Daily Glucose Profiles after Switching from Injectable to Oral Semaglutide in Patients with Type 2 Diabetes Mellitus.

Objective This prospective observational study explored the changes in the daily glycemic profile after switching from injectable to oral semaglutide in patients with type 2 diabetes mellitus. Methods Patients with type 2 diabetes mellitus who were treated with once-weekly 0.5 mg injectable semaglutide and wished to switch to once-daily oral semaglutide participated in this study. Oral semaglutide was initiated at 3 mg and increased to 7 mg a month later, according to the package insert. Before and two months after the switch, participants wore a sensor for continuous glucose monitoring for up to 14 days. We also evaluated the questionnaire-based treatment satisfaction and the preference between the two formulations. Patients Twenty-three patients participated. Results Mean glucose levels significantly increased by 9 mg/dL on average, from 132±20 to 141±27 mg/dL (p=0.047), which was equivalent to a change of 0.2% in the estimated hemoglobin A1c (6.5±0.5% to 6.7±0.7%). The inter-individual variability assessed with standard deviation also significantly increased (p=0.004). The change in treatment satisfaction varied considerably among patients, with no specific trend in the overall population. After trying oral semaglutide, 48% of patients responded that they preferred the oral formulation, while 35% preferred the injectable formulation, and 17% had no preference. Conclusion The mean glucose levels increased by 9 mg/dL on average after switching from once-weekly 0.5 mg injectable semaglutide to once-daily 7 mg oral semaglutide, with an increased inter-individual variability. The change in treatment satisfaction considerably varied among patients.

Association between History of Vaccination and Symptoms at Diagnosis of Coronavirus Disease 2019.

Introduction: We investigated the association between history of vaccination for coronavirus disease 2019 (COVID-19) and symptoms at its diagnosis. Methods: We retrospectively analyzed 2566 consecutive individuals suspected of having COVID-19 and visited a designated clinic between January and September 2022 (1733 were diagnosed with COVID-19, and 816 tested negative for COVID-19) in Japan. The individuals were divided by vaccination history for COVID-19. Results: In the COVID-19-free individuals, the vaccination was not significantly associated with any symptoms. Contrarily, those with COVID-19 demonstrated an inverse relationship between the vaccination and body temperature; the adjusted mean value was higher by 0.01°C, 0.04°C, 0.09°C, 0.27°C, and 0.34°C and 0.48°C in individuals vaccinated 2-4, 4-6, 6-8, 8-10, and >10 months before and those unvaccinated, respectively, than in those vaccinated within 2 months (P = 0.96, 0.41, 0.081, 0.006, 0.004, and <0.001). Furthermore, among the affected population, individuals vaccinated long before or never vaccinated more frequently complained of fatigue and headache; the adjusted odds ratios of those vaccinated >10 months before and those unvaccinated compared with those vaccinated within 2 months were 2.53 and 2.45 for fatigue and 2.53 and 2.17 for headache (all P < 0.05). Contrarily, the prevalence of rhinorrhea, sore throat, and cough was higher in recently vaccinated individuals (adjusted odds ratios of those vaccinated within 2 months versus those unvaccinated, 2.40, 2.46, and 2.46; all P < 0.05). Conclusions: Symptoms at the COVID-19 diagnosis differed with the vaccination history. Information on vaccination history would be worth using when suspecting COVID-19 based on symptoms.

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.

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.

Nighttime home blood pressure lowering effect of esaxerenone in patients with uncontrolled nocturnal hypertension: the EARLY-NH study.

