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Santos GLC, dos Santos CFSM, Rocha GR, Calmon MS, Lemos FFB, Silva LGO, Luz MS, Pinheiro SLR, Botelho ACS, de Melo FF. Beyond glycemic control: Roles for sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in diabetic kidney disease. World J Diabetes 2025; 16:104706. [DOI: 10.4239/wjd.v16.i6.104706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 03/04/2025] [Accepted: 03/28/2025] [Indexed: 06/13/2025] Open
Abstract
The global prevalence of diabetes has surged in recent years, with diabetic kidney disease (DKD) emerging as a major complication. Traditional therapies have had limited success in slowing progression to end-stage kidney disease. However, novel therapies, particularly sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, which were initially developed for hyperglycemia management, have transformed the treatment of obesity, heart failure, cardiovascular disease, and more recently, DKD. SGLT2 inhibitors have consistently and significantly reduced cardiovascular events, albuminuria, and glomerular filtration rate, highlighting their efficacy across diverse clinical presentations for patients with kidney impairment. Although fewer studies have specifically investigated GLP-1 receptor agonists in patients with kidney disease, existing evidence underscores their potential to slow renal disease progression, reduce albuminuria, and improve clinically relevant outcomes. However, further research is needed to better identify patients most likely to benefit from treatment. Together, these therapies represent valuable advancements for DKD, offering significant reductions in morbidity and mortality and shifting the management of the disease by becoming essential pillars for the treatment of these patients.
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Affiliation(s)
- Gabriel LC Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Clara FSM dos Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel R Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Mariana S Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian FB Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luis GO Silva
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel S Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel LR Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Anelise CS Botelho
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício F de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Rajab AM, Pearson S, Ajjan RA. Use of adjunctive glycaemic agents with vascular protective properties in individuals with type 1 diabetes: Potential benefits and risks. Diabetes Obes Metab 2025; 27:2920-2939. [PMID: 40130476 PMCID: PMC12046473 DOI: 10.1111/dom.16332] [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: 12/17/2024] [Revised: 03/02/2025] [Accepted: 03/02/2025] [Indexed: 03/26/2025]
Abstract
Glycaemic therapy in type 1 diabetes (T1D) is focused on insulin, with the majority of studies investigating different insulin preparations, delivery devices and dosing accuracy methods. While insulin deficiency is the key mechanism for hyperglycaemia in T1D, individuals with this condition can also develop insulin resistance (IR), making optimisation of glycaemia more challenging. Importantly, IR in T1D increases the risk of both microvascular and macrovascular complications; yet, it is rarely targeted in routine clinical care. In this narrative review, we briefly discuss the mechanistic pathways for diabetes complications in individuals with T1D, emphasising the adverse role of IR. We subsequently cover the use of adjunctive glycaemic therapies for improving the metabolic profile in T1D, focusing on therapies that have possible or definite cardiovascular or renal protective properties in individuals with type 2 diabetes. These include metformin and agents in the thiazolidinedione, Sodium-Glucose Cotransporter-2 inhibitor (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) groups. In addition to reviewing the role of these agents in improving metabolic parameters, we address their potential vascular and renal protective effects in individuals with T1D. We suggest a pragmatic approach for using these agents in T1D, based on current knowledge of their benefits and risks, while also highlighting gaps in knowledge and areas that require further research. It is hoped that the review raises awareness of the role of adjunctive therapies in T1D and offers healthcare professionals simple guidance on using such agents for the management of high-risk individuals with T1D.
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Affiliation(s)
- Ahmad M. Rajab
- Diabetes CentreSt James's University Hospital, Leeds Teaching Hospitals TrustLeedsUK
| | - Sam Pearson
- Diabetes CentreSt James's University Hospital, Leeds Teaching Hospitals TrustLeedsUK
| | - Ramzi A. Ajjan
- Diabetes CentreSt James's University Hospital, Leeds Teaching Hospitals TrustLeedsUK
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and HealthUniversity of LeedsLeedsUK
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3
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Tsur A, Cahn A, Hanoch L, Pollack R. Kidney outcomes with SGLT2 inhibitors in patients with diabetes and an insulin-deficient phenotype: A real world analysis. Diabetes Obes Metab 2025; 27:3176-3184. [PMID: 40084557 PMCID: PMC12046457 DOI: 10.1111/dom.16329] [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: 12/23/2024] [Revised: 02/15/2025] [Accepted: 03/01/2025] [Indexed: 03/16/2025]
Abstract
AIM Diabetic kidney disease (DKD) is a major complication of diabetes, including in insulin-deficient phenotypes, yet data on kidney outcomes with sodium-glucose cotransporter 2 inhibitors (SGLT2i) in this population are limited. This study investigates the impact of SGLT2i on kidney outcomes in patients with insulin-deficient diabetes using real world data. MATERIALS AND METHODS This retrospective cohort study utilized data from a large Health Maintenance Organization in Israel and included 12,530 propensity score-matched adults with insulin-deficient diabetes. Patients were categorized into SGLT2i users and non-users and followed for a median of 1657 days. The primary outcome was a composite of ≥50% decline in eGFR to <60 mL/min/1.73 m2 or progression to eGFR <15 mL/min/1.73 m2. Secondary outcomes included doubling of serum creatinine and changes in albuminuria category. RESULTS SGLT2i use was associated with a reduced incidence of the primary outcome (6.1% vs. 7.5%; HR 0.79, p < 0.001). Secondary analyses revealed significant reductions in serum creatinine doubling (HR 0.76, p < 0.001) and improvements in albuminuria, with 51% of SGLT2i users transitioning to normoalbuminuria. Benefits were consistent across subgroups. Although diabetic ketoacidosis (DKA) incidence was higher among SGLT2i users (2.81% vs. 2.19%, p = 0.03), the overall frequency was low. CONCLUSIONS SGLT2i demonstrated substantial kidney protection in insulin-deficient patients, extending benefits beyond type 2 diabetes. These findings highlight SGLT2i as a potential therapeutic option for mitigating DKD in high-risk populations.
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Affiliation(s)
- Anat Tsur
- Department of Endocrinology and MetabolismClalit Health ServicesJerusalemIsrael
- The Faculty of MedicineHebrew University of JerusalemJerusalemIsrael
| | - Avivit Cahn
- The Faculty of MedicineHebrew University of JerusalemJerusalemIsrael
- Department of Endocrinology and MetabolismHadassah Medical CenterJerusalemIsrael
| | - Lior Hanoch
- The Faculty of MedicineHebrew University of JerusalemJerusalemIsrael
| | - Rena Pollack
- The Faculty of MedicineHebrew University of JerusalemJerusalemIsrael
- Department of Endocrinology and MetabolismHadassah Medical CenterJerusalemIsrael
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Petersen MC, Jones KE, Markov AM, Salam M, Krutilova P, McKee AM, Bohnert KL, Adamson SE, McGill JB. Effect of dapagliflozin on blood and breath ketones during supervised insulin withdrawal in adults with type 1 diabetes: A randomized crossover trial. Diabetes Obes Metab 2025; 27:3124-3131. [PMID: 40083075 PMCID: PMC12049266 DOI: 10.1111/dom.16324] [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: 12/13/2024] [Revised: 03/01/2025] [Accepted: 03/01/2025] [Indexed: 03/16/2025]
Abstract
AIMS Sodium-glucose cotransporter 2 (SGLT2) inhibitors increase ketoacidosis risk, limiting their use in type 1 diabetes. To better understand the pathophysiology of SGLT2 inhibitor-mediated ketoacidosis, we measured blood glucose, capillary blood and plasma β-hydroxybutyrate (BOHB) and breath acetone (BrACE) during supervised insulin withdrawal in adults with type 1 diabetes with and without dapagliflozin treatment. MATERIALS AND METHODS Twenty adults with type 1 diabetes underwent supervised insulin withdrawal twice in a randomized crossover design: during usual care and after treatment with dapagliflozin (10 mg daily for 2 weeks plus the test day). After insulin withdrawal, capillary blood glucose, BOHB and BrACE measurements were obtained at least hourly until stopping rules were met (>8 h elapsed, symptoms of ketosis, glucose >400 mg/dL, BOHB >4 mmol/L or participant request). RESULTS The peak BOHB and BrACE values achieved during supervised insulin withdrawal were both greater with dapagliflozin than with usual care. Throughout the insulin withdrawal study, dapagliflozin treatment was associated with significantly greater BOHB and BrACE concentrations. The proportions of participants reaching BOHB >1.5 mmol/L and >2.5 mmol/L during supervised insulin withdrawal were greater in the dapagliflozin arm. Blood glucose reached a lower peak in the dapagliflozin arm. CONCLUSIONS In adults with type 1 diabetes undergoing supervised insulin withdrawal, dapagliflozin treatment compared to usual care was associated with greater blood and breath ketone concentrations in the absence of significant hyperglycaemia.
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Affiliation(s)
- Max C. Petersen
- Division of Endocrinology, Metabolism, & Lipid
Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Kai E. Jones
- 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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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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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: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [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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Wan Z, Yuan M, Liu Z, Cai Y, He H, Hao K. Impact of Dapagliflozin on Hepatic Lipid Metabolism and a Dynamic Model of Ketone Body Levels. AAPS J 2025; 27:38. [PMID: 39900889 DOI: 10.1208/s12248-025-01024-x] [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: 11/20/2024] [Accepted: 01/15/2025] [Indexed: 02/05/2025] Open
Abstract
The rising prevalence of metabolic-associated steatotic liver disease emphasizes the need to understand its lipid metabolism. Dapagliflozin may improve hepatic steatosis but could also increase the risk of ketoacidosis by elevating β-hydroxybutyrate (KB) levels. This study investigates dapagliflozin's effects on hepatic lipid metabolism and quantifies KB levels in vivo. Male Sprague-Dawley rats were fed either a normal diet or a high-fat diet (HFD) for 12 weeks. The HFD rats were then divided into four subgroups to receive vehicle, 0.5 mg/kg, 1 mg/kg, and 3 mg/kg of dapagliflozin for four weeks. Free fatty acids (FFA) and KB levels were monitored, while protein and gene expression were analyzed. And a dynamic model of KB was developed for humans based on preclinical data. Dapagliflozin decreased body weight and visceral fat in HFD rats, increasing KB by upregulating CPT1a, HMGCS2, and HMGCL, and downregulating ACC. These changes correlated with reduced liver/fat index, liver pathology score, and oil-red staining area. A pharmacokinetic/pharmacodynamic (PK/PD) model was created from preclinical data to quantify KB levels in rats and validated in humans. Dapagliflozin reduces hepatic steatosis by enhancing fatty acid β-oxidation and ketogenesis and inhibiting fat synthesis. A dynamic model accurately predicts ketone body levels in treated individuals.
