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Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus treated in real-world clinical practice: Results of a 36-month post-marketing surveillance study (J-STEP/LT).
Utsunomiya, K, Koshida, R, Kakiuchi, S, Senda, M, Fujii, S, Kurihara, Y, Gunji, R, Kaku, K
Journal of diabetes investigation. 2021;(2):184-199
Abstract
AIMS/INTRODUCTION Tofogliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that lowers plasma glucose levels by enhancing urinary glucose excretion. After its approval in Japan in 2014 for the treatment of type 2 diabetes mellitus, we carried out a 3-year prospective observational post-marketing surveillance study in Japanese patients (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term [J-STEP/LT]). MATERIALS AND METHODS This surveillance was carried out between September 2014 and February 2019, and recorded safety in terms of adverse drug reactions (ADRs) and ADRs of special interest, and effectiveness in terms of changes in glycated hemoglobin and bodyweight from baseline to last observation carried forward. RESULTS Of 6,897 patients with type 2 diabetes mellitus registered, 6,711 and 6,451 were analyzed for safety and effectiveness, respectively. ADRs were reported in 846 patients (12.61%), with serious ADRs in 101 patients (1.5%). ADRs of special interest included hypoglycemia (62 patients [0.9%]), polyuria/pollakiuria (90 [1.3%]), volume depletion-related disorders (135 [2.0%]), urinary tract infections (91 [1.4%]), genital infections (117 [1.7%]) and skin diseases (53 [0.8%]). One case of diabetic ketoacidosis was reported. The mean ± standard deviation changes from baseline to last observation carried forward in glycated hemoglobin and bodyweight were -0.68 ± 1.34% (n = 6,158, P < 0.0001) and -3.13 ± 4.67 kg (n = 5,213, P < 0.0001), respectively. CONCLUSIONS J-STEP/LT, a 3-year, prospective, observational, post-marketing study in Japan, found no unprecedented ADRs, and consistent reductions from baseline in glycated hemoglobin and bodyweight over the observation period. The present results provide further evidence regarding the safety and tolerability of tofogliflozin in Japanese patients with type 2 diabetes mellitus.
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Empagliflozin and left ventricular diastolic function following an acute coronary syndrome in patients with type 2 diabetes.
Lan, NSR, Yeap, BB, Fegan, PG, Green, G, Rankin, JM, Dwivedi, G
The international journal of cardiovascular imaging. 2021;(2):517-527
Abstract
Sodium-glucose cotransporter 2 inhibitors can improve heart failure outcomes, however, the effects on left ventricular (LV) function remain unclear. This prospective observational study aimed to investigate whether initiating empagliflozin therapy was associated with improved LV diastolic function following an acute coronary syndrome (ACS) in patients with type 2 diabetes (T2D). Patients with ACS and T2D were identified during hospitalisation in a cardiology unit. Empagliflozin was initiated at discharge in eligible patients (i.e. HbA1c > 7%) without contraindications or precautions. Transthoracic echocardiography was performed during admission and after 3-6 months. Changes in echocardiographic parameters were compared between patients initiated on empagliflozin versus not initiated on empagliflozin (control). There were 22 patients in each group (n = 44). Baseline characteristics, medications and echocardiographic parameters were similar except HbA1c (empagliflozin: 9.8 ± 1.6% versus control: 6.6 ± 0.7%, p < 0.001). Baseline LV global longitudinal strain (GLS) (empagliflozin: - 12.4 ± 2.8 versus control: - 13.0 ± 3.6%) and ejection fraction (51.1 ± 11.3 versus 54.9 ± 10.8%) were similar. The difference in change from baseline to follow-up was significant for LV mass index (empagliflozin: - 14.1 ± 21.6 versus control: 3.6 ± 18.7 g/m2, p = 0.006), left atrial volume index (- 2.1 ± 8.1 versus 3.4 ± 9.5 ml/m2, p = 0.045), mitral valve E-wave velocity (- 0.14 ± 0.23 versus 0.03 ± 0.16 m/s, p = 0.007) and average E/e' (- 2.1 ± 2.6 versus 0.9 ± 3.4, p = 0.002). There were no significant between-group differences in change for LV GLS, ejection fraction and volume. In patients with ACS and T2D, addition of empagliflozin to ACS therapy at discharge was associated with a reduction in LV mass and favourable changes in diastolic function parameters. Further studies are warranted to investigate these findings.
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Bisphenol A Exposure in Exclusively Breastfed Infants and Lactating Women: An Observational Cross-sectional Study.