There is limited evidence on the blood pressure (BP)-lowering effect of esaxerenone on home BP, including nighttime BP. Using two newly developed nocturnal home BP monitoring devices (brachial and wrist), this multicenter, open-label, prospective study investigated the nighttime home BP-lowering effect of esaxerenone in patients with uncontrolled nocturnal hypertension being treated with an angiotensin receptor blocker (ARB) or calcium-channel blocker (CCB). In total, 101 patients were enrolled. During the 12-week study period, change in nighttime home systolic/diastolic BP from baseline to end of treatment measured by the brachial device was -12.9/-5.4 mmHg in the total population and -16.2/-6.6 and -10.0/-4.4 mmHg in the ARB and CCB subcohorts, respectively (all p < 0.001). For the wrist device, the change was -11.7/-5.4 mmHg in the total population and -14.6/-6.2 and -8.3/-4.5 mmHg in each subcohort, respectively (all p < 0.001). Similar significant reductions were shown for morning and bedtime home BP and office BP. Urinary albumin-to-creatinine ratio, N-terminal pro-brain natriuretic peptide, and cardio-ankle vascular index improved in the total population and each subcohort. Incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 38.6% and 16.8%, respectively; most were mild or moderate. The most frequent drug-related TEAEs were associated with serum potassium elevation (hyperkalemia, 9.9%; blood potassium increased, 3.0%); however, no new safety concerns were raised. Esaxerenone was effective in lowering nighttime home BP as well as morning and bedtime home BP and office BP, safe, and showed organ-protective effects in patients with uncontrolled nocturnal hypertension. Caution is warranted regarding elevated serum potassium levels. This study investigated the effect of esaxerenone on nighttime home BP and organ damage (UACR and NT-proBNP) in patients with uncontrolled nocturnal hypertension despite treatment with an ARB or CCB. Our results show that safe 24-h BP control and organ protection are possible with esaxerenone.

DAPagliflozin for the attenuation of albuminuria in Patients with hEaRt failure and type 2 diabetes (DAPPER study): a multicentre, randomised, open-label, parallel-group, standard treatment-controlled trial.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the urinary albumin-to-creatinine ratio (UACR) in patients with elevated levels of albuminuria in the presence or absence of heart failure (HF) or type 2 diabetes mellitus (T2D). However, these effects have not yet been reported in the presence of both HF and T2D. This lack of evidence prompted us to conduct a clinical trial on the effects of dapagliflozin on UACR in patients with HF and T2D. Methods: DAPPER is a multicentre, randomised, open-labeled, parallel-group, standard treatment-controlled trial that enrolled patients at 18 medical facilities in Japan. Eligible participants with both HF and T2D and aged between 20 and 85 years were randomly assigned to a dapagliflozin or control (anti-diabetic drugs other than SGLT 2 inhibitors) group with a 1:1 allocation. The primary outcome was changes in UACR from baseline after a two-year observation, and secondary endpoints were cardiovascular (CV) events and parameters related to HF. This trial was registered with the UMIN-CTR registry, UMIN000025102 and the Japan Registry of Clinical Trials, jRCTs051180135. Findings: Between 12 May 2017 and 31 March 2020, 294 patients were randomly assigned to the dapagliflozin group (n = 146) or control group (n = 148). The mean age of patients was 72.1 years and 29% were female. The mean glycated hemoglobin value was 6.9%, mean NT-proBNP was 429.1 pg/mL, mean estimated GFR was 65.7 mL/min/1.73 m2, and median UACR was 25.0 (8.8-74.6) mg/g Cr in the dapagliflozin group and 25.6 (8.2-95.0) mg/g Cr in the control group. Of the 146 patients in the dapagliflozin group, 122 completed the study, and 107 (87.7%) were taking 5 mg of dapagliflozin daily at the end of the observation period. The primary outcome did not significantly differ between the dapagliflozin and control groups. Among the secondary endpoints, the mean decrease in left ventricular end-diastolic dimensions as one of the echocardiographic parameters was larger in the dapagliflozin group than in the control group. The composite endpoint, defined as CV death or hospitalisation for CV events, hospitalisation for HF events, hospitalisation for all causes, and an additional change in prescriptions for heart failure in a two-year observation, was less frequent in the dapagliflozin group than in the control group. Interpretation: Although dapagliflozin at a dose of 5 mg daily did not reduce urinary albumin excretion in patients with HF and T2D from that in the controls, our findings suggest that dapagliflozin decreased CV events and suppressed left ventricular remodeling. Funding: AstraZeneca KK, Ono Pharmaceutical Co., Ltd.