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Affiliation(s)
- Zhijie Wan
- State Key Laboratory of Natural Medicine, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Ming Yuan
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Ziao Liu
- State Key Laboratory of Natural Medicine, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Yuan Cai
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
| | - Hua He
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China.
| | - Kun Hao
- State Key Laboratory of Natural Medicine, Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China.
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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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10
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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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11
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American Diabetes Association Professional Practice Committee, 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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12
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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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13
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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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14
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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: 11] [Impact Index Per Article: 11.0] [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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15
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Hirota Y, Kakei Y, Imai J, Katagiri H, Ebihara K, Wada J, Suzuki J, Urakami T, Omori T, Ogawa W. A multicenter, open-label, single-arm trial of the long-term safety of empagliflozin treatment for refractory diabetes mellitus with insulin resistance (EMPIRE-02). J Diabetes Investig 2024; 15:1211-1219. [PMID: 38702973 PMCID: PMC11363127 DOI: 10.1111/jdi.14226] [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: 02/21/2024] [Revised: 03/26/2024] [Accepted: 04/17/2024] [Indexed: 05/06/2024] Open
Abstract
AIMS/INTRODUCTION Insulin resistance syndrome and lipoatrophic diabetes are rare conditions characterized by the development of treatment-refractory diabetes with severe insulin resistance. We recently conducted a 24 week, multicenter, single-arm trial (EMPIRE-01) that demonstrated a certain level of effectiveness and safety of empagliflozin for these conditions. To evaluate treatment safety over a longer period, we have now performed an additional 28 week trial (EMPIRE-02) that followed on from EMPIRE-01. MATERIALS AND METHODS The primary and secondary outcomes were safety and efficacy evaluations, respectively. All eight subjects of the EMPIRE-01 trial participated in EMPIRE-02. RESULTS Twenty adverse events (AEs) were recorded among five individuals during the combined 52 week treatment period of both trials. Whereas one case of chronic hepatitis B was moderate in severity, all other AEs were mild. There were thus no serious AEs or events necessitating discontinuation or suspension of treatment or a reduction in drug dose. Whereas ketoacidosis or marked increases in serum ketone body levels were not observed, the mean body mass of the subjects was decreased slightly after completion of EMPIRE-02. The improvement in mean values of glycemic parameters observed in EMPIRE-01 was not sustained in EMPIRE-02, mostly because of one individual whose parameters deteriorated markedly, likely as a result of nonadherence to diet therapy. The improvement in glycemic parameters was sustained during EMPIRE-02 after exclusion of this subject from analysis. CONCLUSIONS Empagliflozin demonstrated a certain level of safety and efficacy for the treatment of insulin resistance syndrome and lipoatrophic diabetes over 52 weeks, confirming its potential as a therapeutic option.
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Affiliation(s)
- Yushi Hirota
- Division of Diabetes and Endocrinology, Department of Internal MedicineKobe University Graduate School of MedicineKobeJapan
| | - Yasumasa Kakei
- Clinical and Translational Research CenterKobe University HospitalKobeJapan
| | - Junta Imai
- Department of Metabolism and DiabetesTohoku University Graduate School of MedicineMiyagiJapan
| | - Hideki Katagiri
- Department of Metabolism and DiabetesTohoku University Graduate School of MedicineMiyagiJapan
| | - Ken Ebihara
- Division of Endocrinology and Metabolism, Department of Internal MedicineJichi Medical UniversityTochigiJapan
| | - Jun Wada
- Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Faculty of Medicine, Dentistry, and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
| | - Junichi Suzuki
- Department of Pediatrics and Child HealthNihon University School of MedicineTokyoJapan
| | - Tatsuhiko Urakami
- Department of Pediatrics and Child HealthNihon University School of MedicineTokyoJapan
| | - Takashi Omori
- Division of Clinical Biostatistics, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal MedicineKobe University Graduate School of MedicineKobeJapan
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16
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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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17
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Natale P, Tunnicliffe DJ, Toyama T, Palmer SC, Saglimbene VM, Ruospo M, Gargano L, Stallone G, Gesualdo L, Strippoli GF. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev 2024; 5:CD015588. [PMID: 38770818 PMCID: PMC11106805 DOI: 10.1002/14651858.cd015588.pub2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
BACKGROUND Diabetes is associated with high risks of premature chronic kidney disease (CKD), cardiovascular diseases, cardiovascular death and impaired quality of life. People with diabetes are more likely to develop kidney impairment, and approximately one in three adults with diabetes have CKD. People with CKD and diabetes experience a substantially higher risk of cardiovascular outcomes. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors have shown potential effects in preventing kidney and cardiovascular outcomes in people with CKD and diabetes. However, new trials are emerging rapidly, and evidence synthesis is essential to summarising cumulative evidence. OBJECTIVES This review aimed to assess the benefits and harms of SGLT2 inhibitors for people with CKD and diabetes. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 17 November 2023 using a search strategy designed by an Information Specialist. Studies in the Register are continually identified through regular searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled studies were eligible if they evaluated SGLT2 inhibitors versus placebo, standard care or other glucose-lowering agents in people with CKD and diabetes. CKD includes all stages (from 1 to 5), including dialysis patients. DATA COLLECTION AND ANALYSIS Two authors independently extracted data and assessed the study risk of bias. Treatment estimates were summarised using random effects meta-analysis and expressed as a risk ratio (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The primary review outcomes were all-cause death, 3-point and 4-point major adverse cardiovascular events (MACE), fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, and kidney failure. MAIN RESULTS Fifty-three studies randomising 65,241 people with CKD and diabetes were included. SGLT2 inhibitors with or without other background treatments were compared to placebo, standard care, sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, or insulin. In the majority of domains, the risks of bias in the included studies were low or unclear. No studies evaluated the treatment in children or in people treated with dialysis. No studies compared SGLT2 inhibitors with glucagon-like peptide-1 receptor agonists or tirzepatide. Compared to placebo, SGLT2 inhibitors decreased the risk of all-cause death (20 studies, 44,397 participants: RR 0.85, 95% CI 0.78 to 0.94; I2 = 0%; high certainty) and cardiovascular death (16 studies, 43,792 participants: RR 0.83, 95% CI 0.74 to 0.93; I2 = 29%; high certainty). Compared to placebo, SGLT2 inhibitors probably make little or no difference to the risk of fatal or nonfatal MI (2 studies, 13,726 participants: RR 0.95, 95% CI 0.80 to 1.14; I2 = 24%; moderate certainty), and fatal or nonfatal stroke (2 studies, 13,726 participants: RR 1.07, 95% CI 0.88 to 1.30; I2 = 0%; moderate certainty). Compared to placebo, SGLT2 inhibitors probably decrease 3-point MACE (7 studies, 38,320 participants: RR 0.89, 95% CI 0.81 to 0.98; I2 = 46%; moderate certainty), and 4-point MACE (4 studies, 23,539 participants: RR 0.82, 95% CI 0.70 to 0.96; I2 = 77%; moderate certainty), and decrease hospital admission due to heart failure (6 studies, 28,339 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 17%; high certainty). Compared to placebo, SGLT2 inhibitors may decrease creatinine clearance (1 study, 132 participants: MD -2.63 mL/min, 95% CI -5.19 to -0.07; low certainty) and probably decrease the doubling of serum creatinine (2 studies, 12,647 participants: RR 0.70, 95% CI 0.56 to 0.89; I2 = 53%; moderate certainty). SGLT2 inhibitors decrease the risk of kidney failure (6 studies, 11,232 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 0%; high certainty), and kidney composite outcomes (generally reported as kidney failure, kidney death with or without ≥ 40% decrease in estimated glomerular filtration rate (eGFR)) (7 studies, 36,380 participants: RR 0.68, 95% CI 0.59 to 0.78; I2 = 25%; high certainty) compared to placebo. Compared to placebo, SGLT2 inhibitors incur less hypoglycaemia (16 studies, 28,322 participants: RR 0.93, 95% CI 0.89 to 0.98; I2 = 0%; high certainty), and hypoglycaemia requiring third-party assistance (14 studies, 26,478 participants: RR 0.75, 95% CI 0.65 to 0.88; I2 = 0%; high certainty), and probably decrease the withdrawal from treatment due to adverse events (15 studies, 16,622 participants: RR 0.94, 95% CI 0.82 to 1.08; I2 = 16%; moderate certainty). The effects of SGLT2 inhibitors on eGFR, amputation and fracture were uncertain. No studies evaluated the effects of treatment on fatigue, life participation, or lactic acidosis. The effects of SGLT2 inhibitors compared to standard care alone, sulfonylurea, DPP-4 inhibitors, or insulin were uncertain. AUTHORS' CONCLUSIONS SGLT2 inhibitors alone or added to standard care decrease all-cause death, cardiovascular death, and kidney failure and probably decrease major cardiovascular events while incurring less hypoglycaemia compared to placebo in people with CKD and diabetes.
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Affiliation(s)
- Patrizia Natale
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - David J Tunnicliffe
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Tadashi Toyama
- Department of Nephrology, Kanazawa University, Kanazawa, Japan
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan
| | - Suetonia C Palmer
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | - Valeria M Saglimbene
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Marinella Ruospo
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Letizia Gargano
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Loreto Gesualdo
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Fm Strippoli
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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Koufakis T, Patoulias D, Zografou I, Papanas N, Popovic DS. Drawing lines in the sand: The growing threat of obesity in type 1 diabetes. World J Diabetes 2024; 15:823-827. [PMID: 38766422 PMCID: PMC11099370 DOI: 10.4239/wjd.v15.i5.823] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 01/31/2024] [Accepted: 03/12/2024] [Indexed: 05/10/2024] Open
Abstract
In this editorial, we comment on the article by Zeng et al published in the recent issue of the World Journal of Diabetes in 2024. We focus on the epidemiological, pathophysiological, and clinical interplay between obesity and type 1 diabetes mellitus (T1DM). Overweight and obesity represent a growing threat for modern societies and people with T1DM could not be an exception to this rule. Chronic exogenous insulin administration, genetic and epigenetic factors, and psy-chosocial and behavioral parameters, along with the modern way of life that incorporates unhealthy eating patterns and physical inactivity, set the stage for the increasing obesity rates in T1DM. As our knowledge of the underlying mechanisms that lead to the development of obesity and hyperglycemia expands, it becomes clear that there are overlap zones in the pathophysiology of the two main types of diabetes. Stereotypes regarding strict dividing lines between "autoimmune" and "metabolic" phenotypes increase the risk of trapping physicians into ineffective therapeutic approaches, instead of individualized diabetes care. In this context, the use of adjuncts to insulin therapy that have the potential to alleviate cardiorenal risk and decrease body weight can reduce the burden of obesity in patients with T1DM.
