Changes in serum levels of liver-related parameters, uric acid, and hemoglobin in patients with type 2 diabetes mellitus under treatment with tofogliflozin-a post-hoc analysis of the UTOPIA study.

Aims/Introduction: The aim of the study was to evaluate the effects of tofogliflozin, a selective sodium-glucose cotransporter 2 inhibitor, on circulating levels of hepatic enzymes, uric acid and hemoglobin levels in patients with type 2 diabetes mellitus (T2DM). Materials and methods: We evaluated longitudinal changes in circulating aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), uric acid, and hemoglobin levels in tofogliflozin (n = 169) and conventional treatment groups (n = 170) using data obtained from the UTOPIA trial, a randomized prospective study conducted to evaluate the efficacy of tofogliflozin in preventing atherosclerosis. Results: Within 104 weeks, tofogliflozin treatment, but not conventional treatment, significantly reduced AST, ALT, and γ-GTP levels. This reduction was significantly greater in the tofogliflozin group than in the conventional group. Stratified analysis showed that, in patients with obesity (defined as body mass index (BMI) ≥ 25.0 kg/m2), significant differences were observed in AST, ALT, and γ-GTP changes from baseline to 104 weeks between treatment groups. However, in patients without obesity, there were no significant differences in AST and γ-GTP changes from baseline to 104 weeks between treatment groups. Multivariable regression analysis showed that changes in BMI and HbA1c levels were independently associated with changes in AST, ALT, and γ-GTP levels. The reduction of uric acid and the increase of hemoglobin from baseline to 104 weeks were significantly greater in the tofogliflozin group than in the conventional group. Conclusions: The beneficial effects of tofogliflozin on circulating levels of hepatic enzymes, uric acid, and Hb lasted for 2 years in patients with T2DM. Clinical trial registration: UMIN000017607 (https://www.umin.ac.jp/icdr/index.html). Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00693-x.

Protocol of a Prospective Observational Study on Lifestyle and Quality of Life in Adults with Type 1 Diabetes in Japan.

INTRODUCTION: Recent studies have shown that the quality of life (QOL) of people living with type 1 diabetes (T1D) is poor and must be improved. However, the living situation and QOL of adults living with T1D in Japan have not been fully clarified. This study will examine their lifestyle, QOL, and clinical situation, as well as the relationships between them. METHODS: This is a prospective, 5-year follow-up observational study. Between December 2019 and September 2021, we enrolled adults in Japan who were living with T1D and receiving insulin therapy, and are acquiring longitudinal clinical data and the responses to seven questionnaires regarding lifestyle and QOL. The primary study outcomes are (1) the relationship between Problem Areas in Diabetes (PAID) scores and various factors including demographic data, clinical characteristics, medical history, lifestyle habits, treatment history, biochemical data, and the scores of questionnaires; and (2) the relationship between Beck Depression Inventory (BDI)-II scores and various factors aforementioned. The secondary outcomes are the relationships between various factors aforementioned and each of the following: (1) blood glucose control, (2) blood lipid control, (3) dietary patterns, (4) fear of hypoglycemia, (5) sleep patterns, and (6) physical activity. PLANNED OUTCOME: We registered 352 participants. The median age was 49 (41-63) years, and the median duration of T1D was 13 (8-20) years. All the results will be available in 2026. We expect to clarify the factors associated with decreased QOL, and that this knowledge will contribute to improving QOL in adults in Japan who are living with T1D and receiving insulin therapy. TRIAL REGISTRATION: Clinical Trials.gov identifier, UMIN000044088.

Continuous glucose monitoring-derived time in range and CV are associated with altered tissue characteristics of the carotid artery wall in people with type 2 diabetes.

