Time-series transcriptome analysis of peripheral blood mononuclear cells obtained from individuals who received the SARS-CoV-2 mRNA vaccine.

Messenger ribonucleic acid (mRNA) vaccination against coronavirus disease 2019 (COVID-19) is an effective prevention strategy, despite a limited understanding of the molecular mechanisms underlying the host immune system and individual heterogeneity of the variable effects of mRNA vaccination. We assessed the time-series changes in the comprehensive gene expression profiles of 200 vaccinated healthcare workers by performing bulk transcriptome and bioinformatics analyses, including dimensionality reduction utilizing the uniform manifold approximation and projection (UMAP) technique. For these analyses, blood samples, including peripheral blood mononuclear cells (PBMCs), were collected from 214 vaccine recipients before vaccination (T1) and on Days 22 (T2, after second dose), 90, 180 (T3, before a booster dose), and 360 (T4, after a booster dose) after receiving the first dose of BNT162b2 vaccine (UMIN000043851). UMAP successfully visualized the main cluster of gene expression at each time point in PBMC samples (T1-T4). Through differentially expressed gene (DEG) analysis, we identified genes that showed fluctuating expression levels and gradual increases in expression levels from T1 to T4, as well as genes with increased expression levels at T4 alone. We also succeeded in dividing these cases into five types based on the changes in gene expression levels. High-throughput and temporal bulk RNA-based transcriptome analysis is a useful approach for inclusive, diverse, and cost-effective large-scale clinical studies.

A survey of clinical physician's perceptions of stigma and advocacy in patients with type 2 diabetes in Kanagawa, Japan.

AIMS/INTRODUCTION: To investigate the recognition status of stigma/advocacy in patients with type 2 diabetes in clinical practice settings. METHOD: A questionnaire survey on stigma/advocacy of patients with diabetes was carried out for members of the Kanagawa Physicians Association in July 2021. RESULTS: The respondents consisted of 33 (16.6%) physicians specializing in diabetes (the D group) and 166 (83.4%) non-specialists (the ND group). 100% of the D group and 48.8% of the ND group knew that patients may be prejudiced or discriminated against because of diabetes. In the question of whether they know the terms 'stigma' and 'advocacy', 'know' was 97.0% and 94.0% in the D group, compared with 45.8% and 36.7% in the ND group, respectively. 97.0% of the D group and 19.9% of the ND group know the advocacy activities of the Japanese Diabetes Society (JDS) and the Japan Association for Diabetes Education (JADEC). The specific contents of the stigma were often unknown or never experienced in the ND group. A free description of the strategy for reducing or eliminating stigma was analyzed by text mining. 'Giving consideration to the patients' feelings', 'Commitment to the problem', and 'Dialogue' were frequent, and there was no significant difference between the two groups. CONCLUSIONS: The clinician's understanding of stigma/advocacy associated with having diabetes was insufficient, and activities that alert clinicians to stigma/advocacy, especially those in the ND group, was a theme to be addressed. More awareness-raising activities for stigma/advocacy will lead to better treatment and a better quality of life for patients with diabetes.

The Proportion of Long-term Response to Anti-N IgG Antibody after 12 Months for COVID-19 Subclinical Infections and a Longitudinal Survey for COVID-19 Subclinical Infections in 2021.

Objective To examine the continuation of antibody prevalence status after 12 months and background factors in antibody-positive subjects following asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods We initially determined the SARS-CoV-2 anti-nucleocapsid protein immunoglobulin G (anti-N IgG) antibody prevalence in 1,603 patients, doctors, and nurses at 65 medical institutions in Kanagawa Prefecture, Japan. We then obtained consent from 33 of the 39 subjects who tested positive and performed follow-up for 12 months. Results Follow-up for up to 12 months showed that a long-term response of the anti-N IgG antibody could be detected in 6 of the 33 participants (18.2%). The proportions with hypertension, using an angiotensin-receptor blocker, and without a drinking habit were higher among the participants with a long-term anti-N IgG antibody response for up to 12 months than among those without a long-term antibody response. Conclusions The proportion of individuals with subclinical COVID-19 who continuously had a positive result for the anti-N IgG antibody at 12 months was low.

