Cardiovascular Safety and Sclerostin Inhibition – a mini-review

2021 ◽  
Author(s):  
Bente Lomholt Langdahl ◽  
Lorenz Christian Hofbauer ◽  
John Colin Forfar
Keyword(s):  
Clinical Trials ◽  
Cardiovascular Risk ◽  
Postmenopausal Women ◽  
Cardiovascular Events ◽  
Harmful Effect ◽  
Careful Consideration ◽  
Cardiovascular Safety ◽  
Treatment Groups ◽  
The Media ◽  
Canonical Wnt

Abstract Sclerostin is primarily produced by the osteocytes, inhibits the canonical Wnt pathway and thereby the osteoblasts, and stimulates RANKL release by the osteocytes and thereby osteoclast recruitment. Inhibition of sclerostin therefore causes stimulation of bone formation and inhibition of resorption. In clinical trials romosozumab, an antibody against sclerostin, increases BMD and reduces the risk of fractures compared to placebo and alendronate. The cardiovascular safety of romosozumab was adjudicated in 2 large clinical osteoporosis trials in postmenopausal women. Compared with placebo, the incidence of cardiovascular events was similar in the two treatment groups. Compared to alendronate, the incidence of serious cardiovascular events was higher in women treated with romosozumab. The incidence of serious cardiovascular adverse events was low and posthoc analyses should therefore be interpreted with caution, however, the relative risk seemed unaffected by preexisting cardiovascular disease or risk factors. Sclerostin is expressed in the vasculature, predominantly in vascular smooth muscle cells in the media. However, preclinical and genetic studies have not demonstrated any increased cardiovascular risk with continuously low sclerostin levels or inhibition of sclerostin. Furthermore, no potential mechanisms for such an effect have been identified. In conclusion, while there is no preclinical or genetic evidence of a harmful effect of sclerostin inhibition on cardiovascular safety, the evidence from the large clinical trials in postmenopausal women is conflicting. Romosozumab should therefore be used for the treatment of postmenopausal women with osteoporosis at high risk of fracture after careful consideration of the cardiovascular risk and the balance between benefits and risks.

scholarly journals Microbiota Modulation to Reduce Cardiovascular Risk in HIV Patients: A Systematic Review

2021 ◽  
Author(s):  
Villoslada-Blanco Pablo ◽  
Pérez-Matute Patricia ◽  
Oteo José A
Keyword(s):  
Clinical Trials ◽  
Cardiovascular Risk ◽  
Cardiovascular Events ◽  
Scientific Evidence ◽  
Accelerated Aging ◽  
Hiv Patients ◽  
Fecal Transplantation ◽  
Immunodeficiency Virus ◽  
Adult Humans ◽  
New Biomarkers

Abstract Background: human immunodeficiency virus (HIV) infection is associated with premature and accelerated aging linked to the development of several co-morbidities, such as cardiovascular events, even after controlling for traditional cardiovascular risk factors. Since both traditional and “novel” factors are involved in the increased cardiovascular risk (CVR) observed in HIV-infected patients, new biomarkers could be needed to diagnose, evaluate and prevent the evolution of these events. Furthermore, since microbiota disturbance is involved in HIV-associated co-morbidities, all strategies focused on reversing or modulating gut microbiota (GM) composition and/or functionality could be of interest. In this context, a solid scientific evidence based on well-designed clinical trials is needed to support the use of prebiotics, probiotics, symbiotics and fecal transplantation (FT) to modify GM in HIV-infected patients and, therefore, to reduce the incidence of cardiovascular disease (CVD) in this population. Methods: a search in PubMed has been carried out covering all clinical trials (Clinical Trial filter) including adult humans (19+ years) and whose results have been published in the last 10 years. Besides, the results obtained from ClinicalTrials.gob have been included and described in the present review Thus, we have reviewed the main results obtained from 3 clinical trials concerning the effects of prebiotics, 25 concerning probiotics, 6 concerning symbiotics and 4 concerning FT. Results: none of the trials included in this review investigated if these compounds were able to reduce cardiovascular events in HIV patients. Conclusions: the huge variability observed in the type of compound used, the dose and the length of administration, makes difficult to analyse the results as a proper meta-3 analysis and, therefore, to adopt general recommendations. Thus, there is an urgent need to investigate in this direction through robust and well-designed clinical trials.

scholarly journals Cardiovascular safety of nintedanib in subgroups by cardiovascular risk at baseline in the TOMORROW and INPULSIS trials

2019 ◽  
Vol 54 (3) ◽  
pp. 1801797 ◽  
Author(s):  
Imre Noth ◽  
Marlies Wijsenbeek ◽  
Martin Kolb ◽  
Francesco Bonella ◽  
Lizette Moros ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Cardiovascular Events ◽  
Kinase Inhibitor ◽  
Incidence Rates ◽  
Major Adverse Cardiovascular Events ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cardiovascular Safety ◽  
History Of