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Affiliation(s)
- Theocharis Koufakis
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Ioanna Zografou
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis 68100, Greece
| | - Djordje S Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Center of Vojvodina, Medical Faculty, University of Novi Sad, Novi Sad 21000, Serbia
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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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20
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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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21
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Kueh MTW, Chew NWS, Al-Ozairi E, le Roux CW. The emergence of obesity in type 1 diabetes. Int J Obes (Lond) 2024; 48:289-301. [PMID: 38092958 PMCID: PMC10896727 DOI: 10.1038/s41366-023-01429-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 11/14/2023] [Accepted: 11/23/2023] [Indexed: 02/28/2024]
Abstract
Obesity, a chronic low-grade inflammatory disease represented by multifactorial metabolic dysfunctions, is a significant global health threat for adults and children. The once-held belief that type 1 diabetes is a disease of people who are lean no longer holds. The mounting epidemiological data now establishes the connection between type 1 diabetes and the subsequent development of obesity, or vice versa. Beyond the consequences of the influx of an obesogenic environment, type 1 diabetes-specific biopsychosocial burden further exacerbates obesity. In the course of obesity management discussions, recurring challenges surfaced. The interplay between weight gain and escalating insulin dependence creates a vicious cycle from which patients struggle to break free. In the absence of weight management guidelines and regulatory approval for this population, healthcare professionals must navigate the delicate balance between benefits and risks. The gravity of this circumstance highlights the importance of bringing these topics to the forefront. In this Review, we discuss the changing trends and the biopsychosocial aspects of the intersection between type 1 diabetes and obesity. We highlight the evidence supporting the therapeutic means (i.e., exercise therapy, nutritional therapy, adjunct pharmacotherapy, and bariatric surgery) and directions for establishing a more robust and safer evidence-based approach.
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Affiliation(s)
- Martin T W Kueh
- UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
- Royal College of Surgeons in Ireland & University College Dublin Malaysia Campus, Dublin, Malaysia.
| | - Nicholas W S Chew
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
| | - Ebaa Al-Ozairi
- Dasman Diabetes Institute, Kuwait City, Kuwait
- Department of Medicine, College of Medicine, Jabriya, Kuwait
| | - Carel W le Roux
- Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland.
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22
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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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Hirota Y, Kakei Y, Imai J, Katagiri H, Ebihara K, Wada J, Suzuki J, Urakami T, Omori T, Ogawa W. A Multicenter, Open-Label, Single-Arm Trial of the Efficacy and Safety of Empagliflozin Treatment for Refractory Diabetes Mellitus with Insulin Resistance (EMPIRE-01). Diabetes Ther 2024; 15:533-545. [PMID: 38216831 PMCID: PMC10838887 DOI: 10.1007/s13300-023-01526-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/15/2023] [Indexed: 01/14/2024] Open
Abstract
INTRODUCTION Insulin resistance syndrome and lipoatrophic diabetes are characterized by severe insulin resistance and are often refractory to treatment. Trials assessing the efficacy of antidiabetes drugs for these rare conditions have been limited, however. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower glycemia independently of insulin action, have shown efficacy for type 2 diabetes with insulin resistance. We here investigated the efficacy and safety of the SGLT2 inhibitor empagliflozin for treatment of insulin resistance syndrome and lipoatrophic diabetes. METHODS The trial was conducted at five academic centers in Japan and included seven patients with insulin resistance syndrome and one patient with lipoatrophic diabetes. Participants received 10 mg of empagliflozin daily. If the hemoglobin A1c (HbA1c) level was ≥ 7.0% (52 mmol/mol) after 12 weeks, the dose was adjusted to 25 mg. The study duration was 24 weeks, and the primary outcome was the change in HbA1c level by the end of the treatment period. Safety evaluations were performed for all participants. RESULTS By the end of the 24-week treatment period, the mean HbA1c level for all eight patients had decreased by 0.99 percentage points (10.8 mmol/mol) (95% confidence interval [CI], 0.59 to 1.38 percentage points, 6.6 to 14.9 mmol/mol) and the mean fasting plasma glucose concentration had declined by 63.9 mg/dL (3.55 mmol/L) (95% CI 25.5 to 102.3 mg/dL, 1.42 to 5.68 mmol/L). Continuous glucose monitoring revealed a reduction in mean glucose levels from 164.3 ± 76.1 to 137.6 ± 46.6 mg/dL (9.13 ± 4.23 to 7.65 ± 2.59 mmol/L) as well as an increase in the time in range (70-180 mg/dL) from 58.9 ± 36.1% to 70.8 ± 18.3%. Seventeen mild adverse events were recorded in five individuals throughout the study period. No severe events were reported. The mean body mass showed a slight decrease and the mean serum ketone body concentration showed a slight increase during treatment. CONCLUSION Our results demonstrate that empagliflozin shows a certain level of efficacy and safety for treatment of insulin resistance syndrome and lipoatrophic diabetes. TRIAL REGISTRATION jRCTs2051190029 and NCT04018365.
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Affiliation(s)
- Yushi Hirota
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yasumasa Kakei
- Clinical and Translational Research Center, Kobe University Hospital, Kobe, Japan
| | - Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Ken Ebihara
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
| | - Jun Wada
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Junichi Suzuki
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Tatsuhiko Urakami
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Takashi Omori
- Division of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
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24
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American Diabetes Association Professional Practice Committee, 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: 168] [Impact Index Per Article: 168.0] [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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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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26
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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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27
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Durán-Martínez M, Azriel S, Doulatram-Gamgaram VK, Moreno-Pérez Ó, Pinés-Corrales PJ, Tejera-Pérez C, Merino-Torres JF, Brito-Sanfiel M, Chico A, Marco A, García-Fernández E, Martínez-Montoro JI. Real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes in Spain: The Dapa-ON multicenter retrospective study. DIABETES & METABOLISM 2024; 50:101501. [PMID: 38061425 DOI: 10.1016/j.diabet.2023.101501] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/06/2023] [Accepted: 11/24/2023] [Indexed: 12/26/2023]
Abstract
OBJECTIVE To assess real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes mellitus (T1DM). METHODS We conducted a multicenter retrospective study in Spain including data from 250 people living with T1DM receiving dapagliflozin as add-on therapy to insulin (80.8 % on-label use). The number of diabetic ketoacidosis (DKA) events was calculated over a 12-month follow-up (primary outcome). Changes in body weight, HbA1c, total daily insulin dose, and continuous glucose monitoring (CGM) metrics from baseline (at dapagliflozin prescription) to 12 months were also evaluated. RESULTS A total of five DKA events (2.4 % [95 % CI 0.3;4.5] were reported in patients with a 12-month follow-up, n = 207): two events related to insulin pump malfunction, two events related to concomitant illnesses, and one event related to insulin dose omission. DKA events were more frequent among insulin pump users than among participants on multiple daily injections (7.7 % versus 1.2 %). Four of the reported DKA events occurred within the first six months after initiation of dapagliflozin. No deaths or persistent sequelae due to DKA were reported. No severe hypoglycemia episodes were reported. Significant reductions in mean body weight (-3.3 kg), HbA1c (-0.6 %), and total daily insulin dose (-8.6 %), P < 0.001, were observed 12 months after dapagliflozin prescription. Significant improvements in TIR (+9.3 %), TAR (-7.2 %), TBR (-2.5 %), and coefficient of variation (-5.1 %), P < 0.001, were also observed in the subgroup of patients with available CGM data. Finally, an improvement in urinary albumin-to-creatinine ratio (UACR) was found among participants with UACR ≥ 30 mg/g at baseline (median decrease of 99 mg/g in UACR, P = 0.001). CONCLUSION The use of dapagliflozin in people living with T1DM has an appropriate safety profile after careful selection of participants and implementation of strategies to reduce the risk of DKA (i.e., prescribed according to the recommendations of the European Medicines Agency), and also leads to clinical improvements in this population.
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Affiliation(s)
- María Durán-Martínez
- Department of Endocrinology and Nutrition, Getafe University Hospital, Madrid, Spain; Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Spain
| | - Sharona Azriel
- Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Spain; Department of Endocrinology and Nutrition, Infanta Sofia University Hospital, Madrid, Spain
| | - Viyey Kishore Doulatram-Gamgaram
- Department of Endocrinology and Nutrition, Regional University Hospital of Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma Bionand, Málaga, Spain
| | - Óscar Moreno-Pérez
- Endocrinology and Nutrition Department, Dr. Balmis General University Hospital - Alicante Institute of Sanitary and Biomedical Research (ISABIAL), Alicante, Spain; Clinical Medicine Department, Miguel Hernández University, Elche, Alicante, Spain
| | - Pedro J Pinés-Corrales
- Department of Endocrinology and Nutrition, Albacete University Hospital, Albacete, Spain
| | - Cristina Tejera-Pérez
- Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Ferrol (CHUF/SERGAS), A Coruña, Spain; Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), Santiago de Compostela, Spain
| | - Juan Francisco Merino-Torres
- Department of Endocrinology and Nutrition, University and Polytechnic Hospital La Fe, Valencia, Spain; Joint Research Unit On Endocrinology, Nutrition and Clinical Dietetics, University of Valencia-Health Research Institute La Fe, Valencia, Spain; Medicine Department, Universitat de València, Valencia, Spain
| | - Miguel Brito-Sanfiel
- Department of Endocrinology and Nutrition, Puerta de Hierro University Hospital, Madrid, Spain
| | - Ana Chico
- Department of Endocrinology and Nutrition, Hospital Santa Creu i Sant Pau, Barcelona, Spain; CIBER-BBN, Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Amparo Marco
- Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Spain; Department of Endocrinology and Nutrition, Toledo University Hospital, Toledo, Spain
| | - Elena García-Fernández
- Department of Endocrinology and Nutrition, 12 de Octubre University Hospital, Madrid, Spain
| | - José Ignacio Martínez-Montoro
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Málaga, Spain; Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma Bionand, Málaga, Spain; Faculty of Medicine, University of Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y la Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain.
