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Haff N, Horn DM, Bhatkhande G, Sung M, Colling C, Wood W, Robertson T, Gaposchkin D, Simmons L, Yang J, Yeh J, Crum KL, Hanken KE, Lauffenburger JC, Choudhry NK. Encouraging the prescribing of SGLT2i and GLP-1RA medications to reduce cardiovascular and renal risk in patients with type 2 diabetes: Rationale and design of a randomized controlled trial. Am Heart J 2025; 285:39-51. [PMID: 39986337 PMCID: PMC11981828 DOI: 10.1016/j.ahj.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 02/04/2025] [Accepted: 02/12/2025] [Indexed: 02/24/2025]
Abstract
BACKGROUND Sodium-glucose cotransporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA) medications reduce the risk of cardiovascular and renal complications among patients with type 2 diabetes but are underutilized. There are numerous barriers to prescribing including insurance coverage, medication availability, comfort with prescribing, and diffusion of responsibility of prescribing across specialists. Methods are needed to support prescribing in primary care. METHODS This was a pragmatic, randomized controlled trial testing interventions to increase appropriate SGLT2i and GLP-1RA prescribing. Primary care providers (PCPs) were randomized to 1 of 3 arms: (1) peer champion support (2) peer champion support and information on insurance coverage, or (3) usual care (no intervention). PCPs in both intervention arms received a welcome email and electronic health record (EHR) messages before visits with patients who had sub-optimally controlled diabetes and an indication for 1 of these medications. In the peer champion support only arm the EHR messages included prescribing tips. In the arm that provided peer champion support and information on insurance coverage, EHR messages contained information on medications in each class that would be most affordable for the patient based on their insurance coverage and offered support for prior authorizations if needed. The primary outcome was prescriptions for an SGLT2i or GLP-1RA medication, beginning 3 days before the targeted visit and continuing through 28 days, in each intervention arm compared to control. RESULTS 191 primary care providers were included in the study. 1,389 patients had at least 1 visit scheduled with their PCP during the 6-month intervention period; of these 1,079 patients attended at least 1 of these visits and will be included in the primary outcome analysis. 66 providers (484 patients) received the peer champion intervention alone, 63 providers (446 patients) received the peer champion intervention and information on insurance coverage, and 62 providers (459 patients) received usual care. On average, patients were 66 years old, 46% were female, 61% were white, and 16% were Hispanic. There were small differences between groups with regards to patient sex, race, ethnicity, partner status, and percent with Medicare insurance. CONCLUSIONS These medication classes have the potential to reduce cardiovascular and kidney disease among patients with type 2 diabetes. This study tests interventions to support prescribing of these medications in primary care. CLINICAL TRIAL Clinicaltrials.gov. Unique identifier: (NCT, Registered: NCT05463705).
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Affiliation(s)
- Nancy Haff
- Center for Healthcare Delivery Sciences, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA.
| | - Daniel M Horn
- Harvard Medical School, Boston, MA; Department of Medicine, Massachusetts General Hospital, Boston, MA; Medical Director of Devoted Health, Waltham, MA
| | - Gauri Bhatkhande
- Center for Healthcare Delivery Sciences, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Meekang Sung
- Center for Healthcare Delivery Sciences, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | - Caitlin Colling
- Harvard Medical School, Boston, MA; Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Wendy Wood
- Department of Psychology & Marshall School of Business, University of Southern California, Los Angeles, CA
| | - Ted Robertson
- ideas42, New York, NY; Executive Director of the Center for Healthcare Marketplace Innovation at the University of California, Berkeley, CA
| | - Daniel Gaposchkin
- Harvard Medical School, Boston, MA; Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Leigh Simmons
- Harvard Medical School, Boston, MA; Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Judy Yang
- Harvard Medical School, Boston, MA; Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - James Yeh
- Harvard Medical School, Boston, MA; Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Katherine L Crum
- Center for Healthcare Delivery Sciences, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | - Kaitlin E Hanken
- Center for Healthcare Delivery Sciences, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, MA
| | - Julie C Lauffenburger
- Center for Healthcare Delivery Sciences, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA
| | - Niteesh K Choudhry
- Center for Healthcare Delivery Sciences, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA
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Armillotta M, Angeli F, Paolisso P, Belmonte M, Raschi E, Di Dalmazi G, Amicone S, Canton L, Fedele D, Suma N, Foà A, Bergamaschi L, Pizzi C. Cardiovascular therapeutic targets of sodium-glucose co-transporter 2 (SGLT2) inhibitors beyond heart failure. Pharmacol Ther 2025; 270:108861. [PMID: 40245989 DOI: 10.1016/j.pharmthera.2025.108861] [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: 09/20/2024] [Revised: 02/12/2025] [Accepted: 04/14/2025] [Indexed: 04/19/2025]
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are oral antidiabetic agents that have shown significant improvements in cardiovascular and renal outcomes among patients with heart failure (HF), regardless of diabetic status, establishing them as a cornerstone therapy. In addition to glycemic control and the osmotic diuretic effect, the inhibition of SGLT2 improves endothelial function and vasodilation, optimizing myocardial energy metabolism and preserving cardiac contractility. Moreover, SGLT2 inhibitors may exhibit anti-inflammatory properties and attenuate acute myocardial ischemia/reperfusion injury, thereby reducing cardiac infarct size, enhancing left ventricular function, and mitigating arrhythmias. These pleiotropic effects have demonstrated efficacy across various cardiovascular conditions, ranging from acute to chronic coronary syndromes and extending to arrhythmias, valvular heart disease, cardiomyopathies, cardio-oncology, and cerebrovascular disease. This review provides an overview of the current literature on the potential mechanisms underlying the effectiveness of SGLT2 inhibitors across a wide range of cardiovascular diseases beyond HF.
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Affiliation(s)
- Matteo Armillotta
- Department of Medical and Surgical Sciences - DIMEC - Alma Mater Studiorum, University of Bologna, Bologna, Italy; Cardiovascular Division, Morgagni-Pierantoni University Hospital, Forlì, Italy
| | - Francesco Angeli
- Department of Medical and Surgical Sciences - DIMEC - Alma Mater Studiorum, University of Bologna, Bologna, Italy; Cardiovascular Division, Morgagni-Pierantoni University Hospital, Forlì, Italy
| | | | - Marta Belmonte
- Cardiology Unit, Sant'Andrea University Hospital, Rome, Italy; Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy
| | - Emanuel Raschi
- Department of Medical and Surgical Sciences - DIMEC - Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Guido Di Dalmazi
- Department of Medical and Surgical Sciences - DIMEC - Alma Mater Studiorum, University of Bologna, Bologna, Italy; Division of Endocrinology and Diabetes Prevention and Care Unit, IRCCS, University Hospital of Bologna, Bologna, Italy
| | - Sara Amicone
- Department of Medical and Surgical Sciences - DIMEC - Alma Mater Studiorum, University of Bologna, Bologna, Italy; Cardiovascular Division, Morgagni-Pierantoni University Hospital, Forlì, Italy
| | - Lisa Canton
- Department of Medical and Surgical Sciences - DIMEC - Alma Mater Studiorum, University of Bologna, Bologna, Italy; Cardiovascular Division, Morgagni-Pierantoni University Hospital, Forlì, Italy
| | - Damiano Fedele
- Department of Medical and Surgical Sciences - DIMEC - Alma Mater Studiorum, University of Bologna, Bologna, Italy; Cardiovascular Division, Morgagni-Pierantoni University Hospital, Forlì, Italy
| | - Nicole Suma
- Department of Medical and Surgical Sciences - DIMEC - Alma Mater Studiorum, University of Bologna, Bologna, Italy; Cardiology Unit, IRCCS Azienda Ospedaliera-Universitaria di Bologna, Bologna, Italy
| | - Alberto Foà
- Department of Medical and Surgical Sciences - DIMEC - Alma Mater Studiorum, University of Bologna, Bologna, Italy; Cardiology Unit, IRCCS Azienda Ospedaliera-Universitaria di Bologna, Bologna, Italy
| | - Luca Bergamaschi
- Department of Medical and Surgical Sciences - DIMEC - Alma Mater Studiorum, University of Bologna, Bologna, Italy; Cardiovascular Division, Morgagni-Pierantoni University Hospital, Forlì, Italy
| | - Carmine Pizzi
- Department of Medical and Surgical Sciences - DIMEC - Alma Mater Studiorum, University of Bologna, Bologna, Italy; Cardiovascular Division, Morgagni-Pierantoni University Hospital, Forlì, Italy.
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Fernando K, Connolly D, Darcy E, Evans M, Hinchliffe W, Holmes P, Strain WD. Advancing Cardiovascular, Kidney, and Metabolic Medicine: A Narrative Review of Insights and Innovations for the Future. Diabetes Ther 2025; 16:1155-1176. [PMID: 40272772 PMCID: PMC12085743 DOI: 10.1007/s13300-025-01738-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 04/01/2025] [Indexed: 05/18/2025] Open
Abstract
Cardiovascular, kidney and metabolic (CKM) conditions are interrelated, significantly contributing to morbidity, mortality and healthcare burden. Despite therapeutic advances, traditional disease-specific approaches often fail to address their complex interplay. Key therapeutic agents-including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dual GLP-1/glucose-dependent insulinotropic polypeptide RAs, sodium glucose co-transporter inhibitors and the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone-offer multi-organ benefits. Emerging therapies, such as triple receptor agonists and second-generation MRAs, target new pathways further expanding treatment options for CKM conditions. A holistic CKM management approach must address and recognise that conditions such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, obstructive sleep apnoea and obesity are part of the CKM spectrum. Frailty assessment is also important alongside CKM conditions, warranting comprehensive geriatric assessment and deprescribing when appropriate. Multidisciplinary care-including lifestyle interventions, pathway redesign, pharmacological advances and novel technologies-is essential for improving outcomes. As the CKM landscape evolves, future strategies should prioritise early intervention, personalised treatment and addressing unmet needs in high-risk populations. This review advocates for an integrated CKM framework, exploring treatment strategies, emerging therapies and technological innovations. It also examines the role of artificial intelligence and digital health tools in risk stratification, early diagnosis and long-term condition management, alongside ethical and regulatory considerations.
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Affiliation(s)
| | - Derek Connolly
- Birmingham City Hospital, Birmingham, UK
- Aston University, Birmingham, UK
| | | | - Marc Evans
- University Hospital Llandough, Cardiff, UK
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Garrity K, Putnam N, Kamil ES, Massengill S, Khalid M, Srivastava R, Isaacs J, Salmon E. Comparing adolescent glomerular disease clinical outcomes to the clinical outcomes in childhood, young adult, and adult-onset glomerular disease in the CureGN database. Pediatr Nephrol 2025; 40:1949-1958. [PMID: 39729127 PMCID: PMC12031915 DOI: 10.1007/s00467-024-06566-4] [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: 06/26/2024] [Revised: 09/25/2024] [Accepted: 09/26/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND There is a lack of evidence to suggest that outcomes of adolescent and adult-onset glomerular disease differ. Still, most glomerular disease trials include adults but exclude adolescents. METHODS We designed a retrospective study using the CureGN database to compare individuals with adolescent-onset glomerular disease relative to individuals with older and younger age at onset. The two main outcomes were sustained proteinuria remission off immunosuppression treatment and composite eGFR decline. RESULTS Our data did not show a significant difference in sustained proteinuria remission off treatment or composite eGFR decline between adolescent onset glomerular disease and either childhood (age 5-12), young adult (age 20-29), or adult (age 30-39) onset glomerular disease. Having high-risk APOL1 alleles and hypertension at the time of study enrollment decreased the likelihood of achieving sustained proteinuria remission off treatment. While participants with minimal change disease and IgA nephropathy were similarly likely to achieve sustained proteinuria remission off treatment, participants with focal segmental glomerulosclerosis and membranous nephropathy were less likely to achieve sustained proteinuria remission off treatment compared to participants with minimal change disease. CKD stage, high-risk APOL1 alleles, hypertension stage, and education all significantly impacted the likelihood of progression to the composite eGFR decline outcome. CONCLUSIONS Approximately 25% of each age cohort reached the composite eGFR decline outcome within 5 years. As more glomerular disease clinical trials become available, we must consider opening these trials to people with childhood and adolescent onset disease since like adults they are at high risk of progressive kidney function decline.
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Affiliation(s)
- Kelly Garrity
- Mattel Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
- Medical Univerity of South Carolina, Charleston, SC, USA.
| | | | - Elaine S Kamil
- Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | | | - Myda Khalid
- Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Rachana Srivastava
- Mattel Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Jaya Isaacs
- Montefiore Children's Hospital, Albert Einstein School of Medicine, Bronx, NY, USA
| | - Eloise Salmon
- University of Michigan School of Medicine, Ann Arbor, MI, USA
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Kalia S, Saarela O, Chen T, O'Neill B, Meaney C, Moineddin R, Aliarzadeh B, Sullivan F, Greiver M. Continuous-Time Causal Inference With Marked Point Process Weights: An Example on Sodium-Glucose Co-Transporters 2 Inhibitor Medications and Urinary Tract Infection. Stat Med 2025; 44:e70102. [PMID: 40386859 PMCID: PMC12086771 DOI: 10.1002/sim.70102] [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: 04/20/2024] [Revised: 03/31/2025] [Accepted: 04/08/2025] [Indexed: 05/20/2025]
Abstract
Treatment-confounder feedback is present in time-to-recurrent or longitudinal event analysis when time-dependent confounders are themselves influenced by previous treatments. Conventional models produce misleading statistical inference of causal effects due to conditioning on these factors on the causal pathway. Marginal structural models are often applied to quantify the causal treatment effect, estimated using longitudinal weights that mimic the randomization procedure by balancing the covariate distributions across the treatment groups. The weights are usually constructed in discrete time intervals, which is appropriate if the follow-up visits are scheduled and regular. However, in primary care, visit times can be irregular and informative, and the treatment history consists of duration and doses. This can be modeled through a continuous-time marked point process. We constructed a continuous-time marginal structural model to estimate the effect of cumulative exposure to Sodium-Glucose co-Transporters 2 Inhibitor (SGLT-2i) medications on time-to-recurrent urinary tract infection (UTI). We used a cohort of type II diabetes patients with chronic kidney disease and constructed a marked point process that characterized the recurrent flare episodes of primary care visits (i.e., point process) with marks for the multinominal dose (none, low, high) of SGLT-2i medications and recurrent episodes of UTI. We applied the stabilized and optimal treatment weights to estimate the hypothesized causal effect. Our results are concordant with earlier findings in which the recurrent episodes of UTI did not increase when patients were prescribed low dose or high dose of SGLT-2i medications.
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Affiliation(s)
- Sumeet Kalia
- Department of StatisticsUniversity of ManitobaWinnipegCanada
- Department of Family and Community MedicineUniversity of TorontoTorontoOntarioCanada
| | - Olli Saarela
- Dalla Lana School of Public HealthUniversity of TorontoTorontoOntarioCanada
| | - Tao Chen
- Department of Family and Community MedicineUniversity of TorontoTorontoOntarioCanada
| | - Braden O'Neill
- Department of Family and Community MedicineUniversity of TorontoTorontoOntarioCanada
- Dalla Lana School of Public HealthUniversity of TorontoTorontoOntarioCanada
| | - Christopher Meaney
- Department of Family and Community MedicineUniversity of TorontoTorontoOntarioCanada
| | - Rahim Moineddin
- Department of Family and Community MedicineUniversity of TorontoTorontoOntarioCanada
- Dalla Lana School of Public HealthUniversity of TorontoTorontoOntarioCanada
| | - Babak Aliarzadeh
- Department of Family and Community MedicineUniversity of TorontoTorontoOntarioCanada
| | | | - Michelle Greiver
- Department of Family and Community MedicineUniversity of TorontoTorontoOntarioCanada
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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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Mazzotta R, Garofalo M, Salvi S, Orlandi M, Marcaccini G, Susini P, Checchi L, Palazzuoli A, Di Mario C, Pieroni M, Beltrami M. Early administration of SGLT2 inhibitors in hospitalized patients: A practical guidance from the current evidence. ESC Heart Fail 2025. [PMID: 40247631 DOI: 10.1002/ehf2.15293] [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: 12/13/2024] [Revised: 02/14/2025] [Accepted: 03/24/2025] [Indexed: 04/19/2025] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors represent one of the main cornerstones of heart failure treatment. Nevertheless, while the cardiovascular beneficial effects of these drugs have been clearly demonstrated by several clinical trials, in clinical practice, it remains challenging to identify the appropriate timing to start SGLT2 inhibitors. The potential risk of side effects, like genito-urinary infections and interaction with other drugs, may often lead to delay the prescription of these drugs in the acute setting. However, several studies have demonstrated the safety and the prognostic impact of SGLT2 inhibitors in the hospitalized patient, suggesting that treatment initiation during hospitalization or early post-discharge may represent an ideal therapeutic option. In this review, we discuss the main trials on early administration of SGLT2 inhibitors in acute heart failure supporting early introduction of SGLT2 inhibitors to optimize heart failure treatment. The efficacy and safety of these drugs in patients with acute myocardial infarction are also discussed. Based on the review of existing evidences, a practical flowchart on early administration of SGLT2 inhibitors in the acute setting is proposed.
