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Horton WB, Love KM, Gregory JM, Liu Z, Barrett EJ. Metabolic and vascular insulin resistance: partners in the pathogenesis of cardiovascular disease in diabetes. Am J Physiol Heart Circ Physiol 2025; 328:H1218-H1236. [PMID: 40257392 DOI: 10.1152/ajpheart.00826.2024] [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: 11/27/2024] [Revised: 12/29/2024] [Accepted: 04/16/2025] [Indexed: 04/22/2025]
Abstract
Vascular insulin resistance has emerged as a pivotal factor in the genesis of cardiovascular disease (CVD) in people with diabetes. It forms a complex pathogenic partnership with metabolic insulin resistance to significantly amplify the CVD risk of diabetes and other affected populations. Metabolic insulin resistance (characterized by quantitatively diminished insulin action on glucose metabolism in skeletal muscle, liver, and adipose tissue) is a hallmark of diabetes, obesity, and related conditions. In contrast, vascular insulin resistance is a less appreciated and not well-quantified complication of these conditions. Importantly, an impaired vascular response to insulin contributes directly to vascular dysfunction and over 40 years of research has convincingly shown that vascular and metabolic insulin resistance synergize to create an environment that predisposes individuals to CVD. In this review, we examine the multifaceted vascular actions of insulin, including its roles in regulating blood pressure, blood flow, endothelial health, and arterial stiffness. We also examine how these processes become disrupted in the setting of vascular insulin resistance, which subsequently undermines endothelial function, compromises tissue microvascular perfusion, and promotes vascular rigidity and atherosclerosis. We then highlight potential therapeutic strategies with demonstrated efficacy to improve vascular insulin sensitivity in people with diabetes and suggest that targeting disordered vascular insulin signaling holds promise not only for refining the functional understanding of vascular insulin resistance but also for developing innovative treatments with potential to reduce CVD risk and improve cardiovascular outcomes in people with diabetes.
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Affiliation(s)
- William B Horton
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, United States
| | - Kaitlin M Love
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, United States
| | - Justin M Gregory
- Ian M. Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, United States
| | - Eugene J Barrett
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, United States
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, United States
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Akunjee MM, Khosla SG, Nylen ES, Sen S. SGLT2 inhibitors use in kidney disease: what did we learn? Am J Physiol Endocrinol Metab 2025; 328:E856-E868. [PMID: 40279256 DOI: 10.1152/ajpendo.00034.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/26/2025] [Accepted: 04/18/2025] [Indexed: 04/27/2025]
Abstract
Chronic kidney disease (CKD) increases the risk for cardiovascular morbidity and mortality and it's prevalence continues to rise throughout the world. Newer, more efficacious therapies, slow progression of CKD, decrease long-term sequela like end-stage kidney disease (ESKD) and cardiovascular events, improving survival. Postmarketing cardiovascular outcome trials (CVOT) have demonstrated improved cardiovascular outcomes with the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) like canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin in patients with type 2 diabetes mellitus (T2DM), Similarly, secondary analysis of CVOT and renal outcome trials with the use of SGLT2i in patients without T2DM showed improved renal function and albuminuria. In these studies, nondiabetic CKD was defined as an estimated glomerular filtration rate (eGFR) of 20-75 mL/min/1.73 m2 with albuminuria ranging from 200 to 5,000 mg/g in the absence of diabetes. As a class effect, in addition to modulation of hemodynamic and metabolic activities, SGLT2i exert renal protection by suppressing inflammation and fibrosis. We conducted an extensive search in the PubMed database for original papers published from 2009 through 2024 using keywords such as nondiabetic kidney disease, diabetic kidney disease, SGLT2i, and kidney outcomes. Based on our research of published literature, we present a review and propose, consideration of SGLT2i in nondiabetic kidney disease for long-term cardiovascular and renal benefit (Dharia A, Khan A, Sridhar VS, Cherney DZI. Annu Rev Med 74: 369-384, 2023). We will highlight relevant translational studies to propose a possible cell-based mechanism for cardiovascular benefits noted secondary to use of SGLT2i.
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Affiliation(s)
- Munaza M Akunjee
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Shikha G Khosla
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Eric S Nylen
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Sabyasachi Sen
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
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Bapat P, Dhaliwal S, Song C, Zhang Y, Scarr D, Bakhsh A, Budhram D, Verhoeff NJ, Weisman A, Fralick M, Ivers NM, Cherney DZI, Tomlinson G, Mumford D, Lovblom LE, Perkins BA. Capillary Ketone Level and Future Ketoacidosis Risk in Patients With Type 1 Diabetes Using Sodium-Glucose Cotransporter Inhibitors. Diabetes Care 2025; 48:1016-1021. [PMID: 40267366 DOI: 10.2337/dc25-0125] [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: 01/16/2025] [Accepted: 03/27/2025] [Indexed: 04/25/2025]
Abstract
OBJECTIVE We aimed to determine if routine capillary blood ketone testing on well days predicts future diabetic ketoacidosis (DKA) in type 1 diabetes (T1D) using sodium-glucose cotransporter inhibitors (SGLTi). RESEARCH DESIGN AND METHODS We examined previously collected data from empagliflozin-assigned participants in a T1D trial that included weekly fasted ketone levels. Over 6-12 months, ketone levels were subdivided into 28-day periods, and the outcome was subsequent adjudicated DKA or severe ketosis. RESULTS Among 1,194 participants, 325 had 49 DKA and 568 severe ketosis events. On-treatment maximum ketone levels were higher in the 28 days before an outcome compared with levels in those without an outcome, with area under receiver operating characteristic curve of 0.76 (95% CI 0.71-0.82). Maximum ketone level ≥0.8 mmol/L had sensitivity of 66.0%, specificity of 79.6%, and diagnostic odds ratio of 7.6. CONCLUSIONS Routine surveillance of capillary ketone levels in T1D using SGLTi may represent a DKA mitigation strategy and implies a potential threshold for continuous ketone monitoring.
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Affiliation(s)
- Priya Bapat
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Sharon Dhaliwal
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Cimon Song
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Yucheng Zhang
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of General Internal Medicine, Department of Medicine, University Health Network and Sinai Health, University of Toronto, Toronto, Ontario, Canada
| | - Daniel Scarr
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Abdulmohsen Bakhsh
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Kidney & Pancreas Health Centre, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital & Research Centre, Alfaisal University, Riyadh, Kingdom of Saudi Arabia
| | - Dalton Budhram
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of General Internal Medicine, Department of Medicine, University Health Network and Sinai Health, University of Toronto, Toronto, Ontario, Canada
| | - Natasha J Verhoeff
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Alanna Weisman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Michael Fralick
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of General Internal Medicine, Department of Medicine, University Health Network and Sinai Health, University of Toronto, Toronto, Ontario, Canada
| | - Noah M Ivers
- Department of Family and Community Medicine, Women's College Hospital, Toronto, Ontario, Canada
| | - David Z I Cherney
- Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - George Tomlinson
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
- Biostatistics Department, University Health Network, Toronto, Ontario, Canada
| | - Doug Mumford
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Leif Erik Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
- Biostatistics Department, University Health Network, Toronto, Ontario, Canada
| | - Bruce A Perkins
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Maran A, Boscari F, Fagarazzi C, Crepaldi MC, Vedovato M, Bonora BM, Bruttomesso D, Morieri ML, Fadini GP. Long-term effects of adding an SGLT-2 inhibitor to insulin therapy in patients with type 1 diabetes. An observational study and systematic review of real-world evidence. J Endocrinol Invest 2025:10.1007/s40618-025-02602-8. [PMID: 40347422 DOI: 10.1007/s40618-025-02602-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Accepted: 04/29/2025] [Indexed: 05/12/2025]
Abstract
PURPOSE The addition of SGLT2i to insulin therapy in type 1 diabetes (T1D) is an emerging treatment strategy. This study evaluates the real-world effects of SGLT2i on glycaemic control and other outcomes in individuals with T1D. METHODS In this single-center retrospective study, we included 78 adults with T1D who initiated SGLT2i and were observed for up to 24 months. Data included demographics, laboratory values, diabetic complications, and ongoing therapy. The primary outcome was the change in HbA1c over time. Persistence on therapy and adverse events were also recorded. RESULTS The mean age was 47.2 years, diabetes duration 24.6 years, baseline HbA1c 8.3%, and BMI 29.8 kg/m2. The median persistence on therapy was 14.8 months. HbA1c reduction was significantly associated with persistence (p = 0.01), with a maximum decrease of 0.61% at 6 months (p < 0.001). Time in range improved by 13.7% at 3 months (p < 0.001). Persistent users experienced a maximum weight loss of 2.5 kg at 9 months (p < 0.001). Insulin doses declined significantly (max 15% at 21 months). UACR declined significantly at 15 months (p = 0.025). Treatment discontinuation due to adverse events (mainly genitourinary tract infections) occurred in 25.6% of patients, and 1 episode of diabetic ketoacidosis was recorded. A review of the literature suggests that the observed effects are within the range of benefits reported previously from different countries. CONCLUSION SGLT2i addition to insulin therapy in T1D patients resulted in sustained HbA1c reductions and weight loss. Therapy persistence significantly influenced outcomes, underscoring the importance of patient selection and monitoring for adverse effects.
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Affiliation(s)
- Alberto Maran
- Department of Medicine, University of Padova, Padova, Italy
- Division of Metabolic Disease and Diabetology, University Hospital of Padova, Via Giustiniani 2, Padua, 35128, Italy
| | - Federico Boscari
- Division of Metabolic Disease and Diabetology, University Hospital of Padova, Via Giustiniani 2, Padua, 35128, Italy
| | | | - Maria Cristina Crepaldi
- Division of Metabolic Disease and Diabetology, University Hospital of Padova, Via Giustiniani 2, Padua, 35128, Italy
| | - Monica Vedovato
- Division of Metabolic Disease and Diabetology, University Hospital of Padova, Via Giustiniani 2, Padua, 35128, Italy
| | - Benedetta Maria Bonora
- Department of Medicine, University of Padova, Padova, Italy
- Division of Metabolic Disease and Diabetology, University Hospital of Padova, Via Giustiniani 2, Padua, 35128, Italy
| | - Daniela Bruttomesso
- Division of Metabolic Disease and Diabetology, University Hospital of Padova, Via Giustiniani 2, Padua, 35128, Italy
| | | | - Gian Paolo Fadini
- Department of Medicine, University of Padova, Padova, Italy.
- Division of Metabolic Disease and Diabetology, University Hospital of Padova, Via Giustiniani 2, Padua, 35128, Italy.
- Veneto Institute of Molecular Medicine, Padova, Italy.
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Apostolopoulou M, Lambadiari V, Roden M, Dimitriadis GD. Insulin Resistance in Type 1 Diabetes: Pathophysiological, Clinical, and Therapeutic Relevance. Endocr Rev 2025; 46:317-348. [PMID: 39998445 PMCID: PMC12063105 DOI: 10.1210/endrev/bnae032] [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: 06/23/2024] [Indexed: 02/26/2025]
Abstract
People with type 1 diabetes (T1D) are usually considered to exclusively exhibit β-cell failure, but they frequently also feature insulin resistance. This review discusses the mechanisms, clinical features, and therapeutic relevance of insulin resistance by focusing mainly on human studies using gold-standard techniques (euglycemic-hyperinsulinemic clamp). In T1D, tissue-specific insulin resistance can develop early and sustain throughout disease progression. The underlying pathophysiology is complex, involving both metabolic- and autoimmune-related factors operating synergistically. Insulin treatment may play an important pathogenic role in predisposing individuals with T1D to insulin resistance. However, the established lifestyle-related risk factors and peripheral insulin administration inducing glucolipotoxicity, hyperinsulinemia, hyperglucagonemia, inflammation, mitochondrial abnormalities, and oxidative stress cannot always fully explain insulin resistance in T1D, suggesting a phenotype distinct from type 2 diabetes. The mutual interaction between insulin resistance and impaired endothelial function further contributes to diabetes-related complications. Insulin resistance should therefore be considered a treatment target in T1D. Aside from lifestyle modifications, continuous subcutaneous insulin infusion can ameliorate insulin resistance and hyperinsulinemia, thereby improving glucose toxicity compared with multiple injection insulin treatment. Among other concepts, metformin, pioglitazone, incretin-based drugs such as GLP-1 receptor agonists, sodium-glucose cotransporter inhibitors, and pramlintide can improve insulin resistance, either directly or indirectly. However, considering the current issues of high cost, side effects, limited efficacy, and their off-label status, these agents in people with T1D are not widely used in routine clinical care at present.
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Affiliation(s)
- Maria Apostolopoulou
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibnitz Center for Diabetes Research at Heinrich-Heine University, 40225 Düsseldorf, Germany
- German Center of Diabetes Research (DZD), Partner Düsseldorf, 85764 München-Neuherberg, Germany
| | - Vaia Lambadiari
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibnitz Center for Diabetes Research at Heinrich-Heine University, 40225 Düsseldorf, Germany
- German Center of Diabetes Research (DZD), Partner Düsseldorf, 85764 München-Neuherberg, Germany
| | - George D Dimitriadis
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece
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Welty FK, Parhofer KG, Konstam M, Palmer MK, Greenberg B, Daher R, Clayton T. The Data Monitoring Experience in Empagliflozin Randomized Clinical Trials Between 2011 and 2024. Ther Innov Regul Sci 2025; 59:489-504. [PMID: 40011379 DOI: 10.1007/s43441-025-00749-3] [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: 08/12/2024] [Accepted: 01/20/2025] [Indexed: 02/28/2025]
Abstract
In November 2007, a black box warning was mandated for rosiglitazone in type 2 diabetes mellitus (T2DM) based on an increased risk of ischemic cardiovascular (CV) events. The Food and Drug Administration (FDA) issued a directive that a CV outcomes trial must be done for any new diabetes drug to demonstrate no CV harm. Therefore, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial was started in 2011 alongside 13 additional randomized clinical trials (RCTs) of empagliflozin in T2DM. The results of EMPA-REG OUTCOME set the stage for later RCTs in heart failure. Results from these clinical trials have changed the outlook for patients both with and without T2DM and with and without heart failure. A Program Data Monitoring Committee (DMC) with the same core members was utilized for these trials between 2011 and 2024. This committee is likely to be one of the longest serving DMCs since it served 28 trials with empagliflozin between 2011 and 2024. The committee encountered several important challenges which are discussed in this article. Moreover, the committee provides several important take-home messages which we hope will be of value in discussing issues in creating, developing and running DMCs in the future. These include: 1. Whether and when to be blinded and unblinded; 2. How to proceed when the primary endpoint shows no evidence of benefit, but there is evidence for a mortality benefit; 3. Development of presentation of data using figures and boxplots for rapid review of adverse events and laboratory data to assess clinical challenges; 4. How to manage a catastrophic serious adverse event; 5. Suggestions for an ideal structure of the report for the DMC closed session; and 6. The relation between the DMC, sponsor and Contract Research Organization. Our experience emphasizes the value of continuity with the same members serving over a 13-year period.