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Maffei P, Bettini S, Busetto L, Dassie F. SGLT2 Inhibitors in the Management of Type 1 Diabetes (T1D): An Update on Current Evidence and Recommendations. Diabetes Metab Syndr Obes 2023; 16:3579-3598. [PMID: 37964939 PMCID: PMC10642354 DOI: 10.2147/dmso.s240903] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 10/24/2023] [Indexed: 11/16/2023] Open
Abstract
SGLT2i (sodium glucose transporter type 2 inhibitors) are pharmacological agents that act by inhibiting the SGLT2, by reducing the renal plasma glucose threshold and inducing glycosuria, resulting in a blood glucose lowering effect. In recent years, studies demonstrating some additional positive effects of SGLT2i also in the treatment of T1D have increased progressively. The SGLT2i dapagliflozin and sotagliflozin have been temporarily licensed for use by the European Medical Agency (EMA) as an adjunct to insulin therapy in adults with T1D with a body mass index of 27 kg/m2 or higher. However, in the meantime, the US Food and Drug Administration (FDA) Endocrinologic and Metabolic Drugs Advisory Committee was divided, citing concerns about the main side effects of SGLT2i, especially diabetic ketoacidosis (DKA). The aim of this manuscript was to conduct an update on current evidence and recommendations of the reported use of SGLT2i in the treatment of T1D in humans. Preclinical studies, clinical trial and real world data suggest benefits in glycaemia control and nefro-cardiovascular protection, even though several studies have documented an important increase in the risk of DKA, a serious and life-threatening adverse event of these agents. SGLT2i potentially addresses some of the unmet needs associated with T1D by improving glycaemic control with weight loss and without increasing hypoglycemia, by reducing glycaemic variability. However, due to side effects, EMA recommendation for SGLT2 use on T1D was withdrawn. Further studies will be needed to determine the safety of this therapy in T1D and to define the type of patient who can benefit most from these medications.
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Affiliation(s)
- Pietro Maffei
- Department of Medicine, Padua University, Padua, Italy
| | | | - Luca Busetto
- Department of Medicine, Padua University, Padua, Italy
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Stougaard EB, Amadid H, Søndergaard E, Carstensen B, Jørgensen ME, Nørgaard K, Rossing P, Persson F, Vistisen D. Time Trends in the Incidence of Diabetic Ketoacidosis Leading to Hospital Admission Among Adults With Type 1 Diabetes: A Nationwide Danish Register Study. Diabetes Care 2023; 46:1897-1902. [PMID: 37432944 DOI: 10.2337/dc23-0475] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 06/07/2023] [Indexed: 07/13/2023]
Abstract
OBJECTIVE Diabetic ketoacidosis (DKA) is a life-threatening but preventable complication in people with type 1 diabetes. We aimed to quantify the incidence of DKA according to age and describe the time trend of DKA among adults with type 1 diabetes in Denmark. RESEARCH DESIGN AND METHODS Individuals aged ≥18 years with type 1 diabetes were identified from a nationwide Danish diabetes register. Hospital admissions due to DKA were ascertained from the National Patient Register. The follow-up period was from 1996 to 2020. RESULTS The cohort consisted of 24,718 adults with type 1 diabetes. The incidence rate of DKA per 100 person-years (PY) decreased with increasing age for both men and women. From 20 to 80 years of age, the DKA incidence rate decreased from 3.27 to 0.38 per 100 PY. From 1996 to 2008, the incidence rate of DKA increased for all age-groups, with a subsequent minor decrease in incidence rate until 2020. From 1996 to 2008, the incidence rates increased from 1.91 to 3.77 per 100 PY for a 20-year-old individual and from 0.22 to 0.44 per 100 PY for an 80-year-old individual living with type 1 diabetes. From 2008 to 2020 the incidence rates decreased from 3.77 to 3.27 and from 0.44 to 0.38 per 100 PY, respectively. CONCLUSIONS The incidence rates of DKA are declining for all ages, with an overall decline from 2008 for both men and women. This likely reflects improved diabetes management for individuals with type 1 diabetes in Denmark.
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Affiliation(s)
| | - Hanan Amadid
- Clinical Epidemiology, Steno Diabetes Center Copenhagen, Capital Region, Denmark
| | | | - Bendix Carstensen
- Clinical Epidemiology, Steno Diabetes Center Copenhagen, Capital Region, Denmark
| | - Marit E Jørgensen
- Clinical Epidemiology, Steno Diabetes Center Copenhagen, Capital Region, Denmark
- Steno Diabetes Center Greenland, Nuuk, Greenland
- National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark
| | - Kirsten Nørgaard
- Diabetes Technology Research, Steno Diabetes Center Copenhagen, Capital Region, Denmark
- Department of Clinical Medicine, University of Copenhagen, Capital Region, Denmark
| | - Peter Rossing
- Complication Research, Steno Diabetes Center Copenhagen, Capital Region, Denmark
- Department of Clinical Medicine, University of Copenhagen, Capital Region, Denmark
| | - Frederik Persson
- Complication Research, Steno Diabetes Center Copenhagen, Capital Region, Denmark
| | - Dorte Vistisen
- Clinical Epidemiology, Steno Diabetes Center Copenhagen, Capital Region, Denmark
- Department of Public Health, University of Copenhagen, Capital Region, Denmark
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Sokolov V, Yakovleva T, Penland RC, Boulton DW, Tang W. Effectiveness of dapagliflozin as an insulin adjunct in type 1 diabetes: a semi-mechanistic exposure-response model. Front Pharmacol 2023; 14:1229255. [PMID: 37954838 PMCID: PMC10634426 DOI: 10.3389/fphar.2023.1229255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 10/04/2023] [Indexed: 11/14/2023] Open
Abstract
Introduction: Dapagliflozin-induced improvement of glycemic control in patients with inadequately controlled type 1 diabetes (T1D) is complicated by the delicate balance between blood glucose and exogenous insulin. In this work, we developed a semi-mechanistic population exposure-response model using pooled patient-level data to characterize the joint effect of dapagliflozin and insulin on average daily glucose concentrations and glycated hemoglobin (HbA1c) levels in patients with T1D. Methods: A non-linear mixed-effects model was developed in Monolix (Lixoft, France) and R software (R Project, www.r-project.org) using pooled patient-level data from phase 2 and phase 3 trials (NCT01498185, NCT02460978, NCT02268214). Results: Because of the apparent lack of association between bolus insulin dose and glucose concentrations measured by continuous glucose monitoring the model was able to capture the quantitative link between basal, but not bolus, insulin dose and plasma glucose. Even so, this association remained flat, with a 50% decrease in the basal insulin dose from pretreatment level, resulting in ∼5% increase in glucose exposure. Therefore, dapagliflozin efficacy was not significantly affected by the insulin dose adjustment, with 24-week HbA1c reduction on 10-mg dapagliflozin treatment changing from -0.5 [95% CI: -0.55, -0.45] to -0.42 [95%CI: -0.48, -0.36] after adjustment. At the same time, the analysis revealed ∼2-fold steeper slope of glucose-HbA1c relationship in dapagliflozin-treated patients vs. control group, suggesting the presence of additional dapagliflozin treatment-related benefits, not explained by the dapagliflozin-mediated ∼4% increase in plasma hemoglobin levels. Finally, the efficacy of 5 and 10-mg doses, represented by the mean HbA1c reduction at week 24 of dapagliflozin treatment, was shown to be notably greater than the 1- and 2.5-mg doses. Discussion: This research is an attempt to deconvolute and reconstruct dapagliflozin-HbA1c dose-response relationship in T1D by accounting for the drug's action on both daily insulin dose and plasma glucose on a subject-level. While the model is able to adequately capture the observed data, it also revealed that the variability in CGM is poorly approximated by the variability in insulin dose alone. Furthermore, the slope of CGM/HbA1c relationship may differ depending on the population and treatment scenarios. As such, a deeper dive into the physiological mechanisms is required to better quantify the intricate network of glycemic response under dapagliflozin treatment.
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Affiliation(s)
- Victor Sokolov
- M&S Decisions LLC, Moscow, Russia
- STU “Sirius”, Sochi, Russia
| | | | - Robert C. Penland
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Waltham, MA, United States
| | - David W. Boulton
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Weifeng Tang
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, United States
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Anson M, Zhao SS, Austin P, Ibarburu GH, Malik RA, Alam U. SGLT2i and GLP-1 RA therapy in type 1 diabetes and reno-vascular outcomes: a real-world study. Diabetologia 2023; 66:1869-1881. [PMID: 37505282 PMCID: PMC10473989 DOI: 10.1007/s00125-023-05975-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 06/06/2023] [Indexed: 07/29/2023]
Abstract
AIMS/HYPOTHESIS Insulin is the primary treatment for type 1 diabetes. However, alternative glucose-lowering therapies are used adjunctively, but importantly are off-label in type 1 diabetes. Little work has previously been undertaken to evaluate safety with long-term efficacy and cardio-renal benefits of such therapies. We sought to investigate the real-world impact of sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in individuals with type 1 diabetes in relation to effect on blood glucose levels, adverse events and cardio-renal outcomes. METHODS We performed a retrospective cohort study of all patients aged 18 or over with type 1 diabetes on the TriNetX platform, a global collaborative network providing access to real-time, anonymised medical records. We included patients who had been treated with an SGLT2i or GLP-1 RA for at least 6 months and analysed the efficacy, safety and cardio-renal outcomes 5 years after initiation of therapy. RESULTS We identified 196,691 individuals with type 1 diabetes, 13% of whom were treated with adjunctive glucose-lowering therapy in addition to insulin. Included in the core analysis were 1822 patients treated with a GLP-1 RA and 992 individuals treated with an SGLT2i. Both agents provided clinically meaningful reductions in HbA1c (-2.6 mmol/mol [-0.2%] with SGLT2i and -5.4 mmol/mol [-0.5%] with GLP-1 RA). The SGLT2i treated cohort showed preservation of eGFR over a 5-year period compared with the GLP-1 RA treated cohort (+3.5 ml/min per 1.73 m2 vs -7.2 ml/min per 1.73 m2, respectively), including patients with established chronic kidney disease (CKD). The SGLT2i treated cohort experienced higher rates of diabetic ketoacidosis (DKA) (RR 2.08 [95% CI 1.05, 4.12] p=0.0309) and urinary tract infection/pyelonephritis (RR 2.27 [95% CI 1.12, 4.55] p=0.019) compared with the GLP-1 RA treated cohort. However, the SGLT2i treated cohort were less likely to develop heart failure (RR 0.44 [95% CI 0.23, 0.83] p=0.0092), CKD (RR 0.49 [95% CI 0.28, 0.86] p=0.0118) and be hospitalised for any cause (RR 0.59 [95% CI 0.46, 0.76] p≤0.0001) when compared with the GLP-1 RA treated cohort. CONCLUSIONS/INTERPRETATION Both SGLT2is and GLP-1 RAs have potential benefits as adjunctive agents in type 1 diabetes. SGLT2is provide cardio-renal benefits, despite an increase in the risk of DKA and urinary tract infection compared with GLP-1 RA therapy. Long-term evaluation of the efficacy and safety of these adjunctive therapies is required to guide their use in individuals with type 1 diabetes.
