Clinical Characteristics and Major Adverse Cardiovascular Events in Diabetic and Non-Diabetic Patients with Vasospastic Angina [Response to Letter]

Hiroki Teragawa, Yuko Uchimura, Chikage Oshita, Yu Hashimoto, Shuichi Nomura Department of Cardiovascular Medicine, JR Hiroshima Hospital, Hiroshima, JapanCorrespondence: Hiroki Teragawa, Department of Cardiovascular Medicine, JR Hiroshima Hospital, 3-1-36 Futabanosato, Higashi-ku, Hiroshima, 732-0057, Japan, Tel +81 82 262 1171, Fax +81 82 262 1499, Email [email protected]

Effect of febuxostat on left ventricular diastolic function in patients with asymptomatic hyperuricemia : a sub analysis of the PRIZE Study

Hyperuricemia is related to an increased risk of cardiovascular events from a meta-analysis and antihyperuricemia agents may influence to cardiac function. We evaluated the effect of febuxostat on echocardiographic parameters of diastolic function in patients with asymptomatic hyperuricemia as a prespecified endpoint in the subanalysis of the PRIZE study. Patients in the PRIZE study were assigned randomly to either add-on febuxostat treatment group or control group with only appropriate lifestyle modification. Of the 514 patients in the overall study, 65 patients (31 in the febuxostat group and 34 in the control group) who had complete follow-up echocardiographic data of the ratio of peak early diastolic transmitral flow velocity (E) to peak early diastolic mitral annular velocity (e′) at baseline and after 12 and 24 months were included. The primary endpoint was a comparison of the changes in the E/e′ between the two groups from baseline to 24 months. Interestingly, e′ was slightly decreased in the control group compared with in the febuxostat group (treatment p = 0.068, time, p = 0.337, treatment × Time, p = 0.217). As a result, there were significant increases in E/e′ (treatment p = 0.045, time, p = 0.177, treatment × time, p = 0.137) after 24 months in the control group compared with the febuxostat group. There was no significant difference in the serum levels of N-terminal-pro brain natriuretic peptide and high-sensitive troponin I between the two groups during the study period. In conclusions, additional febuxostat treatment in patients with asymptomatic hyperuricemia for 24 months might have a potential of preventable effects on the impaired diastolic dysfunction

Effect of ipragliflozin on carotid intima-media thickness in type 2 diabetes patients

Aims To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. Methods and results In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0–10.0% (42–86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), −0.0155–0.0182] mm and 0.0015 (95% CI, −0.0155–0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of −0.0001 mm (95% CI, −0.0191–0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [−0.1% (95% CI, −0.2–0.1); P = 0.359]. Conclusion Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes

Effects of canagliflozin on NT-proBNP stratified by left ventricular diastolic function in patients with type 2 diabetes and chronic heart failure : a sub analysis of the CANDLE trial

Background: Identification of the effective subtypes of treatment for heart failure (HF) is an essential topic for optimizing treatment of the disorder. We hypothesized that the beneficial effect of SGLT2 inhibitors (SGLT2i) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) might depend on baseline diastolic function. To elucidate the effects of SGLT2i in type 2 diabetes mellitus (T2DM) and chronic HF we investigated, as a post-hoc sub-study of the CANDLE trial, the effects of canagliflozin on NT-proBNP levels from baseline to 24 weeks, with the data stratified by left ventricular (LV) diastolic function at baseline. Methods: Patients (n = 233) in the CANDLE trial were assigned randomly to either an add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The primary endpoint was a comparison between the two groups of the changes from baseline to 24 weeks in NT-pro BNP levels, stratified according to baseline ventricular diastolic function. Results: The change in the geometric mean of NT-proBNP level from baseline to 24 weeks was 0.98 (95% CI 0.89–1.08) in the canagliflozin group and 1.07 (95% CI 0.97–1.18) in the glimepiride group. The ratio of change with canagliflozin/glimepiride was 0.93 (95% CI 0.82–1.05). Responder analyses were used to investigate the response of an improvement in NT-proBNP levels. Although the subgroup analyses for septal annular velocity (SEP-e′) showed no marked heterogeneity in treatment effect, the subgroup with an SEP-e′ < 4.7 cm/s indicated there was an association with lower NT-proBNP levels in the canagliflozin group compared with that in the glimepiride group (ratio of change with canagliflozin/glimepiride (0.83, 95% CI 0.66–1.04). Conclusions: In the subgroup with a lower LV diastolic function, canagliflozin showed a trend of reduced NT-pro BNP levels compared to that observed with glimepiride. This study suggests that the beneficial effects of canagliflozin treatment may be different in subgroups classified by the severity of LV diastolic dysfunction

Rationale and design of a multicenter randomized study for evaluating vascular function under uric acid control using the xanthine oxidase inhibitor, febuxostat : the PRIZE study

