Renin-Angiotensin-Aldosterone System Modulators in Adults with Hypertension: A Network Meta-Analysis of Randomized Controlled Trials.

被引量：- 发表：1970

Golidocitinib: First Approval.

被引量：- 发表：1970

Slowing the Progression of Chronic Kidney Disease in Patients with Type 2 Diabetes Using Four Pillars of Therapy: The Time to Act is Now.

Chronic kidney disease (CKD) is the most common co-morbidity in patients with type 2 diabetes (T2D) and its presence substantially amplifies the risk for premature death, adverse cardiovascular events, and faster progression of kidney injury to kidney failure. For nearly two decades, the pharmacological blockade of the renin-angiotensin-system (RAS) was the only pillar of therapy to afford cardiorenal protection in these patients. During the last 5 years, newer novel therapies have been added to our therapeutic armamentarium, offering promise for more effective management of diabetic kidney disease in the future. Large phase 3 clinical trials have demonstrated additive cardiorenal protective benefits of sodium-glucose co-transporter type 2 (SGLT-2) inhibitors, the non-steroidal mineralocorticoid-receptor-antagonist (MRA) finerenone, and glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide relative to placebo in patients with albuminuric CKD and T2D who are receiving standard-of-care treatment with a RAS-blocker. These therapies are likely much more effective when administered in a combined therapeutic algorithm, but the potential additive effects of combination therapy remain to be established in ongoing clinical trials. In this article, we assemble four pillars of therapy for the attenuation of residual cardiorenal risk in patients with CKD associated with T2D. We provide evidence from recent randomized trials and we discuss the concept of combined treatment for maximal cardiorenal protection in this high-risk patient population.

被引量：- 发表：1970

Impact of CYP2C19 Genotype Status on Clinical Outcomes in Patients with Symptomatic Coronary Artery Disease, Stroke, and Peripheral Arterial Disease: A Systematic Review and Meta-Analysis.

Clopidogrel is widely used for the secondary prevention of atherothrombotic events in patients with coronary artery disease (CAD), ischemic stroke, and peripheral arterial disease (PAD). CYP2C19 plays a pivotal role in the conversion of clopidogrel to its active metabolite. Clopidogrel-treated carriers of a CYP2C19 loss-of-function allele (LOF) may have a higher risk of new atherothrombotic events. Previous studies on genotype-guided treatment were mainly performed in CAD and showed mixed results. To simultaneously investigate the impact of CYP2C19 genotype status on the rate of atherothrombotic events in the most common types of atherosclerotic disease (CAD, stroke, PAD). A comprehensive search in Pubmed, EMBASE, and MEDLINE from their inception to July 23rd 2023 was performed. Randomized controlled trials (RCTs) comparing genotype-guided and standard antithrombotic treatment, and cohort studies and post hoc analyses of RCTs concerning the association between CYP2C19 genotype status and clinical outcomes in clopidogrel-treated patients were included. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the safety end point major bleeding. Secondary endpoints were myocardial infarction, stent thrombosis, and ischemic stroke. Forty-four studies were identified: 11 studies on CAD, 29 studies on stroke, and 4 studies on PAD. In CAD, genotype-guided therapy significantly reduced the risk of MACE [risk ratio (RR) 0.60, 95% confidence interval (CI) 0.43-0.83], myocardial infarction (RR 0.53, 95% CI 0.42-0.68), and stent thrombosis (RR 0.64, 95% CI 0.43-0.94), compared with standard antithrombotic treatment. The rate of major bleeding did not differ significantly (RR 0.93, 95% CI 0.70-1.23). Most RCTs were performed in patients after percutaneous coronary intervention (9/11). In stroke, LOF carriers had a significantly higher risk of MACE (RR 1.61, 95% CI 1.25-2.08) and recurrent ischemic stroke (RR 1.89, 95% CI 1.48-2.40) compared with non-carriers. No significant differences were found in major bleeding (RR 0.90, 95% CI 0.43-1.89). In the 6955 patients with symptomatic PAD treated with clopidogrel in the EUCLID trial, no differences in MACE or major bleeding were found between LOF carriers and non-carriers. In three smaller studies on patients with PAD treated with clopidogrel after endovascular therapy, CYP2C19 genotype status was significantly associated with atherothrombotic events. Genotype-guided treatment significantly decreased the rate of atherothrombotic events in patients with CAD, especially after PCI. In patients with history of stroke, LOF carriers treated with clopidogrel had a higher risk of MACE and recurrent stroke. The available evidence in PAD with regard to major adverse limb events is too limited to draw meaningful conclusions. PROSPERO identifier no. CRD42020220284.

