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.

Associations of continuous glucose monitoring-assessed glucose variability with intima-media thickness and ultrasonic tissue characteristics of the carotid arteries: a cross-sectional analysis in patients with type 2 diabetes.

BACKGROUND: The association between glucose variability and the progression of atherosclerosis is not completely understood. We aimed to evaluate the associations of glucose variability with the progression of atherosclerosis in the early stages. METHODS: We conducted a cross-sectional analysis to investigate the associations of glucose variability, assessed by continuous glucose monitoring, with intima-media thickness (IMT) and gray-scale median (GSM) of the carotid arteries, which are different indicators for the progression of atherosclerosis. We used baseline data from a hospital-based multicenter prospective observational cohort study among Japanese patients with type 2 diabetes without a history of cardiovascular diseases aged between 30 and 80 years. Continuous glucose monitoring was performed by Freestyle Libre Pro, and glucose levels obtained every 15 min for a maximum of eight days were used to calculate the metrics of glucose variability. IMT and GSM were evaluated by ultrasonography, and the former indicates thickening of intima-media complex in the carotid artery wall, while the latter indicates tissue characteristics. RESULTS: Among 600 study participants (age: 64.9 ± 9.2 (mean ± SD) years; 63.2%: men; HbA1c: 7.0 ± 0.8%), participants with a larger intra- and inter-day glucose variability had a lower GSM and most of these associations were statistically significant. No trend based on glucose variability was shown regarding IMT. Standard deviation of glucose (regression coefficient, ß = - 5.822; 95% CI - 8.875 to - 2.768, P < 0.001), glucose coefficient of variation (ß = - 0.418; - 0.685 to - 0.151, P = 0.002), mean amplitude of glycemic excursion (ß = - 1.689; - 2.567 to - 0.811, P < 0.001), mean of daily differences (ß = - 6.500; - 9.758 to - 3.241, P < 0.001), and interquartile range (ß = - 4.289; - 6.964 to - 1.614, P = 0.002) had a statistically significant association with mean-GSM after adjustment for conventional cardiovascular risk factors, including HbA1c. No metrics of glucose variability had a statistically significant association with IMT. CONCLUSIONS: Continuous glucose monitoring-assessed glucose variability was associated with the tissue characteristics of the carotid artery wall in type 2 diabetes patients without cardiovascular diseases.

Effect of tofogliflozin on arterial stiffness in patients with type 2 diabetes: prespecified sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial.

BACKGROUND: Tofogliflozin, an SGLT2 inhibitor, is associated with favorable metabolic effects, including improved glycemic control and serum lipid profile and decreased body weight, visceral adipose tissue, and blood pressure (BP). This study evaluated the effects of tofogliflozin on the brachial-ankle pulse wave velocity (baPWV) in patients with type 2 diabetes (T2DM) without a history of apparent cardiovascular disease. METHODS: The using tofogliflozin for possible better intervention against atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. As one of the prespecified secondary outcomes, changes in baPWV over 104 weeks were evaluated in 154 individuals (80 in the tofogliflozin group and 74 in the conventional treatment group) who completed baPWV measurement at baseline. RESULTS: In a mixed-effects model, the progression in the right, left, and mean baPWV over 104 weeks was significantly attenuated with tofogliflozin compared to that with conventional treatment (- 109.3 [- 184.3, - 34.3] (mean change [95% CI] cm/s, p = 0.005; - 98.3 [- 172.6, - 24.1] cm/s, p = 0.010; - 104.7 [- 177.0, - 32.4] cm/s, p = 0.005, respectively). Similar findings were obtained even after adjusting the mixed-effects models for traditional cardiovascular risk factors, including body mass index (BMI), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, systolic blood pressure (SBP), hypertension, smoking, and/or administration of drugs, including hypoglycemic agents, antihypertensive agents, statins, and anti-platelets, at baseline. The findings of the analysis of covariance (ANCOVA) models, which included the treatment group, baseline baPWV, and traditional cardiovascular risk factors, resembled those generated by the mixed-effects models. CONCLUSIONS: Tofogliflozin significantly inhibited the increased baPWV in patients with T2DM without a history of apparent cardiovascular disease, suggesting that tofogliflozin suppressed the progression of arterial stiffness. Trial Registration UMIN000017607. Registered 18 May 2015. ( https://www.umin.ac.jp/icdr/index.html ).

Tofogliflozin does not delay progression of carotid atherosclerosis in patients with type 2 diabetes: a prospective, randomized, open-label, parallel-group comparative study.