AIMS/HYPOTHESIS: Previous studies have suggested that glucose variability may accelerate atherosclerosis progression in people with type 2 diabetes. Current guidelines recommend assessing glycaemic control using continuous glucose monitoring (CGM), which provides a comprehensive glycaemic profile to supplement HbA1c measurement. However, the association between CGM-derived metrics and atherosclerosis progression is not entirely clear. METHODS: This exploratory study used baseline data and data obtained after 104 weeks from an ongoing prospective, multicentre, observational study. Six hundred study participants with type 2 diabetes and no apparent history of symptomatic cardiovascular disease underwent CGM and ultrasonographic atherosclerosis measurements of the carotid arteries, including the intima-media thickness (IMT) and grey-scale median (GSM), at baseline and 104 weeks. Non-invasive ultrasonic tissue characterisation of the carotid artery wall or plaque using the GSM reflects vascular composition. Multivariate regression models were used to analyse the association between CGM-derived indices, mainly time in range (TIR) and CV, and changes in carotid atherosclerosis index values. RESULTS: Over the 104-week study period, there were modest increases in mean IMT (from 0.759±0.153 to 0.773±0.152 mm, p<0.001) and thickened-lesion GSM (from 43.5±19.5 to 53.9±23.5 units, p<0.001), but no significant changes in common carotid artery maximum-IMT (from 1.109±0.442 to 1.116±0.469 mm, p=0.453) or mean GSM (from 48.7±19.3 to 49.8±20.8 units, p=0.092). In a linear regression model with adjustment for possible atherosclerotic risk factors, including HbA1c, TIR and CV at baseline were significantly associated with the annual change in mean GSM (regression coefficient per 10% increase in TIR 0.52; 95% CI 0.06, 0.98; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.12; 95% CI -0.22, -0.02; Hochberg-adjusted p value 0.038). TIR and CV at baseline were also significantly associated with the annual change in thickened-lesion GSM (regression coefficient per 10% increase in TIR 0.95; 95% CI 0.12, 1.79; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.19; 95% CI -0.36, -0.01; Hochberg-adjusted p value 0.038). Participants who achieved target CGM-derived metrics at baseline, as proposed by an international consensus, showed significant annual changes in mean GSM compared with those who did not (0.94±6.88 vs -0.21±6.19 units/year, p=0.007). CONCLUSIONS/INTERPRETATION: TIR and CV were significantly associated with changes in the tissue characteristics of the carotid artery wall. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, number UMIN000032325.

Long-term efficacy and safety of early alogliptin initiation in subjects with type 2 diabetes: an extension of the SPEAD-A study.

We previously reported in the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A) that alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuated the progression of carotid atherosclerosis in subjects with type 2 diabetes and no history of cardiovascular disease. This extension study of the SPEAD-A trial investigated whether early alogliptin initiation improved long-term cardiovascular outcomes. The SPEAD-A trial randomized 341 subjects with type 2 diabetes to either alogliptin or conventional treatment to investigate the effects of alogliptin on atherosclerosis. All subjects who completed that trial were eligible for this prospective, observational cohort study. The primary endpoint was the first occurrence of a major cardiovascular event, defined as death due to any cause, acute myocardial infarction, or stroke. During the 520-week follow-up period, composite primary outcome events occurred in only a few subjects in each group [8 (5.4%) in the alogliptin group and 9 in the conventional treatment group (5.9%)]. There were no significant differences in the incidence rate of the primary outcome between the two groups. Post hoc Poisson regression analysis showed no significant difference between the two groups in the incidence rate of composite recurrence events for the same outcomes as the primary endpoint. On the other hand, this incidence rate was significantly lower in subjects who received DPP-4 inhibitors before an initial cardiovascular event than in those who did not (5.8 vs. 13.3 per 1000 person-years, respectively, p = 0.04). Early initiation of alogliptin was not associated with a reduced risk of composite cardiovascular disease, which could be attributed to fewer events and/or the addition of DPP-4 inhibitors during the follow-up period.

Coronary Artery Vorticity to Predict Functional Plaque Progression in Participants with Type 2 Diabetes Mellitus.

