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1.
A 52-week efficacy and safety study of enavogliflozin versus dapagliflozin as an add-on to metformin in patients with type 2 diabetes mellitus: ENHANCE-M extension study.
Sohn, TS, Han, KA, Kim, Y, Lee, BW, Chon, S, Jeong, IK, Hong, EG, Son, JW, Na, J, Cho, JM, et al
Diabetes, obesity & metabolism. 2024
Abstract
AIM: To evaluate the long-term safety and efficacy of enavogliflozin 0.3 mg/day added to metformin in patients with type 2 diabetes mellitus. MATERIALS AND METHODS After 24 weeks of a randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 101) or dapagliflozin 10 mg/day (n = 99) added to metformin, all patients received enavogliflozin 0.3 mg/day plus metformin for an additional 28 weeks during the open-label extension period. RESULTS Eighty-two patients continued enavogliflozin (maintenance group), and 77 were switched from dapagliflozin to enavogliflozin (switch group). All adverse drug reactions (ADR) were mild in severity. In the maintenance group, ADRs (cystitis and vaginal infection) were reported in two patients (2.44%) during 52 weeks. In the switch group, ADR (hypoglycaemia) was reported in one patient (1.30%) during a 28-week open-label extension period. At week 52, glycated haemoglobin and fasting plasma glucose were significantly lower than at the baseline, by 0.85% and 29.08 mg/dl, respectively, in the maintenance group (p < .0001 for both), and by 0.81% and 32.77 mg/dl, respectively, in the switch group (p < .0001 for both). At week 52, 68.92% of patients from the maintenance group and 64.29% from the switch group achieved glycated haemoglobin <7%. A significant increase in the urine glucose-creatinine ratio was observed at week 52, by 58.81 g/g and 63.77 g/g in the maintenance and switch groups, respectively (p < .0001). CONCLUSIONS Enavogliflozin added to metformin was tolerated well for up to 52 weeks and provided continual glycaemic control in type 2 diabetes mellitus, along with a significant increase in the urine glucose-creatinine ratio.
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2.
Efficacy of Gemigliptin Add-on to Dapagliflozin and Metformin in Type 2 Diabetes Patients: A Randomized, Double-Blind, Placebo-Controlled Study (SOLUTION).
Lee, BW, Min, K, Hong, EG, Ku, BJ, Kang, JG, Chon, S, Lee, WY, Park, MK, Kim, JH, Kim, SY, et al
Endocrinology and metabolism (Seoul, Korea). 2023;(3):328-337
Abstract
BACKGRUOUND This study evaluated the efficacy and safety of add-on gemigliptin in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with metformin and dapagliflozin. METHODS In this randomized, placebo-controlled, parallel-group, double-blind, phase III study, 315 patients were randomized to receive either gemigliptin 50 mg (n=159) or placebo (n=156) with metformin and dapagliflozin for 24 weeks. After the 24-week treatment, patients who received the placebo were switched to gemigliptin, and all patients were treated with gemigliptin for an additional 28 weeks. RESULTS The baseline characteristics were similar between the two groups, except for body mass index. At week 24, the least squares mean difference (standard error) in hemoglobin A1c (HbA1c) changes was -0.66% (0.07) with a 95% confidence interval of -0.80% to -0.52%, demonstrating superior HbA1c reduction in the gemigliptin group. After week 24, the HbA1c level significantly decreased in the placebo group as gemigliptin was administered, whereas the efficacy of HbA1c reduction was maintained up to week 52 in the gemigliptin group. The safety profiles were similar: the incidence rates of treatment-emergent adverse events up to week 24 were 27.67% and 29.22% in the gemigliptin and placebo groups, respectively. The safety profiles after week 24 were similar to those up to week 24 in both groups, and no new safety findings, including hypoglycemia, were noted. CONCLUSION Add-on gemigliptin was well tolerated, providing comparable safety profiles and superior efficacy in glycemic control over placebo for long-term use in patients with T2DM who had poor glycemic control with metformin and dapagliflozin.