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Affiliation(s)
- Francine K Welty
- Division of Cardiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA.
| | | | - Marvin Konstam
- The CardioVascular Center, Tufts Medical Center and Tufts University School of Medicine, Boston, MA, USA
| | | | - Barry Greenberg
- Division of Cardiology, University of California at San Diego, La Jolla, CA, USA
| | - Ralph Daher
- Cooper University Healthcare, Camden, NJ, USA
| | - Tim Clayton
- Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK
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Stougaard EB, Curovic VR, Hansen TW. Combining SGLT2is, GLP1-RAs and nsMRAs in Diabetes: A Scoping Review of Current and Future Perspectives. Diabetes Ther 2025; 16:799-811. [PMID: 40088324 PMCID: PMC12006599 DOI: 10.1007/s13300-025-01726-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/07/2025] [Indexed: 03/17/2025] Open
Abstract
Combination therapy is a cornerstone of modern type 2 diabetes management, extending beyond traditional goals of glucose, blood pressure, and lipid control to focus on therapies protecting the heart and kidneys. The introduction of sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide receptor agonists (GLP-1RAs), and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) has reshaped clinical guidelines in recent decades. However, the effects of combining these drug classes remain uncertain. This review evaluates the current evidence on combination therapies involving SGLT2is, GLP-1RAs, and nsMRAs in type 1 and type 2 diabetes, thereby focusing on treatments that in type 2 diabetes have shown cardio-renal protection, while exploring future research directions. In type 2 diabetes, much of the evidence comes from post hoc analyses of trials that primarily examine the effects of single drugs compared with placebo. This limits the ability to draw definitive conclusions about the efficacy and safety of combination therapy. Nonetheless, observational studies indicate that combining SGLT2is and GLP-1RAs may offer superior cardiovascular and mortality benefits compared with monotherapy. Data on kidney outcomes remain limited, but SGLT2is appear particularly effective when kidney protection is the primary goal, regardless of concurrent treatment. The use of nsMRAs is still emerging, and studies investigating their combination with SGLT2is and GLP-1RAs are scarce. In type 1 diabetes, combination therapies have primarily focused on glucose control and safety, with several randomized controlled trials investigating the effects of combining treatments such as SGLT2is and GLP-1RAs with insulin. No current studies have estimated the effects on heart and kidneys. Ongoing and planned studies aim to fill critical gaps in our understanding of combination therapy for type 1 diabetes. These studies hold the promise of determining whether similar risk reductions, as observed in type 2 diabetes, can be achieved, offering hope for improved outcomes in this high-risk population. Currently, in type 2 diabetes, only one ongoing study is testing combination with an SGLT2i and a nsMRA.
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Affiliation(s)
| | | | - Tine Willum Hansen
- Steno Diabetes Center Copenhagen, Borgmester Ib Juuls Vej 83, 2730, Herlev, Denmark.
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
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Jones KE, Petersen MC, Markov AM, Salam M, Krutilova P, McKee AM, Bohnert KL, Adamson SE, McGill JB. Breath Acetone Correlates With Capillary β-hydroxybutyrate in Type 1 Diabetes. J Diabetes Sci Technol 2025:19322968251334640. [PMID: 40260699 PMCID: PMC12014577 DOI: 10.1177/19322968251334640] [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] [Indexed: 04/24/2025]
Abstract
BACKGROUND Breath acetone (BrACE) is an end product of ketone metabolism that is measurable by noninvasive breath ketone analyzers. We assessed the correlation between capillary blood β-hydroxybutyrate (BOHB) and BrACE in people with type 1 diabetes during 14 days of outpatient care with and without dapagliflozin treatment and during supervised insulin withdrawal studies with and without dapagliflozin. METHODS In this randomized crossover study, participants completed two 14-day outpatient periods with or without dapagliflozin 10 mg daily. Each 14-day unsupervised outpatient period was followed by a 1-day supervised insulin withdrawal study. Paired BOHB and BrACE measurements were obtained 3 times daily during outpatient periods, then hourly during supervised insulin withdrawal. The correlation between BrACE and BOHB was assessed by Spearman's ρ. RESULTS Twenty people with type 1 diabetes completed the study. During outpatient periods, BrACE and BOHB were moderately correlated (n = 1425 paired readings; ρ = .41; 95% CI = 0.36 to 0.45; P < .0001). However, BrACE and BOHB were strongly correlated during insulin withdrawal (n = 246 paired values, ρ = .81; 95% CI = 0.77 to 0.85). In ROC analysis, BrACE > 5 ppm demonstrated optimal sensitivity (93%) and specificity (87%) for detecting capillary BOHB ≥ 1.5 mmol/L. No serious adverse events occurred. CONCLUSIONS In adults with type 1 diabetes, measurement of breath acetone provides a noninvasive estimate of blood BOHB concentration. The correlation between BrACE and BOHB was suboptimal during unsupervised outpatient care, but was strong during supervised insulin withdrawal. TRIAL REGISTRATION clinicaltrials.gov (NCT05541484).
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Affiliation(s)
- Kai E. Jones
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Max C. Petersen
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Alexander M. Markov
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Maamoun Salam
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Petra Krutilova
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Alexis M. McKee
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Kathryn L. Bohnert
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Samantha E. Adamson
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Janet B. McGill
- Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
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9
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Nardone M, Kugathasan L, Sridhar VS, Dutta P, Campbell DJ, Layton AT, Perkins BA, Barbour S, Lam TK, Levin A, Lovblom LE, Mucsi I, Rabasa-Lhoret R, Rac VE, Senior P, Sigal RJ, Stanimirovic A, Persson F, Stougaard EB, Doria A, Cherney DZ. Modeling Cardiorenal Protection with Sodium-Glucose Cotransporter 2 Inhibition in Type 1 Diabetes: An Analysis of DEPICT-1 and DEPICT-2. Clin J Am Soc Nephrol 2025; 20:529-538. [PMID: 39918875 PMCID: PMC12007828 DOI: 10.2215/cjn.0000000641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 02/04/2025] [Indexed: 02/09/2025]
Abstract
Key Points Risk modelling analysis of DEPICT trials show that dapagliflozin reduced estimated cardiovascular and kidney disease risk in T1D persons. Greatest reduction in estimated ESKD risk was accompanied by an expected rise in eGFR, after 4 weeks post drug discontinuation. Dedicated outcome trials with SGLT2 inhibitors are warranted in T1D persons with CKD or CVD for best determination of efficacy and risks. Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve glycemia and reduce insulin requirements in type 1 diabetes (T1D) and type 2 diabetes. Although SGLT2 inhibitors lower cardiovascular disease (CVD) and ESKD risk in type 2 diabetes, no dedicated cardiorenal outcome trials in T1D have been conducted to date. Using validated risk prediction models, this study evaluated the effect of SGLT2 inhibition on estimated CVD and ESKD risk in a T1D cohort. Methods Demographics, medical history, and biomarkers were extracted from 1473 participants with T1D enrolled in the Dapagliflozin Evaluation in Patients with Inadequately Controlled Type -1 and -2 trials. Data at baseline, 24, 52, and 56 weeks (4 weeks after drug cessation) were used to estimate 10-year CVD and 5-year ESKD risk using the Steno T1 Risk Engine (SRE) and Scottish Diabetes Research Network (SDRN) risk prediction models. Risk reduction was determined on the basis of relative change in risk from baseline between participants receiving dapagliflozin (pooled 5 and 10 mg) versus placebo. Subgroup analyses were conducted by age, sex, diabetes duration, CVD risk, and CKD status at baseline. Results The relative change in 10-year estimated CVD risk (SRE: –6.50% [–8.04% to –4.95%] and SDRN: –6.77% [–8.40% to –5.13%]; all P < 0.001) and 5-year ESKD risk (SRE: –4.48% [–7.68% to –1.28%]; P = 0.006) were lower at the end of 24 weeks of dapagliflozin treatment compared with placebo. Furthermore, the greatest relative change in 5-year ESKD risk was observed at week 56 (SRE: –12.84% [–16.65% to –9.03%]; P < 0.001), in conjunction with an expected rise in eGFR after drug washout. Subgroup analysis revealed larger relative lowering in 10-year CVD risk in those with CKD compared with those without (SRE: –11.3% versus –5.9%, and SDRN: –11.9% versus –6.1%, respectively; all P interaction < 0.02). Conclusions Dapagliflozin improves estimated CVD and ESKD risk in participants with T1D, emphasizing the need for cardiorenal outcome trials in people living with T1D.
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Affiliation(s)
- Massimo Nardone
- Department of Medicine, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Luxcia Kugathasan
- Department of Medicine, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Vikas S. Sridhar
- Department of Medicine, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Pritha Dutta
- Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada
| | - David J.T. Campbell
- Departments of Medicine, Cardiac Sciences and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Anita T. Layton
- Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada
| | - Bruce A. Perkins
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Sean Barbour
- Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tony K.T. Lam
- Department of Medicine, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Adeera Levin
- Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Leif Erik Lovblom
- Biostatistics Department, University Health Network, Toronto, Ontario, Canada
- Dalla Lana School of Public Health, Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Istvan Mucsi
- Department of Medicine, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Remi Rabasa-Lhoret
- Department of Nutrition, Faculty of Medicine, Montreal Clinical Research Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Valeria E. Rac
- Dalla Lana School of Public Health, Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
- Program for Health System and Technology Evaluation, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Peter Senior
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Ronald J. Sigal
- Departments of Medicine, Cardiac Sciences and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Aleksandra Stanimirovic
- Dalla Lana School of Public Health, Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
- Program for Health System and Technology Evaluation, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | | | | | - Alessandro Doria
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - David Z.I. Cherney
- Department of Medicine, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
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10
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Crispino SP, Segreti A, Nafisio V, Valente D, Crisci F, Ferro A, Cavallari I, Nusca A, Ussia GP, Grigioni F. The Role of SGLT2-Inhibitors Across All Stages of Heart Failure and Mechanisms of Early Clinical Benefit: From Prevention to Advanced Heart Failure. Biomedicines 2025; 13:608. [PMID: 40149587 PMCID: PMC11940307 DOI: 10.3390/biomedicines13030608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 02/24/2025] [Accepted: 02/27/2025] [Indexed: 03/29/2025] Open
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially developed as antihyperglycemic agents, have revolutionized heart failure (HF) management, offering substantial benefits across all stages and phenotypes of the disease. Regardless of left ventricular ejection fraction (LVEF), these agents have proven efficacy in both chronic and acute HF presentations. This review explores SGLT2i applications spanning the HF continuum, from early stages (Stage A) in at-risk individuals to the mitigation of progression in advanced HF (Stage D). Evidence from numerous trials has shown that SGLT2i significantly lower rates of HF hospitalization, improve renal function, and decreases cardiovascular mortality, highlighting their multifaced mechanisms of action in HF care. This review also highlights the potential mechanisms by which SGLT2i exert their beneficial effects on the cardiovascular and renal systems, each contributing to early and sustained clinical improvements. However, the integration of SGLT2i into guideline-directed medical therapy poses practical challenges, including initiation timing, dosing, and monitoring, which are addressed to support effective treatment adaptation across patient populations. Ultimately, this review provides a comprehensive assessment of SGLT2i as a foundational therapy in HF, emphasizing their role as an intervention across multiple stages aimed at improving outcomes across the entire HF spectrum.
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Affiliation(s)
- Simone Pasquale Crispino
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy; (S.P.C.); (V.N.); (D.V.); (F.C.); (A.F.); (I.C.); (A.N.); (G.P.U.); (F.G.)
| | - Andrea Segreti
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy; (S.P.C.); (V.N.); (D.V.); (F.C.); (A.F.); (I.C.); (A.N.); (G.P.U.); (F.G.)
- Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, 00135 Rome, Italy
| | - Vincenzo Nafisio
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy; (S.P.C.); (V.N.); (D.V.); (F.C.); (A.F.); (I.C.); (A.N.); (G.P.U.); (F.G.)
| | - Daniele Valente
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy; (S.P.C.); (V.N.); (D.V.); (F.C.); (A.F.); (I.C.); (A.N.); (G.P.U.); (F.G.)
| | - Filippo Crisci
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy; (S.P.C.); (V.N.); (D.V.); (F.C.); (A.F.); (I.C.); (A.N.); (G.P.U.); (F.G.)
| | - Aurora Ferro
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy; (S.P.C.); (V.N.); (D.V.); (F.C.); (A.F.); (I.C.); (A.N.); (G.P.U.); (F.G.)
| | - Ilaria Cavallari
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy; (S.P.C.); (V.N.); (D.V.); (F.C.); (A.F.); (I.C.); (A.N.); (G.P.U.); (F.G.)
| | - Annunziata Nusca
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy; (S.P.C.); (V.N.); (D.V.); (F.C.); (A.F.); (I.C.); (A.N.); (G.P.U.); (F.G.)
| | - Gian Paolo Ussia
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy; (S.P.C.); (V.N.); (D.V.); (F.C.); (A.F.); (I.C.); (A.N.); (G.P.U.); (F.G.)
| | - Francesco Grigioni
- Department of Cardiovascular Sciences, Fondazione Policlinico Campus Bio-Medico di Roma, 00128 Rome, Italy; (S.P.C.); (V.N.); (D.V.); (F.C.); (A.F.); (I.C.); (A.N.); (G.P.U.); (F.G.)