Improvement of beta-cell function in conjunction with glycemic control after medical nutrition therapy in newly-diagnosed type 2 diabetes mellitus.

BACKGROUND: The current study aimed to reveal the correlation of beta-cell function and insulin sensitivity with glycemic control and weight control before and after medical nutrition therapy (MNT) in patients with newly-diagnosed type 2 diabetes mellitus. METHODS: We retrospectively analyzed consecutive 68 patients with newly-diagnosed type 2 diabetes mellitus who started MNT without antihyperglycemic medications and underwent a 75-g oral glucose tolerance test (OGTT) before and after the therapy. Beta-cell function was evaluated by the OGTT-derived disposition index, whereas insulin sensitivity was evaluated by Matsuda's insulin sensitivity index. RESULTS: After 4.0 ± 1.5 months of MNT, mean HbA1c and body mass index significantly decreased from 9.6 ± 1.8% to 7.2 ± 1.0% and from 26.9 ± 4.1 to 25.4 ± 3.7 kg/m2 (both P < 0.001), while the median disposition index and Matsuda's index significantly increased from 0.34 (0.20-0.68) to 0.88 (0.53-1.52) (P < 0.001) and from 4.70 (2.95-5.93) to 5.17 (3.48-6.89) (P = 0.003), respectively. The disposition index was significantly correlated with HbA1c levels both before and after MNT (r = -0.61 and -0.68; both P < 0.001). The magnitude of the correlation after MNT was not different from that before MNT (P = 0.42). Matsuda's index was correlated not with HbA1c levels but with body mass index, both before (r = 0.07 [P = 0.57] and r = -0.58 [P < 0.001]) and after MNT (r = -0.01 [P = 0.95] and r = -0.52 [P < 0.001]). CONCLUSIONS: Beta-cell function was improved in conjunction with glycemic control after MNT in patients with newly-diagnosed type 2 diabetes mellitus. Insulin sensitivity was linked with weight control rather than glycemic control.

Screening for a Decreased Masticatory Function by a Color-changeable Chewing Gum Test in Patients with Metabolic Disease.

Objective This study aimed to reveal the screening performance of a color-changeable chewing gum test for a decreased masticatory function in the assessment of oral hypofunction in patients with metabolic diseases. Methods We analyzed 1,000 patients with metabolic diseases, including diabetes, dyslipidemia, hypertension, and hyperuricemia. A decreased masticatory function was diagnosed by a gummy jelly test. Patients were asked to chew a test gum, which changed from green to red by thorough mastication, 60 times for 1 minute. The color change was visually evaluated using the color scale, from 1 (green-dominant) to 10 points (red-dominant), and was colorimetrically quantified as delta E in the L*a*b* color space. The screening performance for a decreased masticatory function was evaluated with the receiver operating characteristic (ROC) curve. Results Seventy-seven patients (7.7%) were diagnosed with a decreased masticatory function. The mean color scale and delta E of the gum test were 6.7±1.8 points and 42.9±6.7 units, respectively. The area under the ROC curve was 0.822 (95% confidence interval, 0.768-0.872) for the color scale and 0.838 (0.781-0.890) for delta E (p=0.41). The optimal cut-off point of the color scale was 5.5 (5.0-6.5) points, whereas that of delta E was 37.7 (35.5-38.8) units. The optimal cut-off points were not significantly different between the subgroups divided by clinical characteristics. Conclusions A color-changeable chewing gum test using the color scale as well as delta E would be a useful tool for screening patients with metabolic diseases for a decreased masticatory function in the assessment of oral hypofunction.

Lifestyle changes and their impact on glycemic control and weight control in patients with diabetes during the coronavirus disease 2019 pandemic in Japan.