Heterogeneity assessment of vaccine-induced effects using point-of-care surrogate neutralization test for severe acute respiratory syndrome coronavirus 2.

INTRODUCTION: Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic even after vaccination. We aimed to identify immunological heterogeneity over time in vaccinated healthcare workers using neutralization antibodies and neutralizing activity tests. METHODS: Serum samples were collected from 214 healthcare workers before vaccination (pre) and on days 22, 90, and 180 after receiving the first dose of BNT162b2 vaccine (day 0). Neutralization antibody (NAb, SARS-CoV-2 S-RBD IgM/IgG) titers and two kinds of surrogate virus neutralization tests (sVNTs) were analyzed (UMIN000043851). RESULTS: The NAb (SARS-CoV-2 S-RBD IgG) titer peaked on day 90 after vaccination (30,808.0 µg/ml ± 35,211; p < 0.0001) and declined on day 180 (11,678.0 µg/ml ± 33,770.0; p < 0.0001). The neutralizing activity also peaked on day 90 and declined with larger individual differences than those of IgG titer on day 180 (88.9% ± 15.0%, 64.8% ± 23.7%, p < 0.0001). We also found that the results of POCT-sVNT (immunochromatography) were highly correlated with those of conventional sVNT (ELISA). CONCLUSIONS: Neutralizing activity is the gold standard for vaccine efficacy evaluation. Our results using conventional sVNT showed large individual differences in neutralizing activity reduction on day 180 (64.8% ± 23.7%), suggesting an association with the difference in vaccine efficacy. POCT-sVNT is rapid and user-friendly; it might be used for triage in homes, isolation facilities, and event venues without restrictions on the medical testing environment.

Multinational Observational Study to Understand Insulin Treatment Intensification: Japanese Subgroup Analysis of the MOSAIc Study.

INTRODUCTION: MOSAIc was a multinational, non-interventional, prospective, observational cohort study designed to provide an understanding of the specific challenges associated with intensification of initial insulin therapy in patients with type 2 diabetes mellitus (T2DM). We present a sub-analysis of Japanese patients from MOSAIc, with data analyzed longitudinally over 2 years, to provide insight on how T2DM treatment is intensified. METHODS: Japanese patients with T2DM receiving any insulin therapy for at least 3 months were eligible for study inclusion. Baseline and clinical data were collected during an initial baseline visit and during four subsequent prospective visit windows (within ± 3 months) at 6, 12, 18, and 24 months. Treatment intensification was defined as addition of new insulin, increase in insulin dosage (1-unit change or 10% compared with the previous visit), increase in insulin injection frequency, and/or addition of non-insulin antihyperglycemic agents. RESULTS: Of 116 Japanese patients who completed the study, 50.0% (n = 58) received treatment intensification. Baseline characteristics of patients with treatment intensification included a longer duration of diabetes, higher incidence of baseline microvascular complications, and higher HbA1c compared to those without intensification. There was no significant difference in HbA1c change from baseline between the two groups at any post-baseline visit. Insulin intensification accounted for 61.2% of treatment changes, with non-insulin-related intensification accounting for 36.2% of treatment changes. An increase in insulin dose was the most frequent treatment change (51.7%), followed by the addition of new insulin (22.4%), and an increase in insulin injection frequency (6.9%). CONCLUSION: Real-world data from Japanese patients with T2DM who received treatment intensification showed that an increase in insulin dose and the addition of new insulin were the most frequent treatment intensification methods. HbA1c was maintained through 2 years of treatment. TRIAL REGISTRATION: NCT01400971, ClinicalTrials.gov.