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11
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Hu H, Liu M, Fu Z, Li S, Wang K, Huang Z. The real-world safety profile of empagliflozin: a disproportionality analysis based on the FDA Adverse Event Reporting System (FAERS) database. BMC Pharmacol Toxicol 2025; 26:28. [PMID: 39920869 PMCID: PMC11806693 DOI: 10.1186/s40360-025-00861-y] [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: 11/22/2024] [Accepted: 01/27/2025] [Indexed: 02/09/2025] Open
Abstract
OBJECTIVE This study aimed to investigate the entire adverse events (AEs) spectrum and to identify some new or rare AEs associated with empagliflozin based on the FAERS database. METHODS A retrospective analysis was conducted on AE reports extracted from the FAERS, spanning from the first quarter of 2004 to that of 2023. Disproportionality analysis methods, including the ROR, PRR, BCPNN, and MGPS, were employed to quantify signals of AEs associated with empagliflozin. Additionally, demographic characteristics and time to onset were further elucidated. RESULTS The results showed a total of 20,734 AE reports related to empagliflozin, identifying 322 significant preferred terms (PTs) covering 27 System Organ Classes (SOCs). Empagliflozin was significantly associated with pre-specified AEs compared to other novel antidiabetic medications. Beyond common AEs, unexpected significant AEs such as pancreatitis, gastroenteritis, cerebral infarction, and cardiac operations were identified. The median onset time for empagliflozin-related AEs was 28 days (interquartile range (IQR) 4-154 days), with the majority of AE cases (n = 2,112, 10.19%) occurring within the first month following initiation of empagliflozin therapy. CONCLUSION The clinically observed AEs, along with potential new AE signals associated with empagliflozin were identified based on the FAERS database, which could provide valuable evidence for clinical monitoring, risk identification, and further safety studies of identification.
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Affiliation(s)
- Huiping Hu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Maochang Liu
- Department of Pharmacy, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Administrative Office, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiwen Fu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shijun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaiping Wang
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, Wuhan, China
| | - Zi Huang
- Department of Pharmacy, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, Wuhan, China.
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12
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Halperin IJ, Wicklow B, Amed S, Chambers A, Courage C, Cummings E, Kirkland P, MacKay D, Nakhla M, Punthakee Z, Ryan PM, Sawatsky L, Senior PA, Sidhu BS, Weisman A. Glycemic Management Across the Lifespan for People With Type 1 Diabetes: A Clinical Practice Guideline. Can J Diabetes 2025; 49:5-18. [PMID: 40155190 DOI: 10.1016/j.jcjd.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
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13
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Jones KE, Petersen MC, Markov AM, Salam M, Krutilova P, McKee AM, Bohnert KL, Adamson SE, McGill JB. Breath Acetone Correlates with Capillary β-hydroxybutyrate in Type 1 Diabetes. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.30.25321320. [PMID: 39974120 PMCID: PMC11838673 DOI: 10.1101/2025.01.30.25321320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Background Breath acetone (BrACE) is an end product of ketone metabolism that is measurable by noninvasive breath ketone analyzers. We assessed the correlation between capillary blood β-hydroxybutyrate (BOHB) and BrACE in people with type 1 diabetes (T1D) during 14 days of outpatient care with and without dapagliflozin treatment and during supervised insulin withdrawal studies with and without dapagliflozin. Methods In this randomized crossover study, participants completed 14-day two outpatient periods with or without dapagliflozin 10 mg daily. Each 14-day unsupervised outpatient period was followed by a one-day supervised insulin withdrawal study. Paired BOHB and BrACE measurements were obtained three times daily during outpatient periods, then hourly during supervised insulin withdrawal. The correlation between BrACE and BOHB was assessed by Spearman's ρ. Results Twenty people with T1D completed the study. During outpatient periods, BrACE and BOHB were moderately correlated (n=1425 paired readings; ρ = 0.41; 95% CI: 0.36 to 0.45; P < 0.0001). However, BrACE and BOHB were strongly correlated during insulin withdrawal (n=246 paired values, ρ = 0.81; 95% CI: 0.77 to 0.85). In ROC analysis, BrACE > 5 ppm demonstrated optimal sensitivity (93%) and specificity (87%) for detecting capillary BOHB ≥ 1.5 mmol/L. No serious adverse events occurred. Conclusions In adults with T1D, measurement of breath acetone provides a noninvasive estimate of blood BOHB concentration. The correlation between BrACE and BOHB was suboptimal during unsupervised outpatient care, but was strong during supervised insulin withdrawal.Trial registration: clinicaltrials.gov (NCT05541484).
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Affiliation(s)
- Kai E. Jones
- Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Max C. Petersen
- Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Alexander M. Markov
- Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Maamoun Salam
- Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Petra Krutilova
- Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Alexis M. McKee
- Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Kathryn L. Bohnert
- Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Samantha E. Adamson
- Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Janet B. McGill
- Division of Endocrinology, Metabolism, & Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
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14
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Liu Y, Yang S, Jiang A, Zou D, Chen Z, Su N. Risk of diabetic ketoacidosis caused by sodium glucose cotransporter-2 inhibitors in patients with type 1 diabetes: a systematic review and network meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne) 2025; 15:1453067. [PMID: 39957850 PMCID: PMC11826237 DOI: 10.3389/fendo.2024.1453067] [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: 06/22/2024] [Accepted: 12/03/2024] [Indexed: 02/18/2025] Open
Abstract
Background The benefits of sodium-glucose-cotransporter-2 (SGLT2) inhibitors in the treatment of type 1 diabetes mellitus (T1DM) have been demonstrated, but the occurrence of diabetic ketoacidosis (DKA) limits their use. The risk of DKA associated with different doses of SGLT2 inhibitous in the treatment of T1DM is unknown. We conducted a network meta-analysis to evaluate the incidence of DKA at different doses in the treatment of T1DM. Methods We searched electronic databases and clinical trial registries, including PubMed, Embase (Ovid SP), the Cochrane Central Register of Controlled Trials (Ovid SP), and ClinicalTrials.gov, for randomized controlled trials (RCTs) concerning SGLT2 inhibitors in patients with T1DM from inception to December 2023. Literature screening, quality assessment and data extraction were carried out independently by 2 researchers based on the inclusion and exclusion criteria, and statistical analysis was performed using Stata 15.1 software and R 4.1.3. Results Nineteen clinical studies and one clinical trial were ultimately included. The study involved five different SGLT2 inhibitors. The incidence of DKA in dapagliflozin 5 mg (OR: 2.57, 95% CI: 1.04 to 6.33; P<0.00001), empagliflozin 10 mg (OR: 2.68, 95% CI: 1.11 to 6.49; P<0.00001), sogliflozin 200mg (OR: 4.04, 95% CI: 1.15 to14.18; P<0.00001) and sogliflozin 400mg (OR: 5.96, 95% CI: 2.06 to17.20; P<0.00001) were higher than for the placebo. According to the P scores, SGLT2 inhibitors triggered a lower incidence of DKA than did the placebo. Treatment with 300 mg canagliflozin had the lowest incidence of DKA (P score = 0.8563). Conclusion According to our study, 5 mg dapagliflozin,10 mg empagliflozin 200mg sogliflozin and 400mg sogliflozin resulted in DKA when adjunctive insulin was used to treat T1DM. Other SGLT2 inhibitors seem to be safe. However, SGLT2 inhibitors for treating T1DM are off label in China, and adverse reactions should be closely monitored during administration. Systematic review registration https://www.crd.york.ac.uk/prospero/#loginpage, identifier CRD42023416227.
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Affiliation(s)
- Ying Liu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Shiwen Yang
- Department of Pharmacy, Jiangxi Mental Health Center, Nanchang, China
| | - Aidou Jiang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Dan Zou
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhaoyang Chen
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Na Su
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
- West China School of Pharmacy, Sichuan University, Chengdu, China
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15
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ElSayed NA, McCoy RG, Aleppo G, Balapattabi K, Beverly EA, Briggs Early K, Bruemmer D, Das SR, Echouffo-Tcheugui JB, Ekhlaspour L, Garg R, Khunti K, Kosiborod MN, Lal R, Lingvay I, Matfin G, Pandya N, Pekas EJ, Pilla SJ, Polsky S, Segal AR, Seley JJ, Stanton RC, Bannuru RR. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2025. Diabetes Care 2025; 48:S207-S238. [PMID: 39651970 PMCID: PMC11635050 DOI: 10.2337/dc25-s010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2024]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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16
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Popovic DS, Patoulias D, Koufakis T, Karakasis P, Papanas N. Sodium-Glucose Co-transporter-2 Inhibitors in Type 1 Diabetes Mellitus: The Framework for Recommendations for Their Potential Use. Diabetes Ther 2024; 15:2445-2453. [PMID: 39412607 PMCID: PMC11561202 DOI: 10.1007/s13300-024-01657-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 09/24/2024] [Indexed: 11/14/2024] Open
Abstract
The growing prevalence of overweight/obesity, the persistence of inadequate glycemic control among the majority of affected individuals, and the still unacceptably high risk of cardiovascular morbidity and mortality among population with type 1 diabetes mellitus (T1D), impose an urgent need for the introduction of non-insulin glucose-lowering agents in the therapeutic armamentarium. Given that their antihyperglycemic mechanism of action is independent of endogenous insulin secretion and that the observed cardio-renal benefits are unrelated to their glucose-lowering properties, one can speculate that the use of sodium-glucose co-transporter-2 inhibitors (SGLT2is) could provide benefits in T1D, similar to the ones observed among individuals with type 2 diabetes mellitus, chronic kidney disease (CKD), and heart failure. Available evidence from randomized controlled trials suggests that treatment with SGLT2is as adjunct to insulin in T1D results in modest reductions in glycated hemoglobin and body weight. Additionally, SGLT2is ameliorate albuminuria, and thus delay or prevent the development of CKD in T1D. However, use of SGLT2is is associated with an increased risk of diabetic ketoacidosis (DKA) in T1D. This commentary aims at providing a framework for practical recommendations regarding the potential use of SGLT2is in adults with T1D, based on the individual's risk level for DKA development, the presence of inadequate glycemic control and related cardio-renal complications.
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Affiliation(s)
- Djordje S Popovic
- Medical Faculty, Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, University of Novi Sad, Novi Sad, Serbia
| | - Dimitrios Patoulias
- Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Theocharis Koufakis
- Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paschalis Karakasis
- Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Papanas
- Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece.
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17
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Spellman MJ, Assaf T, Nangia S, Fernandez J, Nicholson KC, Shepard BD. Handling the sugar rush: the role of the renal proximal tubule. Am J Physiol Renal Physiol 2024; 327:F1013-F1025. [PMID: 39447117 PMCID: PMC11687834 DOI: 10.1152/ajprenal.00265.2024] [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: 09/11/2024] [Revised: 10/21/2024] [Accepted: 10/24/2024] [Indexed: 10/26/2024] Open
Abstract
Blood glucose homeostasis is critical to ensure the proper functioning of the human body. Through the processes of filtration, reabsorption, secretion, and metabolism, much of this task falls to the kidneys. With a rise in glucose and other added sugars, there is an increased burden on this organ, mainly the proximal tubule, which is responsible for all glucose reabsorption. In this review, we focus on the current physiological and cell biological functions of the renal proximal tubule as it works to reabsorb and metabolize glucose and fructose. We also highlight the physiological adaptations that occur within the proximal tubule as sugar levels rise under pathophysiological conditions including diabetes. This includes the detrimental impacts of an excess glucose load that leads to glucotoxicity. Finally, we explore some of the emerging therapeutics that modulate renal glucose handling and the systemic protection that can be realized by targeting the reabsorptive properties of the kidney.
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Affiliation(s)
- Michael J Spellman
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Tala Assaf
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Shivani Nangia
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Joel Fernandez
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Kyle C Nicholson
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Blythe D Shepard
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
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Janić M, Janež A, Šabović M, El-Tanani M, Rangraze I, Rizzo M, Lunder M. Glucometabolic Efficacy of the Empagliflozin/Metformin Combination in People with Type 1 Diabetes and Increased Cardiovascular Risk: A Sub-Analysis of a Pilot Randomized Controlled Trial. J Clin Med 2024; 13:6860. [PMID: 39598003 PMCID: PMC11594502 DOI: 10.3390/jcm13226860] [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: 10/10/2024] [Revised: 11/08/2024] [Accepted: 11/12/2024] [Indexed: 11/29/2024] Open
Abstract
Background/Objectives: People with type 1 diabetes have an unmet need for cardiovascular protection due to the lack of new recommended antidiabetic therapies with cardiovascular benefits. We examined whether the addition of an empagliflozin/metformin combination, and each drug alone, can complement insulin to improve glucometabolic parameters in overweight people with type 1 diabetes at high cardiovascular risk. Methods: This pilot, single-center double-blind randomized controlled trial included 40 people with type 1 diabetes. In addition to insulin, they received empagliflozin (25 mg daily), metformin (2000 mg daily), an empagliflozin/metformin combination, or a placebo. The intervention period was 12 weeks. Glycemic parameters, insulin requirements, and blood and urine samples were analyzed. Indices for liver fibrosis were calculated. Due to potential safety concerns, participants regularly measured blood ketone values. Results: The empagliflozin/metformin combination decreased HbA1c (-0.6%, p < 0.05) and weight (-6.1 kg, p < 0.05). Empagliflozin decreased the urinary albumin-to-creatinine ratio (-31.4 ± 4.9%, p = 0.002). The empagliflozin/metformin combination and empagliflozin decreased the estimated daily proteinuria (-34.6 ± 5.0%, p = 0.006 and -35.9 ± 6.2%, p = 0.03, respectively), the calculated FIB-4 (up to -17.8 ± 5.2%, p = 0.04 and -10.7 ± 3.7%, p = 0.02, respectively), and other liver fibrosis indices and uric acid values. No significant side effects occurred during the study. Conclusions: The empagliflozin/metformin combination improved glycemic control, reduced weight and insulin requirements, and produced several additional beneficial metabolic effects in overweight people with type 1 diabetes with increased cardiovascular risk.
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Affiliation(s)
- Miodrag Janić
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.J.); (M.L.)
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
- School of Medicine, Promise Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, 90133 Palermo, Italy;
| | - Andrej Janež
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.J.); (M.L.)
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
| | - Mišo Šabović
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
- Department of Vascular Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
| | - Mohamed El-Tanani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates;
| | - Imran Rangraze
- Internal Medicine Department, Ras Al Khaimah College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates;
| | - Manfredi Rizzo
- School of Medicine, Promise Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, 90133 Palermo, Italy;
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates;
| | - Mojca Lunder
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (A.J.); (M.L.)
