Switching from Conventional Fibrates to Pemafibrate Has Beneficial Effects on the Renal Function of Diabetic Subjects with Chronic Kidney Disease.

Background: Fibrates have renal toxicity limiting their use in subjects with chronic kidney disease (CKD). However, pemafibrate has fewer toxic effects on renal function. In the present analysis, we evaluated the effects of pemafibrate on the renal function of diabetic subjects with or without CKD in a real-world clinical setting. Methods: We performed a sub-analysis of data collected during a multi-center, prospective, observational study of the effects of pemafibrate on lipid metabolism in subjects with type 2 diabetes mellitus complicated by hypertriglyceridemia (the PARM-T2D study). The participants were allocated to add pemafibrate to their existing regimen (ADD-ON), switch from their existing fibrate to pemafibrate (SWITCH), or continue conventional therapy (CTRL). The changes in estimated glomerular filtration rate (eGFR) over 52 weeks were compared among these groups as well as among subgroups created according to CKD status. Results: Data for 520 participants (ADD-ON, n=166; SWITCH, n=96; CTRL, n=258) were analyzed. Of them, 56.7% had CKD. The eGFR increased only in the SWITCH group, and this trend was also present in the CKD subgroup (P<0.001). On the other hand, eGFR was not affected by switching in participants with severe renal dysfunction (G3b or G4) and/or macroalbuminuria. Multivariate analysis showed that being older and a switch from fenofibrate were associated with elevation in eGFR (both P<0.05). Conclusion: A switch to pemafibrate may be associated with an elevation in eGFR, but to a lesser extent in patients with poor renal function.

Glycaemic control efficacy of switching from dipeptidyl peptidase-4 inhibitors to oral semaglutide in subjects with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 2 study).

AIM: To assess whether oral semaglutide provides better glycaemic control, compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) continuation, in people with type 2 diabetes. MATERIALS AND METHODS: In this multicentre, open-label, prospective, randomized, parallel-group comparison study, participants receiving DPP-4is were either switched to oral semaglutide (3-14 mg/day) or continued on DPP-4is. The primary endpoint was the change in glycated haemoglobin (HbA1c) over 24 weeks. Secondary endpoints included changes in metabolic parameters and biomarkers, along with the occurrence of adverse events. Factors associated with HbA1c improvement were also explored. RESULTS: In total, 174 eligible participants were enrolled; 17 dropped out of the study. Consequently, 82 participants in the DPP-4i group and 75 participants in the semaglutide group completed the study and were included in the analysis. Improvement in HbA1c at week 24 was significantly greater when switching to semaglutide compared with DPP-4i continuation [-0.65 (95% confidence interval: -0.79, -0.51) vs. +0.05 (95% confidence interval: -0.07, 0.16) (p < .001)]. Body weight, lipid profiles and liver enzymes were significantly improved in the semaglutide group than in the DPP-4i continuation group. Multiple linear regression analysis revealed that baseline HbA1c and homeostasis model assessment 2-R were independently associated with HbA1c improvement after switching to semaglutide. Seven participants in the semaglutide group discontinued medication because of gastrointestinal symptoms. CONCLUSIONS: Although the potential for gastrointestinal symptoms should be carefully considered, switching from DPP-4is to oral semaglutide may be beneficial for glycaemic control and metabolic abnormalities in people with higher HbA1c and insulin resistance.

Positive association between proinsulin and fatty liver index in people with type 2 diabetes.

The post-hoc study, derived from our previous prospective observational study, investigated the association between fasting serum proinsulin levels and hepatic steatosis in people with type 2 diabetes. The severity of hepatic steatosis was assessed using the fatty liver index. A total of 268 participants were divided into three groups: low (n = 110), moderate (n = 75), and high fatty liver index (n = 83). In both the crude and age/sex-adjusted analysis, logarithm-transformed proinsulin was significantly higher in the high fatty liver index group than in the low or moderate groups (all p < 0.01). The moderate fatty liver index group showed higher logarithm-transformed proinsulin than the low group (both p < 0.01). Positive associations between proinsulin and fatty liver index shown in this study would support an involvement of hepato-pancreatic crosstalk in the pathophysiology of type 2 diabetes.