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Affiliation(s)
- Matthew Anson
- Diabetes & Endocrinology Research and Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool, UK
| | - Sizheng S Zhao
- Centre for Epidemiology Versus Arthritis, Faculty of Biological Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | | | | | | | - Uazman Alam
- Diabetes & Endocrinology Research and Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool, UK.
- Centre for Biomechanics and Rehabilitation Technologies, Staffordshire University, Stoke-on-Trent, UK.
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Steinhorn B, Wiener-Kronish J. Dose-dependent relationship between SGLT2 inhibitor hold time and risk for postoperative anion gap acidosis: a single-centre retrospective analysis. Br J Anaesth 2023; 131:682-686. [PMID: 37541949 DOI: 10.1016/j.bja.2023.06.063] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/17/2023] [Accepted: 06/19/2023] [Indexed: 08/06/2023] Open
Abstract
BACKGROUND Use of sodium-glucose transporter-2 (SGLT2) inhibitors has dramatically increased over the past decade. This medication class predisposes patients to euglycaemic diabetic ketoacidosis, particularly during times of physiologic stress, including fasting and surgery. Beyond case reports and series, a systematic description of perioperative metabolic effects of SGLT2 inhibitors is lacking. METHODS We examined the degree of anion gap acidosis, controlling for non-ketone anions, in patients undergoing surgery at Massachusetts General Hospital in 2016-22. We constructed a multivariable regression model incorporating known non-ketone contributors to the postoperative anion gap (albumin, lactate, estimated glomerular filtration rate, and preoperative anion gap), hold time, and interaction terms between hold time and three previously suggested risk factors for euglycaemic diabetic ketoacidosis: emergency surgery, cardiac surgery, and insulin use. RESULTS In 463 patients on SGLT2 inhibitors, we observed a strong association between decreased hold time and postoperative anion gap (P<0.001 in a univariable analysis; -0.43, 95% confidence interval [-0.76 to -0.11] change in anion gap per day held, P=0.01 in a multivariable analysis). A significant interaction between hold time and emergency surgery was observed, whereas there was no apparent interaction with insulin use or cardiac surgery. CONCLUSIONS These findings provide the first evidence that an anion gap acidosis, likely from ketoacids, develops in all patients who do not hold SGLT2 inhibitors before surgery rather than in an idiosyncratic few. If an SGLT2 inhibitor is unable to be stopped, postoperative monitoring of anion gap and serum ketones can help detect clinically significant euglycaemic diabetic ketoacidosis, particularly in those undergoing emergency surgery.
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Affiliation(s)
- Benjamin Steinhorn
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
| | - Jeanine Wiener-Kronish
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
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Abiru N, Nakatsuji Y, Noguchi M, Tsuboi K. Overlapping risk factors for diabetic ketoacidosis in patients with type 1 diabetes on ipragliflozin: case analysis of spontaneous reports in Japan from a pharmacovigilance safety database. Expert Opin Drug Saf 2023; 22:697-706. [PMID: 36946980 DOI: 10.1080/14740338.2023.2193393] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 03/08/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND In patients with type 1 diabetes mellitus (T1D), sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with an increased risk of diabetic ketoacidosis (DKA). Ipragliflozin is an SGLT2 inhibitor approved in Japan in combination with insulin for patients with T1D. RESEARCH DESIGN AND METHODS Spontaneous safety reports of ipragliflozin adverse drug reactions (ADRs) in patients with T1D were collected during early post-marketing phase vigilance (EPPV; 21 December 2018-20 June 2019). For patients with T1D prescribed ipragliflozin who experienced DKA, we examined DKA event data registered in the manufacturer's safety database (21 December 2018-31 December 2021), including patient background characteristics. RESULTS During EPPV, there were 189 total events (45 serious) of ADRs, including 32 serious events of ketoacidosis. From 2018 to 2021, the major DKA risk factors were sick days, stopping or inappropriately decreasing insulin, insulin pump trouble, and low carbohydrate diet, with substantial overlap among these factors. CONCLUSIONS In Japanese patients with T1D using ipragliflozin, DKA events were linked to several overlapping factors, including sick days and reduced dose/interruption of insulin, whether intentional or unexpected. These results highlight the need for improved patient education regarding ipragliflozin use and appropriate self-management of ketosis from an early stage.
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Affiliation(s)
- Norio Abiru
- Department of Endocrinology and Metabolism, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
- Midori Clinic, Nagasaki, Japan
| | | | | | - Keigo Tsuboi
- Medical Affairs, Astellas Pharma Inc., Tokyo, Japan
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Tian Y, Hu W, Yan Q, Feng B. Benefit or Risk in Patient with Type 1 Diabetes Based on Appropriated Dosage of Dapagliflozin: A Case Report. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59050827. [PMID: 37241059 DOI: 10.3390/medicina59050827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/18/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023]
Abstract
Purpose: Dapagliflozin has been used extensively in patients with type 2 diabetes mellitus (T2DM). However, due to the potential diabetic ketoacidosis (DKA) risk of dapagliflozin, its use in type 1 diabetes mellitus (T1DM) is limited. Here, we reported an obese patient with T1DM and inadequate glycemic control. We carefully recommended she use dapagliflozin as an insulin adjuvant to achieve better glycemia control and to assess possible benefits and risks. Methods and Results: The patient was a 27-year-old female who had underlying T1DM for 17 years with a body weight of 75.0 kg, body mass index (BMI) of 28.2 kg/m2, and glycated hemoglobin (HbA1c) 7.7% when admitted. To treat her diabetes, she had used an insulin pump for 15 years (the recent dosage of insulin was 45 IU/d) and oral metformin for 3 years (0.5 g qid). In order to decrease body weight and achieve better glycemic control, dapagliflozin (FORXIGA, AstraZeneca, Indiana) was administered as an insulin adjuvant. The patient presented sever DKA with a euglycemia (euDKA) after two days of the administration of dapagliflozin at a dose of 10 mg/d. euDKA occurred again after the administration of dapagliflozin at a dose of 3.3 mg/d. However, after using a smaller dose of dapagliflozin (1.5 mg/d), this patient achieved better glycemia control, with a significant reduction in daily insulin dosage and gradual weight loss, without significant hypoglycemia or DKA occurring. At the sixth month of the administration of dapagliflozin, the HbA1c was 6.2% for the patient, her daily insulin dosage was 22.5 IU, and her body weight was 60.2 kg. Conclusions: The appropriate dose of dapagliflozin is critical for a patient with T1DM patient therapy in order to find a correct balance between the benefits and risks.
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Affiliation(s)
- Yan Tian
- Department of Endocrinology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Weiting Hu
- Department of Endocrinology, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan 030002, China
| | - Qun Yan
- Department of Endocrinology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Bo Feng
- Department of Endocrinology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
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Tan X, Pan X, Wu X, Zheng S, Chen Y, Liu D, Zhang X. Glucagon-like peptide-1 receptor agonists as add-on therapy to insulin for type 1 diabetes mellitus. Front Pharmacol 2023; 14:975880. [PMID: 38249345 PMCID: PMC10797415 DOI: 10.3389/fphar.2023.975880] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 01/31/2023] [Indexed: 01/23/2024] Open
Abstract
Background: To assess the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) used as an adjunct to insulin therapy in adults with type 1 diabetes. Methods: A search of electronic databases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) from 1 January 1950 to 23 May 2021 was conducted to find randomized controlled trials. The primary outcome was the change in HbA1c. Eight efficacy and six safety secondary endpoints were evaluated via meta-analysis. Weighted mean difference (WMD) and odds ratio (OR), alongside 95% confidence interval (CI), were calculated using the random effects model. Results: Among 1,379 candidate studies, 11 trials comprising 2,856 participants satisfied the inclusion criteria. Overall, GLP-1 RA adjunctive therapy reduced HbA1c by -0.21% (95% CI, -0.33 to -0.10), weight by -4.04 kg (-4.8 to -3.27), systolic pressure by -2.57 mmHg (-4.11 to -1.03), and diastolic blood pressure by -1.02 mmHg (-1.99 to -0.06). In addition, there was a decrease in prandial insulin dose (WMD, -4.23 IU; 95% CI, -5.26 to -3.20), basal insulin dose (-2.40 IU; -3.93 to -0.87), and total insulin dose (-5.73 IU; -10.61 to -0.86). Moreover, GLP-1 RAs did not increase the incidence of severe hypoglycemia, diabetic ketoacidosis, or severe adverse events. However, GLP-1 RAs increased the incidence of gastrointestinal adverse events (OR, 2.96; 95% CI, 2.33-3.77). Conclusion: Our meta-analysis of randomized clinical trials suggests moderate beneficial effects of GLP-1 RAs on the metabolic profile in patients with type 1 diabetes, without an increased risk of serious adverse events. Clinical Trial Registration: https://www.crd.york.ac.uk/PROSPERO; Identifier: CRD 42020199840.