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
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19
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Mu Y, Luo LB, Huang R, Shen ZY, Huang D, Zhao SH, Yang J, Ma ZG. Cardiac-derived CTRP9 mediates the protection of empagliflozin against diabetes-induced male subfertility in mice. Clin Sci (Lond) 2024; 138:1421-1440. [PMID: 39392219 DOI: 10.1042/cs20241477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 10/12/2024]
Abstract
Previous studies have shown beneficial effects of empagliflozin (Empa), a selective inhibitor of the sodium-glucose cotransporter 2 (SGLT2), on diabetes and cardiovascular outcomes in patients with diabetes. However, whether Empa could ameliorate diabetes mellitus (DM)-induced male spermatogenesis dysfunction remains unclear. Our study aimed to investigate the effect of Empa in the development of DM-induced male spermatogenesis dysfunction and to reveal the molecular mechanisms. DM mice were orally treated with Empa to investigate the effects of Empa on DM-induced male mice spermatogenesis dysfunction. We employed a cardiac-specific C1q/tumor necrosis factor-related protein 9 (CTRP9)-deficient mouse model and a cardiac-specific CTRP9 overexpression mouse model to investigate its role in the protection of Empa against diabetes-induced male subfertility. We found that Empa treatment could improve DM-induced male mice subfertility. Interestingly, we discovered that cardiac-derived CTRP9 was decreased in DM mice and this decrease was prevented by Empa treatment. A CTRP9 blocking antibody or cardiac-specific depletion of CTRP9 abolished the protection of Empa on DM-induced male subfertility. Cardiac-specific CTRP9 overexpression ameliorated DM-induced male subfertility. Mechanistically, we identified that cardiac-derived CTRP9 increased steroidogenesis in mice with diabetes in a PKA-dependent manner. We also provided direct evidence that activation of AMP activated protein kinase α (AMPKα)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signalling pathway by CTRP9 was responsible for the attenuation of ferroptosis in Leydig cells. In conclusions, we supposed that Empa was a potential therapeutic agent against DM-induced male mice spermatogenesis dysfunction.
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Affiliation(s)
- Yang Mu
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Ling-Bo Luo
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Rong Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Zhuo-Yu Shen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Dan Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Shu-Hong Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
| | - Jing Yang
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Zhen-Guo Ma
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
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20
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Rotbain Curovic V, Stougaard EB, Hansen TW. Slowing the progression of diabetic and non-diabetic kidney disease: A summary of the current evidence base for sodium-glucose co-transporter-2 inhibitors. Diabetes Obes Metab 2024; 26 Suppl 6:22-32. [PMID: 39410663 DOI: 10.1111/dom.16007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/25/2024]
Abstract
The global prevalence of chronic kidney disease (CKD) is approximately 9%. CKD is predicted to become the fifth largest global cause of death by 2040. Moreover, CKD causes disability, diminished quality of life and poses a high cost to healthcare systems. Delaying the development and progression of CKD is therefore of the utmost importance. Several kidney-specific outcome trials on sodium-glucose co-transporter-2 inhibitors (SGLT-2s) have recently provided a paradigm shift in the treatment of people with CKD, with or without diabetes, as these agents have been shown to reduce the progression of CKD on top of maximally tolerated renin-angiotensin-aldosterone system (RAAS) blockade. The relative benefit and safety of SGLT-2is seems to be consistent across ethnicities, ages and frailty categories; however, this needs to be tested in dedicated clinical trials. Guidelines make clear recommendations for the prescription of SGLT-2is and RAAS inhibitors as standard of care for people with CKD. Their combination with other newer antidiabetic agents may provide further benefits by targeting different components of CKD mechanisms. Dedicated randomized controlled trials are needed to test whether combination with other agents could extend the use of SGLT2is and identify people in whom a combination of drugs may be most effective. Increased efforts to implement the guidelines on treatment with SGLT-2is for people with CKD are needed, particularly in those at the highest risk of adverse outcomes and without type 2 diabetes. Moreover, strategies to target the equitable use of SGLT-2is are needed.
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Affiliation(s)
| | | | - Tine Willum Hansen
- Steno Diabetes Centre Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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21
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Geng L, Sun B, Chen Y. A meta-analysis of randomized controlled studies examining the effects of sodium-glucose co-transporter-2 inhibitors on peripheral artery disease and risk of amputations. Diabetes Obes Metab 2024; 26:5376-5389. [PMID: 39267269 DOI: 10.1111/dom.15901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 08/09/2024] [Accepted: 08/10/2024] [Indexed: 09/17/2024]
Abstract
AIM Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are used to maintain glycaemic control as well as for their beneficial cardiovascular and renal effects in diabetes patients. However, increased risk of amputation and peripheral artery disease (PAD) have been observed with the use of some SGLT-2is. A meta-analysis was conducted to understand the effect of SGLT-2is on amputation and PAD events using data from randomized controlled trials (RCT). MATERIALS AND METHODS A systematic literature review was conducted using Medline and Central databases for RCTs that involved the administration of SGLT-2is versus placebo/active comparators to diabetic patients. The primary outcome was amputation events and PAD. A random-effects model was used to calculate the pooled odds ratio, and subgroup analyses was performed. RESULTS A total of 51 RCTs were included in the meta-analysis with data from 97 589 patients. Meta-analysis of the data showed that there was a significant increase in PAD risk (p = 0.04) but no significant increase in amputation risk with SGLT-2i use versus placebo/active comparators (p = 0.43). Subgroup analyses demonstrated no significant difference between SGLT-2i type, duration of treatment or patient risk factors on amputation or PAD incidence. However, length of drug treatment (> 100 weeks) was associated with a significant increase in both PAD and amputation risks in the SGLT-2i treatment groups. CONCLUSIONS The results of the meta-analysis showed no significant association between SGLT-2i use and PAD and amputation risks in diabetic patients when used for shorter treatment durations.
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Affiliation(s)
- Li Geng
- Department of Vascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Bing Sun
- Department of Neurology, Changchun Central Hospital, Changchun, China
| | - Yan Chen
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun, China
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22
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Suganuma Y, Ishiguro M, Ohno T, Nishimura R. Elevated urinary albumin predicts increased time in range after initiation of SGLT2 inhibitors in individuals with type 1 diabetes on sensor-augmented pump therapy. Diabetol Int 2024; 15:806-813. [PMID: 39469555 PMCID: PMC11512966 DOI: 10.1007/s13340-024-00743-4] [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: 02/21/2024] [Accepted: 06/10/2024] [Indexed: 10/30/2024]
Abstract
Aims We aimed to investigate potential predictors of effectiveness of SGLT2 inhibitors (SGLT2i) in individuals with type 1 diabetes (T1D) on sensor-augmented pump (SAP) therapy. Methods We included individuals with T1D receiving SAP therapy at our hospital who were newly initiated on SGLT2i between 2019 and 2020 and were followed for at least 1 year. Data on BMI, blood tests, and continuous glucose monitoring (CGM) were compared before and 12 months after initiation of SGLT2i. Predictors of incremental increases in time in range (ΔTIR) were explored using a multiple regression analysis. Cutoff values for the predictors were determined using an ROC curve analysis. Results A total of 17 individuals (females, 70.6%; median age, 44.0 years) were included, excluding three individuals who discontinued SGLT2i due to side effects. During follow-up, their median BMI decreased significantly (P = 0.013), while no significant change was seen in their total daily dose of insulin, basal-to-total insulin ratio. Again, their HbA1c, TIR, and time above range (TAR) improved significantly (P = 0.004, P = 0.003, and P = 0.003, respectively), while their time below range (TBR) showed no significant change. The predictor of increased ΔTIR was high urinary albumin-to-creatinine ratio (UACR) at baseline (P = 0.026) only, with the cutoff value determined to be 28.0 mg/g Cr or higher (AUC = 0.82, P = 0.003). Conclusions It may be suggested that individuals with T1D on SAP therapy and having near-microalbuminuria or higher could be expected to show significant improvement in TIR. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-024-00743-4.
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Affiliation(s)
- Yuka Suganuma
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo, 105-8461 Japan
| | - Mizuki Ishiguro
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo, 105-8461 Japan
| | - Takayuki Ohno
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo, 105-8461 Japan
| | - Rimei Nishimura
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo, 105-8461 Japan
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23
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Cheng Y, Li H, Liu X, Jin X, Han J, Du J, Xu C. Exploring the influencing factors of non-insulin drug prescriptions in discharged patients with type 1 diabetes. Front Endocrinol (Lausanne) 2024; 15:1381248. [PMID: 39398332 PMCID: PMC11467696 DOI: 10.3389/fendo.2024.1381248] [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: 02/03/2024] [Accepted: 08/09/2024] [Indexed: 10/15/2024] Open
Abstract
Objective The aim of this study was to evaluate the admission indicators and characteristics of individuals diagnosed with type 1 diabetes (T1D) to ascertain potential impact on the choice of glucose control therapy after discharge. Methods A total of 398 eligible T1D patients were selected. We conducted multivariable logistic regression analysis to determine the independent influence of predictors on the selection of glucose control therapy after discharge. To explore the influencing factors of different subgroups, we additionally performed subgroup analyses based on gender and age. Results Our study revealed that body mass index (BMI) was noteworthy influence factor for prescription of insulin and non-insulin antidiabetic drug (NIAD prescription) in T1D patients of general population [OR = 1.109 (1.033-1.195), p = 0.006], male [OR = 1.166 (1.040-1.318), p = 0.011] and individuals below the age of 30 years [OR = 1.146 (1.020-1.301), p = 0.028]. Diastolic blood pressure (DBP) was a protective factor for NIAD prescription in the general population [OR = 0.971 (0.949-0.992), p = 0.008] and women [OR = 0.955 (0.923-0.988), p = 0.008]. The other risk factor of NIAD prescription in men was dyslipidemia [OR = 4.824 (1.442-22.246), p = 0.020]. Pulse pressure [OR = 1.036 (1.007-1.068), p = 0.016] constituted an additional risk factor of NIAD prescription among individuals below the age of 30 years. The risk factors of NIAD prescription for people aged 30 to 50 years were length of stay [OR = 1.097 (1.014-1.196), p = 0.026] and initial blood glucose [OR = 1.078 (1.007-1.168), p = 0.047]. In the case of individuals aged above 50 years, physicians exhibited a higher tendency to prescribe supplementary non-insulin medications to men [OR = 9.385 (1.501-87.789), p = 0.029]. Conclusions We identified notable factors that influence discharge prescriptions in patients with T1D. In order to enhance the treatment outcome for the patient, clinicians ought to have a special focus on these indicators or factors.
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Affiliation(s)
- Yikang Cheng
- The First Clinical Institute, Zunyi Medical University, Zunyi, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Haizhen Li
- Department of Endocrinology, Dongying City District People Hospital, Dongying, China
| | - Xin Liu
- Department of Endocrinology and Metabolism, Dongying People's Hospital, Dongying, China
| | - Xiaolong Jin
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Junming Han
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jing Du
- Department of Endocrinology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, China
| | - Chao Xu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, China
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Boeder S, Davies MJ, McGill JB, Pratley R, Girard M, Banks P, Pettus J, Garg S. Beta-Hydroxybutyrate Levels and Risk of Diabetic Ketoacidosis in Adults with Type 1 Diabetes Treated with Sotagliflozin. Diabetes Technol Ther 2024; 26:618-625. [PMID: 38441906 PMCID: PMC11535465 DOI: 10.1089/dia.2023.0605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/14/2024]
Abstract
Introduction: Sodium glucose cotransporter inhibitors may increase beta-hydroxybutyrate (BHB) in insulin-requiring patients. We determined factors associated with BHB changes from baseline (ΔBHB) and diabetic ketoacidosis (DKA) in patients with type 1 diabetes (T1D) receiving sotagliflozin as an insulin adjunct. Research Design and Methods: This post hoc analysis compared ΔBHB levels in adults with T1D receiving sotagliflozin 400 mg or placebo for 6 months. We evaluated clinical and metabolic factors associated with ΔBHB and used logistic regression models to determine predictors associated with BHB values >0.6 and >1.5 mmol/L (inTandem3 population; N = 1402) or with DKA events in a pooled analysis (inTandem1-3; N = 2453). Results: From baseline (median, 0.13 mmol/L), median fasting BHB increased by 0.04 mmol/L (95% confidence interval, 0.03-0.05; P < 0.001) at 24 weeks with sotagliflozin versus placebo; 67% of patients had no or minimal changes in BHB over time. Factors associated with on-treatment BHB >0.6 or >1.5 mmol/L included baseline BHB and sotagliflozin use. Age, insulin pump use, sotagliflozin use, baseline BHB, and ΔBHB were significantly associated with DKA episodes. Independent of treatment, DKA risk increased by 18% with each 0.1-mmol/L increase in baseline BHB and by 8% with each 0.1-mmol/L increase from baseline. Conclusion: Incremental increases in baseline BHB and ΔBHB were associated with a higher DKA risk independent of treatment. Adding sotagliflozin to insulin increased median BHB over 24 weeks in patients with T1D and was associated with increased DKA events. These results highlight the importance of BHB testing and monitoring and individualizing patient education on DKA risk, mitigation, identification, and treatment.
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Affiliation(s)
- Schafer Boeder
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | | | - Janet B. McGill
- Division of Endocrinology, Metabolism and Lipid Research, John T. Milliken Department of Medicine, Washington University, St. Louis, Missouri, USA
| | - Richard Pratley
- AdventHealth Translational Research Institute, Orlando, Florida, USA
| | - Manon Girard
- Lexicon Pharmaceuticals, Inc., The Woodlands, Texas, USA
| | - Phillip Banks
- Lexicon Pharmaceuticals, Inc., The Woodlands, Texas, USA
| | - Jeremy Pettus
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Satish Garg
- Barbara Davis Center for Diabetes at the University of Colorado Denver, Aurora, Colorado, USA
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25
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Mazzotta FA, Lucaccini Paoli L, Rizzi A, Tartaglione L, Leo ML, Popolla V, Barberio A, Viti L, Di Leo M, Pontecorvi A, Pitocco D. Unmet needs in the treatment of type 1 diabetes: why is it so difficult to achieve an improvement in metabolic control? Nutr Diabetes 2024; 14:58. [PMID: 39095349 PMCID: PMC11297181 DOI: 10.1038/s41387-024-00319-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 07/17/2024] [Accepted: 07/23/2024] [Indexed: 08/04/2024] Open
Abstract
The development of advanced diabetes technology has permitted persons with type 1 diabetes mellitus to improve metabolic control significantly, particularly with the development of advanced hybrid closed-loop systems which have improved the quality of life by reducing hypoglycemia, decreasing macroangiopathy and microangiopathy-related complications, ameliorating HbA1c and improving glycemic variability. Despite the progression made over the past few decades, there is still significant margin for improvement to be made in terms of attaining appropriate metabolic control. Various factors are responsible for poor glycemic control including inappropriate carbohydrate counting, repeated bouts of hypoglycemia, hypoglycemia unawareness, cutaneous manifestations due to localized insulin use and prolonged use of diabetes technology, psychosocial comorbidities such as eating disorders or 'diabulimia', the coexistence of insulin resistance among people with type 1 diabetes and the inability to mirror physiological endogenous pancreatic insulin secretion appropriately. Hence, the aim of this review is to highlight and overcome the barriers in attaining appropriate metabolic control among people with type 1 diabetes by driving research into adjunctive treatment for coexistent insulin resistance and developing new advanced diabetic technologies to preserve β cell function and mirror as much as possible endogenous pancreatic functions.