Çiftçi, S, Yalçın, SS, Samur, G
Journal of clinical research in pediatric endocrinology. 2021;(4):375-383
Abstract
OBJECTIVE Bisphenol A (BPA) is a known endocrine disruptor and free BPA will interact with estrogen. BPA is also fat soluble and will therefore contaminate breast milk. The European Food Safety Authority has set a limit for temporary tolerable daily intake of 4 μg/kg body weight/day in breastfeeding infants. The aim of this study was to measure human milk BPA concentrations in Turkish women and thus exclusively breastfed infants’ exposure to BPA. METHODS Healthy, postnatal, exclusively breastfeeding women were recruited and breast milk samples were collected. Free BPA concentration was analyzed in the milk samples using competitive enzyme-linked immunosorbent assay. Participants’ demographic characteristics and nutritional habits were investigated through face-to-face interviews using a detailed questionnaire. RESULTS Eighty women participated. Median milk free BPA level was 0.63 μg/L. There was no statistically significant association between maternal body mass index, birth type, parity, infant birth week, infant birth weight, and human milk BPA concentration. Nevertheless, there was a significant association between human milk BPA level and consumption of fast-food and carbonated drinks (p=0.022 and p=0.018, respectively). Exclusively breastfed infants’ mean BPA exposure was 0.0099±0.0079 μg/kg bw/day. There was a moderate negative significant correlation between infant BPA exposure and infant current body weight (r=0.327, p=0.003). CONCLUSION BPA exposure in exclusively breastfed infants was within accepted limits and the current dietary exposure level of infants in this cohort was safe.
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Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus: Results of 24-month interim analysis of a long-term post-marketing study (J-STEP/LT).
Utsunomiya, K, Kakiuchi, S, Senda, M, Fujii, S, Kurihara, Y, Gunji, R, Koshida, R, Kameda, H, Tamura, M, Kaku, K
Journal of diabetes investigation. 2020;(4):906-916
Abstract
AIMS/INTRODUCTION Tofogliflozin is a potent and highly selective sodium-glucose cotransporter 2 inhibitor, and is currently used to treat patients with type 2 diabetes mellitus. We designed a 3-year study of tofogliflozin in patients with type 2 diabetes mellitus to evaluate the safety and effectiveness in routine clinical practice. The 3- and 12-month interim analysis showed tofogliflozin was well-tolerated, safe and clinically effective. Here, we report the results of the 24-month interim analysis. MATERIALS AND METHODS This is a 3-year prospective, observational and multicenter post-marketing study (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term). RESULTS Of the 6,897 patients enrolled, 6,712 and 6,461 patients were analyzed for the safety and effectiveness of tofogliflozin, respectively. During the 24-month observation period, the incidence rates of adverse drug reactions (ADRs) and serious adverse drug reactions were 11.25 and 1.21%, respectively. As to adverse drug reactions of special interest, the incidence rates of hypoglycemia, polyuria/pollakiuria, volume depletion-related events, urinary tract infections and genital infection were 0.83, 1.28, 1.46, 1.18 and 1.62%, respectively. Renal disorders, and cardiovascular and cerebrovascular disorders occurred in 0.63 and 0.76% of the patients, respectively. Glycated hemoglobin A1c and bodyweight decreased significantly by -0.70% (P < 0.0001) and -2.95 kg (P < 0.0001), respectively, from baseline to week 104 (last observation carried forward). CONCLUSIONS Significant safety concerns have not been observed, and clinical benefit including a long-term reduction in glycated hemoglobin A1c over a 104-week (24 months) observation period with weight loss was suggested in this 24-month interim analysis of the 3-year Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term in routine clinical practice.
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Safety and effectiveness of tofogliflozin in elderly Japanese patients with type 2 diabetes mellitus: A subanalysis of a post-marketing study (J-STEP/EL Study).
Kaku, K, Naito, Y, Senda, M, Kurihara, Y, Gunji, R, Kakiuchi, S, Utsunomiya, K
Journal of diabetes investigation. 2020;(2):405-416
Abstract
AIMS/INTRODUCTION This subanalysis aimed to assess the safety and effectiveness of tofogliflozin by using data from the Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients in an Observational Study of the Elderly to categorize elderly Japanese patients with type 2 diabetes mellitus by the number of concomitant oral antidiabetic drugs (OADs) and insulin use at baseline. MATERIALS AND METHODS Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients in an Observational Study of the Elderly is a 1-year prospective, observational and multicenter post-marketing study that enrolled all patients with type 2 diabetes mellitus aged ≥65 years who started tofogliflozin during the first 3 months after its launch in May 2014 in Japan. RESULTS The safety and effectiveness analysis sets included 1,497 and 1,422 patients, respectively. Overall, 18.10 and 2.20% of the patients experienced adverse drug reactions (ADRs) and serious ADRs, respectively. ADRs of special interest in the total, 0 OAD, one OAD, two OADs, three or more OADs and insulin groups occurred in 12.22, 10.04, 12.35, 13.32, 11.27 and 14.91% of patients, respectively. Volume depletion-related events were the most frequently observed ADRs of special interest. Hypoglycemia occurred in 1.07% of patients. Overall, glycated hemoglobin and bodyweight were significantly decreased, but the estimated glomerular filtration rate was not significantly changed. CONCLUSIONS Our finding suggests that tofogliflozin could be safely and effectively used in elderly Japanese patients with type 2 diabetes mellitus, irrespective of the number of OADs and the use of insulin.
