|
1
|
Chen Q, Anijs RJS, Verlaan JPL, Scheres LJJ, Klok FA, Cannegieter SC. Novel Antidiabetic Drugs and Risk of Venous Thromboembolism: A Literature Review. Semin Thromb Hemost 2025. [PMID: 40154507 DOI: 10.1055/a-2546-0353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
Novel antidiabetic drugs, particularly sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have significantly transformed the management landscape for type 2 diabetes mellitus, cardiovascular diseases, and chronic kidney diseases, owing to their well-established cardiorenal protective effects. Given the shared risk factors and comorbidities, it is relevant to consider the potential risk of venous thromboembolism (VTE) in individuals prescribed these novel antidiabetic medications. This literature review aims to summarize currently available evidence on VTE risk associated with novel antidiabetic drugs, including GLP-1 receptor agonists, dipeptidyl-peptidase IV (DPP-4) inhibitors, and SGLT2 inhibitors. Following a comprehensive search on PubMed using relevant keywords and backward reference searching, we identified 25 publications that directly reported on associations between these medications and VTE risk. Findings from these studies, including seven meta-analyses, reveal inconsistent results: some studies suggest that GLP-1 receptor agonists or DPP-4 inhibitors may be associated with increased risk of VTE, whereas SGLT2 inhibitors do not appear to be associated with VTE and may even be a protective factor. A notable limitation of the existing studies is the significant challenge posed by confounding in observational studies, while the randomized controlled trials (RCTs) often concluded with a limited number of VTE events, if it was studied. Furthermore, all identified studies focused on the risk of primary VTE, leaving an important knowledge gap regarding whether these novel antidiabetic drugs may influence the efficacy or safety of anticoagulants used for preventing VTE recurrence. Addressing these gaps presents an important avenue for future research.
Collapse
Affiliation(s)
- Qingui Chen
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Rayna J S Anijs
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Medicine, Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
- The Knowledge Institute of the Federation of Medical Specialists, Utrecht, The Netherlands
| | - Judith P L Verlaan
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Luuk J J Scheres
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Frederikus A Klok
- Department of Medicine, Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
| | - Suzanne C Cannegieter
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Medicine, Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
| |
Collapse
|
|
2
|
Obaid MI, Shahzad MS, Latif F, Khan MH, Akram M, Mehdi Rizvi SA, Umer Nasrullah RM, Asad D, Obaid MA. Relationship between SGLT2 inhibitor use and specific cancer types: a systematic review and meta-analysis. Future Sci OA 2024; 10:2400797. [PMID: 39344829 PMCID: PMC11444652 DOI: 10.1080/20565623.2024.2400797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 09/02/2024] [Indexed: 10/01/2024] Open
Abstract
Aim: The study aimed to explore the incidence of cancer as an adverse event to SGLT2 inhibitors (SGLT2i) use in Type 2 diabetes.Materials & methods: The study followed PRISMA guidelines to pool RCTs conforming the inclusion criteria. Random effects model was used to pool risk ratios.Results & conclusion: After reviewing 19 studies, the analysis suggested a possible increased risk of reproductive, breast, thyroid, hematologic/lymphatic, urinary, skin and skeletal cancers with SGLT2i use. Conversely, lower incidences of respiratory and cardiovascular cancers were noted. However, these associations lacked statistical significance. Caution is advised in using SGLT2i due to potential cancer risks, especially in diabetic patients prone to cancer. More RCTs are essential due to limited research in this area.
Collapse
Affiliation(s)
- Muhammad Ishtiaq Obaid
- Department of Medicine, Bahria University Medical & Dental College, Karachi, 74400, Pakistan
| | - Mohammad Saiem Shahzad
- Department of Medicine, Bahria University Medical & Dental College, Karachi, 74400, Pakistan
| | - Fakhar Latif
- Department of Medicine, Dow Medical College, Karachi, 74700, Pakistan
| | - Muhammad Hamza Khan
- Department of Medicine, Karachi Medical & Dental College, Karachi, 74700, Pakistan
| | - Moeez Akram
- Department of Medicine, Allama Iqbal Medical College, Lahore, 54700, Pakistan
| | | | | | - Dayab Asad
- Department of Medicine, Jinnah Sindh Medical University, Karachi, 75510, Pakistan
| | - Muhammad Adil Obaid
- Department of Medicine, Jinnah Sindh Medical University, Karachi, 75510, Pakistan
| |
Collapse
|
|
3
|
Hu X, Tan C, Liu X, Zhang N, Wang F, Wang Z. Dapagliflozin Mediates the Protective Effect against atrial fibrillation/atrial flutter and the Reduction in All-Cause Mortality Risk. KARDIOLOGIIA 2024; 64:68-76. [PMID: 39784135 DOI: 10.18087/cardio.2024.12.n2701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 09/03/2024] [Accepted: 09/06/2024] [Indexed: 01/12/2025]
Abstract
OBJECTIVE This study aimed to investigate the association between dapagliflozin and the incidence of atrial fibrillation (AF) and atrial flutter (AFL), along with its impact on all-cause mortality in patients with diabetes mellitus (DM). MATERIAL AND METHODS Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this meta-analysis conducted a comprehensive search across PubMed, Embase, and ClinicalTrials.gov databases up to June 2021. We focused on randomized controlled trials (RCTs) that compared dapagliflozin with a placebo. Trial sequential analysis (TSA) was utilized to assess the reliability of the findings. All statistical analyses were performed using Review Manager software. RESULTS The final analysis included nine studies, encompassing a total of 30,235 patients. The findings indicated a statistically significant reduction in the incidence of AF / AFL in the dapagliflozin group compared to the placebo group (relative risk (RR) = 0.73, 95 % confidence interval (CI) = 0.59 to 0.89, p=0.002), although this result was not corroborated by TSA. The occurrences of AF and all-cause mortality were also lower in the dapagliflozin group than in the placebo group (RR = 0.71, 95 % CI = 0.57 to 0.89, p=0.003 and RR = 0.90, 95 % CI = 0.82 to 0.98, p=0.02, respectively). However, TSA did not confirm these outcomes. CONCLUSION Dapagliflozin appears to offer a significant protective effect against AF / AFL and may reduce the risk of all-cause mortality in patients with DM. However, further research is needed to confirm these findings due to the lack of confirmation by TSA.
Collapse
Affiliation(s)
| | | | - Xingpeng Liu
- Department of Cardiology, Beijing Chaoyang Hospital of Capital Medical University
| | | | | | | |
Collapse
|
|
4
|
Martha S, Jangam PH, Bhansali SG. Influence of Dapagliflozin Dosing on Low-Density Lipoprotein Cholesterol in Type 2 Diabetes Mellitus: A Systematic Literature Review and Meta-Analysis. J Clin Pharmacol 2024; 64:1528-1540. [PMID: 39087862 DOI: 10.1002/jcph.6105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 07/17/2024] [Indexed: 08/02/2024]
Abstract
A systematic literature review and meta-analysis was performed to evaluate the effects of dapagliflozin on low-density lipoprotein (LDL) cholesterol in type 2 diabetes mellitus. Data on changes in LDL cholesterol, adverse cardiac events (ACEs), glycated hemoglobin (HbA1c), and fasting blood glucose (FBG) were pooled in a meta-analysis. Data from dose comparison trials were separately pooled, and meta-analysis was conducted by using RevMan (5.4.1) and R (4.1.2). Dapagliflozin increased LDL cholesterol by 2.33 mg/dL (95% CI, 1.46 to 3.19; I2 = 0%; P < .00001), increased risk of ACEs by 1.56 (95% CI, 1.02 to 2.39; I2 = 0%; P < .04), decreased HbA1c by -0.41% (95% CI, -0.44 to -0.39; I2 = 85%; P < .00001), and decreased FBG by -13.51 mg/dL (95% CI, -14.43 to -12.59; I2 = 92%; P < .00001) versus any placebo or active comparator. Dapagliflozin 10 mg monotherapy increased LDL cholesterol by 1.71 mg/dL (95% CI, -1.20 to 4.62; I2 = 53%; P = .25) versus a 5 mg dose and by 1.04 mg/dL (95% CI, -1.17 to 3.26; I2 = 62%; P = .36) versus a 2.5 mg dose. Dapagliflozin 10 mg monotherapy increased LDL cholesterol by 3.13 mg/dL (95% CI, 1.31 to 4.95; I2 = 0%; P = .0008), increased the risk of ACEs by 1.26 (95% CI, 0.56 to 2.87; I2 = 0%; P = .58), decreased HbA1c by -0.4% (95% CI, -0.45 to -0.35; I2 = 89%; P < .00001), and decreased FBG by -8.39 mg/dL (95% CI, -10 to -6.77; I2 = 96%; P < .00001) versus a placebo or active comparator. Dapagliflozin monotherapy resulted in a minimal but statistically significantly (P = .0002) increase in LDL cholesterol. However, this minor change does not increase the risk of ACEs (P = .17) when compared with placebo or active comparator.
Collapse
Affiliation(s)
- Srinivas Martha
- Excelra Knowledge Solutions, NSL SEZ ARENA, IDA Uppal, Hyderabad, Telangana, India
| | | | - Suraj G Bhansali
- Excelra Knowledge Solutions, NSL SEZ ARENA, IDA Uppal, Hyderabad, Telangana, India
| |
Collapse
|
|
5
|
Geng L, Sun B, Chen Y. A meta-analysis of randomized controlled studies examining the effects of sodium-glucose co-transporter-2 inhibitors on peripheral artery disease and risk of amputations. Diabetes Obes Metab 2024; 26:5376-5389. [PMID: 39267269 DOI: 10.1111/dom.15901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 08/09/2024] [Accepted: 08/10/2024] [Indexed: 09/17/2024]
Abstract
AIM Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are used to maintain glycaemic control as well as for their beneficial cardiovascular and renal effects in diabetes patients. However, increased risk of amputation and peripheral artery disease (PAD) have been observed with the use of some SGLT-2is. A meta-analysis was conducted to understand the effect of SGLT-2is on amputation and PAD events using data from randomized controlled trials (RCT). MATERIALS AND METHODS A systematic literature review was conducted using Medline and Central databases for RCTs that involved the administration of SGLT-2is versus placebo/active comparators to diabetic patients. The primary outcome was amputation events and PAD. A random-effects model was used to calculate the pooled odds ratio, and subgroup analyses was performed. RESULTS A total of 51 RCTs were included in the meta-analysis with data from 97 589 patients. Meta-analysis of the data showed that there was a significant increase in PAD risk (p = 0.04) but no significant increase in amputation risk with SGLT-2i use versus placebo/active comparators (p = 0.43). Subgroup analyses demonstrated no significant difference between SGLT-2i type, duration of treatment or patient risk factors on amputation or PAD incidence. However, length of drug treatment (> 100 weeks) was associated with a significant increase in both PAD and amputation risks in the SGLT-2i treatment groups. CONCLUSIONS The results of the meta-analysis showed no significant association between SGLT-2i use and PAD and amputation risks in diabetic patients when used for shorter treatment durations.
Collapse
Affiliation(s)
- Li Geng
- Department of Vascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Bing Sun
- Department of Neurology, Changchun Central Hospital, Changchun, China
| | - Yan Chen
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
6
|
Wu Y, Huang Z, Qin Y. Efficacy and safety of henagliflozin combined with continuous subcutaneous insulin infusion in the treatment of Chinese inpatients with type 2 diabetes mellitus based on a continuous glucose monitoring system: protocol of a multicentre, open-label, inpatient, randomised, controlled trial. BMJ Open 2024; 14:e084834. [PMID: 39395826 PMCID: PMC11474858 DOI: 10.1136/bmjopen-2024-084834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 09/12/2024] [Indexed: 10/14/2024] Open
Abstract
INTRODUCTION The role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in diabetes treatment is expanding; however, few studies have investigated the efficacy and safety of combining SGLT2is with insulin pump therapy. Notably, there is a scarcity of high-quality, multicentre, clinical trials. Therefore, we aim to conduct a prospective multicentre, randomised, controlled, study to investigate whether treatment of type 2 diabetes patients with continuous subcutaneous insulin infusion (CSII) combined with henagliflozin can reduce the time required for blood glucose control, decrease total insulin requirements, mitigate blood glucose fluctuations and enhance beta-cell function. METHODS AND ANALYSIS In this inpatient, open-label, multicentre, randomised, controlled trial, 200 patients with type 2 diabetes who have not received hypoglycaemic drugs will be randomly allocated at a 1:1 ratio to either the henagliflozin combined with CSII group or the CSII group. The efficacy and safety of treatment in both groups will be compared. We will use a real-time continuous glucose monitoring system for blood glucose monitoring. The primary aim of this study is to compare the time (% time in range (TIR)) in the range of 3.9~10.0 mmol/L blood glucose between the two treatment groups. The secondary outcome measures will include comparisons of the two treatment groups with respect to the (a) time at TIR >70%; (b) mean amplitude of glycaemic excursions; (c) time below range; (d) total insulin dosage; and (e) time above range. ETHICS AND DISSEMINATION This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University and is to be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. The study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER NCT05677334.
