BACKGROUND Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications. METHODS This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. FINDINGS Between March 12, 2013, and May 10, 2016, we ; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043). INTERPRETATION Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding. FUNDING Bayer AG. Methods This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, i...

Aims:To determine the effects of empagliflozin on blood pressure (BP) and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes mellitus (T2DM). Methods:We conducted a post hoc analysis of data from a phase III trial in patients with T2DM and hypertension receiving 12 weeks' empagliflozin and four phase III trials in patients with T2DM receiving 24 weeks' empagliflozin (cohort 1, n = 823; cohort 2, n = 2477). BP was measured using 24-h BP monitoring (cohort 1) or seated office measurements (cohort 2).Results: Empagliflozin reduced systolic BP (SBP) and diastolic BP in both cohorts (p < 0.001 vs placebo), without increasing heart rate. Empagliflozin reduced pulse pressure (PP; adjusted mean difference vs placebo cohort 1: −2.3 mmHg; cohort 2: −2.3 mmHg), mean arterial pressure (MAP; cohort 1, −2.3 mmHg; cohort 2, −2.1 mmHg) and double product (cohort 1, −385 mmHg × bpm; cohort 2, −369 mmHg × bpm) all p < 0.001 vs placebo. There was a trend towards a reduction in the ambulatory arterial stiffness index (AASI) with empagliflozin in cohort 1 (p = 0.059 vs placebo). AASI was not measured in cohort 2. Subgroup analyses showed that there were greater reductions in PP with increasing baseline SBP in cohort 1 (p = 0.092). In cohort 2, greater reductions in MAP were achieved in patients with higher baseline SBP (p = 0.027) and greater reductions in PP were observed in older patients (p = 0.011). Conclusions IntroductionCardiovascular (CV) disease is the major cause of morbidity and mortality in patients with type 2 diabetes (T2DM) [1]. The risk of CV disease in adults with diabetes is double that in adults without diabetes, and diabetes is estimated to account for 10-12% of all vascular deaths [2]. Patients with T2DM often have numerous CV risk factors and a multifactorial approach to addressing CV risk, including controlling glycaemia, blood pressure (BP) and body weight, is recommended in these patients [1,3].The metabolic abnormalities that are characteristic of diabetes, such as hyperglycaemia, excess free fatty acids and insulin resistance, can lead to suppression of nitric oxide production and activation of the renin-angiotensin system, leading to oxidative stress, endothelial dysfunction and activation of the receptor for advanced glycation end products (RAGE) [4][5][6]. These may contribute to hypertension [7] or to increased arterial stiffness related to vascular calcification or accumulation ofCorrespondence to: Odd Erik Johansen, Boehringer Ingelheim Norway KS, Asker, Norway. E-mail: odd_erik.johansen@boehringer-ingelheim.com This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.collagen [8,9] that could partly explain the increased risk of vascular complications associated with T2DM [4].Arterial stiffness is a strong predictor of CV events, heart failure and death [10][11][12]...

Although cardiovascular (CV) mortality is the principal cause of death in individuals with type 2 diabetes (T2DM), reduction of plasma glucose concentration has little effect on CV disease (CVD) risk. Thus, novel strategies to reduce CVD risk in T2DM patients are needed. The recently published BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study demonstrated that in T2DM patients with high CVD risk empagliflozin reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina. Although sodium–glucose cotransporter 2 inhibitors exert multiple metabolic benefits (decreases in HbA1c, body weight, and blood pressure and an increase in HDL cholesterol), all of which could reduce CVD risk, it is unlikely that the reduction in CV mortality can be explained by empagliflozin’s metabolic effects. More likely, hemodynamic effects, specifically reduced blood pressure and decreased extracellular volume, are responsible for the reduction in CV mortality and heart failure hospitalization. In this Perspective, we will discuss possible mechanisms for these beneficial effects of empagliflozin and their implications for the care of T2DM patients.