Persistence of Robust Humoral Immune Response in Coronavirus Disease 2019 Convalescent Individuals Over 12 Months After Infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicits varying degrees of protective immunity conferred by neutralizing antibodies (nAbs). In this study, we report the persistence of nAb responses over 12 months after infection despite their decreasing trend noticed from 6 months. METHODS: The study included sera from 497 individuals who had been infected with SARS-CoV-2 between January and August 2020. Samples were collected at 6 and 12 months after onset. The titers of immunoglobulin (Ig)G to the viral nucleocapsid protein (NP) and receptor-binding domain (RBD) of the spike protein were measured by chemiluminescence enzyme immunoassay. The nAb titer was determined using lentivirus-based pseudovirus or authentic virus. RESULTS: Antibody titers of NP-IgG, RBD-IgG, and nAbs were higher in severe and moderate cases than in mild cases at 12 months after onset. Although the nAb levels were likely to confer adequate protection against wild-type viral infection, the neutralization activity to recently circulating variants in some of the mild cases (~30%) was undermined, implying the susceptibility to reinfection with the variants of concerns (VOCs). CONCLUSIONS: Coronavirus disease 2019 convalescent individuals have robust humoral immunity even at 12 months after infection albeit that the medical history and background of patients could affect the function and dynamics of antibody response to the VOCs.

Study on Continuation of Antibody Prevalence Six Months after Detection of Subclinical Severe Acute Respiratory Syndrome Coronavirus 2 Infections.

Objective To examine the continuation of antibody prevalence and background factors in antibody-positive subjects after asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods A study was carried out to investigate the SARS-CoV-2 antibody (IgG) prevalence. SARS-CoV-2 antibodies (IgG) were measured and analyzed with immunochromatographic tests. Patients Among 1,603 subjects, comprising patients, physicians, and nurses at 65 medical institutes in Kanagawa, Japan, 39 antibody-positive subjects received follow-up for 6 months. Results Of the 33 subjects who consented to the follow-up (23 patients and 10 medical professionals), continued positivity of IgG antibodies was confirmed in 11 of 32 cases (34.4%) after 2 months, 8 of 33 (24.2%) after 4 months, and 8 of 33 (24.2%) after 6 months. A significant difference was found in the sleeping time, drinking habits, hypertension, and use of angiotensin-receptor blockers on comparing subject background characteristics among three groups: patients with antibody production that continued for six months after the first detection of positivity, patients in whom antibody production stopped at four months, and patients in whom antibody production stopped at two months. Conclusion The continuation rate of IgG antibody prevalence was 24.2% at 6 months after the first detection of antibody positivity in cases with asymptomatic coronavirus disease 2019 (COVID-19) infections. This percentage is low compared with the antibody continuation rate in patients who have recovered from symptomatic COVID-19 infection.

Effects of 1-year treatment with canagliflozin on body composition and total body water in patients with type 2 diabetes.

AIM: To characterize the long-term changes in body composition associated with sodium-glucose cotransporter-2 (SGLT2) inhibitors. MATERIALS AND METHODS: In this multicentre, single-arm, open-label study, 107 patients with type 2 diabetes were treated with canagliflozin 100 mg, as add-on therapy, for 12 months. Body composition was measured with a body composition analyser (T-SCAN PLUS) using the impedance method to prospectively analyse changes in body components, including percentage of body fat, body fat mass, total body water, muscle mass and mineral mass. Estimated plasma volume (PV) was calculated using the Kaplan formula. RESULTS: Body weight showed a significant decrease from 1 month to 12 months of treatment with canagliflozin, with a higher rate of decrease in body fat in body composition. A significant decrease in mineral mass was also observed, but its rate was low. Following treatment with canagliflozin, changes in total body water did not affect intracellular water, and a significant decrease in extracellular water, including plasma components, was observed early and was sustained up to 12 months. Protein mass, a component of muscle mass, was not affected, with only a slight decrease in water volume observed. CONCLUSIONS: Canagliflozin decreased extracellular fluid and PV in addition to decreasing fat in the body via calorie loss resulting from urinary glucose excretion. This study suggested that SGLT2 inhibitors might reduce body weight by regulating fat mass or water distribution in the body and might have cardiac and renal protective effects by resetting the homeostasis of fluid balance.

Sustained Neutralizing Antibodies 6 Months Following Infection in 376 Japanese COVID-19 Survivors.