AIMS/INTRODUCTION: This study aimed to reveal lifestyle changes and their impact on glycemic control and weight control in patients with diabetes during the coronavirus disease 2019 (COVID-19) pandemic in Japan. MATERIALS AND METHODS: We retrospectively analyzed 1,402 outpatients with diabetes at a clinic in Osaka, Japan, who responded to an interview sheet regarding lifestyle changes during the COVID-19 pandemic between 28 March and 30 May 2020. The association of lifestyle changes with hemoglobin A1c (HbA1c) and weight changes from February to May 2020 was investigated using the linear regression model. We also investigated the association with clinically important change of HbA1c (by ≥0.3%) and bodyweight (by ≥3%), using the cumulative link model. RESULTS: Leisure time and other outside physical activities were decreased in one-quarter of patients during the COVID-19 pandemic, whereas the amount of meals and snacks was decreased and increased in approximately 10%, respectively. The change in leisure time physical activities was inversely associated with HbA1c and weight changes, whereas the quantitative change of meals with the decline in eating out and that of snacks were positively associated with HbA1c and weight changes (all P < 0.05). The quantitative change of meals without the decline in eating out was also positively associated with weight change (P = 0.012). The cumulative link model for clinically important HbA1c and weight change showed broadly similar associations, except for that between snacks and bodyweight (P = 0.15). CONCLUSIONS: A considerable number of outpatients with diabetes experienced lifestyle changes during the COVID-19 pandemic. The lifestyle changes were associated with HbA1c and weight changes.

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.

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.

Associations between continuous glucose monitoring-derived metrics and diabetic retinopathy and albuminuria in patients with type 2 diabetes.

INTRODUCTION: Preventing the development and progression of diabetic microvascular complications through optimal blood glucose control remains an important challenge. Whether metrics based on continuous glucose monitoring are useful for the management of diabetic microvascular complications is not entirely clear. RESEARCH DESIGN AND METHODS: This is an exploratory analysis of an ongoing prospective, multicenter, 5-year follow-up observational study. Study participants included 999 outpatients with type 2 diabetes who underwent continuous glucose monitoring at baseline. Associations between continuous glucose monitoring-derived metrics and the severity of diabetic retinopathy or albuminuria were investigated using multivariable proportional odds models. RESULTS: The overall prevalence of diabetic retinopathy was 22.2%. Multivariate analysis with proportional odds models demonstrated that continuous glucose monitoring-derived metrics related to intraday and interday glucose variability are significantly associated with the severity of diabetic retinopathy, even after adjusting for various possible risk factors. However, significant relationships were not observed after adjusting for hemoglobin A1c (HbA1c) levels. The prevalence of microalbuminuria and macroalbuminuria was 20.3% and 6.7%, respectively. Similarly, multivariate analysis demonstrated that those metrics are significantly associated with the severity of albuminuria. These relationships remained significant even after further adjusting for HbA1c levels. CONCLUSIONS: Continuous glucose monitoring-derived metrics related to intraday and interday glucose variability are significantly associated with the severity of diabetic retinopathy or albuminuria in patients with type 2 diabetes. Thus, evaluating these metrics might possibly be useful for risk assessment of diabetic microvascular complications.Trial registration number UMIN000032325.

Association of obesity, diabetes, and physical frailty with dental and tongue-lip motor dysfunctions in patients with metabolic disease.