Preferable effects of pemafibrate on liver function and fibrosis in subjects with type 2 diabetes complicated with liver damage.

BACKGROUND: Pemafibrate has been reported to ameliorate lipid profiles and liver dysfunction. However, which patients derive benefit from the hepatoprotective effects of pemafibrate is unclear. METHODS: We conducted a sub-analysis of the PARM-T2D study where subjects with type 2 diabetes complicated by hypertriglyceridemia were prospectively treated with pemafibrate or conventional therapies for 52 weeks. From the original cohort, subjects who had metabolic-associated fatty liver disease without changing their treatment regimens for comorbidities were analyzed. Eligible subjects (n = 293) (average age 61.2 ± 11.7 years, 37.5% female) treated with pemafibrate (pemafibrate, n = 152) or controls who did not change their treatment regimens (controls, n = 141) were divided into three groups based on their alanine aminotransferase (ALT) levels: ALT ≤ upper normal limit (UNL) (pemafibrate, n = 65; controls, n = 50), UNL < ALT ≤ 2×UNL (pemafibrate, n = 58; controls, n = 54), and 2×UNL < ALT (pemafibrate, n = 29; controls, n = 27). RESULTS: Pemafibrate treatment significantly ameliorated ALT levels (from 29 to 22 U/L, p < 0.001 by Wilcoxon's signed-rank test) in the total cohort and subjects with high ALT levels (2×ULN < ALT), and improved liver fibrosis as assessed by the Fibrosis-4 index (mean change - 0.05 (95% confidence interval: -0.22 to - 0.02), p < 0.05 versus baseline by the Mann-Whitney U-test and p < 0.05 versus the ALT ≤ UNL group by the Kruskal-Wallis test followed by Dunn's post-hoc analysis). CONCLUSIONS: The hepatoprotective effects of pemafibrate were dominant in subjects with type 2 diabetes complicated with liver dysfunction. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network Center Clinical Trials Registry (UMIN000037385).

Clinical and molecular delineation of classical-like Ehlers-Danlos syndrome through a comprehensive next-generation sequencing-based screening system.

Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in TNXB. Thus far, 50 patients from 43 families with biallelic TNXB variants have been identified. Accurate detection of TNXB variants is challenging because of the presence of the pseudogene TNXA, which can undergo non-allelic homologous recombination. Therefore, we designed a genetic screening system that is performed using similar operations to other next-generation sequencing (NGS) panel analyses and can be applied to accurately detect TNXB variants and the recombination of TNXA-derived sequences into TNXB. Using this system, we identified biallelic TNXB variants in nine unrelated clEDS patients. TNXA-derived variations were found in >75% of the current cohort, comparable to previous reports. The current cohort generally exhibited similar clinical features to patients in previous reports, but had a higher frequency of gastrointestinal complications (e.g., perforation, diverticulitis, gastrointestinal bleeding, intestinal obstruction, rectal/anal prolapse, and gallstones). This report is the first to apply an NGS-based screening for TNXB variants and represents the third largest cohort of clEDS, highlighting the importance of increasing awareness of the risk of gastrointestinal complications.

Effect of Switching to Once-Weekly Semaglutide on Non-Alcoholic Fatty Liver Disease: The SWITCH-SEMA 1 Subanalysis.