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Affiliation(s)
- Ruggero Mazzotta
- Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Manuel Garofalo
- Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Samuele Salvi
- Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Matteo Orlandi
- Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Gianluca Marcaccini
- Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Pietro Susini
- Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Luca Checchi
- Arrhythmia and Electrophysiology Unit, Careggi University Hospital, Florence, Italy
| | - Alberto Palazzuoli
- Cardiovascular Diseases Unit, Cardio-Thoracic and Vascular Department, Le Scotte Hospital University of Siena, Siena, Italy
| | - Carlo Di Mario
- Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maurizio Pieroni
- Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Matteo Beltrami
- Arrhythmia and Electrophysiology Unit, Careggi University Hospital, Florence, Italy
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Gajić S, Janković S, Stojadinović M, Filić K, Bontić A, Pavlović J, Mrđa I, Petrović K, Hadži-Tanović L, Žunić J, Kostić M, Kezić A, Baralić M. The Effects of SGLT2 Inhibitors on Lipid Profile and Kidney Function in Patients with Chronic Kidney Disease Regardless of Diabetes and Hypertension Status. Metabolites 2025; 15:271. [PMID: 40278400 PMCID: PMC12029240 DOI: 10.3390/metabo15040271] [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: 03/02/2025] [Revised: 03/20/2025] [Accepted: 04/11/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is a progressive, irreversible impairment of kidney function due to various etiologies. Numerous studies have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) slow the progression of CKD, due to their pleiotropic effects. Therefore, there has been an increase in interest in their effects not only on kidney function but also on other parameters in patients with CKD. The aim of the study was to examine the effects of SGLT2i on serum lipid values and kidney function in patients with CKD undergoing SGLT2i treatment. METHODS This study was a retrospective data analysis of 75 patients with CKD on SGLT2i treatment. We compared the values of biochemical parameters, renal function outcomes, and blood pressure at two time points: baseline and 24 months after. RESULTS Total cholesterol (Chol) significantly decreased in all patients, while triglyceride (Tg) and low-density lipoprotein cholesterol (LDLc) levels also decreased in all patients. High-density lipoprotein cholesterol (HDLc) levels increased, but this increase was not significant. Creatinine clearance (Ccr) significantly decreased, and serum urea (Sur) significantly increased in all patients. The proteinuria (Prt) levels did not change significantly. The results showed that the diastolic blood pressure (DBP) significantly decreased in all patients. CONCLUSIONS This study showed that the use of SGLT2i reduced total Chol in all patients with CKD during the 24-month follow-up, regardless of diabetes mellitus (DM) status. No significant differences were observed for the Tg, LDLc, and HDLc values.
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Affiliation(s)
- Selena Gajić
- Clinic of Nephrology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
| | - Stefan Janković
- Faculty of Medicine, University of Belgrade, Dr Subotića Starijeg 8, 11000 Belgrade, Serbia
| | - Milorad Stojadinović
- Clinic of Nephrology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
| | - Kristina Filić
- Clinic of Nephrology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
| | - Ana Bontić
- Clinic of Nephrology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Dr Subotića Starijeg 8, 11000 Belgrade, Serbia
| | - Jelena Pavlović
- Clinic of Nephrology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Dr Subotića Starijeg 8, 11000 Belgrade, Serbia
| | - Ivana Mrđa
- Clinic of Nephrology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
| | - Kristina Petrović
- Clinic of Nephrology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
| | - Lara Hadži-Tanović
- Clinic of Nephrology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
| | - Jelena Žunić
- Faculty of Medicine, University of Belgrade, Dr Subotića Starijeg 8, 11000 Belgrade, Serbia
| | - Mihajlo Kostić
- Faculty of Medicine, University of Belgrade, Dr Subotića Starijeg 8, 11000 Belgrade, Serbia
| | - Aleksandra Kezić
- Clinic of Nephrology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Dr Subotića Starijeg 8, 11000 Belgrade, Serbia
| | - Marko Baralić
- Clinic of Nephrology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Dr Subotića Starijeg 8, 11000 Belgrade, Serbia
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Pan SY, Weng CH, Tsai SF, Lin HJ, Lin JF, Lin CH, Wang IJ, Chou CC. Use of SGLT2 Inhibitors Versus DPP-4 Inhibitors and Age-Related Macular Degeneration in Patients WithType 2 Diabetes: A Multinational Cohort Study. Invest Ophthalmol Vis Sci 2025; 66:58. [PMID: 40257783 PMCID: PMC12020956 DOI: 10.1167/iovs.66.4.58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 03/26/2025] [Indexed: 04/22/2025] Open
Abstract
Purpose To compare the impact of sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase 4 (DPP-4) inhibitors on age-related macular degeneration (AMD) risk among patients with type 2 diabetes mellitus (T2DM). Methods This multinational, retrospective cohort study used electronic medical records from healthcare institutions across 21 countries. Adults 50 years or older with T2DM who had a prior prescription of metformin and initiated SGLT2 or DPP-4 inhibitors from 2013 to 2023 were included. The SGLT2 and DPP-4 inhibitor groups were propensity score matched in a 1:1 ratio to balance baseline characteristics and were followed for up to 5 years to observe the occurrence of AMD. Statistical analysis was performed using the Cox proportional hazards model and Kaplan-Meier analysis. Results Our final analysis included 20,966 T2DM patients prescribed SGLT2 inhibitors and 20,966 prescribed DPP-4 inhibitors. Compared to the DPP-4 inhibitor group, the SGLT2 inhibitor group was associated with significantly lower risks of AMD (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.58-0.85) and dry AMD (HR, 0.61; 95% CI, 0.46-0.80) but not wet AMD (HR, 0.74; 95% CI, 0.48-1.16). SGLT2 inhibitors compared with DPP-4 inhibitors were linked to a reduced risk of AMD in the White population, patients prescribed empagliflozin or dapagliflozin, and individuals with glycated hemoglobin < 8.5%, estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2, hypertension, or dyslipidemia, regardless of body mass index level. Conclusions In patients with T2DM, those prescribed SGLT2 inhibitors may experience lower risks of AMD and dry AMD compared to those prescribed DPP-4 inhibitors.
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Affiliation(s)
- Ssu-Yu Pan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chien-Hsiang Weng
- Department of Family Medicine, Brown University Warren Alpert Medical School, Providence, Rhode Island, United States
- Brown University Health, Providence, Rhode Island, United States
| | - Shang-Feng Tsai
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Department of Life Science, Tunghai University, Taichung, Taiwan
| | - Hui-Ju Lin
- Eye Center, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Jun-Fu Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ching-Heng Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Public Health, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
- Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung, Taiwan
- Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - I-Jong Wang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chien-Chih Chou
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
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10
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Bazzazzadehgan S, Shariat-Madar Z, Mahdi F. Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM. Biomolecules 2025; 15:414. [PMID: 40149950 PMCID: PMC11940602 DOI: 10.3390/biom15030414] [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: 12/30/2024] [Revised: 01/26/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) encompasses a range of clinical manifestations, with uncontrolled diabetes leading to progressive or irreversible damage to various organs. Numerous genes associated with monogenic diabetes, exhibiting classical patterns of inheritance (autosomal dominant or recessive), have been identified. Additionally, genes involved in complex diabetes, which interact with environmental factors to trigger the disease, have also been discovered. These genetic findings have raised hopes that genetic testing could enhance diagnostics, disease surveillance, treatment selection, and family counseling. However, the accurate interpretation of genetic data remains a significant challenge, as variants may not always be definitively classified as either benign or pathogenic. Research to date, however, indicates that periodic reevaluation of genetic variants in diabetes has led to more consistent findings, with biases being steadily eliminated. This has improved the interpretation of variants across diverse ethnicities. Clinical studies suggest that genetic risk information may motivate patients to adopt behaviors that promote the prevention or management of T2DM. Given that the clinical features of certain monogenic diabetes types overlap with T2DM, and considering the significant role of genetic variants in diabetes, healthcare providers caring for prediabetic patients should consider genetic testing as part of the diagnostic process. This review summarizes current knowledge of the most common genetic variants associated with T2DM, explores novel therapeutic targets, and discusses recent advancements in the pharmaceutical management of uncontrolled T2DM.
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Affiliation(s)
- Shadi Bazzazzadehgan
- Department of Pharmacy Administration, School of Pharmacy, University of Mississippi, University, MS 38677, USA;
| | - Zia Shariat-Madar
- Division of Pharmacology, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA;
| | - Fakhri Mahdi
- Division of Pharmacology, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA;
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11
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Collins KE, Gilbert E, Mauduit V, Gaheer P, Elhassan EAE, Benson KA, Osman SM, Hill C, McKnight AJ, Maxwell AP, van der Most PJ, de Borst MH, Guan W, Jacobson PA, Israni AK, Keating BJ, Lord GM, Markkinen S, Helanterä I, Hyvärinen K, Partanen J, Madden SF, Storrar J, Sinha S, Kalra PA, Lanktree MB, Limou S, Cavalleri GL, Conlon PJ. Polygenic risk scores for eGFR are associated with age at kidney failure. J Nephrol 2025:10.1007/s40620-025-02207-7. [PMID: 40029548 DOI: 10.1007/s40620-025-02207-7] [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: 09/02/2024] [Accepted: 01/02/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND The genetic architecture of chronic kidney disease (CKD) is complex, including monogenic and polygenic contributions. CKD progression to kidney failure is influenced by factors including male sex, baseline estimated glomerular filtration rate (eGFR), hypertension, diabetes, proteinuria, and the underlying kidney disease. These traits all have strong genetic components, which can be partially quantified using polygenic risk scores. This paper examines the association between polygenic risk scores for CKD-related traits and age at kidney failure development. METHODS Genome-wide genotype data from 10,586 patients with kidney failure were compiled from 12 cohorts. Polygenic risk scores for hypertension, albuminuria, rapid decline in eGFR, decreased total kidney volume, and decreased eGFR were calculated using weights from published independent population-scale genome-wide association studies. The association between each polygenic risk score and age at kidney failure was investigated using logistic regression models. The association between polygenic risk score and age at kidney failure was also investigated separately for each primary kidney disease. RESULTS Individuals in the highest 10% of polygenic risk score for decreased eGFR developed kidney failure 2 years earlier than those in the bottom 90% (49.9 years and 47.9 years, P = 5e-5). A standard deviation increase in decreased eGFR polygenic risk score was associated with increased odds of developing kidney failure before the age of 60 years (Odds ratio (OR) = 1.05; 95% CI 1.01-1.10; P = 0.01), as was high decreased eGFR polygenic risk score (OR = 1.26; 95% CI 1.08-1.46; P = 0.003). CONCLUSIONS We conclude that decreased eGFR polygenic risk score explains a portion of the variation in age at development of kidney failure.
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Affiliation(s)
- Kane E Collins
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- The Science Foundation Ireland FutureNeuro Centre of Excellence, Dublin, Ireland
- SFI Centre for Research Training in Genomics Data Science, University of Galway, Galway, Ireland
| | - Edmund Gilbert
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- The Science Foundation Ireland FutureNeuro Centre of Excellence, Dublin, Ireland
| | - Vincent Mauduit
- Nantes University, Ecole Centrale Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR1064, Nantes, France
| | - Pukhraj Gaheer
- Division of Nephrology, Departments of Medicine and Health Research Methodology, Evidence and Impact, St. Joseph's Healthcare Hamilton, McMaster University and Population Health Research Institute, Hamilton, ON, Canada
| | - Elhussein A E Elhassan
- Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Katherine A Benson
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- The Science Foundation Ireland FutureNeuro Centre of Excellence, Dublin, Ireland
| | - Shohdan Mohamad Osman
- Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Claire Hill
- Centre for Public Health, Queen's University Belfast, Belfast, UK
| | | | | | - Peter J van der Most
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Martin H de Borst
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Weihua Guan
- Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, MN, USA
| | - Pamala A Jacobson
- Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA
| | - Ajay K Israni
- University of Texas Medical Branch, Galveston, TX, USA
| | - Brendan J Keating
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Graham M Lord
- School of Immunology and Microbial Sciences, University College London, London, UK
| | - Salla Markkinen
- Finnish Red Cross Blood Service, Research and Development, Biomedicum 1, Helsinki, Finland
| | - Ilkka Helanterä
- Helsinki University Hospital, Transplantation and Liver Surgery, Helsinki, Finland
| | - Kati Hyvärinen
- Finnish Red Cross Blood Service, Research and Development, Biomedicum 1, Helsinki, Finland
| | - Jukka Partanen
- Finnish Red Cross Blood Service, Research and Development, Biomedicum 1, Helsinki, Finland
| | - Stephen F Madden
- Data Science Centre, Beaux Lane House, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Joshua Storrar
- Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK
- University of Manchester, Manchester, UK
| | - Smeeta Sinha
- Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK
- University of Manchester, Manchester, UK
| | - Philip A Kalra
- Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK
- University of Manchester, Manchester, UK
| | - Matthew B Lanktree
- Division of Nephrology, Departments of Medicine and Health Research Methodology, Evidence and Impact, St. Joseph's Healthcare Hamilton, McMaster University and Population Health Research Institute, Hamilton, ON, Canada
| | - Sophie Limou
- Nantes University, Ecole Centrale Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR1064, Nantes, France
| | - Gianpiero L Cavalleri
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- The Science Foundation Ireland FutureNeuro Centre of Excellence, Dublin, Ireland
- SFI Centre for Research Training in Genomics Data Science, University of Galway, Galway, Ireland
| | - Peter J Conlon
- Division of Nephrology, Departments of Medicine and Health Research Methodology, Evidence and Impact, St. Joseph's Healthcare Hamilton, McMaster University and Population Health Research Institute, Hamilton, ON, Canada.
- Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.
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12
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Das BB, Niu J. A Systematic Review and Meta-Analysis of the Safety and Efficacy of SGLT2 Inhibitors in Chronic Heart Failure in ACHD Patients. Am J Cardiovasc Drugs 2025; 25:231-240. [PMID: 39621203 PMCID: PMC11811263 DOI: 10.1007/s40256-024-00697-7] [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] [Accepted: 10/18/2024] [Indexed: 01/24/2025]
Abstract
BACKGROUND Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have become a first-line therapy for heart failure (HF) in adults. However, data on their use in HF associated with adult congenital heart disease (ACHD) are limited. This systematic review and meta-analysis evaluated the safety, tolerability, and efficacy of SGLT2is in ACHD HF patients, supplementing guideline-directed medical therapy. METHODS A comprehensive systematic search and meta-analysis were conducted on studies examining SGLT2i use in ACHD HF patients. The primary endpoint was the change in the New York Heart Association (NYHA) functional class (FC), with secondary endpoints including changes in ventricular function and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels. Additionally, the safety and tolerability of SGLT2is were evaluated. RESULTS The meta-analysis included eight studies with 287 patients aged 19-67 years (median age 37.5 years). Adding SGLT2is to combined therapies significantly improved NYHA FC (log odds ratio 1.3, 95% confidence interval [CI] 0.37-2.23, p = 0.01) and reduced NT-proBNP levels (mean difference [MD] -0.43, 95% CI -0.70 to -0.16, p < 0.001). A notable decrease in systolic blood pressure was observed (MD -0.32, 95% CI -0.51 to -0.14, p = 0.00). The adverse effect profile was comparable to that seen in routine HF, with fewer HF hospitalizations post-SGLT2i initiation. Urinary tract infections occurred in 14 patients (5%), with no instances of hypoglycemia or ketoacidosis reported. Medication withdrawal due to adverse effects was noted in 19 patients (7%). CONCLUSIONS SGLT2is are well tolerated in ACHD HF patients. Notably, SGLT2is improved NYHA FC and reduced NT-proBNP levels across a diverse ACHD HF patient cohort. However, further prospective, multicenter studies are needed to confirm the safety and efficacy of SGLT2is in this unique patient population.