Collapse
Affiliation(s)
- Yingling Wu
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhenxing Huang
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yingfen Qin
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| |
Collapse
|
|
7
|
Shah BR, Bajaj HS, Butalia S, Dasgupta K, Eurich DT, Jain R, Leung K, Mansell K, Simpson S. Pharmacologic Glycemic Management of Type 2 Diabetes in Adults---2024 Update. Can J Diabetes 2024; 48:415-424. [PMID: 39550176 DOI: 10.1016/j.jcjd.2024.08.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2024]
|
|
8
|
Rondanelli M, Mansueto F, Gasparri C, Solerte SB, Misiano P, Perna S. Supplementation with Highly Standardized Cranberry Extract Phytosome Achieved the Modulation of Urinary Tract Infection Episodes in Diabetic Postmenopausal Women Taking SGLT-2 Inhibitors: A RCT Study. Nutrients 2024; 16:2113. [PMID: 38999860 PMCID: PMC11242968 DOI: 10.3390/nu16132113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/14/2024] Open
Abstract
Urinary tract infections (UTIs) are the most common bacterial infections in postmenopausal women, and women with diabetes are possibly at a higher risk. The aim of this study is to evaluate the potential benefit on the prevention of UTI episodes, assessed by urinalysis and urine culture (primary outcome) after two, four and six months, of daily oral dietary supplement (120 mg highly standardized cranberry extract phytosome), compared to placebo, in diabetic postmenopausal women taking SGLT-2 inhibitors. Forty-six subjects (mean age 72.45 ± 1.76) completed the study (23 placebo/23 supplement). Considering UTI episodes, during the six-month supplementation period, an increase of 1.321 (95% CI: -0.322; 2.9650) was observed in the placebo group, while it remained at a steady value of 0.393 (95% CI: -4.230; 5.016) in the supplemented group. Regarding UTI episodes, in both groups, interaction between times for supplementation was statistically significant (p = 0.001). In particular, at follow-up 4, 9% of the placebo group showed infection versus only 3% with cranberry supplementation. Glycaemia and glycated hemoglobin values (secondary outcomes) were not modified at the end of six months with respect to the basal values in both groups, as expected. While in terms of quality of life per the SF-12 health questionnaire, there were no differences between the two groups, an improvement in SF-12 quality of life was observed in both groups (six months vs. basal). In conclusion, highly standardized cranberry extract phytosome supplementation reduced UTI recurrence.
Collapse
Affiliation(s)
- Mariangela Rondanelli
- Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy;
| | - Francesca Mansueto
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ‘‘Istituto Santa Margherita’’, University of Pavia, 27100 Pavia, Italy;
| | - Clara Gasparri
- Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona ‘‘Istituto Santa Margherita’’, University of Pavia, 27100 Pavia, Italy;
| | - Sebastiano Bruno Solerte
- Department of Internal Medicine, UOC Geriatrics and Diabetology, University of Pavia, 27100 Pavia, Italy;
| | - Paola Misiano
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Via Pascal 36, 20133 Milan, Italy;
| | - Simone Perna
- Division of Human Nutrition, Department of Food, Environmental and Nutritional Sciences (DeFENS), Università Degli Studi di Milano, 20133 Milan, Italy;
| |
Collapse
|
|
9
|
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: 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] [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.
Collapse
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
| |
Collapse
|
|
10
|
de Germay S, Pambrun E, Pariente A, Grenet G, Bezin J, Faillie JL. Use of sodium-glucose cotransporter-2 inhibitors in France: Analysis of French nationwide health insurance database. Diabetes Obes Metab 2024; 26:1678-1686. [PMID: 38288619 DOI: 10.1111/dom.15472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/04/2024] [Accepted: 01/12/2024] [Indexed: 04/09/2024]
Abstract
AIM Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have been commercialized in France for type 2 diabetes since April 2020 and later for heart and renal diseases. Given the recent developments in treating diabetes and the widening of SGLT-2i indications, we aimed to study changes in the use of glucose-lowering drugs in France and to characterize SGLT-2i new users. METHODS We performed a nationwide utilization study using the French health insurance database. Trends in incidence and prevalence of glucose-lowering drug use were assessed by a repeated cross-sectional study in 2019 and 2021. A cohort study of incident SGLT-2i users was then conducted to describe patient characteristics and the strategy for treating diabetes. RESULTS The prevalence of SGLT-2i use gradually reached 0.1% in the third quarter of 2021 and increased more significantly to 0.2% thereafter. SGLT-2i became the second most prescribed glucose-lowering drug class after metformin at the end of 2021 (0.1%). Among the cohort of 125 387 SGLT-2i new users (mean age 65.0 years; 60.1% of men), 87.6% presented a diabetic comorbidity. The patient profile changed over the study period with an increasing proportion of patients with cardiovascular (28.7% in 2020 vs. 40.2% in 2021) or renal (7.7% in 2020 vs. 11.8% in 2021) comorbidities at initiation. The main combinations used at SGLT-2i initiation were metformin (12.5%) and metformin plus dipeptidyl peptidase-4 inhibitors (8.1%). One-year probability of SGLT-2i persistence was estimated to be 55%. CONCLUSION The expansion of indications for SGLT-2i and the broadening of the target population make it essential to assess the reasons for discontinuation and review their safety profile.
Collapse
Affiliation(s)
- Sibylle de Germay
- Univ. Bordeaux, INSERM, BPH, U1219 Team AHeaD, Bordeaux, France
- Department of Medical Pharmacology, CHU de Bordeaux, Bordeaux, France
| | - Elodie Pambrun
- Univ. Bordeaux, INSERM, BPH, U1219 Team AHeaD, Bordeaux, France
| | - Antoine Pariente
- Univ. Bordeaux, INSERM, BPH, U1219 Team AHeaD, Bordeaux, France
- Department of Medical Pharmacology, CHU de Bordeaux, Bordeaux, France
| | - Guillaume Grenet
- Department of Medical Pharmacotoxicology, Hospices Civils de Lyon, Lyon, France
| | - Julien Bezin
- Univ. Bordeaux, INSERM, BPH, U1219 Team AHeaD, Bordeaux, France
- Department of Medical Pharmacology, CHU de Bordeaux, Bordeaux, France
| | - Jean-Luc Faillie
- Department of Medical Pharmacology and Toxicology, CHU Montpellier; Univ Montpellier, IDESP INSERM, Montpellier, France
| |
Collapse
|
|
11
|
Han Y, Li YF, Ye CW, Gu YY, Chen X, Gu Q, Xu QQ, Wang XM, He SM, Wang DD. Effects of dapagliflozin on body weight in patients with type 2 diabetes mellitus: Evidence‑based practice. Exp Ther Med 2024; 27:173. [PMID: 38476895 PMCID: PMC10928832 DOI: 10.3892/etm.2024.12461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 02/13/2024] [Indexed: 03/14/2024] Open
Abstract
The dose-dependent pharmacological response to dapagliflozin in patients with type 2 diabetes mellitus (T2DM) with regard to weight loss remain unknown. The aim of the present study was to investigate the effects of dapagliflozin on weight loss in patients with T2DM. A total of 8,545 patients with T2DM from 24 randomized controlled trials reported in the literature were selected for inclusion in the study. Data from these trials were analyzed using maximal effect (Emax) models with nonlinear mixed effects modeling; the evaluation index was the body weight change rate from baseline values. Patients treated with 2.5 mg/day dapagliflozin exhibited an Emax of -3.04%, and the time taken for therapy to reach half of the Emax (ET50) was estimated to be 30.8 weeks for patients treated with this dose. Patients treated with 5, 10 and 20 mg/day dapagliflozin exhibited Emax values of -6.57, -4.12 and -3.23%, respectively, and their ET50 values were estimated to be 27.3, 20.4 and 4.23 weeks, respectively. The data indicated ideal linear relationships between individual predictions and observations, suggesting the optimal fitting of the final models. The present study is the first systematic analysis of the effect of dapagliflozin on weight loss in patients with T2DM. The application of dapagliflozin at 5 mg/day exhibited a greater weight loss effect compared with the other doses used, and the weight loss onset time shortened as the dose of dapagliflozin increased.
Collapse
Affiliation(s)
- Yan Han
- Department of Emergency Medicine, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221116, P.R. China
| | - Ya-Feng Li
- Department of Pharmacy, Feng Xian People's Hospital, Xuzhou, Jiangsu 221700, P.R. China
| | - Chao-Wei Ye
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Yao-Yang Gu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Xiao Chen
- School of Nursing, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Qian Gu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Qiang-Qiang Xu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Xian-Ming Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| | - Su-Mei He
- Department of Pharmacy, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, Jiangsu 215153, P.R. China
| | - Dong-Dong Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
| |
Collapse
|
|
12
|
Islam L, Jose D, Alkhalifah M, Blaibel D, Chandrabalan V, Pappachan JM. Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus: A real-world experience. World J Diabetes 2024; 15:463-474. [PMID: 38591092 PMCID: PMC10999032 DOI: 10.4239/wjd.v15.i3.463] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/02/2024] [Accepted: 02/18/2024] [Indexed: 03/15/2024] Open
Abstract
BACKGROUND Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are a class of drugs with modest antidiabetic efficacy, weight loss effect, and cardiovascular benefits as proven by multiple randomised controlled trials (RCTs). However, real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse. AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data. METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs (dapagliflozin, canagliflozin, and empagliflozin) used for treating patients with type 2 diabetes mellitus. Data on the reduction of glycated hemoglobin (HbA1c), body weight, blood pressure (BP), urine albumin creatinine ratio (ACR), and adverse effects were recorded retrospectively. RESULTS Data from 467 patients with a median age of 64 (14.8) years, 294 (62.96%) males and 375 (80.5%) Caucasians were analysed. Median diabetes duration was 16.0 (9.0) years, and the duration of SGLT-2i use was 3.6 (2.1) years. SGLT-2i molecules used were dapagliflozin 10 mg (n = 227; 48.6%), canagliflozin 300 mg (n = 160; 34.3%), and empagliflozin 25 mg (n = 80; 17.1). Baseline median (interquartile range) HbA1c in mmol/mol were: dapagliflozin - 78.0 (25.3), canagliflozin - 80.0 (25.5), and empagliflozin - 75.0 (23.5) respectively. The respective median HbA1c reduction at 12 months and the latest review (just prior to the study) were: 66.5 (22.8) & 69.0 (24.0), 67.0 (16.3) & 66.0 (28.0), and 67.0 (22.5) & 66.5 (25.8) respectively (P < 0.001 for all comparisons from baseline). Significant improvements in body weight (in kilograms) from baseline to study end were noticed with dapagliflozin - 101 (29.5) to 92.2 (25.6), and canagliflozin 100 (28.3) to 95.3 (27.5) only. Significant reductions in median systolic and diastolic BP, from 144 (21) mmHg to 139 (23) mmHg; (P = 0.015), and from 82 (16) mmHg to 78 (19) mmHg; (P < 0.001) respectively were also observed. A significant reduction of microalbuminuria was observed with canagliflozin only [ACR 14.6 (42.6) at baseline to 8.9 (23.7) at the study end; P = 0.043]. Adverse effects of SGLT-2i were as follows: genital thrush and urinary infection - 20 (8.8%) & 17 (7.5%) with dapagliflozin; 9 (5.6%) & 5 (3.13%) with canagliflozin; and 4 (5%) & 4 (5%) with empagliflozin. Diabetic ketoacidosis was observed in 4 (1.8%) with dapagliflozin and 1 (0.63%) with canagliflozin. CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c, body weight, and better than those reported in RCTs, with low side effect profiles. A review of large-scale real-world data is needed to inform better clinical practice decision making.
Collapse
Affiliation(s)
- Lubna Islam
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
| | - Dhanya Jose
- Department of Community Medicine, Goa Medical College, Goa 403202, India
| | - Mohammed Alkhalifah
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Department of Family Medicine, King Faisal Specialist Hospital, Riyadh 11564, Saudi Arabia
| | - Dania Blaibel
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
| | - Vishnu Chandrabalan
- Department of Data Science, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, All Saints Building, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
| |
Collapse
|
|
13
|
Zhang Q, Zhang Q, Yang L, Yang S, Lu Y. Renal, cardiovascular, and safety outcomes of adding sodium-glucose cotransporter-2 inhibitors to insulin therapy in patients with type-2 diabetes: a meta-analysis. Int Urol Nephrol 2024; 56:557-570. [PMID: 37515749 DOI: 10.1007/s11255-023-03719-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/23/2023] [Indexed: 07/31/2023]
Abstract
AIMS To investigate the renal, cardiovascular, and safety outcomes when sodium-glucose cotransporter-2 inhibitors (SGLT2is) were added to insulin therapy in patients with type-2 diabetes mellitus (T2DM). MATERIALS AND METHODS We searched Embase, PubMed, and Cochrane libraries for reports published up to Feb 2023. Randomized controlled trials (RCTs) comparing SGLT2is and insulin combination therapy (SGLT2is + INS group) with insulin therapy alone (INS group) in T2DM were included. RESULTS Fourteen RCTs involving six thousand one hundred twenty subjects with durations of 12-104 weeks were included. Compared with the insulin group, the SGLT2is + INS group showed decreased glycosylated hemoglobin values and insulin dosages (P < 0.00001). Meanwhile, the SGLT2is + INS group had a reduced urinary albumin/creatinine ratio (UACR) by 25.42 mg/g and uric acid concentration (P = 0.030; P = 0.001, respectively) but the estimated glomerular filtration rate (eGFR) and renal-related adverse events were unaffected (P = 0.070; P = 0.880, respectively). Blood pressure and body weight were lower in the SGLT2is + INS group (P < 0.01). However, the risk of genital infection was bigger when SGLT2is were added to insulin therapy (P < 0.00001), but the risks of severe hypoglycemia or urinary tract infection were equal between the two groups (P > 0.05). CONCLUSION Adding SGLT2is to insulin therapy in T2DM patients showed better glucose control and decreased albuminuria, uric acid, blood pressure, and body weight without a reduction in the eGFR.
Collapse
Affiliation(s)
- Qian Zhang
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, 366 Taihu Road, Taizhou, 225300, China
| | - Qingqing Zhang
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, 366 Taihu Road, Taizhou, 225300, China
| | - Liu Yang
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, 366 Taihu Road, Taizhou, 225300, China
- Graduate School of Dalian Medical University, Dalian, 116044, Liaoning, China
| | - Shufang Yang
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, 366 Taihu Road, Taizhou, 225300, China
| | - Yu Lu
- Department of Endocrinology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, 366 Taihu Road, Taizhou, 225300, China.
| |
Collapse
|
|
14
|
Yaribeygi H, Maleki M, Sathyapalan T, Rizzo M, Sahebkar A. Cognitive Benefits of Sodium-Glucose Co-Transporters-2 Inhibitors in the Diabetic Milieu. Curr Med Chem 2024; 31:138-151. [PMID: 36733247 DOI: 10.2174/0929867330666230202163513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 11/19/2022] [Accepted: 11/30/2022] [Indexed: 02/04/2023]
Abstract
Patients with diabetes are at higher risk of cognitive impairment and memory loss than the normal population. Thus, using hypoglycemic agents to improve brain function is important for diabetic patients. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) are a class of therapeutic agents used in the management of diabetes that has some pharmacologic effects enabling them to fight against the onset and progress of memory deficits. Although the exact mediating pathways are not well understood, emerging evidence suggests that SGLT2 inhibition is associated with improved brain function. This study reviewed the possible mechanisms and provided evidence suggesting SGLT2 inhibitors could ameliorate cognitive deficits.