Non-alcoholic fatty liver disease (NAFLD) is an important common comorbidity in individuals with type 2 diabetes (T2DM). Although some glucagon-like peptide-1 receptor agonists (GLP-1RAs) have beneficial effects on NAFLD, the efficacy of once-weekly semaglutide has not been established. This was a subanalysis of the SWITCH-SEMA 1 study, a multicenter, prospective, randomized, parallel-group trial comparing switching from liraglutide or dulaglutide to once-weekly semaglutide in subjects with T2DM (SWITCH) versus continuing current GLP-1RAs (Continue) for 24 weeks. This subanalysis consisted of participants who were suspected to have NAFLD [fatty liver index (FLI) ≥ 30]. In total, 58 participants met the criteria of this subanalysis. There were no statistical differences in baseline characteristics between the SWITCH (n = 31) and Continue groups (n = 27). FLI significantly improved during treatment in the SWITCH group (68.6 to 62.7) but not in the Continue group (71.1 to 72.3) (p < 0.01). The improvement of FLI in the SWITCH group was greater in switching from dulaglutide to semaglutide and significantly correlated with older age (p = 0.016) and lower baseline FLI (p < 0.01). The multiple linear regression analysis revealed that the switch from dulaglutide was associated with an improvement in FLI (p = 0.041). Switching from conventional GLP-1RAs to once-weekly semaglutide might be beneficial for individuals with NAFLD complicated with T2DM.

Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature.

The Ehlers-Danlos Syndromes (EDS), a group of hereditary connective tissue disorders, were classified into 13 subtypes in the 2017 International Classification. Recently, a new subtype of EDS called classical-like EDS type 2 (clEDS2), which is caused by biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene, was identified. We describe the 11th patient (9th family) with clEDS2, who was complicated by a critical vascular event (superior mesenteric artery aneurysm and rupture). A next-generation sequencing panel-based analysis revealed compound heterozygous variants in AEBP1: NM_001129.5:c.[2296G>T]; [2383dup], p.[(Glu766*)]; [(Glu795Glyfs*3)]. Light microscopic analyses showed increased interfibrillar spaces in the reticular dermis, a disorganized arrangement of collagen fibers, and decreased collagen content. An electron microscopic analysis showed the presence of collagen fibrils with irregular contours (flower-like appearance) and small collagen fibrils. A biochemical analysis showed reduced secretion of type I and type III procollagen. Clinical and molecular features of the current patient and all previously reported patients were reviewed comprehensively. Manifestations noted in most cases (>80%) included skin features (hyperextensibility, atrophic scars, easy bruising, excessive skin/skin folding, delayed wound healing, translucency, piezogenic papules), skeletal features (generalized joint hypermobility, dislocations/subluxations, pes planus), dental abnormalities, and neuromuscular abnormalities. Critical complications, each occurring in a single case, included superior mesenteric artery multiple aneurysm and rupture, aortic root dilation requiring surgery, and bowel rupture. Most AEBP1 variants were predicted or experimentally confirmed to lead to nonsense-mediated mRNA decay, whereas one variant resulted in a protein that was retained intracellularly and not secreted. Clinical, molecular, pathological, and biochemical features of the current patient, as well as a review of all previously reported patients, suggest the importance of the aortic carboxypeptidase-like protein encoded by AEBP1 in collagen fibrillogenesis.

Inverse association between glucose variability and body fat in type 2 diabetes with impaired endogenous insulin secretion assessed using continuous glucose monitoring: A prospective observational study.

AIM: To evaluate the contribution of body fat mass and serum adiponectin concentration to glucose variability (GV) stability in people with type 2 diabetes with impaired versus preserved endogenous insulin secretion. MATERIALS AND METHODS: This multicentre prospective observational study included 193 people with type 2 diabetes who underwent ambulatory continuous glucose monitoring, abdominal computed tomography and fasting blood sampling. A fasting C-peptide (FCP) concentration >2 ng/mL was defined as preserved endogenous insulin secretion. The participants were divided into high (FCP > 2 ng/mL) and low FCP subgroups (FCP ≤ 2 ng/mL). Multivariate regression analysis was performed in each subgroup. RESULTS: In the high FCP subgroup, the coefficient of variation (CV) in GV was unrelated to abdominal fat area. In the low FCP subgroup, a high CV was significantly related to small abdominal visceral fat area (ß = -0.11, standard error 0.03; P < 0.05) and to small subcutaneous fat area (ß = -0.09, standard error 0.04; P < 0.05). No significant relationship between serum adiponectin concentration and continuous glucose monitoring-related variables was found. CONCLUSIONS: The contribution of body fat mass to GV depends on the endogenous insulin secretion residue. A small body fat area has independent adverse effects on GV in people with type 2 diabetes and impaired endogenous insulin secretion.