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3.
Efficacy and Safety of Enavogliflozin versus Dapagliflozin as Add-on to Metformin in Patients with Type 2 Diabetes Mellitus: A 24-Week, Double-Blind, Randomized Trial.
Han, KA, Kim, YH, Kim, DM, Lee, BW, Chon, S, Sohn, TS, Jeong, IK, Hong, EG, Son, JW, Nah, JJ, et al
Diabetes & metabolism journal. 2023;(6):796-807
Abstract
BACKGRUOUND Enavogliflozin is a novel sodium-glucose cotransporter-2 inhibitor currently under clinical development. This study evaluated the efficacy and safety of enavogliflozin as an add-on to metformin in Korean patients with type 2 diabetes mellitus (T2DM) against dapagliflozin. METHODS In this multicenter, double-blind, randomized, phase 3 study, 200 patients were randomized to receive enavogliflozin 0.3 mg/day (n=101) or dapagliflozin 10 mg/day (n=99) in addition to ongoing metformin therapy for 24 weeks. The primary objective of the study was to prove the non-inferiority of enavogliflozin to dapagliflozin in glycosylated hemoglobin (HbA1c) change at week 24 (non-inferiority margin of 0.35%) (Clinical trial registration number: NCT04634500). RESULTS Adjusted mean change of HbA1c at week 24 was -0.80% with enavogliflozin and -0.75% with dapagliflozin (difference, -0.04%; 95% confidence interval, -0.21% to 0.12%). Percentages of patients achieving HbA1c <7.0% were 61% and 62%, respectively. Adjusted mean change of fasting plasma glucose at week 24 was -32.53 and -29.14 mg/dL. An increase in urine glucose-creatinine ratio (60.48 vs. 44.94, P<0.0001) and decrease in homeostasis model assessment of insulin resistance (-1.85 vs. -1.31, P=0.0041) were significantly greater with enavogliflozin than dapagliflozin at week 24. Beneficial effects of enavogliflozin on body weight (-3.77 kg vs. -3.58 kg) and blood pressure (systolic/diastolic, -5.93/-5.41 mm Hg vs. -6.57/-4.26 mm Hg) were comparable with those of dapagliflozin, and both drugs were safe and well-tolerated. CONCLUSION Enavogliflozin added to metformin significantly improved glycemic control in patients with T2DM and was non-inferior to dapagliflozin 10 mg, suggesting enavogliflozin as a viable treatment option for patients with inadequate glycemic control on metformin alone.
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4.
Varying Approaches to Management of IgE-Mediated Food Allergy in Children Around the World.
Lloyd, M, Loke, P, Mack, DP, Sicherer, SH, Perkin, MR, Boyle, R, Yin Leung, AS, Lee, BW, Levin, M, Blumchen, K, et al
The journal of allergy and clinical immunology. In practice. 2023;(4):1010-1027.e6
Abstract
Food allergy is a chronic disease that affects individuals of all ages and is a significant public health problem globally. This narrative overview examines clinical management strategies for IgE-mediated food allergy in children around the world to understand variations in practice. Information was drawn from clinical practice guidelines, recent research, the websites of professional and governmental bodies with expertise in food allergy, and clinical experts from a broad cross-section of geographical regions. The structure and delivery of clinical services, allergen avoidance and food labeling, and resources to support the management of allergic reactions in the community are discussed in detail. The adoption of emerging food immunotherapies is also explored. Wide variations in clinical management of food allergy were apparent across the different countries. Common themes were continuing issues with access to specialist care and recognition of the need to balance risk reduction with dietary and social restrictions to avoid unnecessary detrimental impacts on the quality of life of food allergy sufferers. Findings highlight the need for standardized presentation of practice and priorities, and may assist clinicians and researchers when engaging with government and funding agencies to address gaps.
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5.
Association between Impaired Ketogenesis and Metabolic-Associated Fatty Liver Disease.