Collapse
Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Thozhukat Sathyapalan
- Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | - Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, School of Medicine, University of Palermo, 90133, Palermo, Italy
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, Australia
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
15
|
Yaribeygi H, Maleki M, Jamialahmadi T, Shakhpazyan NK, Kesharwani P, Sahebkar A. Nanoparticles with SGLT2 inhibitory activity: Possible benefits and future. Diabetes Metab Syndr 2023; 17:102869. [PMID: 37778134 DOI: 10.1016/j.dsx.2023.102869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/12/2023] [Accepted: 09/21/2023] [Indexed: 10/03/2023]
Abstract
AIM Nano-drug delivery is a rapidly growing approach in medicine that helps design and develop newer forms of drugs with more efficacy and lower adverse effects. Sodium-glucose cotransporter-2 inhibitors are an emerging class of antidiabetic agents that reduce the blood glucose levels by damping glucose reabsorption in renal proximal tubules. METHODS AND RESULTS This mechanism might be followed by some adverse effects that could be prevented by nano-drug delivery. Although we have still limited evidence about nanoforms of sodium-glucose cotransporter-2 inhibitors, current knowledge strongly suggests that nanotechnology can help us design more effective drugs with lower side effects. In recent years, several studies have explored the possible benefits of nanoforms of sodium-glucose cotransporter-2 inhibitors. However, clinical trials are yet to be conducted. CONCLUSION In the current review, we present the latest findings on the development and benefits of nanoforms of sodium-glucose cotransporter-2 inhibitors.
Collapse
Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tannaz Jamialahmadi
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nikolay K Shakhpazyan
- Petrovsky National Science Center of Surgery, 2 Abrikosovsky Lane, 119991, Moscow, Russia
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India; Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India.
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
16
|
Li CX, Liu LY, Zhang CX, Geng XH, Gu SM, Wang YQ, Liu H, Xie Q, Liang S. Comparative safety of different sodium-glucose transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and network meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne) 2023; 14:1238399. [PMID: 37701900 PMCID: PMC10494439 DOI: 10.3389/fendo.2023.1238399] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 07/26/2023] [Indexed: 09/14/2023] Open
Abstract
Backgrounds The safety of different sodium-glucose transporter 2 (SGLT-2) inhibitors remains uncertain due to the lack of head-to-head comparisons. Methods This network meta-analysis (NMA) was performed to compare the safety of nine SGLT-2 inhibitors in patients with type 2 diabetes (T2DM). PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched for studies published in English before August 30, 2022. Published and unpublished randomized controlled trials (RCTs) comparing the safety of individual SGLT-2 inhibitors in patients with T2DM were included. A Bayesian NMA with random effects model was applied. Subgroup and sensitivity analyses were performed. The quality of the evidence was evaluated using the Confidence in Network Meta-Analysis framework. Results Nine SGLT-2 inhibitors were evaluated in 113 RCTs (12 registries) involving 105,293 adult patients. Reproductive tract infections (RTIs) were reported in 1,967 (4.51%) and 276 (1.01%) patients in the SGLT-2 inhibitor and placebo groups, respectively. Furthermore, pollakiuria was reported in 233 (2.66%) and 45 (0.84%) patients, respectively. Compared to placebo, a significantly higher risk of RTIs was observed with canagliflozin, ertugliflozin, empagliflozin, remogliflozin, dapagliflozin, and sotagliflozin, but not with luseogliflozin and ipragliflozin, regardless of gender. An increased risk of pollakiuria was observed with dapagliflozin [odds ratio (OR) 10.40, 95% confidence interval (CI) 1.60-157.94) and empagliflozin (OR 5.81, 95%CI 1.79-32.97). Remogliflozin (OR 6.45, 95%CI 2.18-27.79) and dapagliflozin (OR 1.33, 95%CI 1.10-1.62) were associated with an increased risk of urinary tract infections (UTIs). Instead, the included SGLT-2 inhibitors had a protective effect against acute kidney injury (AKI). No significant differences were found for hypovolemia, renal impairment or failure, fracture, diabetic ketoacidosis (DKA), amputation, and severe hypoglycemia between the SGLT-2 inhibitor and the placebo groups. Conclusion In patients with T2DM, dapagliflozin was associated with an increased risk of RTIs, pollakiuria, and UTIs. Empagliflozin increased the risk of RTIs and pollakiuria. Remogliflozin increased the risk of UTIs. None of the SGLT-2 inhibitors showed a significant difference from the placebo for hypovolemia, renal impairment or failure, fracture, DKA, amputation, and severe hypoglycemia. The findings guide the selection of SGLT-2 inhibitors for patients with T2DM based on the patient's profiles to maximize safety. Systematic review registration https://www.crd.york.ac.uk/prospero, identifier CRD42022334644.
Collapse
Affiliation(s)
- Chun Xing Li
- Department of Pharmacy, Aerospace Center Hospital, Beijing, China
| | - Li Yan Liu
- Department of Pharmacy, Aerospace Center Hospital, Beijing, China
| | - Chen Xiao Zhang
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xu Hua Geng
- Department of Gastroenterology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, China
| | - Si Meng Gu
- Department of Pharmacy, Aerospace Center Hospital, Beijing, China
| | - Yu Qiao Wang
- Department of Pharmacy, Aerospace Center Hospital, Beijing, China
| | - Hua Liu
- Department of Pharmacy, Aerospace Center Hospital, Beijing, China
| | - Qing Xie
- Department of Pharmacy, Aerospace Center Hospital, Beijing, China
| | - Shuo Liang
- Department of Pharmacy, Aerospace Center Hospital, Beijing, China
| |
Collapse
|
|
17
|
AKHANLI P, HEPŞEN S, ARSLAN İE, DÜĞER H, BOSTAN H, KIZILGÜL M, UÇAN B, ÇAKAL E. Impact of 24-week dapagliflozin treatment on body weight, body composition, and cardiac risk indicators of patients with type-2 diabetes mellitus. Turk J Med Sci 2023; 53:1178-1184. [PMID: 38813008 PMCID: PMC10763806 DOI: 10.55730/1300-0144.5683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 10/26/2023] [Accepted: 08/11/2023] [Indexed: 05/31/2024] Open
Abstract
Background/aim To reveal the impacts of dapagliflozin, a sodium glucose transporter-2 inhibitor (SGLT-2i), on body weight and body composition, cardiovascular risk indices, and carotid intima-media thickness (CIMT). Materials and methods The data of patients with type-2 diabetes mellitus (T2DM) who applied to Department of Endocrinology and Metabolic Disorders between September 2019 and 2020, and had started dapagliflozin treatment along with their current medications were recorded retrospectively. Body weights, body compositions measured through bioelectrical impedance, and CIMT with T2DM receiving SGLT-2i treatment and medication were measured at weeks 1, 12, and 24 of 42. The visceral adiposity index (VAI), lipid accumulation product (LAP), and atherogenic index of plasma (AIP) were used to determine the lipid measurements and anthropometric values. Results The mean change in the total body weight and total fat mass was -2.96 and -1.97 kg, respectively (p < 0.001). There was a reduction in total fat mass of 1.23 kg (from 31.4 to 29.3 kg, p < 0.001) and in body fat percentage of 2.5% (from 35.8% to 34.4%, p < 0.001) in the first 12 weeks. A mild increase was observed in both the total fat mass and body fat percentage between weeks 12 and 24, which was not statistically significant (p = 0.783 and p = 0.925, respectively), whereas there was a statistically significant reduction in high-sensitive C-reactive protein (hsCRP), AIP, and CIMT values (p = 0.006, p = 0.035, and p = 0.007, respectively). No changes were observed in the VAI and LAP values (p = 0.985 and p = 0.636, respectively). Conclusion It was observed that dapagliflozin not only contributes to weight and fat loss but also has positive impacts on cardiovascular and atherosclerotic indicators.
Collapse
Affiliation(s)
- Pınar AKHANLI
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Sema HEPŞEN
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - İsmail Emre ARSLAN
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Hakan DÜĞER
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Hayri BOSTAN
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Muhammed KIZILGÜL
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Bekir UÇAN
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| | - Erman ÇAKAL
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara,
Turkiye
| |
Collapse
|
|
18
|
Dagogo-Jack S, Frederich R, Liu J, Cannon CP, Shi H, Cherney DZI, Cosentino F, Masiukiewicz U, Gantz I, Pratley RE. Ertugliflozin Delays Insulin Initiation and Reduces Insulin Dose Requirements in Patients With Type 2 Diabetes: Analyses From VERTIS CV. J Clin Endocrinol Metab 2023; 108:2042-2051. [PMID: 36702781 PMCID: PMC10348468 DOI: 10.1210/clinem/dgac764] [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: 09/13/2022] [Indexed: 01/28/2023]
Abstract
CONTEXT VERTIS CV evaluated the cardiovascular safety of ertugliflozin in patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE The aim of these analyses was to assess the insulin requirements of VERTIS CV patients over the trial duration. METHODS Patients received ertugliflozin 5 mg, 15 mg, or placebo once daily; mean follow-up was 3.5 years. Time to insulin initiation in patients who were insulin naïve at baseline, change in insulin dose in patients receiving baseline insulin, and hypoglycemia incidence in both patient groups were assessed. RESULTS In VERTIS CV, mean duration of type 2 diabetes was 13.0 years; glycated hemoglobin was 8.2%. Among 4348 (53%) insulin-naïve patients, the likelihood of insulin initiation was significantly reduced with ertugliflozin vs placebo (ertugliflozin 5 mg: hazard ratio [HR] 0.70, 95% CI 0.58-0.84; ertugliflozin 15 mg: HR 0.64, 95% CI 0.53-0.78). Time to insulin initiation was delayed with ertugliflozin; the estimated delay in reaching a 10% cumulative incidence of new insulin initiations vs placebo was 399 days with ertugliflozin 5 mg and 669 days with ertugliflozin 15 mg. Among 3898 (47%) patients receiving baseline insulin, the likelihood of requiring a ≥20% increase in insulin dose was significantly reduced with ertugliflozin vs placebo (ertugliflozin 5 mg: HR 0.62, 95% CI 0.52-0.75; ertugliflozin 15 mg: HR 0.51, 95% CI 0.41-0.62). The incidence of hypoglycemia events was not increased with ertugliflozin treatment. CONCLUSION In VERTIS CV patients, ertugliflozin reduced the likelihood of insulin initiation, delayed the time to insulin initiation by up to ∼1.8 years, and reduced insulin dose requirements vs placebo, without increasing hypoglycemia events.
Collapse
Affiliation(s)
- Samuel Dagogo-Jack
- Division of Endocrinology, Diabetes & Metabolism, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | | | - Jie Liu
- Merck & Co., Inc., Rahway, NJ 07065, USA
| | - Christopher P Cannon
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Harry Shi
- Pfizer Inc., New York, NY 10017, USA
| | - David Z I Cherney
- Division of Nephrology, University of Toronto, Toronto, Ontario M5G 2C4, Canada
| | - Francesco Cosentino
- Unit of Cardiology, Karolinska Institute and Karolinska University Hospital, Stockholm SE171 77, Sweden
| | | | - Ira Gantz
- Merck & Co., Inc., Rahway, NJ 07065, USA
| | - Richard E Pratley
- AdventHealth Translational Research Institute, Orlando, FL 32804, USA
| |
Collapse
|
|
19
|
Cesaro A, Acerbo V, Vetrano E, Signore G, Scherillo G, Rotolo FP, De Michele G, Scialla F, Raucci G, Panico D, Gragnano F, Moscarella E, Galiero R, Caturano A, Ruggiero R, Sasso FC, Calabrò P. Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Diabetes and Coronary Artery Disease: Translating the Benefits of the Molecular Mechanisms of Gliflozins into Clinical Practice. Int J Mol Sci 2023; 24:8099. [PMID: 37175805 PMCID: PMC10179032 DOI: 10.3390/ijms24098099] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially developed for the treatment of diabetes due to their antihyperglycemic activity. However, in the light of the most recent clinical studies, they are revolutionizing the approach to cardiovascular disease in patients with and without diabetes. We aimed to generate real-world data about the use of SGLT2i in patients with T2DM and coronary artery disease (CAD), focusing on their effectiveness in glycemic control, adherence, long-term efficacy, and safety outcomes. On the basis of the inclusion and exclusion criteria, 143 patients were enrolled. Patients were treated with canagliflozin (n = 33 patients; 23%), dapagliflozin (n = 52 patients, 36.4%), empagliflozin (n = 48 patients; 33.6%), or ertugliflozin (n = 10 patients; 7%) as monotherapy or in combination with other antidiabetic drugs. All patients performed a clinical visit, and their medical history, blood sampling, and anthropometric parameters were measured at discharge and at 1-year follow-up. The reduction in HbA1c % value at 12 months was significant (8.2 vs. 7.4; p < 0.001). Trends in body weight and body mass index also confirmed the positive effect of the treatment (p < 0.0001), as did the reduction in abdominal adiposity (expressed via waist circumference). At 1-year follow-up, 74.1% of patients were adherent to the treatment, and 81.1% were persistent to the treatment. A total of 27 patients (18.8%) had to discontinue treatment early due to drug intolerance caused by genitourinary infections (11.9%), the drub being permanently ineffective (HbA1c not at target or decreasing: 4.9%), or because of expressing. a desire not to continue (2%). No major drug-related adverse events (diabetic ketoacidosis, Fournier's gangrene, lower-limb amputations) occurred at follow-up, while MACE events occurred in 14 patients (9.8%). In real-world patients with T2DM and CAD, SGLT2i have been effective in long-term glycemic control and the improvement in anthropometric indices with good tolerance, high adherence, persistence to treatment, and no major adverse events at 1-year follow-up.