Improvement of glycaemic control and treatment satisfaction by switching from liraglutide or dulaglutide to subcutaneous semaglutide in patients with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 1 study).

AIM: To investigate the effects of switching from liraglutide or dulaglutide to once-weekly semaglutide on glycaemic control and treatment satisfaction in patients with type 2 diabetes. MATERIALS AND METHODS: In this multicentre, open-labelled, prospective, randomized, parallel-group comparison study, patients treated with liraglutide 0.9-1.8 mg/day (plan A) or dulaglutide 0.75 mg/week (plan B) were either switched to semaglutide or continued current therapy. The primary endpoint was the mean change in glycated haemoglobin over 24 weeks. The secondary endpoints included the changes of Diabetes Treatment Satisfaction Questionnaire scores, body weight and metabolic indices. RESULTS: In total, 110 patients were enrolled, and 10 were excluded; therefore, 37 patients in plan A and 63 patients in plan B completed the study. Glycated haemoglobin levels were significantly reduced in the semaglutide group in both plans [plan A, 7.8% ± 1.0% to 7.8% ± 0.7% (liraglutide) vs. 7.9% ± 0.7% to 7.3% ± 0.7% (semaglutide), p < .01; plan B, 7.8% ± 1.0% to 7.9% ± 1.2% (dulaglutide) vs. 7.8% ± 0.8% to 7.1% ± 0.6% (semaglutide), p < .01]. Semaglutide also improved Diabetes Treatment Satisfaction Questionnaire scores in both groups (plan A, +0.1 vs. +8.3, p < .01; plan B, -1.2 vs. +3.5, p < .01). Switching from dulaglutide yielded greater reductions in body weight and improved metabolic parameters. CONCLUSIONS: Once-weekly semaglutide administration improved glycaemic control and treatment satisfaction after switching from liraglutide or dulaglutide. These results highlighted a useful treatment option for patients with metabolic abnormalities despite glucagon-like receptor-1 receptor agonist treatment.

Add-on imeglimin versus metformin dose escalation regarding glycemic control in patients with type 2 diabetes treated with a dipeptidyl peptidase-4 inhibitor plus low-dose metformin: study protocol for a multicenter, prospective, randomized, open-label, parallel-group comparison study (MEGMI study).

INTRODUCTION: Imeglimin is a novel anti-hyperglycemic drug that improves both insulin resistance and insulin secretion. The effects of imeglimin on glycemic control were confirmed in phase III clinical trials, but little is known about its effectiveness in daily clinical practice settings, especially compared with metformin. Therefore, we aim to clarify the efficacy of imeglimin in patients with type 2 diabetes (T2D) being treated with a dipeptidyl peptidase-4 (DPP-4) inhibitor plus low-dose metformin. RESEARCH DESIGN AND METHODS: This is a multicenter, randomized, prospective, open-label, parallel-group trial. Seventy participants with T2D treated with a DPP-4 inhibitor plus metformin (500-1000 mg/day) for more than 12 weeks and a glycated hemoglobin (HbA1c) level of 52-85 mmol/mol (7.0%-9.9%) will be randomized to receive add-on imeglimin 1000 mg two times per day or metformin dose escalation for 24 weeks. Biochemical analyses and physical assessments will be performed at baseline and at the end of the study, and adverse events will be recorded. The primary endpoint is the change in HbA1c after 24 weeks. The secondary endpoints comprise the changes in blood pressure, pulse rate, body weight, abdominal circumference, and other laboratory parameters; the relationship between improvements of biological parameters including glycemic control and patient background characteristics; and side effects. RESULTS: This study will reveal new insights into the incorporation of imeglimin into the diabetes treatment strategy. CONCLUSIONS: This will be the first randomized controlled trial to compare the efficacy of adding imeglimin versus metformin dose escalation on glycemic control in patients with T2D. TRIAL REGISTRATION NUMBER: jRCT1011220005.

