Teruo Inoue

The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes: The PROLOGUE Randomized Controlled Trial

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

Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial

AbstractBackgroundBecause 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.MethodsA 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,xa0≥65xa0year), HbA1c level (<6.5,xa0≥6.5xa0%), and left ventricular ejection fraction (<40,xa0≥40xa0%). After randomization, all the participants will be given the add-on study drug for 24xa0weeks in addition to their background therapy. The primary endpoint is the percentage change from baseline in NT-proBNP after 24xa0weeks of treatment. The key secondary endpoints after 24xa0weeks 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.DiscussionThe 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.n Trial registration Unique trial Number, UMIN000017669

Long-term effect of sitagliptin on endothelial function in type 2 diabetes: a sub-analysis of the PROLOGUE study

AbstractBackgroundAs a sub-analysis of the PROLOGUE study, we evaluated the long-term effect of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on endothelial function in the conduit brachial artery in patients with type 2 diabetes.MethodsIn the PROLOGUE study, patients were randomly assigned to either add-on sitagliptin treatment (sitagliptin group) or continued conventional antihyperglycemic treatment (conventional group). Among the 463 participants in the PROLOGUE study, FMD was measured in 17 patients in the sitagliptin group and 18 patients in the conventional group at the beginning and after 12 and 24xa0months of treatment.ResultsHbA1c levels were significantly decreased after 12 and 24xa0months of treatment compared to baseline values in both groups (7.0xa0±xa00.4 vs. 6.6xa0±xa00.3 and 6.6xa0±xa00.4xa0% in the sitagliptin group; 7.0xa0±xa00.6 vs. 6.6xa0±xa00.7 and 6.6xa0±xa00.7xa0% in the conventional group; Pxa0<xa00.05, respectively). There was no significant difference between FMD values at baseline and after 12 and 24xa0months in the sitagliptin group (4.3xa0±xa02.6 vs. 4.4xa0±xa02.1 and 4.4xa0±xa02.3xa0%, Pxa0=xa01.0, respectively). Although FMD had a tendency to increase from 4.3xa0±xa02.4xa0% at baseline to 5.2xa0±xa01.9xa0% after 12xa0months and 5.1xa0±xa02.2xa0% after 24xa0months in the conventional group, there was no significant difference between FMD values at baseline and after 12 and 24xa0months (Pxa0=xa00.36 and 0.33, respectively).ConclusionsAdd-on sitagliptin to conventional antihyperglycemic drugs in patients with type 2 diabetes did not alter endothelial function in the conduit brachial artery measured by FMD during a 2-year study period. Sitagliptin may be used without concern for an adverse effect on endothelial function in patients with type 2 diabetes.n Trial registration: University hospital Medical Information Network (UMIN) Center: ID UMIN000004490

Waon Therapy for Managing Chronic Heart Failure – Results From a Multicenter Prospective Randomized WAON-CHF Study –

BACKGROUNDnWaon therapy improves heart failure (HF) symptoms, but further evidence in patients with advanced HF remains uncertain.nnnMETHODSANDRESULTSnIn 19 institutes, we prospectively enrolled hospitalized patients with advanced HF, who had plasma levels of B-type natriuretic peptide (BNP) >500 pg/ml on admission and BNP >300 pg/ml regardless of more than 1 week of medical therapy. Enrolled patients were randomized into Waon therapy or control groups. Waon therapy was performed once daily for 10 days with a far infrared-ray dry sauna maintained at 60℃ for 15 min, followed by bed rest for 30 min covered with a blanket. The primary endpoint was the ratio of BNP before and after treatment. In total, 76 Waon therapy and 73 control patients (mean age 66 years, men 61%, mean plasma BNP 777 pg/ml) were studied. The groups differed only in body mass index and the frequency of diabetes. The plasma BNP, NYHA classification, 6-min walk distance (6MWD), and cardiothoracic ratio significantly improved only in the Waon therapy group. Improvements in NYHA classification, 6MWD, and cardiothoracic ratio were significant in the Waon therapy group, although the change in plasma BNP did not reach statistical significance. No serious adverse events were observed in either group.nnnCONCLUSIONSnWaon therapy, a holistic soothing warmth therapy, showed clinical advantages in safety and efficacy among patients with advanced HF.