BACKGROUND: This study aimed to investigate the preventive effects of tofogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD) by monitoring carotid intima-media thickness (IMT). METHODS: This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study included 340 subjects with T2DM and no history of apparent CVD recruited at 24 clinical units. Subjects were randomly allocated to either the tofogliflozin treatment group (n = 169) or conventional treatment group using drugs other than SGLT2 inhibitors (n = 171). Primary outcomes were changes in mean and maximum common carotid IMT measured by echography during a 104-week treatment period. RESULTS: In a mixed-effects model for repeated measures, the mean IMT of the common carotid artery (mean-IMT-CCA), along with the right and left maximum IMT of the CCA (max-IMT-CCA), significantly declined in both the tofogliflozin (- 0.132 mm, SE 0.007; - 0.163 mm, SE 0.013; - 0.170 mm, SE 0.020, respectively) and the control group (- 0.140 mm, SE 0.006; - 0.190 mm, SE 0.012; - 0.190 mm, SE 0.020, respectively). Furthermore, the tofogliflozin and the conventional treatment group did not significantly differ in the progression of the mean-IMT-CCA (mean change (95% CI) 0.008 (- 0.009, 0.025) mm, P = 0.34), along with the right (mean change (95% CI) 0.027 (- 0.005, 0.059) mm, P = 0.10) and the left max-IMT-CCA (mean change (95% CI) 0.020 (- 0.030, 0.070), P = 0.43). Similar findings were obtained even after adjusting for traditional CV risk factors and/or administration of drugs at baseline. Relative to the control treatment effects, tofogliflozin significantly reduced the HbA1c, blood glucose level, body weight/body mass index, abdominal circumference, and systolic blood pressure, and significantly increased the HDL-C. The total and serious adverse events incidences did not significantly vary between the treatment groups. CONCLUSIONS/INTERPRETATION: No IMT changes were observed between the tofogliflozin and the conventional treatment groups. However, tofogliflozin is a safe and effective treatment option for managing primary CVD risk factors in this population. Clinical Trial Registration UMIN000017607 ( https://www.umin.ac.jp/icdr/index.html ).

Malnutrition defined by global leadership initiative on malnutrition criteria impedes home discharge in acute care hospital admissions.

BACKGROUND & AIMS: Limited evidence exists on the association between malnutrition diagnosis using the Global Leadership Initiative on Malnutrition (GLIM) criteria in hospitalized acute care patients and their outcomes; several aspects still require clarification. This study aimed to evaluate the relationship between malnutrition, as defined by the GLIM criteria, at the time of acute hospital admission and discharge to home. METHODS: This retrospective observational study was conducted at a hospital that provides acute care in Japan. Adult patients admitted between July 2023 and April 2024 were included in this study. The primary outcome was the number of patients discharged to home, with in-hospital mortality as the secondary outcome. To ensure the reliability of the cohort-wide results, background factors were adjusted using propensity score matching. The two groups were compared based on the presence or absence of malnutrition, as defined by the GLIM criteria at admission. Furthermore, multiple logistic regression analysis was conducted, with the outcome as the dependent variable and malnutrition, diagnosed using the GLIM criteria, as the explanatory variable, adjusting for covariates. RESULTS: A total of 1007 patients were included in the final analysis, of whom 492 (49 %) were diagnosed without malnutrition, while 515 (51 %) were diagnosed with malnutrition according to the GLIM criteria. In the multivariate logistic regression analysis after matching, malnutrition defined by the GLIM criteria emerged as an independent factor associated with discharge to home (odds ratio [OR] = 0.37, 95 % confidence interval = 0.25-0.56, P < 0.001) when adjusting for age, sex, and various comorbidities. Among the GLIM sub-criteria, reduced muscle mass, reduced food intake or assimilation, and disease burden or inflammation were independently associated with discharge to home. Notably, disease burden/inflammation exhibited the lowest OR among the GLIM sub-criteria for discharge. CONCLUSION: Malnutrition diagnosed using the GLIM criteria upon admission in patients admitted to a regional hospital providing acute care was associated with decreased rates of discharge to home and increased in-hospital mortality. Specifically, attention should be paid to the criteria for reduced muscle mass and disease burden or inflammation within the GLIM framework.

Preoperative Immunonutrition Significantly Reduced Surgical Site Infection After Urinary Diversion for Invasive Bladder Cancer: A Retrospective Cohort Study.