Aims:To determine the effects of empagliflozin on adiposity indices among patients with type 2 diabetes mellitus.Methods:Changes in weight, waist circumference, estimated total body fat, index of central obesity and visceral adiposity index were assessed using analysis of covariance and testing of treatment by strata for age, sex and baseline waist circumference in patients with type 2 diabetes mellitus randomized to blinded treatment with empagliflozin versus placebo in clinical trials of 12 weeks (cohort 1) or 24 weeks (cohort 2) duration.Results:This study comprised 3300 patients (cohort 1, N = 823; cohort 2, N = 2477). Empagliflozin reduced weight, waist circumference and adiposity indices versus placebo in both cohorts. Adjusted mean (95% confidence interval) change from baseline in empagliflozin versus placebo was −1.7 kg (−2.1 to −1.4 kg) and −1.9 kg (−2.1 to −1.7 kg) for body weight (p < 0.001); −1.3 cm (−1.8 to −0.7 cm) and −1.3 cm (−1.7 to −1.0 cm) for waist circumference (p < 0.001); −0.2% (−0.7% to 0.3%; p = 0.45) and −0.3% (−0.7% to 0.0%; p = 0.08) for estimated total body fat; −0.007 (−0.011 to −0.004) and −0.008 (−0.010 to −0.006) for index of central obesity (p < 0.001); and −0.3 (−0.5 to 0.0; p = 0.07) and −0.4 (−0.7 to −0.1; p = 0.003) for visceral adiposity index in cohorts 1 and 2, respectively. Adipose reductions were seen across most age, sex and waist circumference subgroups.Conclusion:Empagliflozin significantly reduced weight and adiposity indices with the potential to improve cardiometabolic risk among patients with type 2 diabetes mellitus.

Hyperglycemia is the major risk factor for microvascular complications in patients with type 2 diabetes (T2D). However, cardiovascular disease (CVD) is the principal cause of death, and lowering HbA1c has only a modest effect on reducing CVD risk and mortality. The recently published LEADER and SUSTAIN-6 trials demonstrate that, in T2D patients with high CVD risk, the glucagon-like peptide 1 receptor agonists liraglutide and semaglutide reduce the primary major adverse cardiac events (MACE) end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) by 13% and 24%, respectively. The EMPA-REG OUTCOME, IRIS (subjects without diabetes), and PROactive (second principal end point) studies also demonstrated a significant reduction in cardiovascular events in T2D patients treated with empagliflozin and pioglitazone. However, the benefit of these four antidiabetes agents (liraglutide, semaglutide, empagliflozin, and pioglitazone) on the three individual MACE end points differed, suggesting that different underlying mechanisms were responsible for the reduction in cardiovascular events. Since liraglutide, semaglutide, pioglitazone, and empagliflozin similarly lower the plasma glucose concentration but appear to reduce CVD risk by different mechanisms, there emerges the intriguing possibility that, if used in combination, the effects of these antidiabetes agents may be additive or even multiplicative with regard to cardiovascular benefit.

Purpose of Review We aim to provide a comprehensive analysis of hypercoagulability in individuals affected by COVID-19. Our goal is to describe the hypercoagulable state related to the infection and provide guidance regarding the possible benefits of anti-coagulation with the support of evidence from current literature. Recent Findings The incidence of thrombotic disease in individuals affected by COVID-19 is reported as high as 31%. A significant mortality benefit has been observed with the use of therapeutic anticoagulation in high-risk individuals. Literature supports the use of scoring systems, such as the sepsis-induced coagulopathy score, to risk-stratify individuals who might benefit from anticoagulation. Summary COVID-19-induced hypercoagulability has been demonstrated to play a significant role in overall COVID-19 outcomes. Current literature shows promising evidence with the use of therapeutic anticoagulation in high-risk individuals. Further studies are needed to better analyze the risks and benefits of anticoagulation in this specific patient population.

Paraoxonase-1 (PON1) is a high-density lipoprotein-associated esterase and is speculated to play a role in several human diseases including diabetes mellitus and atherosclerosis. Low PON1 activity has been associated with increased risk of major cardiovascular events, therefore a variety of studies have been conducted to establish the cardioprotective properties and clinical relevance of PON1. The major aim of this review was to highlight the important studies and to subsequently assess if PON1 has clinical relevance. A review of the literature showed that there is currently insufficient data to suggest that PON1 has clinical relevance. It is our opinion that robust studies are required to clarify the clinical relevance of PON1.

Aortic stiffness is a hallmark of aging, and classic cardiovascular risk factors play a role in accelerating this process. Current changes in medicine, which focus on preventive care, have led to a growing interest in noninvasive evaluation of aortic stiffness. Aortic stiffness has emerged as a good tool for further risk stratification because it has been linked to increased risk of atherosclerotic heart disease, myocardial infarction, heart failure, and stroke. This has led to the invention and validation of multiple methods to measure aortic stiffness. Pulse wave velocity is emerging as the gold standard for evaluation of aortic stiffness. This review focuses on the pathophysiology involved in aortic stiffness, methods available for evaluation of aortic stiffness, the importance of central pressure as a predictor of future cardiovascular events, and therapies that affect aortic stiffness.