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Affiliation(s)
- Bibhuti B Das
- Division of Pediatric Cardiology, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS, 39216, USA.
| | - Jianli Niu
- Office of Human Research, Memorial Healthcare System, Hollywood, FL, 33021, USA
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13
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Antonazzo IC, Rozza D, Cortesi PA, Fornari C, Zanzottera Ferrari E, Paris C, Eteve-Pitsaer C, Gnesi M, Mele S, D'Amelio M, Maurizi AR, Palladino P, Mantovani LG, Mazzaglia G. Generalizability and treatment with sodium-glucose co-trasporter-2 inhibitors (SGLT2i) among patients with type 2 diabetes: an assessment using an Italian primary care database. Acta Diabetol 2025; 62:343-351. [PMID: 39207490 PMCID: PMC11872765 DOI: 10.1007/s00592-024-02359-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 08/04/2024] [Indexed: 09/04/2024]
Abstract
AIMS This study aimed to assess the proportions of type 2 diabetes (T2D) subjects meeting cardiovascular outcome trials (CVOTs) criteria for sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and estimate SGLT2i utilization, along with associated demographic and clinical characteristics, in a primary care setting. METHODS T2D patients in Italy were selected between January 1, 2021, and December 31, 2022, from The Health Improvement Network (THIN®) database. Representativeness was determined by dividing patients meeting key inclusion criteria for four CVOTs (CANVAS, DECLARE-TIMI 58, EMPA-REG OUTCOME, VERTIS-CV) to the total T2D population. Demographic and clinical characteristics of eligible T2D subjects and SGLT2i users were compared, and logistic regression models assessed the likelihood of receiving SGLT2i. RESULTS Out of 17,102 T2D patients, 8,828 met eligibility criteria for at least one CVOT. DECLARE-TIMI 58 exhibited the highest representativeness (51.1%), compared to CANVAS (21.1%), EMPA-REG OUTCOME (5.5%), and VERTIS-CV (4.9%) trials. Eligible CVOTs patients were older (74.6 vs. 68.3 years), with a longer disease duration (10.2 vs. 9.7 years), and higher established cardiovascular disease (CVD) prevalence (36.0 vs. 27.3%) compared to SGLT2i users. Less than 10% of eligible T2D patients received SGLT2i. Males (OR: 1.43; 95%CI: 1.24-1.66) were more likely to be prescribed SGLT2i than other antidiabetic drugs, while the elderly (80 + vs. 40-64 years, OR: 0.17; 95% CI: 0.14-0.22) were less likely. Eligible T2D patients with CVD reported an increased likelihood of receiving SGLT2is compared to other antidiabetics. CONCLUSION This study highlights significant variability in the proportion of T2D subjects meeting SGLT2i CVOT inclusion criteria, with DECLARE-TIMI-58 being the most represented. Low SGLT2i prescription rates in the Italian primary care setting, along with substantial demographic and clinical differences between SGLT-2i users and T2D eligible patients, emphasize the need for targeted interventions to optimize the use of these medications in primary care settings.
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Affiliation(s)
- Ippazio Cosimo Antonazzo
- Research Centre on Public Health (CESP), University of Milano-Bicocca, Via Pergolesi 33, Monza, MB, Italy
- Unit of Medical Statistics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, 56126, Italy
- Laboratory of Public Health, IRCCS Istituto Auxologico Italiano, Milan, 20149, Italy
| | - Davide Rozza
- Research Centre on Public Health (CESP), University of Milano-Bicocca, Via Pergolesi 33, Monza, MB, Italy
| | - Paolo Angelo Cortesi
- Research Centre on Public Health (CESP), University of Milano-Bicocca, Via Pergolesi 33, Monza, MB, Italy
- Laboratory of Public Health, IRCCS Istituto Auxologico Italiano, Milan, 20149, Italy
| | - Carla Fornari
- Research Centre on Public Health (CESP), University of Milano-Bicocca, Via Pergolesi 33, Monza, MB, Italy.
| | | | - Claire Paris
- Cegedim Health data, Boulogne-Billancourt, France
| | | | - Marco Gnesi
- Medical Evidence, Biopharmaceuticals Medical, AstraZeneca, Milan, Italy
| | | | | | - Anna Rita Maurizi
- Medical Affairs, Biopharmaceuticals Medical, AstraZeneca, Milan, Italy
| | | | - Lorenzo Giovanni Mantovani
- Research Centre on Public Health (CESP), University of Milano-Bicocca, Via Pergolesi 33, Monza, MB, Italy
- Laboratory of Public Health, IRCCS Istituto Auxologico Italiano, Milan, 20149, Italy
| | - Giampiero Mazzaglia
- Research Centre on Public Health (CESP), University of Milano-Bicocca, Via Pergolesi 33, Monza, MB, Italy
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14
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Huang B, Yen CL, Wu CY, Tsai CY, Chen JJ, Hsiao CC, Chen YC, Hsieh IC, Yang HY. SGLT2 inhibitors reduce the risk of renal failure in CKD stage 5 patients with Type 2 DM. Sci Rep 2025; 15:5872. [PMID: 39966427 PMCID: PMC11836049 DOI: 10.1038/s41598-024-81973-z] [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: 08/25/2024] [Accepted: 12/02/2024] [Indexed: 02/20/2025] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as a promising therapy for diabetes and CKD patients. However, the pros and cons of SGLT2i in Type2 diabetes patients with CKD stage 5 remained largely unexplored. By using Taiwan's national health insurance research database (NHIRD), this observational cohort study enrolled T2DM patients with newly identified as having CKD5, and the index date defined as the date of CKD5 identification. The enrollees were divided into 2 groups depending on whether SGLT2 inhibitors were used for more than 3 months or not following the index date. A 1:4 propensity score matching was performed to balance characteristics between two groups. The SGLT2-inhibitor group exhibited significantly lower risks of new-onset ESRD (35.9% vs. 58.2%, hazard ratio [HR] 0.59, 95% confidence interval [CI]: 0.59-0.74). For the risks of MACCEs (16.72% vs. 17.66%, HR 0.84, 95% CI: 0.62-1.15), infections related hospitalization (2.4% vs. 2.61%, HR:1.02, 95% CI:0.80-1.31), Infection-associated mortality (3.45% vs. 4.18% HR:0.80, 95% CI:0.41-1.56) and all-cause mortality (13.79% vs. 13.83%, HR:0.95, 95% CI:0.68-1.32), no significant differences were observed between two groups. In conclusion, we provide evidence suggesting that SGLT2 inhibitors may offer renal protection and did not increase infection risks for CKD5 patients with type2 diabetes.
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Affiliation(s)
- Birdie Huang
- Department of Cardiology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Chieh-Li Yen
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, No. 5, Fusing St., Gueishan District, Taoyuan, 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chao-Yi Wu
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chung-Ying Tsai
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, No. 5, Fusing St., Gueishan District, Taoyuan, 333, Taiwan
| | - Jia-Jin Chen
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, No. 5, Fusing St., Gueishan District, Taoyuan, 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ching-Chung Hsiao
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, No. 5, Fusing St., Gueishan District, Taoyuan, 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yung-Chang Chen
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, No. 5, Fusing St., Gueishan District, Taoyuan, 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - I-Chang Hsieh
- Department of Cardiology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Huang-Yu Yang
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou Branch, No. 5, Fusing St., Gueishan District, Taoyuan, 333, Taiwan.
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
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15
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Zheng Y, Sun J. Long-term effect of sodium-glucose cotransporter 2 inhibitors in kidney functions: A systematic review and meta-analysis. Medicine (Baltimore) 2025; 104:e41422. [PMID: 39960956 PMCID: PMC11835073 DOI: 10.1097/md.0000000000041422] [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: 06/26/2024] [Accepted: 01/15/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors (such as dapagliflozin, empagliflozin, and canagliflozin) are essential for the treatment of type 2 diabetes because they improve the urine excretion of glucose. Although there are advantages, including weight loss and enhanced heart health, caution is necessary because of possible negative effects, such as higher urine output and euglycemic diabetic ketoacidosis. They may slow chronic kidney disease progression, therefore, renal function must be monitored. This study aims to determine the efficacy of SGLT2 inhibitors in the prevention of renal deterioration in terms of reduction of estimated glomerular filtration rate (eGFR) in patients with compromised renal functions. METHODS This study aimed to document the long-term effects of SGLT2 inhibitors on kidney function. PubMed and Google Scholar were the key sources of scholarly publications, and Boolean operators were used to perform exact searches. Nine articles were considered relevant out of a total of 244, following extensive screening of titles, abstracts, and full texts according to PRISMA recommendations. RESULTS This study included randomized, double-blind, placebo-controlled trials evaluating the long-term effects of SGLT2 inhibitors on renal function across patient demographics and locations. Clinical investigations showed different effects on eGFR across control and study groups, suggesting renal protection. A meta-analysis showed that SGLT2 inhibitors enhanced kidney function more than the controls. CONCLUSION This meta-analysis concluded that SGLT2 inhibitors have the potential to prevent eGFR reduction and improve renal function in patients with compromised renal function and underlying conditions such as chronic kidney disease or type 1 and 2 diabetes. However, this meta-analysis showed beneficial results in the prevention of renal deterioration within several follow-up periods, with an average of 11 to 12 months.
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Affiliation(s)
- Yanqun Zheng
- Department of Nephrology, The First People’s Hospital of Linping District, Hangzhou, China
| | - Jia Sun
- Department of Nephrology, The First People’s Hospital of Linping District, Hangzhou, China
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Boima V, Agyekum AB, Ganatra K, Agyekum F, Kwakyi E, Inusah J, Ametefe EN, Adu D. Advances in kidney disease: pathogenesis and therapeutic targets. Front Med (Lausanne) 2025; 12:1526090. [PMID: 40027896 PMCID: PMC11868101 DOI: 10.3389/fmed.2025.1526090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
Chronic kidney disease (CKD) is a global public health issue characterized by progressive loss of kidney function, of which end-stage kidney disease (ESKD) is the last stage. The global increase in the prevalence of CKD is linked to the increasing prevalence of traditional risk factors, including obesity, hypertension, and diabetes mellitus, as well as metabolic factors, particularly insulin resistance, dyslipidemia, and hyperuricemia. Mortality and comorbidities, such as cardiovascular complications, rise steadily as kidney function deteriorates. Patients who progress to ESKD require long-term kidney replacement therapy, such as transplantation or hemodialysis/peritoneal dialysis. It is currently understood that a crucial aspect of CKD involves persistent, low-grade inflammation. In addition, increased oxidative and metabolic stress, endothelial dysfunction, vascular calcification from poor calcium and phosphate metabolism, and difficulties with coagulation are some of the complex molecular pathways underlying CKD-related and ESKD-related issues. Novel mechanisms, such as microbiome dysbiosis and apolipoprotein L1 gene mutation, have improved our understanding of kidney disease mechanisms. High kidney disease risk of Africa has been linked to APOL1 high-risk alleles. The 3-fold increased risk of ESKD in African Americans compared to European Americans is currently mainly attributed to variants in the APOL1 gene in the chromosome 22q12 locus. Additionally, the role of new therapies such as SGLT2 inhibitors, mineralocorticoid receptor antagonists, and APOL1 channel function inhibitors offers new therapeutic targets in slowing down the progression of chronic kidney disease. This review describes recent molecular mechanisms underlying CKD and emerging therapeutic targets.
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Affiliation(s)
- Vincent Boima
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Alex Baafi Agyekum
- National Cardio-Thoracic Center, KorleBu Teaching Hospital, Accra, Ghana
| | - Khushali Ganatra
- Department of Medicine and Therapeutics, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Francis Agyekum
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Edward Kwakyi
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
| | - Jalil Inusah
- Department of Medicine and Therapeutics, Korle-Bu Teaching Hospital, Accra, Ghana
| | - Elmer Nayra Ametefe
- Department of Biochemistry, Cell and Molecular Biology, School of Biological Sciences, College of Basic and Applied Science, University of Ghana, Accra, Ghana
| | - Dwomoa Adu
- Department of Medicine and Therapeutics, University of Ghana Medical School, College of Health Sciences, University of Ghana, Accra, Ghana
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17
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Johannes CB, Ziemiecki R, Pladevall-Vila M, Ebert N, Kovesdy CP, Thomsen RW, Baak BN, García-Sempere A, Kanegae H, Coleman CI, Walsh M, Andersen IT, Rodríguez Bernal C, Robles Cabaniñas C, Christiansen CF, Farjat AE, Gay A, Gee P, Herings RMC, Hurtado I, Kashihara N, Kristensen FPB, Liu F, Okami S, Overbeek JA, Penning-van Beest FJA, Yamashita S, Yano Y, Layton JB, Vizcaya D, Oberprieler NG. Clinical Profile and Treatment Adherence in Patients with Type 2 Diabetes and Chronic Kidney Disease Who Initiate an SGLT2 Inhibitor: A Multi-cohort Study. Diabetes Ther 2025; 16:205-226. [PMID: 39688776 PMCID: PMC11794911 DOI: 10.1007/s13300-024-01671-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: 09/22/2024] [Accepted: 11/11/2024] [Indexed: 12/18/2024] Open
Abstract
INTRODUCTION The clinical landscape for the treatment of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) is rapidly evolving. As part of the FOUNTAIN platform (NCT05526157; EUPAS48148), we described and compared cohorts of adult patients with CKD and T2D initiating a sodium-glucose cotransporter 2 inhibitor (SGLT2i) before the launch of finerenone in Europe, Japan, and the United States (US). METHODS This was a multinational, multi-cohort study of patients with T2D in five data sources: the Danish National Health Registers (DNHR) (Denmark), PHARMO Data Network (The Netherlands), Valencia Health System Integrated Database (VID) (Spain), Japan Chronic Kidney Disease Database Extension (J-CKD-DB-Ex) (Japan), and Optum's de-identified Clinformatics® Data Mart Database (CDM) (US). Eligible patients had CKD (based on either diagnosis codes, eGFR values, and/or urine ACR) and initiated an SGLT2i between 2012 and 2021. Baseline demographic, lifestyle, and clinical characteristics were analyzed, and drug utilization patterns were described. RESULTS The final cohorts included 21,739 patients in DNHR, 381 in PHARMO, 31,785 in VID, 1157 in J-CKD-DB-Ex, and 56,219 in CDM. Across data sources, approximately 41-70% had CKD stage 1 or 2 at baseline; severe CKD (stage 4) was uncommon (1.6-6.7%). The median duration of SGLT2i therapy ranged from 7.5 months in PHARMO to 17.0 months in VID. At least 50% of patients were currently receiving SGLT2i treatment at 1 year after initiation. CONCLUSIONS At a 1-year follow-up, at least half of the patients with CKD and T2D were receiving SGLT2i treatment across the data sources. In patients initiating SGLT2i, treatment options for T2D and CKD were heterogeneous and dynamic within and among data sources.
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Affiliation(s)
| | | | - Manel Pladevall-Vila
- RTI Health Solutions, Barcelona, Spain
- The Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA
| | | | - Csaba P Kovesdy
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Reimar W Thomsen
- Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark
| | - Brenda N Baak
- PHARMO Institute for Drug Outcomes Research, Utrecht, The Netherlands
| | - Aníbal García-Sempere
- Valencia Health System Integrated Database, Health Services Research Unit, Valencia, Spain
| | | | - Craig I Coleman
- University of Connecticut School of Pharmacy, Storrs, CT, USA
- Evidence-Based Practice Center, Hartford Hospital, Hartford, CT, USA
| | - Michael Walsh
- Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Ina Trolle Andersen
- Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark
| | - Clara Rodríguez Bernal
- Valencia Health System Integrated Database, Health Services Research Unit, Valencia, Spain
| | - Celia Robles Cabaniñas
- Valencia Health System Integrated Database, Health Services Research Unit, Valencia, Spain
| | | | | | | | - Patrick Gee
- National Kidney Foundation Advocacy, Richmond, VA, USA
| | - Ron M C Herings
- PHARMO Institute for Drug Outcomes Research, Utrecht, The Netherlands
| | - Isabel Hurtado
- Valencia Health System Integrated Database, Health Services Research Unit, Valencia, Spain
| | - Naoki Kashihara
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan
| | | | | | | | - Jetty A Overbeek
- PHARMO Institute for Drug Outcomes Research, Utrecht, The Netherlands
| | | | | | - Yuichiro Yano
- NCD Epidemiology Research Center, Shiga University of Medical Science, Shiga, Japan
- Department of General Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
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18
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Sun A, Pollock CA, Huang C. Mitochondria-targeting therapeutic strategies for chronic kidney disease. Biochem Pharmacol 2025; 231:116669. [PMID: 39608501 DOI: 10.1016/j.bcp.2024.116669] [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: 09/02/2024] [Revised: 11/06/2024] [Accepted: 11/25/2024] [Indexed: 11/30/2024]
Abstract
Chronic kidney disease (CKD) is a multifactorial health issue characterised by kidney impairment that has significant morbidity and mortality in the global population. Current treatments for CKD fail to prevent progression to end-stage kidney disease, where management is limited to renal replacement therapy or kidney transplantation. Mitochondrial dysfunction has been implicated in the pathogenesis of CKD and can be broadly categorised into abnormalities related to excessive oxidative stress, reduced mitochondrial biogenesis, excess mitochondrial fission and dysregulated mitophagy. Mitochondria-targeting therapeutic strategies target many of the outlined mechanisms of mitochondrial dysfunction, and an overview of recent evidence for mitochondria-targeting therapeutic strategies is explored in this review, including naturally derived compounds and novel approaches such as fusion proteins. Mitochondria-targeting therapeutic strategies using these approaches show the potential to stabilise or improve renal function, and clinical studies are needed to further confirm their safety and efficacy in human contexts.
