Kim
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jihoon Kim
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ki Hong Choi
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Eun Kyoung Kim
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Joo Myung Lee
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeong Hoon Yang
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung-A Chang
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung-Ji Park
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sang-Chol Lee
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seung Woo Park
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jin-Oh Choi
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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10
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Kula AJ, Bartlett D. Cardiorenal syndrome: evolving concepts and pediatric knowledge gaps. Pediatr Nephrol 2025; 40:651-660. [PMID: 39331078 DOI: 10.1007/s00467-024-06517-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/20/2024] [Accepted: 08/20/2024] [Indexed: 09/28/2024]
Abstract
Cardiorenal syndrome (CRS) refers to concomitant dysfunction of both the heart and kidneys. The pathology in CRS is bidirectional. Many individuals with kidney disease will develop cardiovascular complications. Conversely, rates of acute kidney injury and chronic kidney disease are high in cardiac patients. While our understanding of CRS has greatly increased over the past 15 years, most research has occurred in adult populations. Improving cardiorenal outcomes in children and adolescents requires increased collaboration and research that spans organ systems. The purpose of this review is to discuss key features of CRS and help bring to light future opportunities for pediatric-specific research.
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Affiliation(s)
- Alexander J Kula
- Division of Pediatric Nephrology, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 Chicago Ave, Chicago, Il, 60611, USA.
| | - Deirdre Bartlett
- Division of Pediatric Nephrology, Ann & Robert H. Lurie Children's Hospital of Chicago, 225 Chicago Ave, Chicago, Il, 60611, USA
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11
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Martin SS, Aday AW, Allen NB, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Bansal N, Beaton AZ, Commodore-Mensah Y, Currie ME, Elkind MSV, Fan W, Generoso G, Gibbs BB, Heard DG, Hiremath S, Johansen MC, Kazi DS, Ko D, Leppert MH, Magnani JW, Michos ED, Mussolino ME, Parikh NI, Perman SM, Rezk-Hanna M, Roth GA, Shah NS, Springer MV, St-Onge MP, Thacker EL, Urbut SM, Van Spall HGC, Voeks JH, Whelton SP, Wong ND, Wong SS, Yaffe K, Palaniappan LP. 2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation 2025; 151:e41-e660. [PMID: 39866113 DOI: 10.1161/cir.0000000000001303] [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: 01/28/2025]
Abstract
BACKGROUND The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2025 AHA Statistical Update is the product of a full year's worth of effort in 2024 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. This year's edition includes a continued focus on health equity across several key domains and enhanced global data that reflect improved methods and incorporation of ≈3000 new data sources since last year's Statistical Update. RESULTS Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
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12
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Siddiqi TJ, Cherney D, Siddiqui HF, Jafar TH, Januzzi JL, Khan MS, Levin A, Marx N, Rangaswami J, Testani J, Usman MS, Wanner C, Zannad F, Butler J. Effects of Sodium-Glucose Cotransporter-2 Inhibitors on Kidney Outcomes across Baseline Cardiovascular-Kidney-Metabolic Conditions: A Systematic Review and Meta-Analyses. J Am Soc Nephrol 2025; 36:242-255. [PMID: 39230974 PMCID: PMC11801753 DOI: 10.1681/asn.0000000000000491] [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: 04/26/2024] [Accepted: 08/29/2024] [Indexed: 09/06/2024] Open
Abstract
Key Points Sodium-glucose cotransporter-2 (SGLT2) inhibitors slowed the rate of eGFR slope decline in patients with heart failure, CKD, and type 2 diabetes mellitus and in all combinations of multimorbid conditions among these diseases. SGLT2 inhibitors decreased kidney composite outcomes among all disease states and different combinations of multimorbidity, except in patients with heart failure with preserved ejection fraction and heart failure without type 2 diabetes mellitus. SGLT2 inhibitors were found to decrease the risk of kidney failure in patients with type 2 diabetes mellitus and also in those with CKD. Background The effects of sodium-glucose cotransporter-2 inhibitors (SGLT2is) on kidney outcomes in patients with varying combinations of heart failure, CKD, and type 2 diabetes mellitus have not been quantified. Methods PubMed and Scopus were queried up to December 2023 for primary and secondary analyses of placebo-controlled trials of SGLT2is in patients with heart failure, CKD, or type 2 diabetes mellitus. Outcomes of interest were composite kidney end point (combination of eGFR <15 ml/min per 1.73 m2, sustained doubling of serum creatinine, varying percent change in eGFR, and need for KRT), rate of eGFR slope decline, and albuminuria progression. Hazard ratios (HRs) and mean differences with their 95% confidence intervals (CIs) were extracted onto an Excel sheet, and the results were then pooled using a random-effect model through Review Manager (version 5.3, Cochrane Collaboration). Results Eleven trials (n =80,928 patients) were included. Compared with the placebo, SGLT2is reduced the risk of the composite kidney end point by 41% (HR, 0.59; 95% CI, 0.42 to 0.83) in heart failure with reduced ejection fraction, 36% (HR, 0.64; 95% CI, 0.55 to 0.73) in CKD, and 38% (HR, 0.62; 95% CI, 0.56 to 0.69) in type 2 diabetes mellitus. A similar pattern of benefit was observed in combinations of these comorbidities and in patients without baseline heart failure, CKD, or type 2 diabetes mellitus. SGLT2is slowed the rate of eGFR slope decline and reduced the risk of sustained doubling of serum creatinine by 36% (HR, 0.64; 95% CI, 0.56 to 0.72) in the overall population, and a consistent effect on kidney outcomes was observed in most subpopulations with available data. Conclusions SGLT2i improved kidney outcomes in cohorts with heart failure, CKD, and type 2 diabetes mellitus, and these effects were consistent across patients with different combinations of these comorbidities.
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Affiliation(s)
| | - David Cherney
- Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | | | - Tazeen H. Jafar
- Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore
| | - James L. Januzzi
- Massachusetts General Hospital and Baim Institute for Clinical Research, Boston, Massachusetts
| | | | - Adeera Levin
- Division of Nephrology, University of British Columbia, St. Paul's Hospital, Vancouver, British Columbia, Canada
| | - Nikolaus Marx
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Janani Rangaswami
- Division of Nephrology, Washington DV VA Medical Center, Washington, DC
| | - Jeffrey Testani
- Department of Cardiology, Smidt Heart Institute, Los Angeles, California
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | | | - Christoph Wanner
- Renal Research Unit, Comprehensive Heart Failure Center, Department of Clinical Research and Epidemiology, University of Würzburg, Würzburg, Germany
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques, Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
| | - Javed Butler
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
- Baylor Scott and White Research Institute, Baylor Scott and White Health, Dallas, Texas
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13
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Merlo A, D’Elia E, Di Odoardo L, Sciatti E, Senni M. SGLT2 inhibitors and new frontiers in heart failure treatment regardless of ejection fraction and setting. Eur Heart J Suppl 2025; 27:i137-i140. [PMID: 39980771 PMCID: PMC11836731 DOI: 10.1093/eurheartjsupp/suae117] [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] [Indexed: 02/22/2025]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to reduce cardiovascular (CV) mortality and heart failure (HF) hospitalizations, independently from left ventricular ejection fraction (EF). Their efficacy has been assessed both in patients with reduced and preserved EF, with notable benefits in renal outcomes as well. The initiation of SGLT2i in the early phase of hospitalization for acute HF has proven to be safe and beneficial. The EMPULSE and DICTATE-AHF trials support early empagliflozin and dapagliflozin use, respectively, reducing worsening HF events, improving quality of life, and enhancing diuretic efficiency. Notably, these benefits emerge shortly after the initiation of therapy, underscoring the importance of early integration into guideline-directed medical therapy (GDMT). Despite concerns regarding deterioration of renal function, SGLT2i appear to be safe even in patients with low estimated glomerular filtration rates (eGFR). Data suggest that SGLT2i benefits persist without increased safety risks, reassuring clinicians of their efficacy in patients experiencing renal decline. Concerns about volume depletion induced by SGLT2i have also been addressed, with documented enhanced diuresis without adverse renal impacts. Moreover, SGLT2i have been associated with a lower risk of hyperkalaemia events, thus allowing for better optimization of GDMT, including the use of mineralocorticoid receptor antagonists. Overall, these findings highlight the broad CV, renal, and metabolic benefits of SGLT2i, advocating for their early and widespread use in HF management, regardless of EF or eGFR.
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Affiliation(s)
- Anna Merlo
- Cardiovascular Department, Papa Giovanni XXIII Hospital, Piazza OMS 1, 24127 Bergamo, Italy
- University of Milano-Bicocca, Piazza dell'Ateneo Nuovo 1, 20126 Milano, Italy
| | - Emilia D’Elia
- Cardiovascular Department, Papa Giovanni XXIII Hospital, Piazza OMS 1, 24127 Bergamo, Italy
- University of Milano-Bicocca, Piazza dell'Ateneo Nuovo 1, 20126 Milano, Italy
| | - Luca Di Odoardo
- Cardiovascular Department, Papa Giovanni XXIII Hospital, Piazza OMS 1, 24127 Bergamo, Italy
| | - Edoardo Sciatti
- Cardiovascular Department, Papa Giovanni XXIII Hospital, Piazza OMS 1, 24127 Bergamo, Italy
| | - Michele Senni
- Cardiovascular Department, Papa Giovanni XXIII Hospital, Piazza OMS 1, 24127 Bergamo, Italy
- University of Milano-Bicocca, Piazza dell'Ateneo Nuovo 1, 20126 Milano, Italy
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14
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Karagiannidis AG, Theodorakopoulou MP, Alexandrou ME, Iatridi F, Karkamani E, Anastasiou V, Mykoniatis I, Kamperidis V, Strippoli G, Sarafidis P. Sodium-glucose co-transporter 2 inhibitors for all-cause and cardiovascular death in people with different stages of CKD: A systematic review and meta-analysis. Eur J Clin Invest 2025; 55:e14335. [PMID: 39400915 DOI: 10.1111/eci.14335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 10/02/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND Sodium-glucose co-transporter-2 inhibitors (SGLT2is) reduce cardiovascular risk in people with diabetes and established cardiovascular disease, but emerging studies in chronic kidney disease (CKD) have inconsistent results. In this systematic review, we evaluate the effects of SGLT2is on cardiovascular mortality in people with CKD as a whole and across subgroups stratified by baseline kidney function and among people at low, moderate, high and very high risk according to KDIGO- CKD classification system. METHODS Literature search was conducted in PubMed/MEDLINE, Cochrane/CENTRAL, Scopus and Web of Science up to 30 November 2023. We included randomized controlled trials assessing the effect of SGLT2is on cardiovascular mortality in people with CKD. Secondary outcomes included all-cause mortality and major adverse cardiac events (MACE). RESULTS Eleven studies (n = 83,203 participants) were included. In people with CKD, treatment with SGLT2is compared to placebo reduced the risk of cardiovascular death by 14% (hazard ratio [HR] .86; 95%CI .79-.94), all-cause death by 15% (HR .85; 95%CI .79-.91) and MACEs by 13% (HR .87; 95%CI .81-.93). A consistent treatment effect was observed across eGFR-subgroups (≥60 mL/min/1.73 m2: HR .82, 95%CI .65-1.02; <60 mL/min/1.73 m2: HR .86, 95%CI .77-.96, p-subgroup difference = .68) and KDIGO risk-categories (low, moderate, high and very high) (p-subgroup difference = .69) for cardiovascular death; reduction in the risk of all-cause death tended to be greater in the highest KDIGO risk categories. A consistent treatment effect on cardiovascular mortality was observed for different SGLT2is agents studied. Sensitivity analysis for cardiovascular mortality endpoint including studies in diabetic people yielded similar results (HR .86; 95%CI .77-.97). CONCLUSIONS Treatment with SGLT2is led to a significant reduction in the risk of cardiovascular and all-cause mortality in people with different CKD stages. These findings support the use of SGLT2is as an adjunct cardiovascular protective therapy in CKD. PROSPERO REGISTRATION NUMBER PROSPERO registration number: CRD42022382863.
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Affiliation(s)
- Artemios G Karagiannidis
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Marieta P Theodorakopoulou
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria-Eleni Alexandrou
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Fotini Iatridi
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleni Karkamani
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Vasileios Anastasiou
- First Department of Cardiology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Mykoniatis
- First Department of Urology, G. Gennimatas General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Vasileios Kamperidis
- First Department of Cardiology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Giovanni Strippoli
- Department of Precision and Regenerative Medicine and Jonian Area (Dimepre-J), University of Bari, Bari, Italy
- School of Public Health, University of Sydney, Sydney, New South Wales, Australia
| | - Pantelis Sarafidis
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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15
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Gronda E, Iacoviello M, Arduini A, Benvenuto M, Gabrielli D, Bonomini M, Tavazzi L. Gliflozines use in heart failure patients. Focus on renal actions and overview of clinical experience. Eur J Intern Med 2025; 132:1-8. [PMID: 39307625 DOI: 10.1016/j.ejim.2024.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 08/10/2024] [Accepted: 09/04/2024] [Indexed: 02/07/2025]
Abstract
Use of type 2 sodium-glucose cotransporter inhibitors (SGLT2i) gliflozines have first been applied to treatment of diabetic patients. In this setting, unexpected benefits on concomitant heart failure (HF) were seen in large trials. This clinical benefit was initially traced back to their natriuretic properties and as such they were also included in the therapeutic armamentarium of HF treatment. However, further insight into their mechanism of action has clarified their complex interaction with kidney function which better explains their prompt effectiveness in ameliorating HF outcome in the long-term, independent of left ventricular ejection fraction (LVEF) phenotype and concomitant presence of diabetes and/or chronic renal disease. This mainly results from the ability of SGLT2i to counteract the HF-associated hyperactivity of the sympathetic system and neurohormonal activation by modifying the pattern of renal tubular sodium and glucose reabsorption which results in curbing the overall sodium reabsorption. Their action results in decreased kidney workload and related oxygen consumption thus indirectly reducing sympathetic activity. The complex renal functional changes associated with HF and their modifications during SGLT2i administration will be reviewed.