Rationale and design of a multicenter randomized controlled study to evaluate the preventive effect of ipragliflozin on carotid atherosclerosis: the PROTECT study

AbstractBackgroundType 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.MethodsA total of 480 participants with type 2 diabetes mellitus with a HbA1c between 6 and 10xa0% despite receiving diet/exercise therapy and/or standard anti-diabetic agents for at least 3xa0months, will be randomized systematically (1:1) into either ipragliflozin or control (continuation of conventional therapy) groups. After randomization, ipragliflozin (50–100xa0mg 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 24xa0months. 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.DiscussionThe 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.n Trial registration Unique Trial Number, UMIN000018440 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021348)

Which has the stronger impact on coronary artery disease, eicosapentaenoic acid or docosahexaenoic acid?

It has been suggested that n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against cardiovascular diseases, and EPA/arachidonic acid (AA) and DHA/AA ratios in serum are potential risk markers for coronary artery disease (CAD). The purpose of this study was to clarify the clinical significance of the difference in the EPA/AA ratio and the DHA/AA ratio in patients with CAD. In 369 patients with confirmed or suspected CAD who underwent diagnostic coronary angiography, we measured serum levels of EPA, DHA and AA and calculated the EPA/AA and DHA/AA ratios. The EPA/AA ratio was significantly lower in patients with acute coronary syndrome (ACS) than in patients with chronic CAD or chest pain syndrome (0.27±0.19 vs. 0.44±0.20, respectively; P<0.01), whereas the DHA/AA ratio was similar in the two groups (0.78±0.27 vs. 0.79±0.37). Multiple logistic regression analyses using various biomarkers related to coronary risk discriminated ACS from other disease entities and demonstrated that the EPA/AA ratio (odds ratio: 0.0012, 95% confidence interval: 0.00–0.16, P<0.01) but not the DHA/AA ratio (odds ratio: 1.05, 95% confidence interval: 0.98–1.12) was a significant independent predictive factor. Our findings suggest that the EPA/AA ratio might be more closely associated with the pathophysiology of CAD, especially with that of ACS, than the DHA/AA ratio. Our findings suggest that interventions with EPA agents or supplemental EPA intake, compared with DHA agents or supplemental DHA, may confer greater benefit for plaque stabilization to prevent the onset of ACS in patients with CAD.

Repetitive restriction of muscle blood flow enhances mTOR signaling pathways in a rat model

Skeletal muscle is a plastic organ that adapts its mass to various stresses by affecting pathways that regulate protein synthesis and degradation. This study investigated the effects of repetitive restriction of muscle blood flow (RRMBF) on microvascular oxygen pressure (PmvO2), mammalian target of rapamycin (mTOR) signaling pathways, and transcripts associated with proteolysis in rat skeletal muscle. Eleven-week-old male Wistar rats under anesthesia underwent six RRMBF consisting of an external compressive force of 100xa0mmHg for 5xa0min applied to the proximal portion of the right thigh, each followed by 3xa0min rest. During RRMBF, PmvO2 was measured by phosphorescence quenching techniques. The total RNA and protein of the tibialis anterior muscle were obtained from control rats, and rats treated with RRMBF 0–6xa0h after the stimuli. The protein expression and phosphorylation of various signaling proteins were determined by western blotting. The mRNA expression level was measured by real-time RT-PCR analysis. The total muscle weight increased in rats 0xa0h after RRMBF, but not in rats 1–6xa0h. During RRMBF, PmvO2 significantly decreased (36.1xa0±xa05.7 to 5.9xa0±xa01.7xa0torr), and recovered at rest period. RRMBF significantly increased phosphorylation of p70 S6-kinase (p70S6k), a downstream target of mTOR, and ribosomal protein S6 1xa0h after the stimuli. The protein level of REDD1 and phosphorylation of AMPK and MAPKs did not change. The mRNA expression levels of FOXO3a, MuRF-1, and myostatin were not significantly altered. These results suggested that RRMBF significantly decreased PmvO2, and enhanced mTOR signaling pathways in skeletal muscle using a rat model, which may play a role in diminishing muscle atrophy under various conditions in human studies.