Purpose: To investigate whether vorticity could predict functional plaque progression better than high-risk plaque (HRP) and lesion length (LL) in individuals with type 2 diabetes mellitus. Materials and Methods: This single-center prospective study included 61 participants (mean age, 61 years ± 9 [SD]; 43 male participants) who underwent serial coronary CT angiography at 2 years, with 20%-70% stenosis at initial CT between October 2015 and March 2020. The number of the following HRP characteristics was recorded: low attenuation, positive remodeling, spotty calcification, and napkin-ring sign. Vorticity was calculated using a mesh-free simulation. A decrease in CT fractional flow reserve larger than 0.05 indicated functional progression. Models using HRP and LL and vorticity were compared using receiver operating characteristic curve analysis. Results: Of the 94 vessels evaluated, 25 vessels (27%) showed functional progression. Vessels with functional progression showed higher vorticity at distal stenosis (984 sec-1; IQR: 730-1253 vs 443 sec-1; IQR: 295-602; P < .001) than vessels without progression. The area under the receiver operating characteristic curve of vorticity (0.91; 95% CI: 0.84, 0.97) was higher than that of HRP and LL (0.69; 95% CI: 0.56, 0.82; P < .01). Diagnostic accuracy of vorticity (85%; 80 of 94 vessels; 95% CI: 76, 92) was higher than that of HRP and LL (72%; 68 of 94 vessels; 95% CI: 62, 81; P = .004). Conclusion: In participants with type 2 diabetes mellitus, vorticity at distal stenosis was a better predictor of functional plaque progression than HRP and LL.Keywords: Coronary Artery, Vorticity, Functional Plaque Progression, Type 2 Diabetes, Vasculature, CT Angiography, Computational Fluid Dynamics, Fractional Flow Reserve Supplemental material is available for this article. © RSNA, 2023.

Tofogliflozin long-term effects on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes mellitus lacking a history of cardiovascular disease: a 2-year extension study of the UTOPIA trial.

BACKGROUND: This study aimed to assess the long-term effects of tofogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes lacking an apparent history of cardiovascular disease. METHODS: This was a prospective observational 2-year extension study of the "Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)" trial, a 2-year randomized intervention study. The primary endpoints represented changes in the carotid intima-media thickness (IMT). Secondary endpoints included brachial-ankle pulse wave velocity (baPWV) and biomarkers for glucose metabolism, lipid metabolism, renal function, and cardiovascular risks. RESULTS: The mean IMT of the common carotid artery (IMT-CCA) significantly decreased in both the tofogliflozin (- 0.067 mm, standard error 0.009, p < 0.001) and conventional treatment groups (- 0.080 mm, SE 0.009, p < 0.001) throughout the follow-up period; however, no significant intergroup differences in the changes (0.013 mm, 95% confidence interval (CI) - 0.012 to 0.037, p = 0.32) were observed in a mixed-effects model for repeated measures. baPWV significantly increased in the conventional treatment group (82.7 ± 210.3 cm/s, p = 0.008) but not in the tofogliflozin group (- 17.5 ± 221.3 cm/s, p = 0.54), resulting in a significant intergroup difference in changes (- 100.2 cm/s, 95% CI - 182.8 to - 17.5, p = 0.018). Compared to the conventional treatment group, tofogliflozin significantly improved the hemoglobin A1c and high-density lipoprotein cholesterol levels, body mass index, abdominal circumference, and systolic blood pressure. The frequencies of total and serious adverse events did not vary significantly between the groups. CONCLUSIONS: Tofogliflozin was not associated with improved inhibition of carotid wall thickening but exerted long-term positive effects on various cardiovascular risk factors and baPWV while showing a good safety profile.

Impact of COVID-19 pandemic on behavioral changes and glycemic control and a survey of telemedicine in patients with diabetes: A multicenter retrospective observational study.

AIMS/INTRODUCTION: To investigate whether the COVID-19 pandemic affected behavioral changes and glycemic control in patients with diabetes and to conduct a survey of telemedicine during the pandemic. MATERIALS AND METHODS: In this retrospective study, a total of 2,348 patients were included from 15 medical facilities. Patients were surveyed about their lifestyle changes and attitudes toward telemedicine. Hemoglobin A1c (HbA1c) levels were compared among before (from June 1 to August 31, 2019) and in the first (from June 1 to August 31, 2020) and in the second (from June 1 to August 31, 2021) year of the pandemic. A survey of physician attitudes toward telemedicine was also conducted. RESULTS: The HbA1c levels were comparable between 2019 (7.27 ± 0.97%), 2020 (7.28 ± 0.92%), and 2021 (7.25 ± 0.94%) without statistical difference between each of those 3 years. Prescriptions for diabetes medications increased during the period. The frequency of eating out was drastically reduced (51.7% in 2019; 30.1% in 2020), and physical activity decreased during the pandemic (48.1% in 2019; 41.4% in 2020; 43.3% in 2021). Both patients and physicians cited increased convenience and reduced risk of infection as their expectations for telemedicine, while the lack of physician-patient interaction and the impossibility of consultation and examination were cited as sources of concern. CONCLUSIONS: Our data suggest that glycemic control did not deteriorate during the COVID-19 pandemic with appropriate intensification of diabetes treatment in patients with diabetes who continued to attend specialized diabetes care facilities, and that patients and physicians shared the same expectations and concerns about telemedicine.