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Affiliation(s)
- Xinrui Tan
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiongfeng Pan
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Xiaochuan Wu
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Songjia Zheng
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuyao Chen
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Donghai Liu
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xingxing Zhang
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Edwards K, Li X, Lingvay I. Clinical and Safety Outcomes With GLP-1 Receptor Agonists and SGLT2 Inhibitors in Type 1 Diabetes: A Real-World Study. J Clin Endocrinol Metab 2023; 108:920-930. [PMID: 36268825 DOI: 10.1210/clinem/dgac618] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/03/2022] [Indexed: 11/19/2022]
Abstract
CONTEXT Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are used off-label in the management of type 1 diabetes mellitus (T1DM) in real-world practice as adjuvant therapies to insulin. There are few real-world data regarding efficacy and safety of this practice. OBJECTIVE This work aimed to determine the efficacy and safety of GLP-1RAs and sodium-glucose SGLT2is in the management of T1DM in real-world practice. METHODS A retrospective chart review was performed of all instances of GLP-1RA and/or SGLT2i use greater than 90 days in adult patients with T1DM at a single academic center. We report the clinical and safety outcomes over the duration of use. RESULTS We identified 104 patients with T1DM who ever used a GLP-1RA (76 patients) or SGLT2i (39 patients) for more than 90 days. After 1 year of therapy, GLP-1RA users had statistically significant reductions in weight (90.5 kg to 85.4 kg; P < .001), glycated hemoglobin A1c (HbA1c) (7.7% to 7.3%; P = .007), and total daily dose of insulin (61.8 units to 41.9 units; P < .001). SGLT2i users had statistically significant reductions in HbA1c (7.9% to 7.3%; P < .001) and basal insulin (31.3 units to 25.6 units; P = .003). GLP-1RA users compared to SGLT2i users had greater reduction in weight (P = .027) while HbA1c reduction was comparable between the groups. Over a mean total duration of use of 29.5 months/patient for both groups, more SGLT2i users experienced diabetic ketoacidosis (DKA) (12.8% vs 3.9%). Therapy was discontinued because of adverse events 26.9% of the time for GLP-1RA users vs 27.7% for SGLT2i users. CONCLUSION GLP-1RA and SGLT2i use in T1DM is associated with clinically relevant benefits. DKA remains a clinical concern with SGLT2i use, requiring careful patient selection and monitoring, with the risk to benefit ratio of treatment evaluated at an individual level.
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Affiliation(s)
- Khary Edwards
- Department of Internal Medicine/Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857, USA
| | - Xilong Li
- Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857, USA
| | - Ildiko Lingvay
- Department of Internal Medicine/Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857, USA
- Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857, USA
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Stougaard EB, Rossing P, Vistisen D, Banks P, Girard M, Davies MJ, Persson F. Sotagliflozin, a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 inhibitor, reduces the risk of cardiovascular and kidney disease, as assessed by the Steno T1 Risk Engine in adults with type 1 diabetes. Diabetes Obes Metab 2023. [PMID: 36872068 DOI: 10.1111/dom.15047] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/07/2023]
Abstract
AIMS Sotagliflozin (SOTA) as adjunct to insulin therapy improves glycemic control, reduces body weight and blood pressure, and increases time in range in adults with type 1 diabetes (T1D). SOTA demonstrated CV and kidney benefits in high-risk adults with type 2 diabetes. These potential benefits using SOTA for T1D may collectively outweigh the risk of diabetic ketoacidosis. The present analysis estimated the risk of CVD and kidney failure in adults with T1D treated with SOTA. MATERIALS AND METHODS Participant-level data were used from the inTandem trials evaluating 2980 adults with T1D randomized to once-daily placebo, SOTA 200 mg, or SOTA 400 mg for 24 weeks. For each participant, the cumulative risks of developing CVD and kidney failure were estimated using the Steno T1 Risk Engine. A subgroup analysis was performed in participants with BMI ≥ 27 kg/m2 . RESULTS SOTA significantly reduced the predicted 5- and 10-year CVD risk in the SOTA 200 and 400 mg pooled group with a relative change in the SOTA group compared to the relative change in the placebo group of (mean [95%-confidence interval (CI)]) -6.6 (-7.9, -5.3) % and -6.4 (-7.6, -5.1) % (p < 0.0001 for both) respectively. For the 5-year ESKD risk there was a significant reduction with a relative change of -5.0 (-7.6, -2.3) % (p = 0.0003). Similar results were observed with the individual doses and in participants with BMI ≥ 27 kg/m2 . CONCLUSION This analysis provides additional clinical results that may positively balance the benefit/risk assessment of SGLT inhibition use in T1D.
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Affiliation(s)
| | - Peter Rossing
- Complication Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, University of Copenhagen, Herlev, Denmark
| | - Dorte Vistisen
- Clinical Epidemiology, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Public Health, University of Copenhagen, Herlev, Denmark
| | - Phillip Banks
- Lexicon Pharmaceuticals, Inc., The Woodlands, Texas, USA
| | - Manon Girard
- Lexicon Pharmaceuticals, Inc., The Woodlands, Texas, USA
| | | | - Frederik Persson
- Complication Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
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Al-Ozairi E, Irshad M, Taghadom E, Sojan L, Al Kandari J, Alroudhan D, le Roux CW. Glucagon-like peptide-1 agonists combined with sodium-glucose cotransporter-2 inhibitors reduce weight in type 1 diabetes. Obesity (Silver Spring) 2023; 31:716-723. [PMID: 36811241 DOI: 10.1002/oby.23677] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/02/2022] [Accepted: 11/22/2022] [Indexed: 02/24/2023]
Abstract
OBJECTIVE This study evaluated whether adding sodium-glucose cotransporter-2 inhibitors (SGLT2i) and/or glucagon-like peptide-1 receptor agonists (GLP1-RA) to insulin reduced weight and glycemia in people with type 1 diabetes. METHODS This retrospective analysis of electronic health records evaluated 296 people with type 1 diabetes over 12 months after medications were first prescribed. Four groups were defined: control n = 80, SGLT2i n = 94, GLP1-RA n = 82, and combination of drugs (Combo) n = 40. We measured changes at 1 year in weight and glycated hemoglobin (HbA1c). RESULTS The control group did not have changes in weight or glycemic control. The mean (SD) percentage weight loss after 12 months was 4.4% (6.0%), 8.2% (8.5%), and 9.0% (8.4%) in the SGLT2i, GLP1-RA, and Combo groups, respectively (p < 0.001). The Combo group lost the most weight (p < 0.001). The HbA1c reduction was 0.4% (0.7%), 0.3% (0.7%), and 0.6% (0.8%) in the SGLT2i, GLP1-RA, and Combo groups, respectively (p < 0.001). The Combo group had the biggest improvements in glycemic control and total and low-density lipoprotein cholesterol compared with baseline (all p < 0.01). Severe adverse events were similar between all the groups, with no increased risk of diabetic ketoacidosis. CONCLUSIONS The SGLT2i and GLP1-RA agents on their own improved body weight and glycemia, but combining the medications resulted in more weight loss. Treatment intensification appears to result in benefits with no difference in severe adverse events.
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Affiliation(s)
- Ebaa Al-Ozairi
- Dasman Diabetes Institute, Kuwait City, Kuwait
- Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | | | | | - Litty Sojan
- Dasman Diabetes Institute, Kuwait City, Kuwait
| | | | | | - Carel W le Roux
- Diabetes Complications Research Center, UCD Conway Institute, University College Dublin School of Medicine, Dublin, Ireland
- Diabetes Research Centre, Ulster University, Coleraine, UK
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Wang DD, Zhang C, Hu K, He SM, Zhu P, Chen X. Therapeutic effect and rebound evaluation of dapagliflozin on glycated hemoglobin (HbA1c) in type 1 diabetes mellitus patients. Front Pharmacol 2023; 13:972878. [PMID: 36686651 PMCID: PMC9845776 DOI: 10.3389/fphar.2022.972878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 12/13/2022] [Indexed: 01/05/2023] Open
Abstract
Dapagliflozin has been used to treat patients with type 1 diabetes mellitus; however, the actual drug efficacy of dapagliflozin on glycated hemoglobin (HbA1c) and whether there is a rebound from dapagliflozin efficacy on HbA1c remain unknown. The present study aimed to explore the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients. A total of 1,594 type 1 diabetes mellitus patients were enrolled for analysis using a non-linear mixed effect model from randomized controlled trials from published literature works including two 5 mg/day dapagliflozin dosage groups and three 10 mg/day dapagliflozin dosage groups. The change rate of HbA1c from a baseline value was chosen as a dapagliflozin pharmacodynamic evaluation index. After deducting control group effects, the therapeutic effect of 5 and 10 mg/day dapagliflozin on HbA1c in type 1 diabetes mellitus patients had no significant difference. In addition, the actual maximal efficacy (AEmax) of dapagliflozin on HbA1c was -6.24% at week 9. When it reached the AEmax, the dapagliflozin pharmacodynamic rebound on HbA1c occurred, and when the treatment was continued for 0.5 and 1 year, the actual efficacies were -4.70% (75% AEmax) and -3.27% (52% AEmax), respectively. This was the first time to clarify the actual therapeutic effect and rebound situation of dapagliflozin on HbA1c in type 1 diabetes mellitus patients, providing a reference value for clinical practices.
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Affiliation(s)
- Dong-Dong Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy and School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Cun Zhang
- Department of Pharmacy, Xuzhou Oriental Hospital Affiliated to Xuzhou Medical University, Xuzhou, China
| | - Ke Hu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy and School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Su-Mei He
- Department of Pharmacy, Suzhou Science and Technology Town Hospital, Suzhou, China,*Correspondence: Su-Mei He, ; Ping Zhu, ; Xiao Chen,
| | - Ping Zhu
- Department of Endocrinology, Huaian Hospital of Huaian City, Huaian, China,*Correspondence: Su-Mei He, ; Ping Zhu, ; Xiao Chen,
| | - Xiao Chen
- School of Nursing, Xuzhou Medical University, Xuzhou, China,*Correspondence: Su-Mei He, ; Ping Zhu, ; Xiao Chen,
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40
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Timmons JG, Littlejohn L, Boyle JG, Petrie JR. Recent developments in adjunct therapies for type 1 diabetes. Expert Opin Investig Drugs 2022; 31:1311-1320. [PMID: 36655950 DOI: 10.1080/13543784.2022.2159806] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
INTRODUCTION There have been many recent advances in the treatment of type 1 diabetes (T1D) including in insulin formulations, continuous glucose monitoring (CGM) technology and automated insulin delivery. However, long-term optimal glycemic control is still only achieved in a minority. AREAS COVERED Adjunct therapy - the use of therapeutic agents other than insulin - is one strategy aimed at improving outcomes. An ideal adjunct agent would improve glycemic control, reduce weight (or weight gain), reduce insulin requirement and prevent complications (e.g. cardiorenal) without increasing hypoglycemia. The amylin analogue pramlintide has been licensed in the USA, while the sodium glucose co-transporter-2 inhibitor (SGLT2i) dapagliflozin, was briefly (2019 - 2021) licensed for type 1 diabetes in Europe and the UK. However, other agents from the type 2 diabetes (T2D) arena including metformin, other SGLT2is, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-IV (DPP-4) inhibitors have been investigated. EXPERT OPINION As evidence emerges for cardiorenal protection by SGLT2is and GLP-1RAs in T2D, it has become increasingly important to know whether people with T1D can also benefit. Here, we review recent trials of adjunct agents in T1D and discuss the efficacy and safety of these agents (alone and in combination) in an era in which continuous glucose monitoring is becoming standard of care.
