Impact of GLP-1 Receptor Agonist Use in Patients With Steatotic Liver Disease and Type 2 Diabetes: A Retrospective Cohort Study.

Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) help manage type 2 diabetes (T2DM) and may have efficacy in steatotic liver disease. Objective: To determine the prevalence and clinical impact of GLP-1 RA use in patients with T2DM and liver disease. Methods: This was a retrospective study of adult patients with T2DM and nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty liver (NAFL), or nonalcoholic steatohepatitis (NASH) between 1/1/21-12/31/21. Patients with hepatitis B or C, or on pioglitazone were excluded. Eligible patients treated with a GLP-1 RA were compared to controls. The primary outcome was change in Fibrosis-4 (FIB-4) score, with NAFLD Fibrosis Score (NFS) as a secondary outcome. Follow-up scores were calculated from labs within 3 to 15 months after baseline. Results: Of 242 eligible patients, 79 patients (32.6%) were treated with a GLP-1 RA. At baseline, FIB-4 score was lower and NFS was higher in the GLP-1 RA group vs controls (1.80 vs 2.33; P = .101, .36 vs -.47, P < .001; respectively). At follow up, FIB-4 score decreased to 1.77 in the GLP-1 RA group and increased to 2.71 in controls (P = .045). Follow up NFS was stable in the GLP-1 RA group and increased in the control group (.36 vs -.43; P = .308). Conclusion: Patients treated with GLP-1 RAs had less evidence of liver fibrosis progression compared to no treatment, although the differences were small. These results suggest that treatment with GLP-1 RAs may have clinical impact on slowing liver fibrosis, however results should be confirmed in a larger, more diverse sample.

Incidence of transaminitis in adults with cystic fibrosis taking elexacaftor/tezacaftor/ivacaftor.

BACKGROUND: Cystic fibrosis (CF) transmembrane conductance regulator modulators are a cornerstone of CF treatment. However, many patients develop CF liver disease (CFLD) over time, and previous data indicate a risk for transaminase elevation with modulator use. Elexacaftor/tezacaftor/ivacaftor is a commonly prescribed modulator with broad efficacy among CF genomic profiles. Theoretically, elexacaftor/tezacaftor/ivacaftor drug-induced liver injury could exacerbate and further worsen CFLD, but holding modulators can cause a decline in clinical status. OBJECTIVES: This study was designed to determine the real-world incidence of transaminase elevations in adult patients with CF taking elexacaftor/tezacaftor/ivacaftor. METHODS: This exploratory, retrospective descriptive study included all adults with CF-prescribed elexacaftor/tezacaftor/ivacaftor at our institution's outpatient CF clinic. We explored transaminase elevations in 2 separate outcomes: incidence of transaminase elevations of more than 3 times the upper limit of normal (ULN), and transaminase elevations of 25% or more above baseline. RESULTS: 83 patients were prescribed elexacaftor/tezacaftor/ivacaftor. Nine patients (11%) experienced an elevation of more than 3 times ULN and 62 (75%) experienced an elevation of 25% or more above baseline. The median days to transaminase elevation were 108 and 135 days, respectively. Therapy was not discontinued due to transaminase elevations in any of the patients. CONCLUSION: Transaminase elevations among adults taking elexacaftor/tezacaftor/ivacaftor were common but did not result in discontinuation of therapy. Pharmacists should be reassured of the liver safety profile of this important medication for patients with CF.

Rapid infusion of infliximab biosimilars and the incidence and severity of infusion-related reactions in patients with inflammatory bowel disease.