Collapse
Affiliation(s)
- Arturo Cesaro
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| | - Vincenzo Acerbo
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| | - Erica Vetrano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy (F.C.S.)
| | - Giovanni Signore
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| | - Gianmaria Scherillo
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| | - Francesco Paolo Rotolo
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| | - Gianantonio De Michele
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| | - Francesco Scialla
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| | - Giuseppe Raucci
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| | - Domenico Panico
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| | - Felice Gragnano
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| | - Elisabetta Moscarella
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| | - Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy (F.C.S.)
| | - Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy (F.C.S.)
| | - Roberto Ruggiero
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy (F.C.S.)
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy (F.C.S.)
| | - Paolo Calabrò
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, I-80131 Naples, Italy
- Division of Clinical Cardiology, A.O.R.N. “Sant’Anna e San Sebastiano”, I-81100 Caserta, Italy
| |
Collapse
|
|
20
|
Zheng Z, He D, Chen J, Xie X, Lu Y, Wu B, Jiang X. Risk of Urinary Tract Infection in Patients with Type 2 Diabetes Mellitus Treated with Dapagliflozin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Clin Drug Investig 2023; 43:209-225. [PMID: 37010676 DOI: 10.1007/s40261-023-01256-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2023] [Indexed: 04/04/2023]
Abstract
BACKGROUND AND OBJECTIVE To investigate whether dapagliflozin (as a selective inhibitor of sodium-glucose cotransporter 2), increases the risk of urinary tract infection (UTI) in the treatment of type 2 diabetes mellitus (T2DM) remains an ongoing issue. We performed a systematic review and meta-analysis of randomized clinical trials (RCTs) to estimate the short-term and long-term risks of UTI in patients with T2DM who received dapagliflozin at different doses. METHODS The PubMed, EMBASE, and the Cochrane Library and ClinicalTrials.gov website were searched up to December 31, 2022. Only RCTs involving adult T2DM patients with a trial duration of at least 12 weeks were included. The data were summarized using random- or fixed-effects models based on overall heterogeneity. A subgroup analysis was also performed. The review protocol was previously registered in the PROSPERO database (CRD42022299899). RESULTS In total, 42 RCTs involving 35,938 patients were assessed for eligibility. The results showed that dapagliflozin imposed a higher risk of UTI compared to placebo and other active treatments, with a heterogeneity of 11% (odds ratio [OR] 1.17, 95% CI 1.04-1.31, p = 0.006). In the subgroup analysis, dapagliflozin 10 mg/day with a treatment period of > 24 weeks was associated with a significantly higher UTI risk than placebo or other active treatments (OR 1.27, 95% CI 1.13-1.43, p < 0.0001). The ORs for dapagliflozin as monotherapy and combination therapy in the control group were 1.05 (95% CI 0.88-1.25, p = 0.571) and 1.27 (95% CI 1.09-1.48, p = 0.008), respectively. CONCLUSIONS High-dose, long-term treatment, and add-on therapy of dapagliflozin call for careful consideration of the risk of UTI in T2DM patients.
Collapse
Affiliation(s)
- Zhigui Zheng
- Department of Nephropathy, Zhejiang Hospital, Hangzhou, People's Republic of China
| | - Dongyuan He
- Department of Nephropathy, Zhejiang Hospital, Hangzhou, People's Republic of China
| | - Jianguo Chen
- Department of Nephropathy, Zhejiang Hospital, Hangzhou, People's Republic of China
| | - Xiaohui Xie
- Department of Nephropathy, Zhejiang Hospital, Hangzhou, People's Republic of China
| | - Yunan Lu
- Department of Nephropathy, Zhejiang Hospital, Hangzhou, People's Republic of China
| | - Binbin Wu
- Department of Nephropathy, Zhejiang Hospital, Hangzhou, People's Republic of China
| | - Xinxin Jiang
- Department of Nephropathy, Zhejiang Hospital, Hangzhou, People's Republic of China.
| |
Collapse
|
|
21
|
Tsai PC, Chuang WJ, Ko AMS, Chen JS, Chiu CH, Chen CH, Yeh YH. Neutral effects of SGLT2 inhibitors in acute coronary syndromes, peripheral arterial occlusive disease, or ischemic stroke: a meta-analysis of randomized controlled trials. Cardiovasc Diabetol 2023; 22:57. [PMID: 36915157 PMCID: PMC10012509 DOI: 10.1186/s12933-023-01789-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 03/03/2023] [Indexed: 03/15/2023] Open
Abstract
BACKGROUND Patients with type 2 diabetes are at increased risk for cardiovascular diseases. Sodium-glucose transport 2 inhibitors (SGLT2i) have been shown to enhance cardiovascular health since their debut as a second-line therapy for diabetes. Acute coronary syndrome (ACS), peripheral arterial occlusive disease (PAOD), and ischemic stroke (IS) are types of atherosclerotic cardiovascular disease (ASCVD), although the benefits of treating these disorders have not been shown consistently. METHODS We searched four databases (PubMed, Embase, the Cochrane library, and clinicaltrial.gov) for randomized clinical trials (RCTs) until November of 2022. Comparisons were made between SGLT2i-treated and control individuals with type 2 diabetes. Primary outcomes were ACS, PAOD, and IS; secondary outcomes included cardiovascular mortality and all-cause mortality. Risk ratio (RR) and 95% confidence intervals (CI) were determined using a fixed effects model. Cochrane's risk-of-bias (RoB2) instrument was used to assess the validity of each study that met the inclusion criteria. RESULTS We enrolled 79,504 patients with type 2 diabetes from 43 RCTs. There was no difference in the risk of ACS (RR = 0.97, 95% CI 0.89-1.05), PAOD (RR = 0.98, 95% CI 0.78-1.24), or IS (RR = 0.95, 95% CI 0.79-1.14) among patients who took an SGLT2i compared to those who took a placebo or oral hypoglycemic drugs. Subgroup analysis revealed that none of the SGLT2i treatments (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) significantly altered outcomes when analyzed separately. Consistent with prior findings, SGLT2i reduced the risk of cardiovascular mortality (RR = 0.85, 95% CI 0.77-0.93) and all-cause mortality (RR = 0.88, 95% CI 0.82-0.94). CONCLUSION Our results appear to contradict the mainstream concepts regarding the cardiovascular effects of SGLT2i since we found no significant therapeutic benefits in SGLT2i to reduce the incidence of ACS, PAOD, or IS when compared to placebo or oral hypoglycemic drugs.
Collapse
Affiliation(s)
- Pei-Chien Tsai
- Department and Graduate Institute of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
- Healthy Aging Research Center, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Wei-Jung Chuang
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Albert Min-Shan Ko
- Department and Graduate Institute of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Healthy Aging Research Center, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Cardiovascular Department, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
| | - Jui-Shuan Chen
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Cheng-Hsun Chiu
- Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
| | - Chun-Han Chen
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Yung-Hsin Yeh
- Cardiovascular Department, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan.
- School of Medicine, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan.
| |
Collapse
|
|
22
|
Post-Authorization Safety Study of Hospitalization for Acute Kidney Injury in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting. Drug Saf 2023; 46:157-174. [PMID: 36528670 PMCID: PMC9883323 DOI: 10.1007/s40264-022-01263-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2022] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor approved to treat type 2 diabetes mellitus (T2DM), among other conditions. When dapagliflozin was approved in Europe for treating T2DM (2012), potential safety concerns regarding its effect on kidney function resulted in this post-authorization safety study to assess hospitalization for acute kidney injury (hAKI) among dapagliflozin initiators in a real-world setting. OBJECTIVE The aim of this study was to evaluate the incidence of hAKI in adults with T2DM initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). METHODS This noninterventional cohort study identified new users of dapagliflozin and comparator GLDs from November 2012 to February 2019 from three longitudinal, population-based data sources: Clinical Practice Research Datalink (CPRD; United Kingdom), the HealthCore Integrated Research Database (HIRD; United States [US]), and Medicare (US). Electronic algorithms identified occurrences of hAKI, from which a sample underwent validation. Incidence rates for hAKI were calculated, and incidence rate ratios (IRRs) compared hAKI in dapagliflozin with comparator GLDs. Propensity score trimming and stratification were conducted for confounding adjustment. RESULTS In all data sources, dapagliflozin initiators had a lower hAKI incidence rate than comparator GLD initiators (adjusted IRRs: CPRD, 0.44 [95% confidence interval (CI), 0.22-0.86]; HIRD, 0.76 [95% CI, 0.62-0.93]; Medicare, 0.69 [95% CI, 0.59-0.79]). The adjusted IRR pooled across the data sources was 0.70 (95% CI, 0.62-0.78). Results from sensitivity and stratified analyses were consistent with the primary analysis. CONCLUSIONS This study, with > 34,000 person-years of real-world dapagliflozin exposure, suggests a decreased risk of hAKI in patients with T2DM exposed to dapagliflozin, aligning with results from dapagliflozin clinical trials. STUDY REGISTRATION European Union Post-Authorisation Studies Register, EUPAS 11684; ClinicalTrials.gov, NCT02695082.
Collapse
|
|
23
|
Pollack R, Raz I, Wiviott SD, Goodrich EL, Murphy SA, Yanuv I, Rozenberg A, Mosenzon O, Langkilde AM, Gause-Nilsson IAM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS, Cahn A. Efficacy and Safety of Dapagliflozin by Baseline Insulin Regimen and Dose: Post Hoc Analyses From DECLARE-TIMI 58. Diabetes Care 2023; 46:156-164. [PMID: 36399721 DOI: 10.2337/dc22-1318] [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: 07/05/2022] [Accepted: 10/13/2022] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The cardiorenal benefits of adding sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy for patients on insulin, particularly those on intensive regimens that include short-acting (SA) insulin, have not been explored. RESEARCH DESIGN AND METHODS In Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomized to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular (CV), renal, metabolic, and safety outcomes with dapagliflozin versus placebo by insulin dose and regimen were studied with Cox regression models. RESULTS The study included 7,013 insulin users at baseline, with 4,650 (66.3%) patients on regimens including SA insulin. Insulin doses varied, with 2,443 (34.8%) patients receiving <0.5 IU/kg, 2,795 (39.9%) 0.5 to ≤1 IU/kg, and 1,339 (19.1%) >1 IU/kg. Dapagliflozin reduced CV death/hospitalization for heart failure among overall insulin users (hazard ratio [HR] 0.82 [95% CI 0.69-0.97]) and consistently in patients on insulin regimens with or without SA insulin (0.83 [0.67-1.03] and 0.78 [0.57-1.07], respectively, Pinteraction = 0.75). No heterogeneity was observed by insulin dose (Pinteraction = 0.43). The HR for major adverse CV events with dapagliflozin among insulin users (0.84 [0.74-0.97]) was similar irrespective of regimen or dose (Pinteraction = 0.75 and 0.07). Dapagliflozin reduced the rate of adverse renal outcomes overall and consistently across subgroups of insulin users. Decreases in HbA1c, weight, and systolic blood pressure with dapagliflozin were seen regardless of insulin dose or regimen. The known safety profile of dapagliflozin was unchanged in patients on intensive insulin regimens. CONCLUSIONS The benefits and safety of dapagliflozin were maintained in high-risk patients receiving high-dose or intensive insulin regimens including SA insulin.
Collapse
Affiliation(s)
- Rena Pollack
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Itamar Raz
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Stephen D Wiviott
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Erica L Goodrich
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Sabina A Murphy
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Ilan Yanuv
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Aliza Rozenberg
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Ofri Mosenzon
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | | | | | - Deepak L Bhatt
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Lawrence A Leiter
- Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Darren K McGuire
- Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX
- Parkland Health and Hospital System, Dallas, TX
| | - John P H Wilding
- Department of Cardiovascular and Metabolic Medicine, University of Liverpool, Liverpool, U.K
| | - Marc S Sabatine
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Avivit Cahn
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| |
Collapse
|
|
24
|
Lechleitner M, Roden M, Weitgasser R, Ludvik B, Fasching P, Hoppichler F, Kautzky-Willer A, Schernthaner G, Prager R, Kaser S, Wascher TC. [Injection therapy of diabetes]. Wien Klin Wochenschr 2023; 135:45-52. [PMID: 37101024 PMCID: PMC10133050 DOI: 10.1007/s00508-023-02171-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2023] [Indexed: 04/28/2023]
Abstract
The present article is a recommendation of the Austrian Diabetes Association for the practical use of injection therapy (GLP1-receptor agonists and insulin) in type 2 diabetes.
