Lack of impact of ipragliflozin on endothelial function in patients with type 2 diabetes: sub-analysis of the PROTECT study.

BACKGROUND: We assessed the impact of 24 months of treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on endothelial function in patients with type 2 diabetes as a sub-analysis of the PROTECT study. METHODS: In the PROTECT study, patients were randomized to receive either standard antihyperglycemic treatment (control group, n = 241 ) or add-on ipragliflozin treatment (ipragliflozin group, n = 241) in a 1:1 ratio. Among the 482 patients in the PROTECT study, flow-mediated vasodilation (FMD) was assessed in 32 patients in the control group and 26 patients in the ipragliflozin group before and after 24 months of treatment. RESULTS: HbA1c levels significantly decreased after 24 months of treatment compared to the baseline value in the ipragliflozin group, but not in the control group. However, there was no significant difference between the changes in HbA1c levels in the two groups (7.4 ± 0.8% vs. 7.0 ± 0.9% in the ipragliflozin group and 7.4 ± 0.7% vs. 7.3 ± 0.7% in the control group; P = 0.08). There was no significant difference between FMD values at baseline and after 24 months in both groups (5.2 ± 2.6% vs. 5.2 ± 2.6%, P = 0.98 in the ipragliflozin group; 5.4 ± 2.9% vs. 5.0 ± 3.2%, P = 0.34 in the control group). There was no significant difference in the estimated percentage change in FMD between the two groups (P = 0.77). CONCLUSIONS: Over a 24-month period, the addition of ipragliflozin to standard therapy in patients with type 2 diabetes did not change endothelial function assessed by FMD in the brachial artery. TRIAL REGISTRATION: Registration Number for Clinical Trial: jRCT1071220089 ( https://jrct.niph.go.jp/en-latest-detail/jRCT1071220089 ).

Anti-obesity therapy for cardiovascular disease prevention: potential expected roles of glucagon-like peptide-1 receptor agonists.

Obesity is characterized by visceral fat accumulation and various metabolic disturbances that cause metabolic syndrome and obesity-related cardiovascular diseases (ORCVDs). Hence, treatments targeting obesity should also prevent ORCVDs. Nonetheless, lifestyle modification therapy alone is still insufficient to reduce the risk of ORCVDs, although most cardiovascular guidelines still list it as the only treatment for obesity. Additionally, conventional anti-obesity drugs, such as orlistat, phentermine-topiramate, and naltrexone-bupropion, can reduce body weight but have not demonstrated a clear reduction in the risk of ORCVDs. To overcome this unmet clinical need, newer anti-obesity drugs must exhibit not only sufficient and long-lasting weight loss but also obvious cardiovascular benefits. Given recent clinical findings and evidences, in this context glucagon-like peptide-1 receptor agonist is currently available as a candidate that is clinically positioned as a first-line anti-obesity agent for the effective prevention of ORCVDs in people with obesity.

Association between serum insulin levels and heart failure-related parameters in patients with type 2 diabetes and heart failure treated with canagliflozin: a post-hoc analysis of the randomized CANDLE trial.

BACKGROUND: Insulin resistance and hyperinsulinemia in patients with type 2 diabetes (T2D) are adversely associated with the development and worsening of heart failure (HF). Herein, we sought to investigate the effect of canagliflozin on insulin concentrations and the associations of changes in insulin concentrations with HF-related clinical parameters in patients with T2D and HF. METHODS: This was a post-hoc analysis of the investigator-initiated, multicenter, open-label, randomized, controlled CANDLE trial for patients with T2D and chronic HF (UMIN000017669). The endpoints were the effects of 24 weeks of canagliflozin treatment, relative to glimepiride treatment, on insulin concentrations and the relationship between changes in insulin concentrations and clinical parameters of interest, including New York Heart Association (NYHA) classification. The effects of canagliflozin on those parameters were also analyzed by baseline insulin level. RESULTS: Among the participants in the CANDLE trial, a total of 129 patients (canagliflozin, n = 64; glimepiride, n = 65) who were non-insulin users with available serum insulin data both at baseline and week 24 were included in this analysis. Overall, the mean age was 69.0 ± 9.4 years; 75% were male; the mean HbA1c was 6.8 ± 0.7%; and the mean left ventricular ejection fraction was 59.0 ± 14.1%, with parameters roughly balanced between treatment groups. Canagliflozin treatment significantly reduced insulin concentrations at week 24 (p < 0.001), and the between-group difference (canagliflozin minus glimepiride) in those changes was - 3.52 mU/L (95% confidence interval, - 4.85 to - 2.19; p < 0.001). Decreases in insulin concentrations, irrespective of baseline insulin level, were significantly associated with improvement in NYHA class in patients treated with canagliflozin. CONCLUSION: Our findings suggest that canagliflozin treatment in patients with T2D and HF ameliorated excess insulin overload, contributing to the improvement of clinical HF status. TRIAL REGISTRATION: University Medical Information Network Clinical Trial Registry, number 000017669, Registered on May 25, 2015.