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Affiliation(s)
- Francesco Antonio Mazzotta
- Department of Endocrinology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Lorenzo Lucaccini Paoli
- Department of Endocrinology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
| | - Alessandro Rizzi
- Diabetes Care Unit, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Linda Tartaglione
- Diabetes Care Unit, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Maria Laura Leo
- Department of Endocrinology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Valentina Popolla
- Diabetes Care Unit, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Annarita Barberio
- Department of Internal Medicine, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Luca Viti
- Diabetes Care Unit, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Mauro Di Leo
- Diabetes Care Unit, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Alfredo Pontecorvi
- Department of Endocrinology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Dario Pitocco
- Diabetes Care Unit, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
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Templer S, Abdo S, Wong T. Preventing diabetes complications. Intern Med J 2024; 54:1264-1274. [PMID: 39023283 DOI: 10.1111/imj.16455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 05/23/2024] [Indexed: 07/20/2024]
Abstract
The key aim of diabetes management is to prevent complications, which are a major cause of morbidity and mortality. At an individual level, people with diabetes are less likely than they were several decades ago to experience classical macrovascular and microvascular complications as a result of improvements in modifiable cardiovascular risk factors and preventive healthcare. However, a significant burden of diabetes complications persists at a population level because of the increasing incidence of diabetes, as well as longer lifetime exposure to diabetes because of younger diagnosis and increased life expectancy. Trials have shown that the most effective strategy for preventing complications of diabetes is a multifactorial approach focussing simultaneously on the management of diet, exercise, glucose levels, blood pressure and lipids. In addition to the cornerstone strategies of addressing diet, exercise and lifestyle measures, the introduction of newer glucose-lowering agents, including sodium-glucose transport protein 2 inhibitors and glucagon-like peptide-1 agonists, have brought about a paradigm shift in preventing the onset and progression of complications of type 2 diabetes, particularly cardiovascular and renal disease. The improvement in rates of classical complications of diabetes over time has been accompanied by a growing awareness of non-traditional complications, including non-alcoholic fatty liver disease. These emerging complications may not respond to a glycaemic-centred approach alone and highlight the importance of foundational strategies centred on lifestyle measures and supported by pharmaceutical therapy to achieve weight loss and reduce metabolic risk in patients living with diabetes.
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Affiliation(s)
- Sophie Templer
- Department of Endocrinology, Bankstown-Lidcombe Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Sarah Abdo
- Department of Endocrinology, Bankstown-Lidcombe Hospital, Sydney, New South Wales, Australia
- School of Medicine, Western Sydney University, Sydney, New South Wales, Australia
| | - Tang Wong
- Department of Endocrinology, Bankstown-Lidcombe Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- School of Medicine, Western Sydney University, Sydney, New South Wales, Australia
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27
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Zhang J, Li Y, Yang L, Ma N, Qian S, Chen Y, Duan Y, Xiang X, He Y. New advances in drug development for metabolic dysfunction-associated diseases and alcohol-associated liver disease. Cell Biosci 2024; 14:90. [PMID: 38971765 PMCID: PMC11227172 DOI: 10.1186/s13578-024-01267-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/19/2024] [Indexed: 07/08/2024] Open
Abstract
Metabolic disorders are currently threatening public health worldwide. Discovering new targets and developing promising drugs will reduce the global metabolic-related disease burden. Metabolic disorders primarily consist of lipid and glucose metabolic disorders. Specifically, metabolic dysfunction-associated steatosis liver disease (MASLD) and alcohol-associated liver disease (ALD) are two representative lipid metabolism disorders, while diabetes mellitus is a typical glucose metabolism disorder. In this review, we aimed to summarize the new drug candidates with promising efficacy identified in clinical trials for these diseases. These drug candidates may provide alternatives for patients with metabolic disorders and advance the progress of drug discovery for the large disease burden.
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Affiliation(s)
- Jinming Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yixin Li
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, 230001, Anhui, China
| | - Liu Yang
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ningning Ma
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Shengying Qian
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yingfen Chen
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yajun Duan
- Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, 230001, Anhui, China.
| | - Xiaogang Xiang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Yong He
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, China.
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van Raalte DH, Bjornstad P, Cherney DZI, de Boer IH, Fioretto P, Gordin D, Persson F, Rosas SE, Rossing P, Schaub JA, Tuttle K, Waikar SS, Heerspink HJL. Combination therapy for kidney disease in people with diabetes mellitus. Nat Rev Nephrol 2024; 20:433-446. [PMID: 38570632 DOI: 10.1038/s41581-024-00827-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/29/2024] [Indexed: 04/05/2024]
Abstract
Diabetic kidney disease (DKD), defined as co-existing diabetes and chronic kidney disease in the absence of other clear causes of kidney injury, occurs in approximately 20-40% of patients with diabetes mellitus. As the global prevalence of diabetes has increased, DKD has become highly prevalent and a leading cause of kidney failure, accelerated cardiovascular disease, premature mortality and global health care expenditure. Multiple pathophysiological mechanisms contribute to DKD, and single lifestyle or pharmacological interventions have shown limited efficacy at preserving kidney function. For nearly two decades, renin-angiotensin system inhibitors were the only available kidney-protective drugs. However, several new drug classes, including sodium glucose cotransporter-2 inhibitors, a non-steroidal mineralocorticoid antagonist and a selective endothelin receptor antagonist, have now been demonstrated to improve kidney outcomes in people with type 2 diabetes mellitus. In addition, emerging preclinical and clinical evidence of the kidney-protective effects of glucagon-like-peptide-1 receptor agonists has led to the prospective testing of these agents for DKD. Research and clinical efforts are geared towards using therapies with potentially complementary efficacy in combination to safely halt kidney disease progression. As more kidney-protective drugs become available, the outlook for people living with DKD should improve in the next few decades.
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Affiliation(s)
- Daniël H van Raalte
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, VUMC, Amsterdam, The Netherlands.
- Diabetes Center, Amsterdam University Medical Centers, VUMC, Amsterdam, The Netherlands.
- Research Institute for Cardiovascular Sciences, VU University, Amsterdam, The Netherlands.
| | - Petter Bjornstad
- University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Ian H de Boer
- Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, Washington, USA
| | - Paola Fioretto
- Department of Medicine, University of Padua, Unit of Medical Clinic 3, Padua, Italy
| | - Daniel Gordin
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Sylvia E Rosas
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Jennifer A Schaub
- Nephrology Division, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Katherine Tuttle
- Providence Medical Research Center, Providence Inland Northwest Health, Spokane, Washington, USA
- Department of Medicine, University of Washington School of Medicine, Spokane and Seattle, Washington, USA
- Nephrology Division, Kidney Research Institute and Institute of Translational Health Sciences, University of Washington, Spokane and Seattle, Washington, USA
| | - Sushrut S Waikar
- Section of Nephrology, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- The George Institute for Global Health, Sydney, New South Wales, Australia
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29
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Kugathasan L, Sridhar VS, Lytvyn Y, Lovblom LE, Perkins BA, Advani A, Cherney DZI. Effect of hyperglycemia and empagliflozin on markers of cardiorenal injury and inflammation in patients with type 1 diabetes. Diabetes Res Clin Pract 2024; 213:111764. [PMID: 38960044 DOI: 10.1016/j.diabres.2024.111764] [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: 04/16/2024] [Revised: 06/19/2024] [Accepted: 07/01/2024] [Indexed: 07/05/2024]
Abstract
AIMS To investigate the effect of hyperglycemia and empagliflozin on cardiorenal injury and inflammation in patients with uncomplicated type 1 diabetes (T1D). METHODS Serum cardiac (sST2, Gal-3, cTnT), kidney injury (KIM-1, NGAL), inflammatory (sTNFR1, sTNFR2), and hemodynamic (NT-proBNP, EPO) markers were assessed post-hoc in two separate T1D cohorts. The glycemic clamp trial (NCT02344602) evaluated 49 adults with T1D and 27 controls under euglycemic and acute hyperglycemic conditions. The crossover BETWEEN trial (NCT02632747) investigated empagliflozin 25 mg plus ramipril for 4 weeks compared to placebo-ramipril for 4 weeks in 30 adults with T1D. RESULTS In the glycemic clamp study, hyperglycemia acutely increased levels of NT-proBNP (p = 0.0003) and sTNFR2 (p = 0.003). BETWEEN participants treated with empagliflozin exhibited a paradoxical subacute rise in NT-proBNP (p = 0.0147) compared to placebo, independent of hematocrit. Individuals with higher baseline levels of sST2 and sTNFR1 had greater empagliflozin-associated reductions in systolic blood pressure and greater activation of renin-angiotensin-aldosterone system (RAAS) mediators, whereas those with higher baseline levels of KIM-1 and sTNFR1 had greater glomerular filtration rate (GFR) dip. CONCLUSION The protective mechanisms of SGLT2 inhibition on blood pressure, RAAS activation, and renal hemodynamics are apparent in the subset of people with uncomplicated T1D with adverse cardiorenal and inflammatory markers.
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Affiliation(s)
- Luxcia Kugathasan
- Department of Medicine, Division of Nephrology, University Health Network, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada; Temerty Faculty of Medicine, University of Toronto, 2109 Medical Sciences Building, 1 King's College Cir, Toronto, Ontario M5S 1A8, Canada; Cardiovascular Sciences Collaborative Specialization, University of Toronto, 263 McCaul St, P.O. Box 3C, 4th Floor, Rm 413, Toronto, Ontario M5T 1W7, Canada.
| | - Vikas S Sridhar
- Department of Medicine, Division of Nephrology, University Health Network, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada; Temerty Faculty of Medicine, University of Toronto, 2109 Medical Sciences Building, 1 King's College Cir, Toronto, Ontario M5S 1A8, Canada.
| | - Yuliya Lytvyn
- Department of Medicine, Division of Nephrology, University Health Network, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada; Temerty Faculty of Medicine, University of Toronto, 2109 Medical Sciences Building, 1 King's College Cir, Toronto, Ontario M5S 1A8, Canada.
| | - Leif Erik Lovblom
- Biostatistics Department, University Health Network, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada.
| | - Bruce A Perkins
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Ave Toronto, Ontario M5G 1X5, Canada; Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, 6 Queen's Park Crescent West, Third Floor, Toronto, Ontario M5S 3H2, Canada.
| | - Andrew Advani
- Temerty Faculty of Medicine, University of Toronto, 2109 Medical Sciences Building, 1 King's College Cir, Toronto, Ontario M5S 1A8, Canada; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St Michael's Hospital, 209 Victoria St, Toronto, Ontario M5B 1T8, Canada.
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada; Temerty Faculty of Medicine, University of Toronto, 2109 Medical Sciences Building, 1 King's College Cir, Toronto, Ontario M5S 1A8, Canada; Cardiovascular Sciences Collaborative Specialization, University of Toronto, 263 McCaul St, P.O. Box 3C, 4th Floor, Rm 413, Toronto, Ontario M5T 1W7, Canada.
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30
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Moon JS, Kang S, Choi JH, Lee KA, Moon JH, Chon S, Kim DJ, Kim HJ, Seo JA, Kim MK, Lim JH, Song YJ, Yang YS, Kim JH, Lee YB, Noh J, Hur KY, Park JS, Rhee SY, Kim HJ, Kim HM, Ko JH, Kim NH, Kim CH, Ahn J, Oh TJ, Kim SK, Kim J, Han E, Jin SM, Bae J, Jeon E, Kim JM, Kang SM, Park JH, Yun JS, Cha BS, Moon MK, Lee BW. 2023 Clinical Practice Guidelines for Diabetes Management in Korea: Full Version Recommendation of the Korean Diabetes Association. Diabetes Metab J 2024; 48:546-708. [PMID: 39091005 PMCID: PMC11307112 DOI: 10.4093/dmj.2024.0249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 06/20/2024] [Indexed: 08/04/2024] Open
Affiliation(s)
- Jun Sung Moon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Shinae Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Han Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Kyung Ae Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju, Korea
| | - Joon Ho Moon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Suk Chon
- Department of Endocrinology and Metabolism, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University Hospital, Ajou University School of Medicine, Suwon, Korea
| | - Hyun Jin Kim
- Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Korea
| | - Ji A Seo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Mee Kyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Hyun Lim
- Department of Food Service and Nutrition Care, Seoul National University Hospital, Seoul, Korea
| | - Yoon Ju Song
- Department of Food Science and Nutrition, The Catholic University of Korea, Bucheon, Korea
| | - Ye Seul Yang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Hyeon Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - You-Bin Lee
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Junghyun Noh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Kyu Yeon Hur
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong Suk Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Youl Rhee
- Department of Endocrinology and Metabolism, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University Hospital, Ajou University School of Medicine, Suwon, Korea
| | - Hyun Min Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Jung Hae Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Nam Hoon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Chong Hwa Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea
| | - Jeeyun Ahn
- Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Tae Jung Oh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Soo-Kyung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Jaehyun Kim
- Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Eugene Han
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Sang-Man Jin
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jaehyun Bae
- Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea
| | - Eonju Jeon
- Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea
| | - Ji Min Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Seon Mee Kang
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Jung Hwan Park
- Division of Endocrinology & Metabolism, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Jae-Seung Yun
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Bong-Soo Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Min Kyong Moon
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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31
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Annicchiarico A, Barile B, Buccoliero C, Nicchia GP, Brunetti G. Alternative therapeutic strategies in diabetes management. World J Diabetes 2024; 15:1142-1161. [PMID: 38983831 PMCID: PMC11229975 DOI: 10.4239/wjd.v15.i6.1142] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/17/2024] [Accepted: 04/12/2024] [Indexed: 06/11/2024] Open
Abstract
Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreatic β cells, insulin resistance in peripheral tissues, or both, and results in a non-sufficient production of insulin. To adjust blood glucose levels, diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity. With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities, different strategies have been investigated. The first approaches included enhancing endogenous β cell activity or transplanting new islets. The protocol for this kind of intervention has recently been optimized, leading to standardized procedures. It is indicated for diabetic patients with severe hypoglycemia, complicated by impaired hypoglycemia awareness or exacerbated glycemic lability. Transplantation has been associated with improvement in all comorbidities associated with diabetes, quality of life, and survival. However, different trials are ongoing to further improve the beneficial effects of transplantation. Furthermore, to overcome some limitations associated with the availability of islets/pancreas, alternative therapeutic strategies are under evaluation, such as the use of mesenchymal stem cells (MSCs) or induced pluripotent stem cells for transplantation. The cotransplantation of MSCs with islets has been successful, thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms, including exosome release. The use of induced pluripotent stem cells is recent and requires further investigation. The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities, such as wound healing. Despite the number of advantages of the direct injection of MSCs, new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results. In conclusion, this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.
