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Moustafa B, Trifan G. The Role of Diabetes and SGLT2 Inhibitors in Cerebrovascular Diseases. Curr Neurol Neurosci Rep 2025; 25:37. [PMID: 40411658 DOI: 10.1007/s11910-025-01425-7] [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] [Accepted: 05/08/2025] [Indexed: 05/26/2025]
Abstract
PURPOSE OF REVIEW Diabetes is a well-established risk factor for stroke. Understanding the pathophysiology of this connection is crucial to implementing appropriate prevention strategies. Lately, there has been a paradigm shift in the care of individuals with diabetes toward the use of glucose-lowering medications with potential cardiovascular, cerebrovascular or cardiorenal benefits. The aim of this article is to provide a critical analysis of the role of diabetes in cerebrovascular disease and current evidence and recommendations for the use of glucose-lowering medication with particular focus on the sodium glucose cotransporter-2 inhibitor (SGLT2i) class. RECENT FINDINGS Intensive glycemic control in individuals with diabetes reduces the risk of microvascular complications, but there is less clear evidence for decreasing risk of macrovascular events (e.g., stroke). A multifaceted management of diabetes addressing healthy lifestyle practices, glycemic control, and optimization of other cardiovascular risk factors is highly recommended. SGLT2i are the latest class of antihyperglycemic agents available for diabetes management. Canagliflozin and empagliflozin are associated with reduction in major adverse cardiovascular events (MACE). Dapagliflozin did not reduce the rate of MACE but is associated with reduction in heart-failure related death and hospitalization and has the potential to decrease dementia risk. Ertugliflozin decreases rates of hospitalization related to heart failure however it was non-inferior to placebo in reducing MACE. There is increasing evidence that the use of SGLT2i may reduce the risk of stroke, particularly hemorrhagic stroke, in individuals with type 2 diabetes and a high risk of cardiovascular events, and that SGLT2i may also be beneficial for brain health by decreasing risk of cognitive decline and dementia. Antihyperglycemic therapy should be tailored to patients' circumstances. SGLT2i treatment should be considered in patients with type 2 diabetes and established or high-risk cardiovascular disease, heart failure, or chronic kidney disease, to reduce the overall cerebro-cardiovascular and renal risks.
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Affiliation(s)
- Bayan Moustafa
- Mayo Clinic College of Medicine and Science, 1221 Whipple St, Eau Claire, WI, 54703, USA.
| | - Gabriela Trifan
- College of Medicine, University of Illinois at Chicago, 912 S Wood St, Chicago, IL, 60612, USA
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Welty FK, Parhofer KG, Konstam M, Palmer MK, Greenberg B, Daher R, Clayton T. The Data Monitoring Experience in Empagliflozin Randomized Clinical Trials Between 2011 and 2024. Ther Innov Regul Sci 2025; 59:489-504. [PMID: 40011379 DOI: 10.1007/s43441-025-00749-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/20/2025] [Indexed: 02/28/2025]
Abstract
In November 2007, a black box warning was mandated for rosiglitazone in type 2 diabetes mellitus (T2DM) based on an increased risk of ischemic cardiovascular (CV) events. The Food and Drug Administration (FDA) issued a directive that a CV outcomes trial must be done for any new diabetes drug to demonstrate no CV harm. Therefore, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial was started in 2011 alongside 13 additional randomized clinical trials (RCTs) of empagliflozin in T2DM. The results of EMPA-REG OUTCOME set the stage for later RCTs in heart failure. Results from these clinical trials have changed the outlook for patients both with and without T2DM and with and without heart failure. A Program Data Monitoring Committee (DMC) with the same core members was utilized for these trials between 2011 and 2024. This committee is likely to be one of the longest serving DMCs since it served 28 trials with empagliflozin between 2011 and 2024. The committee encountered several important challenges which are discussed in this article. Moreover, the committee provides several important take-home messages which we hope will be of value in discussing issues in creating, developing and running DMCs in the future. These include: 1. Whether and when to be blinded and unblinded; 2. How to proceed when the primary endpoint shows no evidence of benefit, but there is evidence for a mortality benefit; 3. Development of presentation of data using figures and boxplots for rapid review of adverse events and laboratory data to assess clinical challenges; 4. How to manage a catastrophic serious adverse event; 5. Suggestions for an ideal structure of the report for the DMC closed session; and 6. The relation between the DMC, sponsor and Contract Research Organization. Our experience emphasizes the value of continuity with the same members serving over a 13-year period.
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Affiliation(s)
- Francine K Welty
- Division of Cardiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA.
| | | | - Marvin Konstam
- The CardioVascular Center, Tufts Medical Center and Tufts University School of Medicine, Boston, MA, USA
| | | | - Barry Greenberg
- Division of Cardiology, University of California at San Diego, La Jolla, CA, USA
| | - Ralph Daher
- Cooper University Healthcare, Camden, NJ, USA
| | - Tim Clayton
- Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK
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Xu L, Wu Y, Li J, Ding Y, Chow J, Li L, Liu H, Wang Z, Gong T, Li Y, Ma G. Efficacy and safety of 11 sodium-glucose cotransporter-2 inhibitors at different dosages in type 2 diabetes mellitus patients inadequately controlled with metformin: a Bayesian network meta-analysis. BMJ Open 2025; 15:e088687. [PMID: 40010842 PMCID: PMC11877256 DOI: 10.1136/bmjopen-2024-088687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 02/07/2025] [Indexed: 02/28/2025] Open
Abstract
OBJECTIVES Assess the efficacy and safety profiles of different sodium-glucose cotransporter-2 inhibitors (SGLT2is) as an add-on to metformin in type 2 diabetes mellitus (T2DM) patients. DESIGN Bayesian network meta-analysis. DATA SOURCES PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov were searched before 18 December 2024. ELIGIBILITY CRITERIA Randomised controlled trials (RCTs) evaluating T2DM patients taking one of 12 SGLT2is as add-on therapy to metformin. Efficacy outcomes focused on glycated haemoglobin (HbA1c) reduction, fasting plasma glucose (FPG) reduction and weight loss (WL). Safety outcomes included adverse events (AEs), serious AEs (SAEs), hypoglycaemia, urinary tract infections (UTI) and genital infections (GI). DATA EXTRACTION AND SYNTHESIS Two investigators independently extracted data. The quality of the included studies was assessed using the Cochrane Risk of Bias Tool (V.2.0) for RCTs. RESULTS 23 RCTs involving 9144 patients and 11 SGLT2is were included. Compared with placebo, most SGLT2is reduced HbA1c (mean difference (MD), -0.45~-0.80%), FPG (MD, -0.78~-2.02 mmol/L) and body weight (MD, -0.88~-2.67 kg). Only 10 mg of henagliflozin increased the incidence of AEs, and none of the included interventions increased the risks of SAEs or UTIs. 50 mg of empagliflozin exhibited higher risks of hypoglycaemia. Only 10 mg of empagliflozin increased the risk of GI. According to the surface under the cumulative ranking values, SGLT2is with optimal efficacy and safety were 15 mg of ertugliflozin in HbA1c reduction, 300 mg of canagliflozin in FPG reduction, WL and hypoglycaemia, 400 mg of sotagliflozin in total AEs, 10 mg of ertugliflozin and 150 mg of ipragliflozin in SAEs, 12.5 mg of ipragliflozin in UTI and 1 mg of ertugliflozin in GI. CONCLUSIONS As add-on therapy, SGLT2is demonstrated favourable antidiabetic efficacy and acceptable safety. 300 mg of canagliflozin was the best option among the included interventions considering favourable glucose control and WL. Some novel SGLT2is (eg, henagliflozin) exhibited promising efficacy and safety profiles, but more research is needed to validate the findings.
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Affiliation(s)
- Leqing Xu
- Fudan University, Shanghai, Shanghai, China
| | - Yike Wu
- Fudan University, Shanghai, Shanghai, China
| | - Jiyifan Li
- Fudan University, Shanghai, Shanghai, China
| | - Yanan Ding
- Fudan University, Shanghai, Shanghai, China
| | | | | | | | - Zihan Wang
- Fudan University, Shanghai, Shanghai, China
| | | | - Yue Li
- Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Guo Ma
- Fudan University, Shanghai, Shanghai, China
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Volpe S, Vozza A, Lisco G, Fanelli M, Racaniello D, Bergamasco A, Triggiani D, Pierangeli G, De Pergola G, Tortorella C, Moschetta A, Piazzolla G. Sodium-Glucose Cotransporter 2 Inhibitors Improve Body Composition by Increasing the Skeletal Muscle Mass/Fat Mass Ratio in Patients with Type 2 Diabetes: A 52-Week Prospective Real-Life Study. Nutrients 2024; 16:3841. [PMID: 39599627 PMCID: PMC11597755 DOI: 10.3390/nu16223841] [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: 10/10/2024] [Revised: 11/05/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Sodium-glucose cotransporter 2 inhibitors (SGLT2is) induce body weight loss, but their effect on skeletal muscle mass (SMM) and strength needs to be better elucidated. OBJECTIVES This study aimed to evaluate the effects of SGLT2i on SMM in a real-life population setting of patients with type 2 diabetes (T2D). Secondary outcomes included changes in liver steatosis and in anthropometric and glucometabolic parameters. METHODS Seventy-one patients were treated with SGLT2is as an add-on to metformin for 52 consecutive weeks. Visits were scheduled at baseline (T0) and after 6 (T6) and 12 months of therapy (T12) and included the checking of laboratory tests, measurement of anthropometric parameters, bioimpedance analysis of body composition, and abdominal ultrasound (US). RESULTS Fat mass (FM) and visceral adipose tissue (VAT) progressively decreased compared to the baseline (FM: -2.9 ± 0.6 kg at T6; -2.8 ± 0.6 kg at T12; VAT: -0.3 ± 0.1 L at T6; -0.4 ± 0.1 L at T12; all p < 0.01). Changes in SMM were less pronounced (-0.4 ± 0.3 kg at T6, ns; -0.7 ± 0.4 kg at T12, p < 0.05), yielding a beneficial increase in the SMM/FM ratio (+0.3 ± 0.05 at T6 and +0.2 ± 0.05 at T12, all p < 0.01). No significant changes in sarcopenia, sarcopenic obesity, fat-free mass, muscle strength, and water compartments were observed at the end of the follow-up period. Anthropometric and glucometabolic parameters, insulin resistance, liver enzymes, and biometric indices and US grading of hepatic steatosis improved throughout this study. CONCLUSIONS In a real-life setting, SGLT2i therapy is associated with weight loss attributable to FM rather than SMM loss without any relevant deterioration in muscle strength. In addition, SGLT2is proved to have beneficial effects on steatotic liver disease.
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Affiliation(s)
- Sara Volpe
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (S.V.); (A.V.); (M.F.); (D.R.); (A.B.); (D.T.); (G.P.); (C.T.); (A.M.)
| | - Alfredo Vozza
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (S.V.); (A.V.); (M.F.); (D.R.); (A.B.); (D.T.); (G.P.); (C.T.); (A.M.)
| | - Giuseppe Lisco
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (S.V.); (A.V.); (M.F.); (D.R.); (A.B.); (D.T.); (G.P.); (C.T.); (A.M.)
| | - Margherita Fanelli
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (S.V.); (A.V.); (M.F.); (D.R.); (A.B.); (D.T.); (G.P.); (C.T.); (A.M.)
| | - Davide Racaniello
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (S.V.); (A.V.); (M.F.); (D.R.); (A.B.); (D.T.); (G.P.); (C.T.); (A.M.)
| | - Alessandro Bergamasco
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (S.V.); (A.V.); (M.F.); (D.R.); (A.B.); (D.T.); (G.P.); (C.T.); (A.M.)
| | - Domenico Triggiani
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (S.V.); (A.V.); (M.F.); (D.R.); (A.B.); (D.T.); (G.P.); (C.T.); (A.M.)
| | - Giulia Pierangeli
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (S.V.); (A.V.); (M.F.); (D.R.); (A.B.); (D.T.); (G.P.); (C.T.); (A.M.)
| | - Giovanni De Pergola
- Center of Nutrition for the Research and the Care of Obesity and Metabolic Diseases, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy;
| | - Cosimo Tortorella
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (S.V.); (A.V.); (M.F.); (D.R.); (A.B.); (D.T.); (G.P.); (C.T.); (A.M.)
| | - Antonio Moschetta
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (S.V.); (A.V.); (M.F.); (D.R.); (A.B.); (D.T.); (G.P.); (C.T.); (A.M.)
| | - Giuseppina Piazzolla
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy; (S.V.); (A.V.); (M.F.); (D.R.); (A.B.); (D.T.); (G.P.); (C.T.); (A.M.)
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Mariani MV, Manzi G, Pierucci N, Laviola D, Piro A, D'Amato A, Filomena D, Matteucci A, Severino P, Miraldi F, Vizza CD, Lavalle C. SGLT2i effect on atrial fibrillation: A network meta-analysis of randomized controlled trials. J Cardiovasc Electrophysiol 2024; 35:1754-1765. [PMID: 38940255 DOI: 10.1111/jce.16344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 06/29/2024]
Abstract
INTRODUCTION Gliflozins are recommended as first-line treatment in patients with heart failure and/or cardiovascular comorbidities and are demonstrated to reduce atrial fibrillation (AF) occurrence. However, it is not well known which gliflozin yields the larger cardioprotection in terms of AF occurrence reduction. Hence, we aimed to compare data regarding AF recurrence associated with different gliflozins. METHODS An accurate search of online scientific libraries (from inception to June 1, 2023) was performed. Fifty-nine studies were included in the meta-analysis involving 108 026 patients, of whom 60 097 received gliflozins and 47 929 received placebo. RESULTS Gliflozins provided a statistically significant reduction of AF occurrence relative to standard of care therapy in the overall population (relative risks [RR]: 0.8880, 95% CI: [0.8059; 0.9784], p = .0164) and in patients with diabetes and cardiorenal diseases (RR: 0.8352, 95% CI: [0.7219; 0.9663], p = .0155). Dapagliflozin significantly decreased AF occurrence as compared to placebo (0.7259 [0.6337; 0.8316], p < .0001) in the overall population, in patients with diabetes (RR: 0.2482, 95% CI: [0.0682; 0.9033], p = .0345), with diabetes associated with cardiorenal diseases (RR: 0.7192, 95% CI: [0.5679; 0.9110], p = .0063) and in the subanalysis including studies with follow-up ≥1 year (RR: 0.7792, 95% CI: [0.6508; 0.9330], p = .0066). No significant differences in terms of AF protection were found among different gliflozins. CONCLUSIONS Dapagliflozin use was associated with significant reduction in AF risk as compared to placebo in overall population and patients with diabetes, whereas the use of other gliflozins did not significantly reduce AF occurrence.
