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We assessed the prescription patterns of oral antidiabetic drugs in Japanese patients with type 2 diabetes between 2002 and 2020 using data from the Computerized Diabetes Care database. Among 172,960 patients treated with oral antidiabetic drugs, both the sulfonylurea prescription rate and dose decreased from 2002 to 2020. Prescriptions of biguanides, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors increased; their dose and dose frequency remained relatively stable. Trends in oral antidiabetic drug prescriptions changed over time, reflecting guideline recommendations and existing evidence.

Recent major clinical trials of the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have shown that they reduce three‐point major adverse cardiovascular events, cardiovascular death, hospitalization for heart failure (HF) and a composite renal outcome. These beneficial effects of SGLT2 inhibitors are also evident in type 2 diabetes patients with a previous history of atherosclerotic cardiovascular disease or advanced renal disease. HF is a major determinant of the prognosis of diabetes patients. Although HF with low ejection fraction can be effectively treated with antihypertensive drugs, these treatments do not reduce mortality in HF patients with preserved ejection fraction (HFpEF). HFpEF is clinically characterized by left ventricular diastolic dysfunction, perivascular fibrosis and stiffness of cardiomyocytes, defined as “cardiomyopathy”. Therefore, HFpEF is considered to be an entirely separate entity to HF with low ejection fraction. Recent studies have suggested that HFpEF might be treatable using SGLT2 inhibitors, which ameliorate visceral adiposity, insulin resistance, hyperglycemia, hyperlipidemia, volume overload, hypertension and cardiac inflammation. In the final part of the present review, we discuss the biochemical and molecular mechanisms of the effects of SGLT2 inhibitors in type 2 diabetes patients with HFpEF. These involve amelioration of the low nitric oxide production and oxidative stress, a reduction in cardiac inflammatory cytokine signaling, inhibition of Ca2+ overload, and an improvement in cardiac energy metabolism as a result of ketone body production. Investigations of the beneficial effects of SGLT2 inhibitors on cardiorenal outcomes, including hospitalization for HF, are now being carried out in preclinical and clinical studies., Heart failure is a major determinant of life prognosis in diabetes patients. Two potential mechanisms for the progression of heart failure in diabetes are reviewed – the development of heart failure with preserved ejection fraction and heart failure with low ejection fraction. Sodium–glucose cotransporter 2 inhibitors can protect progression of heart failure with preserved ejection fraction in diabetes patients by improving multiple metabolic and hemodynamic derangements, as well as by improving endothelial dysfunction, oxidative stress, pro‐inflammatory cytokine signaling, Ca++ overloading and metabolic crisis in cardiomyocytes in diabetes.

Aims/Introduction Preprandial metformin administration significantly reduces postprandial plasma triglyceride levels in animal studies by reducing intestinal absorption through delayed gastric emptying. However, this effect has not been shown in a clinical study. Therefore, we planned to investigate the efficacy of preprandial metformin administration on postprandial hypertriglyceridemia and the related gastrointestinal effects in patients with type 2 diabetes mellitus. Materials and Methods A total of 11 patients taking single‐dose metformin at 500–1,000 mg, with non‐fasting plasma triglyceride levels of 150–1,000 mg/dL, were recruited at a single university hospital. The difference between preprandial and postprandial metformin administration on postprandial hypertriglyceridemia was examined by a meal test. The gastrointestinal effects of metformin, including stomach heaviness, heartburn and satiety, were also assessed using a visual analog scale. Results The mean bodyweight of patients was 80.6 kg (body mass index 27.9 kg/m2), and the mean non‐fasting plasma triglyceride level was 275.9 ± 57.0 mg/dL. The area under the curve of triglyceride during the meal test was significantly lower in the preprandial protocol than in the postprandial protocol (P

Aims/Introduction Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross‐sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (