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Affiliation(s)
- Edoardo Gronda
- Medicine and Medicine Sub-Specialties Department, Cardio Renal Program, U.O.C. Nephrology, Dialysis and Adult Renal Transplant Program, IRCCS Ca' Granda Foundation, Ospedale Maggiore Policlinico, Milano, Italy.
| | - Massimo Iacoviello
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | | | - Manuela Benvenuto
- Unità Operativa Complessa Cardiologia-UTIC-Emodinamica, PO Giuseppe Mazzini, Teramo, Italy
| | - Domenico Gabrielli
- Unità Operativa Complessa Cardiologia-UTIC, Azienda Ospedaliera San Camillo Forlanini, Roma, Italy
| | - Mario Bonomini
- Department of Medicine and Aging Sciences, University G. D'Annunzio, Chieti-Pescara, Chieti, Italy.
| | - Luigi Tavazzi
- GVM Care & Research, Maria Cecilia Hospital, Cotignola Ravenna, Italy.
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Mc Causland FR, Vaduganathan M, Claggett BL, Kulac IJ, Desai AS, Jhund PS, Henderson AD, Brinker M, Perkins R, Scheerer MF, Schloemer P, Lam CSP, Senni M, Shah SJ, Voors AA, Zannad F, Pitt B, McMurray JJV, Solomon SD. Finerenone and Kidney Outcomes in Patients With Heart Failure: The FINEARTS-HF Trial. J Am Coll Cardiol 2025; 85:159-168. [PMID: 39490700 DOI: 10.1016/j.jacc.2024.10.091] [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: 10/05/2024] [Revised: 10/21/2024] [Accepted: 10/21/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND Finerenone has kidney-protective effects in patients with chronic kidney disease with type 2 diabetes, but effects on kidney outcomes in patients with heart failure with and without diabetes and/or chronic kidney disease are not known. OBJECTIVES The purpose of this study was to examine the effects of finerenone on kidney outcomes in FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure), a randomized trial of finerenone vs placebo among patients with heart failure with mildly reduced or preserved ejection fraction. METHODS We explored the effects of finerenone on the secondary outcome of a sustained ≥50% estimated glomerular filtration rate (eGFR) decline or kidney failure (sustained eGFR decline <15 mL/min/1.73 m2; initiation of maintenance dialysis; renal transplantation). In this prespecified analysis, we also report effects of finerenone on: 1) sustained ≥57% eGFR decline or kidney failure; 2) eGFR slope; and 3) changes in urine albumin/creatinine ratio (UACR). RESULTS Among 6,001 participants, mean baseline eGFR was 62 ± 20 mL/min/1.73 m2; 48% had eGFR <60 mL/min/1.73 m2. Overall, 5,797 had baseline UACR data (median: 18 mg/g [Q1-Q3: 7-67 mg/g]). Over 2.6 years median follow-up, the incidence of the composite kidney outcome (≥50% eGFR decline or kidney failure) was numerically, but nonsignificantly, higher for finerenone vs placebo (75 vs 55 events; HR: 1.33; 95% CI: 0.94-1.89). Similar results were observed for the composite of ≥57% eGFR decline or kidney failure (41 vs 31 events; HR: 1.28; 95% CI: 0.80-2.05), although the overall event frequency was relatively low. During the first 3 months, finerenone led to an acute decline in eGFR of -2.9 mL/min/1.73 m2 (95% CI: -3.4 to -2.4 mL/min/1.73 m2) but did not alter chronic (from 3 months) eGFR slope (+0.2 mL/min/1.73 m2 per year; 95% CI: -0.1 to 0.4 mL/min/1.73 m2 per year), vs placebo. The difference in total slope was -0.7 mL/min/1.73 m2 per year (95% CI: -0.9 to -0.4 mL/min/1.73 m2 per year.). Finerenone reduced UACR by 30% (95% CI: 25%-34%) over 6 months vs placebo, an effect that persisted throughout follow-up. Finerenone reduced the risk of new-onset of microalbuminuria and macroalbuminuria by 24% (HR: 0.76; 95% CI: 0.68-0.83) and 38% (HR: 0.62; 95% CI: 0.53-0.73), respectively. CONCLUSIONS In FINEARTS-HF, a population at low risk of adverse kidney outcomes, finerenone did not significantly modify the kidney composite outcomes. Finerenone led to a greater reduction in initial eGFR, but did not result in a significant difference in chronic eGFR slope vs placebo. Finerenone led to early and sustained reductions in albuminuria and reduced the risk of new-onset micro- and macroalbuminuria. (FINEARTS-HF [Study to Evaluate the Efficacy (Effect on Disease) and Safety of Finerenon on Morbidity (Events Indicating Disease Worsening) & Mortality (Death Rate) in Participants with Heart Failure and Left Ventricular Ejection Fraction (Proportion of Blood Expelled Per Heart Stroke) Greater or Equal to 40%]; NCT04435626).
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Affiliation(s)
| | - Muthiah Vaduganathan
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Brian L Claggett
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ian J Kulac
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Akshay S Desai
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | - Meike Brinker
- Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany
| | - Robert Perkins
- Bayer U.S., U.S. Medical Affairs, Whippany, New Jersey, USA
| | | | | | - Carolyn S P Lam
- National Heart Centre Singapore & Duke-National University of Singapore, Singapore
| | - Michele Senni
- University of Milano-Bicocca ASST Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Sanjiv J Shah
- Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | | | | | - Bertram Pitt
- University of Michigan, Ann Arbor, Michigan, USA
| | | | - Scott D Solomon
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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17
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Núñez-Marín G, Santas E. Cardiorenal Disease and Heart Failure with Preserved Ejection Fraction: Two Sides of the Same Coin. Cardiorenal Med 2025; 15:108-121. [PMID: 39778558 PMCID: PMC11844673 DOI: 10.1159/000543390] [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: 10/29/2024] [Accepted: 12/26/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD) have a strong pathophysiological interrelationship, and their combination worsens prognosis. SUMMARY This article briefly reviews the bidirectional epidemiological burden and the pathophysiological interplay between HFpEF and CKD. It also discusses some of the controversial aspects regarding the diagnosis and screening of HFpEF in CKD patients and focuses on the most effective therapeutic approaches to improve symptoms and prognosis in this high-risk population. KEY MESSAGES Due to its prevalence and prognostic significance, HFpEF screening should be considered in patients with CKD, with careful use of traditional diagnostic tools in this population. Optimal medical therapy has seen major recent advances in patients with both HFpEF and CKD. SGLT2 inhibitors, finerenone, and semaglutide have consistently demonstrated cardio- and renoprotective effects in both conditions.
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Affiliation(s)
- Gonzalo Núñez-Marín
- Cardiology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
- INCLIVA, Valencia, Spain
| | - Enrique Santas
- Cardiology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
- INCLIVA, Valencia, Spain
- Deparment of Medicine, University of Valencia, Valencia, Spain
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18
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Cao MJ, Liang TT, Xu L, Shi FH. Evaluating the overall renal outcomes of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with chronic kidney disease (CKD). Diabetol Metab Syndr 2025; 17:5. [PMID: 39757198 DOI: 10.1186/s13098-024-01547-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 11/29/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Our meta-analysis fills gaps by assessing sodium-glucose cotransporter-2 (SGLT2) inhibitors' renal outcomes in chronic kidney disease (CKD) patients including long-term effects and the subgroup analyses of estimated glomerular filtration rate (eGFR) values and follow-up times. METHODS The literature search of relevant randomized controlled trials (RCTs) was conducted in Medline, Embase, and the Cochrane Central from the inception to 8 June 2023 on patients with CKD treated with SGLT2 inhibitors. We selected medical subject heading (MeSH) terms and free text terms associated with gliflozin and RCT. We calculated odds ratio (OR) or harzard ratio with 95% confidence intervals (CIs) for composite outcomes and dichotomous data, and weighted mean differences (WMD) for changes in eGFR. RESULTS 16 RCTs enrolling 52,306 patients were in the final population, with 26,910 being treated with SGLT2 inhibitors and 25,396 serving as controls were identified. We found that there was no decline in the rate of change in eGFR after 13 weeks and SGLT2 inhibitors treatment significantly improved the rate of change in eGFR after 64 weeks (64-104 weeks: WMD, 1.024 mL/min/1.73m2/per year, 95% CI 0.643-1.406; 104 weeks: 0.978, 0.163-1.794).SGLT2 inhibitors reduced the risk of acute kidney injury (AKI) (OR 0.836; 95% CI 0.747-0.936; I2 = 0%), mainly derived from empagliflozin (P = 0.001) and increased the incidence of volume-related adverse events (AEs) by 23%.However, no statically differences were observed in death due to kidney disease (P = 0.182) or events of eGFR < 15 mL/min/1.73 m2 (P = 0.202). CONCLUSIONS The results of our meta-analysis showed that after 64 weeks of treatment, SGLT2 inhibitors showed a significant benefit on eGFR rate with no further decline after 13 weeks and the improvement was slighter in lower eGFR values. Additionally, SGLT2 inhibitors reduce AKI when using empagliflozin, while there is an increased risk of volume-related AEs exclusively in stage 2 CKD. Trial registration CRD42023437061.
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Affiliation(s)
- Min-Jia Cao
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Ting-Ting Liang
- Department of Pharmacy, Changshu Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, People's Republic of China
| | - Li Xu
- Department of Nursing, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fang-Hong Shi
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
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19
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Mc Causland FR, Vaduganathan M, Claggett B, Gori M, Jhund PS, McGrath MM, Neuen BL, Packer M, Pfeffer MA, Rouleau JL, Senni M, Swedberg K, Zannad F, Zile M, Lefkowitz MP, McMurray JJV, Solomon SD. Angiotensin Receptor Neprilysin Inhibition and Cardiovascular Outcomes Across the Kidney Function Spectrum: The PARAGON-HF Trial. JACC. HEART FAILURE 2025; 13:105-114. [PMID: 39570234 DOI: 10.1016/j.jchf.2024.08.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 11/22/2024]
Abstract
BACKGROUND Lower estimated glomerular filtration rate (eGFR) may be one of the major reasons for hesitation or failure to initiate potentially beneficial therapies in patients with heart failure (HF). OBJECTIVES This study sought to assess if the effects of sacubitril/valsartan (vs valsartan) on cardiovascular outcomes differ according to baseline kidney function in patients with HF with preserved ejection fraction. METHODS The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial was global clinical trial of 4,796 patients with chronic HF and left ventricular ejection fraction (LVEF) ≥45% randomly assigned to sacubitril/valsartan or valsartan. We examined the effect of treatment on cardiovascular outcomes using Cox regression models, stratified by region, and assessed for differential treatment effects according to the baseline eGFR and ejection fraction. RESULTS At randomization, mean eGFR was 67 ± 19 mL/min/1.73 m2; 1,955 (41%) participants had an eGFR <60 mL/min/1.73 m2. Compared with valsartan, sacubitril/valsartan reduced the primary cardiovascular outcome (cardiovascular death and total HF hospitalizations) to a greater extent among those with lower baseline eGFR (P interaction = 0.07 for continuous eGFR), and was most pronounced for those with eGFR ≤45 mL/min/1.73 m2 (RR: 0.69; 95% CI: 0.51-0.94). The influence of eGFR on the treatment effect for cardiovascular death was nonlinear, with the most pronounced treatment effect for those with baseline eGFR <45 mL/min/1.73 m2 (HR: 0.65; 95% CI: 0.43-0.97). In further subgroup analyses according to LVEF and eGFR, the treatment effect for the primary outcome was most pronounced among those with LVEF ≤57% and eGFR ≤45 mL/min/1.73 m2 (HR: 0.66; 95% CI: 0.45-0.97). CONCLUSIONS In the PARAGON-HF trial, the benefits of sacubitril/valsartan to reduce the frequency of HF hospitalizations and cardiovascular death were most apparent in patients with lower baseline eGFR and lower ejection fraction. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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Affiliation(s)
- Finnian R Mc Causland
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
| | - Muthiah Vaduganathan
- Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Brian Claggett
- Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Mauro Gori
- Cardiology Division, Cardiovascular Department, Azienda Ospedaliera Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Pardeep S Jhund
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Martina M McGrath
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA
| | - Brendon L Neuen
- George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia; Department of Renal Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Marc A Pfeffer
- Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Jean L Rouleau
- Institut de Cardiologie de Montréal, Université de Montréal, Montreal, Quebec, Canada
| | - Michele Senni
- Cardiology Division, Cardiovascular Department, Azienda Ospedaliera Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Karl Swedberg
- Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden
| | - Faiez Zannad
- Inserm CIC1433, CHRU de Nancy, Université de Lorraine, Nancy, France
| | - Michael Zile
- Medical University of South Carolina, Charleston, South Carolina, USA; Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina, USA
| | | | - John J V McMurray
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Scott D Solomon
- Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
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20
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Bellos I, Marinaki S, Lagiou P, Benetou V. Comparative Efficacy and Safety of Cardio-Renoprotective Pharmacological Interventions in Chronic Kidney Disease: An Umbrella Review of Network Meta-Analyses and a Multicriteria Decision Analysis. Biomolecules 2024; 15:39. [PMID: 39858434 PMCID: PMC11764242 DOI: 10.3390/biom15010039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 12/28/2024] [Accepted: 12/30/2024] [Indexed: 01/27/2025] Open
Abstract
Sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1a), and non-steroidal mineralocorticoid receptor antagonists (ns-MRA) are promising treatments for chronic kidney disease. This umbrella review of network meta-analyses evaluated their effects on cardiovascular outcomes, kidney disease progression, and adverse events, using the TOPSIS method to identify the optimal intervention based on P-scores. A total of 19 network meta-analyses and 44 randomized controlled trials involving 86,150 chronic kidney disease patients were included. Compared to placebo, SGLT2i were associated with reduced risks of cardiovascular events [Hazard ratio (HR): 0.776, 95% confidence intervals (CI): 0.727-0.998], kidney disease progression (HR: 0.679, 95% CI: 0.629-0.733), acute kidney injury (HR: 0.873, 95% CI: 0.773-0.907), and serious adverse events (HR: 0.881, 95% CI: 0.847-0.916). GLP1a and ns-MRA were also associated with significant reductions in cardiovascular and kidney-specific composite outcomes. Indirect evidence showed that SGLT2i demonstrated a lower risk of kidney disease progression compared to GLP1a (HR: 0.826, 95% CI: 0.716-0.952) and ns-MRA (HR: 0.818, 95% CI: 0.673-0.995), representing the best intervention across all endpoints. In conclusion, while SGLT2i, GLP1a, and ns-MRA all reduce cardiovascular and kidney disease risks in chronic kidney disease, SGLT2i appears to provide the most favorable balance of efficacy and safety.