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Affiliation(s)
- Marco Valerio Mariani
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Giovanna Manzi
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Nicola Pierucci
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Domenico Laviola
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Agostino Piro
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Andrea D'Amato
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Domenico Filomena
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Andrea Matteucci
- Clinical and Rehabilitation Cardiology Division, San Filippo Neri Hospital, Rome, Italy
| | - Paolo Severino
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Fabio Miraldi
- Cardio Thoracic-Vascular and Organ Transplantation Surgery Department, Policlinico Umberto I Hospital, Rome, Italy
| | - Carmine Dario Vizza
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Carlo Lavalle
- Department of Cardiovascular, Respiratory, Nephrological, Aenesthesiological and Geriatric Sciences, "Sapienza" University of Rome, Rome, Italy
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Natale P, Tunnicliffe DJ, Toyama T, Palmer SC, Saglimbene VM, Ruospo M, Gargano L, Stallone G, Gesualdo L, Strippoli GF. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev 2024; 5:CD015588. [PMID: 38770818 PMCID: PMC11106805 DOI: 10.1002/14651858.cd015588.pub2] [Citation(s) in RCA: 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.
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Affiliation(s)
- Patrizia Natale
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - David J Tunnicliffe
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Tadashi Toyama
- Department of Nephrology, Kanazawa University, Kanazawa, Japan
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan
| | - Suetonia C Palmer
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | - Valeria M Saglimbene
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Marinella Ruospo
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Letizia Gargano
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Loreto Gesualdo
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Fm Strippoli
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J) Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari, Italy
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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Zhang HD, Ding L, Mi LJ, Zhang AK, Zhang K, Jiang ZH, Yu FY, Yan XX, Shen YJ, Tang M. Sodium-glucose co-transporter-2 inhibitors for the prevention of atrial fibrillation: a systemic review and meta-analysis. Eur J Prev Cardiol 2024; 31:770-779. [PMID: 37966828 DOI: 10.1093/eurjpc/zwad356] [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: 09/23/2023] [Revised: 10/22/2023] [Accepted: 11/09/2023] [Indexed: 11/16/2023]
Abstract
AIMS Sodium-glucose co-transporter-2 (SGLT2) inhibitors are reported to have cardiac benefits. The effects of SGLT2 inhibitors on the prevention of atrial fibrillation (AF) remain inconclusive. We aimed to investigate whether SGLT2 inhibitors can prevent AF occurrence in patients with cardiometabolic diseases. METHODS AND RESULTS We searched MEDLINE, EMBASE, and the Cochrane CENTRAL database up to 1 July 2023. Randomized, placebo-controlled trials of SGLT2 inhibitors in patients with diabetes, heart failure, chronic kidney diseases (CKDs), or cardiometabolic risk factors were included. The primary outcome was AF occurrence. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated in the overall population and selected subgroups. Forty-six trials comprising 101 100 patients were included. Overall, no significant risk reduction of AF occurrence was observed with SGLT2 inhibitors, although there was a favourable trend (RR 0.90, 95% CI 0.80-1.01). In trials with follow-up durations of over 1 year, a similar result was achieved (RR 0.90, 95% CI 0.80-1.01). The results were consistent across different SGLT2 inhibitors, with RRs (95% CIs) of 0.82 (0.60-1.12) for canagliflozin, 0.87 (0.73-1.03) for dapagliflozin, 0.97 (0.78-1.22) for empagliflozin, 0.99 (0.66-1.50) for sotagliflozin, and 0.87 (0.58-1.29) for ertugliflozin. Analyses in different doses of SGLT2 inhibitors yielded similar results. The associations between SGLT2 inhibitors and AF occurrence were also absent in patients with diabetes, heart failure, and CKDs. CONCLUSION For patients with cardiometabolic diseases or risk factors, SGLT2 inhibitors did not decrease the risk of AF occurrence, regardless of follow-up duration, type or dose of the drug, or the patient population.
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Affiliation(s)
- Hong-Da Zhang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Lei Ding
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Li-Jie Mi
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Ai-Kai Zhang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Kuo Zhang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Zi-Han Jiang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Feng-Yuan Yu
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Xin-Xin Yan
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Yu-Jing Shen
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
| | - Min Tang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China
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8
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Pozzi A, Cirelli C, Merlo A, Rea F, Scangiuzzi C, Tavano E, Iorio A, Kristensen SL, Wong C, Iacovoni A, Corrado G. Adverse effects of sodium-glucose cotransporter-2 inhibitors in patients with heart failure: a systematic review and meta-analysis. Heart Fail Rev 2024; 29:207-217. [PMID: 37917192 DOI: 10.1007/s10741-023-10363-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/11/2023] [Indexed: 11/04/2023]
Abstract
Sodium-glucose cotransoporter-2 inhibitors (SGLT-2Is) improve prognosis in heart failure (HF) patients both with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). However, these drugs can have some side effects. To estimate the relative risk of side effects in HF patients treated with SGLT-2Is irrespective from left ventricular EF and setting (chronic and non-chronic HF). Five randomized controlled trials (RCTs) enrolling patients with HFrEF, 4 RCTs enrolling non-chronic HF, and 3 RCTs enrolling HFpEF were included. Among side effects, urinary infection, genital infection, acute kidney injury, diabetic ketoacidosis, hypoglycemia, hyperkalemia, hypokalemia, bone fractures, and amputations were considered in the analysis. Overall, 24,055 patients were included in the analysis: 9020 (38%) patients with HFrEF, 12,562 (52%) with HFpEF, and 2473 (10%) with non-chronic HF. There were no differences between SGLT-2Is and placebo in the risk to develop diabetic ketoacidosis, hypoglycemia, hyperkalemia, hypokalemia, bone fractures, and amputations. HFrEF patients treated with SGLT-2Is had a significant reduction of acute kidney injury (RR = 0.54 (95% CI 0.33-0.87), p = 0.011), whereas no differences have been reported in the HFpEF group (RR = 0.94 (95% CI 0.83-1.07), p = 0.348) and non-chronic HF setting (RR = 0.79 (95% CI 0.55-1.15), p = 0.214). A higher risk to develop genital infection (overall 2.57 (95% CI 1.82-3.63), p < 0.001) was found among patients treated with SGLT-2Is irrespective from EF (HFrEF: RR = 1.96 (95% CI 1.17-3.29), p = 0.011; HFpEF: RR = 3.04 (95% CI 1.88-4.90), p < 0.001). The risk to develop urinary infections was increased among SGLT-2I users in the overall population (RR = 1.13 (95% CI 1.00-1.28), p = 0.046) and in the HFpEF setting (RR = 1.19 (95% CI 1.02-1.38), p = 0.029), whereas no differences have been reported in HFrEF (RR = 1.05 (95% CI 0.81-1.36), p = 0.725) and in non-chronic HF setting (RR = 1.04 (95% CI 0.75-1.46), p = 0.806). SGLT-2Is increase the risk of urinary and genital infections in HF patients. In HFpEF patients, the treatment increases the risk of urinary infections compared to placebo, whereas SGLT-2Is reduce the risk of acute kidney disease in patients with HFrEF.
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Affiliation(s)
- A Pozzi
- Cardiology Division, Valduce Hospital, Como, Italy.
| | - C Cirelli
- Cardiology Division, Papa Giovanni XXIII Hospital, Bergamo, Italy
- Milano-Bicocca University, Milan, Italy
| | - A Merlo
- Cardiology Division, Papa Giovanni XXIII Hospital, Bergamo, Italy
- Milano-Bicocca University, Milan, Italy
| | - F Rea
- Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
| | - C Scangiuzzi
- Cardiology Division, Papa Giovanni XXIII Hospital, Bergamo, Italy
- Milano-Bicocca University, Milan, Italy
| | - E Tavano
- Cardiology Division, Circolo Hospital, Busto Arsizio, Italy
| | - A Iorio
- Cardiology Division, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - S L Kristensen
- Cardiology Division, Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark
| | - C Wong
- Cardiology Division, North Bristol, Bristol, UK
| | - A Iacovoni
- Cardiology Division, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - G Corrado
- Cardiology Division, Valduce Hospital, Como, Italy
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9
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Xie X, Wu C, Hao Y, Wang T, Yang Y, Cai P, Zhang Y, Huang J, Deng K, Yan D, Lin H. Benefits and risks of drug combination therapy for diabetes mellitus and its complications: a comprehensive review. Front Endocrinol (Lausanne) 2023; 14:1301093. [PMID: 38179301 PMCID: PMC10766371 DOI: 10.3389/fendo.2023.1301093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/27/2023] [Indexed: 01/06/2024] Open
Abstract
Diabetes is a chronic metabolic disease, and its therapeutic goals focus on the effective management of blood glucose and various complications. Drug combination therapy has emerged as a comprehensive treatment approach for diabetes. An increasing number of studies have shown that, compared with monotherapy, combination therapy can bring significant clinical benefits while controlling blood glucose, weight, and blood pressure, as well as mitigating damage from certain complications and delaying their progression in diabetes, including both type 1 diabetes (T1D), type 2 diabetes (T2D) and related complications. This evidence provides strong support for the recommendation of combination therapy for diabetes and highlights the importance of combined treatment. In this review, we first provided a brief overview of the phenotype and pathogenesis of diabetes and discussed several conventional anti-diabetic medications currently used for the treatment of diabetes. We then reviewed several clinical trials and pre-clinical animal experiments on T1D, T2D, and their common complications to evaluate the efficacy and safety of different classes of drug combinations. In general, combination therapy plays a pivotal role in the management of diabetes. Integrating the effectiveness of multiple drugs enables more comprehensive and effective control of blood glucose without increasing the risk of hypoglycemia or other serious adverse events. However, specific treatment regimens should be tailored to individual patients and implemented under the guidance of healthcare professionals.
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Affiliation(s)
- Xueqin Xie
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Changchun Wu
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuduo Hao
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Tianyu Wang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuhe Yang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Peiling Cai
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
| | - Yang Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Academy for Interdiscipline, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jian Huang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Kejun Deng
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Dan Yan
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hao Lin
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
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10
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Fayette L, Sailer MO, Perez‐Pitarch A. Pharmacometrics enhanced Bayesian borrowing approach to improve clinical trial efficiency: Case of empagliflozin in type 2 diabetes. CPT Pharmacometrics Syst Pharmacol 2023; 12:1386-1397. [PMID: 37644910 PMCID: PMC10583245 DOI: 10.1002/psp4.13035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/18/2023] [Accepted: 08/15/2023] [Indexed: 08/31/2023] Open
Abstract
We report use of a pharmacometrics enhanced Bayesian borrowing (PEBB) approach to leverage historical clinical trial data on a drug product to build models, project the outcome of future clinical trials, and borrow information from these projections to improve the efficiency of future target trials. This design takes a two-stage approach. First, a design phase is performed before target trial data are available to determine the operating characteristics and an appropriate tuning parameter that will be used in the subsequent analysis phase of a chosen target trial. Second, once the target trial data are available, the analysis phase is performed with the determined tuning parameter. This step is where borrowing is applied from these projections to inform the results for the target trial. To illustrate how a PEBB could improve the efficiency of clinical trials, we apply our design to trials with empagliflozin for treating patients with type 2 diabetes. We performed a retrospective evaluation applying the method to a phase III target trial and a hypothetical smaller trial. The type I error could be kept below 10% while increasing the trial power and effective sample size. Our findings suggest that a PEBB has the potential to increase the power of clinical trials, while controlling for type I error, by leveraging the information from previous trials through population pharmacokinetic/pharmacodynamic modeling and simulation.
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Affiliation(s)
- Lucie Fayette
- Boehringer Ingelheim Pharma GmbH & Co. KGIngelheimGermany
- Ecole des Ponts, UGEChamps‐sur‐MarneFrance
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11
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Lee EY, Cho JH, Lee WJ, Kim NH, Kim JH, Lee BW. Glucometabolic control of once-weekly dulaglutide switched from DPP4 inhibitor versus daily empagliflozin add-on in patients with type 2 diabetes inadequately controlled with metformin, sulfonylurea, and DPP4 inhibitor: A randomised trial. Diabetes Res Clin Pract 2023; 203:110884. [PMID: 37595844 DOI: 10.1016/j.diabres.2023.110884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/03/2023] [Accepted: 08/15/2023] [Indexed: 08/20/2023]
Abstract
AIMS To compare the effectiveness and safety of empagliflozin and dulaglutide in patients with type 2 diabetes (T2D) inadequately controlled by oral triple therapy. METHODS In this 24-week, multi-center, randomized trial, patients with T2D and HbA1c level ≥7.5% (58 mmol/mol) on metformin, sulfonylurea, and dipeptidyl peptidase 4 inhibitor (DPP4-i) were randomly assigned into two groups: daily empagliflozin add-on or once-weekly dulaglutide switched from DPP4-i. The primary endpoint was changes from baseline HbA1c at 24 weeks. RESULTS In total, 152 patients were recruited to the empagliflozin-added quadruple group (n = 76) or the switched-to-dulaglutide triple group (n = 76). At week 24, both groups showed significant reduction in HbA1c level from baseline with greater reduction with empagliflozin (the mean treatment difference: -0.27% [95% CI -0.50 to -0.04, p = 0.024]) (-2.88 mmol/mol [95% CI -5.37 to -0.39], p = 0.024). Empagliflozin significantly reduced body weight from baseline to week 24 (-1.72 kg [95% CI -1.98 to -0.59, p < 0.001]). No serious adverse events were reported with either empagliflozin or dulaglutide. CONCLUSIONS Empagliflozin, compared with once-weekly dulaglutide switched from DPP4-i, demonstrated greater HbA1c reduction and weight loss in patients with T2D inadequately controlled with metformin, sulfonylurea, and DPP4-i. TRIAL REGISTRATION cris.nih.go.kr (KCT0006157).
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Affiliation(s)
- Eun Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jae-Hyoung Cho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Woo Je Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Nam Hoon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jae Hyeon Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
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12
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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: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [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.