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Long-term empagliflozin therapy improves levels of hepatic fibrosis marker in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus.
Shinozaki, S, Tahara, T, Lefor, AK, Ogura, M
The journal of medical investigation : JMI. 2020;(3.4):280-284
Abstract
The long-term outcomes of patients with non-alcoholic fatty liver disease (NAFLD) treated with sodium-glucose cotransporter-2 inhibitors remain indeterminate. Empagliflozin improves hyperglycemia by increasing glucose excretion in the urine, and it reduces fat volume and insulin resistance. The aim of this study is to assess the effect of long-term empagliflozin therapy on hepatic inflammation, function and fibrosis in patients with NAFLD. This is a two-center retrospective observational study including patients with NAFLD complicated by type 2 diabetes mellitus. We retrospectively reviewed the medical records. Changes in parameters were investigated over one-year empagliflozin treatment. Twenty-four patients treated with empagliflozin were evaluated. Weight, body mass index, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, fasting plasma glucose, hemoglobin A1c, serum insulin and homeostasis model assessment insulin resistance significantly decreased during treatment (p < 0.05). Albumin-bilirubin (ALBI) score, a marker of hepatic function, was significantly improved (p < 0.01). The FIB-4 index and Mac-2 Binding Protein Glucosylation Isomer, markers of hepatic fibrosis, significantly improved (p < 0.01). One-year empagliflozin treatment of patients with NAFLD complicated by type 2 diabetes mellitus significantly improves markers of hepatic inflammation, function and fibrosis. J. Med. Invest. 67 : 280-284, August, 2020.
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Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus in real-world practice: Results of 12-month interim analysis of a long-term post-marketing surveillance study (J-STEP/LT).
Utsunomiya, K, Senda, M, Kakiuchi, S, Kameda, H, Tamura, M, Kurihara, Y, Gunji, R, Fujii, S, Kaku, K
Journal of diabetes investigation. 2020;(1):132-141
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Abstract
AIMS/INTRODUCTION Due to the paucity of tofogliflozin data, we assessed the safety and effectiveness of tofogliflozin among Japanese patients with type 2 diabetes mellitus in the clinical setting, stratifying the patients by age, sex, estimated glomerular filtration (eGFR) rate and body mass index. We report the results of a 12-month interim analysis. MATERIALS AND METHODS This was a 3-year prospective, observational and multicenter post-marketing study (Japanese Study of tofogliflozin with type 2 diabetes mellitus Patients/Long Term). RESULTS Out of 6,897 patients enrolled, the safety and effectiveness analysis populations consisted of 6,712 and 6,449 patients, respectively. During 12 months, adverse drug reactions and their incidence were 9.12 and 0.88%, respectively. The incidence of hypoglycemia was 0.67%. Polyuria/pollakiuria occurred more frequently in patients aged ≥65 years than in patients aged <65 years. Women experienced higher rates of urinary tract and genital infection than men. The lowest eGFR subgroup experienced maximum volume depletion-related events. Cardiovascular and cerebrovascular disorders occurred in 0.55% of the patients. Glycated hemoglobin (HbA1c) and bodyweight significantly decreased by -0.76% and -2.73 kg, respectively, from baseline to the last observation carried forward (P < 0.0001). Except for the lowest eGFR subgroup, other eGFR subgroups showed significantly decreased HbA1c values. All eGFR subgroups showed significantly decreased bodyweight, and all body mass index subgroups showed significantly decreased HbA1c and bodyweight. CONCLUSIONS Our interim 12-month data suggest that tofogliflozin could be used safely and effectively in Japanese patients with type 2 diabetes mellitus, as tofogliflozin was well tolerated with low hypoglycemia risk, and significantly improved HbA1c and bodyweight.
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Efficacy and Safety of SGLT2 Inhibitors in Type 1 Diabetes After the Introduction of an Off-Label Use Protocol for Clinical Practice.