Aims/Introduction Specified Drug Use Results Survey of Ipragliflozin Treatment in Type 2 Diabetic Patients: Long‐term Use is an ongoing postmarketing study of ipragliflozin for long‐term use in Japanese patients with type 2 diabetes mellitus. A subgroup analysis of data from the study was carried out to investigate the impact of obesity on the efficacy and safety of ipragliflozin in this population. Materials and Methods Patients were divided into the following subgroups according to their body mass index (BMI)

Aims/Introduction:Type 2 diabetes mellitus is caused by a relative imbalance between insulin secretion and sensitivity related to the body mass index (BMI). Seven categories of oral antidiabetic drugs (OADs) are available in Japan. It is important to assess the OAD utilization patterns based on patients’ BMI levels., Materials and methods:OAD prescribing patterns from 2002 to 2019 were analyzed using the data collected in the computerized diabetes care database provided by the Japan Diabetes Clinical Data Management Study Group; OAD utilization patterns in 25,751 OAD-treated type 2 diabetes mellitus patients registered in 2019 were analyzed after classifying them into five categories of BMI., Results:Comparing OAD usage between 2002 and 2019, sulfonylureas decreased from 44.5 to 23.2%, and biguanides (BGs) increased from 19.3 to 50.3%. Dipeptidyl peptidase-4 inhibitors (DPP4is) increased to 56.9% in 2019. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) increased to 23.6% in 2019. About 90% of type 2 diabetes mellitus patients had BMI < 30 kg/m2 . DPP4is were the most used OADs in 2019. When BMI exceeded 30 kg/m2 , use of BGs and sodium-glucose cotransporter 2 inhibitors increased, and use of sulfonylureas and DPP4is decreased. Although DPP4is were the most used OADs for patients with BMI 35 kg/m2 after BGs and sodium-glucose cotransporter 2 inhibitors ., Conclusions:DPP4i usage was as high as that of BG in the analysis of Japanese type 2 diabetes mellitus patients with relatively low BMI. This was considered to be a treatment option appropriate for the pathophysiology in Japanese patients.

Recent studies using genetically manipulated mouse models have shown the pivotal role of O‐linked N‐acetylglucosamine modification (O‐GlcNAcylation) in the metabolism of multiple organs. The molecular mechanism involves the sensing of glucose flux by the hexosamine biosynthesis pathway, which leads to the adjustment of cellular metabolism to protect against changes in the environment of each organ through O‐GlcNAcylation. More recently, not only glucose, but also fluxes of amino acids and fatty acids have been reported to induce O‐GlcNAcylation, affecting multiple cellular processes. In this review, we discuss how O‐GlcNAcylation maintains homeostasis in organs that are affected by diabetes mellitus: skeletal muscle, adipose tissue, liver and pancreatic β‐cells. Furthermore, we discuss the importance of O‐GlcNAcylation in the pathogenesis of diabetic complications. By elucidating the molecular mechanisms whereby cellular homeostasis is maintained, despite changes in metabolic flux, these studies might provide new targets for the treatment and prevention of diabetes and its complications., This article briefly reviews recent studies related with role of O‐linked N‐acetylglucosamine modification in specific organs in diabetes and its complications.

Aim/Introduction Diabetes and obesity are important health and economic concerns. We investigated the influence of obesity on diabetes control, the annual medical expenditures, and medications in Japanese patients with type 2 diabetes who were relatively lean in comparison to those in Western countries. Materials and Methods A total of 402 Japanese patients with type 2 diabetes were enrolled and their annual medical expenditures investigated. Obesity was defined as body mass index over 25 kg/m2, according to the obesity classifications from the Japan Society for the Study of Obesity. Results A total of 165 patients (41.0%) were classified as obese. The obese group was younger, had poor glycemic control, and higher frequency of hypertension than the non-obese group. The median total annual medical expenditures for all participants was 269,333 Japanese yen (interquartile: 169,664 to 437,437 Japanese yen), which was equivalent to approximately 2,450 US dollars. The annual medical expenditure was significantly higher in patients with obesity than in non-obese patients (P