Collapse
Affiliation(s)
- Monika Lechleitner
- Avomed-Arbeitskreis für Vorsorgemedizin und Gesundheitsförderung in Tirol, Innsbruck, Österreich
| | - Michael Roden
- Klinik für Endokrinologie und Diabetologie, Medizinische Fakultät, Heinrich-Heine-Universität, Düsseldorf, Deutschland
- Institut für Klinische Diabetologie, Deutsches Diabetes-Zentrum (DDZ), Leibniz-Zentrum für Diabetesforschung, Düsseldorf, Deutschland
- Deutsches Zentrum für Diabetesforschung (DZD e. V.), München-Neuherberg, Deutschland
| | - Raimund Weitgasser
- Abteilung für Innere Medizin, Privatklinik Wehrle-Diakonissen, Salzburg, Österreich
- Universitätsklinik für Innere Medizin I, LKH Salzburg - Universitätsklinikum der Paracelsus Medizinischen Privatuniversität, Salzburg, Österreich
| | - Bernhard Ludvik
- Medizinische Abteilung mit Diabetologie, Endokrinologie und Nephrologie, Klinik Landstraße, Wien, Österreich
| | - Peter Fasching
- Medizinische Abteilung für Endokrinologie, Rheumatologie und Akutgeriatrie, Wilhelminenspital der Stadt Wien, Wien, Österreich
| | - Friedrich Hoppichler
- Abteilung für Innere Medizin, Krankenhaus der Barmherzigen Brüder Salzburg, Salzburg, Österreich
| | - Alexandra Kautzky-Willer
- Gender Medicine Unit, Klinische Abteilung für Endokrinologie und Stoffwechsel, Universitätsklinik für Innere Medizin III, Medizinische Universität Wien, Spitalgasse 23, 1090, Wien, Österreich.
| | - Guntram Schernthaner
- Department of Internal Medicine II, Medizinische Universität Wien, Wien, Österreich
| | - Rudolf Prager
- Stoffwechselzentrum im Rudolfinerhaus, Rudolfinerhaus Privatklinik, Wien, Österreich
| | - Susanne Kaser
- Department für Innere Medizin 1, Medizinische Universität Innsbruck, Innsbruck, Österreich
| | - T C Wascher
- Medizinische Abteilung, Hanusch-Krankenhaus, Wien, Österreich
| |
Collapse
|
|
25
|
Yaribeygi H, Maleki M, Butler AE, Jamialahmadi T, Sahebkar A. Sodium-glucose co-transporter-2 inhibitors and epicardial adiposity. Eur J Pharm Sci 2023; 180:106322. [PMID: 36336279 DOI: 10.1016/j.ejps.2022.106322] [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: 07/05/2022] [Revised: 10/18/2022] [Accepted: 11/02/2022] [Indexed: 11/06/2022]
Abstract
Epicardial adipose tissue is a layer of adipocytes that physiologically surround the myocardium and play some physiologic roles in normal heart function. However, in pathologic conditions, the epicardial adipose tissue can present a potent cardiac risk factor that is capable of impairing heart function through several pathways, increasing the risk of dysrhythmia and creating an inflammatory milieu around the heart tissues. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a relatively newly introduced class of antidiabetes drugs which effectively normalize blood glucose via overt glycosuria. Some recent reports suggest that these drugs are able to modulate epicardial adiposity and decrease the risk of cardiac complications in diabetic patients who are at higher risk of epicardial adiposity-dependent cardiac disorders. If proven to be true, these antidiabetic drugs can provide dual benefits as both hypoglycemic agents and as epicardial adiposity normalizing agents, thus providing cardiac benefits. In this study, we discuss the physiological and pathophysiological importance of epicardial adiposity and the potential positive effects of SGLT2is in the diabetic milieu.
Collapse
Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran.
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya 15503, Bahrain
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
26
|
Danysh HE, Johannes CB, Beachler DC, Layton JB, Ziemiecki R, Arana A, Dinh J, Li L, Calingaert B, Pladevall-Vila M, Hunt PR, Chen H, Karlsson C, Johnsson K, Gilsenan A. Post-Authorization Safety Studies of Acute Liver Injury and Severe Complications of Urinary Tract Infection in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting. Drug Saf 2023; 46:175-193. [PMID: 36583828 PMCID: PMC9883309 DOI: 10.1007/s40264-022-01262-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/22/2022] [Indexed: 12/31/2022]
Abstract
INTRODUCTION At the time of dapagliflozin's approval in Europe (2012) to treat patients with type 2 diabetes mellitus, concerns regarding acute liver injury and severe complications of urinary tract infection (sUTI) led to two post-authorization safety (PAS) studies of these outcomes to monitor the safety of dapagliflozin in real-world use. OBJECTIVE To investigate the incidence of hospitalization for acute liver injury (hALI) or sUTI (pyelonephritis or urosepsis) among patients initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). METHODS These two noninterventional cohort studies identified initiators of dapagliflozin and comparator GLDs in November 2012-February 2019 using data from three longitudinal, population-based data sources: Clinical Practice Research Datalink (UK), the HealthCore Integrated Research Database (USA), and the Medicare database (USA). Outcomes (hALI and sUTI) were identified with electronic algorithms. Incidence rates were estimated by exposure group. Incidence rate ratios (IRRs) were calculated comparing dapagliflozin to comparator GLDs, using propensity score trimming and stratification to address confounding. The sUTI analyses were conducted separately by sex. RESULTS In all data sources, hALI and sUTI incidence rates were generally lower in dapagliflozin initiators than comparator GLD initiators. The adjusted IRR (95% confidence interval) pooled across data sources for hALI was 0.85 (0.59-1.24) and for sUTI was 0.76 (0.60-0.96) in females and 0.74 (0.56-1.00) in males. Findings from sensitivity analyses were largely consistent with the primary analyses. CONCLUSIONS These real-world studies do not suggest increased risks of hALI or sUTI, and they suggest a potential decreased risk of sUTI with dapagliflozin exposure compared with other GLDs.
Collapse
Affiliation(s)
- Heather E. Danysh
- Department of Pharmacoepidemiology and Risk Management, RTI Health Solutions, 307 Waverley Oaks Road, Suite 101, Waltham, MA 02452-8413 USA
| | - Catherine B. Johannes
- Department of Pharmacoepidemiology and Risk Management, RTI Health Solutions, 307 Waverley Oaks Road, Suite 101, Waltham, MA 02452-8413 USA
| | - Daniel C. Beachler
- Department of Safety and Epidemiology, HealthCore, Inc., Wilmington, DE USA
| | - J. Bradley Layton
- Department of Pharmacoepidemiology and Risk Management, RTI Health Solutions, Research Triangle Park, NC USA
| | - Ryan Ziemiecki
- Department of Biostatistics, RTI Health Solutions, Research Triangle Park, NC USA
| | - Alejandro Arana
- Department of Pharmacoepidemiology and Risk Management, RTI Health Solutions, Barcelona, Spain
| | - Jade Dinh
- Department of Research Operations, HealthCore, Inc., Wilmington, DE USA
| | - Ling Li
- Department of Safety and Epidemiology, HealthCore, Inc., Wilmington, DE USA
| | - Brian Calingaert
- Department of Pharmacoepidemiology and Risk Management, RTI Health Solutions, Research Triangle Park, NC USA
| | - Manel Pladevall-Vila
- Department of Pharmacoepidemiology and Risk Management, RTI Health Solutions, Barcelona, Spain ,The Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI USA
| | - Phillip R. Hunt
- BioPharmaceuticals Business Unit, AstraZeneca, Gaithersburg, MD USA
| | - Hungta Chen
- BioPharmaceuticals Business Unit, AstraZeneca, Gaithersburg, MD USA
| | | | | | - Alicia Gilsenan
- Department of Pharmacoepidemiology and Risk Management, RTI Health Solutions, Research Triangle Park, NC USA
| |
Collapse
|
|
27
|
Penland RC, Melin J, Boulton DW, Tang W. Evaluation of the Pharmacokinetics of Dapagliflozin in Patients With Chronic Kidney Disease With or Without Type 2 Diabetes Mellitus. J Clin Pharmacol 2022; 63:551-559. [PMID: 36543754 DOI: 10.1002/jcph.2196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
Evidence shows that sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, can delay the progressive decline of kidney function in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We used a population pharmacokinetics (popPK) model to characterize the pharmacokinetics of dapagliflozin in patients with CKD and compare dapagliflozin systemic exposure in different populations, such as CKD with or without T2DM and T2DM without CKD. A 2-compartmental popPK model was developed from a previous popPK model. The final popPK model was based on 9715 dapagliflozin plasma concentrations from 3055 patients included in clinical studies involving adults with CKD with or without T2DM, adults with T2DM, healthy subjects, and pediatric patients with T2DM. Overall, the apparent clearance for patients treated with dapagliflozin was 21.6 L/h, similar to previous estimates in adults with T2DM and healthy subjects (22.9 L/h). Model-derived area under the plasma concentration-time curve (AUC) was not meaningfully different between patients with CKD with and without T2DM. Median AUC was 1.6-fold higher in adult patients with CKD with T2DM compared with adult patients with T2DM without CKD. Compared with patients with normal kidney function (estimated glomerular filtration rate ≥90 mL/min/1.73 m2 ), median AUC was 2.4-fold higher in patients with CKD (with/without T2DM) with estimated glomerular filtration rate 15-29 mL/min/1.73 m2 owing to decreased renal clearance of dapagliflozin. A higher AUC was observed in patients with a higher age or lower body weight but was not considered clinically relevant. This popPK model adequately described dapagliflozin pharmacokinetics and found that systemic exposure in patients with CKD was consistent, irrespective of T2DM status.
Collapse
Affiliation(s)
- Robert C Penland
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, Boston, Massachusetts, USA
| | - Johanna Melin
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - David W Boulton
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Weifeng Tang
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA
| |
Collapse
|
|
28
|
Yaribeygi H, Maleki M, Butler AE, Jamialahmadi T, Sahebkar A. New insights into cellular links between sodium-glucose cotransporter-2 inhibitors and ketogenesis. J Cell Biochem 2022; 123:1879-1890. [PMID: 36153819 DOI: 10.1002/jcb.30327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/30/2022] [Accepted: 09/02/2022] [Indexed: 12/24/2022]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a newly developed class of highly effective antidiabetic therapies that normalize hyperglycemia via urinary glucose excretion. However, they may be accompanied by certain side effects that negatively impact their therapeutic benefits. SGLT2is induce a metabolic shift from glucose to fatty acids and thus increase lipolysis which, in turn, induces ketogenesis. The complete pathways linking SGLT2is to ketoacidosis have not yet been fully elucidated, though much is now known. Therefore, in this mechanistic study, we present the current knowledge and shed light upon the possible cellular pathways involved. A deeper understanding of the possible links between SGLT2is and ketogenesis could help to prevent adverse side effects in diabetic patients treated with these drugs.
Collapse
Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya, Bahrain
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Medicine, The University of Western Australia, Perth, Australia.,Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
29
|
Olagunju A, Yamani N, Kenny D, Mookadam M, Mookadam F, Unzek S. Potential for sodium-glucose cotransporter-2 inhibitors in the management of metabolic syndrome: A systematic review and meta-analysis. World J Cardiol 2022; 14:599-616. [PMID: 36483765 PMCID: PMC9724001 DOI: 10.4330/wjc.v14.i11.599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 09/17/2022] [Accepted: 10/28/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Landmark trials have established the benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2-Is) in cardiovascular disease including heart failure with reduced and preserved ejection fraction and renal diseases regardless of the presence of diabetes mellitus. However, studies evaluating the role of SGLT2-Is in metabolic syndrome (MetS) are limited.
AIM This study primarily aimed to evaluate the impact of SGLT2-Is on the components of MetS.
METHODS Two independent reviewers and an experienced librarian searched Medline, Scopus and the Cochrane central from inception to December 9, 2021 to identify placebo controlled randomized controlled trials that evaluated the impact of SGLT2-Is on the components of MetS as an endpoint. Pre- and post-treatment data of each component were obtained. A meta-analysis was performed using the RevMan (version 5.3; Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration).
RESULTS Treatment with SGLT2-Is resulted in a decrease in fasting plasma glucose (–18.07 mg/dL; 95%CI: -25.32 to –10.82), systolic blood pressure (–1.37 mmHg; 95%CI: -2.08 to –0.65), and waist circumference (–1.28 cm; 95%CI: -1.39 to –1.18) compared to placebo. The impact on high-density lipoprotein cholesterol was similar to placebo (0.01 mg/dL; 95%CI: -0.05 to 0.07).
CONCLUSION SGLT2-Is have a promising role in the management of MetS.
Collapse
Affiliation(s)
- Abdulbaril Olagunju
- Internal Medicine, Creighton University School of Medicine, Phoenix, AZ 85013, United States
| | - Naser Yamani
- Cardiology, Heart Center, University of Arizona College of Medicine-Phoenix, Banner University Medical Center, Phoenix, AZ 85006, United States
| | - Dorothy Kenny
- Internal Medicine, Creighton University School of Medicine, Phoenix, AZ 85013, United States
| | - Martina Mookadam
- Department of Family Medicine, Mayo Clinic, Scottsdale, AZ 85260, United States
| | - Farouk Mookadam
- Cardiology, Heart Center, University of Arizona College of Medicine-Phoenix, Banner University Medical Center, Phoenix, AZ 85006, United States
| | - Samuel Unzek
- Cardiology, Heart Center, University of Arizona College of Medicine-Phoenix, Banner University Medical Center, Phoenix, AZ 85006, United States
| |
Collapse
|
|
30
|
Uitrakul S, Aksonnam K, Srivichai P, Wicheannarat S, Incomenoy S. The Incidence and Risk Factors of Urinary Tract Infection in Patients with Type 2 Diabetes Mellitus Using SGLT2 Inhibitors: A Real-World Observational Study. MEDICINES (BASEL, SWITZERLAND) 2022; 9:medicines9120059. [PMID: 36547992 PMCID: PMC9785475 DOI: 10.3390/medicines9120059] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/15/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022]
Abstract
Background: The incidence and risk of urinary tract infection (UTI) in patients with type 2 diabetes mellitus (T2DM) who use sodium glucose co-transporter-2 (SGLT2) inhibitors are still controversial. Therefore, this study aimed to investigate the incidence and risk factors of using SGLT2 inhibitors, particularly in Thai patients. Methods: Electronic medication records of all patients, who started the treatment of T2DM between 1 January 2019 and 30 June 2021 at a tertiary hospital in Thailand, were reviewed. The patients were divided into SGLT2 inhibitor and non-SGLT2 inhibitor groups to compare the incidence of UTI. Results: The overall incidence rate of UTI was 33.49% in the SGLT2 inhibitor group and 11.72% in the non-SGLT2 inhibitor group. The incidence rates of UTI were not different between dapagliflozin and empagliflozin treatment (34.00% and 33.03%, respectively). Patients treated with SGLT2 inhibitors had a 3.70 higher risk of UTI compared with those treated with non-SGLT2 inhibitors (95%CI 2.60-5.29). Moreover, the significant risk factors for UTI found in this study were gender, age, and occupation. Conclusions: This study highlighted the high incidence of UTI in patients using dapagliflozin and empagliflozin compared with non-SGLT2 inhibitors. Additionally, patients of female gender and older age had a significantly higher risk of UTI when treated with SGLT2 inhibitors, whereas those with permanent jobs had a lower risk.