WHAT IS KNOWN AND OBJECTIVE: Infliximab is an anti-tumour necrosis factor agent used in the treatment of inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis. While the use of infliximab is well established in the treatment of IBD, there are now four recently FDA-approved infliximab biosimilars that are increasingly used due to their cost-benefit for patients, institutions and payors. In addition, shortening the length of infliximab infusions from 120 min (standard infusion) to 60 min or less (rapid infusion) has been shown to safely provide further cost-benefit while also improving patient convenience. The safety of rapid infusions has been well-established for the infliximab reference product, however, there are limited data available regarding the safety of rapid infusions for infliximab biosimilars. The purpose of this study was to compare the incidence and severity of infusion reactions among patients with IBD receiving rapid infusion of infliximab reference product compared with infliximab biosimilar. METHODS: This was a retrospective analysis of electronic health record data of patients with a diagnosis of IBD receiving an infliximab reference product or infliximab biosimilar infusion between December 2020 and December 2021. Patient-level variables included demographics, immunomodulator use, IBD-related hospitalization and infliximab trough concentration and antibody levels. Infusion-related variables of interest included total number of infusions, drug, dose, dosing interval, infusion time and use of pre-medications. Infusion-related reactions were defined as safety concerns documented by the administering nurse (anaphylaxis, shortness of breath, hypotension, swelling, rash, pruritus, hives, flushing, chest pain, muscle pain, joint pain, fevers, chills, headache or hypertension) or administration of emergency medications. Fisher's exact test was used to compare reaction rates. RESULTS AND DISCUSSION: A total of 188 patients met inclusion criteria for analysis, and a total of 1124 infusions were administered during the study period. There were no statistically significant differences among any of the pre-specified outcomes. There were no differences in the incidence of infusion reactions among rapid infusion (60 min) infliximab and infliximab biosimilars (p = 0.863). Additionally, there were no differences in the incidence of infusion reactions among standard infusion (120 min) infliximab and infliximab biosimilars (p = 0.993). Finally, there were no differences among the rate of infusion reactions between rapid infusion of infliximab biosimilars and standard infusion of infliximab biosimilars (p = 0.536). Eight patients experienced safety issues, with three patients requiring emergency medications (1.6% of 188 patients). WHAT IS NEW AND CONCLUSIONS: Rapid infusions of infliximab biosimilars were not associated with an increase in the incidence of infusion reactions compared with: rapid infusion of infliximab reference product, standard infusion of infliximab biosimilars, or standard infusion of infliximab reference product. This should reassure clinicians that rapid infusions of infliximab biosimilars are safe in clinical practice.

Academic detailing with ambulatory pharmacists to support naloxone counseling.

BACKGROUND: Pharmacists are critical to public health in supporting safe use of prescription opioids by ensuring that all patients are offered and counseled on naloxone. Academic detailing may be an effective educational outreach strategy for improving pharmacists' knowledge and behavior related to naloxone. OBJECTIVE: To describe an academic detailing program to pharmacists on the topic of counseling and promoting naloxone to patients. METHODS: Pharmacists were recruited by convenience sampling. Three pharmacists who were experienced with academic detailing techniques provided the education. Survey data were collected to evaluate the program. RESULTS: Thirty-three pharmacists participated, including 16 sessions that were delivered virtually. The pharmacists worked in a variety of ambulatory settings, including chain or corporate-owned pharmacies (58%), hospital-owned specialty pharmacies (15%), hospital-owned community pharmacies (15%), and independently owned or other pharmacies (12%). Twenty-eight pharmacists (85%) completed an immediate post-session evaluation survey. Twenty-seven pharmacists (96%) indicated they felt the information presented will impact their practice or patient care. Eleven pharmacists (33%) completed a second post-session survey, self-reporting improvements related to counseling patients about naloxone. CONCLUSION: Participating in academic detailing supports community pharmacists' providing patient counseling about naloxone. Further study, particularly related to virtual academic detailing, is necessary to understand the full potential of academic detailing to pharmacists.

The Impact of Transitions of Care Pharmacist Services and Identification of Risk Predictors in Heart Failure Readmission.

BACKGROUND: Heart failure (HF) is a prevalent and costly disease state for adult Americans, with 30-day readmissions rates for patients with HF utilized to limit hospital compensation. OBJECTIVE: To determine the impact of the transitions of care (TOC) service at our institution on 30-day all-cause and HF readmissions and identify predictive risk factors for 30-day all-cause readmission. METHODS: Retrospective chart review of patients aged 18 years and older admitted with HF and all subsequent readmissions between October 1, 2015, and September 30, 2017. A weighted logistic regression model was developed to determine risk factors for 30-day all-cause readmission. RESULTS: There were no significant differences in all-cause or HF readmission rates analyzed by TOC service involvement. Significant risk predictors for 30-day all-cause readmission included discharge to a rehabilitation facility (odds ratio [OR] = 9.3) or home with home health (OR = 1.6) versus home with self-care. Comorbidities associated with an increased risk of 30-day all-cause readmission included diabetes, coronary artery disease, and aortic stenosis. Use of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and spironolactone was associated with decreased risk of 30-day all-cause readmission. CONCLUSION: Identified predictors in the patient population with HF at our institution may be used to target patients at increased risk of all-cause readmission within 30 days.