The Importance of Continuous Glucose Monitoring-derived Metrics Beyond HbA1c for Optimal Individualized Glycemic Control.

CONTEXT: Current guidelines recommend assessing glycemic control using continuous glucose monitoring (CGM) and hemoglobin A1c (HbA1c) measurement. OBJECTIVE: This study aimed to clarify the characteristics of patients who might benefit from CGM metrics in addition to HbA1c monitoring. METHODS: CGM metrics, specifically time in range (TIR), time below range (TBR), and time above range (TAR), were determined in 999 outpatients with type 2 diabetes and compared between HbA1c categories (HbA1c < 53 mmol/mol [7.0%, HbA1c <  53], HbA1c 53-63 mmol/mol [7.0-7.9%, HbA1c 53-63], HbA1c 64-74 mmol/mol [8.0-8.9%, HbA1c 64-74], and HbA1c ≥ 75 mmol/mol [9.0%, HbA1c ≥  75]) and between patients with identical HbA1c categories who were stratified by age, types of antidiabetic agents, and renal function. RESULTS: For HbA1c <  53 category, patients aged ≥ 65 years had a significantly higher nocturnal TBR than those aged < 65 years. For HbA1c <  53 and HbA1c 53-63 categories, patients receiving insulin and/or sulfonylureas had a significantly higher TAR and TBR, and a lower TIR than those not receiving these drugs, and for HbA1c 64-74 category, they had a significantly higher TBR. For HbA1c <  53, HbA1c 53-63, and HbA1c 64-74 categories, patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 had a significantly higher TBR during some periods than those with an eGFR ≥ 60. CONCLUSION: Higher HbA1c levels do not always protect against hypoglycemic episodes. Our data demonstrate that using CGM metrics to complement HbA1c monitoring is beneficial, especially in older people, users of insulin and/or sulfonylureas, and patients with chronic kidney disease.

Changes in Treatment Satisfaction Over 3 Years in Patients With Type 2 Diabetes After Initiating Second-line Treatment.

CONTEXT: J-DISCOVER is a prospective observational cohort study aiming to understand the current management of patients with early-stage type 2 diabetes mellitus (T2DM) in Japan, enrolling patients initiating second-line treatment. OBJECTIVE: The current analysis examined the change in treatment satisfaction during the study period and factors affecting this change among patients in J-DISCOVER. METHODS: We used data from the J-DISCOVER study, in which 1798 patients with T2DM aged ≥ 20 years were enrolled from 142 sites across Japan. Treatment satisfaction was assessed using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). RESULTS: The mean DTSQ treatment satisfaction score increased from 25.9 points at baseline to 27.3 points at 6 months, which was maintained through 36 months. Among the baseline characteristics examined, higher baseline DTSQ treatment satisfaction scores (P < 0.0001), older age (≥ 75 vs < 65 years, P = 0.0096), living alone (P = 0.0356), and type of facility (clinics vs hospitals, P = 0.0044) had a significantly negative impact on the changes in DTSQ treatment satisfaction scores. Improvement in mean glycated hemoglobin (HbA1c) from baseline (7.7%) to 36 months (7.1%) was associated with positive changes in the DTSQ treatment satisfaction score (P = 0.0003). CONCLUSION: Changes in DTSQ treatment satisfaction scores were related to HbA1c improvement, suggesting that the management strategy was appropriately planned for each patient. The results also suggest that the availability of social support for patients with T2DM who are elderly or living alone may be an important factor affecting treatment satisfaction, adherence, and clinical outcomes.

Genetic ablation of p62/SQSTM1 demonstrates little effect on pancreatic ß-cell function under autophagy deficiency.