Aims/Introduction To investigate the current status of achieved blood pressure levels in association with the number of antihypertensive drug classes as of 2013, and to explore the clinical correlates with achievement of target blood pressure in a large-scale cohort of Japanese individuals with type 2 diabetes. Materials and Methods A nationwide survey was carried out including 12,811 individuals with type 2 diabetes. Participants were divided by achieved blood pressure

The specific sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) inhibit glucose reabsorption in proximal renal tubular cells, and both fasting and postprandial glucose significantly decrease because of urinary glucose loss. As a result, pancreatic β‐cell function and peripheral insulin action significantly improve with relief from glucose toxicity. Furthermore, whole‐body energy metabolism changes to relative glucose deficiency and triggers increased lipolysis in fat cells, and fatty acid oxidation and then ketone body production in the liver during treatment with SGLT2 inhibitors. In addition, SGLT2 inhibitors have profound hemodynamic effects including diuresis, dehydration, weight loss and lowering blood pressure. The most recent findings on SGLT2 inhibitors come from results of the Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes trial. SGLT2 inhibitors exert extremely unique and cardio‐renal protection through metabolic and hemodynamic effects, with long‐term durability on the reduction of blood glucose, bodyweight and blood pressure. Although a site of action of SGLT2 inhibitors is highly specific to inhibit renal glucose reabsorption, whole‐body energy metabolism, and hemodynamic and renal functions are profoundly modulated during the treatment of SGLT2 inhibitors. Previous studies suggest multifactorial clinical benefits and safety concerns of SGLT2 inhibitors. Although ambivalent clinical results of this drug are still under active discussion, the present review summarizes promising recent evidence on the cardio‐renal and metabolic benefits of SGLT2 inhibitors in the treatment of type 2 diabetes.

Aims/Introduction In Japan, liraglutide was recently approved for patients with type 2 diabetes. To our knowledge, there are no markers predicting successful switching from insulin therapy to liraglutide monotherapy in Japanese patients with type 2 diabetes and renal impairment. We therefore assessed clinical characteristics predicting successful switching. Materials and Methods We analyzed 21 patients with type 2 diabetes and estimated glomerular filtration rates

Aims/Introduction To realize the effectiveness of a novel system for measuring glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET), outpatients undergoing oral glucose tolerance tests (OGTT) were investigated for the efficacy of screening for glucose intolerance using this system. Materials and Methods Fifty outpatients scheduled to undergo a 75-g OGTT for medical reasons were recruited to the study. An area of skin on the forearm was pretreated with microneedle arrays before the application of hydrogels for interstitial fluid extraction. Plasma glucose (PG) levels were measured every 30 min for 2 h to calculate reference (actual) AUC. The AUC was predicted by MIET on the basis of glucose extracted by the hydrogel using sodium ion levels as the internal standard. Results Good correlation between MIET-predicted and reference AUCs obtained using PG levels was confirmed for a wide AUC range. By introducing a threshold level for AUC to separate glucose intolerance with peak glucose ≥180 mg/dL from normal glucose tolerance, the system was demonstrated to provide better screening accuracy compared with conventional methods that use HbA1c and fasting PG levels. The results of a questionnaire-based survey administered to the subjects suggested that this system was readily accepted by the majority as a painless monitoring method. Conclusions The findings suggest that our glucose AUC measurement system using MIET would be useful for screening of glucose intolerance. In the future, this system may prove to be a useful aid as a screen for glucose intolerance before performing an OGTT for diagnosis.

Aims/Introduction: Activation of the renin-angiotensin system (RAS) in the kidney plays an important role in renal function. The aim of this study was to investigate whether plasma and urinary angiotensinogen levels were associated with renal and cardiovascular prognosis in type 2 diabetic patients. Materials and Methods: We measured plasma and urinary angiotensinogen levels in the observational follow-up cohort of 234 Japanese type 2 diabetic patients (144 with normoalbuminuria, 90 with albuminuria) enrolled between 1998 and 1999 and followed them up until the end of 2008. The associations of these markers with the annual decline in the estimated glomerular filtration rate (eGFR) and incidence of renal and cardiovascular composite endpoints (chronic hemodialysis, myocardial infarction, angina pectoris, stroke and cerebral hemorrhage) were evaluated. Results: At baseline, urinary angiotensinogen levels correlated with urinary albumin-creatinine ratio, urinary β2-microglobulin and inversely with eGFR. In contrast, plasma angiotensinogen levels correlated neither with these renal factors nor with urinary angiotensinogen levels. In the follow-up study (median duration: 9 years), urinary angiotensinogen, but not plasma angiotensinogen, correlated inversely with the annual change in eGFR (r = −0.51, P

