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Background: Serum alkaline phosphatase (ALP) is associated with incident cardiovascular disease (CVD), coronary artery disease, vascular calcification, cerebral small vessel disease and ischemic stroke. Recent studies also associate elevated ALP with impaired cognition, suggesting neuronal or neurovascular dysfunction. To date there is no specific pharmacological means to lower ALP. Bromodomain & extraterminal (BET) proteins bind to acetylated histones on chromatin and regulate gene transcription. Apabetalone (ABET) targets the second bromodomain of BET proteins and inhibits expression of genes that participate in vascular inflammation and calcification, coagulation and the complement pathway. In CVD patients (pts), ABET lowers serum ALP in a dose-dependent manner. Method(s): In phase 2 ABET studies (n=795) up to 26 weeks' duration in CVD pts, we assessed the relationship of ALP and CVD events. In the ongoing phase 3 BETonMACE study with ABET (n=2,425), baseline cognitive function (Montreal Cognitive Assessment, MoCA) and ALP were measured in pts aged 70 yrs and older (n=467). Result(s): In phase 2 studies, CVD events (death, non-fatal MI, coronary revascularization, or hospitalization for CV cause) were lowered by 44% (p=0.02) with ABET. Baseline ALP (median 72 U/L) independently predicted CVD events (hazard ratio [HR] per standard deviation [SD] 1.6, 95% CI 1.2-2.1, p<0.001). Mean ABET decrease in ALP from baseline was 8.45% (p<0.001), or 6.6 U/L. A 1 SD (13.0 U/L) reduction in ALP with ABET was associated with a HR for MACE of 0.58 (95% CI 0.43-0.78, p<0.001). In the BETonMACE trial pts were classified by baseline MoCA >26 (normal, n=221), 21-25 (borderline, n=161), or <21 (impaired, n=85). Pts with impaired cognition had higher ALP (trend p-value 0.006), lower eGFR (66 vs. 71, p=0.04), and higher hsCRP (4.8 vs.1.8, p=0.03). Conclusion(s): Serum ALP is associated with coronary and cerebral vascular disease. ABET is a BET-inhibitor that lowers serum ALP in CVD pts

Background: Virtual histology intravascular ultrasound (VH-IVUS) imaging is an innovative tool for the morphological evaluation of coronary atherosclerosis. Evidence for the effects of statin therapy on VH-IVUS parameters have been inconclusive. Consequently, we performed a systematic review and meta-analysis to investigate the impact of statin therapy on plaque volume and its composition using VH-IVUS. Methods: The search included PubMed, Cochrane Library, Scopus and Embase (through 30 November 2014) to identify prospective studies investigating the effects of statin therapy on plaque volume and its composition using VH-IVUS. Results: We identified nine studies with 16 statin treatment arms and 830 participants. There was a significant effect of statin therapy in reducing plaque volume (standardized mean difference (SMD): -0.137, 95 % confidence interval (CI): -0.255, -0.019; P = 0.023), external elastic membrane volume (SMD: -0.097, 95 % CI: -0.183, -0.011; P = 0.027) but not lumen volume (SMD: -0.025, 95 % CI: -0.110, +0.061; P = 0.574). There was a significant reduction in fibrous plaque volume (SMD: -0.129, 95 % CI: -0.255, -0.003; P = 0.045) and an increase of dense calcium volume (SMD: +0.229, 95 % CI: +0.008, +0.450

Reducing low-density lipoprotein cholesterol (LDL-C) levels using statins is associated with significant reductions in cardiovascular (CV) events in a wide range of patient populations. Although statins are generally considered to be safe, recent studies suggest they are associated with an increased risk of developing Type 2 diabetes (T2D). This led the US Food and Drug Administration (FDA) to change their labelling requirements for statins to include a warning about the possibility of increased blood sugar and HbA1c levels and the European Medicines Agency (EMA) to issue guidance on a small increased risk of T2D with the statin class. This review examines the evidence leading to these claims and provides practical guidance for primary care physicians on the use of statins in people with or at risk of developing T2D. Overall, evidence suggests that the benefits of statins for the reduction of CV risk far outweigh the risk of developing T2D, especially in individuals with higher CV risk. To reduce the risk of developing T2D, physicians should assess all patients for T2D risk prior to starting statin therapy, educate patients about their risks, and encourage risk-reduction through lifestyle changes. Whether some statins are more diabetogenic than others requires further study. Statin-treated patients at high risk of developing T2D should regularly be monitored for changes in blood glucose or HbA1c levels, and the risk of conversion from pre-diabetes to T2D should be reduced by intensifying lifestyle changes. Should a patient develop T2D during statin treatment, physicians should continue with statin therapy and manage T2D in accordance with relevant national guidelines