Bayona Cebada, A, Nattero-Chávez, L, Alonso Díaz, S, Escobar-Morreale, HF, Luque-Ramírez, M
Diabetes technology & therapeutics. 2020;(3):208-215
Abstract
Aims: We evaluated the real-life efficacy and safety of empagliflozin in combination with optimized insulin therapy in patients with type 1 diabetes (T1D). Methods: This was a prospective study, including 27 patients with T1D treated with insulin therapy to whom empagliflozin was added according to an off-label protocol approved for use in clinical practice. The primary end point was the change in HbA1c 52 weeks after the addition of empagliflozin to insulin therapy. Blood pressure (BP), weight, and safety were also assessed. Results: At week 52, the addition of empagliflozin significantly reduced HbA1c from 8.0% ± 0.7% to 7.2% ± 0.8% (P < 0.001). The mean percentage of time in range for capillary glucose monitoring increased from 50% to 62% (P = 0.008) in parallel to a -0.08 IU/(kg·day) reduction in insulin requirements (P = 0.031). There was also a reduction in the body weight (-8 kg) and in systolic BP from 134 to 127 mmHg (P < 0.001). The most commonly reported adverse events were genitourinary infections (10 episodes in 52 weeks of follow-up). One patient developed an episode of mild diabetic ketoacidosis that motivated empagliflozin withdrawal. No severe hypoglycemic events were registered. Conclusions: Our results suggested that the use of empagliflozin following a strict off-label protocol may represent an effective and safe option in real life among patients with T1D, improving metabolic control, and ameliorating some cardiovascular risk factors.
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Weight Outcomes With Empagliflozin as Compared With Liraglutide in Veterans With Type 2 Diabetes Mellitus.
Grabarczyk, TR, Wissman, NK
The Annals of pharmacotherapy. 2020;(10):981-987
Abstract
BACKGROUND Glucagon-like peptide-1 agonists and sodium glucose cotransporter 2 inhibitors are associated with weight loss and improved cardiovascular outcomes, and are increasingly used in pharmacotherapy for type 2 diabetes mellitus (T2DM). OBJECTIVES To compare weight loss outcomes of empagliflozin and liraglutide in patients with T2DM and overweight/obesity not yet prescribed insulin but requiring additional pharmacotherapy to improve glycemic control. METHODS This is an observational, multisite, cohort study of veterans with T2DM prescribed liraglutide or empagliflozin. Participants were prescribed either empagliflozin or liraglutide prior to November 1, 2017, had a hemoglobin A1C (A1C) ≥7.0%, had a body mass index ≥27 kg/m2, and were not treated with insulin at baseline. The primary outcome was change in weight after 1 year using multiple regression. Secondary outcomes were the proportion achieving ≥5% weight loss and change in A1C. RESULTS Weight loss was not significantly different between groups: -2.17 kg (95% CI: -2.91 to -1.42) in the liraglutide group (n = 298) and -2.81 kg (95% CI: -3.43 to -2.20) in the empagliflozin group (n = 247; P > 0.05). After adjusting for covariates, this effect remained nonsignificant. There was no difference in change in A1C between liraglutide (-0.83%; 95% CI: -1.05% to -0.62%) and empagliflozin (-0.71%; 95% CI: -0.89% to -0.53%; P > 0.05). CONCLUSIONS AND RELEVANCE There was no significant difference in weight outcomes after 1 year in veterans treated with liraglutide versus empagliflozin. Because both medications did show modest weight loss, both remain good options for patients needing an additional medication to improve glycemic control that is at least weight neutral.
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Effect of dapagliflozin on arterial stiffness in patients with type 2 diabetes mellitus.
Hidalgo Santiago, JC, Maraver Delgado, J, Cayón Blanco, M, López Saez, JB, Gómez-Fernández, P
Medicina clinica. 2020;(5):171-174
Abstract
INTRODUCTION Oral antidiabetic inhibitors of the sodium-glucose cotransporter (SGLT2i) reduce cardiovascular morbidity and mortality in DM2. The increase in arterial stiffness can participate in this morbidity and mortality. The aim of this study was to analyse the effect of the administration of dapagliflozin on arterial stiffness. PATIENTS AND METHODS Prospective observational study that included 32 patients with DM2. Before starting dapagliflozin, and at 6 and 12 months, biochemical parameters in blood and urine were analysed. Before starting dapagliflozin and at 12 months the velocity of the carotid-femoral pulse (VPc-f) was determined by tonometry. Changes in the variables and their interrelation was analysed by repeated data ANOVA, Wilcoxon's test and multiple regression. RESULTS A significant decrease in the VPc-f was observed. There was no association between decreased VPc-f and changes in blood glucose, uric acid, blood pressure or weight. CONCLUSIONS Dapagliflozin, in subjects with DM2, produces a medium to long-term decrease in arterial stiffness.