Collapse
|
|
31
|
Yaribeygi H, Maleki M, Reiner Ž, Jamialahmadi T, Sahebkar A. Mechanistic View on the Effects of SGLT2 Inhibitors on Lipid Metabolism in Diabetic Milieu. J Clin Med 2022; 11:6544. [PMID: 36362772 PMCID: PMC9653639 DOI: 10.3390/jcm11216544] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 10/28/2022] [Accepted: 11/02/2022] [Indexed: 08/30/2023] Open
Abstract
Chronic hyperglycemia induces pathophysiologic pathways with negative effects on the metabolism of most substrates as well as lipids and lipoproteins, and thereby induces dyslipidemia. Thus, the diabetic milieu is commonly accompanied by different levels of atherogenic dyslipidemia, which is per se a major risk factor for subsequent complications such as atherosclerosis, coronary heart disease, acute myocardial infarction, ischemic stroke, and nephropathy. Therefore, readjusting lipid metabolism in the diabetic milieu is a major goal for preventing dyslipidemia-induced complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of relatively newly introduced antidiabetes drugs (including empagliflozin, canagliflozin, dapagliflozin, etc.) with potent hypoglycemic effects and can reduce blood glucose by inducing glycosuria. However, recent evidence suggests that they could also provide extra-glycemic benefits in lipid metabolism. It seems that they can increase fat burning and lipolysis, normalizing the lipid metabolism and preventing or improving dyslipidemia. Nevertheless, the exact mechanisms involved in this process are not well-understood. In this review, we tried to explain how these drugs could regulate lipid homeostasis and we presented the possible involved cellular pathways supported by clinical evidence.
Collapse
Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Željko Reiner
- Department of Internal Medicine, University Hospital Center Zagreb, 1000 Zagreb, Croatia
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
32
|
Moulton MK, Johnson BR, Lavender DL, Osae SP, Phillips BB, Thomas I, Stone RH. A Scoping Review Evaluating the Effect of SGLT-2 Inhibitors on Insulin Dose Requirements in Insulin-Dependent Patients With Type 2 Diabetes. Ann Pharmacother 2022; 56:1030-1040. [PMID: 35040335 DOI: 10.1177/10600280211071089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE Assess evidence describing the effect of Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors on total daily insulin (TDI) requirements in insulin-dependent patients with type 2 diabetes. DATA SOURCES A scoping review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Protocols and Scoping Reviews (PRISMA-ScR) guidelines. The search was conducted in PubMed; citation mapping was completed in Web of Science. Filters for human studies, English language, and a publication date, from January 1, 2005 to April 12, 2021, were applied. STUDY SELECTION AND DATA EXTRACTION Studies assessing insulin dose requirements with concurrent use of an SGLT2 inhibitor for patients with type 2 diabetes were included. DATA SYNTHESIS Sixteen studies were included and demonstrated that addition of an SGLT2 inhibitor typically reduced TDI requirements. Insulin reductions were often statistically significant, occurring in studies evaluating (1) within subjects who received SGLT2 inhibitors, and (2) between subjects receiving SGLT2 inhibitors versus placebo. Compared with placebo, insulin dose reduction ranged from -0.72 to -19.2 units. However, studies were relatively small, not designed to assess TDI change, and some utilized fixed dose insulin protocols or empiric insulin dose reductions. CONCLUSIONS Lowering insulin requirements may have benefits, such as decreased hypoglycemia risk, insulin resistance, and cost. Addition of an SGLT2 inhibitor may modestly reduce TDI requirements for patients with type 2 diabetes. Evidence indicating SGLT2 inhibitor use reduces TDI may lead to additional implementation in practice and inform future research. Further research is needed to clarify insulin type (i.e., basal or prandial) and degree of TDI reduction expected with addition of an SGLT2 inhibitor.
Collapse
Affiliation(s)
- Morgan K Moulton
- Central Alabama Veterans Health Care System, U.S. Department of Veterans Affairs, Montgomery, AL, USA
| | - Blake R Johnson
- Department of Clinical and Administrative Pharmacy, College of Pharmacy, The University of Georgia, Athens, GA, USA
| | - Devin L Lavender
- Department of Clinical and Administrative Pharmacy, College of Pharmacy, The University of Georgia, Athens, GA, USA
| | - Sharmon P Osae
- Department of Clinical and Administrative Pharmacy, College of Pharmacy, The University of Georgia, Athens, GA, USA
| | - Beth Bryles Phillips
- Department of Clinical and Administrative Pharmacy, College of Pharmacy, The University of Georgia, Athens, GA, USA
| | - Ian Thomas
- UGA Libraries, The University of Georgia, Athens, GA, USA
| | - Rebecca H Stone
- Department of Clinical and Administrative Pharmacy, College of Pharmacy, The University of Georgia, Athens, GA, USA
| |
Collapse
|
|
33
|
Yaribeygi H, Maleki M, Nasimi F, Butler AE, Jamialahmadi T, Sahebkar A. Sodium-glucose co-transporter 2 inhibitors and hematopoiesis. J Cell Physiol 2022; 237:3778-3787. [PMID: 35951776 DOI: 10.1002/jcp.30851] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/19/2022] [Accepted: 07/25/2022] [Indexed: 12/15/2022]
Abstract
Many patients with diabetes mellitus, especially those with chronic kidney disorders, have some degree of anemia due to a spectrum of causes and underlying pathophysiologic pathways. As such, enhancement in erythropoiesis is important in these patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs with confirmed protective effects in kidney and cardiovascular tissues. Recent evidence suggests that these drugs may provide additional benefits in enhancing hematopoietic processes in diabetic patients. Though the exact mediating pathways have not been fully elucidated, cellular mechanisms are likely involved. In the current study, we present the potential pathways by which SGLT2i may modulate hematopoiesis and stimulate erythropoiesis.
Collapse
Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mina Maleki
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Nasimi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Alexandra E Butler
- Department of Research, Royal College of Surgeons in Ireland - Bahrain, Adliya, Bahrain
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, Western Australia, Australia
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
34
|
Cai S, Sun Q, Wang Q, He G, Chen G. Ruthenium-Catalyzed Pyridine-Directed Aryl C-H Glycosylation with Glycosyl Chlorides. J Org Chem 2022; 87:8811-8818. [PMID: 35696353 DOI: 10.1021/acs.joc.2c00815] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Metal-catalyzed C-H glycosylation reactions with glycosyl chloride donors have emerged as a useful strategy for the synthesis of C-glycosides. Previously, palladium and nickel complexes were reported to catalyze C-H glycosylation reactions using amide-linked bidentate auxiliaries. Herein, a ruthenium-catalyzed ortho C-H glycosylation reaction of arenes with various glycosyl chloride donors using a monodentate pyridine directing group is developed. Preliminary mechanistic studies indicated that two-electron oxidative addition and reductive elimination of ruthenocycle intermediate led to the glycosylation products.
Collapse
Affiliation(s)
- Shaokun Cai
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Qikai Sun
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Quanquan Wang
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Gang He
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
| | - Gong Chen
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
| |
Collapse
|
|
35
|
Nigussie KA, Shegena EA, Stephen OP, Namugambe JS, Yadesa TM. Prevalence and factors associated with inappropriate anti- diabetic medication therapy among type 2 diabetes mellitus patients at the medical and surgical wards of Mbarara Regional Referral Hospital, Uganda. PLoS One 2022; 17:e0270108. [PMID: 35767589 PMCID: PMC9242490 DOI: 10.1371/journal.pone.0270108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 06/05/2022] [Indexed: 11/19/2022] Open
Abstract
Background Inappropriate Anti-diabetic Medication Therapy (IADT) refers to a drug-related problem and includes ‘ineffective drug therapy’, ‘unnecessary drug therapy’, ‘dosage too high’, and ‘dosage too low’. This study aimed to determine the prevalence and factors associated with IADT among T2DM patients at Mbarara Regional Referral Hospital, Uganda (MRRH). Method A prospective cross-sectional study was conducted at the medical and surgical wards of MRRH from November 2021 to January 2022. One hundred and thirty-eight adult patients aged 18 years and above, with T2DM, were recruited using consecutive sampling. Patient file reviews and interviewer-administered questionnaire was used for data collection. The data were entered into and analyzed using SPSS version 25. Descriptive analysis was employed to describe the population and determine the prevalence of IADT. Types of IADTs were identified using Cipolle’s DRP classification tool. A univariate and multivariate logistic regression analysis was used to identify factors significantly associated with IADT. The P-value of < 0.05 was considered statistically significant at 95% confidence interval. Results A total of 138 hospitalized T2DM patients were studied. Eighty (58.0%) were females, and 70 (50.7%) were ≥ 60 years of age. Out of a total of 138 participants, 97 experienced at least one IADT, with an estimated prevalence of 70.3%. ‘Dosage too high’ (29.2%) and ‘dosage too low’ (27.9%) were the most common type of IADTs. Age ≥ 60 years (AOR, 8.44; 95% CI, 2.09–10.90; P-value = 0.003), T2DM duration of < 1 year (AOR, 0.37; 95% CI, 0.11–0.35; P-value = 0.019), and HbA1c of < 7% (AOR, 9.97; 95% CI, 2.34–13.57; P-value = 0.002) were found to be factors significantly associated with the occurrence of IADTs. Conclusion The overall prevalence of inappropriate anti-diabetic medication therapy among T2DM patients admitted to medical and surgical wards of MRRH was 70.3%. The most common type of IADT in this study was ‘dosage too high’, accounting for almost one-third followed by ‘dosage too low’ accounting for a quarter of total IADTs. Age greater or equal to 60 years, T2DM duration of < 1 year, and HbA1c of < 7% during the current admission were found to be factors significantly associated with the occurrence of IADTs in hospitalized T2DM patients.
Collapse
Affiliation(s)
- Konjit Abebe Nigussie
- Department of Pharmacy, Mbarara University of Science and Technology, Mbarara, Uganda
- PHARMBIOTRAC, World Bank’s ACE-II Project, Mbarara University of Science and Technology, Mbarara, Uganda
- * E-mail:
| | - Efrata Ashuro Shegena
- Department of Pharmacy, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Obwoya Paul Stephen
- Department of Internal Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | | | - Tadele Mekuriya Yadesa
- Department of Pharmacy, Mbarara University of Science and Technology, Mbarara, Uganda
- PHARMBIOTRAC, World Bank’s ACE-II Project, Mbarara University of Science and Technology, Mbarara, Uganda
- Department of Pharmacy, College of Medicine & Health Sciences, Ambo University, Ambo, Ethiopia
| |
Collapse
|
|
36
|
Thomas C, Wurzer L, Malle E, Ristow M, Madreiter-Sokolowski CT. Modulation of Reactive Oxygen Species Homeostasis as a Pleiotropic Effect of Commonly Used Drugs. FRONTIERS IN AGING 2022; 3:905261. [PMID: 35821802 PMCID: PMC9261327 DOI: 10.3389/fragi.2022.905261] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 05/18/2022] [Indexed: 01/17/2023]
Abstract
Age-associated diseases represent a growing burden for global health systems in our aging society. Consequently, we urgently need innovative strategies to counteract these pathological disturbances. Overwhelming generation of reactive oxygen species (ROS) is associated with age-related damage, leading to cellular dysfunction and, ultimately, diseases. However, low-dose ROS act as crucial signaling molecules and inducers of a vaccination-like response to boost antioxidant defense mechanisms, known as mitohormesis. Consequently, modulation of ROS homeostasis by nutrition, exercise, or pharmacological interventions is critical in aging. Numerous nutrients and approved drugs exhibit pleiotropic effects on ROS homeostasis. In the current review, we provide an overview of drugs affecting ROS generation and ROS detoxification and evaluate the potential of these effects to counteract the development and progression of age-related diseases. In case of inflammation-related dysfunctions, cardiovascular- and neurodegenerative diseases, it might be essential to strengthen antioxidant defense mechanisms in advance by low ROS level rises to boost the individual ROS defense mechanisms. In contrast, induction of overwhelming ROS production might be helpful to fight pathogens and kill cancer cells. While we outline the potential of ROS manipulation to counteract age-related dysfunction and diseases, we also raise the question about the proper intervention time and dosage.
Collapse
Affiliation(s)
- Carolin Thomas
- Laboratory of Energy Metabolism Institute of Translational Medicine Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Lia Wurzer
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Ernst Malle
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Michael Ristow
- Laboratory of Energy Metabolism Institute of Translational Medicine Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | | |
Collapse
|
|
37
|
Angelidi AM, Belanger MJ, Kokkinos A, Koliaki CC, Mantzoros CS. Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy. Endocr Rev 2022; 43:507-557. [PMID: 35552683 PMCID: PMC9113190 DOI: 10.1210/endrev/bnab034] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Indexed: 02/08/2023]
Abstract
Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies to address the global obesity epidemic and its comorbidities. Current pharmacologic options for obesity management are largely limited in number and of modest efficacy/safety profile. Therefore, the need for safe and more efficacious new agents is urgent. Drugs that are currently under investigation modulate targets across a broad range of systems and tissues, including the central nervous system, gastrointestinal hormones, adipose tissue, kidney, liver, and skeletal muscle. Beyond pharmacotherapeutics, other potential antiobesity strategies are being explored, including novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy. The present review summarizes the pathophysiology of energy homeostasis and highlights pathways being explored in the effort to develop novel antiobesity medications and interventions but does not cover devices and bariatric methods. Emerging pharmacologic agents and alternative approaches targeting these pathways and relevant research in both animals and humans are presented in detail. Special emphasis is given to treatment options at the end of the development pipeline and closer to the clinic (ie, compounds that have a higher chance to be added to our therapeutic armamentarium in the near future). Ultimately, advancements in our understanding of the pathophysiology and interindividual variation of obesity may lead to multimodal and personalized approaches to obesity treatment that will result in safe, effective, and sustainable weight loss until the root causes of the problem are identified and addressed.