OBJECTIVE: This study aimed to reveal the clinical features associated with decreased dental (or shearing/crushing) and tongue-lip motor functions in patients with metabolic diseases. METHODS: One thousand patients with metabolic diseases including diabetes, dyslipidemia, hypertension, and hyperuricemia were recruited. Dental function was assessed with a gummy jelly test, wherein glucose elution from a chewed gummy jelly was measured. Tongue-lip motor function was measured as repeatedly pronounced syllables per second. The association of clinical variables with the two functions was analyzed using multivariate linear regression models. RESULTS: The mean measurement of dental function was 202 ± 73 mg/dL, and that of tongue-lip motor function was 5.5 ± 1.0 times/s. Clinical variables independently associated with dental function (mg/dL) were age (adjusted regression coefficient ß = -9.8 per standard deviation [SD]), smoking (ß = -14.4 and -25.9 for past and current smoking, respectively), body mass index (BMI) 25-30 and ≥30 versus 20-25 kg/m2 (ß = -14.7 and -23.1, respectively), diabetes (ß = -11.9), hemoglobin A1c level ≥64 mmol/mol (ß = -14.6), gait speed (ß = 6.2 per SD), and handgrip strength (ß = 7.5 and 7.7 per SD for males and females, respectively) (all P < 0.05). Clinical variables independently associated with tongue-lip motor function (times/s) were age (ß = -0.31 per SD), BMI ≥ 30 versus 20-25 kg/m2 (ß = -0.24), diabetes (ß = -0.22), dyslipidemia (ß = 0.16), gait speed (ß = 0.12 per SD), and handgrip strength (ß = 0.18 and 0.13 per SD for males and females, respectively) (all P < 0.05). CONCLUSIONS: Obesity, diabetes, physical frailty, and old age were shared risk factors for decreased dental and tongue-lip motor functions in patients with metabolic diseases.

Long-term (52-week) efficacy and safety of dapagliflozin as an adjunct to insulin therapy in Japanese patients with type 1 diabetes: Subgroup analysis of the DEPICT-2 study.

AIM: To examine the long-term efficacy and safety of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor used to treat type 1 diabetes, in the Japanese subpopulation of the DEPICT-2 study. MATERIALS AND METHODS: Patients with type 1 diabetes were randomized to dapagliflozin 5 mg (n = 55), dapagliflozin 10 mg (n = 41) or placebo (n = 58) plus insulin for a 24-week, double-blind period followed by a 28-week, single-blind extension phase. RESULTS: From baseline to 24 weeks, dapagliflozin reduced HbA1c compared with placebo (mean change of -0.58% and -0.80% for 5 and 10 mg, respectively), and an HbA1c reduction was observed up to 52 weeks. Compared with placebo, dapagliflozin 5 and 10 mg increased the proportion of patients achieving HbA1c reductions of 0.5% or more without severe hypoglycaemia events and reduced glycaemic variability assessed via continuous glucose monitoring. Both dapagliflozin doses decreased body weight and total daily insulin dose at 24 weeks compared with placebo; these reductions were maintained up to 52 weeks. Diabetic ketoacidosis occurred in both dapagliflozin groups (one and two cases, respectively) but not with placebo. CONCLUSIONS: Efficacy and safety results from the Japanese subpopulation of the DEPICT-2 study were generally consistent with those from the overall population, indicating that long-term dapagliflozin adjunct to insulin therapy improves glycaemic control without an increased risk of hypoglycaemia but with a risk of diabetic ketoacidosis in Japanese patients with type 1 diabetes.

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 ).

Benefit of Early Add-on of Linagliptin to Insulin in Japanese Patients With Type 2 Diabetes Mellitus: Randomized-Controlled Open-Label Trial (TRUST2).

INTRODUCTION: This trial was conducted to assess the long-term safety, efficacy, and benefit of early add-on of linagliptin to insulin in patients with type 2 diabetes mellitus (T2DM). METHODS: This trial enrolled 246 subjects. The subjects were randomized to the linagliptin group or the control group and were observed for 156 weeks. After week 16, subjects in the control group were also allowed to add linagliptin to evaluate the benefit of early add-on of linagliptin to insulin. The primary end point was a change in HbA1c from baseline to week 16. Secondary end points included fasting plasma glucose, daily insulin dose, and frequency of adverse events. RESULTS: HbA1c and fasting plasma glucose levels significantly decreased from baseline to week 16 in the linagliptin group compared with the control group. The significant improvement in HbA1c continued until week 52. The daily insulin dose significantly decreased in the linagliptin group compared with the control group. The frequency of hypoglycemia and adverse events was comparable in both groups. CONCLUSIONS: Add-on of linagliptin to insulin was tolerated, improved glycemic control, and reduced the daily insulin dose. This study demonstrates the long-term safety, efficacy and benefit of early add-on of linagliptin to insulin in Japanese T2DM patients.