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Affiliation(s)
- Ioannis Bellos
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias Str., 115 27 Athens, Greece (V.B.)
- Department of Nephrology and Renal Transplantation, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias Str., 115 27 Athens, Greece;
| | - Smaragdi Marinaki
- Department of Nephrology and Renal Transplantation, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias Str., 115 27 Athens, Greece;
| | - Pagona Lagiou
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias Str., 115 27 Athens, Greece (V.B.)
| | - Vassiliki Benetou
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias Str., 115 27 Athens, Greece (V.B.)
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21
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Metra M, Adamo M, Butler J. Improving Outcome in Patients With Tricuspid Regurgitation: Look At the Kidneys and the Liver! J Am Coll Cardiol 2024; 84:2457-2459. [PMID: 39663006 DOI: 10.1016/j.jacc.2024.09.1238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 12/13/2024]
Affiliation(s)
- Marco Metra
- Cardiology, ASST Spedali Civili and Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy.
| | - Marianna Adamo
- Cardiology, ASST Spedali Civili and Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy
| | - Javed Butler
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA; Baylor Scott and White Research Institute, Baylor Scott and White Health, Dallas, Texas, USA
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22
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Li S, Wu Y, Hu X, Mao X, Liu H, Li D, Xu P, Xia K. Diuretic effect and renal function impact of dapagliflozin in hospitalized patients with HFrEF. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2024; 49:1732-1740. [PMID: 40177756 PMCID: PMC11964808 DOI: 10.11817/j.issn.1672-7347.2024.240294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Indexed: 04/05/2025]
Abstract
OBJECTIVES Patients with heart failure with reduced ejection fraction (HFrEF) often require diuretics during hospitalization to alleviate fluid retention and improve prognosis. However, the diuretic efficacy and renal impact of dapagliflozin in this population remain unclear. This study aims to investigate the effects of dapagliflozin on diuresis and renal function in hospitalized patients with HFrEF. METHODS This retrospective analysis included clinical data from 200 hospitalized HFrEF patients treated at Xiangya Hospital of Central South University between January 2021 and September 2022. Patients were divided into 2 groups based on whether they received dapagliflozin: a standard treatment group (n=120) and a dapagliflozin treatment group (n=80). The following were compared between the 2 groups during hospitalization: The 24-hour average difference of liquid intake and output during the first 5 days, urine output, cumulative urine output, diuretic efficiency, estimated glomerular filtration rate (eGFR), N-terminal pro B-type natriuretic peptide (NT-proBNP), hospitalization costs, drug costs, and cost-effectiveness ratio (C/E). RESULTS 1) Primary outcome: The 24-hour average difference of liquid intake and output during the first 5 days was significantly higher in the dapagliflozin treatment group than in the standard treatment group (P<0.05). 2) Secondary outcomes: The 24-hour average urine volume, cumulative urine volume and diuretic efficiency in the first 5 days of dapagliflozin treatment group were higher than those in the standard treatment group, and the differences were statistically significant (all P<0.05). Among patients with impaired renal function on admission [eGFR between 45 and 90 mL/(min·1.73 m²)], the change in eGFR after treatment was significantly smaller in the dapagliflozin treatment group (P<0.05). For patients with normal renal function on admission [eGFR >90 mL/(min·1.73 m²)], the difference in eGFR changes between 2 groups was not significant (P>0.05). NT-proBNP decreased more in the dapagliflozin treatment group than in the standard treatment group during hospitalization (P<0.05). 3) Other indicators: The length of hospital stay was longer in the dapagliflozin treatment group. However, discharge systolic blood pressure, drug costs, and hospitalization costs were all higher in the standard group, though differences were not statistically significant (all P>0.05). The C/E was more favorable in the dapagliflozin treatment group (425.36 vs. 476.67). CONCLUSIONS In hospitalized patients with chronic HFrEF, dapagliflozin treatment increased 24-hour average difference of liquid intake and output and total urine output, reduced NT-proBNP levels, and showed a milder decline in eGFR in those with pre-existing renal impairment. Discharge blood pressure, drug costs, and hospital stay were not significantly affected. While standard therapy may offer better short-term clinical benefits, dapagliflozin demonstrated a superior short-term cost-effectiveness profile.
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Affiliation(s)
- Shanshan Li
- Phase I Clinical Trial Research Center, Xiangya Hospital, Central South University, Changsha 410008.
| | - Youxuan Wu
- Phase I Clinical Trial Research Center, Xiangya Hospital, Central South University, Changsha 410008
| | - Xiaolei Hu
- Phase I Clinical Trial Research Center, Xiangya Hospital, Central South University, Changsha 410008
| | - Xiaoxiao Mao
- Department of Cardiovascular Diseases, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Huijun Liu
- Department of Cardiovascular Diseases, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Dai Li
- Phase I Clinical Trial Research Center, Xiangya Hospital, Central South University, Changsha 410008
| | - Pingsheng Xu
- Phase I Clinical Trial Research Center, Xiangya Hospital, Central South University, Changsha 410008
| | - Ke Xia
- Department of Cardiovascular Diseases, Xiangya Hospital, Central South University, Changsha 410008, China.
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23
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Vaduganathan M, Neuen BL, McCausland F, Jhund PS, Docherty KF, McMurray JJV, Solomon SD. Why Has it Been Challenging to Modify Kidney Disease Progression in Patients With Heart Failure? J Am Coll Cardiol 2024; 84:2241-2245. [PMID: 39217561 DOI: 10.1016/j.jacc.2024.08.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Affiliation(s)
- Muthiah Vaduganathan
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Brendon L Neuen
- The George Institute for Global Health, Sydney, Australia; Department of Renal Medicine, Royal North Shore Hospital, Sydney, Australia
| | - Finnian McCausland
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Pardeep S Jhund
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Medicine, University of Glasgow, Glasgow, Scotland, United Kingdom
| | - Kieran F Docherty
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Medicine, University of Glasgow, Glasgow, Scotland, United Kingdom
| | - John J V McMurray
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Medicine, University of Glasgow, Glasgow, Scotland, United Kingdom
| | - Scott D Solomon
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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24
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Alsuwayh AF, Altawili M, Alhazmi MF, Alotaibi DFM, Rashed AO, Obaid Abdullah AH, Alkenani AAN, Almohammdi RAS, Alotaibi HFM, Mohamed Alsharif FEA. Potential of Sodium-Glucose Cotransporter-2 Inhibitors in the Management of Heart Failure With Preserved Ejection Fraction: A Narrative Review. Cureus 2024; 16:e73906. [PMID: 39697908 PMCID: PMC11653976 DOI: 10.7759/cureus.73906] [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: 11/17/2024] [Indexed: 12/20/2024] Open
Abstract
Heart failure with preserved ejection fraction presents a major clinical challenge due to its complex pathophysiology and limitations in its therapeutic options. This comprehensive review explores the comparative effectiveness of sodium-glucose cotransporter-2 inhibitors, focusing on their impact on diabetic versus non-diabetic patients, individuals with chronic kidney disease, and the elderly. A comprehensive literature search identified randomized controlled trials, meta-analyses, and clinical studies that evaluated the role of sodium-glucose cotransporter-2 inhibitors in managing heart failure with preserved ejection fraction. Findings indicate that sodium-glucose cotransporter-2 inhibitors significantly reduce heart failure hospitalizations and cardiovascular mortality. Among chronic kidney disease patients with heart failure with preserved ejection fraction, sodium-glucose cotransporter-2 inhibitors showed a decrease in the risk of cardiovascular mortality and hospitalization. Furthermore, their use in elderly patients was associated with improved health-related quality of life and cognitive function, with no notable increase in adverse events. Clinical guidelines increasingly recommend sodium-glucose cotransporter-2 inhibitors as part of heart failure with preserved ejection fraction management. However, further research is required to refine patient-specific strategies and explore additional benefits, such as their cardioprotective role post-myocardial infarction. This review highlights the effectiveness of sodium-glucose cotransporter-2 inhibitors in managing heart failure with preserved ejection fraction across various subgroups. Additionally, integrating these agents into clinical practice has significant potential to improve patient outcomes.
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25
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Piperis C, Marathonitis A, Anastasiou A, Theofilis P, Mourouzis K, Giannakodimos A, Tryfou E, Oikonomou E, Siasos G, Tousoulis D. Multifaceted Impact of SGLT2 Inhibitors in Heart Failure Patients: Exploring Diverse Mechanisms of Action. Biomedicines 2024; 12:2314. [PMID: 39457625 PMCID: PMC11504660 DOI: 10.3390/biomedicines12102314] [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: 09/04/2024] [Revised: 10/02/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Heart failure (HF) is a growing concern due to the aging population and increasing prevalence of comorbidities. Despite advances in treatment, HF remains a significant burden, necessitating novel therapeutic approaches. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have emerged as a promising treatment option, demonstrating benefits across the entire spectrum of HF, regardless of left ventricular ejection fraction (LVEF). This review explores the multifaceted mechanisms through which SGLT2is exert cardioprotective effects, including modulation of energy metabolism, reduction of oxidative stress, attenuation of inflammation, and promotion of autophagy. SGLT2is shift myocardial energy substrate utilization from carbohydrates to more efficient fatty acids and ketone bodies, enhancing mitochondrial function and reducing insulin resistance. These inhibitors also mitigate oxidative stress by improving mitochondrial biogenesis, reducing reactive oxygen species (ROS) production, and regulating calcium-signaling pathways. Inflammation, a key driver of HF progression, is alleviated through the suppression of proinflammatory cytokines and modulation of immune cell activity. Additionally, SGLT2is promote autophagy, facilitating the clearance of damaged cellular components and preserving myocardial structure and function. Beyond their glucose-lowering effects, SGLT2is provide significant benefits in patients with chronic kidney disease (CKD) and HF, reducing the progression of CKD and improving overall survival. The pleiotropic actions of SGLT2is highlight their potential as a cornerstone in HF management. Further research is needed to fully elucidate their mechanisms and optimize their use in clinical practice.