BACKGROUND: Radical cystectomy and ileal conduit have a high incidence of surgical site infection. In this study, we evaluated the effects of preoperative immunonutrition on its incidence following these procedures. MATERIALS AND METHODS: We retrospectively enrolled 86 patients who underwent radical cystectomy and ileal conduit at our hospital between 2014 October and 2021 July. They were sequentially divided into the Immunonutrition group (n = 43) and Control group (n = 43). Patients in the Immunonutrition group drank 4 packs of IMPACT (Nestle, Japan) per day for 5 days before surgery. IMPACT contains arginine and eicosapentaenoic acid. We compared levels of plasma arginine and eicosapentaenoic acid before and after surgery and the rate of surgical site infection between the groups. Factors related to surgical site infection were analyzed using univariate and multivariable logistic regression analysis. RESULTS: No statistically significant differences were observed in patient characteristics between the groups except for surgical operative method (P < .001) and transfusion (P = .009). Levels of plasma arginine and eicosapentaenoic acid were significantly increased the day before surgery in the immunonutrition group (P < .001). However, the levels of plasma arginine on the day after surgery did not vary significantly between the groups. The incidence of surgical site infection was significantly lower in the immunonutrition group (P = .014). Multivariate analyses showed a significant association of surgical site infection with immunonutrition (OR = 0.14, CI 0.03-0.72, P = .019) and with ASA classification (OR = 4.76, CI 1.23-18.40, P = .024). CONCLUSIONS: Preoperative immunonutrition significantly reduced the incidence of surgical site infection following radical cystectomy and ileal conduit.

Effect of protein underdosing on the prognosis of patients with severe acute heart failure in the early acute phase: A single-institutional retrospective cohort study.

BACKGROUND: The appropriate protein dose during the early acute phase of severe acute heart failure (AHF) remains unknown. We hypothesized that protein underdosing during this period may lead to a poor prognosis. Thus, we investigated the relationship between protein sufficiency rate and prognosis during the early acute phase in patients with severe AHF. METHODS: This retrospective observational study investigated patients with AHF requiring invasive mechanical ventilation who were admitted in the intensive care and cardiac care units between January 2015 and August 2021. These patients were ranked according to the tertile of protein sufficiency rate on intubation day 2. Univariate and multivariate logistic regression analyses were performed to determine whether a low protein sufficiency rate on intubation day 2 was an independent factor for in-hospital mortality. Patients were weighted using the inverse probability of treatment weighting (IPTW) method to determine the differences in baseline characteristics. RESULTS: A total of 118 patients were included in the study and divided into low-protein (n = 40) and non-low-protein (n = 78) groups with protein sufficiency rates of ≤10% and >10%, respectively.In the multivariate analysis of in-hospital mortality, low protein sufficiency on day 2 was identified as an independent factor (odds ratio [OR] = 2.77, 95% confidence interval [CI] = 1.05-7.27, P = 0.039). After adjusting for baseline characteristics using the IPTW method, multiple logistic regression analysis of in-hospital mortality revealed low protein sufficiency on day 2 as an independent factor (OR = 3.32, 95% CI = 1.18-9.32, P = 0.023). CONCLUSION: Protein underdosing in the early acute phase of severe AHF may be associated with increased in-hospital mortality.

Association of protein intake during hospitalization with readmission in older adult patients with heart failure at risk of malnutrition.

BACKGROUND: The influence of protein intake during hospitalization on postdischarge readmission in patients with heart failure (HF) is still unclear. This study aimed to investigate the relationship between protein intake and readmission in older adult patients with HF at risk of malnutrition. METHODS: This retrospective observational study was conducted at a single acute care hospital. Patients were diagnosed with HF between April 2017 and March 2019, aged ≥65 years, and had a body mass index <35 and Geriatric Nutritional Risk Index <92 were included in the analysis. The primary outcome was HF-related readmission within 1 year after discharge. The Cox proportional hazards model was used to determine whether protein intake was an independent predictor of readmission within 1 year. RESULTS: Ultimately, 165 patients were included in the analysis: 105 patients did not require readmission, and 60 required readmission because of HF-related events. Multivariate analysis showed that protein intake <1.2 g/kg/day was an independent contributor to readmission in either model (model 1: hazard ratio [HR] = 2.07 [95% CI, 1.07-4.01], P = 0.030; model 2: HR = 2.24 [95% CI, 1.15-4.37], P = 0.018; model 3: HR = 2.70 [95% CI, 1.23-5.94], P = 0.013; and model 4: HR = 2.88 [95% CI, 1.28-6.51], P = 0.011). CONCLUSION: Low protein intake during hospitalization in older adult patients with HF at risk of malnutrition may increase the rate of readmission within 1 year after discharge. Nutrition intervention should be provided to these patients early during their hospitalization to ensure sufficient protein intake to maintain and improve their nutrition status and activity level.

A low serum IGF-1 is correlated with sarcopenia in subjects with type 1 diabetes mellitus: Findings from a post-hoc analysis of the iDIAMOND study.