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Affiliation(s)
- Joseph G Timmons
- School of Cardiovascular & Metabolic Health, BHF Glasgow Cardiovascular Research Centre (GCRC), 126 University Avenue, University of Glasgow, G12 8TA Glasgow, UK
| | - Lucy Littlejohn
- School of Cardiovascular & Metabolic Health, BHF Glasgow Cardiovascular Research Centre (GCRC), 126 University Avenue, University of Glasgow, G12 8TA Glasgow, UK
| | - James G Boyle
- School of Cardiovascular & Metabolic Health, BHF Glasgow Cardiovascular Research Centre (GCRC), 126 University Avenue, University of Glasgow, G12 8TA Glasgow, UK
| | - John R Petrie
- School of Cardiovascular & Metabolic Health, BHF Glasgow Cardiovascular Research Centre (GCRC), 126 University Avenue, University of Glasgow, G12 8TA Glasgow, UK
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Sun W, Kong APS, Yan BP. Impact of early initiation of sodium-glucose cotransporter 2 inhibitor on cardiovascular outcomes in people with diabetes and known or at risk of atherosclerotic cardiovascular disease: Propensity score matched analysis. PLoS One 2022; 17:e0277321. [PMID: 36331955 PMCID: PMC9635734 DOI: 10.1371/journal.pone.0277321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE We aimed to evaluate the impact of early initiation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular (CV) outcomes in people with type 2 diabetes (T2D) with known or at risk of atherosclerotic cardiovascular disease (ASCVD). RESEARCH DESIGN AND METHODS T2D with first prescription of SGLT2i (Dx-to-Rx time) ≤12 months were matched with >12 months using propensity score derived from logistic regression. T2D were divided into 3 groups: (i) known ASCVD; (ii) additional CV risk factor(s) and; (iii) without ASCVD or additional CV risk factors. Incidence rates of 3-point major adverse cardiovascular events (MACE, including non-fatal stroke, non-fatal myocardial infarction and CV death) were compared between Dx-to-Rx time ≤12 months and >12 months across 3 subgroups. RESULTS Median follow-up was 2.8 years (IQR 2.2 to 3.4). Among 29,309 T2D (mean age 57.6±11.4 years, 59.0% men), 23.6% had established ASCVD and 66.6% had additional CV risk factors. Overall, 19.0% of patients had Dx-to-Rx time ≤12 month which was associated with lower rates of MACE [hazard ratio (HR) = 0.27, 95%CI: 0.17-0.42]. Benefits of early initiation of SGLT2i was observed in patients with additional CV risk factors or known ASCVD but not in those without CV risk factors or ASCVD (P for interaction = 0.001). CONCLUSION Early initiation of SGLT2 inhibitor was associated with lower MACE rates in T2D with known or at risk of ASCVD.
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Affiliation(s)
- Wen Sun
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Heart & Vascular Institute, The Chinese University of Hong Kong, Hong Kong, China
| | - Alice P. S. Kong
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Bryan P. Yan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- Heart & Vascular Institute, The Chinese University of Hong Kong, Hong Kong, China
- * E-mail:
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Hropot T, Battelino T, Dovc K. Sodium-Glucose Co-Transporter-2 Inhibitors in Type 1 Diabetes: A Scoping Review. Horm Res Paediatr 2022; 96:620-630. [PMID: 36279850 PMCID: PMC10652647 DOI: 10.1159/000527653] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 08/30/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND With recent developments in diabetes technology, attaining adequate glucose control is more achievable than ever. Despite these improvements, a significant proportion of individuals with type 1 diabetes do not reach recommended glycaemic goals. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are glucose-lowering agents that inhibit the reabsorption of filtered glucose in the kidneys, thus promoting glucosuria. Because the glucose-lowering effect of SGLT2 inhibitors is achieved independently of insulin secretion, it has been speculated whether they could bridge the gap towards achieving glycaemic targets in individuals with type 1 diabetes. SUMMARY Our main goal was to systematically map the current knowledge on the efficacy and safety of SGLT2 inhibitor use in adults with type 1 diabetes and present recent studies regarding the use of SGLT2 inhibitors in youth with type 1 diabetes. Using a scoping review approach, we searched MEDLINE to identify relevant clinical trials of SGLT2 inhibitors as adjunctive therapy to insulin in type 1 diabetes published from January 31, 2012, to January 31, 2022. We included the most relevant, large-scale, and long placebo-controlled clinical trials of SGLT2 inhibitors as an add-on therapy to insulin in adults with type 1 diabetes. Additionally, we included all relevant pilot studies evaluating the use of SGLT2 inhibitors as add-on therapy to insulin in youth with type 1 diabetes. We identified eight placebo-controlled clinical trials in adults with type 1 diabetes meeting our inclusion criteria and two relevant pilot studies in youth with type 1 diabetes. The clinical trials in adults with type 1 diabetes confirmed the efficacy of SGLT2 inhibitors as add-on therapy to insulin. However, this was associated with an increased incidence of diabetic ketoacidosis (DKA) versus placebo in all identified clinical trials. The two relevant pilot studies in youth with type 1 diabetes showed promising results of SGLT2 inhibitor use as an add-on therapy to insulin, especially when combined with a fully closed-loop system. KEY MESSAGES SGLT2 inhibitors, as an add-on therapy to insulin, improve glycaemic outcomes in adults with type 1 diabetes with a potential cost of increasing DKA risk. The use of add-on SGLT2 inhibitors to insulin shows promising results in youth with type 1 diabetes. Moreover, SGLT2 inhibitors as add-on therapy in combination with closed-loop insulin therapy could provide additional benefits in improving glycaemic control. The current role of SGLT2 inhibitors as an adjunct therapy to insulin in individuals with type 1 diabetes is yet to be determined.
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Affiliation(s)
- Tim Hropot
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tadej Battelino
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, Ljubljana, Slovenia
| | - Klemen Dovc
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, Ljubljana, Slovenia
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Davidson JA, Sukor N, Hew F, Mohamed M, Hussein Z. Safety of sodium-glucose cotransporter 2 inhibitors in Asian type 2 diabetes populations. J Diabetes Investig 2022; 14:167-182. [PMID: 36260389 PMCID: PMC9889611 DOI: 10.1111/jdi.13915] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 09/02/2022] [Accepted: 09/10/2022] [Indexed: 02/04/2023] Open
Abstract
The prevalence of type 2 diabetes mellitus continues to increase in many Asian countries, with possible contributing factors, such as younger-onset disease, diabetes development at lower body mass index, higher visceral fat accumulation and poorer β-cell function, among Asian populations. Sodium-glucose cotransporter 2 inhibitors have been shown to confer favorable effects in type 2 diabetes mellitus patients, such as improved glycemic control, weight and blood pressure reduction, and importantly, cardiorenal benefits. Sodium-glucose cotransporter 2 inhibitors are generally well-tolerated, and have a well-defined safety profile based on evidence from numerous clinical trials and post-marketing pharmacovigilance reporting. To our knowledge, this review is the first to provide a comprehensive coverage of the adverse events of sodium-glucose cotransporter 2 inhibitors, as well as their management and counseling aspects for Asian type 2 diabetes mellitus populations.
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Affiliation(s)
- Jaime A Davidson
- Touchstone Diabetes CenterThe University of Texas Southwestern Medical CenterDallasTexasUSA
| | - Norlela Sukor
- Universiti Kebangsaan Malaysia Medical CentreKuala LumpurMalaysia
| | - Fen‐Lee Hew
- Subang Jaya Medical CentreSubang JayaSelangorMalaysia
| | - Mafauzy Mohamed
- School of Medical SciencesUniversiti Sains MalaysiaKelantanMalaysia
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Bloomgarden Z, Schatz D. Small steps forward: Adjunctive therapy for T1D. J Diabetes 2022; 14:642-645. [PMID: 36205524 PMCID: PMC9574725 DOI: 10.1111/1753-0407.13326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/21/2022] [Indexed: 11/30/2022] Open
Affiliation(s)
- Zachary Bloomgarden
- Department of Medicine, Division of Endocrinology, Diabetes and Bone DiseaseIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Desmond Schatz
- Diabetes Institute, University of Florida College of MedicineGainesvilleFloridaUSA
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Melin J, Tang W, Rekić D, Hamrén B, Penland RC, Boulton DW, Parkinson J. Dapagliflozin Pharmacokinetics Is Similar in Adults With Type 1 and Type 2 Diabetes Mellitus. J Clin Pharmacol 2022; 62:1227-1235. [PMID: 35403243 PMCID: PMC9545191 DOI: 10.1002/jcph.2062] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 04/07/2022] [Indexed: 11/07/2022]
Abstract
Dapagliflozin improves glycemic control in patients with type 2 diabetes mellitus (T2DM) and is approved in Japanese patients with type 1 diabetes mellitus (T1DM) with inadequate glycemic control. The objectives of this work were to characterize the dapagliflozin pharmacokinetics (PK) in patients with T1DM, assess the influence of covariates on dapagliflozin PK, and compare dapagliflozin systemic exposure between patients with T1DM and T2DM. Population PK analysis was performed using a nonlinear mixed-effect modeling approach. The analysis included 5793 dapagliflozin plasma concentrations from 1150 adult patients with T1DM (global population), who were on routine insulin therapy, collected from 1 phase 2 (NCT01498185) and 2 phase 3 (DEPICT-1, NCT02268214; DEPICT-2, NCT02460978) studies. Covariate effects were investigated using stepwise covariate modeling. Model-derived area under the concentration-time curve (AUC) in patients with T1DM was compared to AUC in patients with T2DM (using data from historical dapagliflozin studies). The final 2-compartmental model adequately described the dapagliflozin concentrations in patients with T1DM. The estimated apparent clearance was 20.5 L/h. Renal function (measured as estimated glomerular filtration rate), sex, and body weight were identified as covariates, where patients with better renal function, male patients, and heavier patients had lower dapagliflozin systemic exposure. Among the covariates studied, none of the covariates affected dapagliflozin systemic exposure >1.4-fold compared to a reference individual and were therefore deemed to be not clinically relevant. Dapagliflozin systemic exposure was comparable between patients with T1DM and T2DM.