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Affiliation(s)
- Christos Piperis
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Anastasios Marathonitis
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Artemis Anastasiou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Panagiotis Theofilis
- 1st Department of Cardiology, “Hippokration” General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Mourouzis
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Alexios Giannakodimos
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Elsi Tryfou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Gerasimos Siasos
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Dimitris Tousoulis
- 1st Department of Cardiology, “Hippokration” General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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26
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Lopez-Usina A, Mantilla-Cisneros C, Llerena-Velastegui J. Comprehensive Benefits of Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure With Reduced Ejection Fraction: A Literature Review. J Clin Med Res 2024; 16:449-464. [PMID: 39544327 PMCID: PMC11557505 DOI: 10.14740/jocmr6033] [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: 08/19/2024] [Accepted: 09/04/2024] [Indexed: 11/17/2024] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially developed for type 2 diabetes, have emerged as a promising treatment for heart failure with reduced ejection fraction (HFrEF). They show significant cardiovascular benefits, including reduced cardiovascular mortality and heart failure hospitalizations. This review consolidates knowledge on the efficacy of SGLT2 inhibitors in HFrEF, focusing on their mechanisms of action, clinical benefits, and patient outcomes. To consolidate existing knowledge on the efficacy of SGLT2 inhibitors in reducing cardiovascular mortality in HFrEF, with an emphasis on pathophysiology, clinical benefits, and patient outcomes, major medical databases such as PubMed, Scopus, and Web of Science were reviewed, prioritizing research published from 2020 to 2024. Key studies and clinical trials, including DAPA-HF and EMPEROR-Reduced, were analyzed to understand the impacts of SGLT2 inhibitors on HFrEF management. The review highlights the multifaceted mechanisms by which SGLT2 inhibitors exert their cardiovascular benefits, including osmotic diuresis, natriuresis, improved myocardial energetics, and anti-inflammatory and antifibrotic effects. Clinical trials have consistently demonstrated significant reductions in cardiovascular mortality and hospitalizations among HFrEF patients treated with SGLT2 inhibitors. These benefits are observed across diverse demographic and clinical subgroups, indicating their broad applicability in clinical practice. SGLT2 inhibitors significantly advance HFrEF management, reducing cardiovascular mortality and hospitalizations. However, gaps remain in long-term outcomes, early diagnostic indicators, and mechanisms of action. Future research should address these gaps and explore personalized medicine to optimize treatment. Integrating SGLT2 inhibitors into standard HFrEF management guidelines, supported by updated policies and educational initiatives for healthcare providers, will be crucial to maximize their therapeutic potential and improve patient outcomes.
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Affiliation(s)
| | | | - Jordan Llerena-Velastegui
- Medical School, Pontifical Catholic University of Ecuador, Quito, Ecuador
- Research Center, Center for Health Research in Latin America (CISeAL), Quito, Ecuador
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Lu H, Chatur S, Lee S, Inciardi RM, Abanda M, Mc Causland FR, Kalayci A, Taheri KK, Shah AM, Cikes M, Claggett BL, Prasad N, Lam CSP, O'Meara E, Wang X, McMurray JJV, Pfeffer MA, Hegde SM, Solomon SD, Skali H. Relationship Between Cardiac Structure and Function With Renal Function Trajectory and Outcomes in Patients With Heart Failure: Insights From the PARAGON-HF Trial. Circ Heart Fail 2024; 17:e011942. [PMID: 39212045 DOI: 10.1161/circheartfailure.124.011942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 08/01/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Renal dysfunction is common and associated with a poor prognosis in patients with heart failure. However, the association of cardiac structure and function with decline in kidney function in this population is unknown. We aimed to assess the association between individual measures of cardiac structure and function with changes in renal function and renal outcomes in patients with heart failure with preserved ejection fraction. METHODS Patients enrolled in the PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction) echocardiographic substudy were included. The association between each echocardiographic parameter (expressed in standardized units) and changes over time in estimated glomerular filtration rate was calculated with repeated-measures mixed-effect models. Multivariable Cox proportional hazards models were used to identify individual cardiac parameters associated with the composite renal outcome (≥50% decline in estimated glomerular filtration rate relative to baseline, development of end-stage renal disease, or death attributable to renal causes), after adjusting for covariates. RESULTS Among 1097 patients (mean age 74±8 years and 53% women), over a median follow-up of 2.9 years, 28 composite renal events (0.9 per 100 person-years) occurred. Higher left ventricular (LV) mass index and higher E/average e' ratio were associated with significantly more profound annual decline in estimated glomerular filtration rate (for both, -0.4 [95% CI, -0.7 to -0.1] mL/min/1.73 m2/y per 1 higher SD). Higher LV mass index, LV end-diastolic volume index, right ventricular end-diastolic area, and a lower right ventricular fractional area change were each associated with a significantly higher risk for the composite renal outcome. CONCLUSIONS In the PARAGON-HF echocardiographic substudy, higher LV mass and filling pressures were independently associated with more profound kidney function decline, and higher LV mass and volume, as well as impaired right ventricular structure and function, were each associated with renal events. Assessing these parameters may help identify patients with heart failure with preserved ejection fraction at higher risk for adverse renal events and indicate potential therapeutic targets. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.
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Affiliation(s)
- Henri Lu
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Safia Chatur
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Sahmin Lee
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Riccardo M Inciardi
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Martin Abanda
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Finnian R Mc Causland
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Arzu Kalayci
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Kimia Karimi Taheri
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Amil M Shah
- Division of Cardiovascular Medicine, University of Texas Southwestern Medical Center, Dallas (A.M.S.)
| | - Maja Cikes
- Department of Cardiovascular Diseases, University of Zagreb School of Medicine, University Hospital Centre Zagreb, Croatia (M.C.)
| | - Brian L Claggett
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Narayana Prasad
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Carolyn S P Lam
- National Heart Centre Singapore and Duke-National University of Singapore, Singapore (C.S.P.L.)
| | - Eileen O'Meara
- Department of Cardiology, Montreal Heart Institute, Université de Montréal, Québec, QC, Canada (E.O.)
| | - Xiaowen Wang
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - John J V McMurray
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, Scotland, United Kingdom (J.J.V.M.)
| | - Marc A Pfeffer
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Sheila M Hegde
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Scott D Solomon
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Hicham Skali
- Division of Cardiovascular Medicine, (H.L., S.C., S.L., M.A., A.K., K.K.T., B.L.C., N.P., X.W., M.A.P., S.M.H., S.D.S., H.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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von Haehling S, Assmus B, Bekfani T, Dworatzek E, Edelmann F, Hashemi D, Hellenkamp K, Kempf T, Raake P, Schütt KA, Wachter R, Schulze PC, Hasenfuss G, Böhm M, Bauersachs J. Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment. Clin Res Cardiol 2024; 113:1287-1305. [PMID: 38602566 PMCID: PMC11371894 DOI: 10.1007/s00392-024-02396-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/02/2024] [Indexed: 04/12/2024]
Abstract
The aetiology of heart failure with preserved ejection fraction (HFpEF) is heterogenous and overlaps with that of several comorbidities like atrial fibrillation, diabetes mellitus, chronic kidney disease, valvular heart disease, iron deficiency, or sarcopenia. The diagnosis of HFpEF involves evaluating cardiac dysfunction through imaging techniques and assessing increased left ventricular filling pressure, which can be measured directly or estimated through various proxies including natriuretic peptides. To better narrow down the differential diagnosis of HFpEF, European and American heart failure guidelines advocate the use of different algorithms including comorbidities that require diagnosis and rigorous treatment during the evaluation process. Therapeutic recommendations differ between guidelines. Whilst sodium glucose transporter 2 inhibitors have a solid evidence base, the recommendations differ with regard to the use of inhibitors of the renin-angiotensin-aldosterone axis. Unless indicated for specific comorbidities, the use of beta-blockers should be discouraged in HFpEF. The aim of this article is to provide an overview of the current state of the art in HFpEF diagnosis, clinical evaluation, and treatment.
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Affiliation(s)
- Stephan von Haehling
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Robert-Koch-Strasse 40, 37075, Göttingen, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany.
| | - Birgit Assmus
- Department of Cardiology and Angiology, Universitätsklinikum Gießen und Marburg, Giessen, Germany
| | - Tarek Bekfani
- Department of Cardiology and Angiology, Universitätsklinikum Magdeburg, Magdeburg, Germany
| | - Elke Dworatzek
- Institute of Gender in Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Frank Edelmann
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité - Medical Heart Center of Charité and German Heart Institute Berlin, Campus Virchow-Klinikum, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Djawid Hashemi
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité - Medical Heart Center of Charité and German Heart Institute Berlin, Campus Virchow-Klinikum, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Digital Clinician Scientist Program, Berlin, Germany
| | - Kristian Hellenkamp
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Robert-Koch-Strasse 40, 37075, Göttingen, Germany
| | - Tibor Kempf
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
| | - Philipp Raake
- I. Medical Department, Cardiology, Pneumology, Endocrinology and Intensive Care Medicine, University Hospital Augsburg, University of Augsburg, Augsburg, Germany
| | - Katharina A Schütt
- Department of Internal Medicine I, University Hospital RWTH Aachen, Aachen, Germany
| | - Rolf Wachter
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Robert-Koch-Strasse 40, 37075, Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany
- Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | - Paul Christian Schulze
- Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany
| | - Gerd Hasenfuss
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Robert-Koch-Strasse 40, 37075, Göttingen, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany
| | - Michael Böhm
- Kardiologie, Angiologie und Internistische Intensivmedizin, Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Saarland University, Homburg, Germany
| | - Johann Bauersachs
- Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
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Wang X, He M, Jin D, Sun C, Lu H. Effect of SGLT-2 inhibitors on acute kidney injury in patients with heart failure: a systematic review and meta-analysis. Diabetol Metab Syndr 2024; 16:207. [PMID: 39192267 DOI: 10.1186/s13098-024-01446-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 08/12/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND Sodium glucose cotransporter-2 (SGLT-2) inhibitors are known to reduce hospitalization and cardiovascular mortality in various heart failure (HF) populations, potentially through enhanced excretion of water and sodium. However, there are concerns regarding the risk of acute kidney injury (AKI) associated with their use. This meta-analysis aimed to unravel the effects of SGLT-2 inhibitors on risk of AKI in a variety of patients with HF. METHODS This study conducted a comprehensive literature search using PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov for studies published up to January 1, 2024. Data were analyzed using both random-effects or fixed-effects models to estimate the overall relative risk (RR) with a 95% confidence interval (CI). RESULTS Our analysis included 25,172 patients with HF from 16 randomized controlled trials. Treatment with SGLT-2 inhibitors led to a 28% reduction in the risk of AKI progression compared to placebo (RR 0.72, 95% CI 0.61-0.85, p<0.0001), without an increased risk of hypotension (RR 1.21, 95% CI 0.87-1.70, p = 0.26) and hypovolemia (RR 2.26, 95% CI: 0.70-7.33, p = 0.17). Notably, SGLT-2 inhibitors significantly decreased AKI in specific subgroups, including patients with HF with reduced ejection fraction (RR 0.59, 95% CI 0.43-0.80, p = 0.0007), those treated with empagliflozin (RR 0.70, 95% CI 0.57-0.88, p = 0.002) or dapagliflozin (RR 0.74, 95% CI 0.57-0.98, p = 0.04), in studies with a follow-up of at least 1 year (RR 0.67, 95% CI 0.55-0.82, p = 0.0001), and in patients aged 65 years or older (RR 0.72, 95% CI 0.61-0.85, p < 0.0001). CONCLUSION Use of SGLT-2 inhibitors did not increase the incidence of AKI regardless of the ejection fraction environment (chronic and acute), type of SGLT-2 inhibitors, or patient age.
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Affiliation(s)
- Xianghong Wang
- Department of Endocrinology and Metabolism, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Zhuhai, China
| | - Meihong He
- The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China
| | - Donghua Jin
- Department of Intensive Care Unit, The Third People's Hospital of Zhengzhou, Henan, China
| | - Chuanchuan Sun
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Hongyun Lu
- Department of Endocrinology and Metabolism, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Zhuhai, China.
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Theodorakopoulou MP, Alexandrou ME, Tsitouridis A, Kamperidis V, Pella E, Xanthopoulos A, Ziakas A, Triposkiadis F, Vassilikos V, Papagianni A, Sarafidis P. Effects of sodium-glucose co-transporter 2 inhibitors on heart failure events in chronic kidney disease: a systematic review and meta-analysis. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2024; 10:329-341. [PMID: 38218589 DOI: 10.1093/ehjcvp/pvae003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 08/05/2023] [Accepted: 01/11/2024] [Indexed: 01/15/2024]
Abstract
AIMS Sodium-glucose co-transporter 2 (SGLT-2) inhibitors significantly reduce the risk for hospitalizations for heart failure (HF) in patients with diabetes, and HF; findings in patients with chronic kidney disease (CKD) are not uniform. We aimed to perform a meta-analysis exploring the effect of SGLT-2 inhibitors on HF events in patients with CKD and across subgroups defined by baseline kidney function. METHODS AND RESULTS A systematic search in major electronic databases was performed. Randomized controlled trials (RCTs) providing data on the effect of SGLT-2 inhibitors on the primary outcome, time to hospitalization or urgent visit for worsening HF in patients with prevalent CKD at baseline or across subgroups stratified by baseline estimated glomerular-filtration-rate (eGFR) were included. Twelve studies (n = 89,191 participants) were included in the meta-analysis. In patients with CKD, treatment with SGLT-2 inhibitors reduced the risk for HF events by 32% compared to placebo [hazard ratio (HR) 0.68; 95% confidence interval (CI) 0.63-0.73]. Reduction in HF events with SGLT-2 inhibitors was more prominent in patients with eGFR <60 ml/min/1.73 m2 (HR 0.68; 95% CI 0.62-0.74) than in those with eGFR ≥60 ml/min/1.73 m2 (HR 0.76; 95% CI 0.69-0.83). Subgroup analysis according to type of SGLT-2 inhibitor showed a consistent treatment effect across all studied agents (p-subgroup-analysis = 0.44). Sensitivity analysis including data from studies including only diabetic patients showed an even more pronounced effect in eGFR subgroup <60 ml/min/1.73 m2 (HR 0.62; 95% CI 0.54-0.70). CONCLUSION Treatment with SGLT-2 inhibitors led to a significant reduction in HF events in patients with CKD. Such findings may change the landscape of prevention of HF events in patients with advanced CKD. PROSPERO Registration number CRD42022382857.