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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
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13
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Dissanayake H, Dilrukshi S, Ratnasamy V, Soysa P, Samarathunga T, Bandara P, De Silva L, Katulanda P. Empagliflozin in South Asians with type 2 diabetes: Real world data on effects on cardiometabolic parameters, safety and determinants of response to therapy from a diabetes practice in Sri Lanka. Prim Care Diabetes 2023; 17:98-104. [PMID: 36460591 DOI: 10.1016/j.pcd.2022.11.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 10/19/2022] [Accepted: 11/19/2022] [Indexed: 12/05/2022]
Abstract
AIMS SGLT2 inhibitors provide cardiovascular and renal protection in people with type 2 diabetes (T2DM). Real-world data on their effect on improving glucose and cardiovascular risk factors, and adverse effects in South Asians are limited. METHODS We retrospectively analyzed clinical, demographic, anthropometric and biochemical data among adults with T2DM, commenced on empagliflozin and followed up for at least one month in a diabetes clinic in Colombo. RESULTS Among 1523 participants (men 49.6 %, age 54.9 (± 10.8) years, diabetes duration 11.5 (± 7.6) years, body mass index 28.2 (± 4.5 kg/m2), over a median follow up of 12 months (range: 1-24 months), reduction in HbA1c, weight, systolic blood pressure (SBP) and urine albumin-creatinine ratio were evident within the first month. Benefits sustained up to two-years (mean changes from baseline: HbA1c - 0.31 (± 1.49), weight - 1.14 (± 4.17), SBP - 3.44 (± 21.75), UACR - 19.84 (± 108.22) follow up. eGFR declined by the third month, returned to baseline by 12th and remained stable over 24 months. Higher baseline HbA1c, weight and SBP predicted greater decline in HbA1c, weight and SBP respectively. Weight reduction independently predicted the SBP reduction. Eighteen participants per 100 patient-years discontinued therapy due to adverse effects: genital mycotic infections and features of hypovolaemia were the commonest. We observed only two events of diabetic ketoacidosis. CONCLUSIONS Empagliflozin effectively improves glucose, weight and SBP and retards progression of renal impairment in South Asians with T2D. Genital mycotic infections and hypovolaemia were the commonest reasons for discontinuation. Careful patient selection and advice can avoid other sinister complications.
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Affiliation(s)
- Harsha Dissanayake
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka; Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka.
| | - Shani Dilrukshi
- University Medical Unit, National Hospital of Sri Lanka, Sri Lanka
| | | | - Pasindu Soysa
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka
| | - Thilina Samarathunga
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka
| | - Prabhath Bandara
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka
| | - Laksara De Silva
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka
| | - Prasad Katulanda
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka; Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka; Cruddas Link Fellow, Harris Manchester College, University of Oxford, UK
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14
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Iuliano S, Greco EA, Mirabelli M, Chiefari E, Caroleo P, Puccio L, Giuliano S, Foti DP, Brunetti A, Aversa A. Predicting the response to SGLT-2 inhibitors as add-on therapy to multiple day injection insulin with glycated albumin: a pilot study. Minerva Endocrinol (Torino) 2022; 47:379-387. [PMID: 35103458 DOI: 10.23736/s2724-6507.22.03691-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Achieving optimal glycemic targets is the main therapeutic goal in patients with type 2 diabetes (T2D) mellitus. HbA1c is the reference biomarker for monitoring glycemic control; however, in specific conditions affecting erythrocyte turnover or in patients on multiple daily injection (MDI) insulin regimens, the determination of glycated albumin (GA) may be preferable. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a novel class of antidiabetic drugs that lower plasma glucose concentrations quickly, with insulin-independent mechanisms. Herein, we explored the role of GA in predicting the short-term response to SGLT-2 inhibitors as add-on to MDI insulin. METHODS Sixteen patients with long-standing, poorly controlled T2D on MDI insulin starting an SGLT-2 inhibitor were subjected to plasma GA and HbA1c measurements at 30 days intervals for up to 3 months in order to examine the temporal changes of these glycemic biomarkers. RESULTS At the end of the study, grossly coincident with the life span of erythrocytes, a significant decrease in median HbA1c was observed, (from 8.7 [range: 8.2-9.3%] at baseline to 7.2 [range: 7.0-7.9%]), with the advantage of less insulin dose requirements. However, significant, and incremental reductions in median GA determinations could be already evident after 30 days (-3.5 [range: -7.5, -2.5%]) and 60 days (-6.4 [range: -10.5, -4.7%]) from the start of SGLT-2 inhibitor treatment and persisted for up to 3 months (-8.6 [range: -12.1, 6.1%]). The decrements of HbA1c observed at the 3-month visit were highly correlated with the concurrent absolute reductions of plasma GA (ρ=0.550, P=0.027), whereas a borderline significance could be demonstrated with reference to reductions in plasma GA at 30 and 60 days. CONCLUSIONS Although limited by the small number of participants, these preliminary findings suggest that GA, rather than HbA1c, could represent a useful and reliable biomarker in T2D to monitor the early glucose-lowering effects of antidiabetic drugs with rapid onset of action, such as SGLT-2 inhibitors and MDI insulin.
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Affiliation(s)
- Stefano Iuliano
- Department of Experimental and Clinical Medicine, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - Emanuela A Greco
- Department of Health Sciences, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - Maria Mirabelli
- Department of Health Sciences, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - Eusebio Chiefari
- Department of Health Sciences, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | | | | | - Stefania Giuliano
- Department of Health Sciences, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - Daniela P Foti
- Department of Experimental and Clinical Medicine, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - Antonio Brunetti
- Department of Health Sciences, The Magna Græcia University of Catanzaro, Catanzaro, Italy -
| | - Antonio Aversa
- Department of Experimental and Clinical Medicine, The Magna Græcia University of Catanzaro, Catanzaro, Italy
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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: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [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.
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Matsumura T, Makabe T, Ueda S, Fujimoto Y, Sadahiro K, Tsuruyama S, Ookubo Y, Kondo T, Araki E. Clinical Benefit of Switching from Low-Dose to High-Dose Empagliflozin in Patients with Type 2 Diabetes. Diabetes Ther 2022; 13:1621-1634. [PMID: 35840857 PMCID: PMC9399319 DOI: 10.1007/s13300-022-01296-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 06/29/2022] [Indexed: 11/03/2022] Open
Abstract
INTRODUCTION Sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors ameliorate blood glucose levels in patients with type 2 diabetes mellitus (T2DM) by inhibiting the reabsorption of glucose from the kidneys, thus increasing urinary glucose excretion. Most SGLT2 inhibitors have been reported to exert dose-dependent effects. However, little is known about the benefits of increasing the dose of SGLT2 inhibitors in clinical use. The aim of the present study was to investigate the effect of increasing the dose of the SGLT2 inhibitor empagliflozin in T2DM. METHODS We collected 52 subjects with T2DM with inadequate glycemic control. The dose of empagliflozin was increased from 10 to 25 mg, taken once daily, and the alterations in glycemic control and several other clinical parameters were evaluated. RESULTS The increased dose of empagliflozin significantly ameliorated glycemic control. In addition, body weight (BW), body mass index (BMI), triglyceride (TG), and γ-glutamyltranspeptidase (GGT) were significantly decreased and hematocrit (Hct) was increased. Multivariate logistic regression analyses revealed that baseline diastolic blood pressure (DBP) (odds ratio 1.093, 95% CI 1.019-1.156, P = 0.012) and baseline TG (odds ratio 1.012, 95% CI 1.001-1.023, P = 0.026) were retained as independent predictors for the improvement of hemoglobin A1c (HbA1c) levels. Moreover, multivariate stepwise regression analyses revealed that changes in high-density lipoprotein cholesterol (β - 0.264, 95% CI - 1.217 to 0.000, P = 0.049) and HbA1c (β 0.302, 95% CI 0.077-1.096, P = 0.025) were retained as independent predictors for changes in BMI. CONCLUSION Increasing the dose of empagliflozin significantly ameliorated BW, BMI, GGT, TG, fasting plasma glucose and HbA1c and increased Hct in patients with T2DM. Moreover, baseline DBP and TG were independent predictors for the improvement of HbA1c. These findings may provide useful information when considering increasing the dosage of SGLT2 inhibitors in patients with T2DM who have inadequate glycemic control. TRIAL REGISTRATION UMIN Clinical Trials Registry (UMIN000041543).
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Affiliation(s)
- Takeshi Matsumura
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
| | - Tomoko Makabe
- Department of Pharmacy, Nishinihon Hospital, Kumamoto, Japan
| | - Seiko Ueda
- Department of Pharmacy, Nishinihon Hospital, Kumamoto, Japan
| | - Yuki Fujimoto
- Department of Nursing, Nishinihon Hospital, Kumamoto, Japan
| | - Kayo Sadahiro
- Department of Pharmacy, Nishinihon Hospital, Kumamoto, Japan
| | | | - Yuma Ookubo
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Tatsuya Kondo
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
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Efficacy and Safety of Empagliflozin in Type 2 Diabetes Mellitus Saudi Patients as Add-On to Antidiabetic Therapy: A Prospective, Open-Label, Observational Study. J Clin Med 2022; 11:jcm11164769. [PMID: 36013008 PMCID: PMC9410062 DOI: 10.3390/jcm11164769] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/17/2022] Open
Abstract
The Saudi Food and Drug Authority (SFDA) approved sodium-glucose cotransporter-2 (SGLT2) inhibitors in 2018. The efficacy and safety of empagliflozin (EMPA) have been confirmed in the U.S., Europe, and Japan for patients with type 2 diabetes mellitus (T2DM); however, analogous evidence is lacking for Saudi T2DM patients. Therefore, the current study aimed to assess the efficacy and safety of EMPA in Saudi patients (n = 256) with T2DM. This is a 12-week prospective, open-label, observational study. Adult Saudi patients with T2DM who had not been treated with EMPA before enrolment were eligible. The exclusion criteria included T2DM patients less than 18 years of age, adults with type one diabetes, pregnant women, paediatric population. The results related to efficacy included a significant decrease in haemoglobin A1c (HbA1c) (adjusted mean difference −0.93% [95% confidence interval (CI) −0.32, −1.54]), significant improvements in fasting plasma glucose (FPG) (−2.28 mmol/L [95% CI −2.81, −1.75]), and a reduction in body weight (−0.874 kg [95% CI −4.36, −6.10]) following the administration of 25 mg of EMPA once daily as an add-on to ongoing antidiabetic therapy after 12 weeks. The primary safety endpoints were the change in the mean blood pressure (BP) values, which indicated significantly reduced systolic and diastolic BP (−3.85 mmHg [95% CI −6.81, −0.88] and −0.06 mmHg [95% CI −0.81, −0.88], respectively) and pulse rate (−1.18 [95% CI −0.79, −3.15]). In addition, kidney function was improved, with a significant reduction in the urine albumin/creatinine ratio (UACR) (−1.76 mg/g [95% CI −1.07, −34.25]) and a significant increase in the estimated glomerular filtration rate (eGFR) (3.54 mL/min/1.73 m2 [95% CI 2.78, 9.87]). Furthermore, EMPA reduced aminotransferases (ALT) in a pattern (reduction in ALT > AST). The adjusted mean difference in the change in ALT was −2.36 U/L [95% CI −1.031, −3.69], while it was −1.26 U/L [95% CI −0.3811, −2.357] for AST and −1.98 U/L [95% CI −0.44, −3.49] for GGT. Moreover, in the EMPA group, serum high-density lipoprotein (HDL) significantly increased (0.29 mmol/L [95% CI 0.74, 0.15]), whereas a nonsignificant increase was seen in low-density lipoprotein (LDL) (0.01 mmol/L [95% CI 0.19, 0.18]) along with a significant reduction in plasma triglyceride (TG) levels (−0.43 mmol/L [95% CI −0.31, −1.17]). Empagliflozin once daily is an efficacious and tolerable strategy for treating Saudi patients with insufficiently controlled T2DM as an add-on to ongoing antidiabetic therapy.
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18
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Bilgin S, Kurtkulagi O, Duman TT, Tel BMA, Kahveci G, Kiran M, Erge E, Aktas G. Sodium glucose co-transporter-2 inhibitor, Empagliflozin, is associated with significant reduction in weight, body mass index, fasting glucose, and A1c levels in Type 2 diabetic patients with established coronary heart disease: the SUPER GATE study. Ir J Med Sci 2022; 191:1647-1652. [PMID: 34476725 PMCID: PMC8412859 DOI: 10.1007/s11845-021-02761-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 08/25/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Empagliflozin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, yielded significant beneficiaries in the treatment of type 2 diabetes mellitus (T2DM). It is particularly benefited the diabetic subjects with heart conditions. AIMS We aimed to obtain a real-world data about the effects of empagliflozin add-on treatment on metabolic parameters, cardiovascular risk factors, and anthropometric measures in patients with T2DM. METHODS Type 2 diabetic patients with established coronary heart disease whom empagliflozin added to their treatment were enrolled in the study. Anthropometric measures, clinical and laboratory data, were obtained before and at the 6th month of the empagliflozin treatment. All data before and at the 6th month were compared. RESULTS Body weight (p < 0.001), body mass index (p < 0.001), waist (p < 0.001) and hip (p < 0.001) circumferences, systolic blood pressure (p = 0.006), heart rate (p = 0.01), LDL cholesterol (p = 0.01), fasting plasma glucose (p < 0.001), and HbA1c (p < 0.001) levels were significantly reduced on 6th month of empagliflozin treatment compared to the baseline values. Estimated GFR (p = 0.66), serum creatinine (p = 0.8), uric acid (p = 0.40), total cholesterol (p = 0.053), triglyceride (p = 0.057), and HDL (p = 0.09) levels were not significantly changed. CONCLUSIONS We suggest that empagliflozin treatment may improve anthropometric measures, metabolic parameters, and blood pressure and does not cause deterioration in kidney functions in type 2 diabetic patients with established coronary heart disease.
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Affiliation(s)
- Satilmis Bilgin
- Abant Izzet, Baysal University Hospital , Department of Internal Medicine, Bolu, Turkey
| | - Ozge Kurtkulagi
- Abant Izzet, Baysal University Hospital , Department of Internal Medicine, Bolu, Turkey
| | | | | | - Gizem Kahveci
- Abant Izzet, Baysal University Hospital , Department of Internal Medicine, Bolu, Turkey
| | - Murat Kiran
- Abant Izzet, Baysal University Hospital , Department of Internal Medicine, Bolu, Turkey
| | - Eray Erge
- Abant Izzet, Baysal University Hospital , Department of Internal Medicine, Bolu, Turkey
| | - Gulali Aktas
- Abant Izzet, Baysal University Hospital , Department of Internal Medicine, Bolu, Turkey.
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Kroopnick JM, Davis SN. The role of Recent Pharmacotherapeutic Options on the Management of Treatment Resistant Type 2 Diabetes. Expert Opin Pharmacother 2022; 23:1259-1271. [PMID: 35765193 DOI: 10.1080/14656566.2022.2089021] [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] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Type 2 diabetes mellitus is a complex progressive disease leading to chronic hyperglycemia due to insulin resistance and pancreatic beta-cell failure. Intensification of treatment regimens is often necessary due to the overall decline in insulin secretion. Unfortunately, many patients are unable to achieve optimal glycemic control despite the standard of care and thus may be classified as 'treatment resistant'. AREAS COVERED Newer pharmacotherapeutic agents, either injectable or oral, such as Glucagon-like-peptide-1 receptor agonists (GLP-1RA) and Sodium-glucose Cotransporter-2 (SGLT2) inhibitors are, herein, described. These agents can be used as single agents or fixed combinations that reduce glycemia while lessening the risk for hypoglycemia and renal and cardiovascular diseases. EXPERT OPINION If individualized target HbA1c is not obtained despite diet, lifestyle, and metformin therapy, then additional oral and injectable therapies should be considered. This may include newer agents such as GLP-1RA and SGLT2 inhibitors alone or in combination that provide renal protection and reduce cardiovascular and hypoglycemic risks. These newer agents have substantial potential for lowering HbA1c through differing but complementary mechanisms. Use of new insulin analogs with GLP-1RA preparations either alone or in fixed-ratio combinations, such as glargine/lixisenatide and degludec/liraglutide, can also reduce the multiple drug adherence burden while improving glycemic control.