Autophagy is known to play an essential role in intracellular quality control through the degradation of damaged organelles and components. We previously demonstrated that ß-cell-specific autophagy deficient mice, which lack Atg7, exhibited impaired glucose tolerance, accompanied by the accumulation of sequestosome 1/p62 (hereafter referred to as p62). Whereas p62 has been reported to play essential roles in regulating cellular homeostasis in the liver and adipose tissue, we previously showed that ß-cell-specific p62 deficiency does not cause any apparent impairment in glucose metabolism. In the present study, we investigated the roles of p62 in ß cells under autophagy-deficient conditions, by simultaneously inactivating both Atg7 and p62 in a ß-cell specific manner. Whereas p62 accumulation was substantially reduced in the islets of Atg7 and p62 double-deficient mice, glucose tolerance and insulin secretion were comparable to Atg7 single-deficient mice. Taken together, these findings suggest that the p62 accumulation appears to have little effect on ß-cell function under conditions of autophagy inhibition.

Human Cathelicidin Peptide LL-37 Induces Cell Death in Autophagy-Dysfunctional Endothelial Cells.

Human cathelicidin LL-37 is an antimicrobial peptide that has a broad spectrum of antimicrobial activities but also acts on host cells to exert immunomodulatory functions. It has been suggested that the increase of LL-37 in atherosclerotic aortas and the dysregulated autophagy of endothelial cells are involved in the pathogenesis of atherosclerosis. In this study, to elucidate the role of LL-37 in atherosclerosis, we investigated the effect of LL-37 on autophagy in endothelial cells using HUVECs. First, LL-37 upregulated LC3-II (an autophagosomal membrane marker) and enhanced the formation of LC3-positive puncta in the cells, suggesting that LL-37 induces autophagy in endothelial cells. Second, LL-37 was associated with p62, which recognizes ubiquitinated proteins and transfers them to autophagosomes, suggesting that LL-37 is ubiquitinated and recognized by p62. Third, the degradation of LL-37 was delayed, and LL-37 induced cell death in atg7 knockdown cells, which was accompanied by the formation of protein aggregates in the cells. Taken together, these observations suggest that LL-37 induces autophagy in endothelial cells but enhances cell death in autophagy-dysfunctional conditions, in which the intracellular degradation of LL-37 is disturbed. Thus, LL-37 may exert an adverse action on autophagy-dysfunctional endothelial cells to induce cell death in the pathogenesis of atherosclerosis.

Associations between continuous glucose monitoring-derived metrics and HbA1c in patients with type 2 diabetes mellitus.

AIMS: The aim of this study was to define the relationship between time in range (TIR) and hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM). METHODS: The glycemic profile of 999 Japanese patients was analyzed with FreeStyle Libre Pro Continuous Glucose Monitoring (FLP-CGM) while they continued their prescribed glucose-lowering medications. FLP-CGM data recorded over 8 consecutive days were analyzed. RESULTS: The regression model for HbA1c on TIR was HbA1c = 9.4966-0.0309 × TIR. The predicted HbA1c level for TIR of 70% was 7.33% and is higher than reports subjecting mostly T1DM. The TIR corresponding to HbA1c 7.0% was 80.64%. The patients with low TIR tended to have long duration of diabetes, used high dose of daily insulin, high body mass index, high HbA1c, liver dysfunction and high triglyceride. Relatively higher percentages of patients of this group used sulfonylureas, glucagon like peptide-1 receptor agonists and insulin. CONCLUSIONS: Our data showed predicted HbA1c corresponding to TIR is largely depends on study population, thus is not uniform. Our results provide new insights on the management of T2DM. However, caution should be exercised in extending the HbA1C-TIR relationship using FLP-CGM to any other sensors since there could be a risk of hypoglycemia in doing so.

Phase I/IIa Feasibility Trial of Autologous Quality- and Quantity-Cultured Peripheral Blood Mononuclear Cell Therapy for Non-Healing Extremity Ulcers.