Anti-diabetic agent-related hypoglycemia is a serious complication in type 2 diabetic patients on hemodialysis. Therefore, we assessed the efficacy and tolerability of 24 weeks of monotherapy with vildagliptin, a dipeptidyl peptidase four inhibitor, which is a new class of antidiabetic agent. This open-label, single-arm clinical trial was performed on 26 patients on hemodialysis. The primary assessments were changes in postprandial glucose level and glycated albumin (GA). During the study, three patients dropped out, and data from 23 patients were analyzed. Significant reductions were seen in postprandial glucose (−2.60 ± 3.80 mmol/L, P

Aims/Introduction: Although increases in urinary protein excretion generally precede a decline in the glomerular filtration rate, non-proteinuric renal impairment is common in patients with diabetes. In the present study, we examined the relationship between indices of arterial stiffness and renal function in type 2 diabetic patients without proteinuria. Methods: Blood sampling, 24-h urine collection, brachial–ankle pulse wave velocity, and 24-h ambulatory blood pressure monitoring were performed in type 2 diabetic patients without overt proteinuria. The ambulatory arterial stiffness index was calculated as (1 – the regression slope of diastolic/systolic ambulatory blood pressure). Estimated glomerular filtration rate (eGFR)was calculated using the simplified prediction equation proposed by the Japanese Society of Nephrology. Results: Of 213 non-proteinuric patients with type 2 diabetes, 60 (28.2%) had a reduced eGFR (

Aims/Introduction: Platelet-derived microparticles (PDMP) are released from the platelets either after activation or in response to physical stimulation in vivo. The present study examined the association between blood pressure and PDMP, and the effects of high-dose angiotensin receptor blockers (ARB) on PDMP in patients with type 2 diabetes. Materials and Methods: The study subjects consisted of 28 type 2 diabetes patients with blood pressure ≥130/80 mmHg who were treated with valsartan (80 mg daily). The patients were randomly assigned to take either 80 mg of telmisartan (Tel group) or 160 mg of valsartan (Val group) and then were followed up for 24 weeks. Thereafter, the patients were switched to combination therapy (5 mg of amlodipine with 40 mg of telmisartan [Tel group] or 80 mg of valsartan [Val group]) for 12 weeks. Results: Although the ambulatory blood pressure did not change, the PDMP levels were significantly decreased from baseline to week 24 (high dose ARB). In contrast, combination therapy reduced both blood pressure and PDMP levels compared with the baseline. Although the PDMP level was significantly correlated with the morning BP elevation at baseline and week 36 (combination therapy), this same relationship was not found at week 24. There were no significant differences in the blood pressure and PDMP levels between the two groups. Conclusions: Patients with morning hypertension might be at risk for cardiovascular diseases. High-dose renin-angiotensin system inhibition and blood pressure control are both considered to reduce cardiovascular events in patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00048.x, 2010)

Anti‐diabetic agent‐related hypoglycemia is a serious complication in type 2 diabetic patients on hemodialysis. Therefore, we assessed the efficacy and tolerability of 24 weeks of monotherapy with vildagliptin, a dipeptidyl peptidase four inhibitor, which is a new class of antidiabetic agent. This open‐label, single‐arm clinical trial was performed on 26 patients on hemodialysis. The primary assessments were changes in postprandial glucose level and glycated albumin (GA). During the study, three patients dropped out, and data from 23 patients were analyzed. Significant reductions were seen in postprandial glucose (−2.60 ± 3.80 mmol/L, P