Effects of pemafibrate on lipid metabolism in patients with type 2 diabetes and hypertriglyceridemia: A multi-center prospective observational study, the PARM-T2D study.

AIMS: Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, was shown to ameliorate lipid abnormalities in a phase III clinical trial of patients with type 2 diabetes mellitus (T2DM). However, its efficacy has not been demonstrated in real-world clinical practice in patients with T2DM. METHODS: We performed a multi-center prospective observational study of the use of pemafibrate in patients with T2DM and hypertriglyceridemia versus conventional therapy, with or without a fibrate. The primary outcomes were the changes from baseline in fasting serum triglyceride (TG) and high-density lipoprotein-cholesterol (HDL-C) concentrations at week 52. RESULTS: We recruited 650 patients, and data from 504 (252 per group) were analyzed after propensity score matching. In the pemafibrate group, both TG and HDL-C showed significant improvements (p < 0.001), and several indices reflecting TG-rich lipoproteins, low-density lipoprotein-cholesterol particle size, and liver enzyme elevations were significantly ameliorated compared with the control group, but there was no difference in glycemic control markers. One of the key secondary endpoints showed that switching from conventional fibrates to pemafibrate improved eGFR but increased uric acid concentration. CONCLUSIONS: In patients with T2DM, pemafibrate has superior effects on lipid profile as well as liver and renal dysfunction to conventional fibrates.

The agreement between measured HbA1c and optimized target HbA1c based on the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8): A cross-sectional study of elderly patients with diabetes.

AIM: To investigate the achievement of individualized target HbA1c based on the Japanese guideline after geriatric assessment with the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8) and to evaluate patient characteristics acting as barriers to achieving the target HbA1c in elderly outpatients with diabetes. METHODS: This cross-sectional study enrolled 303 Japanese outpatients aged ≥65 years with diabetes. Their health status was measured using the DASC-8. The target HbA1c was optimized for each patient by the guideline based on the DASC-8 score and use of drugs potentially associated with severe hypoglycemia. Patient characteristics related to the agreement between measured HbA1c and target HbA1c were extracted by multivariate logistic regression analysis. RESULTS: The mean age was 73.0 years and the mean body mass index (BMI) was 24.2 kg/m2 . The agreement between measured HbA1c and target HbA1c was 43.9% (95% confidence interval: 38.4%-50.0%). In multivariate logistic regression analysis, the agreement in patients with drugs potentially associated with severe hypoglycemia was significantly lower than in those without these drugs (37.8% vs. 60.5%, P = 0.0004). In patients with these drugs, higher BMI (P = 0.0271) and higher fasting plasma glucose (P = 0.0034) were independent related factors for measured HbA1c being higher than target HbA1c. Vulnerable elderly patients (P = 0.0116) and not taking sodium glucose co-transporter-2 (SGLT2) inhibitor (P = 0.0186) were independent related factors for inappropriately lower HbA1c. CONCLUSIONS: The agreement between measured HbA1c and target HbA1c was low in elderly patients with diabetes. Geriatr Gerontol Int 2022; 22: 560-567.

Development of a hyperosmolar-hyperglycemic state and possible fulminant type 1 diabetes mellitus during the treatment of a case of adenocarcinoma of the lung and interstitial pneumonia.