Comparison of cardiovascular outcomes between SGLT2 inhibitors in diabetes mellitus.

BACKGROUND: There have been scarce data comparing cardiovascular outcomes between individual sodium-glucose cotransporter-2 (SGLT2) inhibitors. We aimed to compare the subsequent cardiovascular risk between individual SGLT2 inhibitors. METHODS: We analyzed 25,315 patients with diabetes mellitus (DM) newly taking SGLT2 inhibitors (empagliflozin: 5302, dapagliflozin: 4681, canagliflozin: 4411, other SGLT2 inhibitors: 10,921). We compared the risks of developing heart failure (HF), myocardial infarction (MI), angina pectoris (AP), stroke, and atrial fibrillation (AF) between individual SGLT2 inhibitors. RESULTS: Median age was 52 years, and 82.5% were men. The median fasting plasma glucose and HbA1c levels were 149 (Q1-Q3:127-182) mg/dL and 7.5 (Q1-Q3:6.9-8.6) %. During a mean follow-up of 814 ± 591 days, 855 HF, 143 MI, 815 AP, 340 stroke, and 139 AF events were recorded. Compared with empagliflozin, the risk of developing HF, MI, AP, stroke, and AF was not significantly different in dapagliflozin, canagliflozin, and other SGLT inhibitors. For developing HF, compared with empagliflozin, hazard ratios of dapagliflozin, canagliflozin, and other SGLT2 inhibitors were 1.02 (95% confidence interval [CI] 0.81-1.27), 1.08 (95% CI 0.87-1.35), and 0.88 (95% CI 0.73-1.07), respectively. Wald tests showed that there was no significant difference in the risk of developing HF, MI, AP, stroke, and AF among individual SGLT2 inhibitors. We confirmed the robustness of these results through a multitude of sensitivity analyses. CONCLUSION: The risks for subsequent development of HF, MI, AP, stroke, and AF were comparable between individual SGLT2 inhibitors. This is the first study comparing the wide-range cardiovascular outcomes of patients with DM treated with individual SGLT2 inhibitors using large-scale real-world data.

New Strategy to Prevent Acute Myocardial Infarction by Public Education　- A Position Statement of the Committee on Public Education About Emergency Medical Care of the Japanese Circulation Society.

Although many efforts have been made to prevent death from acute myocardial infarction (MI) by quick revascularization therapy and use of mechanical circulation support devices, and to prevent the occurrence of acute MI by optimal medical therapy, acute MI is still a leading cause of death worldwide. Because the majority of fatal MI cases occur outside hospital and death occurs so rapidly after MI onset, it is difficult to effectively prevent deaths from acute MI by improving the in-hospital treatment strategy of acute MI or by reducing the prehospital delay in the treatment. Therefore, we need a new strategy to prevent death from acute MI, mainly by preventing the occurrence of acute MI itself. In this review, we summarize the present status and propose a new strategy, the "STOP MI Campaign", to prevent acute MI by public education.

Differences in lipid metabolism between anagliptin and sitagliptin in patients with type 2 diabetes on statin therapy: a secondary analysis of the REASON trial.

BACKGROUND: Anagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain. AIM AND METHODS: We therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353). RESULTS: There was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 µg/mL vs. 52 weeks, 1.4 ± 1.0 µg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 µg/mL vs. 52 weeks, 1.3 ± 0.7 µg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06). CONCLUSION: These findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. https://clinicaltrials.gov/ct2/show/NCT02330406; registered January 5, 2015.

α-Glucosidase inhibitor miglitol attenuates glucose fluctuation, heart rate variability and sympathetic activity in patients with type 2 diabetes and acute coronary syndrome: a multicenter randomized controlled (MACS) study.