Objective: There is scarce evidence regarding the long-term persistence of neutralizing antibodies among coronavirus disease 2019 (COVID-19) survivors. This study determined neutralizing antibody titers (NT50) and antibodies against spike protein (SP) or nucleocapsid protein (NP) antigens approximately 6 months after the diagnosis of COVID-19. Methods: COVID-19 survivors in Japan were recruited. Serum samples and data related to patients' characteristics and COVID-19 history were collected. NT50 and titers of antibodies against NP and SP antigens were measured at 20-32 weeks after the first positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results. Factors associated with NT50 were identified using the multivariable linear regression and the correlations among NT50 and titers of immunoglobulin G (IgG) and total immunoglobulins (Igs) against NP and SP were assessed by Spearman's correlation. Results: Among 376 participants (median [range] days after testing positive for SARS-CoV-2, 180 (147-224); median [range] years of age, 50 (20-78); 188 [50%] male), most tested positive for NT50 (n = 367, 98%), SP-IgG (n = 344, 91%), SP-total Ig (n = 369, 98%), NP-IgG (n = 314, 84%), and NP-total Ig (n = 365, 97%). Regression analysis indicated that higher BMI, fever, and the requirement of mechanical ventilation or extracorporeal membrane oxygenation were significantly associated with higher NT50. Anti-SP antibodies correlated moderately with NT50 (Spearman's correlation: 0.63 for SP IgG; 0.57 for SP-total Ig), while the correlation was weak for anti-NP antibodies (0.37 for NP IgG; 0.32 for NP-total Ig). Conclusions: Most COVID-19 survivors had sustained neutralizing antibodies and tested positive for SP-total Ig and NP-total Ig approximately 6 months after infection.

Survey of the current status of subclinical coronavirus disease 2019 (COVID-19).

OBJECTIVES: We investigated relationships between subclinical COVID-19 (coronavirus disease 2019) and background factors. METHODS: We determined SARS-CoV-2 antibody (IgG) prevalence in 1603 patients, doctors, and nurses in 65 medical institutions in Kanagawa Prefecture, Japan and investigated their background factors. Antibodies (IgG) against SARS-CoV-2 were analyzed by Immunochromatographic test. RESULTS: The 39 subjects (2.4%) were found to be IgG antibody-positive: 29 in the patient group (2.9%), 10 in the doctor/nurse group (2.0%), and 0 in the control group. After adjustment for age, sex, and the antibody prevalence in the control group, antibody prevalence was 2.7% in the patient group and 2.1% in the doctor/nurse group. There was no significant difference between the antibody-positive subjects and the antibody-negative subjects in any background factors investigated including overseas travel, contact with overseas travelers, presence/absence of infected individuals in the living area, use of trains 5 times a week or more, BCG vaccination, and use of ACE inhibitor and ARB. CONCLUSIONS: Antibody prevalence in the present survey at medical institution is higher than that in Tokyo and in Osaka measured by the government suggesting that subclinical infections are occurring more frequently than expected. No background factor that influenced antibody-positive status due to subclinical infection was identified.

A Study of Seasonal Variation in the Effect of Add-On Sitagliptin on Blood Glucose Control in Insulin-Treated Patients With Type 2 Diabetes.

BACKGROUND: There are several reports of seasonal variation in hemoglobin A1c (HbA1c) in patients with type 2 diabetes (T2DM), but no reports of seasonal variation in the effect of add-on drugs on blood glucose control in insulin-treated patients. METHODS: Using data collected from 630 patients in a multicenter study, we compared the amount of change in HbA1c after 1, 3, 6, 9, and 12 months of add-on administration of sitagliptin in insulin-treated patients divided into four groups based on the month when sitagliptin was started. RESULTS: A significantly larger decrease in HbA1c at 6 months from baseline was observed in the group that started add-on sitagliptin in February to April than in the other three groups. However, the amount of change in HbA1c at 12 months did not differ among the groups. CONCLUSIONS: The consideration of seasonal variation enables more accurate evaluation of a drug's short-term effect on blood glucose control.

Effects of ipragliflozin on the development and progression of kidney disease in patients with type 2 diabetes: An analysis from a multicenter prospective intervention study.