Nintedanib is a tyrosine kinase inhibitor used to treat idiopathic pulmonary fibrosis (IPF). We investigated the cardiovascular safety of nintedanib using pooled data from the TOMORROW and INPULSIS trials.Cardiovascular events were assessed post hoc in patients with a history of atherosclerotic cardiovascular disease (CVD) and/or one or more cardiovascular risk factors at baseline (“higher cardiovascular risk”) and patients with no history of atherosclerotic CVD and no cardiovascular risk factors at baseline (“lower cardiovascular risk”).Incidence rates were calculated for 1231 patients (n=723 nintedanib and n=508 placebo), of whom 89.9% had higher cardiovascular risk. Incidence rates of major adverse cardiovascular events were similar in the nintedanib and placebo groups in patients with higher cardiovascular risk (3.88 (95% CI 2.58–5.84) and 3.49 (95% CI 2.10–5.79) per 100 patient-years, respectively) and lower cardiovascular risk (4.78 (95% CI 1.54–14.82) and 5.37 (95% CI 1.73–16.65) per 100 patient-years, respectively). Incidence rates of myocardial infarction in the nintedanib and placebo groups, respectively, were 3.03 (95% CI 1.91–4.81) and 1.16 (95% CI 0.48–2.79) per 100 patient-years in patients with higher cardiovascular risk and 1.59 (95% CI 0.22–11.29) and 1.78 (95% CI 0.25–12.64) per 100 patient-years in patients with lower cardiovascular risk. Incidence rates of other ischaemic heart disease in the nintedanib and placebo groups, respectively, were 1.85 (95% CI 1.02–3.34) and 3.28 (95% CI 1.94–5.54) per 100 patient-years in patients with higher cardiovascular risk and 0 and 1.80 (95% CI 0.25–12.78) per 100 patient-years in patients with lower cardiovascular risk.These data help to establish the cardiovascular safety profile of nintedanib in IPF.

Conditional estimation and inference to address observed covariate imbalance in randomized clinical trials

2018 ◽  
Vol 16 (2) ◽  
pp. 122-131 ◽  
Author(s):  
Zhiwei Zhang ◽  
Linli Tang ◽  
Chunling Liu ◽  
Vance W Berger
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Real Data ◽  
Careful Consideration ◽  
Conditional Inference ◽  
Variance Estimator ◽  
Treatment Difference ◽  
Difference Estimator ◽  
Treatment Groups ◽  
Conditional Estimation

Background Baseline covariate imbalance (between treatment groups) is a common problem in randomized clinical trials which often raises questions about the validity of trial results. Answering these questions requires careful consideration of the statistical implications of covariate imbalance. The possibil ity of having covariate imbalance contributes to the marginal variance of an unadjusted treatment difference estimator, which can be reduced by making appropriate adjustments. Actual observed imbalance introduces a conditional bias into an unadjusted estimator, which may increase the conditional size of an unadjusted test. Methods This article provides conditional estimation and inference procedures to address the conditional bias due to observed imbalance. Interestingly, it is possible to use the same adjusted treatment difference estimator to address the marginal variance issue and the conditional bias issue associated with covariate imbalance. Its marginal variance estimator tends to be conservative for conditional inference, and we propose a conditionally appropriate variance estimator. We also provide an estimator of the conditional bias in an unadjusted treatment difference estimator, together with a conditional variance estimator. Results The proposed methodology is illustrated with real data from a stroke trial and evaluated in simulation experiments based on the same trial. The simulation results show that covariate imbalance can result in a substantial conditional bias and that the proposed methods deal with the conditional bias quite effectively. Discussion We recommend that the proposed methodology be used routinely to address the observed covariate imbalance in randomized clinical trials.

scholarly journals Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Events: A Meta-Analysis of Randomized Clinical Trials

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Matteo Monami ◽  
Francesco Cremasco ◽  
Caterina Lamanna ◽  
Claudia Colombi ◽  
Carla Maria Desideri ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cardiovascular Events ◽  
Randomized Trials ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Diabetic Patients ◽  
Cardiovascular Safety ◽  
Type 2 Diabetic Patients ◽  
Receptor Agonists

Objective. Data from randomized clinical trials with metabolic outcomes can be used to address concerns about potential issues of cardiovascular safety for newer drugs for type 2 diabetes. This meta-analysis was designed to assess cardiovascular safety of GLP-1 receptor agonists.Design and Methods. MEDLINE, Embase, and Cochrane databases were searched for randomized trials of GLP-1 receptor agonists (versus placebo or other comparators) with a duration ≥12 weeks, performed in type 2 diabetic patients. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for major cardiovascular events (MACE), on an intention-to-treat basis, excluding trials with zero events.Results. Out of 36 trials, 20 reported at least one MACE. The MH-OR for all GLP-1 receptor agonists was 0.74 (0.50–1.08),P=.12(0.85 (0.50–1.45),P=.55, and 0.69 (0.40–1.22),P=.20, for exenatide and liraglutide, resp.). Corresponding figures for placebo-controlled and active comparator studies were 0.46 (0.25–0.83),P=.009, and 1.05 (0.63–1.76),P=.84, respectively.Conclusions. To date, results of randomized trials do not suggest any detrimental effect of GLP-1 receptor agonists on cardiovascular events. Specifically designed longer-term trials are needed to verify the possibility of a beneficial effect.

Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials

2005 ◽  
Vol 10 (2_suppl) ◽  
pp. S19-S25 ◽  
Author(s):  
Rainer H Böger
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Clinical Trials ◽  
Cardiovascular Risk ◽  
Cardiovascular Events ◽  
Asymmetric Dimethylarginine ◽  
Total Mortality ◽  
No Production ◽  
Increased Risk ◽  
Diverse Patient Populations

Evidence has accumulated that asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. ADMA inhibits vascular NO production at concentrations found in pathophysiological conditions; it also causes local vasoconstriction when infused intra-arterially. ADMA is increased in the plasma of humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, chronic heart failure, and other clinical conditions. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation or reduced NO metabolite levels. In several prospective and cross-sectional studies, ADMA has evolved as a marker of cardiovascular risk. Moreover, prospective clinical studies have suggested that it may play a role as a novel cardiovascular risk factor. Zoccali and coworkers were the first to show that elevated ADMA is associated with a three-fold increased risk of future severe cardiovascular events and mortality in patients undergoing hemodialysis. Valkonen and coworkers demonstrated in a nested case-control study that elevated ADMA was associated with a four-fold increased risk for acute coronary events in clinically healthy, nonsmoking men. In patients with stable angina pectoris, preinterventional ADMA indicates the risk of developing restenosis or severe clinical events after coronary intervention. Furthermore, in humans with no underlying cardiovascular disease who are undergoing intensive care unit treatment, ADMA is a marker of the mortality risk. A number of additional prospective clinical trials are currently under way in diverse patient populations, among them individuals with congestive heart failure, cardiac transplantation patients, and patients with pulmonary hypertension. In summary, an increasing number of prospective clinical trials have shown that the association between elevated ADMA levels and major cardiovascular events and total mortality is robust and extends to diverse patient populations. However, we need to define more clearly in the future who will profit from ADMA determination, in order to use this novel risk marker as a more specific diagnostic tool.

scholarly journals Are There Any Beneficial Effects of Spirulina Supplementation for Metabolic Syndrome Components in Postmenopausal Women?

Marine Drugs ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. 651
Author(s):  
Elena Bobescu ◽  
Andreea Bălan ◽  
Marius Alexandru Moga ◽  
Andreea Teodorescu ◽  
Maria Mitrică ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Clinical Trials ◽  
Postmenopausal Women ◽  
Cardiovascular Events ◽  
Filamentous Cyanobacterium ◽  
Beneficial Effects ◽  
Positive Effects ◽  
The Metabolic Syndrome ◽  
Postmenopausal Period ◽  
Metabolic Syndrome Components

Spirulina is a phytosynthetic filamentous cyanobacterium with microscopic dimensions, which naturally grows in the highly-salted alkaline lakes of Africa, Mexico, America, and Asia. Several bioactive peptides extracted from Spirulina were demonstrated to possess antimicrobial, antiviral, antitumor, immunomodulatory, antiallergic and antihypertensive properties. It has been reported that the consumption of Spirulina could prevent or manage metabolic syndrome components. In women, metabolic disorders are more prevalent during menopause. Postmenopausal women present higher waist circumference, increased blood pressure, hypertriglyceridemia, hyperglycemia, and decreased HDL-cholesterol values, leading to an increased risk of cardiovascular events. Therefore, in order to prevent cardiovascular diseases, it is essential to manage the components of the metabolic syndrome during the postmenopausal period. As recent reports indicated the efficiency of Spirulina supplementation in the management of the metabolic syndrome components, our study aims to review all the clinical trials conducted on this topic. Our main objective is to have a better understanding of whether and how this cyanobacterium could manage the abnormalities included in the metabolic syndrome and if it could be used as a therapeutic approach in postmenopausal women with this condition. We selected relevant articles from PubMed, Google Scholar and CrossRef databases, and a total number of 20 studies met our criteria. All included clinical trials indicated that Spirulina has positive effects in managing metabolic syndrome components. Spirulina is a valuable cyanobacterium that can be used as a food supplement for the management of metabolic syndrome, and it is able to reduce the risk of cardiovascular events. The optimal dose and period of administration remain a debated subject, and future investigations are required. Considering the beneficial effects reported against each component of the metabolic syndrome, Spirulina could also be effective in the postmenopausal period, when this syndrome is the most prevalent, but there is a strong need for human clinical trials in order to sustain this observation.

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