Bae, J, Lee, BW
Biomolecules. 2023;(10)
Abstract
Metabolic (dysfunction) associated fatty liver disease (MAFLD) is generally developed with excessive accumulation of lipids in the liver. Ketogenesis is an efficient pathway for the disposal of fatty acids in the liver and its metabolic benefits have been reported. In this review, we examined previous studies on the association between ketogenesis and MAFLD and reviewed the candidate mechanisms that can explain this association.
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6.
Effectiveness and safety of teneligliptin added to patients with type 2 diabetes inadequately controlled by oral triple combination therapy: A multicentre, randomized, double-blind, and placebo-controlled study.
Lee, M, Lee, WJ, Kim, JH, Lee, BW
Diabetes, obesity & metabolism. 2022;(6):1105-1113
Abstract
AIM: To investigate the effectiveness and safety of teneligliptin over placebo in patients with type 2 diabetes (T2D) inadequately controlled by triple therapy. MATERIALS AND METHODS This trial was a prospective, multicentre, randomized, double-blind, placebo-controlled study. The 12-week double-blind period was followed by a 12-week, open-label clinical trial. One hundred patients with T2D who failed to achieve the glycaemic target (7.1% ≤ HbA1c ≤ 9.0%) with conventional triple oral antidiabetic drugs (OADs) of metformin, sulphonylurea, and sodium-glucose co-transporter-2 inhibitor were assigned randomly 1:1 into teneligliptin and placebo-teneligliptin groups. The primary endpoint was mean change in HbA1c level from baseline in each group at 12 weeks. RESULTS For a total of 99 patients (n = 51 for the teneligliptin group, and n = 48 for the placebo-teneligliptin group), the mean age and duration of diabetes were 60.7 and 13.6 years, respectively, and HbA1c was 7.8% at baseline. At 12 weeks, the teneligliptin group achieved a significant reduction in HbA1c from baseline (-0.9% ± 0.6%, P < .001), with an intergroup difference of -0.75% compared with the placebo group (95% CI [-0.99%, -0.51%], P < .001). At the end of the 24-week treatment period, both groups showed significant reductions in HbA1c level from baseline (placebo-teneligliptin group, -0.8% ± 0.6% [P < .001], teneligliptin group, -0.9% ± 0.6% [P < .001]), without significant intergroup difference (-0.17%, 95% CI [-0.41%, 0.07%], P = .156). There was no significant difference between the groups in the rate of adverse events (placebo-teneligliptin group, n = 3 [6.3%]; teneligliptin group, n = 11 [11.1%]; P = .550), and the safety profiles were favourable in both groups. CONCLUSIONS The current study shows that teneligliptin could be a valid option as a fourth OAD for the treatment of patients with T2D inadequately controlled with a triple combination of OADs.
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7.
Short Term Isocaloric Ketogenic Diet Modulates NLRP3 Inflammasome Via B-hydroxybutyrate and Fibroblast Growth Factor 21.
Kim, ER, Kim, SR, Cho, W, Lee, SG, Kim, SH, Kim, JH, Choi, E, Kim, JH, Yu, JW, Lee, BW, et al
Frontiers in immunology. 2022;:843520
Abstract
UNLABELLED A ketogenic diet (KD) is known to have beneficial health effects. Various types of KD interventions have been applied to manage metabolic syndrome based on modification of diet parameters such as duration of intervention, macronutrient components, and total calories. Nevertheless, the beneficial health impact of isocaloric KD is largely unknown, especially in healthy subjects. The present study investigated the acute effects of a 3-day isocaloric KD. In this non-randomized intervention study, we recruited 15 healthy volunteers aged 24-38 years (7 men and 8 women) and placed them on an isocaloric KD restricting intake of carbohydrates but not energy (75% fat, 20% protein, 5% carbohydrate) for 3 days. Biochemical profiles and laboratory measurements were performed. Peripheral blood monocular cells were cultured, and measured cell stimulated cytokines. After short-term isocaloric KD, subjects lost body weight and serum free fatty acid levels were increased. These results accompanied elevated serum β-hydroxybutyrate (BHB) concentration and fibroblast growth factor 21 (FGF21) levels and improved insulin sensitivity. Regarding the direct effect of BHB on inflammasome activation, interleukin-1β (IL-1β) and tumor necrosis factor-α secretion in response to adenosine triphosphate or palmitate stimulation in human macrophages decreased significantly after isocaloric KD. In ex-vivo experiments with macrophages, both FGF21 and BHB further reduced IL-1β secretion compared to either BHB or FGF21 alone. The inhibitory effect of FGF21 on IL-1β secretion was blunted with bafilomycin treatment, which blocked autophagy flux. In conclusion, isocaloric KD for 3 days is a promising approach to improve metabolic and inflammatory status. CLINICAL TRIAL REGISTRATION clinicaltrials.gov (NCT02964572).