AIMS/INTRODUCTION: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. METHODS: This was an investigator-initiated multicenter prospective intervention study in which ipragliflozin (50 mg) was administered once daily, and glycemic control, estimated glomerular filtration rate (eGFR) and adverse events were evaluated until 104 weeks after starting research. RESULTS: There were 407 patients analyzed. In the eGFR ≥90 group and eGFR ≥60 to <90 group, eGFR had significantly decreased compared with baseline at all time points from 4 to 104 weeks. There were significant increases in the eGFR ≥45 to <60 groups compared with baseline at 36 weeks (2.3 ± 1.0) and 52 weeks (2.6 ± 1.2). Comparison between the eGFR <60, urine albumin-to-creatinine ratio >300 group and the eGFR <60, urine albumin-to-creatinine ratio <300 group showed a greater reduction in eGFR in the former (-5.4 ± 2.4 vs 3.3 ± 1.1) at 12 weeks and was maintained to 104 weeks. In any group, eGFR did not significantly decrease until 104 weeks compared with 4 weeks. The urine albumin-to-creatinine ratio after 52 weeks and after 104 weeks was significantly decreased compared with baseline in the eGFR ≥90 group. CONCLUSIONS: Ipragliflozin lowers eGFR and corrects hyperfiltration in patients with high eGFR (eGFR ≥60). In patients with low eGFR (eGFR ≥30 to <60), ipragliflozin has the possibility of increasing eGFR and exerting a renoprotective effect.

Canagliflozin Increases Calorie Intake in Type 2 Diabetes Without Changing the Energy Ratio of the Three Macronutrients: CANA-K Study.

Background: Sodium/glucose cotransporter-2 (SGLT2) inhibitors improve glycemic control and reduce body weight by increasing glycosuria. Although a compensatory increase of food intake has been reported, the long-term effect of SGLT2 inhibitors on food intake remains unclear. This study investigated the influence of canagliflozin on calorie and nutrient intake over 1 year. Materials and Methods: Patients with type 2 diabetes (n = 107) were enrolled and followed prospectively while receiving canagliflozin at 100 mg/day for 12 months. Intake of nutrients was investigated by using the food frequency questionnaire. Hemoglobin A1c, body weight, and satisfaction with diabetes treatment (assessed by the Diabetes Treatment Satisfaction Questionnaire: DTSQ) were also investigated. Results: The baseline total energy intake was 1723 ± 525 kcal/day and it showed a persistent increase during treatment with canagliflozin, being 132 kcal higher at 6 months (P = 0.0058) and 113 kcal higher at 12 months (P = 0.0516). Intake of all three macronutrients (carbohydrate, protein, and fat) was significantly increased after 6 months of canagliflozin treatment (P = 0.0129, P = 0.0160, and P = 0.0314, respectively), but their ratio was unchanged. The DTSQ score improved significantly and both hemoglobin A1c and body weight showed a significant decrease throughout treatment (all P < 0.0001). Conclusions: After patients with type 2 diabetes commenced canagliflozin, their calorie intake increased without changing the ratio of the three macronutrients. Despite elevation of the calorie intake, glycemic control improved and weight loss was achieved. Satisfaction with treatment of diabetes also increased.

Efficacy and Safety of Alogliptin in Elderly Patients With Type 2 Diabetes Mellitus.

BACKGROUND: In Japan, with increasing age of the population, diabetic patients often become in need of hemodialysis due to diabetic nephropathy, and thus there is a demand for development of diabetic treatments that take into account renal effects in the elderly. No previous studies of alogliptin had focused on Japanese elderly subjects; we therefore assessed the effects of alogliptin in elderly individuals using available data. METHODS: Laboratory data were compiled for 1 year at intervals of 3 months following the start of alogliptin treatment. The subjects were divided into three groups by age: < 65 years (n = 110), 65 - 74 years (n = 87), and ≥ 75 years (n = 93). Laboratory values in comparison with baseline were compared within groups at various time points, and changes from baseline were compared among the different groups. RESULTS: Hemoglobin A1c (HbA1c) levels decreased significantly from baseline values in all groups at and after month 3: the change at month 12 was -0.74±1.45% for the age group < 65, -0.47±1.02% for the age group 65 - 74, and -0.42±1.11% for the age group ≥ 75. The 12-month change in estimated glomerular filtration rate (eGFR) was -6.5 ± 12.0 for the age group < 65, -2.0 ± 8.4 for the age group 65 - 74, and -1.5 ± 10.0 for the age group ≥ 75; the reduction in the age group < 65 was significant, whereas the reduction in the age groups ≥ 65 was not. CONCLUSIONS: Alogliptin significantly lowers HbA1c levels in the elderly and can be used without posing any safety issues, including renal effects, thus contributing to safe blood glucose control in clinical practice.

