Search

Background: Type 2 diabetes mellitus is associated strongly with an increased risk of micro- and macro-vascular complications, leading to impaired quality of life and shortened life expectancy. In addition to appropriate glycemic control, multi-factorial intervention for a wide range of risk factors, such as hypertension and dyslipidemia, is crucial for management of diabetes. A recent cardiovascular outcome trial in diabetes patients with higher cardiovascular risk demonstrated that a SGLT2 inhibitor markedly reduced mortality, but not macro-vascular events. However, to date there is no clinical evidence regarding the therapeutic effects of SGLT2 inhibitors on arteriosclerosis. The ongoing PROTECT trial was designed to assess whether the SGLT2 inhibitors, ipragliflozin, prevented progression of carotid intima-media thickness in Japanese patients with type 2 diabetes mellitus., Methods: A total of 480 participants with type 2 diabetes mellitus with a HbA1c between 6 and 10 % despite receiving diet/exercise therapy and/or standard anti-diabetic agents for at least 3 months, will be randomized systematically (1:1) into either ipragliflozin or control (continuation of conventional therapy) groups. After randomization, ipragliflozin (50-100 mg once daily) will be added on to the background therapy in participants assigned to the ipragliflozin group. The primary endpoint of the study is the change in mean intima-media thickness of the common carotid artery from baseline to 24 months. Images of carotid intima-media thickness will be analyzed at a central core laboratory in a blinded manner. The key secondary endpoints include the change from baseline in other parameters of carotid intima-media thickness, various metabolic parameters, and renal function. Other cardiovascular functional tests are also planned for several sub-studies., Discussion: The PROTECT study is the first to assess the preventive effect of ipragliflozin on progression of carotid atherosclerosis using carotid intima-media thickness as a surrogate marker. The study has potential to clarify the protective effects of ipragliflozin on atherosclerosis. Trial registration Unique Trial Number, JPRN/UMIN000018440 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021348 ).

Background: Experimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM)., Methods and Findings: We used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged ≥30 y with T2DM (6.2% ≤ HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of -0.009 mm (97.2% CI -0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72% ± 0.05%, p = 0.008; group mean difference -0.159, 95% CI -0.278 to -0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation., Conclusions: In the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment., Trial Registration: University Hospital Medical Information Network Clinical Trials Registry UMIN000004490.

Background: Because type 2 diabetes mellitus is associated strongly with an increased risk of cardiovascular diseases, the number of patients with diabetes with chronic heart failure is increasing steadily. However, clinical evidence of therapeutic strategies in such patients is still lacking. A recent randomized, placebo-controlled trial in patients with type 2 diabetes with high cardiovascular risk demonstrated that the SGLT2 inhibitor, empagliflozin, reduced the incidence of hospitalization for heart failure. Because SGLT2 inhibitors cause a reduction in body weight and blood pressure in addition to improving glycemic control, they have the potential to exert beneficial effects on the clinical pathophysiology of heart failure. The aim of the ongoing CANDLE trial is to test the safety and non-inferiority of canagliflozin, another SGLT2 inhibitor, compared with glimepiride, a sulfonylurea agent, in patients with type 2 diabetes mellitus and chronic heart failure., Methods: A total of 250 patients with type 2 diabetes who are drug-naïve or taking any anti-diabetic agents and suffering from chronic heart failure with a New York Heart Association classification I to III will be randomized centrally into either canagliflozin or glimepiride groups (1: 1) using the dynamic allocation method stratified by age (<65, ≥65 year), HbA1c level (<6.5, ≥6.5 %), and left ventricular ejection fraction (<40, ≥40 %). After randomization, all the participants will be given the add-on study drug for 24 weeks in addition to their background therapy. The primary endpoint is the percentage change from baseline in NT-proBNP after 24 weeks of treatment. The key secondary endpoints after 24 weeks of treatment are the change from baseline in glycemic control, blood pressure, body weight, lipid profile, quality of life score related to heart failure, and cardiac and renal function., Discussion: The CANDLE trial is the first to assess the safety and non-inferiority of canagliflozin in comparison with glimepiride in patients with type 2 diabetes with chronic heart failure. This trial has the potential to evaluate the clinical safety and efficacy of canagliflozin on heart failure. Trial registration Unique trial Number, UMIN000017669.

An impaired endothelial function has been recognized in the early stage of atherosclerosis, and is a major factor affecting the future development of cardiovascular events. Type 2 diabetes mellitus (T2DM) is widely prevalent, and is one of the most important risk factors for cardiovascular disease. T2DM is associated with increases in both morbidity and mortality, particularly from cardiovascular disease.New therapies based on the incretin hormone and its actions are now becoming widely used, and appear to offer advantages over conventional therapies by keeping the body weight steady and limiting hypoglycemia, while also achieving attractive glycemic control. However, there is little data available about the effects of incretins on the cardiovascular system.This review will focus on the effects of incretin therapies, including glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase (DPP)-4 inhibitors, on the endothelial function, and will discuss the potential mechanisms underlying these effects.

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)-β, 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.