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Affiliation(s)
- Annie Sun
- Kolling Institute, Sydney Medical School Northern, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia
| | - Carol A Pollock
- Kolling Institute, Sydney Medical School Northern, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia
| | - Chunling Huang
- Kolling Institute, Sydney Medical School Northern, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
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19
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Wisbaum A, Gaudreau S, Cloutier I, Robert P, Kolment R, Beauchesne MF, Couture J. Real-Time Use of SGLT2i Verified in Pre-dialysis: The RSVP Cross-sectional Study. Ann Pharmacother 2025; 59:13-22. [PMID: 38736313 PMCID: PMC11566075 DOI: 10.1177/10600280241245995] [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: 05/14/2024] Open
Abstract
BACKGROUND The use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in nephrology practice is increasingly becoming standard of care in patients with diabetes or those with proteinuria. OBJECTIVES The primary outcome was to identify the proportion of pre-dialysis patients with chronic kidney disease (CKD) G3a, G3b, or G4 prescribed an SGLT2i and describe their characteristics. METHODS This was a retrospective, multicentric, cross-sectional study of patients with CKD followed at 4 pre-dialysis clinics in the province of Quebec, Canada. We collected data of multiple covariates associated with prescribing SGLT2i in patients over 18 years of age with CKD G3a, G3b, or G4. We then performed a multivariate logistic regression to assess their associations. RESULTS Of the 874 patients included, 22.7% were prescribed an SGLT2i. Factors most strongly associated included male sex (odds ratio [OR] = 4.88, 95% CI = 2.38-10.03), being prescribed metformin (OR = 4.30, 95% CI = 2.23-8.31), having type 2 diabetes (OR = 4.00, 95% CI = 1.86-8.62), or having an albumin-to-creatinine ratio greater than 300 mg/g (OR = 1.84, 95% CI = 1.08-3.14). The majority of patients (60.4%) had their SGLT2i initiated by the pre-dialysis clinic and the most frequent adverse event was an initial increase in serum creatinine 1 week after starting treatment (33.9%). CONCLUSION AND RELEVANCE An increasing number of patients with CKD are being prescribed SGLT2i. Nonetheless, significant disparities in sex, severity of disease, and comorbidities remain. We suggest that specific strategies be put in place to promote prescribing of SGLT2i in women and other at-risk populations, in particular among nephrology teams, to improve patient care.
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Affiliation(s)
- Aylon Wisbaum
- Santé Mont Royal Medical Center, Montreal, QC, Canada
| | - Sandrine Gaudreau
- Centre Intégré Universitaire de Santé et de Services Sociaux de l’Est-de-l’Île-de-Montréal, Montreal, QC, Canada
| | - Isabelle Cloutier
- Department of Pharmacy, Institut Universitaire de Cardiologie et de Pneumologie de Québec—Université Laval, Québec City, QC, Canada
| | - Pascale Robert
- Department of Pharmacy, Hôpital Régional de Rimouski, Rimouski, QC, Canada
| | - Regina Kolment
- Department of Pharmacy, Centre Hospitalier du Centre Intégré Universitaire de Santé et de Services Sociaux de Memphrémagog, QC, Canada
| | | | - Jodianne Couture
- Pharmacy Department, CIUSSS de l’Estrie-CHUS, Sherbrooke, QC, Canada
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20
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Miguel V, Shaw IW, Kramann R. Metabolism at the crossroads of inflammation and fibrosis in chronic kidney disease. Nat Rev Nephrol 2025; 21:39-56. [PMID: 39289568 DOI: 10.1038/s41581-024-00889-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/15/2024] [Indexed: 09/19/2024]
Abstract
Chronic kidney disease (CKD), defined as persistent (>3 months) kidney functional loss, has a growing prevalence (>10% worldwide population) and limited treatment options. Fibrosis driven by the aberrant accumulation of extracellular matrix is the final common pathway of nearly all types of chronic repetitive injury in the kidney and is considered a hallmark of CKD. Myofibroblasts are key extracellular matrix-producing cells that are activated by crosstalk between damaged tubules and immune cells. Emerging evidence indicates that metabolic alterations are crucial contributors to the pathogenesis of kidney fibrosis by affecting cellular bioenergetics and metabolite signalling. Immune cell functions are intricately connected to their metabolic characteristics, and kidney cells seem to undergo cell-type-specific metabolic shifts in response to damage, all of which can determine injury and repair responses in CKD. A detailed understanding of the heterogeneity in metabolic reprogramming of different kidney cellular subsets is essential to elucidating communication processes between cell types and to enabling the development of metabolism-based innovative therapeutic strategies against CKD.
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Affiliation(s)
- Verónica Miguel
- Department of Medicine 2, Nephrology, Rheumatology and Immunology, RWTH Aachen University, Medical Faculty, Aachen, Germany
| | - Isaac W Shaw
- Department of Medicine 2, Nephrology, Rheumatology and Immunology, RWTH Aachen University, Medical Faculty, Aachen, Germany
| | - Rafael Kramann
- Department of Medicine 2, Nephrology, Rheumatology and Immunology, RWTH Aachen University, Medical Faculty, Aachen, Germany.
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands.
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21
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Taylor S, Zinabu SW, McMillan E, Ocampo E, Edmonds A, Lyles S, Pempeh J, Yates K, Micheal M. Breaking Barriers: Tackling Racial and Socioeconomic Disparities in the Prescription of Life-Saving SGLT2 Inhibitors for Proteinuria. Cureus 2025; 17:e77159. [PMID: 39925502 PMCID: PMC11805696 DOI: 10.7759/cureus.77159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 01/08/2025] [Indexed: 02/11/2025] Open
Abstract
INTRODUCTION The underutilization of sodium-glucose co-transporter type 2 inhibitors (SGLT2i), despite their proven cardiovascular and renal benefits, raises concerns about healthcare equity. SGLT2i effectively reduces proteinuria, a key indicator of kidney disease, making them an essential treatment for individuals with or without diabetes, particularly those at higher risk, such as the Black American population, who have a higher prevalence of proteinuria. However, studies show disparities in SGLT2i prescriptions with race, ethnicity, and socioeconomic status contributing to lower utilization rates among vulnerable populations. This study aims to explore SGLT2i prescription patterns in Maryland, focusing on patients with proteinuria to address these disparities and improve access to care. OBJECTIVE The objective of the study was to identify racial and socioeconomic disparities in access to SGLT2i. METHODS This retrospective cohort study utilized de-identified electronic health records (EHR) sourced from the Epic database across the University of Maryland Medical System (UMMS), spanning a 10-year period from January 1, 2014, to December 31, 2023, and evaluated SGLT2i prescription patterns among patients with proteinuria. RESULT Of the 5,866,616 patients in the UMMS system, 28,136 were diagnosed with proteinuria, of whom 4,360 (15.5%) were prescribed SGLT2i medications. Among those receiving prescriptions, 37.9% self-identified as Black American, while 54.7% identified as White American. Notable geographical disparities were observed in prescription rates. In affluent areas such as Fulton, MD (zip code 20759), only 0.046% of patients with proteinuria received SGLT2i prescriptions, compared to 1.4% in the lower-income area of West Baltimore, MD (zip code 21223). Bivariate analysis revealed significant disparities in SGLT2i prescription rates, with Black American patients having lower odds of receiving prescriptions compared to White American patients (OR = 0.68, p < 0.001) and affluent areas like Fulton showing significantly lower odds compared to lower-income areas like West Baltimore (OR = 0.31, p < 0.001). These disparities persisted in multivariate analysis, where Black American patients had adjusted PR (AOR) of 0.72 (p = 0.002) relative to White American patients, and West Baltimore residents had higher odds (AOR = 1.72, p = 0.01) compared to significantly reduced odds in Fulton (AOR = 0.35, p = 0.02). CONCLUSION This study reveals significant disparities in the prescription of SGLT2i among patients with proteinuria in Maryland, United States, highlighting the influence of socioeconomic factors on access to these vital treatments. Despite the established benefits of SGLT2i in managing proteinuria and reducing the risk of kidney and cardiovascular disease, systemic inequities persist, potentially leaving high-risk populations underserved. These findings call for a deeper examination of the structural and systemic barriers contributing to these disparities, as well as the development of strategies to promote equitable access to care. Ensuring that all patients, regardless of their background or socioeconomic status, have access to evidence-based therapies is essential for improving outcomes and reducing healthcare inequities.
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Affiliation(s)
- Shay Taylor
- Internal Medicine, Howard University College of Medicine, Washington, DC, USA
| | | | - Elijah McMillan
- Internal Medicine, Howard University College of Medicine, Washington, DC, USA
| | - Emmanuel Ocampo
- Internal Medicine, Howard University College of Medicine, Washington, DC, USA
| | - Alexis Edmonds
- Internal Medicine, Howard University College of Medicine, Washington, DC, USA
| | - Sierra Lyles
- Internal Medicine, Howard University College of Medicine, Washington, DC, USA
| | - John Pempeh
- Internal Medicine, Howard University Hospital, Washington, DC, USA
| | - Kira Yates
- Internal Medicine, Howard University College of Medicine, Washington, DC, USA
| | - Miriam Micheal
- Internal Medicine, Howard University College of Medicine, Washington, DC, USA
- Internal Medicine, University of Maryland School of Medicine, Baltimore, USA
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22
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Seif El-Din Z, Afify M, Zayed E, Elsabaawy D, Tharwa ES, Elsharawy A, Abdelsameea E, Rady MA. Dapagliflozin as an oral antihyperglycemic agent in the management of diabetes mellitus in patients with liver cirrhosis. World J Exp Med 2024; 14:95272. [PMID: 39713077 PMCID: PMC11551699 DOI: 10.5493/wjem.v14.i4.95272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 08/18/2024] [Accepted: 08/28/2024] [Indexed: 10/31/2024] Open
Abstract
BACKGROUND The use of dapagliflozin in patients with cirrhosis has been relatively restricted due to concerns regarding its overall safety and pharmacological profile in this population. AIM To determine the safety and effectiveness of dapagliflozin in the co-management of diabetes mellitus and cirrhosis with or without ascites. METHODS The patients studied were divided into two groups: 100 patients in the control group received insulin, while 200 patients received dapagliflozin. These patients were classified as Child A, B, or C based on the Child-Pugh classification. Child A or B and Child C were administered doses of 10 mg and 5 mg of dapagliflozin, respectively. RESULTS The rate of increased diuretics dose was markedly elevated in the group that received insulin compared to the group that received dapagliflozin. In addition, dapagliflozin treatment substantially reduced weight, body mass index, and fasting blood glucose compared to the insulin group during follow-up. However, there were no significant differences in hemoglobin A1c, liver function, or laboratory investigations between both groups during the follow-up period. The incidence of hypoglycemia, hepatic encephalopathy, variceal bleeding, and urinary tract infection was significantly higher in the insulin group compared to the dapagliflozin group. In contrast, the dapagliflozin group experienced significantly higher rates of frequent urination and dizziness. In addition, the insulin group exhibited a marked worsening of ascites compared to the dapagliflozin group. CONCLUSION Dapagliflozin demonstrated safety and efficacy in the treatment of diabetic patients who have cirrhosis with or without ascites. This resulted in an improvement of ascites, as well as a decrease in diuretic dose and Child-Pugh score.
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Affiliation(s)
- Zeinab Seif El-Din
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Mohammed Afify
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Essam Zayed
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Dalia Elsabaawy
- Department of Clinical Pharmacy, Pharmacy College, Menoufia University, Shebin El-Kom 32511, Egypt
| | - El Sayed Tharwa
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Ahmed Elsharawy
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Eman Abdelsameea
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
| | - Mohamed Akl Rady
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom 32511, Egypt
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23
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Price EL, Cotten SW. Influence of Race Modifiers in Estimated Glomerular Filtration Rate Calculations on Medication Dosing, Access, and Transplant Eligibility. Clin Lab Med 2024; 44:705-717. [PMID: 39490126 DOI: 10.1016/j.cll.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2024]
Abstract
The 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimation of glomerular filtration rate (GFR) lower values for Black individuals relative to previous equations, which may change medication eligibility or trigger the need to reevaluate dosing decisions. Major drug classes such as antibiotics, antidiabetic medications, cardiovascular agents, medications for the treatment of psychiatric illness, and chemotherapy drugs all have estimated GFR thresholds for prescribing eligibility. However, the use of strict thresholds for medication eligibility should be heavily scrutinized, and individualized comprehensive approaches should be used for patients on the cusps of these thresholds.
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Affiliation(s)
- Emery L Price
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 300 Brinkhous-Bullitt Building, CB #7525, Chapel Hill, NC 27599-7525, USA
| | - Steven W Cotten
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Core Laboratory -Room 1075 PST, UNC Hospitals, 101 Manning Drive, Chapel Hill, NC 27514, USA.
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24
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Boeckhaus J, Gale DP, Simon J, Ding J, Zhang Y, Bergmann C, Turner AN, Hall M, Sayer JA, Srivastava S, Kang HG, Cerkauskaite-Kerpauskiene A, Gillion V, Claes KJ, Krueger B, de Fallois J, Walden U, Choi M, Schueler M, Mueller RU, Todorova P, Hohenstein B, Zeisberg M, Friede T, Knebelmann B, Halbritter J, Gross O. SGLT2-Inhibition in Patients With Alport Syndrome. Kidney Int Rep 2024; 9:3490-3500. [PMID: 39698346 PMCID: PMC11652101 DOI: 10.1016/j.ekir.2024.09.014] [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: 07/23/2024] [Revised: 09/07/2024] [Accepted: 09/16/2024] [Indexed: 12/20/2024] Open
Abstract
Introduction Large-scale trials showed positive outcomes of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in adults with chronic kidney disease (CKD). Whether the use of SGLT2i is safe and effective in patients with the common hereditary CKD Alport syndrome (AS) has not yet been investigated specifically in larger cohorts. Methods This observational, multicenter, international study (NCT02378805) assessed 112 patients with AS after start of SGLT2i. The study's primary end point was change of albuminuria in albumin/g creatinine from the start of therapy. Results Compared to randomized trials investigating the effect of SGLT2i in CKD, the adult patients in this study were younger (aged 38 ± 14 years) and had a better estimated glomerular filtration rate (eGFR, 63 ± 35 ml/min per 1.73 m2; n = 98). Maximum follow-up was 32 months. Compared to baseline, at the first 3 follow-up visits (months 1 to 3, 4 to 8, and 9 to 15) after initiation of SGLT2i therapy, a significant reduction of albuminuria in mg albumin/g creatinine (>30%) was observed. Mean loss of eGFR was 9 ± 12 ml/min per 1.73 m2 almost 1 year after initiation of SGLT2i therapy (n = 35). At a total of 71 patient-years at risk, 0.24 adverse events (AEs) per patient-year on SGLT2i were reported. Conclusion This study indicates that, additive to renin-angiotensin system (RAS)-inhibition (RASi), SGLT2i have the potential to reduce the amount of albuminuria in patients with AS. Future studies are needed to investigate the long-term effects of SGLT2i on CKD progression in patients with AS to assess whether the observed reduction in albuminuria translates to a delay in kidney failure (KF).
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Affiliation(s)
- Jan Boeckhaus
- Clinic for Nephrology and Rheumatology, University Medical Center Goettingen, Germany
| | - Daniel P. Gale
- Department of Renal Medicine, University College London, London, UK
- National Registry of Rare Kidney Diseases, Bristol, UK
| | - James Simon
- Department of Kidney Medicine, Medical Specialties Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jie Ding
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Yanqin Zhang
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | | | | | | | - John A. Sayer
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Renal Services, Newcastle upon Tyne National Health Service Foundation Trust, Newcastle upon Tyne, UK
- National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK
| | - Shalabh Srivastava
- South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK
- Newcastle University, Newcastle Upon Tyne, UK
| | - Hee Gyung Kang
- Departments of Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea
- Departments of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | | | - Valentine Gillion
- Nephrology Department, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Kathleen J. Claes
- Department of Nephrology and Renal Transplantation, UZ Leuven, Leuven, Belgium
- Department of Microbiology, Immunology, and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Bastian Krueger
- Division of Nephrology, Department of Internal Medicine, University of Leipzig Medical Center, Leipzig, Germany
| | - Jonathan de Fallois
- Division of Nephrology, Department of Internal Medicine, University of Leipzig Medical Center, Leipzig, Germany
| | - Ulrike Walden
- Paediatric and Adolescent Medicine, University Medical Center Augsburg, Augsburg, Germany
| | - Mira Choi
- Department of Nephrology and Medical Intensive Care, Charité- Universitätsmedizin Berlin, Berlin, Germany
| | - Markus Schueler
- Department of Nephrology and Medical Intensive Care, Charité- Universitätsmedizin Berlin, Berlin, Germany
| | - Roman-Ulrich Mueller
- Department II of Internal Medicine and Center for Rare Diseases Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
| | - Polina Todorova
- Department II of Internal Medicine and Center for Rare Diseases Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Bernd Hohenstein
- Nephrologisches Zentrum Villingen-Schwenningen, Villingen-Schwenningen, Germany
| | - Michael Zeisberg
- Clinic for Nephrology and Rheumatology, University Medical Center Goettingen, Germany
| | - Tim Friede
- Department of Medical Statistics, University Medical Center Goettingen, Goettingen, Germany
| | - Bertrand Knebelmann
- Faculté de médecine, Université Paris Cité, Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Service de Néphrologie, Paris, France
| | - Jan Halbritter
- Department of Nephrology and Medical Intensive Care, Charité- Universitätsmedizin Berlin, Berlin, Germany
| | - Oliver Gross
- Clinic for Nephrology and Rheumatology, University Medical Center Goettingen, Germany
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Sula Karreci E, Jacas S, Donovan O, Pintye D, Wiley N, Zsengeller ZK, Schlondorff J, Alper SL, Friedman DJ, Pollak MR. Differing sensitivities to angiotensin converting enzyme inhibition of kidney disease mediated by APOL1 high-risk variants G1 and G2. Kidney Int 2024; 106:1072-1085. [PMID: 39181397 PMCID: PMC11585418 DOI: 10.1016/j.kint.2024.07.026] [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: 11/10/2023] [Revised: 07/10/2024] [Accepted: 07/26/2024] [Indexed: 08/27/2024]
Abstract
Apolipoprotein L1 (APOL1) variants G1 and G2 contribute to the excess risk of kidney disease in individuals of recent African ancestry. Since disease mechanisms and optimal treatments remain controversial, we study the effect of current standard-of-care drugs in mouse models of APOL1 kidney disease. Experiments were performed in APOL1 BAC-transgenic mice, which develop proteinuria and glomerulosclerosis following injection with a pCpG-free IFN-γ plasmid. Proteinuric, plasmid injected G1/G1 and G2/G2 mice were randomized to drug treatment or no treatment. Lisinopril, dapagliflozin, and hydralazine were administered in drinking water starting day seven. The urine albumin/creatinine ratio was measured twice weekly, and the kidneys examined histologically with the focal segmental glomerulosclerosis score computed from periodic acid-Shiff-stained sections. The angiotensin converting enzyme inhibitor lisinopril, at standard dose, reduced proteinuria by approximately 90-fold and reduced glomerulosclerosis in the APOL1 G1/G1 BAC-transgenic mice. These effects were independent of blood pressure. Dapagliflozin did not alter disease progression in either G1/G1 or G2/G2 mice. Proteinuria reduction and glomerulosclerosis in G2/G2 BAC-transgenic mice required lisinopril doses two times higher than were effective in G1/G1 mice but achieved a much smaller benefit. Therefore, in these BAC-transgenic mouse models of APOL1 disease, the anti-proteinuric and anti-glomerulosclerotic effects of standard dose lisinopril were markedly effective in G1/G1 compared with G2/G2 APOL1 mice. Comparable reduction in blood pressure by hydralazine treatment provided no such protection. Neither G1/G1 nor G2/G2 mice showed improvement with the sodium-glucose cotransporter-2 inhibition dapagliflozin. Thus, it remains to be determined if similar differences in ACE inhibitor responsiveness are observed in patients.