Efficacy and Safety of Adding Sitagliptin in Type 2 Diabetes Patients on Insulin: Age-Stratified Comparison at One Year in the ASSIST-K Study.

BACKGROUND: Sitagliptin, the first dipeptidyl peptidase-4 inhibitor, has demonstrated efficacy and safety as monotherapy and as add-on therapy to oral antidiabetic agents or insulin. However, there have been few reports about sitagliptin in elderly patients. The ASSIST-K observational study was performed in patients with type 2 diabetes mellitus (T2DM) receiving sitagliptin as add-on therapy to insulin. Changes of hemoglobin A1c (HbA1c), body weight, and the estimated glomerular filtration rate (eGFR), as well as adverse events, were investigated over 12 months in age-stratified groups. METHODS: Among outpatients with T2DM treated at member institutions of Kanagawa Physicians Association, those starting sitagliptin as add-on therapy to insulin were followed for 12 months. HbA1c (National Glycohemoglobin Standardization Program), body weight, and eGFR were the efficacy endpoints, while adverse events were investigated to assess safety. Patients were stratified into three age groups (≤ 64 years, 65 - 74 years, and ≥ 75 years) for comparison of the endpoints. RESULTS: Among 937 patients on insulin before starting sitagliptin, 821 patients were analyzed after excluding those without HbA1c data at baseline and 12 months. The two groups of elderly patients (65 - 74 years and ≥75 years) had more complications and their HbA1c was lower at initiation of sitagliptin therapy. The dose of sitagliptin, daily number of insulin injections, and number of concomitant oral antidiabetic agents were all lower in the elderly patients. HbA1c showed a significant decrease after initiation of sitagliptin in all age groups, and there were no significant intergroup differences in the change of HbA1c at 12 months. Body weight did not change significantly in any group. eGFR decreased significantly in all groups, with no significant intergroup differences at 12 months. Regarding adverse events, there were no significant intergroup differences in the incidence of severe hypoglycemia, gastrointestinal symptoms, or constipation. CONCLUSIONS: Despite baseline differences in demographic factors and medications, sitagliptin showed good efficacy and safety in all age groups of patients receiving it as add-on therapy to insulin during routine management of T2DM. Adding sitagliptin to insulin achieves similar efficacy and safety outcomes at 12 months in both elderly and non-elderly T2DM patients.

Effects of a novel selective peroxisome proliferator-activated receptor-α modulator, pemafibrate, on hepatic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance.

AIMS/INTRODUCTION: Pemafibrate is a novel selective peroxisome proliferator-activated receptor-α modulator with potent triglyceride-lowering and high-density lipoprotein cholesterol-raising effects. We showed that pemafibrate decreased the homeostatic model assessment for insulin resistance in patients with dyslipidemia. To investigate how pemafibrate improves insulin sensitivity, we used a hyperinsulinemic-euglycemic clamp technique to determine the splanchnic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance. MATERIALS AND METHODS: A total of 27 patients with hypertriglyceridemia and insulin resistance were randomly assigned to receive pemafibrate (0.4 mg/day, b.i.d.) or placebo treatment for 12 weeks. The hyperinsulinemic-euglycemic clamp test combined with oral glucose loading was carried out at weeks 0 and 12 to evaluate the splanchnic and peripheral glucose uptake. RESULTS: Pemafibrate, but not the placebo, significantly increased the splanchnic glucose uptake rate from baseline (19.6 ± 5.9% with P = 0.005 and 2.1 ± 7.4% with P = 0.78, respectively), although no significant difference between the groups was observed (P = 0.084). Conversely, peripheral glucose uptake rate was not significantly altered. Pemafibrate, compared with the placebo, significantly decreased plasma triglycerides (-61.4 ± 16.4% vs -2.5 ± 41.4%, P = 0.001), free fatty acids (-24.8 ± 23.2% vs 2.0 ± 26.8%, P = 0.016) and gamma-glutamyl transpeptidase (-30 ± 46 vs 10 ± 19 U/L, P = 0.009) levels, and significantly increased fibroblast growth factor 21 (457.7 ± 402.1 vs -41.7 ± 37.4 pg/mL, P = 0.007) levels. CONCLUSIONS: Pemafibrate increased splanchnic glucose uptake from baseline in patients with hypertriglyceridemia.