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Affiliation(s)
- Alessia Annicchiarico
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Barbara Barile
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Cinzia Buccoliero
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Grazia Paola Nicchia
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
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32
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Peter PR, Inzucchi SE. Use of Sodium-Glucose Cotransporter Inhibitors in Type 1 Diabetes: The Promise and the Perils. Endocr Pract 2024; 30:577-583. [PMID: 38548175 DOI: 10.1016/j.eprac.2024.03.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 03/14/2024] [Accepted: 03/21/2024] [Indexed: 04/26/2024]
Abstract
OBJECTIVE Despite improvements in glucose monitoring technologies, insulin formulations and insulin delivery systems, too many patients with type 1 diabetes (T1D) continue to struggle to meet their glycemic goals. As a result, they suffer from high rates of microvascular and macrovascular disease. Titration of insulin therapy, while essential to the care of these patients, is often limited by undesirable side effects of hypoglycemia and weight gain. Sodium-glucose cotransporter (SGLT) inhibitors have been proposed as a potential adjunctive therapy to insulin that may offset some of these effects, while simultaneously enabling patients with T1D to potentially reap the cardiovascular and renal benefits afforded by these agents in those with type 2 diabetes. This review summarizes and contextualizes the clinical trial data that has emerged with these agents in this specific population. METHODS A clinical review based on current literature was generated by the authors. RESULTS This review summarizes the data from several clinical trial programs investigating the use of SGLT inhibitors in T1D, describing the potential benefits and the ketosis-related adverse events of these agents (including euglycemic DKA), along with a discussion of possible mitigation strategies to reduce this risk. CONCLUSION Although theoretically SGLT inhibitors have the potential to improve metabolic, cardiovascular, and renal outcomes in patients with T1D, the risks of diabetic ketoacidosis currently represent an important limitation to the widespread use of these agents. If treatment is undertaken, caution must be taken, with implementation of effective mitigation strategies being essential.
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Affiliation(s)
- Patricia R Peter
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Silvio E Inzucchi
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
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33
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Lapuerta P, Urbina S, He J, Wittle A, Li C, Li T, Wang H, Hompesch M. A Randomized Crossover Trial of Mixed Meal Tolerance Test Response in People with Type 1 Diabetes on Insulin Pump Therapy and YG1699 or Dapagliflozin. Clin Pharmacol Ther 2024; 115:1383-1390. [PMID: 38456487 DOI: 10.1002/cpt.3225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 02/13/2024] [Indexed: 03/09/2024]
Abstract
YG1699 is a novel inhibitor of sodium-glucose cotransporter 1 (SGLT1) and SGLT2. This double-blind, 3-way crossover trial compared YG1699 to dapagliflozin as an adjunct to insulin in people with type 1 diabetes (T1D) on insulin pump therapy. Treatment periods included four mixed meal tolerance tests (MMTTs) and insulin withdrawal tests per person. Nineteen adults with T1D were randomized to YG1699 10 mg, YG1699 25 mg, and dapagliflozin 10 mg once daily for 1 week in different orders. The primary end point was the difference in area under the curve (AUC) in plasma glucose (AUC0-120min) after an MMTT between treatment groups. Mean change in plasma glucose after an MMTT (AUC0-120min) was lower for YG1699 10 mg vs. dapagliflozin (89.51% of baseline vs. 102.13%, 90% confidence interval (CI) vs. dapagliflozin, -6% to -16%, P = 0.0003) and for YG1699 25 mg (84.83% vs. 102.13%, 90% CI vs. dapagliflozin -13% to -22%, P < 0.0001). At 120 minutes, mean glucose values on no treatment, dapagliflozin, YG1699 10 mg, and YG1699 25 mg were 149 (SE 7.6), 141 (SE 6.1), 128 (SE 6.9), and 115 (SE 7.8) mg/dL, respectively. Insulin dose requirements were lower for YG1699 10 mg and 25 mg vs. dapagliflozin for bolus insulin, and for YG1699 10 mg vs. dapagliflozin for total daily insulin. Safety profiles were similar between treatment groups. YG1699 reduced post-prandial glucose more than dapagliflozin in people with T1D on insulin pump therapy. The results were consistent with dual SGLT1/SGLT2 inhibition by YG1699.
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Affiliation(s)
- Pablo Lapuerta
- Youngene Therapeutics Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai, China
| | | | - Jiaojuan He
- Youngene Therapeutics Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai, China
| | - Alyssa Wittle
- Atorus Research, LLC., Mountain Lakes, New Jersey, USA
| | - Chenghai Li
- Youngene Therapeutics Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai, China
| | - Tong Li
- Youngene Therapeutics Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai, China
| | - Helen Wang
- Youngene Therapeutics Co., Ltd., Zhangjiang Hi-Tech Park, Shanghai, China
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Nakamura Y, Horie I, Kitamura T, Kusunoki Y, Nishida K, Yamamoto A, Hirota Y, Fukui T, Maeda Y, Minami M, Matsui T, Kawakami A, Abiru N. Glucagon secretion and its association with glycaemic control and ketogenesis during sodium-glucose cotransporter 2 inhibition by ipragliflozin in people with type 1 diabetes: Results from the multicentre, open-label, prospective study. Diabetes Obes Metab 2024; 26:1605-1614. [PMID: 38253809 DOI: 10.1111/dom.15458] [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: 11/24/2023] [Revised: 12/27/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024]
Abstract
AIM Clinical trials showed the efficacy of sodium-glucose cotransporter 2 inhibitors for type 1 diabetes (T1D) by significant reductions in body weight and glycaemic variability, but elevated susceptibility to ketoacidosis via elevated glucagon secretion was a potential concern. The Suglat-AID evaluated glucagon responses and its associations with glycaemic control and ketogenesis before and after T1D treatment with the sodium-glucose cotransporter 2 inhibitor, ipragliflozin. METHODS Adults with T1D (n = 25) took 50-mg open-labelled ipragliflozin daily as adjunctive to insulin. Laboratory/clinical data including continuous glucose monitoring were collected until 12 weeks after the ipragliflozin initiation. The participants underwent a mixed-meal tolerance test (MMTT) twice [before (first MMTT) and 12 weeks after ipragliflozin treatment (second MMTT)] to evaluate responses of glucose, C-peptide, glucagon and β-hydroxybutyrate. RESULTS The area under the curve from fasting (0 min) to 120 min (AUC0-120min) of glucagon in second MMTT were significantly increased by 14% versus first MMTT. The fasting and postprandial β-hydroxybutyrate levels were significantly elevated in second MMTT versus first MMTT. The positive correlation between postprandial glucagon secretion and glucose excursions observed in first MMTT disappeared in second MMTT, but a negative correlation between fasting glucagon and time below range (glucose, <3.9 mmol/L) appeared in second MMTT. The percentage changes in glucagon levels (fasting and AUC0-120min) from baseline to 12 weeks were significantly correlated with those in β-hydroxybutyrate levels. CONCLUSIONS Ipragliflozin treatment for T1D increased postprandial glucagon secretion, which did not exacerbate postprandial hyperglycaemia but might protect against hypoglycaemia, leading to reduced glycaemic variability. The increased glucagon secretion might accelerate ketogenesis when adequate insulin is not supplied.
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Affiliation(s)
- Yuta Nakamura
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ichiro Horie
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tadahiro Kitamura
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Yoshiki Kusunoki
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kenro Nishida
- Division of Diabetes and Endocrinology, Kumamoto Central Hospital, Kumamoto, Japan
| | - Akane Yamamoto
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yushi Hirota
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomoyasu Fukui
- Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Yasutaka Maeda
- Minami Diabetes Clinical Research Center, Clinic Masae Minami, Fukuoka, Japan
| | - Masae Minami
- Minami Diabetes Clinical Research Center, Clinic Masae Minami, Fukuoka, Japan
| | - Takanori Matsui
- Faculty of Bioscience and Biotechnology, Fukui Prefectural University, Fukui, Japan
| | - Atsushi Kawakami
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Norio Abiru
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Popovic DS, Karakasis P, Koufakis T, Fragakis N, Papanas N, Mitrovic M, Gouveri E, Patoulias D. Effect of sodium-glucose cotransporter-2 inhibitors on continuous glucose monitoring metrics, as adjunctive to insulin in adults with type 1 diabetes mellitus: a meta-analysis of randomized controlled trials. Metabolism 2024; 153:155791. [PMID: 38232802 DOI: 10.1016/j.metabol.2024.155791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/22/2023] [Accepted: 01/09/2024] [Indexed: 01/19/2024]
Abstract
AIMS This meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2is) on continuous glucose monitoring metrics as adjunctive to insulin in adults with type 1 diabetes mellitus (T1D). METHODS A systematic literature search was conducted through Medline (via PubMed), Cochrane Library and Google Scholar until October 25, 2023. Dual-independent study selection, data extraction and quality assessment were conducted. Results were summarized with random effects meta-analysis. RESULTS Eight RCTs were identified, involving a total of 2310 T1D patients. The use of SGLT2is on top of standard insulin therapy was associated with a significantly higher time in range (TIR) compared to placebo (mean difference (MD) 9.7 %; 95 % confidence interval (CI) [8.3, 1.11]; P < 0.001). The time above range was significantly lower in patients receiving SGLT2is (MD -8.71 %; 95 % CI [-11.62, -5.79]; P < 0.001), whereas no difference was observed regarding the time below range (TBR) (MD 0.34 %; 95 % CI [-0.17, 0.85]; P = 0.19). A significantly lower sensor-recorded mean daily glucose was noted in the group receiving SGLT2is (MD -16.55 mg/dL; 95 % CI [-19.82, -13.29]; P < 0.001). When considering the metrics of glucose variability, SGLT2is demonstrated a significant favorable effect on the mean amplitude of glucose excursions (MD -16.92 mg/dL; 95 % CI [-25.31, -8.13]; P < 0.001) and the mean standard deviation of weekly glucose levels (MD -7.67 mg/dL; 95 % CI [-11, -4.35]; P < 0.001). No significant effect was observed concerning the coefficient of variation (MD -1 %; 95 % CI [-2.39, 0.4]; P = 0.16). Regarding safety outcomes, SGLT2is were significantly linked to higher odds of diabetic ketoacidosis compared to insulin alone (OR 3.18; 95 % CI [1.79, 5.66]; P < 0.001), with no significant impact on severe hypoglycemia events (OR 1; 95 % CI [0.54, 1.85]; P = 0.1). CONCLUSION Our findings suggest that in individuals with T1D, adjunct therapy with SGLT2is provides a significant benefit in terms of TIR and reduced glucose variability, without an increase in TBR.
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Affiliation(s)
- Djordje S Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Medical Faculty, University of Novi Sad, Novi Sad, Serbia.
| | - Paschalis Karakasis
- Second Department of Cardiology, Aristotle University of Thessaloniki, Hippokration General Hospital, Greece
| | - Theocharis Koufakis
- Second Propaedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Fragakis
- Second Department of Cardiology, Aristotle University of Thessaloniki, Hippokration General Hospital, Greece
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Milena Mitrovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Medical Faculty, University of Novi Sad, Novi Sad, Serbia
| | - Evanthia Gouveri
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Dimitrios Patoulias
- Outpatient Department of Cardiometabolic Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Greece
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Kugathasan L, Sridhar VS, Tommerdahl KL, Xu C, Bjornstad P, Advani A, Cherney DZI. Minireview: Understanding and targeting inflammatory, hemodynamic and injury markers for cardiorenal protection in type 1 diabetes. Metabolism 2024; 153:155785. [PMID: 38215965 DOI: 10.1016/j.metabol.2024.155785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/16/2023] [Accepted: 01/03/2024] [Indexed: 01/14/2024]
Abstract
The coexistence of cardiovascular disease (CVD) and diabetic kidney disease (DKD) is common in people with type 1 diabetes (T1D) and is strongly associated with an increased risk of morbidity and mortality. Hence, it is imperative to explore robust tools that can accurately reflect the development and progression of cardiorenal complications. Several cardiovascular and kidney biomarkers have been identified to detect at-risk individuals with T1D. The primary aim of this review is to highlight biomarkers of injury, inflammation, or renal hemodynamic changes that may influence T1D susceptibility to CVD and DKD. We will also examine the impact of approved pharmacotherapies for type 2 diabetes, including renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) on candidate biomarkers for cardiorenal complications in people with T1D and discuss how these changes may potentially mediate kidney and cardiovascular protection. Identifying predictive and prognostic biomarkers for DKD and CVD may highlight potential drug targets to attenuate cardiorenal disease progression, implement novel risk stratification measures in clinical trials, and improve the assessment, diagnosis, and treatment of at-risk individuals with T1D.
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Affiliation(s)
- Luxcia Kugathasan
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Cardiovascular Sciences Collaborative Specialization, University of Toronto, Toronto, Canada
| | - Vikas S Sridhar
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kalie L Tommerdahl
- Section of Endocrinology, Department of Pediatrics, University of Colorado, Aurora, CO, USA; Barbara Davis Center for Diabetes, Aurora, CO, USA
| | - Cheng Xu
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Section of Endocrinology, Department of Pediatrics, University of Colorado, Aurora, CO, USA; Division of Nephrology, Department of Medicine, University of Colorado, Aurora, CO, USA
| | - Andrew Advani
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Cardiovascular Sciences Collaborative Specialization, University of Toronto, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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Tecce N, de Alteriis G, de Alteriis G, Verde L, Tecce MF, Colao A, Muscogiuri G. Harnessing the Synergy of SGLT2 Inhibitors and Continuous Ketone Monitoring (CKM) in Managing Heart Failure among Patients with Type 1 Diabetes. Healthcare (Basel) 2024; 12:753. [PMID: 38610175 PMCID: PMC11011472 DOI: 10.3390/healthcare12070753] [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: 02/20/2024] [Revised: 03/25/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Heart failure (HF) management in type 1 diabetes (T1D) is particularly challenging due to its increased prevalence and the associated risks of hospitalization and mortality, driven by diabetic cardiomyopathy. Sodium-glucose cotransporter-2 inhibitors (SGLT2-is) offer a promising avenue for treating HF, specifically the preserved ejection fraction variant most common in T1D, but their utility is hampered by the risk of euglycemic diabetic ketoacidosis (DKA). This review investigates the potential of SGLT2-is in T1D HF management alongside emergent Continuous Ketone Monitoring (CKM) technology as a means to mitigate DKA risk through a comprehensive analysis of clinical trials, observational studies, and reviews. The evidence suggests that SGLT2-is significantly reduce HF hospitalization and enhance cardiovascular outcomes. However, their application in T1D patients remains limited due to DKA concerns. CKM technology emerges as a crucial tool in this context, offering real-time monitoring of ketone levels, which enables the safe incorporation of SGLT2-is into treatment regimes by allowing for early detection and intervention in the development of ketosis. The synergy between SGLT2-is and CKM has the potential to revolutionize HF treatment in T1D, promising improved patient safety, quality of life, and reduced HF-related morbidity and mortality. Future research should aim to employ clinical trials directly assessing this integrated approach, potentially guiding new management protocols for HF in T1D.