Investigation of the Effect of Canagliflozin on the Disposition Index, a Marker of Pancreatic Beta Cell Function, in Patients with Type 2 Diabetes.

AIM: Our aim was to investigate the effects of add-on canagliflozin with glimepiride dose adjustment or glimepiride dose adjustment on pancreatic beta cell function in patients with type 2 diabetes mellitus and inadequate glycemic control despite stable triple therapy (metformin, teneligliptin, and glimepiride) plus diet/exercise therapy. METHODS: Forty patients on stable triple therapy were randomized to glimepiride dose adjustment without (glimepiride group) or with add-on canagliflozin 100 mg (canagliflozin group) for 24 weeks. The glimepiride dose was adjusted every 4 weeks based on continuous glucose monitoring over the previous 2 weeks according to a prespecified algorithm. After the 24-week treatment period, the patients returned to the pre-intervention regimen for 1 week (wash-out period). Patients underwent 75 g OGTTs at the start of the run-in period and at the end of the wash-out period. The primary endpoint was the change in disposition index (DI). RESULTS: Thirty-nine patients completed the study (canagliflozin, n = 19; glimepiride, n = 20). The change in DI was +5.1% and -11.0% in the canagliflozin and glimepiride groups, respectively, with a between-group difference ratio of 18.0% (P = 0.330). HbA1c, fasting plasma glucose, body weight, and daily-life continuous glucose monitoring-derived parameters improved in the canagliflozin group. Hypoglycemia occurred in 60% (44 episodes) and 70% (79 episodes) of patients in the canagliflozin and glimepiride groups, respectively. The change in DI was significantly correlated with the changes in glycemic control and variability in overall cohort. CONCLUSION: Adding canagliflozin to the triple therapy improved beta cell function by 18%, but it did not reach statistical significance. This study also demonstrated a correlation between the change in DI and glycemic control. As canagliflozin improved both glucose level and variability with relatively lower risk of hypoglycemia compared with glimepiride dose adjustment, adding canagliflozin to the triple therapy may be clinically beneficial. TRIAL REGISTRATION: UMIN000030208/jRCTs051180036.

Applications of physical performance measures to routine diabetes care for frailty prevention concept: fundamental data with grip strength, gait speed, timed chair stand speed, standing balance, and knee extension strength.

INTRODUCTION: Progression of muscle strength weakening will lead to a poor physical performance and disability. While this is particularly important in patients with diabetes, the associations of reduced muscle strength measured by grip strength with clinical features and physical performance remain unclear. We investigated clinical features and physical performance measures in association with grip strength in elderly people with diabetes in a primary care setting. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted enrolling 634 male and 323 female Japanese patients with type 2 diabetes aged 60 years or older. First, grip strength was measured and the associations of gender-specific grip strength with clinical features were evaluated. Second, in patients with a grip strength below the gender-specific median, physical performance measures, including gait speed, timed chair stand speed, knee extension strength, standing balance, and short physical performance battery scores, were investigated. Patients with and without a low performance defined by Asian Working Group for Sarcopenia were compared in terms of clinical features and physical performance measures. RESULTS: Grip strength decreased according to aging and longer duration of diabetes and was independently related to body mass index, glycated hemoglobin A1c (HbA1c), serum albumin, albuminuria, neuropathy, and stroke in male patients, and to body mass index and albuminuria in female patients. The physical performance measures became worse proportionally to a decrease in the grip strength. Patients with a low performance exhibited a significantly older age, lower grip strength and serum albumin, higher albuminuria, and poorer physical performance measures than those without. CONCLUSIONS: Reduced grip strength was associated with glycemic exposure indicators of age-related duration, HbA1c, and vascular complications. The physical performance measures became worse with decreasing grip strength. Measurements of grip strength and physical performance in patients with diabetes may help promote intervention to prevent frailty in future studies.

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 ).