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Affiliation(s)
- Esilida Sula Karreci
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts; USA.
| | - Sonako Jacas
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Olivia Donovan
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Diana Pintye
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Nicholas Wiley
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Zsuzsanna K Zsengeller
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Johannes Schlondorff
- Division of Nephrology, Department of Medicine, The Ohio State University, Wexner School of Medicine, Columbus, Ohio, USA
| | - Seth L Alper
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts; USA
| | - David J Friedman
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts; USA
| | - Martin R Pollak
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts; USA
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Tansawet A, Looareesuwan P, Teza H, Boongird S, McKay GJ, Attia J, Pattanaprateep O, Thakkinstian A. Effects of sodium-glucose cotransporter-2 inhibitors on chronic kidney disease progression: a multi-state survival model. Diabetol Metab Syndr 2024; 16:281. [PMID: 39578825 PMCID: PMC11585174 DOI: 10.1186/s13098-024-01522-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 11/12/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Current guidelines recommend good glycemic control in patients with type 2 diabetes (T2D) to limit the progression of associated complications with combination therapies. This study aimed to compare the rate of chronic kidney disease (CKD) progression between patients who did or did not receive sodium-glucose cotransporter-2 inhibitors (SGLT2i) using a multistate model with two intermediate states (i.e., CKD stage 4 (CKD4) and 5 (CKD5)) and one absorbing state (i.e., death). METHODS Data from patients with T2D and CKD stage 3 (CKD3) were retrieved for analysis. Patients treated with SGLT2i were matched 1:2 by prescription date with non-SGLT2i patients. The multistate model was constructed from Cox survival regression models specific to each transition stage. Cumulative failure and transition probabilities were estimated from bootstrapping. RESULTS Data from 6582 patients (2194 and 4388 patients in the SGLT2i and non-SGLT2i groups, respectively) were analyzed. At 10-year follow-up, patients in the SGLT2i group were more likely to remain at CKD3 compared to the non-SGLT2i group: 82.3% (95% CI 79.9%, 84.6%) vs 60.4% (57.6%, 63.4%). Transition probabilities to CKD4, CKD5, and death were lower in the SGLT2i group than non-SGLT2i group: 11.3% (9.5%, 13.3%) vs 19.8% (17.4%, 22.2%), 2.4% (1.5%, 3.4%) vs 7.4% (5.8%, 9.0%), and 4.1% (2.9%, 5.3%) vs 12.4% (10.3%, 14.6%), respectively. CONCLUSION SGLT2i may delay the decline in renal function and slow CKD progression compared to standard care without SGLT2i.
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Affiliation(s)
- Amarit Tansawet
- Department of Research and Medical Innovation, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
| | - Panu Looareesuwan
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 4th Floor Sukho Place Building, 218/11 Sukhothai Road, Dusit, Bangkok, 10300, Thailand.
| | - Htun Teza
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 4th Floor Sukho Place Building, 218/11 Sukhothai Road, Dusit, Bangkok, 10300, Thailand
| | - Sarinya Boongird
- Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Gareth J McKay
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
| | - John Attia
- School of Medicine and Public Health, and Hunter Medical Research Institute, University of Newcastle, New Lambton, NSW, Australia
| | - Oraluck Pattanaprateep
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 4th Floor Sukho Place Building, 218/11 Sukhothai Road, Dusit, Bangkok, 10300, Thailand
| | - Ammarin Thakkinstian
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 4th Floor Sukho Place Building, 218/11 Sukhothai Road, Dusit, Bangkok, 10300, Thailand
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Angjeli A, Montada-Atin T, Nisenbaum R, Dacouris N, Nash M, Prasad GR, Zaltzman J. Single Center Experience With Sodium-Glucose Co-Transporter-2 Inhibitors (SGLT2i) in Kidney Transplant Recipients With Diabetes. Can J Kidney Health Dis 2024; 11:20543581241293202. [PMID: 39534785 PMCID: PMC11555736 DOI: 10.1177/20543581241293202] [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: 04/22/2024] [Accepted: 09/25/2024] [Indexed: 11/16/2024] Open
Abstract
Background Sodium-glucose co-tranporter-2 inhibitors have been shown to be safe and effective in patients with type 2 diabetes for improving glycemia. Furthermore large, randomized control trials have shown cardiovascular and renal benefits. However, limited safety and efficacy data is available in kidney transplant patients with diabetes. Objective To investigate the safety and efficacy of SGLT2i use on stability of renal function in adult kidney transplant recipients (KTR) with type 2 diabetes mellitus (DM2) or New Onset Diabetes After Transplantation (NODAT). Design We performed a single center, retrospective cohort study pre- and post-SGLT2i exposure. Patients Adults with DM2 or NODAT who received a living or deceased kidney transplant (Tx) and started on an SGLT2i post-Tx were reviewed. Patients who had type 1 diabetes were excluded. Measurements and Methods The baseline was the SGLT2i start date. We reviewed available data from 24 months (M) before and after SGLT2i initiation. The primary endpoints were the effects of SGLT2i use on stability of renal function using serum creatinine and eGFR, change in urine albumin excretion(uACR), and glycosylated hemoglobin (A1C). Secondary endpoints compared blood pressure, body mass index and adverse reactions at baseline and quarterly after SGLT2i initiation. Results 125 KTRs were included in cohort: NODAT (52, 42%), DM2 (73, 58%); female (33, 27%); mean age at Tx 55 years (25-75); LD (56, 45%), DD (69, 55%); mean duration of Tx (6.8 years, 0.1-42.5); study follow-up (1.8 years, 0.3-4.9).The mean eGFR remained stable pre-SGLT2i at 64.6 mL/min/1.73m2, vs post at 64.3 mL/min/1.73m2. There was no difference in mean A1C after SGLT2i initiation. The slope of uACR using natural log transformation pre-SGLT2i compared with post-SGLT2i slope reduced from +0.7 (0.03, 0.11) to -0.04 (-0.01, -0.35) mg/mmol/3mths (P = .002). The risk of developing new genital mycotic infections among all patients was 4% (95% CI 1.3%-9.1%) While there was no significant difference in UTI before (13.6%) and after (12%) SGLT2i use (P = .68), there was a higher risk of UTI seen in patients with a previous history of UTI (23.5%) vs no previous history (10.2%) post initiation. There was no significant increase in AKI pre 8%, post 10.4%, P = .51. There was a single DKA event pre- and post-SGLT2. Limitations The limitations of this study include its retrospective nonrandomized nature. Conclusion In this retrospective analysis, SGLT2i use in KTR appears to be safe and efficacious with stable renal function and glycemic control, alongside improvements in uACR. There was a low risk of new genital yeast infections after SGLT2i start. UTI occurrence was higher in patients with a previous history of UTI compared with those with no previous history.
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Affiliation(s)
- Albi Angjeli
- Kidney Research Program, St. Michael’s Hospital, Unity Health Toronto, ON, Canada
| | - Tess Montada-Atin
- Kidney and Metabolism Program, St. Michael’s Hospital, Unity Health Toronto, ON, Canada
- Lawrence Bloomberg Faculty of Nursing, University of Toronto, ON, Canada
| | - Rosane Nisenbaum
- Applied Health Research Centre, St. Michael’s Hospital, Unity Health Toronto, ON, Canada
| | - Niki Dacouris
- Kidney Research Program, St. Michael’s Hospital, Unity Health Toronto, ON, Canada
| | - Michelle Nash
- Kidney Research Program, St. Michael’s Hospital, Unity Health Toronto, ON, Canada
| | - G.V. Ramesh Prasad
- Kidney and Metabolism Program, St. Michael’s Hospital, Unity Health Toronto, ON, Canada
- Department of Medicine, University of Toronto, ON, Canada
- Division of Nephrology, University of Toronto, ON, Canada
| | - Jeffrey Zaltzman
- Kidney and Metabolism Program, St. Michael’s Hospital, Unity Health Toronto, ON, Canada
- Department of Medicine, University of Toronto, ON, Canada
- Division of Nephrology, University of Toronto, ON, Canada
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Lopes AC, Lourenço O, Morgado M. SGLT2i and GLP1RA effects in patients followed in a hospital diabetology consultation. Expert Rev Clin Pharmacol 2024; 17:1081-1088. [PMID: 39450504 DOI: 10.1080/17512433.2024.2421872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 10/26/2024]
Abstract
BACKGROUND We aimed to investigate the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) in patients with type 2 diabetes mellitus (T2DM) in clinical practice. RESEARCH DESIGN AND METHODS A total of 340 patients were included. Data on age, gender, antidiabetic medications, and bioanalytical parameters were collected at baseline and one year later. Were analyzed estimated glomerular filtration rate (eGFR), blood sodium and potassium levels, blood pressure, weight, cardiovascular risk, and glycated hemoglobin (HbA1c). RESULTS Patients treated with SGLT2i exhibited a significant improvement in eGFR at the endpoint compared to baseline (p = 0.006). Both treatment groups experienced reductions in systolic blood pressure at the endpoint; especially patients treated with SGLT2i (p = 0.0002). GLP1RA treatment resulted in a statistically significant weight reduction from baseline to endpoint (p < 0.0001), with a higher percentage of patients achieving ≥ 5% weight loss compared to the non-GLP1RA group (33.6% vs. 19.8%). Both SGLT2i and GLP1RA treatments significantly reduced cardiovascular risk scores (p = 0.004 and p = 0.002, respectively). Additionally, both treatments were associated with a significant reduction in HbA1c levels at the endpoint (p = 0.010 and p = 0.002, respectively). CONCLUSIONS Our findings suggest that SGLT2i and GLP1RA offer beneficial effects in patients with T2DM.
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Affiliation(s)
- António Cabral Lopes
- Pharmaceutical Services Local Health Unit of Guarda (ULS da Guarda), Guarda, Portugal
- Pharmaceutical Services Local Health Unit of Aveiro Region (ULS da Região de Aveiro), Aveiro, Portugal
- Faculty of Health Sciences, FCS-UBI, University of Beira Interior, Covilhã, Portugal
| | - Olga Lourenço
- Faculty of Health Sciences, FCS-UBI, University of Beira Interior, Covilhã, Portugal
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Manuel Morgado
- Faculty of Health Sciences, FCS-UBI, University of Beira Interior, Covilhã, Portugal
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
- Pharmaceutical Services, Local Health Unit of Cova da Beira (ULS Cova da Beira), Covilhã, Portugal
- Clinical Academic Center of Beiras (CACB), UBImedical, Covilhã, Portugal
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Ikeme JC, Madden E, Lamprea-Montealegre JA, Chu CD, Shlipak MG, McCoy IE, Estrella MM. Association of Kidney Function with Sodium-Glucose Co-Transporter 2 Inhibitor Discontinuation among US Veterans. Clin J Am Soc Nephrol 2024; 19:1426-1434. [PMID: 39167449 PMCID: PMC11556927 DOI: 10.2215/cjn.0000000000000536] [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: 02/14/2024] [Accepted: 08/16/2024] [Indexed: 08/23/2024]
Abstract
Key Points Patients started on sodium-glucose co-transporter-2 inhibitors (SGLT2i) had a 23% risk of discontinuation at 1 year; 41% of these discontinuations occurred within the first 3 months. Patients with lower kidney function were more likely to experience discontinuation. Higher rates of SGLT2i discontinuation in patients with CKD may limit the cardiokidney benefits of SGLT2i in real-world practice. Background The effect of sodium-glucose co-transporter-2 inhibitors (SGLT2i) on cardiovascular disease and CKD may be limited if discontinued in persons with CKD. We sought to determine whether CKD at SGLT2i initiation was associated with subsequent discontinuation. Methods This cohort study used electronic health record data of patients who initiated SGLT2i in the Veterans Health Administration from January 2017 through December 2021. The primary exposure was eGFR category at the time of SGLT2i initiation. The risk of SGLT2i discontinuation, defined by a provider order or expiration of an SGLT2i prescription without resumption in the following 180 days, was estimated using proportional hazards models with inverse probability weights for censoring due to death. Analyses were stratified by year of SGLT2i initiation. Results Among the 222,772 patients initiating an SGLT2i during the study period, the median age was 68 (interquartile range, 60–73) years, 95% were male, and median (interquartile range) eGFR was 73 (58–89) ml/min per 1.73 m2. Median follow-up was 1.6 years; 32% experienced SGLT2i discontinuation. Cumulative risk of discontinuation at 1 year was 21%–27% across calendar years; approximately 41% of these discontinuations occurred within the first 3 months. There was a graded association between lower baseline eGFR and greater risk of discontinuation; this association attenuated across calendar years. Those initiating an SGLT2i in 2017 with baseline eGFR of 45–59 and 30–44 had 1.34- (95% confidence interval [CI], 1.21 to 1.49) and 2.04-fold (95% CI, 1.58 to 2.63) risks of discontinuation, respectively, compared with those with eGFR ≥60 ml/min per 1.73 m2. These hazard ratios reduced to 1.05 (95% CI, 1.02 to 1.10) and 1.20 (95% CI, 1.14 to 1.26), respectively, in those initiated in 2021. Conclusions A substantial proportion of patients experience SGLT2i discontinuation within a year of initiation. Those with lower eGFR had higher discontinuation rates; however, this trend attenuated over time. Additional studies identifying and addressing factors leading to discontinuation are needed to fully realize the benefits of SGLT2i.