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Affiliation(s)
- Nicola Tecce
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131 Napoli, Italy; (G.d.A.); (A.C.)
| | - Giorgio de Alteriis
- Department of Industrial Engineering, University of Naples Federico II, Piazzale Tecchio 80, 80125 Naples, Italy;
| | - Giulia de Alteriis
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131 Napoli, Italy; (G.d.A.); (A.C.)
| | - Ludovica Verde
- Centro Italiano per la Cura e il Benessere del Paziente con Obesità (C.I.B.O), Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131 Napoli, Italy;
| | - Mario Felice Tecce
- Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy;
| | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131 Napoli, Italy; (G.d.A.); (A.C.)
- Cattedra Unesco “Educazione alla Salute e Allo Sviluppo Sostenibile”, University Federico II, 80131 Napoli, Italy
| | - Giovanna Muscogiuri
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131 Napoli, Italy; (G.d.A.); (A.C.)
- Cattedra Unesco “Educazione alla Salute e Allo Sviluppo Sostenibile”, University Federico II, 80131 Napoli, Italy
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Kugathasan L, Sridhar VS, Lovblom LE, Matta S, Saliba A, Debnath S, AlAkwaa FM, Nair V, Bjornstad P, Kretzler M, Perkins BA, Sharma K, Cherney DZI. Interactive Effects of Empagliflozin and Hyperglycemia on Urinary Amino Acids in Individuals With Type 1 Diabetes. Diabetes 2024; 73:401-411. [PMID: 38015810 DOI: 10.2337/db23-0694] [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: 08/29/2023] [Accepted: 11/19/2023] [Indexed: 11/30/2023]
Abstract
Optimizing energy use in the kidney is critical for normal kidney function. Here, we investigate the effect of hyperglycemia and sodium-glucose cotransporter 2 (SGLT2) inhibition on urinary amino acid excretion in individuals with type 1 diabetes (T1D). The open-label ATIRMA trial assessed the impact of 8 weeks of 25 mg empagliflozin orally once per day in 40 normotensive normoalbuminuric young adults with T1D. A consecutive 2-day assessment of clamped euglycemia and hyperglycemia was evaluated at baseline and posttreatment visits. Principal component analysis was performed on urinary amino acids grouped into representative metabolic pathways using MetaboAnalyst. At baseline, acute hyperglycemia was associated with changes in 25 of the 33 urinary amino acids or their metabolites. The most significant amino acid metabolites affected by acute hyperglycemia were 3-hydroxykynurenine, serotonin, glycyl-histidine, and nicotinic acid. The changes in amino acid metabolites were reflected by the induction of four biosynthetic pathways: aminoacyl-tRNA; valine, leucine, and isoleucine; arginine; and phenylalanine, tyrosine, and tryptophan. In acute hyperglycemia, empagliflozin significantly attenuated the increases in aminoacyl-tRNA biosynthesis and valine, leucine, and isoleucine biosynthesis. Our findings using amino acid metabolomics indicate that hyperglycemia stimulates biosynthetic pathways in T1D. SGLT2 inhibition may attenuate the increase in biosynthetic pathways to optimize kidney energy metabolism. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Luxcia Kugathasan
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Cardiovascular Sciences Collaborative Specialization, University of Toronto, Toronto, Ontario, Canada
| | - Vikas S Sridhar
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Leif Erik Lovblom
- Biostatistics Department, University Health Network, Toronto, Ontario, Canada
| | - Shane Matta
- Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX
- Division of Nephrology, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX
| | - Afaf Saliba
- Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX
- Division of Nephrology, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX
| | - Subrata Debnath
- Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX
- Division of Nephrology, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX
| | - Fadhl M AlAkwaa
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Viji Nair
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Petter Bjornstad
- Division of Nephrology, Department of Medicine, University of Colorado, Aurora, CO
- Section of Endocrinology, Department of Pediatrics, University of Colorado, Aurora, CO
| | - Matthias Kretzler
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI
| | - Bruce A Perkins
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kumar Sharma
- Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX
- Division of Nephrology, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Cardiovascular Sciences Collaborative Specialization, University of Toronto, Toronto, Ontario, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Bielka W, Przezak A, Molęda P, Pius-Sadowska E, Machaliński B. Double diabetes-when type 1 diabetes meets type 2 diabetes: definition, pathogenesis and recognition. Cardiovasc Diabetol 2024; 23:62. [PMID: 38341550 PMCID: PMC10859035 DOI: 10.1186/s12933-024-02145-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
Currently, the differentiation between type 1 diabetes (T1D) and type 2 diabetes (T2D) is not straightforward, and the features of both types of diabetes coexist in one subject. This situation triggered the need to discriminate so-called double diabetes (DD), hybrid diabetes or type 1.5 diabetes, which is generally described as the presence of the insulin resistance characteristic of metabolic syndrome in individuals diagnosed with T1D. DD not only raises the question of proper classification of diabetes but is also associated with a significantly greater risk of developing micro- and macroangiopathic complications, which was independent of glycaemic control. When considering the global obesity pandemic and increasing incidence of T1D, the prevalence of DD may also presumably increase. Therefore, it is of the highest priority to discover the mechanisms underlying the development of DD and to identify appropriate methods to prevent or treat DD. In this article, we describe how the definition of double diabetes has changed over the years and how it is currently defined. We discuss the accuracy of including metabolic syndrome in the DD definition. We also present possible hypotheses connecting insulin resistance with T1D and propose possible methods to identify individuals with double diabetes based on indirect insulin resistance markers, which are easily assessed in everyday clinical practice. Moreover, we discuss adjuvant therapy which may be considered in double diabetic patients.
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Affiliation(s)
- Weronika Bielka
- Department of Diabetology and Internal Diseases, Pomeranian Medical University, 72-009, Police, Poland.
| | - Agnieszka Przezak
- Department of Diabetology and Internal Diseases, Pomeranian Medical University, 72-009, Police, Poland
| | - Piotr Molęda
- Department of Diabetology and Internal Diseases, Pomeranian Medical University, 72-009, Police, Poland
| | - Ewa Pius-Sadowska
- Department of General Pathology, Pomeranian Medical University, 70-111, Szczecin, Poland
| | - Bogusław Machaliński
- Department of General Pathology, Pomeranian Medical University, 70-111, Szczecin, Poland
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Nan J, Wang D, Zhong R, Liu F, Luo J, Tang P, Song X, Zhang L. Sodium glucose cotransporter2 inhibitors for type 1 diabetes mellitus: A meta-analysis of randomized controlled trials. Prim Care Diabetes 2024; 18:17-24. [PMID: 37980217 DOI: 10.1016/j.pcd.2023.10.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/08/2023] [Accepted: 10/22/2023] [Indexed: 11/20/2023]
Abstract
AIMS Sodium glucose cotransporter2 (SGLT2) inhibitors are controversial in the treatment of type 1 diabetes mellitus (T1DM). This study is a systematic evaluation of the safety of SGLT2 inhibitors usage in T1DM. METHODS Comprehensive literature search in six databases from inception to September 2022. Randomized controlled trials (RCTs) of T1DM treated with SGLT2 inhibitor vs. placebo were included. Data were extracted from the literature that met the inclusion criteria. After quality evaluation by the Cochrane risk bias assessment tool, meta-analysis was performed using Revman 5.4 and Stata 17.1. RESULTS The study consisted of 16 RCTs with 7192 patients. The results indicated that SGLT2inhibitors reduce glycated hemoglobin (HbA1c, Mean difference (MD)- 0.29%, P < 0.05), fasting plasma glucose (FPG, MD-0.85 mmol/L, P < 0.05), mean amplitude of glucose excursions (MAGE, 15.75 mg/dL, P < 0.05), body weight (MD-3.49 kg, P < 0.05), and total insulin dosage (MD-7.14 IU/day, P < 0.05). Furthermore, cautious SGLT2 inhibitors did not induce the risk of hypoglycemia (RR1.00, P = 0.86), urinary tract infections (RR1.02, P = 0.085), and diarrhea (RR1.34, P = 0.523). CONCLUSION Based on this meta-analysis, SGLT22 inhibitors reduce insulin dosage without increasing the risk of hypoglycemia and diabetic ketoacidosis for type 1 diabetes mellitus in 1month.
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Affiliation(s)
- Juanli Nan
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Dekai Wang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Ruxian Zhong
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Fen Liu
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Jingmei Luo
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Ping Tang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Xiaoxiao Song
- School of Public Health, Kunming Medical University, Kunming 650500, China
| | - Lihua Zhang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China.
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Abstract
PURPOSE OF REVIEW Obesity is an epidemic in the United States with serious concomitant co-morbid conditions; people living with type 1 diabetes mellitus (T1D) are not immune to the risk either. Weight gain in T1D is likely multifactorial, due to genetic, environmental and treatment-related factors. FDA-approved and other adjunctive weight loss therapies may benefit people living with T1D but there are risks to consider when providing recommendations or prescribing medications. RECENT FINDINGS We performed a PubMed search of studies assessing clinical outcomes of both approved and off-label medications used in the treatment of type 1 diabetes. Search terms included 'type 1 diabetes, obesity' and the following: (1) metformin, (2) pramlintide, (3) glucagon-like peptide-1 (GLP-1) receptor agonists, (4) dual GLP-1 and gastric inhibitory polypeptide (GIP) agonists, (5) sodium-glucose cotransporter-2 (SGLT-2) inhibitors, (6) surgical treatment of obesity, (7) insulin pump, (8) insulin, (9) medical nutrition therapy, (10) diabetes self-management education, (11) exercise, (12) naltrexone-buproprion, (13) orlistat, and (14) phentermine-topiramate. SUMMARY Weight loss treatments provide a wide-range of benefits in reducing both morbidity and mortality in those who are obese. Treatments also have varying adverse effect profiles which may impact T1D treatment. In this review, we aim to summarize study outcomes in people with T1D, including risks and benefits, of on- and off-label weight loss treatments.
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Affiliation(s)
- Matthew Freeby
- David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Subramanian S, Khan F, Hirsch IB. New advances in type 1 diabetes. BMJ 2024; 384:e075681. [PMID: 38278529 DOI: 10.1136/bmj-2023-075681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2024]
Abstract
Type 1 diabetes is an autoimmune condition resulting in insulin deficiency and eventual loss of pancreatic β cell function requiring lifelong insulin therapy. Since the discovery of insulin more than 100 years ago, vast advances in treatments have improved care for many people with type 1 diabetes. Ongoing research on the genetics and immunology of type 1 diabetes and on interventions to modify disease course and preserve β cell function have expanded our broad understanding of this condition. Biomarkers of type 1 diabetes are detectable months to years before development of overt disease, and three stages of diabetes are now recognized. The advent of continuous glucose monitoring and the newer automated insulin delivery systems have changed the landscape of type 1 diabetes management and are associated with improved glycated hemoglobin and decreased hypoglycemia. Adjunctive therapies such as sodium glucose cotransporter-1 inhibitors and glucagon-like peptide 1 receptor agonists may find use in management in the future. Despite these rapid advances in the field, people living in under-resourced parts of the world struggle to obtain necessities such as insulin, syringes, and blood glucose monitoring essential for managing this condition. This review covers recent developments in diagnosis and treatment and future directions in the broad field of type 1 diabetes.
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Affiliation(s)
- Savitha Subramanian
- University of Washington Diabetes Institute, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA
| | - Farah Khan
- University of Washington Diabetes Institute, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA
| | - Irl B Hirsch
- University of Washington Diabetes Institute, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA
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ElSayed NA, Aleppo G, Bannuru RR, Bruemmer D, Collins BS, Das SR, Ekhlaspour L, Hilliard ME, Johnson EL, Khunti K, Kosiborod MN, Lingvay I, Matfin G, McCoy RG, Perry ML, Pilla SJ, Polsky S, Prahalad P, Pratley RE, Segal AR, Seley JJ, Stanton RC, Gabbay RA. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care 2024; 47:S179-S218. [PMID: 38078592 PMCID: PMC10725811 DOI: 10.2337/dc24-s010] [Citation(s) in RCA: 155] [Impact Index Per Article: 155.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Sridhar VS, Limonte CP, Groop PH, Heerspink HJL, Pratley RE, Rossing P, Skyler JS, Cherney DZI. Chronic kidney disease in type 1 diabetes: translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes. Diabetologia 2024; 67:3-18. [PMID: 37801140 DOI: 10.1007/s00125-023-06015-1] [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: 04/26/2023] [Accepted: 07/21/2023] [Indexed: 10/07/2023]
Abstract
Current management of chronic kidney disease (CKD) in type 1 diabetes centres on glycaemic control, renin-angiotensin system inhibition and optimisation of risk factors including blood pressure, lipids and body weight. While these therapeutic approaches have significantly improved outcomes among people with type 1 diabetes and CKD, this population remains at substantial elevated risk for adverse kidney and cardiovascular events, with limited improvements over the last few decades. The significant burden of CKD and CVD in type 1 diabetes populations highlights the need to identify novel therapies with the potential for heart and kidney protection. Over the last decade, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide 1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists have emerged as potent kidney-protective and/or cardioprotective agents in type 2 diabetes. The consistent, substantial kidney and cardiovascular benefits of these agents has led to their incorporation into professional guidelines as foundational care for type 2 diabetes. Furthermore, introduction of these agents into clinical practice has been accompanied by a shift in the focus of diabetes care from a 'glucose-centric' to a 'cardiorenal risk-centric' approach. In this review, we evaluate the potential translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes with the lens of preventing the development and progression of CKD.