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Affiliation(s)
- Jeffrey M Kroopnick
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Stephen N Davis
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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20
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Singh AK, Singh R. Relook at DPP-4 inhibitors in the era of SGLT-2 inhibitors. World J Diabetes 2022; 13:466-470. [PMID: 35800411 PMCID: PMC9210541 DOI: 10.4239/wjd.v13.i6.466] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/19/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
SGLT-2 inhibitors (SGLT-2Is) have significantly improved cardio-renal outcomes and are preferred agents in people with cardiovascular diseases, heart failure, and diabetic kidney disease. Similarly, GLP-1 receptor agonists (GLP-1RAs) have significantly improved atherosclerotic cardiovascular outcomes. To this end, DPP-4 inhibitors (DPP-4Is) are cardiac-neutral drugs. While long-acting GLP-1RAs have shown a favorable HbA1c lowering compared to DPP-4Is, there is no clinically meaningful HbA1c lowering difference between SGLT-2Is vs DPP-4Is. Moreover, the glucose-lowering potential of SGLT-2Is gets compromised with a progressive decline in renal functions, unlike DPP-4Is. Furthermore, the HbA1c lowering potential of DPP-4Is is favorable in people with T2DM having a modest baseline HbA1c (8.0%-8.5%) compared with SGLT-2Is which lowers HbA1c larger in a background of higher baseline HbA1c (> 8.5%-9.0%). These findings suggest that the role of DPP-4Is in the management of type 2 diabetes mellitus cannot be completely ignored even in the era of SGLT-2Is.
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Affiliation(s)
- Awadhesh Kumar Singh
- Department of Diabetes & Endocrinology, G.D Hospital & Diabetes Institute, Kolkata 700013, West Bengal, India
| | - Ritu Singh
- Department of Diabetes & Endocrinology, G.D Hospital & Diabetes Institute, Kolkata 700013, West Bengal, India
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21
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Real-world evaluation of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors for managing type 2 diabetes mellitus: a retrospective multi-ethnic cohort study. J Diabetes Metab Disord 2022; 21:521-555. [PMID: 35673518 PMCID: PMC9167339 DOI: 10.1007/s40200-022-01004-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/07/2022] [Indexed: 11/29/2022]
Abstract
Abstract Purpose Sodium-glucose co-transporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors are increasingly used as second-line therapies in patients with type 2 diabetes. The aim of this study was to assess the real-world effects of SGLT2 inhibitors in a multi-ethnic population in Singapore. Methods This retrospective cohort study examined patients diagnosed with and treated for diabetes from the Ministry of Health’s administrative database. Differences in outcomes between treatment groups were assessed using Poisson regression. Demographics, clinical characteristics, previous diagnoses and hospitalisations, and diabetes medication history were used for propensity score matching. Subgroup analyses by ethnicity were performed. Effect size was estimated using risk ratios (RRs) with 95% confidence intervals (CIs). Results Patients initiating SGLT2 inhibitors were more likely to achieve glycaemic control target than DPP4 inhibitor-treated patients (RR 1.09; 95% CI 1.04, 1.14). This was observed only in patients of Chinese ethnicity. A higher risk of diabetic ketoacidosis in SGLT2 inhibitor initiators was not observed. SGLT2 inhibitors were associated with reduced risk of hypoglycaemia (RR 0.69; 95% CI 0.59, 0.82) and urinary tract infection (RR 0.52; 95% CI 0.43, 0.63) but was not statistically significant for hypoglycaemia in Malay patients. Compared to DPP4 inhibitors, SGLT2 inhibitors were associated with 12% and 34% reduction in any-cause hospitalisation and all-cause mortality, respectively, potentially resulting in more than $50 million savings over 10 years. Conclusion SGLT2 inhibitors were associated with improvements in glycaemic control, reduced risk of complications, and was well tolerated. Ethnicity also plays a role and should be considered in future studies.
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22
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Real-world assessment of effectiveness and safety profile of remogliflozin etabonate in management of type 2 diabetes mellitus. Int J Diabetes Dev Ctries 2022. [DOI: 10.1007/s13410-022-01074-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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23
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Paudel S, John PP, Poorbaghi SL, Randis TM, Kulkarni R. Systematic Review of Literature Examining Bacterial Urinary Tract Infections in Diabetes. J Diabetes Res 2022; 2022:3588297. [PMID: 35620571 PMCID: PMC9130015 DOI: 10.1155/2022/3588297] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 04/11/2022] [Indexed: 11/18/2022] Open
Abstract
This systematic review addresses the central research question, "what is known from the published, peer-reviewed literature about the impact of diabetes on the risk of bacterial urinary tract infections (UTI)?" We examine the results from laboratory studies where researchers have successfully adapted mouse models of diabetes to study the pathophysiology of ascending UTI. These studies have identified molecular and cellular effectors shaping immune defenses against infection of the diabetic urinary tract. In addition, we present evidence from clinical studies that in addition to diabetes, female gender, increased age, and diabetes-associated hyperglycemia, glycosuria, and immune impairment are important risk factors which further increase the risk of UTI in diabetic individuals. Clinical studies also show that the uropathogenic genera causing UTI are largely similar between diabetic and nondiabetic individuals, although diabetes significantly increases risk of UTI by drug-resistant uropathogenic bacteria.
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Affiliation(s)
- Santosh Paudel
- Department of Biology, University of Louisiana at Lafayette, Lafayette, LA, USA 70504
| | - Preeti P. John
- Department of Biology, University of Louisiana at Lafayette, Lafayette, LA, USA 70504
| | | | - Tara M. Randis
- Department of Pediatrics, University of South Florida, Tampa, FL, USA 33620
| | - Ritwij Kulkarni
- Department of Biology, University of Louisiana at Lafayette, Lafayette, LA, USA 70504
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Pinto LC, Rados DV, Remonti LR, Viana MV, Leitão CB, Gross JL. Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2022; 66:68-76. [PMID: 35263050 PMCID: PMC9991024 DOI: 10.20945/2359-3997000000440] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 10/25/2021] [Indexed: 11/23/2022]
Abstract
The lowest dosage of empagliflozin (10 mg) showed similar benefits on glycated hemoglobin (HbA1c) level, body weight, blood pressure, and total and cardiovascular mortality in comparison with the highest available dose (25 mg) in the EMPAREG trial. These findings have not been clearly demonstrated for canagliflozin and dapagliflozin. The objective was to compare the effect of different doses of SGLT2 inhibitors commercially available in Brazil on HbA1c and body weight of patients with type 2 diabetes. MEDLINE, Cochrane and Embase databases were searched from inception until 11th October 2021 for randomized controlled trials of SGLT2 inhibitors in type 2 diabetes patients, lasting at least 12 weeks. HbA1c and body weight variations were described using standard mean difference. We performed direct and indirect meta-analysis, as well as a meta-regression with medication doses as covariates. Eighteen studies were included, comprising 16,095 patients. In the direct meta-analysis, SGLT2 inhibitors reduced HbA1c by 0.62% (95% CI -0.66 to -0.59) and body weight by 0.60 kg (95% CI -0.64 to -0.55). In the indirect meta-analysis, canagliflozin 300 mg ranked the highest regarding reductions in HbA1c and body weight. The remaining medications and dosages were clinically similar, despite some statistically significant differences among them. Canagliflozin 300 mg seems to be more potent in reducing HbA1c and body weight in patients with type 2 diabetes. The remaining SGLT2 inhibitors at different doses lead to similar effects for both outcomes. Whether these glycemic and weight effects are reflected in lower mortality and cardiovascular events is still uncertain and may be a topic for further studies.
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Affiliation(s)
- Lana C Pinto
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil,
| | - Dimitris V Rados
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil
| | - Luciana R Remonti
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil
| | - Marina V Viana
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil
| | - Cristiane B Leitão
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil
| | - Jorge L Gross
- Divisão de Endocrinologia, Hospital de Clínicas de Porto Alegre, Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, RS, Brasil
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25
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Lee MH, Neeland IJ, de Albuquerque Rocha N, Hughes C, Malloy CR, Jin ES. A randomized clinical trial evaluating the effect of empagliflozin on triglycerides in obese adults: Role of visceral fat. Metabol Open 2022; 13:100161. [PMID: 35024596 PMCID: PMC8728102 DOI: 10.1016/j.metop.2021.100161] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/21/2021] [Accepted: 12/21/2021] [Indexed: 01/10/2023] Open
Abstract
Background Empagliflozin, a sodium glucose cotransporter 2 inhibitor, is a medication to treat type 2 diabetes. The effect of empagliflozin in persons without diabetes has received less attention. Here we conducted a randomized, double-blind placebo-controlled clinical trial to examine the effect of empagliflozin on plasma triglycerides in obese non-diabetic adults. Methods Participants (n = 35; BMI ≥ 30 kg/m2) underwent body composition assessments using MRI, and were randomly assigned to either placebo or empagliflozin (10 mg/d) for three months. At the baseline and post-treatment visit, after an overnight fast, blood was drawn for biochemical analysis. Participants received [U–13C3]glycerol orally followed by multiple blood draws over 3 h to examine glycerol incorporation into triglycerides using NMR spectroscopy. Results The changes in blood triglyceride concentration with empagliflozin therapy related to the mass of baseline visceral adipose tissue (VAT; r = 0.53, p = 0.04). Empagliflozin slightly lowered triglycerides in obese subjects with low VAT, but increased triglycerides in the subjects with high VAT. Consistently, empagliflozin effectively suppressed triglyceride synthesis following [U–13C3]glycerol administration in the subjects with low VAT (p < 0.05), but not in the subjects with high VAT. The subjects with high VAT lost body weight after three months of empagliflozin treatment. In all subjects, about 20% of the triglyceride backbone originated from mitochondrial metabolism of glycerol. Conclusions The effect of empagliflozin on triglycerides in obese adults differed depending on VAT. Empagliflozin suppressed triglyceride synthesis in the subjects with low VAT, but tended to increase triglycerides in those with high VAT.
Visceral fat modulates the effect of empagliflozin on triglycerides in obese adults. Empagliflozin suppresses triglyceride synthesis in obese adults with low visceral fat. Empagliflozin tends to increase triglycerides in obese adults with high visceral fat. Empagliflozin induces weight loss in obese adults with high visceral fat.
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Affiliation(s)
- Min Hee Lee
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Ian J. Neeland
- Department of Medicine, University Hospitals Cleveland Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | | | - Connor Hughes
- Department of Internal Medicine, University of Texas Southwestern Medical Center, USA
| | - Craig R. Malloy
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, USA
- Department of Radiology, University of Texas Southwestern Medical Center, USA
- VA North Texas Health Care System, Dallas, TX, 75216, USA
| | - Eunsook S. Jin
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, USA
- Corresponding author. Advanced Imaging Research Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8568, USA.
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26
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Jiang Y, Yang P, Fu L, Sun L, Shen W, Wu Q. Comparative Cardiovascular Outcomes of SGLT2 Inhibitors in Type 2 Diabetes Mellitus: A Network Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne) 2022; 13:802992. [PMID: 35370961 PMCID: PMC8967154 DOI: 10.3389/fendo.2022.802992] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/13/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND A network meta-analysis of randomized controlled trials (RCTs) was conducted to explore the cardiovascular outcomes of all the kind and dosages of sodium-glucose cotransport-2 (SGLT2) inhibitors in type 2 diabetes mellitus (T2DM) patients. METHOD AND RESULT The Cochrane Library, PubMed, and Embase databases were systematically searched for studies to compare the therapeutic effects of different SGLT2 inhibitors in T2DM patients. The effect measurements estimate chosen were odds ratios (ORs) and their corresponding 95% confidence interval (CI). Forty-seven RCTs involving a total of 70574 participants were eligible for direct and indirect comparisons. In direct comparison, treatment with dapagliflozin 5mg showed significantly lower risk of all-cause mortality compared with treatment with dapagliflozin 2.5mg (OR 0.09, 95% CI 0.01-0.70). According to NMA, interestingly, empagliflozin 10mg/25mg, and canagliflozin 100mg was associated with significantly lower risks of all-cause mortality compared with placebo (OR of 0.70, 95% CI 0.58-0.85; 0.69, 95% CI 0.57-0.84; and 0.83, 95% CI 0.73-0.95, respectively). Compared with placebo, dapagliflozin 10mg, empagliflozin 10mg and 25mg displayed the lower risks for cardiovascular events (OR 0.78, 95% CI 0.44-1.00; OR 0.47, 95% CI 0.22-0.93; and 0.43, 95% CI 0.24-0.74, respectively) by direct comparison. Moreover, canagliflozin 100/300mg showed significantly higher risks of cardiovascular events compared with empagliflozin 10mg (OR of 4.83, 95% CI 1.14-20.46 and 5.31, 95% CI 1.26-22.34, respectively) and empagliflozin 25mg (4.23, 95% CI 1.13-15.83 and 4.65, 95% CI 1.25-17.27, respectively) according to NMA. There were non-significant differences among all interventions in volume depletion in traditional pairwise meta-analysis. While in NMA, canagliflozin 100/300mg were associated with significantly increased risks of volume depletion compared with placebo (OR of 1.47, 95% CI 1.08-1.99 and 2.19, 95% CI 1.66-2.90, respectively). CONCLUSION In the limitations of the NMA, this study showed that empagliflozin might be better than other SGLT2 inhibitors with low risks of all-cause mortality and cardiovascular events in patients with T2DM suggesting the need for ad hoc RCTs.