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Affiliation(s)
- Marieta P Theodorakopoulou
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki GR54642, Greece
| | - Maria-Eleni Alexandrou
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki GR54642, Greece
| | - Alexandros Tsitouridis
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki GR54642, Greece
| | - Vasileios Kamperidis
- First Department of Cardiology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eva Pella
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki GR54642, Greece
| | | | - Antonios Ziakas
- First Department of Cardiology, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Vassilios Vassilikos
- Third Department of Cardiology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Aikaterini Papagianni
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki GR54642, Greece
| | - Pantelis Sarafidis
- First Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki GR54642, Greece
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Yu PL, Yu Y, Li S, Mu BC, Nan MH, Pang M. Dapagliflozin in heart failure and type 2 diabetes: Efficacy, cardiac and renal effects, safety. World J Diabetes 2024; 15:1518-1530. [PMID: 39099807 PMCID: PMC11292345 DOI: 10.4239/wjd.v15.i7.1518] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/12/2024] [Accepted: 05/14/2024] [Indexed: 07/08/2024] Open
Abstract
BACKGROUND Heart failure (HF), especially HF with reduced ejection fraction (HFrEF), presents complex challenges, particularly in the aging population where it often coexists with type 2 diabetes mellitus (T2DM). AIM To analyze the effect of dapagliflozin treatment on cardiac, renal function, and safety in patients with HFrEF combined with T2DM. METHODS Patients with T2DM complicated with HFrEF who underwent treatment in our hospital from February 2018 to March 2023 were retrospectively analyzed as the subjects of this study. The propensity score matching method was used, and a total of 102 eligible samples were scaled. The clinical efficacy of the two groups was evaluated at the end of the treatment, comparing the results of blood glucose, insulin, cardiac function, markers of myocardial injury, renal function indexes, and 6-min walk test (6MWT) before and after the treatment. We compared the occurrence of adverse effects on the treatment process of the two groups of patients. The incidence of adverse outcomes in patients within six months of treatment was counted. RESULTS The overall clinical efficacy rate of patients in the study group was significantly higher than that of patients in the control group (P = 0.013). After treatment, the pancreatic beta-cell function index, left ventricular ejection fraction, and glomerular filtration rate of patients in the study group were significantly higher than control group (P < 0.001), while their fasting plasma glucose, 2-h postprandial glucose, glycosylated hemoglobin, insulin resistance index, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, cardiac troponin I, creatine kinase-MB, N-terminal pro b-type natriuretic peptide, serum creatinine, and blood urea nitrogen were significantly lower than those of the control group. After treatment, patients in the study group had a significantly higher 6MWT than those in the control group (P < 0.001). Hypoglycemic reaction (P = 0.647), urinary tract infection (P = 0.558), gastrointestinal adverse effect (P = 0.307), respiratory disturbance (P = 0.558), and angioedema (P = 0.647) were not statistically different. There was no significant difference between the incidence of adverse outcomes between the two groups (P = 0.250). CONCLUSION Dapagliflozin significantly enhances clinical efficacy, cardiac and renal function, and ambulatory capacity in patients with HFrEF and T2DM without an increased risk of adverse effects or outcomes.
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Affiliation(s)
- Pei-Ling Yu
- The Second Department of Cardiology, The Second Affiliated Hospital of Liaoning Hospital of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
| | - You Yu
- The Second Department of Cardiology, The Second Affiliated Hospital of Liaoning Hospital of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
| | - Shuang Li
- The Second Department of Cardiology, The Second Affiliated Hospital of Liaoning Hospital of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
| | - Bai-Chen Mu
- The Second Department of Cardiology, The Second Affiliated Hospital of Liaoning Hospital of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
| | - Ming-Hua Nan
- The Second Department of Cardiology, The Second Affiliated Hospital of Liaoning Hospital of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
| | - Min Pang
- Department of Outpatient, The Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
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Ostrominski JW, Greene SJ, Patel RB, Solomon NC, Chiswell K, DeVore AD, Butler J, Heidenreich PA, Huang JC, Kittleson MM, Joynt Maddox KE, Linganathan KK, McDermott JJ, Owens AT, Peterson PN, Solomon SD, Vardeny O, Yancy CW, Fonarow GC, Vaduganathan M. Kidney Outcomes Among Medicare Beneficiaries After Hospitalization for Heart Failure. JAMA Cardiol 2024; 9:667-672. [PMID: 38809567 PMCID: PMC11137656 DOI: 10.1001/jamacardio.2024.1108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 03/28/2024] [Indexed: 05/30/2024]
Abstract
Importance Kidney health has received increasing focus as part of comprehensive heart failure (HF) treatment efforts. However, the occurrence of clinically relevant kidney outcomes in contemporary populations with HF has not been well studied. Objective To examine rates of incident dialysis and acute kidney injury (AKI) among Medicare beneficiaries after HF hospitalization. Design, Setting, and Participants This retrospective cohort study evaluated adults aged 65 years or older who were hospitalized for HF across 372 sites in the Get With The Guidelines-Heart Failure registry in the US between January 1, 2014, and December 31, 2018. Patients younger than 65 years or requiring dialysis either during or prior to hospitalization were excluded. Data were analyzed from May 4, 2021, to March 8, 2024. Main Outcomes and Measures The primary outcome was inpatient dialysis initiation in the year after HF hospitalization and was ascertained via linkage with Medicare claims data. Other all-cause and cause-specific hospitalizations were also evaluated. The covariate-adjusted association between discharge estimated glomerular filtration rate (eGFR) and 1-year postdischarge outcomes was examined using Cox proportional hazards regression models. Results Overall, among 85 298 patients included in the analysis (mean [SD] age, 80 [9] years; 53% women) mean (SD) left ventricular ejection fraction was 47% (16%) and mean (SD) eGFR was 53 (29) mL/min per 1.73 m2; 54 010 (63%) had an eGFR less than 60 mL/min per 1.73 m2. By 1 year after HF hospitalization, 6% had progressed to dialysis, 7% had progressed to dialysis or end-stage kidney disease, and 7% had been readmitted for AKI. Incident dialysis increased steeply with lower discharge eGFR category: compared with patients with an eGFR of 60 mL/min per 1.73 m2 or more, individuals with an eGFR of 45 to less than 60 and of less than 30 mL/min per 1.73 m2 had higher rates of dialysis readmission (45 to <60: adjusted hazard ratio [AHR], 2.16 [95% CI, 1.86-2.51]; <30: AHR, 28.46 [95% CI, 25.25-32.08]). Lower discharge eGFR (per 10 mL/min per 1.73 m2 decrease) was independently associated with a higher rate of readmission for dialysis (AHR, 2.23; 95% CI, 2.14-2.32), dialysis or end-stage kidney disease (AHR, 2.34; 95% CI, 2.24-2.44), and AKI (AHR, 1.25; 95% CI, 1.23-1.27), with similar findings for all-cause mortality, all-cause readmission, and HF readmission. Baseline left ventricular ejection fraction did not modify the covariate-adjusted association between lower discharge eGFR and kidney outcomes. Conclusions and Relevance In this study, older adults with HF had substantial risk of kidney complications, with an estimated 6% progressing to dialysis in the year after HF hospitalization. These findings emphasize the need for health care approaches prioritizing kidney health in this high-risk population.
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Affiliation(s)
- John W. Ostrominski
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Stephen J. Greene
- Duke Clinical Research Institute, Durham, North Carolina
- Division of Cardiology, Duke University School of Medicine, Durham, North Carolina
| | - Ravi B. Patel
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | | | - Karen Chiswell
- Duke Clinical Research Institute, Durham, North Carolina
| | - Adam D. DeVore
- Duke Clinical Research Institute, Durham, North Carolina
- Division of Cardiology, Duke University School of Medicine, Durham, North Carolina
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, Texas
- Department of Medicine, University of Mississippi Medical Center, Jackson
| | - Paul A. Heidenreich
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California
| | | | - Michelle M. Kittleson
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai, Los Angeles, California
| | - Karen E. Joynt Maddox
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri
| | | | | | - Anjali Tiku Owens
- Heart and Vascular Center, Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia
| | - Pamela N. Peterson
- Department of Medicine, Denver Health Medical Center, Denver, Colorado
- Department of Medicine, Anschutz Medical Center, Aurora, Colorado
| | - Scott D. Solomon
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Orly Vardeny
- Center for Care Delivery and Outcomes Research, Minneapolis Veterans Affairs Health Care System, University of Minnesota, Minneapolis
| | - Clyde W. Yancy
- Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Gregg C. Fonarow
- Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan UCLA Medical Center, Los Angeles, California
| | - Muthiah Vaduganathan
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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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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Usman MS, Bhatt DL, Hameed I, Anker SD, Cheng AYY, Hernandez AF, Jones WS, Khan MS, Petrie MC, Udell JA, Friede T, Butler J. Effect of SGLT2 inhibitors on heart failure outcomes and cardiovascular death across the cardiometabolic disease spectrum: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2024; 12:447-461. [PMID: 38768620 DOI: 10.1016/s2213-8587(24)00102-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 05/22/2024]
Abstract
BACKGROUND Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been studied in patients with heart failure, type 2 diabetes, chronic kidney disease, atherosclerotic cardiovascular disease, and acute myocardial infarction. Individual trials were powered to study composite outcomes in one disease state. We aimed to evaluate the treatment effect of SGLT2 inhibitors on specific clinical endpoints across multiple demographic and disease subgroups. METHODS In this systematic review and meta-analysis, we queried online databases (PubMed, Cochrane CENTRAL, and SCOPUS) up to Feb 10, 2024, for primary and secondary analyses of large trials (n>1000) of SGLT2 inhibitors in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease (including acute myocardial infarction). Outcomes studied included composite of first hospitalisation for heart failure or cardiovascular death, first hospitalisation for heart failure, cardiovascular death, total (first and recurrent) hospitalisation for heart failure, and all-cause mortality. Effect sizes were pooled using random-effects models. This study is registered with PROSPERO, CRD42024513836. FINDINGS We included 15 trials (N=100 952). Compared with placebo, SGLT2 inhibitors reduced the risk of first hospitalisation for heart failure by 29% in patients with heart failure (hazard ratio [HR] 0·71 [95% CI 0·67-0·77]), 28% in patients with type 2 diabetes (0·72 [0·67-0·77]), 32% in patients with chronic kidney disease (0·68 [0·61-0·77]), and 28% in patients with atherosclerotic cardiovascular disease (0·72 [0·66-0·79]). SGLT2 inhibitors reduced cardiovascular death by 14% in patients with heart failure (HR 0·86 [95% CI 0·79-0·93]), 15% in patients with type 2 diabetes (0·85 [0·79-0·91]), 11% in patients with chronic kidney disease (0·89 [0·82-0·96]), and 13% in patients with atherosclerotic cardiovascular disease (0·87 [0·78-0·97]). The benefit of SGLT2 inhibitors on both first hospitalisation for heart failure and cardiovascular death was consistent across the majority of the 51 subgroups studied. Notable exceptions included acute myocardial infarction (22% reduction in first hospitalisation for heart failure; no effect on cardiovascular death) and heart failure with preserved ejection fraction (26% reduction in first hospitalisation for heart failure; no effect on cardiovascular death). INTERPRETATION SGLT2 inhibitors reduced heart failure events and cardiovascular death in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease. These effects were consistent across a wide range of subgroups within these populations. This supports the eligibility of a large population with cardiorenal-metabolic diseases for treatment with SGLT2 inhibitors. FUNDING None.