An 85-year-old man was being treated with anti-cancer drugs for adenocarcinoma of the lung and was on a tapering dose of prednisolone for interstitial pneumonia. He attended our hospital complaining of fatigue, thirst, and polyuria in September 2020. His postprandial plasma glucose concentration was 976 mg/dL, his glycated hemoglobin was 8.0%, his plasma osmolality was 342 mOsm/kg H2O, his urine ketone body content was 1 +, and his blood pH was 7.356. Therefore, we diagnosed a hyperosmolar-hyperglycemic state and he was admitted to the hospital for treatment. He had had no previous upper respiratory symptoms, and his postprandial plasma glucose and glycated hemoglobin were normal 13 days before he was first assessed (90 mg/dL and 5.9%, respectively). On admission, his serum pancreatic exocrine enzyme activities were high and he was negative for islet-specific autoantibodies. His serum C-peptide concentration was 0.60 ng/mL, suggesting that his endogenous insulin secretion was partially intact at that time. Although he did not meet the diagnostic criteria, we suspected him of having fulminant type 1 diabetes mellitus, because of the abrupt onset of hyperosmolar-hyperglycemic state. His general condition was improved by fluid and insulin administration. His human leukocyte antigen genotype was DRB1*04:05 DQB1*04:01:01, which is a disease susceptibility haplotype for fulminant type 1 diabetes mellitus. In addition, his prednisolone treatment may have caused an autoimmune abnormality, further predisposing toward the development of fulminant type 1 diabetes mellitus.

Effects of switching from a dipeptidyl peptidase-4 inhibitor to oral semaglutide on glucose metabolism in patients with type 2 diabetes: protocol for a multicentre, prospective, randomised, open-label, parallel-group comparison study (the SWITCH-SEMA 2 study).

INTRODUCTION: Incretin-based therapies exert antihyperglycaemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent fashion. The first-in-class oral glucagon-like peptide-1 receptor agonist semaglutide has potent effects on glycaemic and weight control, but little evidence has been published for the superiority of semaglutide for glycaemic control in patients after switching from a dipeptidyl peptidase-4 (DPP-4) inhibitor. Therefore, we aim to verify the efficacy of oral semaglutide in patients with T2D being treated with a DPP-4 inhibitor. METHODS AND ANALYSIS: This study is a multicentre, prospective, randomised, open-label, parallel-group trial. In total, 172 participants with T2D who have been treated with a DPP-4 inhibitor for more than 12 weeks and who have a glycated haemoglobin (HbA1c) level of 7.0%-9.9% will be randomised to continue using their existing DPP-4 inhibitor or switch to oral semaglutide for 24 weeks. Biochemical analyses and physical assessment will be performed, and adverse events will be recorded at baseline and at the end of the study. The primary endpoint will be the effect of oral semaglutide on the change in HbA1c. The secondary endpoints will be the mean changes in body weight, abdominal circumference, systolic and diastolic blood pressure (BP), pulse rate, the relationship between improvement of metabolic parameters including HbA1c and patient background characteristics, side effects and other laboratory parameters. ETHICS AND DISSEMINATION: This will be the first study to compare the effects of switching from a DPP-4 inhibitor to oral semaglutide on glycaemic control in patients with T2D. The results will be disseminated in peer-reviewed journals and at scientific conferences. Hokkaido University Certified Review Board (CRB no.1180001) has approved the protocol (no. 020-013). TRIAL REGISTRATION NUMBER: UMIN000045270 in the University Hospital Medical Information Network; jRCT1011210032 in the Japan Registry of Clinical Trials.

Postoperative thyroid storm after radical nephrectomy for renal cell carcinoma with inferior vena cava tumor thrombus.