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Affiliation(s)
- Johanna Melin
- Clinical Pharmacology & Quantitative PharmacologyClinical Pharmacology & Safety SciencesR&DAstraZenecaGothenburgSweden
| | - Weifeng Tang
- Clinical Pharmacology & Quantitative PharmacologyClinical Pharmacology & Safety SciencesR&DAstraZenecaGaithersburgMarylandUSA
| | - Dinko Rekić
- Clinical Pharmacology & Quantitative PharmacologyClinical Pharmacology & Safety SciencesR&DAstraZenecaGothenburgSweden
| | - Bengt Hamrén
- Clinical Pharmacology & Quantitative PharmacologyClinical Pharmacology & Safety SciencesR&DAstraZenecaGothenburgSweden
| | - Robert C. Penland
- Clinical Pharmacology & Quantitative PharmacologyClinical Pharmacology & Safety SciencesR&DAstraZenecaBostonMassachusettsUSA
| | - David W. Boulton
- Clinical Pharmacology & Quantitative PharmacologyClinical Pharmacology & Safety SciencesR&DAstraZenecaGaithersburgMarylandUSA
| | - Joanna Parkinson
- Clinical Pharmacology & Quantitative PharmacologyClinical Pharmacology & Safety SciencesR&DAstraZenecaGothenburgSweden
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Cao X, Du X, Jiao H, An Q, Chen R, Fang P, Wang J, Yu B. Carbohydrate-based drugs launched during 2000 -2021. Acta Pharm Sin B 2022; 12:3783-3821. [PMID: 36213536 PMCID: PMC9532563 DOI: 10.1016/j.apsb.2022.05.020] [Citation(s) in RCA: 111] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/18/2022] [Accepted: 05/12/2022] [Indexed: 01/09/2023] Open
Abstract
Carbohydrates are fundamental molecules involved in nearly all aspects of lives, such as being involved in formating the genetic and energy materials, supporting the structure of organisms, constituting invasion and host defense systems, and forming antibiotics secondary metabolites. The naturally occurring carbohydrates and their derivatives have been extensively studied as therapeutic agents for the treatment of various diseases. During 2000 to 2021, totally 54 carbohydrate-based drugs which contain carbohydrate moities as the major structural units have been approved as drugs or diagnostic agents. Here we provide a comprehensive review on the chemical structures, activities, and clinical trial results of these carbohydrate-based drugs, which are categorized by their indications into antiviral drugs, antibacterial/antiparasitic drugs, anticancer drugs, antidiabetics drugs, cardiovascular drugs, nervous system drugs, and other agents.
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Affiliation(s)
- Xin Cao
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Xiaojing Du
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Heng Jiao
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Quanlin An
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Ruoxue Chen
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Pengfei Fang
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
| | - Jing Wang
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
| | - Biao Yu
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
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Abstract
Adult-onset autoimmune (AOA) diabetes pathophysiology starts with immune changes, followed by dysglycaemia and overt disease. AOA diabetes can occur as classic type 1 diabetes when associated with severe loss of insulin secretion. More frequently, it is diagnosed as latent autoimmune diabetes in adults, a slowly progressing form with late onset, a long period not requiring insulin, and it is often misdiagnosed as type 2 diabetes. As its clinical presentation varies remarkably and immune markers often lack specificity, it is challenging to classify each case ad hoc, especially when insulin treatment is not required at diagnosis. Proper care of AOA diabetes aims to prevent complications and to improve quality of life and life expectancy. To achieve these goals, attention should be paid to lifestyle factors, with the aid of pharmacological therapies properly tailored to each individual clinical setting. Given the heterogeneity of the disease, choosing the right therapy for AOA diabetes is challenging. Most of the trials testing disease-modifying therapies for autoimmune diabetes are conducted in people with childhood onset, whereas non-insulin diabetes therapies have mostly been studied in the larger population with type 2 diabetes. More randomized controlled trials of therapeutic agents in AOA diabetes are needed.
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Mascolo A, Di Napoli R, Balzano N, Cappetta D, Urbanek K, De Angelis A, Scisciola L, Di Meo I, Sullo MG, Rafaniello C, Sportiello L. Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: A brief summary. Front Cardiovasc Med 2022; 9:1010693. [PMID: 36211584 PMCID: PMC9532622 DOI: 10.3389/fcvm.2022.1010693] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/01/2022] [Indexed: 11/13/2022] Open
Abstract
A new therapeutic class of oral agents firstly used for the treatment of type 2 diabetes mellitus is represented by gliflozines or sodium-glucose co-transporter 2 (SGLT2) inhibitors. SGLT2 inhibitors might be effective alone or in combination with any other drugs. This therapeutic class currently includes five agents: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin. SGLT2 inhibitors prevent the renal reabsorption of filtered glucose and sodium by blocking the SGLT2 co-transporters in the proximal convoluted renal tubule, facilitating glucose excretion in the urine (glycosuria) and lowering blood glucose levels. SGLT2 inhibitors have also shown to have pleiotropic effects and determine cardiovascular and renal prevention, thus leading to an extension of their therapeutic indication to include the heart failure. Despite their clinical benefits, warnings about adverse events have been implemented by Regulatory Agencies in the product's information since their introduction to the market. In particular, SGLT2 inhibitors have shown a strong impact on a high number of risk factors. They can cause hypoglycaemia, hypotension, lower limb amputation, fractures, genito-urinary infections, and diabetic ketoacidosis with different frequencies of onset. Despite some of these events are rare, they can lead to serious and dangerous complications, highlighting the importance of a strict monitoring of patients. Overall, SLGT-2 inhibitors are effective antidiabetic drugs with favorable advantages in renal and cardiovascular protection, and with a generally well-tolerated safety profile. This review aims to summarize the safety profile of SGLT2 inhibitors available in the market.
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Affiliation(s)
- Annamaria Mascolo
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Naples, Italy
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Raffaella Di Napoli
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Naples, Italy
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Nunzia Balzano
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Naples, Italy
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Donato Cappetta
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Konrad Urbanek
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy
- CEINGE-Biotecnologie Avanzate, Naples, Italy
| | - Antonella De Angelis
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Lucia Scisciola
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Irene Di Meo
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Giuseppa Sullo
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Naples, Italy
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Concetta Rafaniello
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Naples, Italy
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Liberata Sportiello
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Naples, Italy
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Naples, Italy
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Efficacy of Dapagliflozin in Patients with Diabetes Mellitus Complicated with Coronary Artery Disease and Its Impact on the Vascular Endothelial Function. DISEASE MARKERS 2022; 2022:4829750. [PMID: 36118673 PMCID: PMC9481371 DOI: 10.1155/2022/4829750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022]
Abstract
Objective. To investigate the efficacy of dapagliflozin for diabetes mellitus complicated by coronary artery diseases and its impact on vascular endothelial function. Methods. Between August 2020 and August 2021, 80 patients with coronary heart disease complicated by type 2 diabetes mellitus were recruited and randomly assigned to receive either dapagliflozin (5 mg daily) plus original oral hypoglycemic agents (dapagliflozin group) or original oral hypoglycemic agents alone (control group). Outcome measures included blood pressure, blood glucose, cholesterol levels, vascular endothelial function, cardiovascular events, and drug-related adverse events. Results. The two groups had similar outcome indices upon admission (
). After 20 weeks of medication, the two groups of patients showed similar blood pressure, hemoglobin A1c (HbA1c), and low-density lipoprotein (LDL-C) levels versus those before treatment (
), and no significant differences were found in intergroup comparison neither (
). Dapagliflozin plus conventional hypoglycemic agents resulted in a significantly higher reactive hyperemia index (RHI) value, fewer cases with abnormal vascular endothelial function, and fewer major cardiovascular events during treatment versus the sole use of conventional hypoglycemic agents (
). There was no significant difference in drug-related adverse events between the two groups (
). Conclusion. Dapagliflozin improves the vascular endothelial functions of patients with diabetes mellitus complicated by coronary artery disease with a high safety profile and favorable efficacy.
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Abiru N, Shoji S, Kosakai Y, Snijder R, Asakawa K, Rokuda M. Demographic and clinical characteristics of patients with type 1 diabetes mellitus initiating sodium-glucose cotransporter 2 inhibitors in Japan: A real-world administrative database analysis. Diabetes Res Clin Pract 2022; 190:109973. [PMID: 35760156 DOI: 10.1016/j.diabres.2022.109973] [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: 04/06/2022] [Revised: 06/10/2022] [Accepted: 06/20/2022] [Indexed: 11/03/2022]
Abstract
AIMS To investigate the baseline demographic and clinical characteristics of patients with type 1 diabetes mellitus (T1DM) newly treated with a sodium-glucose cotransporter 2 inhibitor (SGLT2i) as an add-on to insulin, or treated with insulin alone or in combination with oral anti-diabetic drugs other than an SGLT2i. METHODS Retrospective study using data from the JMDC database (December 21, 2018, to October 31, 2020). Included patients with T1DM treated with an SGLT2i (add-on to insulin) (n = 1027) or with insulin (n = 4320). Baseline demographic and clinical characteristics were summarized, and change in insulin dose and efficacy outcomes, including hemoglobin A1c (HbA1c) and body mass index (BMI), before and after the first SGLT2i or insulin prescription were evaluated. RESULTS The SGLT2i add-on group had higher HbA1c and BMI than the insulin group. Daily insulin doses decreased from immediately before to after the first SGLT2i prescription. HbA1c and BMI improved from baseline to after the first SGLT2i prescription. CONCLUSIONS This large real-world study reported the baseline demographic and clinical characteristics of patients with T1DM newly treated with an SGLT2i in Japan. The findings may guide the appropriate use of SGLT2i and support large-scale database studies in T1DM research.
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Affiliation(s)
- Norio Abiru
- Department of Endocrinology and Metabolism, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
| | - Shingo Shoji
- Medical Affairs, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
| | - Yoshinori Kosakai
- Medical Affairs, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
| | - Robert Snijder
- Advanced Informatics & Analytics, Astellas Pharma Europe B.V, Sylviusweg 62, 2333 BE Leiden, The Netherlands.
| | - Keiko Asakawa
- Medical Affairs, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
| | - Mitsuhiro Rokuda
- Medical Affairs, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
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