被引量：- 发表：1970

Cefepime-Taniborbactam: A Novel Cephalosporin/β-Lactamase Inhibitor Combination.

Taniborbactam (formerly known as VNRX-5133) is a novel bicyclic boronate β-lactamase inhibitor of serine β-lactamases (SBLs) [Ambler classes A, C, and D] and metallo-β-lactamases (MBLs) [Ambler class B], including NDM and VIM, but not IMP. Cefepime-taniborbactam is active in vitro against most isolates of carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA), including both carbapenemase-producing and carbapenemase-non-producing CRE and CRPA, as well as against multidrug-resistant (MDR), ceftazidime-avibactam-resistant, meropenem-vaborbactam-resistant, and ceftolozane-tazobactam-resistant Enterobacterales and P. aeruginosa. The addition of taniborbactam to cefepime resulted in a > 64-fold reduction in MIC90 compared with cefepime alone for a 2018-2021 global collection of > 13,000 clinical isolates of Enterobacterales. In the same study, against > 4600 P. aeruginosa, a fourfold MIC reduction was observed with cefepime-taniborbactam, compared with cefepime alone. Whole genome sequencing studies have shown that resistance towards cefepime-taniborbactam in Enterobacterales arises due to the presence of multiple resistance mechanisms, often in concert, including production of IMP, PBP3 alterations, permeability (porin) defects, and upregulation of efflux pumps. In P. aeruginosa, elevated cefepime-taniborbactam MICs are also associated with the presence of multiple, concurrent mechanisms, most frequently IMP, PBP3 mutations, and upregulation of efflux pumps, as well as AmpC (PDC) overexpression. The pharmacokinetics of taniborbactam are dose proportional, follow a linear model, and do not appear to be affected when combined with cefepime. Taniborbactam's approximate volume of distribution (Vd) at steady state is 20 L and the approximate elimination half-life (t½) is 2.3 h, which are similar to cefepime. Furthermore, like cefepime, taniborbactam is primarily cleared renally, and clearance corresponds with renal function. Pharmacodynamic studies (in vitro and in vivo) have reported that cefepime-taniborbactam has bactericidal activity against various β-lactamase-producing Gram-negative bacilli that are not susceptible to cefepime alone. It has been reported that antimicrobial activity best correlated with taniborbactam exposure (area under the curve). A phase III clinical trial showed that cefepime-taniborbactam (2 g/0.5 g administered as an intravenous infusion over 2 h) was superior to meropenem for the treatment of complicated urinary tract infection (cUTI), including acute pyelonephritis, caused by Enterobacterales species and P. aeruginosa while demonstrating similar safety compared with meropenem. The safety and tolerability of taniborbactam and cefepime-taniborbactam has been reported in one pharmacokinetic trial, and in two pharmacokinetic trials and one phase III clinical trial, respectively. Cefepime-taniborbactam appears to be well tolerated in both healthy subjects and patients. Headache and gastrointestinal upset are the most common drug-related adverse effects associated with cefepime-taniborbactam use. Cefepime-taniborbactam will likely have a role in the treatment of infections proven or suspected to be caused by MDR Gram-negative bacteria, including Enterobacterales and P. aeruginosa. In particular, it may be useful in the treatment of infections caused by isolates that harbor an MBL (NDM, VIM) enzyme, although further clinical data are needed. Additional safety and efficacy studies may support indications for cefepime-taniborbactam beyond cUTI.

被引量：- 发表：1970