BACKGROUND: Little is known about clinical associations between glucose fluctuations including hypoglycemia, heart rate variability (HRV), and the activity of the sympathetic nervous system (SNS) in patients with acute phase of acute coronary syndrome (ACS). This pilot study aimed to evaluate the short-term effects of glucose fluctuations on HRV and SNS activity in type 2 diabetes mellitus (T2DM) patients with recent ACS. We also examined the effect of suppressing glucose fluctuations with miglitol on these variables. METHODS: This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group comparative study included 39 T2DM patients with recent ACS, who were randomly assigned to either a miglitol group (n = 19) or a control group (n = 20). After initial 24-h Holter electrocardiogram (ECG) (Day 1), miglitol was commenced and another 24-h Holter ECG (Day 2) was recorded. In addition, continuous glucose monitoring (CGM) was performed throughout the Holter ECG. RESULTS: Although frequent episodes of subclinical hypoglycemia (≤4.44 mmo/L) during CGM were observed on Day 1 in the both groups (35% of patients in the control group and 31% in the miglitol group), glucose fluctuations were decreased and the minimum glucose level was increased with substantial reduction in the episodes of subclinical hypoglycemia to 7.7% in the miglitol group on Day 2. Holter ECG showed that the mean and maximum heart rate and mean LF/HF were increased on Day 2 in the control group, and these increases were attenuated by miglitol. When divided 24-h time periods into day-time (0700-1800 h), night-time (1800-0000 h), and bed-time (0000-0700 h), we found increased SNS activity during day-time, increased maximum heart rate during night-time, and glucose fluctuations during bed-time, which were attenuated by miglitol treatment. CONCLUSIONS: In T2DM patients with recent ACS, glucose fluctuations with subclinical hypoglycemia were associated with alterations of HRV and SNS activity, which were mitigated by miglitol, suggesting that these pathological relationships may be a residual therapeutic target in such patients. Trial registration Unique Trial Number, UMIN000005874 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000006929 ).

Possible effects of glimepiride beyond glycemic control in patients with type 2 diabetes: a preliminary report.

BACKGROUND: The purpose of this study was to elucidate the effects of glimepiride on the levels of biomarkers related to cardiovascular regulation in patients with type 2 diabetes mellitus. METHODS AND RESULTS: Thirty-four patients with type 2 diabetes received glimepiride for 24 weeks. Significant decreases in the levels of glyceraldehyde-derived advanced glycation end products, (glycer-AGE: toxic AGE), eotaxin and fibroblast growth factor (FGF)-2 were recognized after the administration of glimepiride. Moreover, there were trends for there to be increases in the levels of granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF), and decreases in the levels of fractalkine, soluble CD40 ligand (sCD40L), macrophage inflammatory protein (MIP)-ß, vascular endothelial growth factor (VEGF) and soluble receptor for AGE (sRAGE). CONCLUSIONS: Glimepiride may have potent anti-oxidative, anti-inflammatory and angiogenic properties and it may potentially repair tissue damage by decreasing the levels of toxic AGE and increasing colony-stimulating factors.

Recent understandings about hypertension management in type 2 diabetes: What are the roles of SGLT2 inhibitor, GLP-1 receptor agonist, and finerenone?

Diabetes and hypertension often coexist, with about half of patients with diabetes also having hypertension. The risk of cardiovascular disease increases by three to six-fold with the coexistence of diabetes and hypertension; therefore, the management of blood pressure to prevent cardiovascular disease is a particularly important issue in patients with diabetes. Clinical trial findings have resulted in recommendations to control blood pressure to <130/80 mmHg in Japanese patients with diabetes. However, the target blood pressure and selection of anti-hypertensive medications should vary depending on the duration of diabetes and comorbidities, and guidelines and clinical trial results should be interpreted flexibly to provide anti-hypertensive treatment tailored to individual patients. In recent years, a number of drugs have emerged that have significant cardio-renal protective effects in patients with diabetes, and a typical example is sodium-glucose cotransporter 2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonist (GLP-1RA), and nonsteroidal mineralocorticoid receptor antagonist, finerenone. They have also shown modest but significant blood pressure-lowering effects. In the future, beyond considering the thresholds for how far to lower blood pressure, blood pressure management in patients with diabetes will require understanding the additive cardioprotective value of drugs aimed at lowering blood pressure and the quality of blood pressure lowering. Clinical questions of blood pressure lowering in patients with diabetes GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium-glucose cotransporter 2 inhibitor.

Empagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in routine care in East Asia: Results from the EMPRISE study.