AIM: Our previous study revealed that sarcopenia was frequently observed in subjects with type 1 diabetes mellitus (T1DM). However, the factors associated with sarcopenia that are related to T1DM have not yet been clarified. Insulin-like growth factor-1 (IGF-1) has been shown to play a role in skeletal muscle growth, differentiation, and regeneration. The present study, therefore, investigated the association between the serum IGF-1 level and sarcopenia and low skeletal muscle mass in subjects with T1DM. METHODS: This cross-sectional study enrolled subjects with T1DM (n = 168) and without diabetes (n = 59) who had had their clinical data on serum IGF-1 collected in the iDIAMOND study. RESULTS: The z-score of serum IGF-1 was significantly lower in the subjects with T1DM than that in those without diabetes (p < 0.001). Among subjects with T1DM, the z-score of serum IGF-1 was significantly lower in sarcopenic subjects than in non-sarcopenic subjects. The multivariable logistic regression analysis showed that the serum IGF-1 z-score was an independent determinant of sarcopenia and a low skeletal muscle mass index, but not low grip strength nor slow gait speed in subjects with T1DM. CONCLUSIONS: A low serum IGF-1 level is correlated with sarcopenia and low skeletal muscle mass in subjects with T1DM.

High prevalence and clinical impact of dynapenia and sarcopenia in Japanese patients with type 1 and type 2 diabetes: Findings from the Impact of Diabetes Mellitus on Dynapenia study.

AIMS/INTRODUCTION: The present study aimed to clarify the prevalence and clinical characteristics of sarcopenia and dynapenia, which are muscle weakness with and without low muscle mass, respectively, in Japanese patients with type 1 diabetes mellitus and type 2 diabetes mellitus. MATERIALS AND METHODS: This cross-sectional study enrolled 1,328 participants with type 1 diabetes (n = 177), type 2 diabetes (n = 645) and without diabetes (n = 506). Sarcopenia was defined as a low grip strength and slow gait speed with low skeletal muscle mass index, whereas dynapenia was defined as low strengths of grip and knee extension with a normal skeletal muscle mass index. Participants without sarcopenia and dynapenia were defined as robust. RESULTS: Among participants aged ≥65 years, sarcopenia and dynapenia were observed in 12.2% and 0.5% of individuals without diabetes, 42.9% and 11.4% of type 1 diabetes patients, and 20.9% and 13.9% of type 2 diabetes patients. In both type 1 diabetes and type 2 diabetes patients, sarcopenic patients were significantly older and thinner, and showed a significantly higher rate of diabetic neuropathy than robust patients. In patients with type 1 diabetes and type 2 diabetes, dynapenic patients were older, and showed a higher rate of diabetic neuropathy and lower estimated glomerular filtration rate than robust patients. Patients complicated with sarcopenia and dynapenia showed a significantly lower physical quality of life and higher rate of incidental falls than robust patients. CONCLUSIONS: Sarcopenia and dynapenia were more frequent in patients with type 1 diabetes and type 2 diabetes than in individuals without diabetes, which might contribute to their impaired quality of life and incidental falls.

The Influence of Tofogliflozin on Treatment-Related Quality of Life in Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: Treatment-related quality of life (QOL) is an important aspect of diabetes management. We evaluated the influence of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, tofogliflozin, on treatment-related QOL in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: This is the prespecified subanalysis study of the "Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)" trial. Treatment-related QOL was evaluated at baseline, week 26, week 52, and week 104 after the initiation of the study using the Diabetes Therapy-Related QOL questionnaire (DTR-QOL). Among the 340 patients in the original UTOPIA study, a total of 252 patients (127, tofogliflozin group; 125, conventional treatment group) who completed the DTR-QOL questionnaire at baseline were the study subjects of the current subanalysis. RESULTS: The tofogliflozin and conventional treatment groups exhibited almost comparable baseline clinical characteristics, while the use of antihypertensive drugs and lipid-lowering agents was significantly lower in the tofogliflozin treatment group than in the conventional treatment group. Tofogliflozin treatment increased the total score of DTR-QOL7 from baseline (P < 0.001), while conventional treatment did not change it. There were statistically significant differences in delta change in the total DTR-QOL7 score and DTR-QOL7 Q4, Q5, Q6, and Q7 scores from the baseline to week 104 between the treatment groups. Delta changes in HbA1c (Spearman's correlation coefficient, ρ = - 0.30, P < 0.001), fasting blood glucose (ρ = - 0.16, P = 0.031), BMI (ρ = - 0.19, P = 0.008), and waist circumference (ρ = - 0.17, P = 0.024) at week 104 were negatively associated with delta change in the total QOL7 score. CONCLUSIONS: Our data indicated that tofogliflozin treatment improved treatment-related QOL compared to conventional treatment in Japanese patients with T2DM, in accordance with the improvement of major cardiovascular risk factors. TRIAL REGISTRATION: UMIN000017607.