Type 2 diabetes mellitus (T2DM) is widely prevalent and a critical risk factor for cardiovascular disease that increases both morbidity and mortality. Recently, new therapies based on the actions of the incretin hormones have become widely used, offering advantages over conventional treatments by limiting hypoglycemia and achieving glycemic control. Moreover, many experimental studies have suggested that GLP-1 and related drugs exert cardioprotective effects on atherosclerosis and cardiac dysfunction both in vitro and in vivo. However, there is thus far little clinical evidence supporting the efficacy of incretin therapy in patients with cardiovascular disease. This review focuses on the effects of GLP-1-related therapy on cardiac function from the bench to the bed, with a discussion of possible underlying mechanisms.

Background: Recently, incretin hormones, including glucagon-like peptide-1 (GLP-1) analogue and dipeptidyl peptidase-4 (DPP-4) inhibitor, have been found to regulate glucose metabolism. The aim of this study was to elucidate the efficacy and safety of the clinical usage of DPP-4 inhibitors in Japan., Methods: This study was designed as a prospective, open-label, multi-center trial. Patients with diabetes mellitus type 2 (T2DM) with poor glycemic profiles (HbA1c ≥ 6.2%) in spite of receiving a medical diet, therapeutic exercise, and/or medications were eligible for this study. The participants received 50 to 100 mg of the DPP-4 inhibitor sitagliptin once daily for 12 months., Results: One hundred and eighty-eight subjects were enrolled. After 12 months of sitagliptin treatment, HbA1c levels decreased (7.65% ± 1.32% to 7.05% ± 1.10%, p < 0.001) as well as fasting plasma glucose (FPG) (145 ± 52 mg/dl to 129 ± 43 mg/dl, p = 0.005). The rate of glycemic control achieved (in accordance with the guidelines of the Japanese Diabetes Society) significantly increased. Blood pressure and serum levels of triglycerides and total cholesterol decreased significantly. Furthermore, the Pittsburgh Sleep Quality Index (PSQI) and Diabetes Symptomatic Scores improved significantly. Adverse events such as hypoglycemia and loss of consciousness occurred in twenty three subjects (11%)., Conclusions: These results suggest that the actions of DPP-4 inhibitors improve not only glycemic control, but also blood pressure, lipid profiles, and quality of life (QOL). Sitagliptin is a sound agent for use in the comprehensive treatment of patients with T2DM.

The telomere length and subtelomeric methylated status of peripheral blood leukocytes has been reported to be correlated with many kinds of pathophysiological conditions. However, the correlation between the telomeric parameters and clinical laboratory data in metabolic disorders is not well known. This study investigated the correlation between the telomere length and subtelomeric methylated status in peripheral leukocytes and the laboratory data of male outpatients with combined metabolic disorders and no clinical history of cardiovascular or cerebrovascular event were assessed, to find good clinical laboratory markers reflecting the biological aging. The laboratory data were collected in 26 Japanese male outpatients with diabetes mellitus and hyperlipidemia, and no history of cardiovascular or cerebrovascular event, and the telomeric parameters in their peripheral leukocytes were determined by Southern blot with methylation-sensitive and insensitive isoschizomers. Any correlations between the laboratory data and the telomeric parameters were assessed. The patients showed a significant negative correlation among the bilirubin and creatine phosphokinase with the aging-associate change of the telomeric and subtelomeric parameters. Lowered serum bilirubin and creatinine phosphokinase level correlated to genomic aging represented by telomere attrition of patients with metabolic disorders.

This study was conducted to examine telomere biology in terms of improving insulin sensitivity in a type 2 diabetic animal model: Otsuka Long-Evans Tokushima fatty (OLETF) rats. To improve insulin sensitivity, pioglitazone (PG; 10 mg.kg(-1).day(-1)) was administrated to OLETF rats from 20 to 40 wk of age, and the effects of treatment were compared with those in untreated OLETF or control Long-Evans Tokushima Otsuka fatty rats. At the end of the study, the homeostasis model assessment of insulin resistance significantly increased in OLETF rats but decreased in OLETF rats treated with PG. No shortening of telomere length was observed in the heart tissue of OLETF rats, whereas telomerase activity was decreased in OLETF heart tissue. The mRNA expression of both telomerase reverse transcriptase and telomere repeat binding factor 2 was downregulated in the hearts of OLETF rats. The protein expression of phospho-Akt, insulin-like growth factor, and endothelial nitric oxide synthase was reduced in OLETF rats. On the other hand, myocardial matrix metalloproteinase-9 expression was elevated in OLETF rats. The changes observed in OLETF rats were inhibited by PG treatment. However, protein and mRNA expression of Sirt1, a lifespan modulator, were attenuated in OLETF rat hearts, although they were enhanced in OLETF rats with PG treatment. Myocardial fibrosis was less extensive and diastolic dysfunction more greatly ameliorated in PG-treated OLETF rats than in OLETF rats. These findings suggest that improving insulin sensitivity via the activation of peroxisom proliferator-activated receptor-gamma may exert regulatory effects on cardiac telomere biology and may have desirable morphological and functional effects on the diabetic heart.