Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT Studies)
ABSTRACT Cardiovascular disease, the most common cause of death with a functioning graft among kidney transplant recipients, can be exacerbated by immunosuppressive drugs, particularly the calcineurin inhibitors. Belatacept, a selective co-stimulation blocker, may provide a better cardiovascular/metabolic risk profile than current immunosuppressants.
Cardiovascular and metabolic endpoints from two Phase III studies (BENEFIT and BENEFIT-EXT) of belatacept-based regimens in kidney transplant recipients were assessed at month 12. Each study assessed belatacept in more intensive (MI) and less intensive (LI) regimens versus cyclosporine A (CsA). These secondary endpoints included changes in blood pressure, changes in serum lipids, and the incidence of new-onset diabetes after transplant (NODAT).
A total of 1209 patients were randomized and transplanted across the two studies. Mean systolic blood pressure was 6 to 9 mm Hg lower and mean diastolic blood pressure was 3 to 4 mm Hg lower in the MI and LI groups versus CsA (P ≤ 0.002) across both studies at month 12. Non-HDL cholesterol was lower in the belatacept groups versus CsA (P<0.01 MI or LI vs. CsA in each study). Serum triglycerides were lower in the belatacept groups versus CsA (P<0.02 MI or LI vs. CsA in each study). NODAT occurred less often in the belatacept groups versus CsA in a prespecified pooled analysis (P<0.05 MI or LI vs. CsA).
At month 12, belatacept regimens were associated with better cardiovascular and metabolic risk profiles, with lower blood pressure and serum lipids and less NODAT versus CsA. The overall profile of belatacept will continue to be assessed over the 3-year trials.
- SourceAvailable from: Felix S Seibert
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- "Interestingly, mTOR inhibitors even have antiarteriosclerotic properties . Belatacept has a favorable cardiovascular risk profile compared with CNI as well  . To date, however, data on the effect of belatacept on arterial stiffness are lacking. "
ABSTRACT: Pulse wave velocity (PWV) is a marker of arterial stiffness and predicts cardiovascular events in the nontransplantation population. Cardiovascular events (CVE) are the leading cause of death and one of the leading causes of graft failure in renal transplant recipients. The present prospective study investigates whether there is a correlation between PWV and CVE in renal transplant recipients. A prospective study assessing the incidence of a composite cardiovascular endpoint within ≥3 years after pulse wave analysis was performed in 64 stable renal transplant recipients. Measurement of PWV, augmentation index (AI75), and aortic systolic pressure was conducted using the SphygmoCor (AtCor) device. The composite endpoint of the study was the incidence of either death, myocardial infarction, stroke, or admission for symptomatic intermittent claudication or decompensated congestive heart failure. Fifteen patients (23%) reached the composite endpoint during a follow-up of 4.4 years. Binary logistic regression using PWV, AI75, central aortic systolic pressure, peripheral systolic pressure, and pulse pressure as covariates revealed that PWV was significantly associated with cardiovascular events (10.1 ± 3.6 m/s in subjects reaching the endpoint vs 8.5 ± 1.5 m/s in subjects not reaching the endpoint; P = .048). Increased arterial stiffness as assessed by PWV predicts CVE in renal transplant recipients and may be regarded as a footprint of accelerated arteriosclerosis for those patients. Copyright © 2015 Elsevier Inc. All rights reserved.Transplantation Proceedings 03/2015; 47(2):388-393. DOI:10.1016/j.transproceed.2014.12.014 · 0.95 Impact Factor
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- "Belatacept regimens were noninferior to cyclosporine in terms of patient and graft survival, and they were associated to a better graft function and a reduced incidence of chronic nephropathy. Of note, betalacept was also associated to reduced blood pressure , lower lipid levels and reduced incidence of new onset diabetes after transplant, improving the cardiovascular risk profile . On the opposite, there was a higher rate of acute rejection episodes and an increased incidence of posttransplant lymphoproliferative disorder (PTLD) compared with the cyclosporine group (mainly during intensive treatment). "
ABSTRACT: Costimulatory pathways play a key role in immunity, providing the second signal required for a full activation of adaptive immune response. Different costimulatory families (CD28, TNF-related, adhesion and TIM molecules), characterized by structural and functional analogies, have been described. Costimulatory molecules modulate T cell activation, B cell function, Ig production, cytokine release and many other processes, including atherosclerosis. Patients suffering from renal diseases present significant alterations of the costimulatory pathways, which might make them particularly liable to infections. These alterations are further pronounced in patients undergoing kidney transplantation. In these patients, different costimulatory patterns have been related to distinct clinical features. The importance that costimulation has gained during the last years has led to development of several pharmacological approaches to modulate this critical step in the immune activation. Different drugs, mainly monoclonal antibodies targeting various costimulatory molecules (i.e. anti-CD80, CTLA-4 fusion proteins, anti-CD154, anti-CD40, etc.) were designed and tested in both experimental and clinical studies. The results of these studies highlighted some criticisms, but also some promising findings and now costimulatory blockade is considered a suitable strategy, with belatacept (a CTLA-4 fusion protein) being approved as the first costimulatory blocker for use in renal transplantation. In this review, we summarize the current knowledge on costimulatory pathways in the setting of kidney transplantation. We describe the principal costimulatory molecule families, their role and clinical significance in patients undergoing renal transplantation and the new therapeutic approaches that have been developed to modulate the costimulatory pathways.International Reviews Of Immunology 10/2013; 33(3). DOI:10.3109/08830185.2013.829470 · 5.28 Impact Factor
Article: Belatacept[Show abstract] [Hide abstract]
ABSTRACT: Belatacept is a second-generation cytotoxic T-lymphocyte-associated antigen-4-Ig fusion protein, which down-regulates T-cell response, and is used in the prophylaxis of organ rejection in adults receiving a kidney transplant. This article reviews the pharmacologic properties of belatacept and its clinical efficacy and tolerability in kidney transplant recipients. In the well designed, phase III trials BENEFIT and BENEFIT-EXT (in patients receiving kidneys from living/standard-criteria or extended-criteria donors, respectively), a belatacept-based treatment regimen was noninferior to a cyclosporine (ciclosporin)-based regimen with regard to patient and graft survival and acute graft rejection rate, and was significantly superior to the cyclo-sporine-based regimen with regard to the rate of renal impairment (in BENEFIT only), at 12 months. Belatacept-based treatment showed long-term efficacy and remained effective after 2, 3, and 4 years with regard to these endpoints. Belatacept was generally well tolerated in patients with kidney transplants from living, standard-criteria, or extended-criteria donors. The most serious adverse events that have been reported with belatacept treatment are post-transplant lymphoproliferative disorder, other malignancies, and serious infections. At month 12, the incidence of new-onset diabetes mellitus after transplant was significantly lower with belatacept than with cyclosporine, and belatacept recipients had significantly lower blood pressure and a significantly smaller increase in certain lipid levels than cyclosporine recipients.BioDrugs 12/2012; 26(6). DOI:10.1007/BF03261898 · 2.12 Impact Factor