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Affiliation(s)
- Jesse C. Ikeme
- Kidney Health Research Collaborative, University of California, San Francisco, California
- Division of Nephrology, Department of Medicine, University of California, San Francisco, California
| | - Erin Madden
- Kidney Health Research Collaborative, University of California, San Francisco, California
- San Francisco VA Health Care System, San Francisco, California
| | - Julio A. Lamprea-Montealegre
- Kidney Health Research Collaborative, University of California, San Francisco, California
- Division of Cardiology, Department of Medicine, University of California, San Francisco, California
| | - Chi D. Chu
- Kidney Health Research Collaborative, University of California, San Francisco, California
- Division of Nephrology, Department of Medicine, University of California, San Francisco, California
| | - Michael G. Shlipak
- Kidney Health Research Collaborative, University of California, San Francisco, California
- San Francisco VA Health Care System, San Francisco, California
- Division of General Internal Medicine, Department of Medicine, University of California, San Francisco, California
| | - Ian E. McCoy
- Division of Nephrology, Department of Medicine, University of California, San Francisco, California
| | - Michelle M. Estrella
- Kidney Health Research Collaborative, University of California, San Francisco, California
- Division of Nephrology, Department of Medicine, University of California, San Francisco, California
- San Francisco VA Health Care System, San Francisco, California
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Agarwal A, Zeng X, Li S, Rayner D, Foroutan F, Aertgeerts B, Coyac F, Farhoumand PD, Demaine A, Heen AF, Jha V, Machuve E, Nagler E, Tunnicliffe DJ, Guyatt GH, Vandvik PO, Ponte B, Agoritsas T. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors for adults with chronic kidney disease: a clinical practice guideline. BMJ 2024; 387:e080257. [PMID: 39353639 DOI: 10.1136/bmj-2024-080257] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
CLINICAL QUESTION What is the impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on survival and on cardiovascular and kidneyoutcomes for adults living with chronic kidney disease (CKD)? CURRENT PRACTICE Few therapies slow kidney disease progression and improve long term prognosis for adults living with CKD. SGLT-2 inhibitors have demonstrated cardiovascular and kidney benefits in adults with CKD with and without type 2 diabetes. Existing guidance for SGLT-2 inhibitors does not account for the totality of current best evidence for adults with CKD and does not provide fully stratified treatment effects and recommendations across all risk groups based on risk of CKD progression and complications. RECOMMENDATIONS The guideline panel considered evidence regarding benefits and harms of SGLT-2 inhibitor therapy for adults with CKD over a five year period, along with contextual factors, and provided the following recommendations:1. For adults at low risk of CKD progression and complications, we suggest administering SGLT-2 inhibitors (weak recommendation in favour)2. For adults at moderate risk of CKD progression and complications, we suggest administering SGLT-2 inhibitors (weak recommendation in favour)3. For adults at high risk of CKD progression and complications, we recommend administering SGLT-2 inhibitors (strong recommendation in favour)4. For adults at very high risk of CKD progression and complications, we recommend administering SGLT-2 inhibitors (strong recommendation in favour).Recommendations are applicable to all adults with CKD, irrespective of type 2 diabetes status. HOW THIS GUIDELINE WAS CREATED An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified typical risk strata of adults with CKD (from low to very high risk of CKD progression and related complications) using the classification system developed by Kidney Disease Improving Global Outcomes (KDIGO), and applied an individual patient perspective in moving from evidence to recommendations. Effects of SGLT-2 inhibitors were interpreted in absolute terms applicable to different risk strata with varying baseline risks for outcomes of benefit over a five year period. The panel explicitly considered the balance of benefits, harms, and burdens of starting an SGLT-2 inhibitor, incorporating the values and preferences of adults with different risk profiles. Interactive evidence summaries and decision aids accompany multilayered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that allows reuse and adaptation. THE EVIDENCE A linked systematic review and pairwise meta-analysis (13 trials including 29 614 participants) of benefits and harms associated with SGLT-2 inhibitors in adults with CKD with or without type 2 diabetes informed guidance. Among individuals at very high risk of CKD progression and complications, moderate to high certainty evidence shows SGLT-2 inhibitors (relative to placebo or standard care without SGLT-2 inhibitors) decrease all-cause and cardiovascular mortality, hospitalisation for heart failure, kidney failure, non-fatal myocardial infarction, and non-fatal stroke. Among individuals at high risk, moderate to high certainty evidence shows SGLT-2 inhibitors result in similar benefits across outcomes except demonstrating little or no effect on hospitalisation for heart failure and kidney failure. Among individuals at moderate and low risk, moderate to high certainty evidence shows SGLT-2 inhibitors probably reduce all-cause mortality and non-fatal stroke, with little or no effect for other outcomes of benefit. Risk-stratified estimates were unavailable for outcomes of harm; the panel therefore considered absolute effects summarised across risk strata. SGLT-2 inhibitors are associated with little or no effect on acute kidney injury requiring dialysis, bone fractures, lower limb amputations, ketoacidosis, genital infections, or symptomatic hypovolaemia, although a residual possibility of harms at the individual patient level remains. UNDERSTANDING THE RECOMMENDATION In order to apply recommendations, clinicians must appropriately identify adults with CKD, consider the underlying aetiology, and risk stratify them based on glomerular filtration rate (estimated or measured) and degree of albuminuria. In addition to classifying individuals into risk strata, further estimation of a given patient's risk based on the extent of their kidney disease and other comorbidities may be warranted to inform individual-level decisions and shared decision making. Available risk calculators may help estimate a given patient's risk of CKD progression and complications.
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Affiliation(s)
- Arnav Agarwal
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5
- Department of Health Research Methods, Evidence and Impact, HSC 2C, Hamilton, Ontario, Canada, L8S 4L8
- MAGIC Evidence Ecosystem Foundation, Oslo, Norway, 0282
- . Both authors contributed equally (co-first authors)
| | - Xiaoxi Zeng
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China, 610041
- MAGIC Evidence Ecosystem Foundation, Oslo, Norway, 0282
- . Both authors contributed equally (co-first authors)
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China, 610041
- Chinese Evidence-Based Medicine Center, Cochrane China Center and MAGIC China Center, West China Hospital, Sichuan University, Chengdu, China, 610041
| | - Daniel Rayner
- Department of Health Research Methods, Evidence and Impact, HSC 2C, Hamilton, Ontario, Canada, L8S 4L8
| | - Farid Foroutan
- Department of Health Research Methods, Evidence and Impact, HSC 2C, Hamilton, Ontario, Canada, L8S 4L8
- MAGIC Evidence Ecosystem Foundation, Oslo, Norway, 0282
- Ted Rogers Center for Heart Research, Toronto, Ontario, Canada, M5G 1X8
| | - Bert Aertgeerts
- Academic Centre for General Practice, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium, 3000
- CEBAM, Belgian Centre for Evidence-Based Medicine, Cochrane Belgium, Leuven, Belgium, 3000
| | | | - Pauline Darbellay Farhoumand
- Division of General Internal Medicine, Department of Medicine, Hôpitaux Universitaire de Genève and University of Geneva, Geneva, Switzerland, 1205
| | | | - Anja Fog Heen
- MAGIC Evidence Ecosystem Foundation, Oslo, Norway, 0282
- Department of Medicine, Lovisenberg Diaconal Hospital, Oslo, Norway, 0456
| | - Vivekanand Jha
- George Institute for Global Health, Elegance Tower, Jasola District Centre, New Delhi, India, 110025
- School of Public Health, Imperial College London, London, UK, SW7 2AZ
- Prasanna School of Public Health, Manipal Academy of Higher Education, Madhav Nagar, Eshwar Nagar, Manipal, Karnataka, India, 576104
| | | | - Evi Nagler
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium, 9000
| | - David J Tunnicliffe
- Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia, 2006
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia, 2145
| | - Gordon H Guyatt
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5
- Department of Health Research Methods, Evidence and Impact, HSC 2C, Hamilton, Ontario, Canada, L8S 4L8
- MAGIC Evidence Ecosystem Foundation, Oslo, Norway, 0282
| | - Per Olav Vandvik
- MAGIC Evidence Ecosystem Foundation, Oslo, Norway, 0282
- Department of Medicine, Innlandet Hospital Trust, Gjøvik, Norway, 2819
| | - Belen Ponte
- Division of Nephrology and Hypertension, Department of Medicine, University of Geneva, University Hospitals of Geneva, Geneva, Switzerland, 1205
- . Both authors contributed equally (co-last authors)
| | - Thomas Agoritsas
- Department of Health Research Methods, Evidence and Impact, HSC 2C, Hamilton, Ontario, Canada, L8S 4L8
- MAGIC Evidence Ecosystem Foundation, Oslo, Norway, 0282
- Division of General Internal Medicine, Department of Medicine, Hôpitaux Universitaire de Genève and University of Geneva, Geneva, Switzerland, 1205
- . Both authors contributed equally (co-last authors)
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Kim K, Crook J, Lu CC, Nyman H, Sarker J, Nelson R, LaFleur J. Healthcare Costs Across Diabetic Kidney Disease Stages: A Veterans Affairs Study. Kidney Med 2024; 6:100873. [PMID: 39247400 PMCID: PMC11380387 DOI: 10.1016/j.xkme.2024.100873] [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: 09/10/2024] Open
Abstract
Background In the United States, diabetic kidney disease (DKD) affects about one-third of individuals with type 2 diabetes, causing significant economic burdens on the health care system and affecting patients' quality of life. Objective The aim of the study was to quantify the burden of care in patients at different stages of DKD and to monitor shifts in healthcare costs throughout these stages. Methods This study used data from the Veterans Affairs National database, focusing on US veterans diagnosed with DKD between January 2016 and March 2022. Aggregated all-cause health care costs per month were summarized using descriptive statistics. We used a generalized linear model to calculate the cost of DKD patent care based on the stages, dialysis phase, and kidney replacement therapy. Results The cohort of 685,288 patients with DKD was predominantly male (96.51%), White (74.42%), and non-Hispanic (93.54%). The mean (SD) per-patient per-month costs were $1,597 ($3,178), $1,772 ($4,269), $2,857 ($13,072), $3,722 ($12,134), $5,505 ($14,639), and $6,999 ($16,901) for stages 1, 2, 3a, 3b, 4 and 5 respectively. The average monthly expenditure for patients receiving long-term dialysis was $12,299. Costs peaked sharply during the first month of kidney replacement therapy at $38,359 but subsequently decreased to $6,636 after 1 year. Conclusions The economic implications of DKD are profound, emphasizing the need for efficient early detection and disease management strategies. Preventing patients from progressing to advanced DKD stage will minimize the economic repercussions of DKD and will assist health care systems in optimizing resource allocation.
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Affiliation(s)
- Kibum Kim
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois Chicago, Chicago, IL
- Department of Pharmacotherapy, University of Utah, Salt Lake City, UT
- Salt Lake City VA Health Care System, Salt Lake City, UT
| | - Jacob Crook
- Salt Lake City VA Health Care System, Salt Lake City, UT
- Division of Epidemiology, University of Utah, Salt Lake City
| | - Chao-Chin Lu
- Salt Lake City VA Health Care System, Salt Lake City, UT
| | - Heather Nyman
- Department of Pharmacotherapy, University of Utah, Salt Lake City, UT
- Salt Lake City VA Health Care System, Salt Lake City, UT
| | - Jyotirmoy Sarker
- Department of Pharmacy Systems, Outcomes and Policy, University of Illinois Chicago, Chicago, IL
| | - Richard Nelson
- Salt Lake City VA Health Care System, Salt Lake City, UT
- Division of Epidemiology, University of Utah, Salt Lake City
| | - Joanne LaFleur
- Department of Pharmacotherapy, University of Utah, Salt Lake City, UT
- Salt Lake City VA Health Care System, Salt Lake City, UT
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Miguel V, Alcalde-Estévez E, Sirera B, Rodríguez-Pascual F, Lamas S. Metabolism and bioenergetics in the pathophysiology of organ fibrosis. Free Radic Biol Med 2024; 222:85-105. [PMID: 38838921 DOI: 10.1016/j.freeradbiomed.2024.06.001] [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: 04/07/2024] [Revised: 05/15/2024] [Accepted: 06/02/2024] [Indexed: 06/07/2024]
Abstract
Fibrosis is the tissue scarring characterized by excess deposition of extracellular matrix (ECM) proteins, mainly collagens. A fibrotic response can take place in any tissue of the body and is the result of an imbalanced reaction to inflammation and wound healing. Metabolism has emerged as a major driver of fibrotic diseases. While glycolytic shifts appear to be a key metabolic switch in activated stromal ECM-producing cells, several other cell types such as immune cells, whose functions are intricately connected to their metabolic characteristics, form a complex network of pro-fibrotic cellular crosstalk. This review purports to clarify shared and particular cellular responses and mechanisms across organs and etiologies. We discuss the impact of the cell-type specific metabolic reprogramming in fibrotic diseases in both experimental and human pathology settings, providing a rationale for new therapeutic interventions based on metabolism-targeted antifibrotic agents.
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Affiliation(s)
- Verónica Miguel
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
| | - Elena Alcalde-Estévez
- Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain; Department of Systems Biology, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Alcalá de Henares, Spain
| | - Belén Sirera
- Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain
| | - Fernando Rodríguez-Pascual
- Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain
| | - Santiago Lamas
- Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain.
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Bhanushali KB, Asnani HK, Nair A, Ganatra S, Dani SS. Pharmacovigilance study for SGLT 2 inhibitors- Safety review of real-world data & randomized clinical trials. Curr Probl Cardiol 2024; 49:102664. [PMID: 38789017 DOI: 10.1016/j.cpcardiol.2024.102664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 05/26/2024]
Abstract
PURPOSE Despite effectiveness of sodium-glucose cotransporter 2 (SGLT 2) inhibitors, concerns have been raised about the potential side effects of these drugs. Thus, a pharmaco-vigilance study was designed that aims to identify any discrepancies between the reported adverse events & assess the safety profile of SGLT2 inhibitors. METHODS We studied diabetic ketoacidosis (DKA), euglycemic DKA, amputation, urinary tract infection (UTI), mycotic genital infection & hypotension associated with empagliflozin, dapagliflozin, canagliflozin & ertugliflozin in RCTs and reporting databases. WHO's VigiBase, FAERS, EMA's EudraVigilance & DAEN were thoroughly studied to obtain spontaneously reported real-world adverse events. RESULTS Different SGLT2 inhibitors exhibit varied side effect profiles. Additionally, the findings suggest that adverse events may be more likely to occur in a broader population in the real world than in a highly inclusive clinical trial subset CONCLUSION: Our study provides comparison of the real world reported adverse events to adverse events reported in the clinical trials studying the efficacy of SGLT 2 inhibitors.
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Wu L, Rodriguez M, Hachem KE, Tang WHW, Krittanawong C. Management of patients with heart failure and chronic kidney disease. Heart Fail Rev 2024; 29:989-1023. [PMID: 39073666 DOI: 10.1007/s10741-024-10415-9] [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] [Accepted: 07/01/2024] [Indexed: 07/30/2024]
Abstract
Chronic kidney disease (CKD) and heart failure are often co-existing conditions due to a shared pathophysiological process involving neurohormonal activation and hemodynamic maladaptation. A wide range of pharmaceutical and interventional tools are available to patients with CKD, consisting of traditional ones with decades of experience and newer emerging therapies that are rapidly reshaping the landscape of medical care for this population. Management of patients with heart failure and CKD requires a stepwise approach based on renal function and the clinical phenotype of heart failure. This is often challenging due to altered drug pharmacokinetics interactions with various degrees of kidney function and frequent adverse effects from the therapy that lead to poor patient tolerance. Despite a great body of clinical evidence and guidelines that have offered various treatment options for patients with heart failure and CKD, respectively, patients with CKD are still underrepresented in heart failure clinical trials, especially for those with advanced CKD and end-stage renal disease (ESRD). Future studies are needed to better understand the generalizability of these therapeutic options among heart failures with different stages of CKD.
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Affiliation(s)
- Lingling Wu
- Cardiovascular Division, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Mario Rodriguez
- John T Milliken Department of Medicine, Division of Cardiovascular disease, Section of Advanced Heart Failure and Transplant, Barnes-Jewish Hospital, Washington University in St. Louis School of Medicine, St. Louis, USA
| | - Karim El Hachem
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY, USA
| | - W H Wilson Tang
- Department of Cardiovascular Medicine, Heart Vascular and Thoracic Institute, Cleveland, Clinic, Cleveland, OH, USA
| | - Chayakrit Krittanawong
- Cardiology Division, Section of Cardiology, NYU Langone Health and NYU School of Medicine, 550 First Avenue, New York, NY, 10016, USA.
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Sun M, Lu Z, Chen WM, Lv S, Fu N, Yang Y, Wang Y, Miao M, Wu SY, Zhang J. Metformin monotherapy versus predominantly older non-metformin antidiabetic medications for cerebrovascular risk in early type 2 diabetes management. Diabetes Obes Metab 2024; 26:3914-3925. [PMID: 38952343 DOI: 10.1111/dom.15739] [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: 05/18/2024] [Revised: 06/06/2024] [Accepted: 06/07/2024] [Indexed: 07/03/2024]
Abstract
AIM Choosing the initial treatment for type 2 diabetes (T2D) is pivotal, requiring consideration of solid clinical evidence and patient characteristics. Despite metformin's historical preference, its efficacy in preventing cerebrovascular events lacked empirical validation. This study aimed to evaluate the associations between first-line monotherapy (metformin or non-metformin antidiabetic medications) and cerebrovascular complications in patients with T2D without diabetic complications. METHODS We analysed 9090 patients with T2D without complications who were prescribed either metformin or non-metformin medications as initial therapy. Propensity score matching ensured group comparability. Cox regression analyses, stratified by initial metformin use, assessed cerebrovascular disease risk, adjusting for multiple covariates and using competing risk analysis. Metformin exposure was measured using cumulative defined daily doses. RESULTS Metformin users had a significantly lower crude incidence of cerebrovascular diseases compared with non-users (p < .0001). Adjusted hazard ratios (aHRs) consistently showed an association between metformin use and a lower risk of overall cerebrovascular diseases (aHRs: 0.67-0.69) and severe events (aHRs: 0.67-0.69). The association with reduced risk of mild cerebrovascular diseases was significant across all models (aHRs: 0.73-0.74). Higher cumulative defined daily doses of metformin correlated with reduced cerebrovascular risk (incidence rate ratio: 0.62-0.94, p < .0001), indicating a dose-dependent effect. CONCLUSION Metformin monotherapy is associated with a reduced risk of cerebrovascular diseases in early-stage T2D, highlighting its dose-dependent efficacy. However, the observed benefits might also be influenced by baseline differences and the increased risks associated with other medications, such as sulphonylureas. These findings emphasize the need for personalized diabetes management, particularly in mitigating cerebrovascular risk in early T2D stages.