Collapse
Affiliation(s)
- Angeliki M Angelidi
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Matthew J Belanger
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Chrysi C Koliaki
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Christos S Mantzoros
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
38
|
Chertow GM, Vart P, Jongs N, Langkilde AM, McMurray JJV, Correa-Rotter R, Rossing P, Sjöström CD, Stefansson BV, Toto RD, Wheeler DC, Heerspink HJL. Quételet (body mass) index and effects of dapagliflozin in chronic kidney disease. Diabetes Obes Metab 2022; 24:827-837. [PMID: 34984791 DOI: 10.1111/dom.14641] [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: 10/21/2021] [Revised: 12/28/2021] [Accepted: 01/01/2022] [Indexed: 01/08/2023]
Abstract
AIM To assess the effects of dapagliflozin in patients with chronic kidney disease (CKD) and albuminuria, with and without type 2 diabetes, stratified by the Quételet (body mass) index (BMI). METHODS We randomized 4304 adult patients with an estimated glomerular filtration rate (eGFR) of 25-75 ml/min/1.73m2 and urinary albumin-to-creatinine ratio of 200-5000 mg/g to dapagliflozin 10 mg/day or placebo. The primary outcome was a composite of sustained decline in eGFR of 50% or more, kidney failure, or death from kidney or cardiovascular causes. Secondary outcomes included kidney composite endpoint (primary composite endpoint without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure/ cardiovascular death), and all-cause mortality. We categorized participants according to World Health Organization BMI criteria: lean/ideal (<25 kg/m2 ), overweight (25-< 30 kg/m2 ), grade 1 obesity (30-<35 kg/m2 ), and grade 2/3 obesity (≥35 kg/m2 ). RESULTS Of 4296 (99.8%) randomized participants, 888 (20.7%), 1491 (34.7%), 1136 (26.4%), and 781 (18.2%) were categorized as lean/ideal, overweight, grade 1 obesity, and grade 2/3 obesity, respectively. Median follow-up was 2.4 years. Benefits of dapagliflozin were observed independent of baseline BMI for primary and secondary endpoints. Hazard ratios (95% CI) for dapagliflozin versus placebo for the primary composite endpoint were 0.60 (0.43, 0.85), 0.55 (0.40, 0.75), 0.71 (0.49, 1.04), and 0.57 (0.37, 0.87) among participants in the lean/ideal, overweight, grade 1 obesity, and grade 2/3 obesity groups (interaction P = .72). CONCLUSION Among participants with CKD and albuminuria, with or without type 2 diabetes, kidney and cardiovascular benefits of dapagliflozin were evident and consistent across the BMI spectrum.
Collapse
Affiliation(s)
- Glenn M Chertow
- Departments of Medicine and Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA
| | - Priya Vart
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Niels Jongs
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Anna Maria Langkilde
- Late-Stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - John J V McMurray
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Ricardo Correa-Rotter
- The National Medical Science and Nutrition Institute Salvador Zubiran, Mexico City, Mexico
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - C David Sjöström
- Late-Stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Bergur V Stefansson
- Late-Stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Robert D Toto
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - David C Wheeler
- Department of Renal Medicine, University College London, London, UK
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- The George Institute for Global Health, Sydney, Australia
| |
Collapse
|
|
39
|
Varadhan A, Stephan K, Gupta R, Vyas AV, Ranchal P, Aronow WS, Hawwa N, Lanier GM. Growing role of SGLT2i in heart failure: evidence from clinical trials. Expert Rev Clin Pharmacol 2022; 15:147-159. [PMID: 35264076 DOI: 10.1080/17512433.2022.2051480] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION : There is an unmet need for therapies that improve overall mortality and morbidity for patients with preserved ejection fraction, who comprise roughly half of all heart failure (HF) cases. The growing role of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in cardiovascular outcomes provide a paradigm shift in the treatment of HF. AREAS COVERED : This review article provides a general overview of the growing role of SGLT2is and summarizes the mechanism of action, side effects, and contraindications for the treatment of HF. We also discuss recent clinical trials measuring the effects of different SGLT2is as possible treatment options for HF with reduced ejection fraction and HF with mid-range and preserved EF. We conducted a review of all the randomized, controlled studies with SGLT2is in patients with known heart failure with and without type-2 diabetes (T2DM). We performed a literature search in PubMed, Google Scholar, the Web of Science, and the Cochrane Library while screening results by the use of titles and abstracts. EXPERT OPINION : The promising pathophysiological profile of SGLT2i and their role in cardioprotective effects demonstrate an invaluable discovery in the management of patients with HF irrespective of their diabetes status.
Collapse
Affiliation(s)
- Ajay Varadhan
- University of South Florida, Morsani College of Medicine, Tampa, Florida, USA
| | - Katarina Stephan
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Rahul Gupta
- Lehigh Valley Heart Institute, Lehigh Valley Health Network, Allentown, PA, USA
| | - Apurva V Vyas
- Lehigh Valley Heart Institute, Lehigh Valley Health Network, Allentown, PA, USA
| | - Purva Ranchal
- Department of Internal Medicine, Boston University, Boston, MA
| | - Wilbert S Aronow
- Department of Cardiology, Westchester Medical Center, Valhalla, NY, USA
| | - Nael Hawwa
- Lehigh Valley Heart Institute, Lehigh Valley Health Network, Allentown, PA, USA
| | - Gregg M Lanier
- Department of Cardiology, Westchester Medical Center, Valhalla, NY, USA
| |
Collapse
|
|
40
|
Čertíková Chábová V, Zakiyanov O. Sodium Glucose Cotransporter-2 Inhibitors: Spotlight on Favorable Effects on Clinical Outcomes beyond Diabetes. Int J Mol Sci 2022; 23:2812. [PMID: 35269954 PMCID: PMC8911473 DOI: 10.3390/ijms23052812] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/28/2022] [Accepted: 03/02/2022] [Indexed: 12/16/2022] Open
Abstract
Sodium glucose transporter type 2 (SGLT2) molecules are found in proximal tubules of the kidney, and perhaps in the brain or intestine, but rarely in any other tissue. However, their inhibitors, intended to improve diabetes compensation, have many more beneficial effects. They improve kidney and cardiovascular outcomes and decrease mortality. These benefits are not limited to diabetics but were also found in non-diabetic individuals. The pathophysiological pathways underlying the treatment success have been investigated in both clinical and experimental studies. There have been numerous excellent reviews, but these were mostly restricted to limited aspects of the knowledge. The aim of this review is to summarize the known experimental and clinical evidence of SGLT2 inhibitors' effects on individual organs (kidney, heart, liver, etc.), as well as the systemic changes that lead to an improvement in clinical outcomes.
Collapse
Affiliation(s)
- Věra Čertíková Chábová
- Department of Nephrology, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 12800 Prague 2, Czech Republic;
| | | |
Collapse
|
|
41
|
Täger T, Atar D, Agewall S, Katus HA, Grundtvig M, Cleland JGF, Clark AL, Fröhlich H, Frankenstein L. Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials. Heart Fail Rev 2021; 26:1421-1435. [PMID: 32314085 PMCID: PMC8510986 DOI: 10.1007/s10741-020-09954-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2D). The comparative efficacy of individual SGLT2i remains unclear. We searched PubMed, www.clinicaltrials.gov and the Cochrane Central Register of Controlled Trials for randomised controlled trials exploring the use of canagliflozin, dapagliflozin, empagliflozin or ertugliflozin in patients with T2D. Comparators included placebo or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints were cardiovascular mortality and worsening heart failure (HF). Evidence was synthesised using network meta-analysis (NMA). Sixty-four trials reporting on 74,874 patients were included. The overall quality of evidence was high. When compared with placebo, empagliflozin and canagliflozin improved all three endpoints, whereas dapagliflozin improved worsening HF. When compared with other SGLT2i, empagliflozin was superior for all-cause and cardiovascular mortality reduction. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Ertugliflozin had no effect on any of the three endpoints investigated. Sensitivity analyses including extension periods of trials or excluding studies with a treatment duration of < 52 weeks confirmed the main results. Similar results were obtained when restricting mortality analyses to patients included in cardiovascular outcome trials (n = 38,719). Empagliflozin and canagliflozin improved survival with empagliflozin being superior to the other SGLT2i. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Prospective head-to-head comparisons would be needed to confirm these results.
Collapse
Affiliation(s)
- Tobias Täger
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Dan Atar
- Department of Cardiology, Oslo University Hospital, Ulleval and Institute of Clinical Sciences, University of Oslo, Oslo, Norway
| | - Stefan Agewall
- Department of Cardiology, Oslo University Hospital, Ulleval and Institute of Clinical Sciences, University of Oslo, Oslo, Norway
| | - Hugo A Katus
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Morten Grundtvig
- Medical Department, Innlandet Hospital Trust Division Lillehammer, Lillehammer, Norway
| | - John G F Cleland
- National Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Imperial College, London, and Robertson Centre for Biostatistics & Clinical Trials, Glasgow, UK
| | - Andrew L Clark
- Castle Hill Hospital of the University of Hull, Cottingham, UK
| | - Hanna Fröhlich
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Lutz Frankenstein
- Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
| |
Collapse
|
|
42
|
Bagepally BS, Chaikledkaew U, Youngkong S, Anothaisintawee T, Thavorncharoensap M, Dejthevaporn C, Thakkinstian A. Cost-Utility Analysis of Dapagliflozin Compared to Sulfonylureas for Type 2 Diabetes as Second-Line Treatment in Indian Healthcare Payer's Perspective. CLINICOECONOMICS AND OUTCOMES RESEARCH 2021; 13:897-907. [PMID: 34712053 PMCID: PMC8548256 DOI: 10.2147/ceor.s328433] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 09/07/2021] [Indexed: 11/23/2022] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) is a leading health issue, causing economic burden in India. Pharmacotherapy is a major cost driver in diabetic care usually funded through out of pocket expenditure; however, there has been a very limited economic evaluation evidence to guide the choice of diabetes pharmacotherapy in India. Therefore, this study aims to evaluate the long-term cost-effectiveness of dapagliflozin (sodium glucose transporter 2 inhibitor) compared to commonly used sulfonylureas as second-line drugs in Indian patients with T2DM. Methods Cost-utility analysis was employed to estimate the costs and health outcomes using a Markov model with 1-year cycle length during a lifetime horizon based on an Indian payer’s perspective. A treatment pathway with dapagliflozin as second-line therapy was compared to sulfonylureas after failure of initial metformin therapy. Clinical and cost data were collected from literature reviews and available secondary data sources. Both costs and outcomes were discounted at a 3% annual discount rate. The results were presented as the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were performed to test parameter uncertainties. Results Compared to sulfonylurea, dapagliflozin was estimated to incur an additional cost of ₹182,632 (US$2,446) with an expected 3.49 life years (LY) or 1.72 quality adjusted life years (QALY) gained, resulting in an ICER of ₹52,270 (US$699) per LY gained, or ₹106,133 (US$1,421) per QALY gained. Uncertainty analyses showed that the ICER values were not sensitive to changes in most parameters. Conclusion Dapagliflozin would be cost-effective compared to sulfonylureas as the second line added to metformin for T2DM patients based on an Indian payer’s perspective.
Collapse
Affiliation(s)
- Bhavani Shankara Bagepally
- Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand.,Department of Non-Communicable Diseases, ICMR-National Institute of Epidemiology, Chennai, India
| | - Usa Chaikledkaew
- Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand.,Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Sitaporn Youngkong
- Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand.,Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Thunyarat Anothaisintawee
- Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand.,Department of Family Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Montarat Thavorncharoensap
- Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand.,Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | | | - Ammarin Thakkinstian
- Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand.,Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| |
Collapse
|
|
43
|
Odutayo A, da Costa BR, Pereira TV, Garg V, Iskander S, Roble F, Lalji R, Hincapié CA, Akingbade A, Rodrigues M, Agarwal A, Lawendy B, Saadat P, Udell JA, Cosentino F, Grant PJ, Verma S, Jüni P. Sodium-Glucose Cotransporter 2 Inhibitors, All-Cause Mortality, and Cardiovascular Outcomes in Adults with Type 2 Diabetes: A Bayesian Meta-Analysis and Meta-Regression. J Am Heart Assoc 2021; 10:e019918. [PMID: 34514812 PMCID: PMC8649541 DOI: 10.1161/jaha.120.019918] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Background This study aimed to assess the effectiveness of sodium‐glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes. Methods and Results We conducted a Bayesian meta‐analysis of randomized controlled trials comparing sodium‐glucose cotransporter 2 inhibitors with placebo. We used meta‐regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty‐three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all‐cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63–0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69–1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72–1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61–1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63–1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71–1.08), with a 90.1% to 98.7% probability for the true RR to be <1.00 for both outcomes. There was little evidence for ertugliflozin and sotagliflozin versus placebo for reducing all‐cause and cardiovascular mortality. There was no association between treatment effects for all‐cause and cardiovascular mortality and the control group event rates. There was evidence for a reduction in the incidence of heart failure for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin versus placebo (probability RR <1.00 of ≥99.3%) and weaker, albeit positive, evidence for acute myocardial infarction for the first 3 agents (probability RR <1.00 of 89.0%–95.2%). There was little evidence of any agent except canagliflozin for reducing the incidence of stroke. Conclusions Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all‐cause and cardiovascular mortality versus placebo. Treatment effects of sodium‐glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.