Non-healing wounds are among the main causes of morbidity and mortality. We recently described a novel, serum-free ex vivo expansion system, the quantity and quality culture system (QQc), which uses peripheral blood mononuclear cells (PBMNCs) for effective and noninvasive regeneration of tissue and vasculature in murine and porcine models. In this prospective clinical study, we investigated the safety and efficacy of QQ-cultured peripheral blood mononuclear cell (MNC-QQ) therapy for chronic non-healing ischemic extremity wounds. Peripheral blood was collected from 9 patients with 10 chronic (>1 month) non-healing wounds (8 males, 1 female; 64-74 years) corresponding to ischemic extremity ulcers. PBMNCs were isolated and cultured using QQc. Within a 20-cm area surrounding the ulcer, 2 × 107 cells were injected under local anesthesia. Wound healing was monitored photometrically every 2 weeks. The primary endpoint was safety, whereas the secondary endpoint was efficacy at 12-week post-injection. All patients remained ambulant, and no deaths, other serious adverse events, or major amputations were observed for 12 weeks after cell transplantation. Six of the 10 cases showed complete wound closure with an average wound closure rate of 73.2% ± 40.1% at 12 weeks. MNC-QQ therapy increased vascular perfusion, skin perfusion pressure, and decreased pain intensity in all patients. These results indicate the feasibility and safety of MNC-QQ therapy in patients with chronic non-healing ischemic extremity wounds. As the therapy involves transplanting highly vasculogenic cells obtained from a small blood sample, it may be an effective and highly vasculogenic strategy for limb salvage.

Identification of Risk Factors for Coronary Artery Disease in Asymptomatic Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Patients with diabetes mellitus (DM) are a high-risk group for coronary artery disease (CAD). In the present study, we investigated predictive factors to identify patients at high risk of CAD among asymptomatic patients with type 2 DM based on coronary computed tomographic angiography (CCTA) findings. METHODS: A single-center prospective study was performed on 452 consecutive patients with type 2 DM who were provided with a weekly hospital-based diabetes education program between 3 October 2015, and 31 March 2020. A total of 161 consecutive asymptomatic patients (male/female: 111/50, age: 57.3 ± 9.3 years) with type 2 DM without any known CAD underwent CCTA. Based on conventional coronary risk factors and non-invasive examination, i.e., measurement of intima-media thickness, subcutaneous and visceral fat area, a stress electrocardiogram test, and the Agatston score, patients with obstructive CAD, CT-verified high-risk plaques (CT-HRP), and optimal revascularization within 90 days were evaluated. RESULTS: Current smoking (OR, 4.069; 95% C.I., 1.578-10.493, p = 0.0037) and the Agatston score ≥100 (OR, 18.034; 95% C.I., 6.337-51.324, p = 0.0001) were independent predictive factors for obstructive CAD, while current smoking (OR, 5.013; 95% C.I., 1.683-14.931, p = 0.0038) was an independent predictive factor for CT-HRP. Furthermore, insulin treatment (OR, 5.677; 95% C.I., 1.223-26.349, p = 0.0266) was the only predictive factor that correlated with optimal revascularization within 90 days. CONCLUSIONS: In asymptomatic patients with type 2 DM, current smoking, an Agatston score ≥100, and insulin treatment were independent predictive factors of patients being at high-risk for CAD. However, non-invasive examinations except for Agatston score were not independent predictors of patients being at high risk of CAD.

Evaluation of the effect of tofogliflozin on the tissue characteristics of the carotid wall-a sub-analysis of the UTOPIA trial.

BACKGROUND: Since sodium-glucose cotransporter 2 (SGLT2) inhibitors have a pleiotropic antiatherogenic effect, they are expected to attenuate the progression of atherosclerosis. However, whether SGLT2 inhibitors affect the tissue characteristics of the human arterial wall remains unclear. This study aimed to evaluate the effects of tofogliflozin, a selective SGLT2 inhibitor, on the tissue characteristics of the human arterial wall in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD). METHODS: The present study was a post hoc analysis based on data obtained from the Using Tofogliflozin for Possible Better Intervention against Atherosclerosis for Type 2 Diabetes Patients (UTOPIA) trial, which was a multicenter prospective, randomized, open-label, blinded-endpoint study conducted to evaluate the efficacy of tofogliflozin in preventing the progression of atherosclerosis in patients with T2DM. We evaluated the longitudinal change in the ultrasonic tissue characteristics of the carotid wall using gray-scale median (GSM), an established index of ultrasonic tissue characteristics. The right and left intima-medial areas were delineated, and the GSM values were evaluated (right GSM-CCA and left GSM-CCA). The average values of the right and left carotid arteries were defined as "mean GSM-CCA value." RESULTS: In a mixed-effects model for repeated measures, mean GSM-CCA, along with the right and left GSM-CCA values, did not significantly change in either the tofogliflozin (n = 168) or conventional treatment group (n = 169). In addition, the tofogliflozin and conventional treatment groups did not significantly differ regarding the change of the mean GSM-CCA (mean difference [95% CI] - 1.24[- 3.87, 1.38], P = 0.35), along with the right (mean difference [95% CI] - 2.33[- 5.70, 1.05], P = 0.18) and the left GSM-CCA (mean difference [95% CI] - 0.29 [- 3.53, 2.95], P = 0.86) values. Similar findings were obtained even after adjusting for traditional cardiovascular risk factors and/or the administration of drugs at baseline. CONCLUSIONS: The tissue characteristics of the carotid arterial wall did not change in either the tofogliflozin or conventional treatment group during the 104-week treatment period, and there was no significant difference between the treatment groups. Clinical trial registration UMIN000017607 ( https://www.umin.ac.jp/icdr/index.html ).