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Affiliation(s)
| | - Deepak L Bhatt
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ishaque Hameed
- Department of Medicine, Medstar Health, Baltimore, MD, USA
| | - Stefan D Anker
- Department of Internal Medicine and Cardiology, Campus Virchow-Klinikum, German Heart Center Charité, Charité-University Medicine Berlin, Corporate Member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany; BIH Center for Regenerative Therapies (BCRT), Charité-University Medicine Berlin, Corporate Member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
| | - Alice Y Y Cheng
- Department of Medicine, Division of Endocrinology and Metabolism, University of Toronto, Toronto, ON, Canada
| | - Adrian F Hernandez
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; Division of Cardiology, Duke University School of Medicine, Durham, NC, USA
| | - William Schuyler Jones
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; Division of Cardiology, Duke University School of Medicine, Durham, NC, USA
| | - Muhammad Shahzeb Khan
- Division of Cardiology, Duke University School of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Mark C Petrie
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Jacob A Udell
- Women's College Hospital and Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Tim Friede
- Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany
| | - Javed Butler
- Baylor Scott and White Research Institute, Baylor Scott and White Health, Dallas, TX, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
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Gippini A, Prado A. Earlier onset of treatment improves the nephroprotective effect of dapagliflozin. Nefrologia 2024; 44:431-433. [PMID: 39002997 DOI: 10.1016/j.nefroe.2023.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/16/2023] [Accepted: 05/19/2023] [Indexed: 07/15/2024] Open
Affiliation(s)
- Antonio Gippini
- Endocrinologist, Endocrinology Service, Hospitalary Complex Ourense, National Health System, Spain.
| | - Alberto Prado
- Pharmacist, Master in Statistics, Cardiovascular Renal Metabolism (CVRM), Medical Department, AstraZeneca, Spain
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Kondo T, Jhund PS, Gasparyan SB, Yang M, Claggett BL, McCausland FR, Tolomeo P, Vadagunathan M, Heerspink HJL, Solomon SD, McMurray JJV. A hierarchical kidney outcome using win statistics in patients with heart failure from the DAPA-HF and DELIVER trials. Nat Med 2024; 30:1432-1439. [PMID: 38710952 PMCID: PMC11108780 DOI: 10.1038/s41591-024-02941-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 03/21/2024] [Indexed: 05/08/2024]
Abstract
Win statistics offer a new approach to the analysis of outcomes in clinical trials, allowing the combination of time-to-event and longitudinal measurements and taking into account the clinical importance of the components of composite outcomes, as well as their relative timing. We examined this approach in a post hoc analysis of two trials that compared dapagliflozin to placebo in patients with heart failure and reduced ejection fraction (DAPA-HF) and mildly reduced or preserved ejection fraction (DELIVER). The effect of dapagliflozin on a hierarchical composite kidney outcome was assessed, including the following: (1) all-cause mortality; (2) end-stage kidney disease; (3) a decline in estimated glomerular filtration rate (eGFR) of ≥57%; (4) a decline in eGFR of ≥50%; (5) a decline in eGFR of ≥40%; and (6) participant-level eGFR slope. For this outcome, the win ratio was 1.10 (95% confidence interval (CI) = 1.06-1.15) in the combined dataset, 1.08 (95% CI = 1.01-1.16) in the DAPA-HF trial and 1.12 (95% CI = 1.05-1.18) in the DELIVER trial; that is, dapagliflozin was superior to placebo in both trials. The benefits of treatment were consistent in participants with and without baseline kidney disease, and with and without type 2 diabetes. In heart failure trials, win statistics may provide the statistical power to evaluate the effect of treatments on kidney as well as cardiovascular outcomes.
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Affiliation(s)
- Toru Kondo
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Pardeep S Jhund
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Samvel B Gasparyan
- Late-Stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Mingming Yang
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Brian L Claggett
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Finnian R McCausland
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Paolo Tolomeo
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Muthiah Vadagunathan
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands
| | - Scott D Solomon
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - John J V McMurray
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
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37
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Bonacchi G, Rossi VA, Garofalo M, Mollace R, Uccello G, Pieragnoli P, Checchi L, Perrotta L, Voltolini L, Ricciardi G, Beltrami M. Pathophysiological Link and Treatment Implication of Heart Failure and Preserved Ejection Fraction in Patients with Chronic Kidney Disease. Biomedicines 2024; 12:981. [PMID: 38790943 PMCID: PMC11117953 DOI: 10.3390/biomedicines12050981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 04/22/2024] [Accepted: 04/24/2024] [Indexed: 05/26/2024] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) results from a complex interplay of age, genetic, cardiac remodeling, and concomitant comorbidities including hypertension, obesity, diabetes, and chronic kidney disease (CKD). Renal failure is an important comorbidity of HFpEF, as well as a major pathophysiological mechanism for those patients at risk of developing HFpEF. Heart failure (HF) and CKD are intertwined conditions sharing common disease pathways; the so-called "kidney tamponade", explained by an increase in intracapsular pressure caused by fluid retention, is only the latest model to explain renal injury in HF. Recognizing the different phenotypes of HFpEF remains a real challenge; the pathophysiological mechanisms of renal dysfunction may differ across the HF spectrum, as well as the prognostic role. A better understanding of the role of cardiorenal interactions in patients with HF in terms of symptom status, disease progression, and prognosis remains essential in HF management. Historically, patients with HF and CKD have been scarcely represented in clinical trial populations. Current concerns affect the practical approach to HF treatment, and, in this context, physicians are frequently hesitant to prescribe and titrate both new and old treatments. Therefore, the extensive application of HF drugs in diverse HF subtypes with numerous comorbidities and different renal dysfunction etiologies remains a controversial matter of discussion. Numerous recently introduced drugs, such as sodium-glucose-linked transporter 2 inhibitors (SGLT2i), constitute a new therapeutic option for patients with HF and CKD. Because of their protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. The present review delves into the phenotype of patients with HFpEF and CKD from a pathophysiological perspective, proposing a treatment approach that suggests a practical stepwise algorithm for the proper application of life-saving therapies in clinical practice.
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Affiliation(s)
- Giacomo Bonacchi
- Cardiomyopathy Unit, Careggi University Hospital, 50134 Florence, Italy;
| | | | - Manuel Garofalo
- Arrhythmia and Electrophysiology Unit, Careggi University Hospital, 50134 Florence, Italy; (M.G.); (P.P.); (L.C.); (L.P.); (G.R.)
| | - Rocco Mollace
- Department of Experimental Medicine, Tor Vergata University, 00133 Rome, Italy;
- Cardiology Unit, Humanitas Gavazzeni, 24125 Bergamo, Italy
| | - Giuseppe Uccello
- Division of Cardiology, “A. Manzoni” Hospital—ASST Lecco, 23900 Lecco, Italy;
| | - Paolo Pieragnoli
- Arrhythmia and Electrophysiology Unit, Careggi University Hospital, 50134 Florence, Italy; (M.G.); (P.P.); (L.C.); (L.P.); (G.R.)
| | - Luca Checchi
- Arrhythmia and Electrophysiology Unit, Careggi University Hospital, 50134 Florence, Italy; (M.G.); (P.P.); (L.C.); (L.P.); (G.R.)
| | - Laura Perrotta
- Arrhythmia and Electrophysiology Unit, Careggi University Hospital, 50134 Florence, Italy; (M.G.); (P.P.); (L.C.); (L.P.); (G.R.)
| | - Luca Voltolini
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy;
- Thoracic Surgery Unit, Careggi University Hospital, 50134 Florence, Italy
| | - Giuseppe Ricciardi
- Arrhythmia and Electrophysiology Unit, Careggi University Hospital, 50134 Florence, Italy; (M.G.); (P.P.); (L.C.); (L.P.); (G.R.)
| | - Matteo Beltrami
- Cardiomyopathy Unit, Careggi University Hospital, 50134 Florence, Italy;
- Arrhythmia and Electrophysiology Unit, Careggi University Hospital, 50134 Florence, Italy; (M.G.); (P.P.); (L.C.); (L.P.); (G.R.)
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Preda A, Montecucco F, Carbone F, Camici GG, Lüscher TF, Kraler S, Liberale L. SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits. Cardiovasc Res 2024; 120:443-460. [PMID: 38456601 PMCID: PMC12001887 DOI: 10.1093/cvr/cvae047] [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: 10/19/2023] [Revised: 01/03/2024] [Accepted: 02/05/2024] [Indexed: 03/09/2024] Open
Abstract
An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated overview of the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With landmark randomized controlled trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed.
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Affiliation(s)
- Alberto Preda
- Department of Clinical Cardiology, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
| | - Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
| | - Giovanni G Camici
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Royal Brompton and Harefield Hospitals and Imperial College and King’s College, London, United Kingdom
| | - Simon Kraler
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Internal Medicine, Cantonal Hospital Baden, Baden, Switzerland
| | - Luca Liberale
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
- IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
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Shiau CH, Tsau LY, Kao CC, Peng YC, Bai CH, Wu JC, Hou WH. Efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients with chronic kidney disease: a systematic review and meta-analysis. Int Urol Nephrol 2024; 56:1359-1381. [PMID: 37752340 DOI: 10.1007/s11255-023-03789-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 08/24/2023] [Indexed: 09/28/2023]
Abstract
PURPOSE Owing to the pharmacological mechanism, sodium-glucose cotransporter 2 inhibitors (SGLT2is) may be less effective in patients with reduced renal functions, but no systematic review or meta-analysis addressed chronic kidney disease (CKD) patients specifically. We aimed to assess the efficacy and safety of SGLT2is in CKD patients. METHODS We conducted a systematic review and meta-analysis of randomized controlled trials. Mean difference (MD) were pooled for the decline of glomerular filtration rate (eGFR) and change in urine albumin-to-creatinine ratio (uACR). Hazard ratio (HR) and rate ratio (RR) were pooled for composite of renal outcomes and adverse effects. RESULTS Thirty articles were identified. Overall MD in rate of eGFR decline was 0.02 (P = 0.05), with a borderline significant difference favoring SGLT2is, while the change in uACR from baseline was - 141.34 mg/g and hazard ratio of composite renal outcomes was 0.64 significantly favoring SGLT2is. Subgroup analyses showed that the long-term renal function, participants with baseline macroalbuminuria, and stage 4 CKD patients had significantly slower eGFR decline rate in SGLT2is compared to the placebo group. Risks of genital mycotic infection and ketoacidosis were significantly higher among the SGLT2is group than placebo. CONCLUSION For CKD patients, no matter diabetic or non-diabetic, our study showed potential renoprotective effects favoring SGLT2is in overall and long-term phase, and in patients with macroalbuminuria or stage 4 CKD. However, only slight increased risk of adverse effects among the SGLT2is group is observed. Therefore, we concluded that in CKD patients, prescribing SGLT2is was safe and had renal benefits.
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Affiliation(s)
- Chu-Hsuan Shiau
- Department of Education, Taipei Medical University Hospital, Taipei, Taiwan
- Department of Urology, Taipei Medical University Hospital, Taipei, Taiwan
| | - Li-Yun Tsau
- Graduate Institute of Clinical Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chih-Chin Kao
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Medical University-Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yu-Ching Peng
- Department of Education, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chyi-Huey Bai
- School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan
| | - Jeng-Cheng Wu
- Department of Education, Taipei Medical University Hospital, Taipei, Taiwan.
- Department of Urology, Taipei Medical University Hospital, Taipei, Taiwan.
- Taipei Medical University-Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei, Taiwan.
- Department of Education and Humanities in Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
| | - Wen-Hsuan Hou
- Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Cochrane Taiwan, Taipei Medical University, Taipei, Taiwan.
- International Ph.D. Program in Gerontology and Long-Term Care, College of Nursing, Taipei Medical University, Taipei, Taiwan.
- Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei, Taiwan.
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Campbell P, Rutten FH, Lee MM, Hawkins NM, Petrie MC. Heart failure with preserved ejection fraction: everything the clinician needs to know. Lancet 2024; 403:1083-1092. [PMID: 38367642 DOI: 10.1016/s0140-6736(23)02756-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/22/2023] [Accepted: 12/06/2023] [Indexed: 02/19/2024]
Abstract
Heart failure with preserved ejection fraction (HFpEF) is increasingly recognised and diagnosed in clinical practice, a trend driven by an ageing population and a rise in contributing comorbidities, such as obesity and diabetes. Representing at least half of all heart failure cases, HFpEF is recognised as a complex clinical syndrome. Its diagnosis and management are challenging due to its diverse pathophysiology, varied epidemiological patterns, and evolving diagnostic and treatment approaches. This Seminar synthesises the latest insights on HFpEF, integrating findings from recent clinical trials, epidemiological research, and the latest guideline recommendations. We delve into the definition, pathogenesis, epidemiology, diagnostic criteria, and management strategies (non-pharmacological and pharmacological) for HFpEF. We highlight ongoing clinical trials and future developments in the field. Specifically, this Seminar offers practical guidance tailored for primary care practitioners, generalists, and cardiologists who do not specialise in heart failure, simplifying the complexities in the diagnosis and management of HFpEF. We provide practical, evidence-based recommendations, emphasising the importance of addressing comorbidities and integrating the latest pharmacological treatments, such as SGLT2 inhibitors.