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Affiliation(s)
- Vikas S Sridhar
- Division of Nephrology, University Health Network, University of Toronto, Toronto, ON, Canada.
| | - Christine P Limonte
- Division of Nephrology, University of Washington, Seattle, WA, USA
- Kidney Research Institute, University of Washington, Seattle, WA, USA
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- The George Institute for Global Health, Sydney, Australia
| | | | - Peter Rossing
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Jay S Skyler
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - David Z I Cherney
- Division of Nephrology, University Health Network, University of Toronto, Toronto, ON, Canada
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Neumiller JJ, Alicic RZ, Tuttle KR. Optimization of guideline-directed medical therapies in patients with diabetes and chronic kidney disease. Clin Kidney J 2024; 17:sfad285. [PMID: 38213492 PMCID: PMC10783256 DOI: 10.1093/ckj/sfad285] [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] [Received: 09/29/2023] [Indexed: 01/13/2024] Open
Abstract
Diabetes is the leading cause of chronic kidney disease (CKD) and kidney failure worldwide. CKD frequently coexists with heart failure and atherosclerotic cardiovascular disease in the broader context of cardio-kidney-metabolic syndrome. Diabetes and CKD are associated with increased risk of all-cause and cardiovascular death as well as decreased quality of life. The role of metabolic and hemodynamic abnormalities has long been recognized as an important contributor to the pathogenesis and progression of CKD in diabetes, while a more recent and growing body of evidence supports activation of both systemic and local inflammation as important contributors. Current guidelines recommend therapies targeting pathomechanisms of CKD in addition to management of traditional risk factors such as hyperglycemia and hypertension. Sodium-glucose cotransporter-2 inhibitors are recommended for treatment of patients with CKD and type 2 diabetes (T2D) if eGFR is ≥20 ml/min/173 m2 on a background of renin-angiotensin system inhibition. For patients with T2D, CKD, and atherosclerotic cardiovascular disease, a glucagon-like peptide-1 receptor agonist is recommended as additional risk-based therapy. A non-steroidal mineralocorticoid receptor antagonist is also recommended as additional risk-based therapy for persistent albuminuria in patients with T2D already treated with renin-angiotensin system inhibition. Implementation of guideline-directed medical therapies is challenging in the face of rapidly accumulating knowledge, high cost of medications, and lack of infrastructure for optimal healthcare delivery. Furthermore, studies of new therapies have focused on T2D and CKD. Clinical trials are now planned to inform the role of these therapies in people with type 1 diabetes (T1D) and CKD.
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Affiliation(s)
- Joshua J Neumiller
- College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
- Providence Medical Research Center, Providence Inland Northwest Health, Spokane, WA, USA
| | - Radica Z Alicic
- Providence Medical Research Center, Providence Inland Northwest Health, Spokane, WA, USA
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Katherine R Tuttle
- Providence Medical Research Center, Providence Inland Northwest Health, Spokane, WA, USA
- Department of Medicine, University of Washington, Seattle, WA, USA
- Nephrology Division, Kidney Research Institute, and Institute of Translational Health Sciences, University of Washington, Seattle, WA, USA
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Scarr D, Lovblom E, Ye H, Liu H, Bakhsh A, Verhoeff NJ, Wolever TMS, Lawler PR, Sharma K, Cherney DZI, Perkins BA. Ketone production and excretion even during mild hyperglycemia and the impact of sodium-glucose co-transporter inhibition in type 1 diabetes. Diabetes Res Clin Pract 2024; 207:111031. [PMID: 38036220 DOI: 10.1016/j.diabres.2023.111031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/18/2023] [Accepted: 11/26/2023] [Indexed: 12/02/2023]
Abstract
AIMS We aimed to determine if ketone production and excretion are increased even at mild fasting hyperglycemia in type 1 diabetes (T1D) and if these are modified by ketoacidosis risk factors, including sodium-glucose co-transporter inhibition (SGLTi) and female sex. METHODS In secondary analysis of an 8-week single-arm open-label trial of empagliflozin (NCT01392560) we evaluated ketone concentrations during extended fasting and clamped euglycemia (4-6 mmol/L) and mild hyperglycemia (9-11 mmol/L) prior to and after treatment. Plasma and urine beta-hydroxybutyrate (BHB) concentrations and fractional excretion were analyzed by metabolomic analysis. RESULTS Forty participants (50 % female), aged 24 ± 5 years, HbA1c 8.0 ± 0.9 % (64 ± 0.08 mmol/mol) with T1D duration of 17.5 ± 7 years, were studied. Increased BHB production even during mild hyperglycemia (median urine 6.3[3.5-13.6] vs. 3.5[2.2-7.0] µmol/mmol creatinine during euglycemia, p < 0.001) was compensated by increased fractional excretion (0.9 % [0.3-1.6] vs. 0.4 % [0.2-0.9], p < 0.001). SGLTi increased production and attenuated the increased BHB fractional excretion (decreased to 0.3 % during mild hyperglycemia, p < 0.001), resulting in higher plasma concentrations (increased to 0.21 [0.05-0.40] mmol/L, p < 0.001), particularly in females (interaction p < 0.001). CONCLUSIONS Even mild hyperglycemia is associated with greater ketone production, compensated by urinary excretion, in T1D. However, SGLTi exaggerates production and partially reduces compensatory excretion, particularly in women.
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Affiliation(s)
- Daniel Scarr
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Erik Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Hongping Ye
- Center for Renal Precision Medicine, Division of Nephrology, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States
| | - Hongyan Liu
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Abdulmohsen Bakhsh
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Kidney & Pancreas Health Centre, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia; Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Natasha J Verhoeff
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Thomas M S Wolever
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Patrick R Lawler
- McGill University Health Centre, Montreal, Canada; The Peter Munk Cardiac Centre at University Health Network, University of Toronto, Canada
| | - Kumar Sharma
- Center for Renal Precision Medicine, Division of Nephrology, Department of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Bruce A Perkins
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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Papaetis GS. SGLT2 inhibitors, intrarenal hypoxia and the diabetic kidney: insights into pathophysiological concepts and current evidence. Arch Med Sci Atheroscler Dis 2023; 8:e155-e168. [PMID: 38283924 PMCID: PMC10811536 DOI: 10.5114/amsad/176658] [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: 10/15/2023] [Accepted: 12/08/2023] [Indexed: 01/30/2024] Open
Abstract
Approximately 20-40% of all diabetic patients experience chronic kidney disease, which is related to higher mortality (cardiovascular and all-cause). A large body of evidence suggests that renal hypoxia is one of the main forces that drives diabetic kidney disease, both in its early and advanced stages. It promotes inflammation, generation of intrarenal collagen, capillary rarefaction and eventually accumulation of extracellular matrix that destroys normal renal architecture. SGLT2 inhibitors are unquestionably a practice-changing drug class and a valuable weapon for patients with type 2 diabetes and chronic kidney disease. They have achieved several beneficial kidney effects after targeting multiple and interrelated signaling pathways, including renal hypoxia, independent of their antihyperglycemic activities. This manuscript discusses the pathophysiological concepts that underly their possible effects on modulating renal hypoxia. It also comprehensively investigates both preclinical and clinical studies that explored the possible role of SGLT2 inhibitors in this setting, so as to achieve long-term renoprotective benefits.
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Affiliation(s)
- Georgios S. Papaetis
- K.M.P THERAPIS Paphos Medical Center, Internal Medicine and Diabetes Clinic, Paphos, Cyprus
- CDA College, Paphos, Cyprus
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Forner P, Snaith J, Greenfield JR. Prescribing patterns of adjunctive therapy for the treatment of type 1 diabetes mellitus among Australian endocrinologists. Intern Med J 2023. [PMID: 38158765 DOI: 10.1111/imj.16312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 11/29/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Many people living with type 1 diabetes (type 1 diabetes mellitus (T1DM)) do not meet glycaemic targets. Adjunctive therapies have both risks and metabolic benefits and may have a role in selected patients. AIM To review the prescribing patterns of adjunctive therapy for the treatment of T1DM diabetes in Australia. METHODS We conducted an online survey of Australian endocrinologists and endocrinology registrars. We surveyed the frequency of, motivations and concerns regarding the prescription of metformin, dipeptidyl peptidase-4 (DPP-IV) inhibitors, sodium-glucose transport protein 2 (SGLT-2) inhibitors and glucagon-like peptide 1 receptor agonist (GLP1RA) in T1DM. RESULTS Fifty-two practitioners participated. Most respondents (94%) had prescribed adjuncts for the treatment of T1DM in some form. Weight (89%), large insulin doses (73%), glycaemic variability (52%), high HbA1c (48%) and the presence of cardiovascular disease (48%) were the most common factors determining the use of adjuncts. The most commonly prescribed adjuncts were metformin (94%) and SGLT-2 inhibitors (65%). Respondents who had never prescribed an SGLT-2 inhibitor (n = 18) reported risk of diabetic ketoacidosis (DKA) (100%), off-label status (39%), lack of evidence (39%), withdrawal of support from the European Medicines Agency (17%) and cost (17%) as factors contributing to their decision. Thirty-one respondents (60%) had prescribed a GLP1RA. Among those who had never prescribed a GLP1RA (n = 21), off-label status (57%), lack of evidence (48%), cost (38%) and expected lack of efficacy (14%) were factors affecting their decision. Only five respondents (10%) had prescribed a DPP-IV inhibitor. CONCLUSION Australian endocrinologists commonly prescribe adjuncts to address cardiometabolic concerns in T1DM. DKA risk and off-label status are significant factors contributing to reluctance to prescribe.
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Affiliation(s)
- Patrice Forner
- Department of Diabetes and Endocrinology, St Vincent's Hospital, Sydney, New South Wales, Australia
- St Vincent's Healthcare Campus, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Jennifer Snaith
- Department of Diabetes and Endocrinology, St Vincent's Hospital, Sydney, New South Wales, Australia
- St Vincent's Healthcare Campus, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- Clinical Diabetes, Appetite and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Jerry R Greenfield
- Department of Diabetes and Endocrinology, St Vincent's Hospital, Sydney, New South Wales, Australia
- St Vincent's Healthcare Campus, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- Clinical Diabetes, Appetite and Metabolism, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
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Xie X, Wu C, Hao Y, Wang T, Yang Y, Cai P, Zhang Y, Huang J, Deng K, Yan D, Lin H. Benefits and risks of drug combination therapy for diabetes mellitus and its complications: a comprehensive review. Front Endocrinol (Lausanne) 2023; 14:1301093. [PMID: 38179301 PMCID: PMC10766371 DOI: 10.3389/fendo.2023.1301093] [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: 09/24/2023] [Accepted: 11/27/2023] [Indexed: 01/06/2024] Open
Abstract
Diabetes is a chronic metabolic disease, and its therapeutic goals focus on the effective management of blood glucose and various complications. Drug combination therapy has emerged as a comprehensive treatment approach for diabetes. An increasing number of studies have shown that, compared with monotherapy, combination therapy can bring significant clinical benefits while controlling blood glucose, weight, and blood pressure, as well as mitigating damage from certain complications and delaying their progression in diabetes, including both type 1 diabetes (T1D), type 2 diabetes (T2D) and related complications. This evidence provides strong support for the recommendation of combination therapy for diabetes and highlights the importance of combined treatment. In this review, we first provided a brief overview of the phenotype and pathogenesis of diabetes and discussed several conventional anti-diabetic medications currently used for the treatment of diabetes. We then reviewed several clinical trials and pre-clinical animal experiments on T1D, T2D, and their common complications to evaluate the efficacy and safety of different classes of drug combinations. In general, combination therapy plays a pivotal role in the management of diabetes. Integrating the effectiveness of multiple drugs enables more comprehensive and effective control of blood glucose without increasing the risk of hypoglycemia or other serious adverse events. However, specific treatment regimens should be tailored to individual patients and implemented under the guidance of healthcare professionals.
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Affiliation(s)
- Xueqin Xie
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Changchun Wu
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuduo Hao
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Tianyu Wang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuhe Yang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Peiling Cai
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
| | - Yang Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Academy for Interdiscipline, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jian Huang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Kejun Deng
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Dan Yan
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hao Lin
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
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Elbarbary NS, Ismail EAR. Mitigating iftar-related glycemic excursions in adolescents and young adults with type 1 diabetes on MiniMed™ 780G advanced hybrid closed loop system: a randomized clinical trial for adjunctive oral vildagliptin therapy during Ramadan fasting. Diabetol Metab Syndr 2023; 15:257. [PMID: 38057844 DOI: 10.1186/s13098-023-01232-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 11/25/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND Ramadan Iftar meal typically causes glucose excursions. Dipeptidyl peptidase-4 inhibitors increase glucagon-like peptide-1 and thus, decrease blood glucose levels with low risk of hypoglycemia. AIM To investigate the efficacy and safety of vildagliptin as an add-on therapy on glucose excursions of Iftar Ramadan meals among adolescents and young adults with type 1 diabetes mellitus (T1DM) using advanced hybrid closed-loop (AHCL) treatment. METHODS Fifty T1DM patients on MiniMed™ 780G AHCL were randomly assigned either to receive vildagliptin (50 mg tablet) with iftar meal during Ramadan month or not. All participants received pre-meal insulin bolus based on insulin-to-carbohydrate ratio (ICR) for each meal constitution. RESULTS Vildagliptin offered blunting of post-meal glucose surges (mean difference - 30.3 mg/dL [- 1.7 mmol/L] versus - 2.9 mg/dL [- 0.2 mmol/L] in control group; p < 0.001) together with concomitant exceptional euglycemia with time in range (TIR) significantly increased at end of Ramadan in intervention group from 77.8 ± 9.6% to 84.7 ± 8.3% (p = 0.016) and time above range (180-250 mg/dL) decreased from 13.6 ± 5.1% to 9.7 ± 3.6% (p = 0.003) without increasing hypoglycemia. A significant reduction was observed in automated daily correction boluses and total bolus dose by 23.9% and 16.3% (p = 0.015 and p < 0.023, respectively) with less aggressive ICR settings within intervention group at end of Ramadan. Coefficient of variation was improved from 37.0 ± 9.4% to 31.8 ± 7.1%; p = 0.035). No severe hypoglycemia or diabetic ketoacidosis were reported. CONCLUSION Adjunctive vildagliptin treatment mitigated postprandial hyperglycemia compared with pre-meal bolus alone. Vildagliptin significantly increased TIR while reducing glycemic variability without compromising safety. Trial registration This trial was registered under ClinicalTrials.gov Identifier no. NCT06021119.
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Affiliation(s)
- Nancy Samir Elbarbary
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, 25 Ahmed Fuad St. Saint Fatima, Heliopolis, Cairo, 11361, Egypt.
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