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Affiliation(s)
- Yu Jiang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Pingping Yang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Linghua Fu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lizhe Sun
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wen Shen
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qinghua Wu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Khan A, Khan IA, Abidi H, Ahmed M. Comparison of empagliflozin and vildagliptin for efficacy and safety in type 2 diabetes mellitus in the Pakistani population. Front Endocrinol (Lausanne) 2022; 13:926633. [PMID: 36060955 PMCID: PMC9428695 DOI: 10.3389/fendo.2022.926633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is a chronic disease that needs early management to prevent complications and premature mortality. Therefore, it is essential to select evidence-based drugs available to control diabetes and limit the progression to related complications. This study aimed to compare the efficacy and safety of empagliflozin and vildagliptin in people with type 2 DM. METHODS This was an open-label, parallel randomized controlled trial (NCT05359432) conducted at two tertiary care hospitals in Karachi, Pakistan. After obtaining consent, participants were randomized into two groups. The first group was given empagliflozin (10 mg once or two times daily) with metformin, and the second group got vildagliptin (50 mg once or two times daily) with metformin. HbA1c, high-density lipoprotein (HDL) levels, systolic blood pressure, fasting blood glucose, and body weight were measured at the baseline and 24-week visits. RESULTS A total of 120 patients fulfilled the selection criteria and then underwent randomization to be placed into empagliflozin and vildagliptin groups. The mean change in HbA1c (-0.97% ± 0.68 for empagliflozin and -0.82% ± 1.57 for vildagliptin) was statistically similar in both groups (p-value = 0.980). No statistically significant difference was observed between the two groups for safety parameters such as eGFR (p = 0.46), serum ALT (p = 0.13), LDL (p = 0.23), total cholesterol (p = 0.49), and triglycerides (p = 0.49). CONCLUSION Results of the study highlight that vildagliptin and empagliflozin have a significant beneficial effect in reducing HbA1c, fasting blood glucose, systolic blood pressure, and weight of participants. Both drugs had no differences when compared on safety parameters.
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Affiliation(s)
- Asima Khan
- School of Public Health, Dow University of Health Sciences, Karachi, Pakistan
| | - Izhan A. Khan
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Hussain Abidi
- Clinical Research Operations, Getz Pharma, Karachi, Pakistan
| | - Mansoor Ahmed
- School of Public Health, Dow University of Health Sciences, Karachi, Pakistan
- *Correspondence: Mansoor Ahmed,
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Wang DD, Mao YZ, Yang Y, Wang TY, Zhu P, He SM, Chen X. Effects of Sodium-Glucose Cotransporter-2 Inhibitors on Weight in Type 2 Diabetes Mellitus and Therapeutic Regimen Recommendation. J Diabetes Res 2022; 2022:4491900. [PMID: 35342769 PMCID: PMC8956429 DOI: 10.1155/2022/4491900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 02/17/2022] [Accepted: 03/01/2022] [Indexed: 12/13/2022] Open
Abstract
AIMS The present study is aimed at exploring the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on weight in type 2 diabetes mellitus (T2DM) and therapeutic regimen recommendations. METHODS 20,019 patients with T2DM were enrolled. The maximal effect (E max) models, whose evaluation index was change rate of body weight from baseline value, were used to analyze data using nonlinear mixed effect modeling (NONMEM). RESULTS For SGLT-2 inhibitors, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and tofogliflozin, the E max, and treatment duration to reach half of the maximal effects (ET50) were -3.72% and 3.35 weeks, -5.59% and 16.8 weeks, -2.84% and 3.42 weeks, -3.43% and 3.09 weeks, -3.04% and 4.38 weeks, and -2.45% and 3.16 weeks, respectively. In addition, for T2DM patients, 100 mg/day canagliflozin needs to be taken 13.4 weeks for the plateau of effect on weight; 10 mg/day empagliflozin needs to be taken 67.2 weeks for the plateau of effect on weight; 5 mg/day ertugliflozin needs to be taken 13.68 weeks for the plateau of effect on weight; 50 mg/day ipragliflozin needs to be taken 12.36 weeks for the plateau of effect on weight; 2.5 mg/day luseogliflozin needs to be taken 17.52 weeks for the plateau of effect on weight; 20 mg/day tofogliflozin needs to be taken 12.64 weeks for the plateau of effect on weight. CONCLUSIONS This was the first study to explore effects of SGLT-2 inhibitors on weight in T2DM; meanwhile, the optimum dosages and treatment durations on weight from canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and tofogliflozin were recommended, respectively.
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Affiliation(s)
- Dong-Dong Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Yi-Zhen Mao
- School Infirmary, Jiangsu Normal University, Xuzhou, Jiangsu 221132, China
| | - Yang Yang
- Department of Pharmacy, The Affiliated Changzhou Children's Hospital of Nantong University, Changzhou 213003, China
| | - Tian-Yun Wang
- Department of Pharmacy, Huaian Hospital of Huaian City, Huaian, Jiangsu 223200, China
| | - Ping Zhu
- Department of Endocrinology, Huaian Hospital of Huaian City, Huaian, Jiangsu 223200, China
| | - Su-Mei He
- Department of Pharmacy, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou Jiangsu 215153, China
| | - Xiao Chen
- Department of Pharmacy, Children's Hospital of Fudan University, Shanghai 201102, China
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Lund SS, Sattar N, Salsali A, Neubacher D, Ginsberg HN. Potential contribution of haemoconcentration to changes in lipid variables with empagliflozin in patients with type 2 diabetes: A post hoc analysis of pooled data from four phase 3 randomized clinical trials. Diabetes Obes Metab 2021; 23:2763-2774. [PMID: 34463415 PMCID: PMC9290508 DOI: 10.1111/dom.14534] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/10/2021] [Accepted: 08/24/2021] [Indexed: 01/24/2023]
Abstract
AIM To examine the association between changes in lipids and markers of haemoconcentration (haematocrit and serum albumin) with empagliflozin, a sodium-glucose co-transporter-2 inhibitor, in patients with type 2 diabetes (T2D) using pooled data from four phase 3 randomized trials. MATERIALS AND METHODS Patients with T2D received placebo (n = 825), empagliflozin 10 mg (n = 830) or 25 mg (n = 822) for 24 weeks. In post hoc mediation analyses, we assessed total changes in LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoprotein (Apo) B, and Apo A-I, and changes in these variables associated with, and independent of, changes in haematocrit and serum albumin at week 24 using ANCOVA models. RESULTS Empagliflozin versus placebo increased serum LDL-cholesterol, HDL-cholesterol, and Apo A-I, decreased triglycerides (empagliflozin 10 mg only), and (non-significantly) increased Apo B. Empagliflozin modestly increased haematocrit and serum albumin. In mediation analyses, haematocrit changes (increases) with empagliflozin were associated with significant changes (increases) in all lipid variables, including Apo B. Except for triglycerides (non-significant), similar lipid variable associations were observed with serum albumin changes. Haematocrit- and serum albumin-independent changes in lipids with empagliflozin were significant for HDL-cholesterol (increases), mostly significant for triglycerides (decreases), and less so for other lipid fractions. CONCLUSION Haematocrit and serum albumin increases were associated with increases in lipid fractions with empagliflozin. Empagliflozin-associated changes in serum lipids, particularly LDL-cholesterol increases, may be partly attributable to haemoconcentration resulting from increased urinary volume and subsequent volume contraction.
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Affiliation(s)
- Søren S. Lund
- Boehringer Ingelheim International GmbHIngelheimGermany
| | | | - Afshin Salsali
- Boehringer Ingelheim Pharmaceuticals, IncRidgefieldConnecticutUSA
| | | | - Henry N. Ginsberg
- Vagelos College of Physicians and Surgeons of Columbia UniversityNew YorkNew YorkUSA
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Wu Q, Liu M, Fang Z, Li C, Zou F, Hu L, Zhang W. Efficacy and safety of empagliflozin at different doses in patients with type 2 diabetes mellitus: A network meta-analysis based on randomized controlled trials. J Clin Pharm Ther 2021; 47:270-286. [PMID: 34544199 DOI: 10.1111/jcpt.13521] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/07/2021] [Accepted: 08/17/2021] [Indexed: 12/24/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE As an oral hypoglycaemic drug that significantly reduces cardiovascular risk, empagliflozin is often used in patients with type 2 diabetes mellitus (T2DM). However, the dosage and administration of empagliflozin are still controversial clinically. To determine the most appropriate dose, we performed this network meta-analysis. METHODS We identified randomized controlled trials (RCTs) about empagliflozin from eight databases. We analysed the pharmacodynamics, adverse effects (AEs), and pharmacokinetics of empagliflozin at different doses. RESULTS We identified 8264 articles, of which 23 RCTs with 10518 patients were included. Regarding haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), high-daily doses (10, 25, 50 mg) were significantly better than low doses (1, 2.5, 5 mg). For total AEs, there was a dose-response trend in which safety decreased with increasing doses. According to SUCRA sequencing, the order for lowering HbA1c was 25 > 50 > 10 > 5 > 1 mg, for lowering FPG was 50 > 25 > 10 > 5 > 2.5 > 1 mg and for safety was 1> 5 > 10 > 25> 2.5 > 50 mg. When considering HbA1c, FPG and total AEs, we performed a hierarchical cluster analysis and network meta-analysis to find that 25 mg performed best among different doses, which was more significant after long-term use (≥ 12 weeks). Pharmacokinetic parameters exhibited significant dose-response relationships. WHAT IS NEW AND CONCLUSION High-daily doses (10, 25, 50 mg) had better efficacy than low doses (1, 2.5, 5 mg). When considering HbA1c, FPG and total AEs, 25 mg performed best among the different doses in patients with T2DM.
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Affiliation(s)
- Qian Wu
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Miaowen Liu
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Zige Fang
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Chenxi Li
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Fang Zou
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
| | - Lei Hu
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
| | - Wenxiong Zhang
- Department of Cardio-Thoracic Surgery, The second affiliated hospital of Nanchang University, Nanchang, China
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Herrington WG, Savarese G, Haynes R, Marx N, Mellbin L, Lund LH, Dendale P, Seferovic P, Rosano G, Staplin N, Baigent C, Cosentino F. Cardiac, renal, and metabolic effects of sodium-glucose co-transporter 2 inhibitors: a position paper from the European Society of Cardiology ad-hoc task force on sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail 2021; 23:1260-1275. [PMID: 34184823 DOI: 10.1002/ejhf.2286] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 11/07/2022] Open
Abstract
In 2015, the first large-scale placebo-controlled trial designed to assess cardiovascular safety of glucose-lowering with sodium-glucose co-transporter 2 (SGLT2) inhibition in type 2 diabetes mellitus raised hypotheses that the class could favourably modify not only risk of atherosclerotic cardiovascular disease, but also hospitalization for heart failure, and the development or worsening of nephropathy. By the start of 2021, results from 10 large SGLT2 inhibitor placebo-controlled clinical outcome trials randomizing ∼71 000 individuals have confirmed that SGLT2 inhibitors can provide clinical benefits for each of these types of outcome in a range of different populations. The cardiovascular and renal benefits of SGLT2 inhibitors appear to be larger than their comparatively modest effect on glycaemic control or glycosuria alone would predict, with three trials recently reporting that clinical benefits extend to individuals without diabetes mellitus who are at risk due to established heart failure, or albuminuric chronic kidney disease. This European Society of Cardiology position paper summarizes reported results from these 10 large clinical outcome trials considering separately each of the different types of cardiorenal benefit, summarizes key molecular and pathophysiological mechanisms, and provides a synopsis of metabolic effects and safety. We also describe ongoing placebo-controlled trials among individuals with heart failure with preserved ejection fraction and among individuals with chronic kidney disease.
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Affiliation(s)
- William G Herrington
- Medical Research Council Population Health Research Unit at the University of Oxford, part of the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK
- Oxford Kidney Unit, Churchill Hospital, Oxford, UK
| | - Gianluigi Savarese
- Cardiology Unit, Department of Medicine, Karolinska Institute: Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Richard Haynes
- Medical Research Council Population Health Research Unit at the University of Oxford, part of the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK
- Oxford Kidney Unit, Churchill Hospital, Oxford, UK
| | - Nikolaus Marx
- Department of Internal Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Linda Mellbin
- Cardiology Unit, Department of Medicine, Karolinska Institute: Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Lars H Lund
- Cardiology Unit, Department of Medicine, Karolinska Institute: Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Paul Dendale
- Heart Centre Hasselt, Jessa Hospital, Hasselt, Belgium
- Faculty of Medicine & Life Sciences, Hasselt University, Hasselt, Belgium
| | - Petar Seferovic
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Giuseppe Rosano
- Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy
| | - Natalie Staplin
- Medical Research Council Population Health Research Unit at the University of Oxford, part of the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK
| | - Colin Baigent
- Medical Research Council Population Health Research Unit at the University of Oxford, part of the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (NDPH), University of Oxford, Oxford, UK
| | - Francesco Cosentino
- Cardiology Unit, Department of Medicine, Karolinska Institute: Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
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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.
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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
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Hussain M, Elahi A, Iqbal J, Bilal Ghafoor M, Rehman H, Akhtar S. Comparison of Efficacy and Safety Profile of Sodium-Glucose Cotransporter-2 Inhibitors as Add-On Therapy in Patients With Type 2 Diabetes. Cureus 2021; 13:e14268. [PMID: 33954073 PMCID: PMC8090899 DOI: 10.7759/cureus.14268] [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] [Accepted: 04/03/2021] [Indexed: 11/18/2022] Open
Abstract
Background Type 2 diabetes is a chronic metabolic disorder that is escalating at an alarming rate worldwide. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are recent oral antihyperglycemic drugs (OADs) with a unique mechanism of action. Objectives This study aimed compared the efficacy and safety profiles of two SGLT-2 inhibitors, empagliflozin and dapagliflozin, in patients with type 2 diabetes as add-on therapy to traditional first-line OADs. Methods We conducted a randomized controlled trial comparing empagliflozin and dapagliflozin in patients with type 2 diabetes. Patients were included in the study if they had type 2 diabetes with inadequate glycemic control, defined as glycated hemoglobin (HbA1c) of 7.5% to 11.0%, treated with conventional first-line OADs. Study participants were randomly assigned into two groups. Group A patients received oral empagliflozin, 10 to 25 mg, and Group B patients received oral dapagliflozin, 5 to 10 mg, for 12 weeks. The primary endpoint was the efficacy profile for each SGLT-2 agent in terms of body weight changes, body mass index (BMI), fasting blood glucose (FBG), and HbA1c. The secondary endpoint was to determine the safety and tolerability profiles of each SGLT-2 agent. Results After 12 weeks of treatment, the mean body weight was reduced significantly in both groups from baseline (empagliflozin: -3.2 kg ± 5.5 kg, p = 0.003; dapagliflozin -2.1 kg ± 4.6 kg, p = 0.008). However, the mean body weight reduction between groups was not statistically significant (p = 0.078). BMI was significantly reduced in both groups (empagliflozin from 28.5 ± 4.9 kg/m2 to 25.8 ± 5.2 kg/m2, p = 0.002; dapagliflozin from 29 ± 5.2 kg/m2 to 27.7 ± 4.8 kg/m2, p = 0.003). However, the patients who received empagliflozin experienced a significantly greater reduction in BMI than patients who received dapagliflozin (p = 0.007). The mean FBG was also reduced in both study groups (empagliflozin: -88.5 mg/dL ± 39.7 mg/dl, p = 0.003; dapagliflozin: -59.8 mg/dL ± 48.5 mg/dL; p = 0.007). However, the patients who received empagliflozin experienced a significantly greater reduction in mean FBG than patients who received dapagliflozin (p = 0.001). HbA1c was also significantly reduced in both groups (empagliflozin: -2.1% ± 1.1%, p = 0.002; dapagliflozin: -1.4% ± 0.9%; p = 0.004). However, patients who received empagliflozin experienced a significantly greater reduction in HbA1c than patients who received dapagliflozin (p = 0.001). The tolerability profiles of both SGLT-2 agents were quite good, and no major adverse effects were reported in the study groups. Urinary infection occurred more often in patients who received dapagliflozin (9.3%) than in patients who received empagliflozin (4.5%; p = 0.002). Patients in the dapagliflozin group also had a higher incidence of genital infections (7.3%) than those in the empagliflozin group (3.8%; p = 0.001). Conclusion Both empagliflozin and dapagliflozin demonstrated excellent efficacy and safety profiles in our study. These agents should be considered as add-on therapy in patients with type 2 diabetes taking conventional first-line OADs.