Risk Factor Analysis for Type 2 Diabetes Patients About Hypoglycemia Using Continuous Glucose Monitoring: Results from a Prospective Observational Study.

Introduction: To determine the relationship between hypoglycemia and glucose variability in outpatients with type 2 diabetes mellitus (T2DM). Materials and Methods: The study participants were 999 outpatients with T2DM who used the FreeStyle Libre Pro for continuous glucose monitoring (FLP-CGM). Hypoglycemia was defined as glucose level of <3.0 mM, and the frequency of episodes and duration of hypoglycemia were evaluated by comparing patients who did or did not achieve time-below-range <3.0 mM (TBR<3.0) of <1% of the time. The association of TBR<3.0 and long% coefficient of variation (%CV) with medications used was examined using multivariate analysis with a proportional odds model. Results: The average TBR<3.0 was 0.33% (4.75 min). The TBR<3.0 >1% group comprised 71/999 patients. Patients of the TBR<3.0 >1% group had lower body mass index, longer disease duration, and poorer renal function. For the TBR<3.0 >1% group, the predicted cutoff values were 7.19 mM average glucose (AG), and 30.30% for %CV. When AG <7.19 mM and %CV >30.30% were considered as hypoglycemic risk factors, the frequency and duration of hypoglycemia increased as the risk factor values increased. In multivariate analysis, sulfonylurea (SU) use, insulin use, and low blood glucose index correlated significantly with increased length of TBR<3.0 and %CV, even after adjustment for concomitant diabetes medications. Conclusion: In T2DM, maintaining TBR<3.0 <1% requires to keep AG >7.2 mM and %CV <30%, in addition to comprehensive management of CGM metrics. Since SU and insulin use is associated with prolonged TBR<3.0 and increased %CV, their doses should be adjusted to avoid excessive fall in AG and raising %CV.

Retrospective Study on the Effects of Glucose Abnormality on COVID-19 Outcomes in Japan.

INTRODUCTION: To investigate the effects of glucose abnormality on outcomes of hospitalized coronavirus disease 2019 (COVID-19) patients in Japan. METHODS: This study retrospectively analyzed 393 COVID-19 patients admitted at Juntendo University Hospital. Patients were divided into subgroups according to history of diabetes and blood glucose (BG) levels and subsequently compared in terms of in-hospital death, invasive ventilation, or a composite of both. RESULTS: Patients with glucose abnormality demonstrated more risk factors for serious COVID-19, such as high body mass index, dyslipidemia, and hypertension, and higher biomarkers for inflammation compared to those with normal BG levels. Oxygen inhalation and steroid use were more frequent among patients with than without glucose abnormality. Invasive ventilation was more frequent in patients with diabetes (9.5% vs. 3.2%, p = 0.033) and BG ≥ 140 mg/dl (11.0% vs. 3.1%, p = 0.009) compared with those without diabetes and BG < 140 mg/dl, respectively. Logistic regression analysis showed that BG ≥ 140 mg/dl was a risk factor for invasive ventilation [odds ratio (OR) 2.87, 95% CI 1.04-7.68, p = 0.037] or the composite outcome (OR 3.03, 95% CI 1.21-7.38, p = 0.015) even after adjusting for by age and gender. Kaplan-Meier analysis showed that glucose abnormality was significantly associated with invasive ventilation and that BG ≥ 140 mg/dl was a risk factor for invasive ventilation [hazard ratio (HR) 2.68, 95% CI 1.05-6.82, p = 0.039] and the composite of death and invasive ventilation (HR 2.77, 95% CI 1.21-6.37, p = 0.016) regardless of age and gender. CONCLUSIONS: Glucose abnormality, particularly BG ≥ 140 mg/dl, was associated with serious outcomes among Japanese COVID-19 patients, suggesting the need to consider high BG as a major risk factor for poor clinical course also in Japan.