Collapse
Affiliation(s)
- Ayodele Odutayo
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada
| | - Bruno R da Costa
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada
| | - Tiago V Pereira
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada.,Department of Health Sciences University of Leicester UK
| | - Vinay Garg
- Faculty of Medicine Department of Medicine University of Toronto Ontario Canada
| | - Samir Iskander
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada
| | - Fatimah Roble
- Faculty of Medicine Department of Medicine University of Toronto Ontario Canada
| | - Rahim Lalji
- Department of Chiropractic Medicine Faculty of Medicine University of Zurich and Balgrist University Hospital Zurich Switzerland.,Epidemiology, Biostatistics and Prevention Institute University of Zurich Zurich Switzerland
| | - Cesar A Hincapié
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada.,Department of Chiropractic Medicine Faculty of Medicine University of Zurich and Balgrist University Hospital Zurich Switzerland.,Epidemiology, Biostatistics and Prevention Institute University of Zurich Zurich Switzerland
| | | | - Myanca Rodrigues
- Health Research Methodology Graduate Program Department of Health Research Methods, Evidence & Impact Faculty of Health Sciences McMaster University Hamilton Ontario Canada
| | - Arnav Agarwal
- Faculty of Medicine Department of Medicine University of Toronto Ontario Canada
| | - Bishoy Lawendy
- Faculty of Medicine Department of Medicine University of Toronto Ontario Canada
| | - Pakeezah Saadat
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada
| | - Jacob A Udell
- Faculty of Medicine Department of Medicine University of Toronto Ontario Canada
| | - Francesco Cosentino
- Cardiology Unit Department of Medicine Solna Karolinska Institute &Karolinska University Hospital Stockholm Sweden
| | - Peter J Grant
- Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds/Leeds Teaching Hospitals NHS TrustLIGHT Laboratories Leeds UK
| | - Subodh Verma
- Departments of Surgery, and Pharmacology and Toxicology University of Toronto Ontario Canada
| | - Peter Jüni
- Department of Medicine and Institute of Health Policy, Management and Evaluation Applied Health Research Centre (AHRC) Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of Toronto Canada
| |
Collapse
|
|
44
|
Effects of Dapagliflozin Adjunct to Insulin on Glycemic Variations in Patients with Newly Diagnosed Type 2 Diabetes: A Randomized, Controlled, Open-Labeled Trial. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6618257. [PMID: 34497852 PMCID: PMC8419509 DOI: 10.1155/2021/6618257] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 08/10/2021] [Indexed: 01/10/2023]
Abstract
Background This study is aimed at investigating whether dapagliflozin adjunct to insulin therapy further improves glycemic control compared to insulin therapy alone in patients with newly diagnosed type 2 diabetes (T2D). Methods This single-centre, randomized, controlled, open-labeled trial recruited newly diagnosed T2D patients. Subjects were randomized 1 : 1 to the dapagliflozin add-on to continuous subcutaneous insulin infusion (CSII) group (DAPA) or the CSII therapy group for 5 weeks. Standard meal tests were performed 3 times at days -3, 7, and 35 for glucose, C-peptide, and insulin level determination. Two-time continuous glucose monitoring (CGM) was performed at baseline and at the end of the study. The primary endpoint was the difference in the mean amplitude of glycemic excursions (MAGEs) between the groups. Results A total of 66 subjects completed the study, with 34 and 32 patients in the DAPA and CSII groups, respectively. Patients in the DAPA group exhibited significant decreases in MAGE levels at the endpoint. We also observed that patients in the DAPA group had a lower homoeostasis model assessment insulin resistance (HOMA-IR) and a higher homoeostasis model assessment B (HOMA-B) value at 1 week and 5 weeks compared to those with insulin therapy, respectively. In addition, our data showed that patients in the DAPA group showed a significantly lower insulin dose (0.07 U/kg) and weighed less than those in the CSII group. Conclusion Our data indicate that dapagliflozin adjunct to insulin is a safe and effective therapy for improving glycemic variations, insulin sensitivity, and weight loss in newly diagnosed T2D patients.
Collapse
|
|
45
|
Siamashvili M, Davis SN. Sodium-glucose cotransporter 2 inhibitors for the management of type 2 diabetes. Expert Opin Pharmacother 2021; 22:2181-2198. [PMID: 34388350 DOI: 10.1080/14656566.2021.1967320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Sodium-glucose cotransporter (SGLT) 2 inhibitors reduce glucose reabsorption in the kidney, increase glucosuria, and improve glycemia. Besides glycemic efficacy, the class also lowers risk of cardiovascular and renal disease. AREAS COVERED The authors describe late phase trials of empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin. Safety and efficacy endpoints in monotherapy, combination therapy, cardiovascular, and renal outcomes trials have been identified and presented. EXPERT OPINION SGLT2 inhibitors appear to be safe and effective agents that improve glycemia when used alone or in combination with any other approved antihyperglycemic medications. Other beneficial effects include reductions in body weight and blood pressure, improvements in renal outcomes, all-cause mortality, cardiovascular mortality, and worsening heart failure.
Collapse
Affiliation(s)
- Maka Siamashvili
- School of Medicine, University of Maryland, Baltimore, Maryland, USA
| | - Stephen N Davis
- School of Medicine, University of Maryland, Baltimore, Maryland, USA
| |
Collapse
|
|
46
|
Lipscombe L, Butalia S, Dasgupta K, Eurich DT, MacCallum L, Shah BR, Simpson S, Senior PA. Pharmacologic Glycemic Management of Type 2 Diabetes in Adults: 2020 Update. Can J Diabetes 2021; 44:575-591. [PMID: 32972640 DOI: 10.1016/j.jcjd.2020.08.001] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Lorraine Lipscombe
- Division of Endocrinology, Department of Medicine, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Sonia Butalia
- Division of Endocrinology, Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Kaberi Dasgupta
- Divisions of Internal Medicine, Clinical Epidemiology, and Endocrinology and Metabolism, Department of Medicine; Centre for Outcomes Research and Evaluation, Research Institute, McGill University Health Centre, Montreal, Quebec, Canada
| | - Dean T Eurich
- School of Public Health, University of Alberta, Edmonton, Alberta, Canada
| | - Lori MacCallum
- Banting & Best Diabetes Centre, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
| | - Baiju R Shah
- Division of Endocrinology and Metabolism, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Medicine and Institute for Health Policy Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
| | - Scot Simpson
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Peter A Senior
- Division of Endocrinology and Metabolism, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
47
|
Nicholson MK, Ghazal Asswad R, Wilding JP. Dapagliflozin for the treatment of type 2 diabetes mellitus - an update. Expert Opin Pharmacother 2021; 22:2303-2310. [PMID: 34281456 DOI: 10.1080/14656566.2021.1953471] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Diabetes is a global health concern with a prevalence of 463 million people. Importantly, despite the availability of numerous antidiabetic medications, type 2 diabetes mellitus (T2DM) is still associated with significant morbidity and mortality worldwide. One particular drug of interest is dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is commonly used in the treatment of Type 2 Diabetes Mellitus (T2DM). AREAS COVERED This review outlines the current use and pharmacology of dapagliflozin, with a specific focus on recent evidence regarding benefits in patients with cardiovascular and chronic kidney disease. The article includes an overview of the efficacy and safety of this drug and provides the reader with the expert opinion and perspectives of the authors. EXPERT OPINION Increasing evidence of the beneficial effects on morbidity and mortality in patients with Type 2 diabetes and concurrent heart failure, acute MI and renal failure are likely to see the usage of dapagliflozin in patients with these comorbidities increase over the next 5 years.
Collapse
Affiliation(s)
- Martha K Nicholson
- Department of Diabetes and Endocrinology, Liverpool University Hospitals NHS Foundation Trust, Clinical Sciences Centre, Aintree University Hospital, Liverpool, UK.,Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Randa Ghazal Asswad
- Department of Diabetes and Endocrinology, Liverpool University Hospitals NHS Foundation Trust, Clinical Sciences Centre, Aintree University Hospital, Liverpool, UK.,Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - John Ph Wilding
- Department of Diabetes and Endocrinology, Liverpool University Hospitals NHS Foundation Trust, Clinical Sciences Centre, Aintree University Hospital, Liverpool, UK.,Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| |
Collapse
|
|
48
|
Araki E, Mathieu C, Shiraiwa T, Maeda H, Ikeda H, Thoren F, Arya N, Asano M, Iqbal N. Long-term (52-week) efficacy and safety of dapagliflozin as an adjunct to insulin therapy in Japanese patients with type 1 diabetes: Subgroup analysis of the DEPICT-2 study. Diabetes Obes Metab 2021; 23:1496-1504. [PMID: 33620762 PMCID: PMC8251623 DOI: 10.1111/dom.14362] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 02/09/2021] [Accepted: 02/16/2021] [Indexed: 12/24/2022]
Abstract
AIM To examine the long-term efficacy and safety of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor used to treat type 1 diabetes, in the Japanese subpopulation of the DEPICT-2 study. MATERIALS AND METHODS Patients with type 1 diabetes were randomized to dapagliflozin 5 mg (n = 55), dapagliflozin 10 mg (n = 41) or placebo (n = 58) plus insulin for a 24-week, double-blind period followed by a 28-week, single-blind extension phase. RESULTS From baseline to 24 weeks, dapagliflozin reduced HbA1c compared with placebo (mean change of -0.58% and -0.80% for 5 and 10 mg, respectively), and an HbA1c reduction was observed up to 52 weeks. Compared with placebo, dapagliflozin 5 and 10 mg increased the proportion of patients achieving HbA1c reductions of 0.5% or more without severe hypoglycaemia events and reduced glycaemic variability assessed via continuous glucose monitoring. Both dapagliflozin doses decreased body weight and total daily insulin dose at 24 weeks compared with placebo; these reductions were maintained up to 52 weeks. Diabetic ketoacidosis occurred in both dapagliflozin groups (one and two cases, respectively) but not with placebo. CONCLUSIONS Efficacy and safety results from the Japanese subpopulation of the DEPICT-2 study were generally consistent with those from the overall population, indicating that long-term dapagliflozin adjunct to insulin therapy improves glycaemic control without an increased risk of hypoglycaemia but with a risk of diabetic ketoacidosis in Japanese patients with type 1 diabetes.
Collapse
Affiliation(s)
- Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Chantal Mathieu
- Clinical and Experimental EndocrinologyUniversity of LeuvenLeuvenBelgium
| | | | | | | | | | - Niki Arya
- Biopharmaceuticals R&D, AstraZenecaGaithersburgMarylandUSA
| | | | - Nayyar Iqbal
- Biopharmaceuticals R&D, AstraZenecaGaithersburgMarylandUSA
| |
Collapse
|
|
49
|
Lingvay I, Greenberg M, Gallo S, Shi H, Liu J, Gantz I. Efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus and established cardiovascular disease using insulin: A VERTIS CV substudy. Diabetes Obes Metab 2021; 23:1640-1651. [PMID: 33769675 PMCID: PMC8252001 DOI: 10.1111/dom.14385] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/22/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023]
Abstract
AIM To assess the efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) and established atherosclerotic cardiovascular disease (ASCVD) inadequately controlled by insulin. MATERIALS AND METHODS VERTIS CV was the cardiovascular outcome study for ertugliflozin. Patients were randomly assigned to placebo, or ertugliflozin 5 mg or 15 mg once daily. We report the results of a substudy in patients on a stable dose of insulin ≥20 units/d. The primary endpoint was glycated haemoglobin (HbA1c) change from baseline to 18 weeks. Secondary endpoints were changes in fasting plasma glucose (FPG), body weight (BW), the proportion of patients with HbA1c <53 mmol/mol (<7%), systolic blood pressure (SBP), diastolic blood pressure and insulin dose. RESULTS Of 8246 patients randomized in VERTIS CV, 1065 were included in the substudy (68.2% men, mean [SD] age 64.8 [7.8] years, T2DM duration 16.7 [9.0] years, HbA1c 8.4 [1.0]%). At week 18, the least squares (LS) mean change from baseline in HbA1c was significantly greater with ertugliflozin 5 mg and 15 mg versus placebo (placebo-adjusted LS mean change -0.58%, 95% confidence interval [CI] -0.71, -0.44 and -0.65%, 95% CI -0.78, -0.51, respectively; P < 0.001 for both). Ertugliflozin significantly reduced FPG, BW and SBP. In women, the incidence of genital mycotic infections was higher with ertugliflozin (3.5%) versus placebo (0.0%). The incidence of symptomatic hypoglycaemia was similar across treatment groups. CONCLUSIONS Ertugliflozin added to insulin improved glycaemic control, BW and SBP versus placebo at 18 weeks in patients with T2DM and ASCVD.
Collapse
Affiliation(s)
| | | | | | | | - Jie Liu
- Merck & Co., Inc.KenilworthNew JerseyUSA
| | - Ira Gantz
- Merck & Co., Inc.KenilworthNew JerseyUSA
| |
Collapse
|
|
50
|
Shi N, Shi Y, Xu J, Si Y, Yang T, Zhang M, Ng DM, Li X, Xie F. SGLT-2i and Risk of Malignancy in Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. Front Public Health 2021; 9:668368. [PMID: 34164370 PMCID: PMC8215266 DOI: 10.3389/fpubh.2021.668368] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/03/2021] [Indexed: 12/25/2022] Open
Abstract
Background: Currently, the association between sodium-glucose cotransporter 2 inhibitor (SGLT-2i) and malignancy risk has yet to be fully elucidated. This meta-analysis aimed to determine the relationship between SGLT-2i and malignancy risk in type 2 diabetes (T2D) patients. Methods: We searched PubMed, ScienceDirect, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science to identify randomized controlled trials (RCTs) published up to August 2020 related to T2D patients treated with SGLT-2i vs. placebo or other hypoglycemic agents. The meta-analysis's primary outcome was malignancies' incidence, and the results were evaluated using risk ratio (RR) and 95% confidence interval (CI). Results: We reviewed 76 articles (77 RCTs), comprising 45,162 and 43,811 patients in SGLT-2i and control groups, respectively. Compared with the control group, SGLT-2i had no significant association with augmented overall malignancy risk in T2D patients (RR = 1.05, 95% CI = 0.97–1.14, P = 0.20), but ertugliflozin may upsurge the risk (RR = 1.80, 95% CI = 1.02–3.17, P = 0.04). Compared with active hypoglycemic agents, dapagliflozin may increase (RR = 2.71, 95% CI = 1.46–6.43, P = 0.02) and empagliflozin may decrease (RR = 0.67, 95% CI = 0.45–0.98, P = 0.04) the malignancy risk. Compared with placebo, empagliflozin may exhibit risk increase (RR = 1.25, 95% CI = 1.05–1.49, P = 0.01), primarily in digestive system (RR = 1.48, 95% CI = 0.99–2.21, P = 0.05). Conclusions: Our results proposed that in diverse comparisons, ertugliflozin and dapagliflozin seemed to increase the malignancy risk in T2D patients. Empagliflozin may cause malignancy risk reduction compared with active hypoglycemic agents but increase overall risk primarily in the digestive system compared with placebo. In short, the relationship between SGLT-2i and malignancy in T2D patients remains unclear.
Collapse
Affiliation(s)
- Nanjing Shi
- Department of Endocrinology, Affiliated Hangzhou First People' Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yetan Shi
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jingsi Xu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuexiu Si
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Tong Yang
- Department of Tumor High Intensity Focused Ultrasound Therapy, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Mengting Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | | | - Xiangyuan Li
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Fei Xie
- Department of Endocrinology, Ningbo Yinzhou No. 2 Hospital, Ningbo, China
| |
Collapse
|