The wound healing response after implantation of a drug‑eluting stent is impaired persistently in the long term

A 70-year-old man underwent stent implantation for right coronary artery (RCA) lesions with a bare metal stent (BMS) and two sirolimus-eluting stents (SES). However, as both the BMS and SES stented sites developed restenosis after 13xa0months, he underwent target lesion revascularization using directional coronary atherectomy (DCA). On histopathology, the restenosis lesion at the SES-deployed site showed greater inflammation and less re-endothelialization than that at the BMS-deployed site. Three months later, the SES-deployed site developed a second restenosis, in which paclitaxel-eluting stents (PES) were implanted (PES-in-SES), while the BMS-deployed site was restenosis free. Five years later, restenosis was absent in these RCA lesions. However, by optical coherence tomography and/or coronary angioscopy, the PES-in-SES site in the RCA showed poor neointimal coverage over the stent struts and yellowish neointima, suggesting lipid-rich neoatheroma formation, whereas at the BMS site appropriate white neointima formation was observed. Drug-eluting stents still have problems of persistent inflammation, inappropriate neointima formation, and neoatherosclerosis. Although we are now in the era of second generation DESs in which better stent performance would be promising, we should remember that we are obliged to continue to follow-up all patients in whom first generation DESs such as SES or PES have been placed.

Effect of a cardiac rehabilitation program on exercise oscillatory ventilation in Japanese patients with heart failure.

Although exercise oscillatory ventilation has emerged as a potent independent risk factor for adverse prognosis in heart failure, it is not well known whether cardiac rehabilitation can improve oscillatory ventilation. In this study, we investigated the magnitude of oscillations in ventilation before and after cardiac rehabilitation in chronic heart failure patients with exercise oscillatory ventilation. Cardiac rehabilitation (5-month program) was performed in 26 patients with chronic heart failure who showed an oscillatory ventilation pattern during cardiopulmonary exercise testing (CPX). After the 5-month rehabilitation program was completed, the patients again underwent CPX. To determine the magnitude of oscillations in ventilation, the amplitude and cycle length of the oscillations were calculated and compared with several other parameters, including biomarkers that have established prognostic value in heart failure. At baseline before cardiac rehabilitation, both oscillation amplitude (Rxa0=xa00.625, Pxa0<xa00.01) and cycle length (Rxa0=xa00.469, Pxa0<xa00.05) were positively correlated with the slope of minute ventilation vs. carbon dioxide production. Plasma BNP levels were positively correlated with amplitude (Rxa0=xa00.615, Pxa0<xa00.01) but not cycle length (Rxa0=xa00.371). Cardiac rehabilitation decreased oscillation amplitude (Pxa0<xa00.01) but failed to change cycle length. The change in amplitude was positively correlated with the change in BNP levels (Rxa0=xa00.760, Pxa0<xa00.01). Multiple regression analysis showed that only the change in amplitude was an independent predictor of the change in BNP levels (Rxa0=xa00.717, Pxa0<xa00.01). A 5-month cardiac rehabilitation program improves exercise oscillatory ventilation in chronic heart failure patients by reducing the oscillation amplitude. This effect is associated with a reduction of plasma BNP levels, potentially contributing to an improvement of heart failure.

Comparison of the performance of zotarolimus- and everolimus-eluting stents by optical coherence tomography and coronary angioscopy

Overall stent performance should be characterized by geometric luminal gain acquisition, neointimal coverage of the stent struts, and stabilization of the underlying inflammatory neoatheroma. The aim of this study was to compare the performance of zotarolimus-eluting stent (ZES), everolimus-eluting stent (EES) and bare metal stent (BMS) using optical coherence tomography (OCT) and coronary angioscopy. For 36 stented coronary lesions (BMS, 12 lesions; ZES, 11 lesions; EES, 13 lesions) in 27 patients, we calculated neointimal area and uncovered stent strut rate based on OCT findings at 10xa0months after stent placement. The grades of neointimal coverage and yellow color, both of which were classified from 0 to 3, were also assessed by coronary angioscopy. The plaque area of the ZES lesions was larger than that of the EES lesions (Pxa0<xa00.05) but smaller than that of the BMS lesions (Pxa0<xa00.05). The OCT-based uncovered rate of the ZES lesions was less than that of the EES lesions (Pxa0<xa00.01), but similar to that of the BMS lesions. The stent coverage grade by angioscopy was higher in the ZES lesions than in the EES lesions (Pxa0<xa00.05), but similar to the BMS lesions. The yellow grade was less in the ZES lesions than in the EES lesions (Pxa0<xa00.01), but similar to the BMS lesions. ZES might be better than BMS in terms of neointimal thickening, and better than EES in terms of neointimal coverage as well as prevention of neoatheroma formation. ZES may have superior performance compared with EES.