Effects of GLP-1 Receptor Agonists on Cardiovascular Outcomes in Patients with Type 2 Diabetes and Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Aim To evaluate the cardiovascular outcomes of glucagon-like peptide-1 receptor agonists (GLP1-RA) in patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD). Materials and Methods We searched PubMed, Ovid MEDLINE, CINAHL, and Web of Science databases for randomized controlled trials reporting event rates for a composite cardiovascular outcome of cardiovascular death, myocardial infarction, and stroke in patients with T2DM and CKD receiving GLP1-RA or placebo. Studies were restricted to those reporting specific event rates for patients with CKD separately from the overall population. We conducted a meta-analysis using a random-effects model. This meta-analysis was registered on PROSPERO (CRD42022320157). Results A total of four studies comprising 7130 patients was included in our analysis. Four different GLP1-RA were assessed in a population with CKD defined as estimated glomerular filtration rate (eGFR) \u3c60 ml/min/1.73 m2. Treatment with GLP1-RA was not associated with a significant reduction in the composite cardiovascular end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (odds ratio (OR) 0.80; 95% confidence interval (CI), 0.59–1.07; p = 0.13) among patients with T2DM and CKD. Individual components of the composite cardiovascular end point were assessed in two trials and did not show evidence of an effect of GLP1-RA in reducing cardiovascular end points. Conclusions Pooled analysis of clinical trials reporting separate cardiovascular events rates in patients with T2DM and CKD did not find GLP1-RA to be associated with a reduction in composite cardiovascular event rates. Select GLP1-RA may offer cardiovascular event reduction in patients with T2DM and CKD, but this does not appear to be a class effect. Use of GLP1-RA with demonstrated cardiovascular benefits should be preferred in patients with CKD and T2DM to further reduce cardiovascular risk

Design, Implementation, and Evaluation of a Pharmacist-Led Outpatient Benzodiazepine-Tapering Clinic

Background Benzodiazepines are commonly used among older adults, despite well-known risks. Clinical pharmacists can lead tapering efforts, leveraging their clinical expertise and relieving time-pressured primary care providers. Objectives The objective of this study is to describe the design, implementation, and evaluation of an outpatient pharmacist-led benzodiazepine-tapering clinic. Practice description The clinic is based within a community medical group associated with a large academic health system in Los Angeles, California. Practice innovation The clinic is staffed by clinical pharmacists and supervised by a psychiatrist. The initial visit consists of patient education, design of patient-driven tapering schedule, and medical history review. Follow-up phone/video visits are used to monitor withdrawal symptoms and provide support. Evaluation methods We used chart review to assess tapering status among those enrolled in the tapering clinic versus those who did not enroll. We compared outcomes across the 2 groups using bivariate statistics. Results From March 2017 to May 2019, 176 patients were referred to the clinic; 17 were deemed ineligible. Of the 159 patients contacted, 62 patients enrolled in the clinic; 97 patients did not enroll. Among patients in the clinic, 13 (27%) of patients were tapered down, 29 (60%) completely tapered off, 6 (13%) were unable to taper, and 14 (23%) were in the process of tapering. In contrast, among patients who did not enroll, 3 (4%) of patients were tapered down, 15 (20%) completely tapered off, 57 (76%) were unable to taper, and 22 (22%) were in the process of tapering. Ninety percent of patients had at least some benzodiazepine tapering when enrolled in the clinic compared to 41% among not enrolled in the clinic (P\u3c0.001). Conclusion A pharmacist-led benzodiazepine-tapering clinic can be an effective way to engage patients motivated to taper down. Lessons learned include the importance of ensuring referring providers adequately counsel patients prior to referral

Comparison of Human Adult Stem Cells from Adipose Tissue and Bone Marrow in the Treatment of Experimental Autoimmune Encephalomyelitis

Introduction. While administration of ex vitro culture-expanded stem cells has been used to study immunosuppressive mechanisms in multiple models of autoimmune diseases, less is known about the uncultured, nonexpanded stromal vascular fraction (SVF)-based therapy. The SVF is composed of a heterogeneous population of cells and has been used clinically to treat acute and chronic diseases, alleviating symptoms in a range of tissues and organs. Methods. In this study, the ability of human SVF cells was compared with culture-expanded adipose stem cells (ASCs) and bone-derived marrow stromal cells (BMSCs) as a treatment of myelin oligodendrocyte glycoprotein (35-55)-induced experimental autoimmune encephalitis in C57Bl/6J mice, a well-studied multiple sclerosis model (MS). A total of 1 x 106 BMSCs, ASCs, or SVF cells were administered intraperitoneally concomitantly with the induction of disease. Mice were monitored daily for clinical signs of disease by three independent, blinded investigators and rated on a scale of 0 to 5. Spinal cords were obtained after euthanasia at day 30 and processed for histological staining using luxol fast blue, toluidine blue, and hematoxylin and eosin to measure myelin and infiltrating immune cells. Blood was collected from mice at day 30 and analyzed by enzyme-linked immunosorbent assay to measure serum levels of inflammatory cytokines. Results: The data indicate that intraperitoneal administration of all cell types significantly ameliorates the severity of disease. Furthermore, the data also demonstrate, for the first time, that the SVF was as effective as the more commonly cultured BMSCs and ASCs in an MS model. All cell therapies also demonstrated a similar reduction in tissue damage, inflammatory infiltrates, and sera levels of IFNγ and IL-12. While IFNγ levels were reduced to comparable levels between treatment groups, levels of IL-12 were significantly lower in SVF-treated than BMSC-treated or ASC-treated mice. Conclusions: Based on these data, it is evident that SVF cells have relevant therapeutic potential in an animal model of chronic MS and might represent a valuable tool for stem cell-based therapy in chronic inflammatory disease of the central nervous system. SVF offers advantages of direct and rapid isolation procedure in a xenobiotic-free environment

Proteasome assembly triggers a switch required for active-site maturation.

The processing of propeptides and the maturation of 20S proteasomes require the association of beta rings from two half proteasomes. We propose an assembly-dependent activation model in which interactions between helix (H3 and H4) residues of the opposing half proteasomes are prerequisite for appropriate positioning of the S2-S3 loop; such positioning enables correct coordination of the active-site residue needed for propeptide cleavage. Mutations of H3 or H4 residues that participate in the association of two half proteasomes inhibit activation and prevent, in nearly all cases, the formation of full proteasomes. In contrast, mutations affecting interactions with residues of the S2-S3 loop allow the assembly of full, but activity impacted, proteasomes. The crystal structure of the inactive H3 mutant, Phe145Ala, shows that the S2-S3 loop is displaced from the position observed in wild-type proteasomes. These data support the proposed assembly-dependent activation model in which the S2-S3 loop acts as an activation switch