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Affiliation(s)
- Patricia Campbell
- Department of Cardiology, Southern Trust, Craigavon Area Hospital, Portadown, UK.
| | - Frans H Rutten
- Department of General Practice and Nursing Science, Julius Centre, University Medical Centre, Utrecht University, Utrecht, Netherlands
| | - Matthew My Lee
- School of Cardiovascular and Metabolic Health, University of Glasgow, British Heart Foundation Glasgow Cardiovascular Research Centre, Glasgow, UK
| | - Nathaniel M Hawkins
- Division of Cardiology, University of British Columbia, Faculty of Medicine, Vancouver, BC, Canada
| | - Mark C Petrie
- School of Cardiovascular and Metabolic Health, University of Glasgow, British Heart Foundation Glasgow Cardiovascular Research Centre, Glasgow, UK
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41
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Cleland JGF. Nature and Magnitude of the Benefits of Dapagliflozin and Empagliflozin for Heart Failure. Circulation 2024; 149:839-842. [PMID: 38466791 DOI: 10.1161/circulationaha.123.068089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Affiliation(s)
- John G F Cleland
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Health, University of Glasgow, United Kingdom
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42
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Hasan I, Rashid T, Jaikaransingh V, Heilig C, Abdel-Rahman EM, Awad AS. SGLT2 inhibitors: Beyond glycemic control. J Clin Transl Endocrinol 2024; 35:100335. [PMID: 38525377 PMCID: PMC10957445 DOI: 10.1016/j.jcte.2024.100335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 03/08/2024] [Accepted: 03/11/2024] [Indexed: 03/26/2024] Open
Abstract
Multiple randomized controlled trials have extensively examined the therapeutic effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors, ushering in a transformative approach to treating individuals with type 2 diabetes mellitus (DM). Notably, emerging reports have drawn attention to the potential positive impacts of SGLT2 inhibitors in nondiabetic patients. In an effort to delve into this phenomenon, a comprehensive systematic literature review spanning PubMed (NLM), Medline (Ovid), and Cochrane Library, covering publications from 2000 to 2024 was undertaken. This systematic review encompassed twenty-six randomized control trials (RCTs) involving 35,317 participants. The findings unveiled a multifaceted role for SGLT2 inhibitors, showcasing their ability to enhance metabolic control and yield cardioprotective effects through a reduction in cardiovascular death (CVD) and hospitalization related to heart failure (HF). Additionally, a renalprotective effect was observed, evidenced by a slowdown in chronic kidney disease (CKD) progression and a decrease in albuminuria. Importantly, these benefits were coupled with an acceptable safety profile. The literature also points to various biological plausibility and underlying mechanistic pathways, offering insights into the association between SGLT2 inhibitors and these positive outcomes in nondiabetic individuals. Current research trends indicate a continual exploration of additional role for SGLT2 inhibitors in. Nevertheless, further research is imperative to fully elucidate the mechanisms and long-term outcomes associated with the nondiabetic use of SGLT2 inhibitors.
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Affiliation(s)
- Irtiza Hasan
- University of Florida College of Medicine-Jacksonville, FL, USA
| | - Tasnuva Rashid
- University of Florida College of Medicine-Jacksonville, FL, USA
| | | | - Charles Heilig
- University of Florida College of Medicine-Jacksonville, FL, USA
| | | | - Alaa S. Awad
- University of Florida College of Medicine-Jacksonville, FL, USA
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43
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Tuttle ML, Fang JC, Sarnak MJ, McCallum W. Epidemiology and Management of Patients With Kidney Disease and Heart Failure With Preserved Ejection Fraction. Semin Nephrol 2024; 44:151516. [PMID: 38704338 PMCID: PMC11283973 DOI: 10.1016/j.semnephrol.2024.151516] [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] [Indexed: 05/06/2024]
Abstract
Heart failure with preserved ejection fraction (HFpEF) comprises approximately one-half of all diagnoses of heart failure. There is significant overlap of this clinical syndrome with chronic kidney disease (CKD), with many shared comorbid conditions. The presence of CKD in patients with HFpEF is one of the most powerful risk factors for adverse clinical outcomes, including death and heart failure hospitalization. The pathophysiology linking HFpEF and CKD remains unclear, but it is postulated to consist of numerous bidirectional pathways, including endothelial dysfunction, inflammation, obesity, insulin resistance, and impaired sodium handling. The diagnosis of HFpEF requires certain criteria to be satisfied, including signs and symptoms consistent with volume overload caused by structural or functional cardiac abnormalities and evidence of increased cardiac filling pressures. There are numerous overlapping metabolic clinical syndromes in patients with HFpEF and CKD that can serve as targets for intervention. With an increasing number of therapies available for HFpEF and CKD as well as for obesity and diabetes, improved recognition and diagnosis are paramount for appropriate management and improved clinical outcomes in patients with both HFpEF and CKD.
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Affiliation(s)
| | - James C Fang
- Cardiovascular Medicine, University of Utah School of Medicine, Salt Lake City, UT
| | - Mark J Sarnak
- Division of Nephrology, Tufts Medical Center, Boston, MA
| | - Wendy McCallum
- Division of Nephrology, Tufts Medical Center, Boston, MA.
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Lucà F, Oliva F, Abrignani MG, Di Fusco SA, Gori M, Giubilato S, Ceravolo R, Temporelli PL, Cornara S, Rao CM, Caretta G, Pozzi A, Binaghi G, Maloberti A, Di Nora C, Di Matteo I, Pilleri A, Gelsomino S, Riccio C, Grimaldi M, Colivicchi F, Gulizia MM. Heart Failure with Preserved Ejection Fraction: How to Deal with This Chameleon. J Clin Med 2024; 13:1375. [PMID: 38592244 PMCID: PMC10933980 DOI: 10.3390/jcm13051375] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/11/2024] [Accepted: 02/14/2024] [Indexed: 04/10/2024] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is characterized by a notable heterogeneity in both phenotypic and pathophysiological features, with a growing incidence due to the increase in median age and comorbidities such as obesity, arterial hypertension, and cardiometabolic disease. In recent decades, the development of new pharmacological and non-pharmacological options has significantly impacted outcomes, improving clinical status and reducing mortality. Moreover, a more personalized and accurate therapeutic management has been demonstrated to enhance the quality of life, diminish hospitalizations, and improve overall survival. Therefore, assessing the peculiarities of patients with HFpEF is crucial in order to obtain a better understanding of this disorder. Importantly, comorbidities have been shown to influence symptoms and prognosis, and, consequently, they should be carefully addressed. In this sense, it is mandatory to join forces with a multidisciplinary team in order to achieve high-quality care. However, HFpEF remains largely under-recognized and under-treated in clinical practice, and the diagnostic and therapeutic management of these patients remains challenging. The aim of this paper is to articulate a pragmatic approach for patients with HFpEF focusing on the etiology, diagnosis, and treatment of HFpEF.
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Affiliation(s)
- Fabiana Lucà
- Cardiology Department, Grande Ospedale Metropolitano, 89129 Reggio Calabria, Italy
| | - Fabrizio Oliva
- Cardiology Department De Gasperis Cardio Center, Niguarda Hospital, 20162 Milan, Italy (A.M.)
| | | | | | - Mauro Gori
- Cardiovascular Department, Azienda Ospedaliera Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy
| | - Simona Giubilato
- Cardiology Department, Ospedale Lamezia Terme, 88046 Catanzaro, Italy
| | - Roberto Ceravolo
- Cardiac Rehabilitation Unitof Maugeri, IRCCS, 28010 Gattico-Veruno, Italy
| | | | - Stefano Cornara
- Arrhytmia Unit, Division of Cardiology, Ospedale San Paolo, Azienda Sanitaria Locale 2, 17100 Savona, Italy;
| | | | - Giorgio Caretta
- Levante Ligure Sant’Andrea Hospital, ASL 5 Liguria, 19121 La Spezia, Italy
| | - Andrea Pozzi
- Cardiology Division, Valduce Hospital, 22100 Como, Italy
| | - Giulio Binaghi
- Department of Cardiology, Azienda Ospedaliera Brotzu, 09134 Cagliari, Italy
| | - Alessandro Maloberti
- Cardiology Department De Gasperis Cardio Center, Niguarda Hospital, 20162 Milan, Italy (A.M.)
| | - Concetta Di Nora
- Department of Cardiothoracic Science, Azienda Sanitaria UniversitariaIntegrata di Udine, 33100 Udine, Italy
| | - Irene Di Matteo
- Cardiology Department De Gasperis Cardio Center, Niguarda Hospital, 20162 Milan, Italy (A.M.)
| | - Anna Pilleri
- Department of Cardiology, Azienda Ospedaliera Brotzu, 09134 Cagliari, Italy
| | - Sandro Gelsomino
- Cardiovascular Research Institute, Maastricht University, 6229 HX Maastricht, The Netherlands
| | - Carmine Riccio
- Cardiovascular Department, Sant’Anna e San Sebastiano Hospital, 81100 Caserta, Italy
| | - Massimo Grimaldi
- Department of Cardiology, General Regional Hospital “F. Miulli”, 70021 Bari, Italy
| | - Furio Colivicchi
- Cardiology Department, San Filippo Neri Hospital, ASL Roma 1, 00135 Rome, Italy
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Rodriguez‐Valadez JM, Tahsin M, Masharani U, Park M, Hunink MGM, Yeboah J, Li L, Weber E, Berkalieva A, Avezaat L, Max W, Fleischmann KE, Ferket BS. Potential Mediators for Treatment Effects of Novel Diabetes Medications on Cardiovascular and Renal Outcomes: A Meta-Regression Analysis. J Am Heart Assoc 2024; 13:e032463. [PMID: 38362889 PMCID: PMC11010086 DOI: 10.1161/jaha.123.032463] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/30/2023] [Indexed: 02/17/2024]
Abstract
BACKGROUND Prior research suggests clinical effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are mediated by changes in glycated hemoglobin, body weight, systolic blood pressure, hematocrit, and urine albumin-creatinine ratio. We aimed to confirm these findings using a meta-analytic approach. METHODS AND RESULTS We updated a systematic review of 9 GLP-1RA and 13 SGLT2i trials and summarized longitudinal mediator data. We obtained hazard ratios (HRs) for cardiovascular, renal, and mortality outcomes. We performed linear mixed-effects modeling of LogHRs versus changes in potential mediators and investigated differences in meta-regression associations among drug classes using interaction terms. HRs generally became more protective with greater glycated hemoglobin reduction among GLP-1RA trials, with average HR improvements of 20% to 30%, reaching statistical significance for major adverse cardiovascular events (ΔHR, 23%; P=0.02). Among SGLT2i trials, associations with HRs were not significant and differed from GLP1-RA trials for major adverse cardiovascular events (Pinteraction=0.04). HRs for major adverse cardiovascular events, myocardial infarction, and stroke became less efficacious (ΔHR, -15% to -34%), with more weight loss for SGLT2i but not for GLP-1RA trials (ΔHR, 4%-7%; Pinteraction<0.05). Among 5 SGLT2i trials with available data, HRs for stroke became less efficacious with larger increases in hematocrit (ΔHR, 123%; P=0.09). No changes in HRs by systolic blood pressure (ΔHR, -11% to 9%) and urine albumin-creatinine ratio (ΔHR, -1% to 4%) were found for any outcome. CONCLUSIONS We confirmed increased efficacy findings for major adverse cardiovascular events with reduction in glycated hemoglobin for GLP1-RAs. Further research is needed on the potential loss of cardiovascular benefits with increased weight loss and hematocrit for SGLT2i.
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Affiliation(s)
- José M. Rodriguez‐Valadez
- Institute for Healthcare Delivery Science, Icahn School of Medicine at Mount SinaiNew YorkNYUSA
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Malak Tahsin
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Umesh Masharani
- Department of MedicineUniversity of CaliforniaSan FranciscoCAUSA
| | - Meyeon Park
- Department of MedicineUniversity of CaliforniaSan FranciscoCAUSA
- Division of NephrologyUniversity of CaliforniaSan FranciscoCAUSA
| | - M. G. Myriam Hunink
- Department of EpidemiologyErasmus MCRotterdamthe Netherlands
- Department of RadiologyErasmus MCRotterdamthe Netherlands
- Center for Health Decision Sciences, Harvard TH Chan School of Public HealthBostonMAUSA
| | - Joseph Yeboah
- Section of Cardiovascular Medicine, Internal MedicineWake Forest University School of MedicineWinston SalemNCUSA
| | - Lihua Li
- Institute for Healthcare Delivery Science, Icahn School of Medicine at Mount SinaiNew YorkNYUSA
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Ellerie Weber
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Asem Berkalieva
- Institute for Healthcare Delivery Science, Icahn School of Medicine at Mount SinaiNew YorkNYUSA
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Luuk Avezaat
- Department of EpidemiologyErasmus MCRotterdamthe Netherlands
| | - Wendy Max
- Institute for Health & Aging and Department of Social and Behavioral SciencesUniversity of CaliforniaSan FranciscoCAUSA
| | - Kirsten E. Fleischmann
- Department of MedicineUniversity of CaliforniaSan FranciscoCAUSA
- Division of CardiologyUniversity of CaliforniaSan FranciscoCAUSA
| | - Bart S. Ferket
- Institute for Healthcare Delivery Science, Icahn School of Medicine at Mount SinaiNew YorkNYUSA
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount SinaiNew YorkNYUSA
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46
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Fu WJ, Huo JL, Mao ZH, Pan SK, Liu DW, Liu ZS, Wu P, Gao ZX. Emerging role of antidiabetic drugs in cardiorenal protection. Front Pharmacol 2024; 15:1349069. [PMID: 38384297 PMCID: PMC10880452 DOI: 10.3389/fphar.2024.1349069] [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: 12/06/2023] [Accepted: 01/26/2024] [Indexed: 02/23/2024] Open
Abstract
The global prevalence of diabetes mellitus (DM) has led to widespread multi-system damage, especially in cardiovascular and renal functions, heightening morbidity and mortality. Emerging antidiabetic drugs sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) have demonstrated efficacy in preserving cardiac and renal function, both in type 2 diabetic and non-diabetic individuals. To understand the exact impact of these drugs on cardiorenal protection and underlying mechanisms, we conducted a comprehensive review of recent large-scale clinical trials and basic research focusing on SGLT2i, GLP-1RAs, and DPP-4i. Accumulating evidence highlights the diverse mechanisms including glucose-dependent and independent pathways, and revealing their potential cardiorenal protection in diabetic and non-diabetic cardiorenal disease. This review provides critical insights into the cardiorenal protective effects of SGLT2i, GLP-1RAs, and DPP-4i and underscores the importance of these medications in mitigating the progression of cardiovascular and renal complications, and their broader clinical implications beyond glycemic management.