Three-Year Glycaemic Control and Management in Patients with Type 2 Diabetes Initiating Second-Line Treatment in Japan: A Prospective Observational Study, J-DISCOVER.

INTRODUCTION: J-DISCOVER is a prospective, observational cohort study that aimed to understand characteristics, glycaemic control, comorbidities and real-world management of patients with early-stage type 2 diabetes mellitus (T2DM) in Japan, by enrolling patients initiating second-line treatment from both diabetes specialist and non-specialist care settings. METHODS: As part of the global DISCOVER programme, J-DISCOVER enrolled 1798 patients with T2DM aged at least 20 years old from 142 sites across Japan, from September 2014 to December 2015, and followed these patients for 3 years. Glycaemic control, body mass index (BMI), blood pressure, lipid profiles, treatment patterns, and prevalence of CKD and retinopathy were examined from baseline to 6, 12, 24 and 36 months, stratified by class of second-line treatment. RESULTS: At baseline, the median time after T2DM diagnosis was 3.1 years and mean glycated haemoglobin (HbA1c) was 7.7%. The mean individualized HbA1c target was 6.7 ± 0.5%, and 55.3% of patients were set the target of < 7.0%. HbA1c reductions were noted from 6 months and mean HbA1c was 7.1% at 36 months. The proportion of patients with HbA1c < 7.0% increased from 28.8% at baseline to 53.3% at 36 months, and the achievement rate of individualized HbA1c targets increased from 6.1% to 30.3%. Only two cases of severe hypoglycaemia occurred during the study. No major changes in BMI, blood pressure, lipid profile or prescription of antihypertensive or dyslipidaemia medications were observed. The frequencies of screening to detect retinopathy and chronic kidney disease (CKD) were 17.0-21.0% and 14.5-16.0%, respectively, during the follow-up period. The prevalence of CKD, but not retinopathy, increased over the follow-up period. CONCLUSIONS: This study provided an overview of the 3-year management of early-stage T2DM in patients initiating second-line treatment. Contemporary management improved glycaemic control with an acceptable risk-benefit balance, although hurdles remain to sufficient implementation of guideline-recommended treatments in current clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02226822.

Relationship between blood glucose variability in ambulatory glucose profile and standardized continuous glucose monitoring metrics: Subanalysis of a prospective cohort study.

AIM: To clarify the relationship between ambulatory glucose profile (AGP) indexes and standardized continuous glucose monitoring (CGM) metrics in patients with type 2 diabetes (T2D). METHODS: This is an exploratory, cross-sectional analysis of baseline data collected from a prospective, multicentre, 5-year follow-up observational study conducted and published previously by our group. The study participants were 999 outpatients with T2D who used CGM at baseline, and had no apparent history of cardiovascular disease. We investigated the relationship between average interquartile range (IQR) and time in range (TIR). We also calculated, for the first time, the cutoff values to achieve the TIR target values. RESULTS: In both the TIR more than 70% and TIR more than 90% achievement groups, the average IQR was notably small compared with the non-achievement groups. Particularly in comparison of the TIR quartiles, the average IQR became significantly smaller as the TIR became larger. The average IQR correlated negatively with TIR, and the cutoff values for TIR of more than 70% achievement and TIR of more than 90% achievement were an average IQR (>70%/>90%) of 2.13/1.85 mmol/L. CONCLUSION: Our results showed a negative correlation between TIR and the range of blood glucose variations visually represented in AGP. The results also showed that the range of blood glucose variations in AGP is associated with indices of intraday and interday blood glucose variations and also with hypoglycaemia. Our results may provide new perspectives in the assessment and application of AGP in the clinical setting.