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Affiliation(s)
- Mingyang Sun
- Department of Anaesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Zhongyuan Lu
- Department of Anaesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
| | - Wan-Ming Chen
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan
- Artificial Intelligence Development Centre, Fu Jen Catholic University, Taipei, Taiwan
| | - Shuang Lv
- Department of Anaesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Ningning Fu
- Department of Anaesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Yitian Yang
- Department of Anaesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Yangyang Wang
- Department of Anaesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Mengrong Miao
- Department of Anaesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Szu-Yuan Wu
- Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan
- Artificial Intelligence Development Centre, Fu Jen Catholic University, Taipei, Taiwan
- Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan
- Big Data Centre, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
- Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan
- Cancer Centre, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
- Centres for Regional Anaesthesia and Pain Medicine, Taipei Municipal Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Department of Management, College of Management, Fo Guang University, Yilan, Taiwan
| | - Jiaqiang Zhang
- Department of Anaesthesiology and Perioperative Medicine, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
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Shao YHJ, Chen WT, Yu SMW, Tsou LLA, Hsu YH, Wu MS, Kao YH, Chou CL, Hsiao PJ. Investigation of cardiorenal outcomes and incidence of genitourinary tract infection after combined SGLT2 inhibitor and ACEI/ARB use in patients with chronic kidney disease stages 3-5: A real-world retrospective cohort study in Taiwan. Int J Med Sci 2024; 21:2109-2118. [PMID: 39239537 PMCID: PMC11373557 DOI: 10.7150/ijms.96969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 07/22/2024] [Indexed: 09/07/2024] Open
Abstract
Background: Sodium‒glucose cotransporter-2 (SGLT2) inhibitors offer glycaemic and cardiorenal benefits in the early stage of chronic kidney disease (CKD). However, the use of SGLT2 inhibitors may increase the risk of genitourinary tract infection (GUTI). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may also cause deterioration of kidney function. The long-term follow-up of cardiorenal outcomes and GUTI incidence in patients with advanced CKD receiving SGLT2 inhibitors combined with ACEIs/ARBs should be further investigated. Methods: We analysed data from 5,503 patients in Taiwan's Taipei Medical University Research Database (2016-2020) who were part of a pre-end-stage renal disease (ESRD) program (CKD stages 3-5) and received ACEIs/ARBs. SGLT2 inhibitor users were matched 1:4 with nonusers on the basis of sex, CKD, and program entry duration. Results: The final cohort included 205 SGLT2 inhibitor users and 820 nonusers. SGLT2 inhibitor users experienced a significant reduction in ESRD/dialysis risk (aHR = 0.35, 95% CI = 0.190.67), and SGLT2 inhibitor use was not significantly associated with acute kidney injury or acute kidney disease risk. Among SGLT2 inhibitor users, those with a history of cardiovascular disease (CVD) had greater CVD rates. Conversely, those without a CVD history had lower rates of congestive heart failure, arrhythmia, acute pulmonary oedema, and acute myocardial infarction, although the differences were not statistically significant. Notably, SGLT2 inhibitor usage was associated with a greater GUTI incidence (aHR = 1.78, 95% CI = 1.122.84) shortly after initiation, irrespective of prior GUTI history status. Conclusion: Among patients with CKD stages 3-5, SGLT2 inhibitor use was linked to increased GUTI incidence, but it also significantly reduced the ESRD/dialysis risk without an episodic AKI or AKD risk. Clinical physicians should consider a personalized medicine approach by balancing GUTI episodes and cardiorenal outcomes for advanced CKD patients receiving SGLT2 inhibitors.
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Affiliation(s)
- Yu-Hsuan Joni Shao
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei, Taiwan
- Health and Clinical Research Data Center, Office of Data Science, Taipei Medical University, Taipei, Taiwan
| | - Wan-Ting Chen
- Health and Clinical Research Data Center, Office of Data Science, Taipei Medical University, Taipei, Taiwan
| | - Samuel Mon-Wei Yu
- Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
| | - Liam Li-An Tsou
- Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
- Biochemistry, Department of Chemistry, Hofstra University, Hempstead, New York, USA
| | - Yung-Ho Hsu
- Taipei Medical University-Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Division of Nephrology, Department of Internal Medicine, Hsin Kuo Min Hospital, Taipei Medical University, Taoyuan City, Taiwan
| | - Mai-Szu Wu
- Taipei Medical University-Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Yung-Hsi Kao
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Chu-Lin Chou
- Taipei Medical University-Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Division of Nephrology, Department of Internal Medicine, Hsin Kuo Min Hospital, Taipei Medical University, Taoyuan City, Taiwan
| | - Po-Jen Hsiao
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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Bailey CJ. Diabetes and gout: another role for SGLT2 inhibitors? Ther Adv Endocrinol Metab 2024; 15:20420188241269178. [PMID: 39131662 PMCID: PMC11311190 DOI: 10.1177/20420188241269178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 06/20/2024] [Indexed: 08/13/2024] Open
Affiliation(s)
- Clifford J. Bailey
- College of Health and Life Sciences, Aston University, Gosta Green, Birmingham B4 7ET, UK
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Tangri N, Ferguson TW, Bamforth RJ, Leon SJ, Arnott C, Mahaffey KW, Kotwal S, Heerspink HJL, Perkovic V, Fletcher RA, Neuen BL. Machine learning for prediction of chronic kidney disease progression: Validation of the Klinrisk model in the CANVAS Program and CREDENCE trial. Diabetes Obes Metab 2024; 26:3371-3380. [PMID: 38807510 DOI: 10.1111/dom.15678] [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: 04/05/2024] [Revised: 04/26/2024] [Accepted: 05/04/2024] [Indexed: 05/30/2024]
Abstract
AIM To validate the Klinrisk machine learning model for prediction of chronic kidney disease (CKD) progression in patients with type 2 diabetes in the pooled CANVAS/CREDENCE trials. MATERIALS AND METHODS We externally validated the Klinrisk model for prediction of CKD progression, defined as 40% or higher decline in estimated glomerular filtration rate (eGFR) or kidney failure. Model performance was assessed for prediction up to 3 years with the area under the receiver operating characteristic curve (AUC), Brier scores and calibration plots of observed and predicted risks. We compared performance of the model with standard of care using eGFR (G1-G4) and urine albumin-creatinine ratio (A1-A3) Kidney Disease Improving Global Outcomes (KDIGO) heatmap categories. RESULTS The Klinrisk model achieved an AUC of 0.81 (95% confidence interval [CI] 0.78-0.83) at 1 year, and 0.88 (95% CI 0.86-0.89) at 3 years. The Brier scores were 0.020 (0.018-0.022) and 0.056 (0.052-0.059) at 1 and 3 years, respectively. Compared with the KDIGO heatmap, the Klinrisk model had improved performance at every interval (P < .01). CONCLUSIONS The Klinrisk machine learning model, using routinely collected laboratory data, was highly accurate in its prediction of CKD progression in the CANVAS/CREDENCE trials. Integration of the model in electronic medical records or laboratory information systems can facilitate risk-based care.
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Affiliation(s)
- Navdeep Tangri
- Chronic Disease Innovation Centre, Seven Oaks General Hospital, Winnipeg, Canada
- Department of Medicine, University of Manitoba, Winnipeg, Canada
| | - Thomas W Ferguson
- Chronic Disease Innovation Centre, Seven Oaks General Hospital, Winnipeg, Canada
- Department of Medicine, University of Manitoba, Winnipeg, Canada
| | - Ryan J Bamforth
- Chronic Disease Innovation Centre, Seven Oaks General Hospital, Winnipeg, Canada
| | - Silvia J Leon
- Chronic Disease Innovation Centre, Seven Oaks General Hospital, Winnipeg, Canada
| | - Clare Arnott
- The George Institute for Global Health, University of New South Wales, Sydney, Australia
- Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia
| | | | - Sradha Kotwal
- The George Institute for Global Health, University of New South Wales, Sydney, Australia
- Department of Nephrology, Prince of Wales Hospital, Sydney, Australia
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands
| | - Vlado Perkovic
- The George Institute for Global Health, University of New South Wales, Sydney, Australia
| | - Robert A Fletcher
- The George Institute for Global Health, University of New South Wales, Sydney, Australia
| | - Brendon L Neuen
- The George Institute for Global Health, University of New South Wales, Sydney, Australia
- Department of Renal Medicine, Royal North Shore Hospital, Sydney, Australia
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Lahane GP, Dhar A, Bhat A. Therapeutic approaches and novel antifibrotic agents in renal fibrosis: A comprehensive review. J Biochem Mol Toxicol 2024; 38:e23795. [PMID: 39132761 DOI: 10.1002/jbt.23795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 06/20/2024] [Accepted: 07/24/2024] [Indexed: 08/13/2024]
Abstract
Renal fibrosis (RF) is one of the underlying pathological conditions leading to progressive loss of renal function and end-stage renal disease (ESRD). Over the years, various therapeutic approaches have been explored to combat RF and prevent ESRD. Despite significant advances in understanding the underlying molecular mechanism(s), effective therapeutic interventions for RF are limited. Current therapeutic strategies primarily target these underlying mechanisms to halt or reverse fibrotic progression. Inhibition of transforming growth factor-β (TGF-β) signaling, a pivotal mediator of RF has emerged as a central strategy to manage RF. Small molecules, peptides, and monoclonal antibodies that target TGF-β receptors or downstream effectors have demonstrated potential in preclinical models. Modulating the renin-angiotensin system and targeting the endothelin system also provide established approaches for controlling fibrosis-related hemodynamic changes. Complementary to pharmacological strategies, lifestyle modifications, and dietary interventions contribute to holistic management. This comprehensive review aims to summarize the underlying mechanisms of RF and provide an overview of the therapeutic strategies and novel antifibrotic agents that hold promise in its treatment.
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Affiliation(s)
- Ganesh Panditrao Lahane
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad, Telangana, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad, Telangana, India
| | - Audesh Bhat
- Centre for Molecular Biology, Central University of Jammu, Samba, Jammu and Kashmir, India
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Al-Tarawneh LM, Al-Adwan AJ, Al-Shaikhly FA, Almomani MM, Oduibat RT. Dapagliflozin in Heart Failure and Acute Myocardial Infarction: A Systematic Review of the Association in Diabetic Patients. Cureus 2024; 16:e65914. [PMID: 39221294 PMCID: PMC11364978 DOI: 10.7759/cureus.65914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
This systematic review explores the impact of dapagliflozin on heart failure (HF) and acute myocardial infarction (MI) in patients with type 2 diabetes mellitus. By analyzing recent studies, including both randomized controlled trials (RCTs) and retrospective analyses, this review provides insights into the cardiovascular effects of this sodium-glucose cotransporter 2 (SGLT2) inhibitor. The findings consistently demonstrate the benefits of dapagliflozin in reducing HF-related hospitalizations and improving outcomes for patients with established HF. These positive effects appear to extend beyond glycemic control, suggesting multiple mechanisms of action. The impact of dapagliflozin on acute MI outcomes is less clear, with mixed results across studies. Importantly, dapagliflozin shows promise in improving the quality of life of patients and is generally well-tolerated. The review suggests that dapagliflozin may play a significant role in managing cardiovascular risk in diabetic patients, particularly those with or at risk of HF. While the evidence is encouraging, the review also highlights areas requiring further investigation. These include determining the patient subgroups most likely to benefit from dapagliflozin, elucidating the precise mechanisms underlying its cardioprotective effects, and carrying out long-term outcome studies.
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Affiliation(s)
| | | | | | | | - Rahaf T Oduibat
- Medicine and Surgery, Jordan University Hospital, Amman, JOR
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Forelli N, Eaton D, Patel J, Bowman CE, Kawakami R, Kuznetsov IA, Li K, Brady C, Bedi K, Yang Y, Koya K, Megill E, Kanter DS, Smith LG, Bowman GR, Snyder N, Edwards J, Margulies K, Arany Z. SGLT2 inhibitors activate pantothenate kinase in the human heart. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.26.605401. [PMID: 39091820 PMCID: PMC11291109 DOI: 10.1101/2024.07.26.605401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Inhibitors of sodium glucose cotransporter-2 (SGLT2i) demonstrate strong symptomatic and mortality benefits in the treatment of heart failure but appear to do so independently of SGLT2. The relevant pharmacologic target of SGLT2i remains unclear. We show here that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme that initiates the conversion of pantothenate (vitamin B5) to coenzyme-A (CoA), an obligate co-factor for all major pathways of fuel use in the heart. Using stable-isotope infusion studies, we show that SGLT2i promote pantothenate consumption, activate CoA synthesis, rescue decreased levels of CoA in human failing hearts, and broadly stimulate fuel use in ex vivo perfused human cardiac blocks from patients with heart failure. Furthermore, we show that SGLT2i bind to PANK1 directly at physiological concentrations and promote PANK1 enzymatic activity in assays with purified components. Novel in silico dynamic modeling identified the site of SGLT2i binding on PANK1 and indicated a mechanism of activation involving prevention of allosteric inhibition of PANK1 by acyl-CoA species. Finally, we show that inhibition of PANK1 prevents SGLT2i-mediated increased contractility of isolated adult human cardiomyocytes. In summary, we demonstrate robust and specific off-target activation of PANK1 by SGLT2i, promoting CoA synthesis and efficient fuel use in human hearts, providing a likely explanation for the remarkable clinical benefits of SGLT2i.
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Affiliation(s)
- Nicholas Forelli
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Deborah Eaton
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Jiten Patel
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Caitlyn E. Bowman
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Ryo Kawakami
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Ivan A. Kuznetsov
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Kristina Li
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Claire Brady
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Kenneth Bedi
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Yijun Yang
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Kaustubh Koya
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Emily Megill
- Aging & Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA
| | - Daniel S. Kanter
- Aging & Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA
| | - Louis G. Smith
- Departments of Biochemistry & Biophysics, and Bioengineering, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Gregory R. Bowman
- Departments of Biochemistry & Biophysics, and Bioengineering, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Nathaniel Snyder
- Aging & Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA
| | - Jonathan Edwards
- Division of Cardiology, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Kenneth Margulies
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Zoltan Arany
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Moral Berrio E, De La Flor JC, Arambarri Segura M, Rodríguez-Doyágüez P, Martínez Calero A, Zamora R, Cieza-Terrones M, Yuste-Lozano C, Sánchez de la Nieta García MD, Nieto Iglesias J, Vozmediano Poyatos C. Effects of Sodium-Glucose Cotransporter 2 Inhibitors in Diabetic and Non-Diabetic Patients with Advanced Chronic Kidney Disease in Peritoneal Dialysis on Residual Kidney Function: In Real-World Data. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1198. [PMID: 39202480 PMCID: PMC11356563 DOI: 10.3390/medicina60081198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/20/2024] [Accepted: 07/22/2024] [Indexed: 09/03/2024]
Abstract
Background and Objectives: Peritoneal dialysis (PD) is a renal replacement therapy modality in which the dialysis dose can be individually adapted according to the patients' residual kidney function (RKF). RKF is a crucial factor for technique and patient survival. Pharmacological strategies aimed at slowing the loss of RKF in patients on PD are limited. Therefore, we aimed to assess the potential effects and safety of sodium-glucose cotransporter 2 (SGLT-2) inhibitors on the preservation of RKF in patients with and without type 2 diabetes mellitus (T2DM) on PD during an average follow-up of 6 months. Materials and Methods: In this retrospective observational, single-center study on real-world data, we included patients from the Peritoneal Dialysis Unit of the Hospital General Universitario de Ciudad Real, who started treatment with SGLT-2 inhibitors during the period from December 2022 to December 2023. Data on analytical and clinical parameters, RKF, and peritoneal membrane transport function were retrospectively collected at months 0, 3, and 6. Results: Out of 31 patients in our unit, 16 prevalent patients initiated treatment with SGLT-2 inhibitors (13 empagliflozin and 3 dapagliflozin). A total of 62.5% were male and the mean age was 67.3 years. The baseline peritoneal ultrafiltration was higher in the non-diabetic patient (NDMP) group than in the diabetic patient (DMP) group. However, the residual diuresis volume, 24 h residual renal clearance rate of urea in urine, and 24 h proteinuria were higher in the DMP group than in the NDMP group. At the sixth month, patients in both groups preserved RKF and diuresis, with a trend towards a non-significant reduction in proteinuria and blood pressure. Only two patients of the DMP group presented adverse effects. Conclusions: The use of SGLT-2 inhibitors in our sample of patients with and without T2DM on PD appears to be safe and effective to preserve RKF.