Effects of Statins for Secondary Prevention on Functioning and Other Outcomes Among Nursing Home Residents.

OBJECTIVES: Studies examining the effects of statins after acute myocardial infarction (AMI) excluded frail older adults, especially nursing home (NH) residents, and few examined functional outcomes. Older NH residents may benefit less from statins and be particularly susceptible to adverse drug events like myopathy-related functional decline. We evaluated the effects of statins on 1-year functional decline, rehospitalization, and death in NH residents. DESIGN: We conducted a retrospective cohort study using 2007-2010 linked national data from Minimum Data Set (MDS) assessments, Medicare claims, and Online Survey Certification and Reporting System records. SETTING AND PARTICIPANTS: We included US NH residents 65 years and older who were statin nonusers, were hospitalized for AMI between May 2007 and March 2010, and returned to the NH. MEASURES: Outcomes were functional decline, death, and rehospitalization in the first year after post-AMI NH admission. New statin users were 1:1 propensity-score matched to nonusers to adjust for 92 characteristics. We estimated hazard ratios (HRs) and restricted mean survival time differences with 95% confidence intervals (CIs) comparing individuals who did vs did not initiate statin therapy after AMI hospitalization. RESULTS: Propensity-score matching yielded a cohort of 5440 residents. Mean age was 83 years and 69% were female. Statin use was associated with a reduction in mortality (HR 0.80, 95% CI 0.73-0.87), corresponding to a mean of 15.9 (95% CI 9.9-22.0) days of extended life expectancy. No overall differences in rehospitalization (HR 1.06, 95% CI 0.98-1.14) or functional decline (HR 1.00, 95% CI 0.88-1.14) were observed. CONCLUSIONS AND IMPLICATIONS: Statins may reduce 1-year mortality by 20% without affecting function among older NH residents who wish to live longer after AMI. During shared decision making with these patients or their representatives, clinicians should consider communicating that the average benefit of statins is 16 days of additional survival over 1 year.

Development of Activity-Based Chemical Probes for Human Sirtuins.

Sirtuins consume stoichiometric amounts of nicotinamide adenine dinucleotide (NAD+) to remove an acetyl group from lysine residues. These enzymes have been implicated in regulating various cellular events and have also been suggested to mediate the beneficial effects of calorie restriction (CR). However, controversies on sirtuin biology also peaked during the past few years because of conflicting results from different research groups. This is partly because these enzymes have been discovered recently and the intricate interaction loops between sirtuins and other proteins make the characterization of them extremely difficult. Current molecular biology and proteomics techniques report protein abundance rather than active sirtuin content. Innovative chemical tools that can directly probe the functional state of sirtuins are desperately needed. We have obtained a set of powerful activity-based chemical probes that are capable of assessing the active content of sirtuins in model systems. These probes consist of a chemical "warhead" that binds to the active site of active enzyme and a handle that can be used for the visualization of these enzymes by fluorescence. In complex native proteome, the probes can selectively "highlight" the active sirtuin components. Furthermore, these probes were also able to probe the dynamic change of sirtuin activity in response to cellular stimuli. These chemical probes and the labeling strategies will provide transformative technology to allow the direct linking of sirtuin activity to distinct physiological processes. They will create new opportunities to investigate how sirtuins provide health benefits in adapting cells to environmental cues and provide critical information to dissect sirtuin regulatory networks.

Trichostatin A inhibits deacetylation of histone H3 and p53 by SIRT6.

SIRT6 is an epigenetic modification enzyme that regulates gene transcription through its deacetylase activity. In addition to histone protein, SIRT6 also modify other proteins and enzymes, some of which are central players in metabolic reprogramming and aging process. Therefore, SIRT6 has emerged as a therapeutic target for the treatment of metabolic disorder and age-related diseases. Here, we report that SIRT6 deacetylates lysine 382 of p53 in short synthetic peptide sequence and in full length p53. Further studies showed that the deacetylation of H3K9Ac and p53K382Ac are insensitive to nicotinamide inhibition, but are sensitive to trichostatin A (TSA) inhibition. Detailed kinetic analysis revealed that TSA competes with the peptide substrate for inhibition, and this inhibition is unique to SIRT6 in the sirtuin family. Taken together, this study not only suggests potential roles of SIRT6 in regulating apoptosis and stress resistance via direct deacetylation of p53, but also provides lead compound for the development of potent and selective SIRT6 inhibitors.