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8.
Effect of Dapagliflozin as an Add-on Therapy to Insulin on the Glycemic Variability in Subjects with Type 2 Diabetes Mellitus (DIVE): A Multicenter, Placebo-Controlled, Double-Blind, Randomized Study.
Lee, SH, Min, KW, Lee, BW, Jeong, IK, Yoo, SJ, Kwon, HS, Choi, YH, Yoon, KH
Diabetes & metabolism journal. 2021;(3):339-348
Abstract
BACKGROUND Glycemic variability is associated with the development of diabetic complications and hypoglycemia. However, the effect of sodium-glucose transporter 2 (SGLT2) inhibitors on glycemic variability is controversial. We aimed to examine the effect of dapagliflozin as an add-on therapy to insulin on the glycemic variability assessed using continuous glucose monitoring (CGM) in subjects with type 2 diabetes mellitus. METHODS In this multicenter, placebo-controlled, double-blind, randomized study, 84 subjects received 10 mg of dapagliflozin (n=41) or the placebo (n=43) for 12 weeks. CGM was performed before and after treatment to compare the changes in glycemic variability measures (standard deviation [SD], mean amplitude of glycemic excursions [MAGEs]). RESULTS At week 12, significant reductions in glycosylated hemoglobin (-0.74%±0.66% vs. 0.01%±0.65%, P<0.001), glycated albumin (-3.94%±2.55% vs. -0.67%±2.48%, P<0.001), and CGM-derived mean glucose (-41.6±39.2 mg/dL vs. 1.1±46.2 mg/dL, P<0.001) levels were observed in the dapagliflozin group compared with the placebo group. SD and MAGE were significantly decreased in the dapagliflozin group, but not in the placebo group. However, the difference in ΔSD and ΔMAGE failed to reach statistical significance between two groups. No significant differences in the incidence of safety endpoints were observed between the two groups. CONCLUSION Dapagliflozin effectively decreased glucose levels, but not glucose variability, after 12 weeks of treatment in participants with type 2 diabetes mellitus receiving insulin treatment. The role of SGLT2 inhibitors in glycemic variability warrants further investigations.
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9.
Glycaemic control with add-on thiazolidinedione or a sodium-glucose co-transporter-2 inhibitor in patients with type 2 diabetes after the failure of an oral triple antidiabetic regimen: A 24-week, randomized controlled trial.
Bae, J, Huh, JH, Lee, M, Lee, YH, Lee, BW
Diabetes, obesity & metabolism. 2021;(2):609-618
Abstract
AIM: To evaluate the effectiveness and safety of adding either a sodium-glucose co-transporter-2 inhibitor (SGLT2i) or thiazolidinedione (TZD) in patients with type 2 diabetes (T2D) inadequately controlled with triple therapy. MATERIALS AND METHODS In this prospective, open-label, multicentre, 24-week clinical trial, we randomly assigned 119 patients with T2D who failed to achieve glycaemic control (7% < HbA1c ≤ 10%) with conventional triple oral antidiabetic agents (OADs; metformin, sulphonylurea and dipeptidyl peptide-4 [DPP-4] inhibitor) into two groups who received either an SGLT2i or TZD. The primary endpoint was mean change in HbA1c level between the two groups at 24 weeks. RESULTS In total, 119 patients were enrolled in the SGLT2i (n = 60) and TZD (n = 59) groups. Mean age of the study subjects was 61.86 years, and the mean duration of T2D was 13.89 years. After 24 weeks, both groups showed significant reductions in HbA1c (from 7.94% ± 0.74% to 6.97% ± 0.84% in the SGLT2i group and from 8.00% ± 0.78% to 7.18% ± 0.98% in the TZD group), without a significant between-group difference (P = .235). A significant body mass index (BMI) reduction was noted in the SGLT2i group, whereas an increase in BMI was noted in the TZD group (-0.79 ± 1.37 vs. 0.92 ± 0.86 kg/m2 , P < .001). Other safety profiles were favourable in both groups. CONCLUSIONS The current study shows that an SGLT2i or TZD could be a valid option as a fourth OAD for treatment of patients with T2D inadequately controlled with a triple combination of OADs.