INTRODUCTION: Thyroid storm is a rare life-threating condition. We report a case of thyroid storm after radical nephrectomy for renal cell carcinoma with inferior vena cava tumor thrombus. CASE PRESENTATION: A 76-year-old man with a left renal tumor and tumor thrombus extending into the inferior vena cava underwent left radical nephrectomy and thrombectomy. After the surgery, his postoperative course rapidly deteriorated, including central nervous system disturbance, fever, tachycardia, congestive heart failure, and hepatic manifestation. Thyroid function test revealed perioperative hyperthyroidism. Corticosteroids and inorganic iodide improved his condition, suggesting that he developed thyroid storm after surgery. He was discharged 5 months after surgery and has been free from disease recurrence for more than 2 years. CONCLUSION: Thyroid storm after surgery is rare. However, this postoperative complication is important because it is fatal if not diagnosed and treated properly.

Lowering of blood pressure and pulse rate by switching from DPP-4 inhibitor to luseogliflozin in patients with type 2 diabetes complicated with hypertension: A multicenter, prospective, randomized, open-label, parallel-group comparison trial (LUNA study).

AIMS: Sodium-glucose cotransporter-2 inhibitor (SGLT2i) reduces clinic blood pressure (BP), but the effects on BP circadian rhythm remain unclear. The present study aimed to determine the nighttime antihypertensive effect of SGLT2i compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) in patients with type 2 diabetes and hypertension. MATERIALS AND METHODS: In this randomized, open-label, parallel-group trial, patients treated with DPP-4i were either switched to luseogliflozin 2.5 mg/day (Luseo group;n = 30) or continued DPP-4i (DPP-4i group;n = 26). The patients undertook 24-h ambulatory BP monitoring before and 8 weeks after the group allocation. The primary endpoint was mean change in nighttime systolic BP (SBP). RESULTS: Nighttime SBP, as well as daytime SBP, was significantly reduced in the Luseo group compared with the DPP-4i group (nighttime, -4.0 ± 11.4 vs. 3.6 ± 10.7 mmHg,P = 0.01; daytime, -4.4 ± 10.9 vs. 3.7 ± 11.9 mmHg,P = 0.01). Similarly, nighttimepulse rate(PR) was significantly reduced in the Luseo group (-2.0 ± 4.8 vs. 0.9 ± 4.8 bpm,P = 0.03). The proportion of patients with abnormal BP circadian rhythms (non-dipper pattern plus riser pattern) was significantly lower in the Luseo group (36.6% vs. 56.7%,P < 0.05). CONCLUSIONS: Switching from DPP-4i to luseogliflozin decreased nighttime SBP and PR; moreover, BP circadian rhythm was improved.

Acromegaly Cases Exhibiting Increased Growth Hormone Levels during Oral Glucose Loading with Preadministration of Dipeptidyl Peptidase-4 Inhibitor.

Objective Glucose-dependent insulinotropic polypeptide (GIP) is speculated to worsen growth hormone (GH) hypersecretion in acromegaly and to be a cause of paradoxical increases in GH (PI-GH) during 75-g oral glucose tolerance testing (75-g OGTT). Dipeptidyl peptidase-4 inhibitors (DPP4is), which increase the circulating concentration of active GIP, are frequently administered to diabetic patients, including those with acromegaly. We aimed to determine whether or not the administration of a DPP4i increases GH concentration, especially in patients demonstrating PI-GH during a DPP4i-OGTT, in which a DPP4i was administered immediately before 75-g OGTT. Methods This prospective cross-sectional study was carried out on acromegalic patients admitted to Hokkaido University hospital between June 2011 and May 2018. The participants underwent both 75-g OGTT and DPP4i-OGTT. For those who underwent surgery, immunohistochemical staining and quantitative polymerase chain reaction (PCR) for the GIP receptor (GIPR) were performed on the resected pituitary adenomas. Results Twenty-five percent of the participants had PI-GH confirmed (3 of 12 cases). Two of the three participants who demonstrated PI-GH exhibited higher circulating GH concentrations during DPP4i-OGTT than during OGTT. The increase in plasma glucose was reduced during DPP4i-OGTT compared to during 75-g OGTT, suggesting that the increase in GH during DPP4i-OGTT was due not to high glucose concentrations but instead increased GIP caused by the administration of DPP4i. The adenoma from one participant with PI-GH displayed positive immunostaining for GIPR and a higher GIPR messenger ribonucleic acid (mRNA) expression than the others. Conclusion DPP4i may enhance the GH secretion response during glucose loading, especially in individuals with PI-GH.