Tofogliflozin decreases body fat mass and improves peripheral insulin resistance.

The impact of tofogliflozin, a sodium-glucose co-transporter-2 inhibitor, on peripheral glucose uptake in patients with type 2 diabetes mellitus (T2DM) was investigated using the hyperinsulinaemic-euglycaemic clamp method in a single-arm, open-label study. The following variables were compared between before and after tofogliflozin administration for 12 weeks in 16 patients with T2DM who were receiving dipeptidyl peptidase-4 inhibitor treatment: body weight (BW); blood pressure; glucose metabolism; liver function; lipid profile; and body composition. Peripheral glucose uptake (M value and M/I ratio) was examined by the hyperinsulinaemic-euglycaemic clamp method. After 12 weeks, there was a significant decrease (P < .001) in glycated haemoglobin, BW, body fat mass and lean body mass. Peripheral glucose uptake, which indicates insulin sensitivity, increased significantly (M value by 0.90 and M/I ratio by 0.49; both P < .05). The change in the M value after 12 weeks of tofogliflozin therapy was correlated with the change in body fat mass (P < .05). Tofogliflozin significantly improved insulin sensitivity and peripheral glucose uptake in patients with T2DM. These improvements were significantly correlated with reduction in body fat mass.

Effectiveness of Ipragliflozin for Reducing Hemoglobin A1c in Patients With a Shorter Type 2 Diabetes Duration: Interim Report of the ASSIGN-K Study.

BACKGROUND: Ipragliflozin is a selective sodium glucose co-transporter 2 inhibitor. The ASSIGN-K study is investigating the efficacy and safety of ipragliflozin for type 2 diabetes mellitus (T2DM) in the real-world clinical setting. METHODS: Japanese T2DM patients with inadequate glycemic control despite diet and exercise with/without pharmacotherapy were enrolled in an investigator-driven, multicenter, prospective, observational study examining the efficacy and safety of ipragliflozin treatment (50 mg/day for 52 weeks). We performed interim analysis after 24 weeks. RESULTS: In 367 patients completing 24-week ipragliflozin therapy, hemoglobin A1c (HbA1c) decreased significantly from 8.07% at baseline to 7.26% in week 24 (P < 0.001). The change in HbA1c from treatment initiation to week 24 was -0.88% in patients < 65 years old versus -0.55% in those ≥ 65 years and -0.92% in men versus -0.70% in women (all P < 0.001). When baseline HbA1c was < 7%, 7% to < 8%, and ≥ 8%, the change was -0.18%, -0.45%, and -1.48%, respectively (P = 0.5352, P < 0.001, and P < 0.001, respectively). When baseline body mass index (BMI) was < 25, 25 to < 30, and ≥ 30, the change was -1.05%, -0.65%, and -0.87%, respectively (all P < 0.001). Multiple regression analysis showed that HbA1c decreased more in patients with a higher baseline HbA1c or shorter duration of diabetes. An HbA1c < 7% was achieved in 33.3% of the patients, and their baseline HbA1c was significantly lower than that of patients failing to achieve it (P < 0.001). Adverse events (AEs) occurred in 106/451 patients (23.5%), including 29.1% of patients aged 65 or older. Common AEs were vulvovaginal candidiasis (3.1%) and genital pruritus (1.8%). Serious AEs included urinary tract infection, unstable angina, and ketosis, which occurred in patients who did not suspend medication during acute illness. CONCLUSIONS: Ipragliflozin significantly improved HbA1c in T2DM patients with inadequate glycemic control. Improvement in HbA1c was significant irrespective of age, sex, baseline HbA1c, or BMI, but efficacy was greater with a higher baseline HbA1c and shorter duration of diabetes. For safe continuation of treatment, patients should be advised to suspend medication during acute illness.