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10.
Efficacy and Tolerability of Pitavastatin Versus Pitavastatin/Fenofibrate in High-risk Korean Patients with Mixed Dyslipidemia: A Multicenter, Randomized, Double-blinded, Parallel, Therapeutic Confirmatory Clinical Trial.
Ihm, SH, Chung, WB, Lee, JM, Hwang, BH, Yoo, KD, Her, SH, Song, WH, Chae, IH, Park, TH, Kim, JH, et al
Clinical therapeutics. 2020;(10):2021-2035.e3
Abstract
PURPOSE Dyslipidemia is an important risk factor for cardiovascular disease (CVD). Statins are known to effectively reduce not only low-density lipoprotein cholesterol (LDL-C) level but also death and nonfatal myocardial infarction due to coronary heart disease. The risk for CVD from atherogenic dyslipidemia persists when elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C) levels are not controlled with statin therapy. Therefore, statin/fenofibrate combination therapy is more effective in reducing CVD risk. Here, we assessed the efficacy and tolerability of pitavastatin/fenofibrate combination therapy in patients with mixed dyslipidemia and a high risk for CVD. METHODS This multicenter, randomized, double-blind, parallel-group, therapeutic-confirmatory clinical trial evaluated the efficacy and tolerability of fixed-dose combination therapy with pitavastatin/fenofibrate 2/160 mg in Korean patients with a high risk for CVD and a controlled LDL-C level (<100 mg/dL) and a TG level of 150-500 mg/dL after a run-in period with pitavastatin 2 mg alone. In the 8-week main study, 347 eligible patients were randomly assigned to receive pitavastatin 2 mg with or without fenofibrate 160 mg after a run-in period. In the extension study, patients with controlled LDL-C and non-HDL-C (<130 mg/dL) levels were included after the completion of the main study. All participants in the extension study received the pitavastatin/fenofibrate combination therapy for 16 weeks for the assessment of the tolerability of long-term treatment. FINDINGS The difference in the mean percentage change in non-HDL-C from baseline to week 8 between the combination therapy and monotherapy groups was -12.45% (95% CI, -17.18 to -7.72), and the combination therapy was associated with a greater reduction in non-HDL-C. The changes in lipid profile, including apolipoproteins, fibrinogen, and high-sensitivity C-reactive protein from baseline to weeks 4 and 8 were statistically significant with combination therapy compared to monotherapy at all time points. Furthermore, the rates of achievement of non-HDL-C and apolipoprotein B targets at week 8 in the combination therapy and monotherapy groups were 88.30% versus 77.98% (P = 0.0110) and 78.94% versus 68.45% (P = 0.0021), respectively. The combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy. IMPLICATIONS In these Korean patients with mixed dyslipidemia and a high risk for CVD, combination therapy with pitavastatin/fenofibrate was associated with a greater reduction in non-HDL-C compared with that with pitavastatin monotherapy, and a significantly improvement in other lipid levels. Moreover, the combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy. Therefore, pitavastatin/fenofibrate combination therapy could be effective and well tolerated in patients with mixed dyslipidemia. ClinicalTrials.gov identifier: NCT03618797.