Background: Xanthine oxidase inhibitors are anti-hyperuricemic drugs that decrease serum uric acid levels by inhibiting its synthesis. Xanthine oxidase is also recognized as a pivotal enzyme in the production of oxidative stress. Excess oxidative stress induces endothelial dysfunction and inflammatory reactions in vascular systems, leading to atherosclerosis. Many experimental studies have suggested that xanthine oxidase inhibitors have anti-atherosclerotic effects by decreasing in vitro and in vivo oxidative stress. However, there is only limited evidence on the clinical implications of xanthine oxidase inhibitors on atherosclerotic cardiovascular disease in patients with hyperuricemia. We designed the PRIZE study to evaluate the effects of febuxostat on a surrogate marker of cardiovascular disease risk, ultrasonography-based intima-media thickness of the carotid artery in patients with hyperuricemia. Methods: The study is a multicenter, prospective, randomized, open-label and blinded-endpoint evaluation (PROBE) design. A total of 500 patients with asymptomatic hyperuricemia (uric acid >7.0 mg/dL) and carotid intima-media thickness ≥1.1 mm will be randomized centrally to receive either febuxostat (10–60 mg/day) or non-pharmacological treatment. Randomization is carried out using the dynamic allocation method stratified according to age (<65, ≥65 year), gender, presence or absence of diabetes mellitus, serum uric acid (<8.0, ≥8.0 mg/dL), and carotid intima-media thickness (<1.3, ≥1.3 mm). In addition to administering the study drug, we will also direct lifestyle modification in all participants, including advice on control of body weight, sleep, exercise and healthy diet. Carotid intima-media thickness will be evaluated using ultrasonography performed by skilled technicians at a central laboratory. Follow-up will be continued for 24 months. The primary endpoint is percentage change in mean intima-media thickness of the common carotid artery 24 months after baseline, measured by carotid ultrasound imaging. Conclusions: PRIZE will be the first study to provide important data on the effects of febuxostat on atherosclerosis in patients with asymptomatic hyperuricemia

Febuxostat and carotid atherosclerosis in asymptomatic hyperuricemia

Background An elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia. Methods and findings The study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10–60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat − control], −0.007 mm [95% confidence interval (CI) −0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, −0.016 mm [95% CI −0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI −0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI −0.5% to 3.3%] in the control group (n = 193); mean between-group difference, −0.2% [95% CI −2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI −0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, −2.62 mg/dL [95% CI −2.86 mg/dL to −2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia. Conclusions In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population

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

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

Moderate alcohol consumption is associated with better endothelial function: a cross sectional study

<p>Abstract</p> <p>Background</p> <p>Moderate alcohol consumption is protective against coronary artery disease. Endothelial dysfunction contributes to atherosclerosis and the pathogenesis of cardiovascular disease. The effects of alcohol consumption on endothelial function may be relevant to these cardiovascular outcomes, but very few studies have examined the effect of alcohol consumption on endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery in humans.</p> <p>Methods</p> <p>In the population-based Northern Manhattan Study (NOMAS), we performed a cross-sectional analysis of lifetime alcohol intake and brachial artery FMD during reactive hyperemia using high-resolution B-mode ultrasound images among 884 stroke-free participants (mean age 66.8 years, women 56.6%, Hispanic 67.4%, black 17.4%, and white 15.2%).</p> <p>Results</p> <p>The mean brachial FMD was 5.7% and the median was 5.5%. Compared to non-drinkers, those who drank >1 drink/month to 2 drinks/day were more likely to have FMD above the median FMD (5.5%) (unadjusted OR 1.7, 95% CI 1.2–2.4, p = 0.005). In multivariate analysis, the relationship between moderate alcohol consumption and FMD remained significant after adjusting for multiple traditional cardiovascular risk factors, including sex, race-ethnicity, body mass index, diabetes mellitus, coronary artery disease, Framingham risk score, medication use (adjusted OR 1.8, 95%CI 1.1–3.0, p = 0.03). No beneficial effect on FMD was seen for those who drank more than 2 drinks/day.</p> <p>Conclusion</p> <p>In conclusion, consumption of up to 2 alcoholic beverages per day was independently associated with better FMD compared to no alcohol consumption in this multiethnic population. This effect on FMD may represent an important mechanism in explaining the protective effect of alcohol intake on cardiovascular disease.</p

Akt regulation of glycolysis mediates bioenergetic stability in epithelial cells

Cells use multiple feedback controls to regulate metabolism in response to nutrient and signaling inputs. However, feedback creates the potential for unstable network responses. We examined how concentrations of key metabolites and signaling pathways interact to maintain homeostasis in proliferating human cells, using fluorescent reporters for AMPK activity, Akt activity, and cytosolic NADH/NAD+ redox. Across various conditions, including glycolytic or mitochondrial inhibition or cell proliferation, we observed distinct patterns of AMPK activity, including both stable adaptation and highly dynamic behaviors such as periodic oscillations and irregular fluctuations that indicate a failure to reach a steady state. Fluctuations in AMPK activity, Akt activity, and cytosolic NADH/NAD+ redox state were temporally linked in individual cells adapting to metabolic perturbations. By monitoring single-cell dynamics in each of these contexts, we identified PI3K/Akt regulation of glycolysis as a multifaceted modulator of single-cell metabolic dynamics that is required to maintain metabolic stability in proliferating cells