Dipeptidyl peptidase-4 inhibitor might exacerbate Graves' disease: A multicenter observational case-control study.

Dipeptidyl peptidase-4 (DPP-4), namely CD26, is expressed on the surface of immune cells, suggesting that inhibition of DPP-4 might affect the immune system. The current multicenter observational case-control study was carried out to investigate the effects of DPP-4 inhibitor (DPP-4i) administration on Graves' disease (GD) activity. This study comprised patients with GD and type 2 diabetes, who were administered an oral hypoglycemic agent including DPP-4i. Exacerbation of GD was defined as an increase of antithyroid drug dose by 6 months after oral hypoglycemic agent administration. A total of 80 patients were enrolled and divided into an exacerbation group or a non-exacerbation group. The frequency of DPP-4i administration was significantly higher in the exacerbation group (88%) than that in the non-exacerbation group (31%). In multivariate logistic regression analysis, there was a significant association between DPP-4i administration and GD exacerbation (odds ratio 7.39). The current study suggests that DPP-4i administration is associated with GD exacerbation.

Log-linear relationship between endogenous insulin secretion and glycemic variability in patients with type 2 diabetes on continuous glucose monitoring.

The contribution of endogenous insulin secretion to glycemic variability (GV) may differ between patients with impaired insulin secretion and those with preserved secretion. Our objective was to determine the linearity of the relationship between fasting C-peptide (CPR) as a marker of endogenous insulin secretion and GV in type 2 diabetes (T2DM), regardless of the type of antidiabetic treatment. We conducted a prospective observational study using continuous glucose monitoring obtained from 284 Japanese outpatients with T2DM with various HbA1c values and antidiabetic treatment. We constructed a prediction curve of base-line CPR versus coefficient of variation (CV) and identified the clinical factors associated with CV using multiple regression analysis. Fasting CPR showed a significant negative log-linear relationship with CV (P < 0.0001), and the latter being strikingly high in the low-CPR group. The multiple regression analysis showed that low CPR was an independent predictor of high CV (P < 0.0001). The significant correlations were sustained in both patients with/without insulin treatment. The contribution of endogenous insulin secretion to GV depends on the extent of insulin secretion impairment. Fasting CPR may represent a useful indicator of GV instability in T2DM.

The association between hypoglycemia and glycemic variability in elderly patients with type 2 diabetes: a prospective observational study.

BACKGROUND: This study aimed to explore predictive factors of time below target glucose range (TBR) ≥ 1% among patients' characteristics and glycemic variability (GV) indices using continuous glucose monitoring data in elderly patients with type 2 diabetes. METHODS: We conducted a prospective observational study on 179 (71 female) Japanese outpatients with type 2 diabetes aged ≥ 65 years. The characteristics of the participants with TBR ≥ 1% were evaluated by multivariate logistic regression analysis. Receiver-operating characteristic (ROC) curve analyses of GV indices, comprising coefficient of variation (CV), standard deviation, and mean amplitude of glycemic excursions, were performed to identify the optimal index for the identification of patients with TBR ≥ 1%. RESULTS: In the multivariate logistic regression analysis, none of the clinical characteristics, including HbA1c and C-peptide index, were independent markers for TBR ≥ 1%, while all three GV indices showed significant associations with TBR ≥ 1%. Among the three GV indices, CV showed the best performance based on the area under the curve in the ROC curve analyses. CONCLUSIONS: Among elderly patients with type 2 diabetes, CV reflected TBR ≥ 1% most appropriately among the GV indices examined. Trial registration UMIN-CTR: UMIN000029993. Registered 16 November 2017.