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Affiliation(s)
- Esperanza Moral Berrio
- Department of Nephrology, Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain; (E.M.B.); (M.A.S.); (A.M.C.); (M.D.S.d.l.N.G.); (J.N.I.); (C.V.P.)
| | - José C. De La Flor
- Department of Nephrology, Hospital Central de la Defensa Gómez Ulla, 28047 Madrid, Spain
- Department of Medicine and Medical Specialties, Faculty of Medicine, Alcala University, 28805 Madrid, Spain
| | - Minerva Arambarri Segura
- Department of Nephrology, Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain; (E.M.B.); (M.A.S.); (A.M.C.); (M.D.S.d.l.N.G.); (J.N.I.); (C.V.P.)
| | | | - Alberto Martínez Calero
- Department of Nephrology, Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain; (E.M.B.); (M.A.S.); (A.M.C.); (M.D.S.d.l.N.G.); (J.N.I.); (C.V.P.)
| | - Rocío Zamora
- Department of Nephrology, Hospital Universitario General Villalba, 28400 Madrid, Spain;
| | | | | | - María Dolores Sánchez de la Nieta García
- Department of Nephrology, Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain; (E.M.B.); (M.A.S.); (A.M.C.); (M.D.S.d.l.N.G.); (J.N.I.); (C.V.P.)
| | - Javier Nieto Iglesias
- Department of Nephrology, Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain; (E.M.B.); (M.A.S.); (A.M.C.); (M.D.S.d.l.N.G.); (J.N.I.); (C.V.P.)
| | - Carmen Vozmediano Poyatos
- Department of Nephrology, Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain; (E.M.B.); (M.A.S.); (A.M.C.); (M.D.S.d.l.N.G.); (J.N.I.); (C.V.P.)
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Sattar N, Lee MMY, McGuire DK. What the SELECT trial of semaglutide means for clinicians. Nat Med 2024; 30:1830-1831. [PMID: 38796654 DOI: 10.1038/s41591-024-03013-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2024]
Affiliation(s)
- Naveed Sattar
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK.
| | - Matthew M Y Lee
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Darren K McGuire
- Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center and Parkland Health, Dallas, TX, USA
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Mallappallil M, Sasidharan S, Sabu J, John S. Treatment of Type 2 Diabetes Mellitus in Advanced Chronic Kidney Disease for the Primary Care Physician. Cureus 2024; 16:e64663. [PMID: 39149651 PMCID: PMC11326530 DOI: 10.7759/cureus.64663] [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: 07/16/2024] [Indexed: 08/17/2024] Open
Abstract
Diabetes mellitus (DM) is a common cause of chronic kidney disease (CKD), leading to the need for renal replacement therapy (RRT). RRT includes hemodialysis (HD), peritoneal dialysis (PD), kidney transplantation (KT), and medical management. As CKD advances, the management of DM may change as medication clearance, effectiveness, and side effects can be altered due to decreasing renal clearance. Medications like metformin that were safe to use early in CKD may build up toxic levels of metabolites in advanced CKD. Other medications, like sodium-glucose co-transporter 2 inhibitors, which work by excreting glucose in the urine, may not be able to work effectively in advanced CKD due to fewer working nephrons. Insulin breakdown may take longer, and both formulation and dosing may need to be changed to avoid hypoglycemia. While DM control contributes to CKD progression, effective DM control continues to be important even after patients have been placed on RRT. Patients on RRT are frequently taken care of by a team of providers, including the primary care physician, both in and outside the hospital. Non-nephrologists who are involved with the care of a patient treated with RRT need to be adept at managing DM in this population. This paper aims to outline the management of type 2 DM in advanced CKD.
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Affiliation(s)
- Mary Mallappallil
- Internal Medicine and Nephrology, New York City (NYC) Health + Hospitals/Kings County Hospital Center, Brooklyn, USA
- Internal Medicine and Nephrology, State University of New York (SUNY) Downstate University of Health Sciences, Brooklyn, USA
| | - Sandeep Sasidharan
- Internal Medicine and Nephrology, State University of New York (SUNY) Downstate University of Health Sciences, Brooklyn, USA
- Internal Medicine and Nephrology, New York City (NYC) Health + Hospitals/Kings County Hospital Center, Brooklyn, USA
| | - Jacob Sabu
- Internal Medicine, State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, USA
| | - Sabu John
- Internal Medicine and Cardiology, New York City (NYC) Health + Hospitals/Kings County Hospital Center, Brooklyn, USA
- Internal Medicine and Cardiology, State University of New York (SUNY) Downstate University of Health Sciences, Brooklyn, USA
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Sammut-Powell C, Sisk R, Vazquez-Mendez E, Vasnawala H, Goncalves S, Edge M, Cameron R. Global Validation of a Model to Predict Reduced Estimated GFR in People With Type 2 Diabetes Without Diagnosis of CKD. Kidney Int Rep 2024; 9:2047-2055. [PMID: 39081746 PMCID: PMC11284396 DOI: 10.1016/j.ekir.2024.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 03/31/2024] [Accepted: 04/01/2024] [Indexed: 08/02/2024] Open
Abstract
Introduction A minimal-resource model for predicting reduced kidney function among people with type 2 diabetes and no diagnosis of chronic kidney disease (CKD) stages 3 to 5 was previously developed in a UK population to pre-screen for undiagnosed CKD. This study aims to evaluate the performance of the model on a global population and assess its adequacy with and without regional adjustment. Methods A retrospective observational study was performed using data collected from the iCaReMe global registry (NCT03549754) and the DISCOVER study (NCT02322762 and NCT02226822). Patients were grouped by their World Health Organization classified region. An estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2 was the marker of reduced kidney function. A regional-intercept recalibration was applied to adjust for regional variation. Discrimination and calibration were evaluated for the UK-developed and recalibrated models. Results A total of 14,180 patients (46 countries, 6 regions) were identified with type 2 diabetes, no previous diagnosis of CKD stages 3 to 5, and had a serum creatinine measurement or eGFR recorded. The UK model underestimated risk when applied globally and was deemed inadequate. The model with regional adjustment achieved the target sensitivity (80.5%; 95% confidence interval [CI]: 78.8%-82.3%) and demonstrated a relative improvement of 51.5% (95% CI: 48.1%-55.1%) in the positive predictive value (PPV), compared to a screen-all approach. Conclusion The regional-adjusted model demonstrated adequate performance globally. Incorporating the model within practice could help clinicians to risk-stratify and prioritize patients at high risk. This could enable improved efficiency via risk-tailored screening, particularly in lower-middle-income countries (LMICs).
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Singh R, Chandi SK, Sran S, Aulakh SK, Nijjar GS, Singh K, Singh S, Tanvir F, Kaur Y, Sandhu APS. Emerging Therapeutic Strategies in Cardiovascular Diseases. Cureus 2024; 16:e64388. [PMID: 39131016 PMCID: PMC11317025 DOI: 10.7759/cureus.64388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2024] [Indexed: 08/13/2024] Open
Abstract
Cardiovascular diseases (CVDs), including ischemic heart disease and stroke, are the leading cause of mortality worldwide, causing nearly 20 million deaths annually. Traditional therapies, while effective, have not curbed the rising prevalence of CVDs driven by aging populations and lifestyle factors. This review highlights innovative therapeutic strategies that show promise in improving patient outcomes and transforming cardiovascular care. Emerging pharmacological treatments, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors, introduce novel mechanisms to complement existing therapies, significantly reducing cardiovascular events and mortality. These advancements emphasize the necessity of ongoing clinical trials and research to discover new therapeutic targets. Advanced biological therapies, including gene therapy, stem cell therapy, and RNA-based treatments, offer groundbreaking potential for repairing and regenerating damaged cardiovascular tissues. Despite being in various stages of clinical validation, early results are promising, suggesting these therapies could fundamentally change the CVD treatment landscape. Innovative medical devices and technologies, such as implantable devices, minimally invasive procedures, and wearable technology, are revolutionizing CVD management. These advancements facilitate early diagnosis, continuous monitoring, and effective treatment, driving care out of hospitals and into homes, improving patient outcomes and reducing healthcare costs. Personalized medicine, driven by genetic profiling and biomarker identification, allows for tailored therapies that enhance treatment efficacy and minimize adverse effects. However, the adoption of these emerging therapies faces significant challenges, including regulatory hurdles, cost and accessibility issues, and ethical considerations. Addressing these barriers and fostering interdisciplinary collaboration are crucial for accelerating the development and implementation of innovative treatments. Integrating emerging therapeutic strategies in cardiovascular care holds immense potential to transform CVD management. By prioritizing future research and overcoming existing challenges, a new era of personalized, effective, and accessible cardiovascular care can be achieved.
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Affiliation(s)
- Rajinderpal Singh
- Internal Medicine, Government Medical College Amritsar, Amritsar, IND
| | | | - Seerat Sran
- Internal Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
| | - Smriti K Aulakh
- Internal Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
| | | | | | - Sumerjit Singh
- Medicine, Government Medical College Amritsar, Amritsar, IND
| | - Fnu Tanvir
- Medicine, Government Medical College Amritsar, Amritsar, IND
| | - Yasmeen Kaur
- Medicine, Government Medical College Amritsar, Amritsar, IND
| | - Ajay Pal Singh Sandhu
- Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
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Fang Y, Chen L, Sun S, Ran X. Sodium-Glucose Transporter 2 Inhibitors in Heart Failure: An Overview of Systematic Reviews. J Cardiovasc Dev Dis 2024; 11:198. [PMID: 39057618 PMCID: PMC11276734 DOI: 10.3390/jcdd11070198] [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: 05/16/2024] [Revised: 06/20/2024] [Accepted: 06/26/2024] [Indexed: 07/28/2024] Open
Abstract
Background: Several studies have shown that sodium-dependent glucose transporter 2 inhibitors can be used in the treatment of heart failure. This article summarized systematic reviews of sodium-dependent glucose transporter 2 inhibitors in the treatment of heart failure in order to evaluate efficacy and safety. Methods: We systematically searched eight electronic databases from inception to July 2023. We used Assessment of Multiple Systematic Reviews 2 to evaluate the methodological quality, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 to assess report quality, Risk of Bias in Systematic Review to assess the risk of bias, and Grading of Recommendations Assessment, Development, and Evaluation to rate the quality of evidence. Outcome: A total of 36 systematic reviews were included. Our results were classified as clear evidence of benefit: hospitalization for heart failure; possible benefit: cardiovascular death (mortality) and renal outcome composite; clear evidence of no effect or equivalence: atrial arrhythmias, ventricular arrhythmia, atrial fibrillation, and hypotension; possible harm: genital infection; insufficient evidence to draw a conclusion: atrial flutter, major adverse cardiovascular events, urinary tract infection, acute kidney injury, hypoglycemia, and bone fracture. Conclusions: Sodium-dependent glucose transporter 2 inhibitors are beneficial for the treatment of heart failure, especially in terms of heart failure hospitalization.
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Affiliation(s)
- Yixuan Fang
- Department of Endocrinology & Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.F.); (L.C.); (S.S.)
- Innovation Center for Wound Repair, Diabetic Foot Care Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lihong Chen
- Department of Endocrinology & Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.F.); (L.C.); (S.S.)
- Innovation Center for Wound Repair, Diabetic Foot Care Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shiyi Sun
- Department of Endocrinology & Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.F.); (L.C.); (S.S.)
- Innovation Center for Wound Repair, Diabetic Foot Care Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xingwu Ran
- Department of Endocrinology & Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.F.); (L.C.); (S.S.)
- Innovation Center for Wound Repair, Diabetic Foot Care Center, West China Hospital, Sichuan University, Chengdu 610041, China
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Lee OYA, Wong ANN, Ho CY, Tse KW, Chan AZ, Leung GPH, Kwan YW, Yeung MHY. Potentials of Natural Antioxidants in Reducing Inflammation and Oxidative Stress in Chronic Kidney Disease. Antioxidants (Basel) 2024; 13:751. [PMID: 38929190 PMCID: PMC11201162 DOI: 10.3390/antiox13060751] [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: 04/19/2024] [Revised: 06/13/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
Chronic kidney disease (CKD) presents a substantial global public health challenge, with high morbidity and mortality. CKD patients often experience dyslipidaemia and poor glycaemic control, further exacerbating inflammation and oxidative stress in the kidney. If left untreated, these metabolic symptoms can progress to end-stage renal disease, necessitating long-term dialysis or kidney transplantation. Alleviating inflammation responses has become the standard approach in CKD management. Medications such as statins, metformin, and GLP-1 agonists, initially developed for treating metabolic dysregulation, demonstrate promising renal therapeutic benefits. The rising popularity of herbal remedies and supplements, perceived as natural antioxidants, has spurred investigations into their potential efficacy. Notably, lactoferrin, Boerhaavia diffusa, Amauroderma rugosum, and Ganoderma lucidum are known for their anti-inflammatory and antioxidant properties and may support kidney function preservation. However, the mechanisms underlying the effectiveness of Western medications and herbal remedies in alleviating inflammation and oxidative stress occurring in renal dysfunction are not completely known. This review aims to provide a comprehensive overview of CKD treatment strategies and renal function preservation and critically discusses the existing literature's limitations whilst offering insight into the potential antioxidant effects of these interventions. This could provide a useful guide for future clinical trials and facilitate the development of effective treatment strategies for kidney functions.
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Affiliation(s)
- On Ying Angela Lee
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; (O.Y.A.L.)
| | - Alex Ngai Nick Wong
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; (O.Y.A.L.)
| | - Ching Yan Ho
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; (O.Y.A.L.)
| | - Ka Wai Tse
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; (O.Y.A.L.)
| | - Angela Zaneta Chan
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - George Pak-Heng Leung
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China;
| | - Yiu Wa Kwan
- The School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Martin Ho Yin Yeung
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China; (O.Y.A.L.)
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
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Palomo-Piñón S, Aguilar-Alonso JA, Chávez-Iñiguez JS, Hernández-Arellanes FE, Mariano-Murga JA, Flores-Rodríguez JC, Pérez-López MJ, Pazos-Pérez F, Treviño-Becerra A, Guillen-Graf AE, Ramos-Gordillo JM, Trinidad-Ramos P, Antonio-Villa NE. Strategies to address diabetic kidney disease burden in Mexico: a narrative review by the Mexican College of Nephrologists. Front Med (Lausanne) 2024; 11:1376115. [PMID: 38962740 PMCID: PMC11219582 DOI: 10.3389/fmed.2024.1376115] [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: 01/24/2024] [Accepted: 06/07/2024] [Indexed: 07/05/2024] Open
Abstract
Chronic kidney disease (CKD) is a growing global public health challenge worldwide. In Mexico, CKD prevalence is alarmingly high and remains a leading cause of morbidity and mortality. Diabetic kidney disease (DKD), a severe complication of diabetes, is a leading determinant of CKD. The escalating diabetes prevalence and the complex regional landscape in Mexico underscore the pressing need for tailored strategies to reduce the burden of CKD. This narrative review, endorsed by the Mexican College of Nephrologists, aims to provide a brief overview and specific strategies for healthcare providers regarding preventing, screening, and treating CKD in patients living with diabetes in all care settings. The key topics covered in this review include the main cardiometabolic contributors of DKD (overweight/obesity, hyperglycemia, arterial hypertension, and dyslipidemia), the identification of kidney-related damage markers, and the benefit of novel pharmacological approaches based on Sodium-Glucose Co-Transporter-2 Inhibitors (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA). We also address the potential use of novel therapies based on Mineralocorticoid Receptor Antagonists (MRAs) and their future implications. Emphasizing the importance of multidisciplinary treatment, this narrative review aims to promote strategies that may be useful to alleviate the burden of DKD and its associated complications. It underscores the critical role of healthcare providers and advocates for collaborative efforts to enhance the quality of life for millions of patients affected by DKD.
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Affiliation(s)
- Silvia Palomo-Piñón
- Vicepresidente del Colegio de Nefrólogos de México AC, Mexico City, Mexico
- Directora General del Registro Nacional de Hipertensión Arterial México (RIHTA) Grupo de Expertos en Hipertensión Arterial México (GREHTA), Mexico City, Mexico
| | | | | | - Felipe Ericel Hernández-Arellanes
- Departamento de Nefrología, Hospital de Especialidades Dr. Antonio Fraga Mouret, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | | | | | - María Juana Pérez-López
- Departamento de Nefrología, Hospital de Especialidades Dr. Antonio Fraga Mouret, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Fabiola Pazos-Pérez
- Nefrología, UMAE Hospital de Especialidades Dr. Bernardo Sepúlveda Gutiérrez, Centro Medico Siglo XXI, Mexico City, Mexico
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Yau K, Kuah R, Cherney DZI, Lam TKT. Obesity and the kidney: mechanistic links and therapeutic advances. Nat Rev Endocrinol 2024; 20:321-335. [PMID: 38351406 DOI: 10.1038/s41574-024-00951-7] [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] [Accepted: 01/02/2024] [Indexed: 02/19/2024]
Abstract
Obesity is strongly associated with the development of diabetes mellitus and chronic kidney disease (CKD), but there is evidence for a bidirectional relationship wherein the kidney also acts as a key regulator of body weight. In this Review, we highlight the mechanisms implicated in obesity-related CKD, and outline how the kidney might modulate feeding and body weight through a growth differentiation factor 15-dependent kidney-brain axis. The favourable effects of bariatric surgery on kidney function are discussed, and medical therapies designed for the treatment of diabetes mellitus that lower body weight and preserve kidney function independent of glycaemic lowering, including sodium-glucose cotransporter 2 inhibitors, incretin-based therapies and metformin, are also reviewed. In summary, we propose that kidney function and body weight are related in a bidirectional fashion, and that this interrelationship affects human health and disease.
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Affiliation(s)
- Kevin Yau
- Division of Nephrology, Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Rachel Kuah
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada.
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada.
| | - Tony K T Lam
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada.
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