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Affiliation(s)
- Mazhar Hussain
- Pharmacology, Sheikh Zayed Medical College and Hospital, Rahim Yar Khan, PAK
| | - Asim Elahi
- Internal Medicine, Pikeville Medical Center, Pikeville, USA
| | - Javed Iqbal
- Medicine, Sheikh Zayed Medical College and Hospital, Rahim Yar Khan, PAK
| | | | - Habib Rehman
- Medicine, Sheikh Zayed Medical College and Hospital, Rahim Yar Khan, PAK
| | - Shoaib Akhtar
- Medicine, Sheikh Zayed Medical College and Hospital, Rahim Yar Khan, PAK
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Inzucchi SE, Davies MJ, Khunti K, Trivedi P, George JT, Zwiener I, Johansen OE, Sattar N. Empagliflozin treatment effects across categories of baseline HbA1c, body weight and blood pressure as an add-on to metformin in patients with type 2 diabetes. Diabetes Obes Metab 2021; 23:425-433. [PMID: 33084149 PMCID: PMC7839733 DOI: 10.1111/dom.14234] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 10/07/2020] [Accepted: 10/14/2020] [Indexed: 12/17/2022]
Abstract
AIM To investigate the association of different categories of baseline cardio-metabolic risk factors on the treatment effects of empagliflozin 10 and 25 mg when added as second-line therapy to metformin in patients with type 2 diabetes (T2D). MATERIALS AND METHODS Patients aged 18 years or older with HbA1c 7.0%-10.0% were included. Analysis of covariance compared change from baseline to weeks 24 and 76 in HbA1c, body weight (BW) and systolic blood pressure (SBP) by respective baseline categories (HbA1c <8.5/≥8.5%; BW <80/80-90/>90 kg, SBP <130/130-140/>140 mmHg). Analyses were also conducted with a model using continuous covariates of cardio-metabolic factors. RESULTS In total, 637 patients (56.7% males; mean [SD] age 55.7 [9.9] years, HbA1c 7.9% [0.9%], BW 81.2 [18.8] kg, SBP 129.4 [14.6] mmHg) received one or more dose of either empagliflozin 10 mg (n = 217) or 25 mg (n = 213), or placebo (n = 207). At both time points, empagliflozin 10/25 mg versus placebo significantly (P < .0001) reduced HbA1c and BW, with greater reductions in HbA1c at higher baseline HbA1c (P interaction week 24/76 categorical and continuous models: .0290/.1431 and .0004/.0042, respectively) and in BW (P interaction .1340/.0012 and .0202/<.0001, respectively). Both empagliflozin doses also significantly lowered SBP versus placebo at both time points, with similar efficacy by subgroups of baseline SBP. Adverse events were consistent with the established empagliflozin safety profile across treatment groups. CONCLUSIONS Empagliflozin, as add-on to metformin, decreases HbA1c and BW, particularly in patients with higher HbA1c and BW baseline values, and effectively lowers SBP.
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Affiliation(s)
| | | | - Kamlesh Khunti
- Diabetes Research Centre, University of LeicesterLeicesterUK
| | | | | | | | | | - Naveed Sattar
- Institute of Cardiovascular & Medical Sciences, University of GlasgowGlasgowUK
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Jia S, Wang Z, Han R, Zhang Z, Li Y, Qin X, Zhao M, Xiang R, Yang J. Incretin mimetics and sodium-glucose co-transporter 2 inhibitors as monotherapy or add-on to metformin for treatment of type 2 diabetes: a systematic review and network meta-analysis. Acta Diabetol 2021; 58:5-18. [PMID: 32514989 DOI: 10.1007/s00592-020-01542-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Although there are many different methods of treating type 2 diabetes (T2D), it is still difficult to draw coincident conclusions concerning the efficacy and safety of different classes of new drugs, and the recommendation level of them has still kept uncertain as second anti-diabetic agents. Therefore, the aim of this study was to summarize evidence on the efficacy and safety of DPP-4is, GLP-1RAs and SGLT-2is as monotherapy or add-on to metformin (Met) for treatment of T2D. MATERIALS AND METHODS We searched PubMed, Embase, Cochrane library and ClinicalTrials.gov for relevant articles in keeping with established methods using terms associated with anti-diabetic agents up to February, 2020, with no start date restriction. Weighted mean difference and risk ratios with 95% confidence intervals were calculated within traditional and network meta-analysis. Primary outcomes were the mean change in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG) change and the frequency of hypoglycemic events from baseline after 12 weeks of treatment. RESULTS In total, 64 eligible studies comprising 37,780 patients and 7 treatment strategies were included. The results of primary outcomes showed that GLP-1RAs were significantly more effective than DPP-4is or SGLT-2is in reducing HbA1c when add-on to Met. For FPG, both GLP-1RAs and SGLT-2is significantly reduced FPG compared with DPP-4is whether add-on to Met or not. For hypoglycemia, monotherapy has a lower risk than combination therapy except for SGLT-2is. Ranking probability analysis indicated that GLP-1RAs and SGLT-2is, respectively, reduced HbA1c and FPG most when add-on to Met. Meanwhile, GLP-1RAs took the lowest risk to induce the hypoglycemia, whereas GLP-1RAs plus Met the highest. CONCLUSIONS Both GLP-1RAs and SGLT-2is have their own advantages in efficacy and safety. Monotherapy is beneficial for reducing the risk of hypoglycemia. The recommendation should be a patient-centered approach when selecting treatment choices.
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Affiliation(s)
- Shubing Jia
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Zhiying Wang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Ruobing Han
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Zinv Zhang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yuping Li
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xiaotong Qin
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mingyi Zhao
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Rongwu Xiang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Jingyu Yang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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Hui C, Tomilov A, Garcia C, Jiang X, Fash DM, Khdour OM, Rosso C, Filippini G, Prato M, Graham J, Hecht S, Havel P, Cortopassi G. Novel idebenone analogs block Shc's access to insulin receptor to improve insulin sensitivity. Biomed Pharmacother 2020; 132:110823. [PMID: 33045613 DOI: 10.1016/j.biopha.2020.110823] [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: 07/19/2020] [Revised: 09/26/2020] [Accepted: 09/26/2020] [Indexed: 10/23/2022] Open
Abstract
There has been little innovation in identifying novel insulin sensitizers. Metformin, developed in the 1920s, is still used first for most Type 2 diabetes patients. Mice with genetic reduction of p52Shc protein have improved insulin sensitivity and glucose tolerance. By high-throughput screening, idebenone was isolated as the first small molecule 'Shc Blocker'. Idebenone blocks p52Shc's access to Insulin Receptor to increase insulin sensitivity. In this work the avidity of 34 novel idebenone analogs and 3 metabolites to bind p52Shc, and to block the interaction of p52Shc with the Insulin receptor was tested. Our hypothesis was that if an idebenone analog bound and blocked p52Shc's access to insulin receptor better than idebenone, it should be a more effective insulin sensitizing agent than idebenone itself. Of 34 analogs tested, only 2 both bound p52Shc more tightly and/or blocked the p52Shc-Insulin Receptor interaction more effectively than idebenone. Of those 2 only idebenone analog #11 was a superior insulin sensitizer to idebenone. Also, the long-lasting insulin-sensitizing potency of idebenone in rodents over many hours had been puzzling, as the parent molecule degrades to metabolites within 1 h. We observed that two of the idebenone's three metabolites are insulin sensitizing almost as potently as idebenone itself, explaining the persistent insulin sensitization of this rapidly metabolized molecule. These results help to identify key SAR = structure-activity relationship requirements for more potent small molecule Shc inhibitors as Shc-targeted insulin sensitizers for type 2 diabetes.
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Affiliation(s)
- ChunKiu Hui
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA, 95616, USA.
| | - Alexey Tomilov
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA, 95616, USA.
| | - Chase Garcia
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA, 95616, USA.
| | - XiaoSong Jiang
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA, 95616, USA.
| | - David M Fash
- Center for BioEnergetics, Biodesign Institute, Arizona State University, 1001 S McAllister Ave, Tempe, AZ, 85287, USA.
| | - Omar M Khdour
- Center for BioEnergetics, Biodesign Institute, Arizona State University, 1001 S McAllister Ave, Tempe, AZ, 85287, USA.
| | - Cristian Rosso
- Department of Chemical and Pharmaceutical Sciences, CENMAT, Center of Excellence for Nanostructured Materials, INSTM UdR, Trieste, University of Trieste, Via Licio Giorgieri 1, Trieste, 34127, Italy.
| | - Giacomo Filippini
- Department of Chemical and Pharmaceutical Sciences, CENMAT, Center of Excellence for Nanostructured Materials, INSTM UdR, Trieste, University of Trieste, Via Licio Giorgieri 1, Trieste, 34127, Italy.
| | - Maurizio Prato
- Department of Chemical and Pharmaceutical Sciences, CENMAT, Center of Excellence for Nanostructured Materials, INSTM UdR, Trieste, University of Trieste, Via Licio Giorgieri 1, Trieste, 34127, Italy; Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramón 182, 20014, Donostia San Sebastián, Spain; Basque Fdn Sci, Ikerbasque, Bilbao, 48013, Spain.
| | - James Graham
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA, 95616, USA.
| | - Sidney Hecht
- Center for BioEnergetics, Biodesign Institute, Arizona State University, 1001 S McAllister Ave, Tempe, AZ, 85287, USA; School of Molecular Sciences, Arizona State University, Tempe, AZ, 85287, USA.
| | - Peter Havel
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA, 95616, USA.
| | - Gino Cortopassi
- Department of Molecular Biosciences, 1089 Veterinary Medicine Dr., VM3B, UC Davis, CA, 95616, USA.
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Perry RJ, Shulman GI. Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks. J Biol Chem 2020; 295:14379-14390. [PMID: 32796035 DOI: 10.1074/jbc.rev120.008387] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/11/2020] [Indexed: 12/16/2022] Open
Abstract
In a healthy person, the kidney filters nearly 200 g of glucose per day, almost all of which is reabsorbed. The primary transporter responsible for renal glucose reabsorption is sodium-glucose cotransporter-2 (SGLT2). Based on the impact of SGLT2 to prevent renal glucose wasting, SGLT2 inhibitors have been developed to treat diabetes and are the newest class of glucose-lowering agents approved in the United States. By inhibiting glucose reabsorption in the proximal tubule, these agents promote glycosuria, thereby reducing blood glucose concentrations and often resulting in modest weight loss. Recent work in humans and rodents has demonstrated that the clinical utility of these agents may not be limited to diabetes management: SGLT2 inhibitors have also shown therapeutic promise in improving outcomes in heart failure, atrial fibrillation, and, in preclinical studies, certain cancers. Unfortunately, these benefits are not without risk: SGLT2 inhibitors predispose to euglycemic ketoacidosis in those with type 2 diabetes and, largely for this reason, are not approved to treat type 1 diabetes. The mechanism for each of the beneficial and harmful effects of SGLT2 inhibitors-with the exception of their effect to lower plasma glucose concentrations-is an area of active investigation. In this review, we discuss the mechanisms by which these drugs cause euglycemic ketoacidosis and hyperglucagonemia and stimulate hepatic gluconeogenesis as well as their beneficial effects in cardiovascular disease and cancer. In so doing, we aim to highlight the crucial role for selecting patients for SGLT2 inhibitor therapy and highlight several crucial questions that remain unanswered.
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Affiliation(s)
- Rachel J Perry
- Departments of Cellular and Molecular Physiology and Internal Medicine (Endocrinology), Yale School of Medicine, New Haven, Connecticut, USA
| | - Gerald I Shulman
- Departments of Cellular and Molecular Physiology and Internal Medicine (Endocrinology), Yale School of Medicine, New Haven, Connecticut, USA
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Scheen AJ. SGLT2 Inhibitors as Add-On Therapy to Metformin for People with Type 2 Diabetes: A Review of Placebo-Controlled Trials in Asian versus Non-Asian Patients. Diabetes Metab Syndr Obes 2020; 13:2765-2779. [PMID: 32821142 PMCID: PMC7417649 DOI: 10.2147/dmso.s193528] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 07/08/2020] [Indexed: 12/13/2022] Open
Abstract
Metformin remains the first pharmacological choice for treating hyperglycemia in type 2 diabetes (T2DM) in most international guidelines. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are increasingly used as add-on therapy. T2DM pathophysiology is different in Asian and non-Asian (mainly Caucasian) patients. The aim of this systematic review is to compare the efficacy of SGLT2is vs placebo added to metformin in randomized controlled trials (RCTs: range 12-52 weeks) in Asian versus non-Asian patients with T2DM. The primary endpoint is the reduction in glycated hemoglobin (HbA1c) from baseline and key secondary endpoints are reductions in fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Systematic literature search collected 7 RCTs (3 with 2 doses) in Asian patients (10 analyses, n=1164, iSGLT2: canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, tofogliflozin)) and 10 RCTs (6 with two doses) in non-Asian patients (16 analyses, n=2482, iSGLT2: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin). Baseline values of HbA1c (7.98±0.19 vs 7.89±0.27%), FPG (8.80 ±0.46 vs 9.11±0.49 mmol/l) and SBP (128.4±1.6 vs 130.2±3.1 mmHg) were not significantly different in Asian vs non-Asian patients, but BW was lower in Asian patients (71.6±4.8 vs 88.0±2.5 kg, p<0.001). The placebo-adjusted weighed mean differences (WMD, 95% CI) were similar in Asian versus non-Asian patients regarding the reductions in HbA1c -0.60 (-0.68, -0.53) % versus -0.54 (-0.59, -0.49) % (p=0.568), FPG -1.37 (-1.53, -1.22) mmol/l vs -1.37 (-1.47, -1.27) mmol/l (p=0.627), BW when expressed in percentage of baseline BW -2.23 (-2.55, -1.90) % vs -2.16 (-2.37, -1.96) % (p=0.324), and SBP -4.53 (-5.53, -3.53) mmHg vs -4.06 (-4.83, -3.29) mmHg) (p=0.223). In conclusion, clinical efficacy of SGLT2i, as an add-on treatment to metformin monotherapy in patients with T2DM, is similar in Asian versus non-Asian patients, despite known ethnic differences in phenotype and pathophysiology of T2DM.