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Affiliation(s)
- Wen-Jia Fu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Jin-Ling Huo
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zi-Hui Mao
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Shao-Kang Pan
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Dong-Wei Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zhang-Suo Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Peng Wu
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
| | - Zhong-Xiuzi Gao
- Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
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Berezin AE, Berezina TA. Plausible prediction of renoprotective effects of sodium-glucose cotransporter-2 inhibitors in patients with chronic kidney diseases. J Int Med Res 2024; 52:3000605241227659. [PMID: 38329077 PMCID: PMC10854388 DOI: 10.1177/03000605241227659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 12/20/2023] [Indexed: 02/09/2024] Open
Abstract
This narrative review was conducted due to uncertainty in predicting the beneficial impact of sodium-glucose cotransporter-2 (SGLT2) inhibitors on a dip of estimated glomerular filtration rate (eGFR), regardless of albuminuria presence, with the aim of elucidating plausible predictors of kidney function outcome among patients treated with SGLT2 inhibitors. The PubMed and Web of Science databases were searched in May 2023 for relevant articles published in English between 2013 and 2023. A total of 25 full-length scientific publications (comprising 11 large randomized trials and two cohort studies) were included for analysis. The majority of studies demonstrated a limited value of conventional biomarkers, such as initial decline in eGFR, a trajectory of eGFR during SGLT2 inhibitor administration, and urine albumin-to-creatinine ratio (UACR), in prediction of renoprotection. Included studies showed that the tendency to decreased eGFR, UACR, hemoglobin, glycosylated hemoglobin, lipid profile, serum uric acid, inflammatory biomarkers and natriuretic peptides did not predict clinical outcomes in groups without heart failure (HF) treated with SGLT2 inhibitors. In HF groups, biomarkers of inflammation, kidney injury, oxidative stress, mitochondrial dysfunction, ketogenesis, energy metabolism, and adipose tissue dysfunction (adropin and irisin), were detected with the aim of finding potential biomarkers. Biomarkers of adipose tissue dysfunction and inflammation may be promising for predicting SGLT2 inhibitor benefit compared with N-terminal pro-B-type natriuretic peptide and energy metabolism indicators.
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Affiliation(s)
- Alexander E Berezin
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University, Salzburg, Austria
| | - Tetiana A Berezina
- Department of Internal Medicine and Nephrology, VitaCenter, Zaporozhye, Ukraine
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Mc Causland FR, Claggett BL, Vaduganathan M, Desai A, Jhund P, Vardeny O, Fang JC, de Boer RA, Docherty KF, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Saraiva JFK, McGrath MM, Shah SJ, Verma S, Langkilde AM, Petersson M, McMurray JJV, Solomon SD. Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial. JAMA Cardiol 2024; 9:144-152. [PMID: 37952176 PMCID: PMC10641768 DOI: 10.1001/jamacardio.2023.4664] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 10/20/2023] [Indexed: 11/14/2023]
Abstract
Importance An initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure. Objective To examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. Design, Setting, and Participants This was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were analyzed from February to October 2023. Intervention Dapagliflozin, 10 mg per day, or placebo. Main Outcomes and Measures In this prespecified analysis, the frequency of an initial eGFR decline (baseline to month 1) was compared between dapagliflozin and placebo. Cox models adjusted for baseline eGFR and established prognostic factors were fit to estimate the association of an initial eGFR decline with cardiovascular (cardiovascular death or heart failure event) and kidney (≥50% eGFR decline, eGFR<15 or dialysis, death from kidney causes) outcomes, landmarked at month 1, stratified by diabetes. Results Study data from 5788 participants (mean [SD] age, 72 [10] years; 3253 male [56%]) were analyzed. The median (IQR) change in eGFR level from baseline to month 1 was -1 (-6 to 5) with placebo and -4 (-9 to 1) with dapagliflozin (difference, -3; P < .001). A higher proportion of patients assigned to dapagliflozin developed an initial eGFR decline greater than 10% vs placebo (1144 of 2892 [40%] vs 737 of 2896 [25%]; odds ratio, 1.9; 95% CI, 1.7-2.1; P difference <.001). An initial eGFR decline of greater than 10% (vs ≤10%) was associated with a higher risk of the primary cardiovascular outcome among those randomized to placebo (adjusted hazard ratio [aHR], 1.33; 95% CI, 1.10-1.62) but not among those randomized to dapagliflozin (aHR, 0.90; 95% CI, 0.74-1.09; P for interaction = .01). Similar associations were observed when alternative thresholds of initial eGFR decline were considered and when analyzed as a continuous measure. An initial eGFR decline of greater than 10% was not associated with adverse subsequent kidney composite outcomes in dapagliflozin-treated patients (aHR, 0.94; 95% CI, 0.49-1.82). Conclusions and Relevance Among patients with HFmrEF or HFpEF treated with dapagliflozin, an initial eGFR decline was frequent but not associated with subsequent risk of cardiovascular or kidney events. These data reinforce clinical guidance that SGLT2is should not be interrupted or discontinued in response to an initial eGFR decline. Trial Registration ClinicalTrials.gov Identifier: NCT03619213.
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Affiliation(s)
- Finnian R. Mc Causland
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Brian L. Claggett
- Harvard Medical School, Boston, Massachusetts
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Muthiah Vaduganathan
- Harvard Medical School, Boston, Massachusetts
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Akshay Desai
- Harvard Medical School, Boston, Massachusetts
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Pardeep Jhund
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, Scotland
| | - Orly Vardeny
- Minneapolis VA Center for Care Delivery and Outcomes Research, University of Minnesota, Minneapolis
| | - James C. Fang
- University of Utah School of Medicine, Salt Lake City
| | - Rudolf A. de Boer
- Erasmus MC, Cardiovascular Institute, Thorax Center, Department of Cardiology, Rotterdam, the Netherlands
| | - Kieran F. Docherty
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, Scotland
| | | | | | | | - Carolyn S. P. Lam
- National Heart Center Singapore and Duke–National University of Singapore, Singapore
| | | | - Jose F. Kerr Saraiva
- Cardiovascular Division, Instituto de Pesquisa Clínica de Campinas, Campinas, Brazil
| | - Martina M. McGrath
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Sanjiv J. Shah
- Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | | | - Anna Maria Langkilde
- Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden
| | - Magnus Petersson
- Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden
| | - John J. V. McMurray
- British Heart Foundation Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, Scotland
| | - Scott D. Solomon
- Harvard Medical School, Boston, Massachusetts
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
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Berezina TA, Fushtey IM, Berezin AA, Pavlov SV, Berezin AE. Predictors of Kidney Function Outcomes and Their Relation to SGLT2 Inhibitor Dapagliflozin in Patients with Type 2 Diabetes Mellitus Who Had Chronic Heart Failure. Adv Ther 2024; 41:292-314. [PMID: 37935870 PMCID: PMC10796534 DOI: 10.1007/s12325-023-02683-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/07/2023] [Indexed: 11/09/2023]
Abstract
INTRODUCTION Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have a favorable impact on the kidney function in patients with heart failure (HF), while there is no clear evidence of what factors predict this effect. The aim of the study was to identify plausible predictors for kidney function outcome among patients with HF and investigate their association with SGLT2i. METHODS We prospectively enrolled 480 patients with type 2 diabetes mellitus (T2DM) treated with diet and metformin and concomitant chronic HF and followed them for 52 weeks. In the study, we determined kidney outcome as a composite of ≥ 40% reduced estimated glomerular filtration rate from baseline, newly diagnosed end-stage kidney disease or kidney replacement therapy. The relevant medical information and measurement of the biomarkers (N-terminal natriuretic pro-peptide, irisin, apelin, adropin, C-reactive protein, tumor necrosis factor-alpha) were collected at baseline and at the end of the study. RESULTS The composite kidney outcome was detected in 88 (18.3%) patients of the entire population. All patients received guideline-recommended optimal therapy, which was adjusted to phenotype/severity of HF, cardiovascular risk and comorbidity profiles, and fasting glycemia. Levels of irisin, adropin and apelin significantly increased in patients without clinical endpoint, whereas in those with composite endpoint the biomarker levels exhibited a decrease with borderline statistical significance (p = 0.05). We noticed that irisin ≤ 4.50 ng/ml at baseline and a ≤ 15% increase in irisin serum levels added more valuable predictive information than the reference variable. However, the combination of irisin ≤ 4.50 ng/ml at baseline and ≤ 15% increase in irisin serum levels (area under curve = 0.91; 95% confidence interval = 0.87-0.95) improved the discriminative value of each biomarker alone. CONCLUSION We suggest that low levels of irisin and its inadequate increase during administration of SGLT2i are promising predictors for unfavorable kidney outcome among patients with T2DM and concomitant HF.
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Affiliation(s)
- Tetiana A Berezina
- Department of Internal Medicine and Nephrology, VitaCenter, Zaporozhye, 69000, Ukraine
| | - Ivan M Fushtey
- Department of Internal Medicine, Zaporozhye Medical Academy of Postgraduate Education, Zaporozhye, 69096, Ukraine
| | - Alexander A Berezin
- Department of Internal Medicine, Zaporozhye Medical Academy of Postgraduate Education, Zaporozhye, 69096, Ukraine
- Department of Psychosomatic Medicine and Psychotherapy, Klinik Barmelweid, 5017, Erlinsbach, Switzerland
| | - Sergii V Pavlov
- Department Clinical and Laboratory Diagnostics, Zaporozhye State Medical University, Zaporozhye, 69035, Ukraine
| | - Alexander E Berezin
- Department of Cardiology, Vita Center, Zaporozhye, 69000, Ukraine.
- Division of Cardiology, Department of Internal Medicine II, Paracelsus Medical University Salzburg, 5020, Salzburg, Austria.
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Cannarella R, Condorelli RA, Leanza C, Garofalo V, Aversa A, Papa G, Calogero AE, La Vignera S. Dapagliflozin improves erectile dysfunction in patients with type 2 diabetes mellitus: An open-label, non-randomized pilot study. Diabet Med 2024; 41:e15217. [PMID: 37669131 DOI: 10.1111/dme.15217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/09/2023] [Accepted: 08/28/2023] [Indexed: 09/07/2023]
Abstract
INTRODUCTION The role of dapagliflozin on erectile dysfunction (ED), a condition widely affecting patients with type 2 diabetes mellitus (T2DM), has not yet been studied. AIM The aim of the study was to evaluate the effects of dapagliflozin alone or in combination with tadalafil on ED in patients with T2DM. METHODS This was an open-label, non-randomized pilot study involving 30 Caucasian male patients with T2DM and severe ED. They were equally divided into three groups, assigned to treatment with tadalafil 5 mg/day (Group 1), tadalafil 5 mg/day plus dapagliflozin 10 mg/day (Group 2) and dapagliflozin 10 mg/day (Group 3) for 3 months. The presence and the severity of ED were evaluated at enrolment and after treatment, by the International Index of Erectile Function 5-item (IIEF-5) questionnaire and the dynamic penile echo colour Doppler ultrasound (PCDU) examination. RESULTS At the end of treatment, the three groups showed a significant improvement in IIEF-5 score, by 294%, 375% and 197%, in Groups 1, 2 and 3, respectively. PCDU evaluation showed a significant increase in peak systolic velocity by 178.9%, 339% and 153%; acceleration time was significantly shortened in Group 2 (-26.2%) and was significantly lower than in Group 1 and 3 (-7.2% and -6.6%), while no significant difference was found in end-diastolic velocity after treatment. The greatest rates of improvement were observed in Group 2 for all the end points. CONCLUSIONS Dapagliflozin improves ED in patients with T2DM and enhances the efficacy of tadalafil. Further studies are needed to confirm our results explain the mechanism(s) by which dapagliflozin exerts its effects on ED.
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Affiliation(s)
- Rossella Cannarella
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
- Glickman Urological & Kidney Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Rosita A Condorelli
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Claudia Leanza
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Vincenzo Garofalo
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Antonio Aversa
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Giuseppe Papa
- Unit of Metabolic and Endocrine Disease, Centro Catanese di Medicina e Chirurgia Clinic, Catania, Italy
| | - Aldo E Calogero
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Sandro La Vignera
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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