AIMS/INTRODUCTION: The EMPA-REG OUTCOME® trial demonstrated benefits of empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), on cardiovascular, renal outcomes and all-cause mortality in patients with type 2 diabetes and established cardiovascular disease. The EMPRISE study program evaluates how these effects translate in a broad population of patients with type 2 diabetes in routine clinical care across countries. MATERIALS AND METHODS: The study included patients ≥18 years with type 2 diabetes initiating empagliflozin or any dipeptidyl peptidase-4 inhibitors (DPP-4i) from large administrative databases in Japan, South Korea, and Taiwan. Propensity score-matched (1:1) 'as-treated' analyses comparing the risk of cardiovascular outcomes and all-cause mortality between empagliflozin and DPP-4i use were performed in each country. Pooled hazard ratios (pHR) with 95% confidence intervals (CI) were computed using random effects meta-analysis models comparing both empagliflozin and SGLT2i with DPP-4i use, respectively. Intention-to-treat and subgroup analyses in patients with/without cardiovascular disease and in patients receiving 10 mg empagliflozin were performed. RESULTS: The study included 28,712 and 70,233 matched patient pairs for empagliflozin/DPP-4i and SGLT2i/DPP-4i analyses, respectively. The risk of composite outcomes including (i) hospitalization for heart failure (HHF) and all-cause mortality was lower with empagliflozin (pHR 0.76, 95% CI 0.67-0.86) and SGLT2i (0.71, 0.65-0.77); (ii) combined myocardial infarction, stroke, and all-cause mortality was also lower with empagliflozin (0.74, 0.61-0.88) and SGLT2i (0.69, 0.60-0.78) compared to DPP-4i. The intention-to-treat and three subgroup analyses were consistent with results of the main analyses. CONCLUSIONS: The results suggest that both empagliflozin and SGLT2i compared with DPP-4i are associated with a lower risk of cardiovascular events and all-cause mortality in routine clinical care in East Asia.

The associations of the national health and productivity management program with corporate profits in Japan.

OBJECTIVES: Using a dataset from a survey on national health and productivity management, we identified health and productivity factors associated with organizational profitability. METHODS: The Ministry of Economy, Trade and Industry conducted an annual survey on Health and Productivity Management between 2014 and 2021. We assessed the associations of organizational health and productivity management using survey questions collected in 2017 and 2018, with the rate of change in profits from 2017 and 2018 to 2020. We identified factors associated with organizational profitability using eXtreme Gradient Boosting, and calculated SHapley Additive exPlanation (SHAP) values for each factor. RESULTS: Among 1,593 companies (n= 4,359,834 employees), the mean age of employees at baseline was 40.3 years and the proportion of women was 25.8%. A confusion matrix for evaluating model performance had an accuracy of 0.997, precision of 0.993, recall of 0.997, and area under the precision-recall curve of 0.999. The most important factors related to an increase in corporate profits were the percentage of current smokers (SHAP value, 0.121), per-employee cost of health services (0.084) and medical services (0.050); the percentage of full-time employees working in sales departments (0.074) and distribution or customer service departments (0.054); the percentage of employees who slept well (0.055); and the percentage of employees within a company who regularly exercised (0.043). CONCLUSIONS: Employees' lifestyle-related health risk factors and organizations' management systems were associated with organizational profitability. Lifestyle medicine professionals may demonstrate a significant return on investment by creating a healthier and more productive workforce.

[Effects of incretin on cardiovascular disease and risk factors].

Diabetes is an important poor prognostic factor for ischemic heart disease and other cardiovascular diseases. Various study results have previously shown that new diabetes therapeutic agents including GLP-1 agonists and DPP-4 inhibitors have been suggested to be able to not only improve the pathology of diabetes, but also improve cardiovascular risk and be useful in prognosis. This report describes the effects of incretin on the cardiovascular system and its expected efficacy in reducing cardiovascular risk.

Emerging roles of sodium-glucose cotransporter 2 inhibitors in cardiology.

The ultimate goal of treatment in people with diabetes mellitus is to prevent development of cardiovascular (CV) disease, resulting in prolongation of healthy life expectancy. Although impaired glycemic metabolism has a central role in its pathology, a number of studies have demonstrated that remedy for its imbalance cannot necessarily be accomplished as a therapeutic goal. A comprehensive medical approach against multi-factorial pathologies in diabetes, such as insulin resistance, obesity, hypertension, and dyslipidemia, in addition to diet and exercise therapy should be rather performed in the routine clinical setting. Along with such conceptual transition, what is required in anti-diabetes agents has also changed, and several anti-diabetes agents have been newly placed on the market in this decade. Such agents are required to undergo global pre- or post-marketing clinical trials assessing CV safety. A growing body of clinical evidence from those trials is now accumulating, and empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has first demonstrated significant risk reduction, relative to placebo, in CV death, overall mortality, and hospitalization for worsened heart failure in high-risk patients with diabetes mellitus. An SGLT2 inhibitor is a unique glucose-lowering agent and at the same time has multifaceted effects on hemodynamic and metabolic parameters beyond glycemic control. A major mode of action of SGLT2 inhibitors appears to be 'glycosuria' and 'natriuresis,' leading to amelioration of systemic glycemic homeostasis and potential cardio-renal protection. However, the precise mechanisms by which SGLT2 inhibitors affect benefits on the CV systems are yet to be fully elucidated. Thus, although we are now facing several unanswered concerns lurking behind the successful trial, SGLT2 inhibitors surely play several important roles in high-quality management of not only diabetes, but also CV medicine. This review summarizes our current understandings and future perspectives of SGLT2 inhibitors in CV medicine.