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Affiliation(s)
- André J Scheen
- Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège University, Liège, Belgium
- Clinical Pharmacology Unit, CHU Liège, Center for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium
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Kinduryte Schorling O, Clark D, Zwiener I, Kaspers S, Lee J, Iliev H. Pooled Safety and Tolerability Analysis of Empagliflozin in Patients with Type 2 Diabetes Mellitus. Adv Ther 2020; 37:3463-3484. [PMID: 32372290 PMCID: PMC7370973 DOI: 10.1007/s12325-020-01329-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Indexed: 12/25/2022]
Abstract
INTRODUCTION The aim of this analysis was to characterize the safety and tolerability of empagliflozin in patients with type 2 diabetes mellitus (T2DM) who were randomized to empagliflozin (10/25 mg) or placebo in clinical trials. METHODS Pooled data from 20 trials were analyzed for patients with T2DM treated with empagliflozin 10 mg (n = 4858), empagliflozin 25 mg (n = 5057), or placebo (n = 4904). The dataset comprised 15 randomized phase I-III trials, an extension trial and dose escalation studies. Adverse events (AEs) were assessed descriptively in participants who took ≥ 1 dose of study drug. AE incidence rates per 100 patient-years were calculated to adjust for differences in drug exposure between trials. RESULTS Total exposure was 16,480 and 7857 patient-years in the pooled empagliflozin 10/25 mg and placebo groups, respectively. The incidence of any AEs, AEs leading to treatment discontinuation, severe AEs, and serious AEs was similar across groups. The frequency of serious AEs requiring hospitalization was 18.6% for the empagliflozin 10/25 mg group and 21.3% for the placebo group. The empagliflozin 10/25 mg group was not associated with a higher rate of confirmed hypoglycemia versus placebo, except in patients co-administered insulin and/or a sulfonylurea (31.5% vs. 30.2%, respectively). The incidence of events consistent with urinary tract infections (UTI) was also similar for the empagliflozin 10/25 mg group versus placebo (9.27 vs. 9.70/100 patient-years, respectively). History of UTI was identified as a risk factor for UTI during treatment. Events consistent with genital infections occurred more frequently with empagliflozin 10/25 mg than placebo (3.54 vs. 0.95/100 patient-years, respectively). The frequency of AEs consistent with volume depletion was similar across groups, but higher with empagliflozin 10/25 mg than placebo in patients aged 75 to < 85 years and those on loop diuretics at baseline. CONCLUSION This comprehensive analysis confirms that both empagliflozin 10 mg and 25 mg are well tolerated in patients with T2DM, reinforcing the established clinical safety profile of empagliflozin.
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Gan S, Dawed AY, Donnelly LA, Nair ATN, Palmer CNA, Mohan V, Pearson ER. Efficacy of Modern Diabetes Treatments DPP-4i, SGLT-2i, and GLP-1RA in White and Asian Patients With Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Diabetes Care 2020; 43:1948-1957. [PMID: 33534728 PMCID: PMC7372059 DOI: 10.2337/dc19-2419] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 03/15/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The pathophysiology of type 2 diabetes differs markedly by ethnicity. PURPOSE A systematic review and meta-analysis was conducted to assess the impact of ethnicity on the glucose-lowering efficacy of the newer oral agents, sodium-glucose cotransporter 2 inhibitors (SGLT-2i), glucagon-like peptide 1 receptor agonists (GLP-1RA), and dipeptidyl peptidase 4 inhibitors (DPP-4i), using evidence from randomized clinical trials (RCTs). DATA SOURCES A literature search was conducted in PubMed of all randomized, placebo-controlled trials of DPP-4i, SGLT-2i, and GLP-1RA. The search strategy was developed based on Medical Subject Headings (MeSH) terms and keywords. STUDY SELECTION A total of 64 studies that qualified for meta-analysis after full-text review based on predefined inclusion and exclusion criteria-RCTs with at least 50 patients in each arm, >70% of population from Asian or white group, duration ≥24 weeks, and publication up to March 2019-were selected for systematic review and meta-analysis. DATA EXTRACTION Data extraction was done for aggregated study-level data by two independent researchers. Absolute changes in HbA1c (%) from baseline to 24 weeks between the drug and placebo were considered as the primary end point of the study. DATA SYNTHESIS Change in HbA1c was evaluated by computing mean differences and 95% CIs between treatment and placebo arms. LIMITATIONS The study is based on summarized data and could not be separated based on East Asians and South Asians. CONCLUSIONS The glucose-lowering efficacy of SGLT-2i, and to a lesser extent DPP-4i, was greater in studies of predominantly Asian ethnicity compared with studies of predominantly white ethnicity. There was no difference seen by ethnicity for GLP-1RA.
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Affiliation(s)
| | | | | | | | | | - Viswanathan Mohan
- Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, Chennai, India
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Sánchez-García A, Simental-Mendía M, Millán-Alanís JM, Simental-Mendía LE. Effect of sodium-glucose co-transporter 2 inhibitors on lipid profile: A systematic review and meta-analysis of 48 randomized controlled trials. Pharmacol Res 2020; 160:105068. [PMID: 32652200 DOI: 10.1016/j.phrs.2020.105068] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 07/03/2020] [Accepted: 07/03/2020] [Indexed: 12/13/2022]
Abstract
Previous studies have suggested additional beneficial effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors including the lipid-lowering effect; however, results on lipid profile are controversial. Thus, this meta-analysis aimed to determine the effect of SGLT2 inhibitors treatment on lipid levels in patients with type 2 diabetes. Randomized controlled trials assessing the impact of SGLT2 inhibitors on lipid parameters were searched in PubMed-MEDLINE, SCOPUS, Web of Science, and Google Scholar databases. Meta-analysis was conducted using a random-effects model and generic inverse variance method. Meta-analysis of 48 randomized controlled trials revealed that SGLT2 inhibitors therapy had a significant increase on total cholesterol (WMD: 0.09 mmol/L, 95 % CI: 0.05, 0.13, I2 = 79 %, p < 0.0001), LDL-cholesterol (WMD: 0.10 mmol/L, 95 % CI: 0.07, 0.12, I2 = 94 %, p < 0.00001), HDL-cholesterol (WMD: 0.06 mmol/L, 95 % CI: 0.05, 0.08, I2 = 99 %, p < 0.00001), and non-HDL-cholesterol (WMD: 0.09 mmol/L, 95 % CI: 0.06, 0.12, I2 = 96 %, p < 0.00001). Additionally, SGLT2 inhibitors administration showed a significant decrease in triglyceride levels (WMD: -0.10 mmol/L, 95 % CI: -0.13, -0.07, I2 = 96 %, p < 0.00001). Finally, no significant alteration was found on LDL/HDL ratio after SGLT2 inhibitors treatment (WMD: -0.01 mmol/L, 95 % CI: -0.05, 0.03, I2 = 99 %, p = 0.65). In conclusion, SGLT2 inhibitors significantly increase total cholesterol, LDL-cholesterol, non-HDL-cholesterol, and HDL-cholesterol, and decrease triglyceride levels.
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Affiliation(s)
- Adriana Sánchez-García
- Universidad Autónoma de Nuevo León, Endocrinology Division, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Monterrey, NL, Mexico
| | - Mario Simental-Mendía
- Universidad Autónoma de Nuevo León, Department of Orthopedics and Traumatology, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Monterrey, NL, Mexico
| | - Juan Manuel Millán-Alanís
- Universidad Autónoma de Nuevo León, Plataforma Invest-KER Unit México, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Monterrey, NL, Mexico
| | - Luis E Simental-Mendía
- Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, México.
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Uhrig JL, Page SO, Mishriky BM, Patil SP, Powell JR, Sewell K, Mian MR, Cummings DM. Should Baseline Hemoglobin A 1c or Dose of SGLT-2i Guide Treatment With SGLT-2i Versus DPP-4i in People With Type 2 Diabetes? A Meta-Analysis and Systematic Review. J Clin Pharmacol 2020; 60:980-991. [PMID: 32396236 DOI: 10.1002/jcph.1599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/03/2020] [Indexed: 12/25/2022]
Abstract
Our aim was to explore whether the baseline hemoglobin A1c or the dose of sodium glucose cotransporter-2 inhibitor (SGLT-2i) chosen better predicted the efficacy of SGLT-2i versus dipeptidyl peptidase-4 inhibitor (DPP-4i) in type 2 diabetes. We searched for randomized trials that compared SGLT-2i with DPP-4i in type 2 diabetes and reported a change in hemoglobin A1c over time. We created 2 separate analyses (one based on baseline hemoglobin A1c and the other according to US Food and Drug Administration [FDA]-approved SGLT-2i dose). Thirteen trials were included. In the analysis according to baseline hemoglobin A1c , there was a significantly greater reduction in hemoglobin A1c when baseline hemoglobin A1c was ≥8.5%, favoring SGLT-2i over DPP-4i but not when baseline hemoglobin A1c was <8.5% (mean difference [95%CI], -0.36% [-0.53% to -0.18%] and 0.04% [-0.09% to 0.17%], respectively). On restricting the analysis to trials stratifying hemoglobin A1c to <8.0% or ≥8.0%, results did not change. In the analysis based on FDA-approved SGLT-2i doses, higher SGLT-2i doses caused a significantly greater hemoglobin A1c reduction at ≤26 and ≥52 weeks compared with the highest DPP-4i doses (mean difference [95%CI], -0.11% [-0.18% to -0.04%] and -0.24% [-0.34% to -0.15%], respectively). Lower SGLT-2i doses caused a significantly greater hemoglobin A1c reduction at ≥52 weeks but not at ≤26 weeks compared with the highest DPP-4i doses (mean difference [95%CI], -0.12% [-0.23% to -0.02%] and 0.01% [-0.05% to 0.07%], respectively). In people with type 2 diabetes and a baseline hemoglobin A1c ≥ 8.0%, SGLT-2i produced significantly greater reductions in hemoglobin A1c compared with DPP-4i and may be preferred. SGLT-2i dose titration to a higher FDA-approved dose is recommended in suitable patients.
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Affiliation(s)
- Jarrod L Uhrig
- Department of Endocrinology, Carilion Clinic, Roanoke, Virginia, USA
| | - Stephanie O Page
- Department of Family Medicine, Mount Sinai Hospital, New York, New York, USA
| | - Basem M Mishriky
- Department of Internal Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Shivajirao P Patil
- Department of Family Medicine, East Carolina University, Greenville, North Carolina, USA
| | - James R Powell
- Department of Internal Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Kerry Sewell
- Laupus Health Sciences Library, East Carolina University, Greenville, North Carolina, USA
| | - Muna R Mian
- Department of Internal Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Doyle M Cummings
- Department of Family Medicine, East Carolina University, Greenville, North Carolina, USA
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The effect of low and high dose empagliflozin on HbA1c and lipid profile in type 2 diabetes mellitus: A real-world data. North Clin Istanb 2020; 7:167-173. [PMID: 32259039 PMCID: PMC7117635 DOI: 10.14744/nci.2019.22697] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 11/09/2019] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE: This study aims to evaluate the efficacy and safety of the addition of 10 or 25 mg of empagliflozin to patients with type 2 diabetes mellitus using a maximum tolerable dose of metformin and gliclazide. METHODS: A total of 60 patients who had been receiving a maximum tolerable dose of metformin plus gliclazide. was divided into two groups in this study. In the first group (Group 1, n=32), 10 mg empagliflozin was added to the current treatment once a day, and in the second group (Group 2, n=28) 25 mg empagliflozin was added to the same treatment once a day. Biochemical results, weight and blood pressure changes of the patients in both groups were evaluated before and after 12 weeks of empagliflozin addition. Patients who developed urinary tract and genital infections after treatment were recorded. RESULTS: There was a statistically significant decrease in HbA1c in both groups after empagliflozin treatment (Group 1, p<0.001 and Group2, p=0.001). When the lipid profile was evaluated, no significant difference was found between basal and post-treatment parameters (p>0.05). Patients in Group 1 and Group 2 lost 2.6±1.2 and 3.8±2.0 kg of body weight, respectively (p<0.0001 for each). There were also significant reductions in systolic and diastolic blood pressure for groups 1 and 2 (p<0.0001 for each). Although there was a numerical increase in the urinary tract and genital infections in both groups after empagliflozin treatment, there was no statistically significant difference compared to the pre-treatment period (p>0.05). CONCLUSION: Two doses of empagliflozin added to the present treatments showed a dose-independent improvement in glycemic control and a neutral effect on lipid metabolism.
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Control of 24-hour blood pressure with SGLT2 inhibitors to prevent cardiovascular disease. Prog Cardiovasc Dis 2020; 63:249-262. [PMID: 32275926 DOI: 10.1016/j.pcad.2020.04.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 04/06/2020] [Indexed: 02/07/2023]
Abstract
The presence of hypertension (HTN) in patients with diabetes mellitus (DM) further worsens cardiovascular disease (CVD) prognosis. In addition, masked HTN and abnormal circadian blood pressure (BP) variability are common among patients with DM. Clinical trial data show that sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve CVD prognosis and prevent progression of renal dysfunction in high-risk patients with type 2 DM (T2DM). Consistent reductions in 24-hour, daytime and nocturnal BP have been documented during treatment with SGLT2i in patients with DM and HTN, and these reductions are of a magnitude that is likely to be clinically significant. SGLT2i agents also appear to have beneficial effects on morning, evening and nocturnal home BP. Greater reductions in BP during treatment with SGLT2i have been reported in patient subgroups with higher body mass index, and in those with higher baseline BP. Other documented beneficial effects of SGLT2i include reductions in arterial stiffness and the potential to decrease the apnea-hypopnea index in patients with DM and obstructive sleep apnea. Recent guidelines highlight the important role of SGLT2i as part of the pharmacological management of patients with DM and HTN, and recommend consideration of SGLT2i early in the clinical course to reduce all-cause and CVD mortality in patients with T2DM and CVD. Overall, available data support a role for SGLT2i as effective BP-lowering agents in patients with T2DM and poorly controlled HTN, irrespective of baseline glucose control status. Sustained improvements in 24-hour BP and the 24-hour BP profile are likely to contribute to the CVD benefits of SGLT2i treatment.