Ipragliflozin Improves Glycemic Control and Decreases Body Fat in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Ipragliflozin, a sodium-glucose transporter 2 inhibitor, was administered to patients with type 2 diabetes mellitus for 24 weeks to evaluate its effect on glycemic control and body composition. METHODS: This was an investigator-initiated multicenter prospective intervention study in which ipragliflozin (50 mg) was administered once daily and glycemic control, blood pressure, body weight (BW), body composition (measured by a biological impedance method), the lipid profile, and adverse events were evaluated after 4, 12, and 24 weeks of treatment. RESULTS: Efficacy and safety up to 24 weeks of ipragliflozin therapy were analyzed in 367 patients and 451 patients, respectively. Hemoglobin A1c decreased significantly from 8.07% at the start of ipragliflozin therapy to 7.26% in week 24 (P < 0.001). Fasting and postprandial blood glucose levels were significantly reduced by ipragliflozin. In week 24, there were significant decreases from baseline in BW (-2.6 kg), waist circumference (-2.9 cm), and body fat mass (-1.9 kg) (P < 0.001). The body water mass and mineral mass were decreased significantly by 0.5 and by 0.1 kg, respectively (P < 0.001), whereas the protein mass did not change significantly. Intracellular water mass did not change significantly, whereas extracellular water mass showed a significant decrease of 0.5 kg (P < 0.001). Muscle mass did not change in the upper and lower limbs, but that of the trunk decreased significantly (P < 0.001). There was a significant decrease in the fasting triglyceride level and a significant increase in fasting high-density lipoprotein cholesterol level, while low-density lipoprotein cholesterol was unchanged. Adverse events occurred in 23.5% of the patients, with a high frequency of genital infections, such as vulvovaginal candidiasis (3.1%) and genital pruritus (1.8%). Adverse drug reactions were noted in 13.7% of the patients. CONCLUSIONS: Administration of ipragliflozin for 24 weeks improved glycemic control and decreased BW. Reduction of body fat accounted for more than 70% of the total weight loss and reduction of extracellular water accounted for about 20%.

Primary Care-Based Investigation of the Effect of Sitagliptin on Blood Pressure in Hypertensive Patients With Type 2 Diabetes.

BACKGROUND: The influence of long-term sitagliptin therapy on office blood pressure (BP) and home BP has been unclear. METHODS: In a retrospective cohort study of 454 patients with type 2 diabetes, the following variables were analyzed before and at 3, 6, 9, and 12 months after initiation of sitagliptin therapy: office systolic blood pressure (SBP), office diastolic blood pressure (DBP), office pulse rate, morning home SBP, morning home DBP, morning home pulse rate, evening home SBP, evening home DBP, evening home pulse rate, hemoglobin A1c (HbA1c), plasma glucose, lipid profile, and renal function parameters. RESULTS: The office SBP showed a significant decrease after 6 and 12 months of sitagliptin therapy (P < 0.01 and P < 0.01, respectively), while office DBP was decreased significantly at all time points of evaluation (3, 6, 9, and 12 months: P < 0.05, P < 0.001, P < 0.001, and P < 0.05, respectively). Analysis of covariance revealed a significant decrease in office SBP after 6 and 12 months, as well as significant reduction of office DBP after 6 and 9 months. Morning home SBP and DBP were significantly reduced after 6 months, as was evening home DBP after 6 and 12 months, but there was no significant decrease in evening home SBP. HbA1c and plasma glucose levels were significantly reduced at all time points of evaluation. Examination of the lipid profile revealed that total cholesterol, low-density lipoprotein cholesterol, and triglycerides were also decreased at all time points of evaluation, while high-density lipoprotein cholesterol was significantly reduced after 3, 9, and 12 months. Significant reduction of the estimated glomerular filtration rate was observed after 6, 9, and 12 months, and the urinary albumin/creatinine ratio was significantly lower at 9 and 12 months. Serum creatinine was increased significantly at all time points of evaluation. CONCLUSIONS: BP was slightly but significantly reduced from 6 months after initiation of sitagliptin therapy, indicating that this antidiabetic drug has pleiotropic effects, including an antihypertensive effect.