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Hu M, Cai X, Yang W, Zhang S, Nie L, Ji L. Effect of Hemoglobin A1c Reduction or Weight Reduction on Blood Pressure in Glucagon-Like Peptide-1 Receptor Agonist and Sodium-Glucose Cotransporter-2 Inhibitor Treatment in Type 2 Diabetes Mellitus: A Meta-Analysis. J Am Heart Assoc 2020; 9:e015323. [PMID: 32223390 PMCID: PMC7428598 DOI: 10.1161/jaha.119.015323] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have shown their beneficial effects on cardiovascular outcomes and multiple cardiovascular risk factors, including hypertension. However, the mechanism of blood pressure (BP)-lowering effects of these agents has not been elucidated. This study aims to evaluate the effect of hemoglobin A1c reduction or body weight reduction with GLP-1RA treatment and SGLT2i treatment on BP changes in patients with type 2 diabetes mellitus. Methods and Results Studies were identified by a search of MEDLINE, EMBASE, and the Cochrane Central Register until June 2019. Meta-regression analysis was performed to evaluate the association between hemoglobin A1c reduction or body weight reduction and changes of BP. A total of 184 trials were included. Both GLP-1RA and SGLT2i led to significant reductions in systolic BP (weighted mean difference, -2.856 and -4.331 mm Hg, respectively; P<0.001 for both) and diastolic BP (weighted mean difference, -0.898 and -2.279 mm Hg, respectively; P<0.001 for both). For both drug classes, hemoglobin A1c reduction was not independently associated with systolic BP reduction or diastolic BP reduction. In GLP-1RA treatment, weight reduction was positively associated with systolic BP reduction and diastolic BP reduction (β=0.821 and β=0.287, respectively; P<0.001 for both). In SGLT2i treatment, weight loss was significantly associated with systolic BP reduction (β=0.820; P=0.001) but was not associated with diastolic BP reduction. Conclusions Treatment with GLP-1RA and SGLT2i led to significant reductions in BP in patients with type 2 diabetes mellitus. Weight reduction was significantly and independently associated with BP reductions in GLP-1RA treatment and SGLT2i treatment.
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Affiliation(s)
- Mengdie Hu
- Department of Endocrinology and Metabolism Peking University People's Hospital Beijing China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism Peking University People's Hospital Beijing China
| | - Wenjia Yang
- Department of Endocrinology and Metabolism Peking University People's Hospital Beijing China
| | - Simin Zhang
- Department of Endocrinology and Metabolism Peking University People's Hospital Beijing China
| | - Lin Nie
- Department of Endocrinology and Metabolism Beijing Airport Hospital Beijing China
| | - Linong Ji
- Department of Endocrinology and Metabolism Peking University People's Hospital Beijing China
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Scheen AJ. Reduction in HbA1c with SGLT2 inhibitors vs. DPP-4 inhibitors as add-ons to metformin monotherapy according to baseline HbA1c: A systematic review of randomized controlled trials. DIABETES & METABOLISM 2020; 46:186-196. [PMID: 32007623 DOI: 10.1016/j.diabet.2020.01.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/13/2020] [Accepted: 01/18/2020] [Indexed: 12/18/2022]
Abstract
AIMS This study compared the reduction of glycated haemoglobin (HbA1c) with sodium-glucose cotransporter type-2 inhibitors (SGLT2is) vs. dipeptidyl peptidase-4 inhibitors (DPP-4is) as add-ons to metformin in patients with type 2 diabetes mellitus (T2DM), with a specific focus on HbA1c changes according to baseline HbA1c. MATERIALS AND METHODS Electronic databases were scrutinized for randomized controlled trials (RCTs) evaluating the reduction of HbA1c from baseline (Δ HbA1c) with an SGLT2i or DPP-4i in patients with T2DM not well controlled by metformin monotherapy. The endpoint was Δ HbA1c using both indirect and direct comparisons. RESULTS Overall, Δ HbA1c was slightly greater with SGLT2is (-0.80±0.20% from 8.03±0.35%; 44 analyses, 29 RCTs, 15 with two doses, n=9321) than with DPP-4is (-0.71±0.23% from 8.05±0.43%; 61 analyses, 59 RCTs, n=17,914; P=0.0354). When the mean baseline HbA1c was<8% ([64mmol/mol] 7.79±0.15% vs. 7.71±0.23%), Δ HbA1c averaged -0.735±0.17% vs. -0.62±0.16% (P=0.0117) with SGLT2is vs. DPP-4is, respectively. However, this difference vanished when the mean baseline HbA1c was≥8% (-0.87±0.22% from 8.27±0.32% with SGLT2is vs. -0.80±0.24% from 8.35±0.33% with DPP-4is; P=0.2756). The relationship between Δ HbA1c and baseline HbA1c was only slightly stronger with SGLT2is (slope: -0.39, r2=-0.43; P<0.0001) than with DPP-4is (slope: -0.26, r2=-0.25; P<0.0001). CONCLUSION Because of the small difference in Δ HbA1c whatever the baseline HbA1c level with SGLT2is vs. DPP-4is as add-ons to metformin, choosing between these glucose-lowering agents in clinical practice should be based on other efficacy criteria (such as weight and blood pressure changes, cardiovascular and renal protection) or on safety profiles rather than on HbA1c levels.
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Affiliation(s)
- A J Scheen
- Division of diabetes, nutrition and metabolic disorders, department of medicine, CHU Liège, Liège University, Liège, Belgium; Clinical pharmacology unit, Centre for interdisciplinary research on medicines (CIRM), CHU Liège, Liège University, Liège, Belgium.
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Kamalinia S, Josse RG, Donio PJ, Leduc L, Shah BR, Tobe SW. Risk of any hypoglycaemia with newer antihyperglycaemic agents in patients with type 2 diabetes: A systematic review and meta-analysis. Endocrinol Diabetes Metab 2020; 3:e00100. [PMID: 31922027 PMCID: PMC6947712 DOI: 10.1002/edm2.100] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 10/11/2019] [Accepted: 10/13/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES For patients with type 2 diabetes, newer antihyperglycaemic agents (AHA), including the dipeptidyl peptidase IV inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium glucose co-transporter 2 inhibitors (SGLT2i) offer a lower risk of hypoglycaemia relative to sulfonylurea or insulin. However, it is not clear how AHA compare to placebo on risk of any hypoglycaemia. This study evaluates the risk of any and severe hypoglycaemia with AHA and metformin relative to placebo. DESIGN A systematic review and meta-analysis was conducted of randomized, placebo-controlled trials ≥12 weeks in duration. MEDLINE, Embase and the Cochrane Library were searched up to April 16, 2019. Studies allowing use of other diabetes medications were excluded. Mantel-Haenszel risk ratio with 95% confidence intervals were used to pool estimates based on class of AHA and number of concomitant therapies used. PATIENTS Eligible studies enrolled patients with type 2 diabetes ≥18 years of age. RESULTS 144 studies met our inclusion criteria. Any hypoglycaemia was not increased with AHA when used as monotherapy (DPP4i (RR 1.12; 95% CI 0.81-1.56), GLP1RA (1.77; 0.91-3.46), SGLT2i (1.34; 0.83-2.15)), or as add-on to metformin (DPP4i (0.95; 0.67-1.35), GLP1RA (1.24; 0.80-1.91), SGLT2i (1.29; 0.91-1.83)) or as triple therapy (1.13; 0.67-1.91). However, metformin monotherapy (1.73; 1.02-2.94) and dual therapy initiation (3.56; 1.79-7.10) was associated with an increased risk of any hypoglycaemia. Severe hypoglycaemia was rare not increased for any comparisons. CONCLUSIONS Metformin and the simultaneous initiation of dual therapy, but not AHA used alone or as single add-on combination therapy, was associated with an increased risk of any hypoglycaemia relative to placebo.
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Affiliation(s)
- Sanaz Kamalinia
- Institute of Medical SciencesUniversity of TorontoTorontoONCanada
| | - Robert G. Josse
- St. Michael's HospitalTorontoONCanada
- Department of MedicineUniversity of TorontoTorontoONCanada
| | | | | | - Baiju R. Shah
- Department of MedicineUniversity of TorontoTorontoONCanada
- Sunnybrook Research InstituteTorontoONCanada
| | - Sheldon W. Tobe
- Institute of Medical SciencesUniversity of TorontoTorontoONCanada
- Department of MedicineUniversity of TorontoTorontoONCanada
- Northern Ontario School of MedicineSudburyONCanada
- Sunnybrook Research InstituteTorontoONCanada
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Gupta A, Mittal S, Dhingra R, Dhingra N. Turning Foes to Friends: Knocking Down Diabetes Associated SGLT2 Transporters and Sustaining Life. Curr Diabetes Rev 2020; 16:716-732. [PMID: 31951170 DOI: 10.2174/1573399816666200117155016] [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: 08/02/2019] [Revised: 11/01/2019] [Accepted: 12/12/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND The discovery of Sodium-Glucose co-transporter-2 (SGLT2) inhibitors had rewritten the treatment of diabetes mellitus with an impressive fall in the incidence of death and associated complications. INTRODUCTION The SGLT2 inhibitors by inhibiting the SGLT2 in the proximal nephron, helps in reducing the reabsorption of approximately 90% of the filtered glucose and increased urinary glucose excretion (UGE). METHODS The literature related to SGLT2 inhibitors has been thoroughly explored from various available public domains and reviewed extensively for this article. Detailed and updated information related to SGLT2 inhibitors with a major focus on the recently approved Ertuglifolzin is structured in this review. RESULT The present review is an effort to understand the management of diabetes mellitus over the past few decades with a special focus on the role of SGLT2 receptor in the causes of therapeutic and preventive strategies for diabetes mellitus. Pragmatic placement of the currently available Canagliflozin, Dapagliflozin, and Empagliflozin as oral antidiabetic agents has been done. Well accommodated stereochemistry and a high docking score of Ertugliflozin in ligand-receptor simulation studies attribute to its high potency. CONCLUSION This review highlights the unique mechanism of SGLT2 Inhibitors coupled with pleiotropic benefits on weight and blood pressure, which make it an attractive choice of therapy to diabetic patients, not controlled by other medications.
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Affiliation(s)
- Ankit Gupta
- Department of Pharmaceutical Chemistry, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | - Sheenu Mittal
- Department of Pharmaceutical Chemistry, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | - Richa Dhingra
- Department of Pharmaceutical Chemistry, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | - Neelima Dhingra
- Department of Pharmaceutical Chemistry, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
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Zou CY, Liu XK, Sang YQ, Wang B, Liang J. Effects of SGLT2 inhibitors on cardiovascular outcomes and mortality in type 2 diabetes: A meta-analysis. Medicine (Baltimore) 2019; 98:e18245. [PMID: 31804352 PMCID: PMC6919451 DOI: 10.1097/md.0000000000018245] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Optimal glycemic control is required to restrain the increase of cardiovascular events in patients with type 2 diabetes. The effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular events and mortality in those patients are not well established. This meta-analysis was conducted to assess the effects of SGLT2 inhibitors on cardiovascular events and mortality in patients with type 2 diabetes. METHODS We conducted a systematic literature search of Medline, Embase and Cochrane Library and included randomized controlled trials (RCTs) of 3 different SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin) that evaluated the effects on cardiovascular outcomes and mortality in the final meta-analysis. The intervention arm was defined either as SGLT2 inhibitor monotherapy or as SGLT2 inhibitor add-on to other non-SGLT2 inhibitor antidiabetic agents (ADAs). RESULTS Forty-two trials with a total of 61,076 patients with type 2 diabetes were included in the meta-analysis. Compared with the control, SGLT2 inhibitor treatment was associated with a reduction in the incidence of major adverse cardiovascular events (MACEs) (OR = 0.86, 95% CI 0.80-0.93, P < .0001), myocardial infarction (OR = 0.86, 95% CI 0.79-0.94, P = .001), cardiovascular mortality (OR = 0.74, 95% CI 0.67-0.81, P < .0001) and all cause mortality (OR = 0.85, 95% CI 0.79-0.92, P < .0001). However, the risk of ischemic stroke was not reduced after SGLT2 inhibitor treatment in patients with type 2 diabetes (OR = 0.95, 95% CI 0.85-1.07, P = .42). CONCLUSION These data suggest a decreased risk of harm with SGLT2 inhibitor as a class with respect to cardiovascular events and mortality.
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Affiliation(s)
- Cai-Yan Zou
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University; Affiliated to Medical School of Southeast University
| | - Xue-Kui Liu
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University; Affiliated to Medical School of Southeast University
| | - Yi-Quan Sang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University; Affiliated to Medical School of Southeast University
| | - Ben Wang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University; Affiliated to Medical School of Southeast University
| | - Jun Liang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University; Affiliated to Medical School of Southeast University
- Xuzhou Institute of Medical Science, Xuzhou Institute of Diabetes, Xuzhou, Jiangsu, China
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Kalra J, Mangali SB, Dasari D, Bhat A, Goyal S, Dhar I, Sriram D, Dhar A. SGLT1 inhibition boon or bane for diabetes-associated cardiomyopathy. Fundam Clin Pharmacol 2019; 34:173-188. [PMID: 31698522 DOI: 10.1111/fcp.12516] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 09/18/2019] [Accepted: 10/14/2019] [Indexed: 12/29/2022]
Abstract
Chronic hyperglycaemia is a peculiar feature of diabetes mellitus (DM). Sequential metabolic abnormalities accompanying glucotoxicity are some of its implications. Glucotoxicity most likely corresponds to the vascular intricacy and metabolic alterations, such as increased oxidation of free fatty acids and reduced glucose oxidation. More than half of those with diabetes also develop cardiac abnormalities due to unknown causes, posing a major threat to the currently available marketed preparations which are being used for treating these cardiac complications. Even though impairment in cardiac functioning is the principal cause of death in individuals with type 2 diabetes (T2D), reducing plasma glucose levels has little effect on cardiovascular disease (CVD) risk. In vitro and in vivo studies have demonstrated that inhibitors of sodium glucose transporter (SGLT) represent a putative therapeutic intervention for these pathological conditions. Several clinical trials have reported the efficacy of SGLT inhibitors as a novel and potent antidiabetic agent which along with its antihyperglycaemic activity possesses the potential of effectively treating its associated cardiac abnormalities. Thus, hereby, the present review highlights the role of SGLT inhibitors as a successful drug candidate for correcting the shifts in deregulation of cardiac energy substrate metabolism together with its role in treating diabetes-related cardiac perturbations.
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Affiliation(s)
- Jaspreet Kalra
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Suresh Babu Mangali
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Deepika Dasari
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Audesh Bhat
- Centre for Molecular Biology, Central University of Jammu, Jammu, 181143, India
| | - Srashti Goyal
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Indu Dhar
- Department of Clinical Science, University of Bergen, Bergen, 5009, Norway
| | - Dharamrajan Sriram
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
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