Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program.

BACKGROUND: The glucagon-like peptide-1 receptor agonist, semaglutide, improved health status and reduced body weight in patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with Obesity and HFpEF) program. Whether benefits were due to mechanical unloading or effects on HF pathobiology is uncertain. OBJECTIVES: This study sought to determine if semaglutide 2.4 mg reduced N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with obesity-related HFpEF and compare treatment responses by baseline NT-proBNP. METHODS: This was a prespecified secondary analysis of pooled data from 2 double-blind, placebo-controlled, randomized trials (STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes]) testing effects of semaglutide in patients with obesity-related HFpEF. The main outcomes were change in NT-proBNP at 52 weeks and change in the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and body weight by baseline NT-proBNP. RESULTS: In total, 1,145 patients were randomized. Semaglutide compared with placebo reduced NT-proBNP at 52 weeks (estimated treatment ratio: 0.82; 95% CI: 0.74-0.91; P = 0.0002). Improvements in health status were more pronounced in those with higher vs lower baseline NT-proBNP (estimated difference: tertile 1: 4.5 points, 95% CI: 0.8-8.2; tertile 2: 6.2 points, 95% CI: 2.4-10.0; tertile 3: 11.9 points, 95% CI: 8.1-15.7; P interaction = 0.02; baseline NT-proBNP as a continuous variable: P interaction = 0.004). Reductions in body weight were consistent across baseline NT-proBNP levels (P interaction = 0.21). CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide reduced NT-proBNP. Participants with higher baseline NT-proBNP had a similar degree of weight loss but experienced larger reductions in HF-related symptoms and physical limitations with semaglutide than those with lower NT-proBNP.

Let Kids Play: Using Virtual Reality as a Substitute for General Anesthesia for Minor Procedures in Pediatric Population.

BACKGROUND: In the pediatric population, virtual reality (VR) has been used as an adjunct to augment analgesia and reduce the need for opioids. In this study, we review our experience using VR in lieu of anesthesia or sedation to enable minor procedures in children. METHODS: A retrospective chart review study was performed on patients who presented to our institution from 2019 to 2022 for hormone implant placement, exchange, or removal with VR distraction. Demographic and procedure information was recorded. The primary outcome was successful procedure completion without requiring pharmacologic sedation or analgesia. RESULTS: A total of 111 patients underwent the following minor procedures with VR and without anesthesia or sedation. Fourteen patients had multiple encounters resulting in a total of 126 encounters. The median age was 11 [6] years. 43 patients were female, 23 were female to male, 6 were non-binary, 7 were male, and 32 were male to female. 58 % had private insurance. Most common diagnosis was precocious puberty (54 %) followed by gender dysphoria (46 %). Most common procedure was implant placement (72 %). 69 % of procedures were performed in the clinic and 31 % in the OR. All procedures were completed without requiring the administration of additional sedation or anesthesia. None of the patients required intravenous catheter placement for the procedure. No intra-procedural complications were recorded. CONCLUSION: VR is a feasible option that can spare children from sedation or general anesthesia for minor procedures. VR may enable minor procedures in children to be successfully performed in clinic setting.

Building Provider-Caregiver Partnerships: Curricula for Medical Students and Residents.

PROBLEM: A disconnect exists between caregivers and health care providers, resulting in fragmented communication, which increases caregiver stress and compromises patient care. Although providers have a responsibility to recognize caregiver burden, they receive scant training on issues important to caregivers. APPROACH: From 2014 to 2017, as part of the Building Caregiver Partnerships Through Interprofessional Education project-a collaborative effort between Northeast Ohio Medical University and Summa Health-the authors developed curricula to foster effective partnerships between health care providers and caregivers by exposing medical students and residents to highly personal caregiving narratives. The curricula center on a short film featuring 4 families representing diverse caregiving experiences. The authors crafted several discussion guides, case-based learning exercises, structured clinical encounters, team-based simulations, and clinical cases as companion educational tools for the film. OUTCOMES: Medical students reported the educational tools piloted to be valuable in broadening their understanding of caregivers' needs, while residents reported the educational tools piloted to also be valuable in improving their communication and building partnerships with caregivers. Undergraduate and graduate faculty reported finding the pilots valuable. NEXT STEPS: Future goals include conducting an outcome evaluation, based on ACGME milestones, to identify and examine clinical outcomes to determine whether communication increases and quality of care improves as a result of the project. The authors would also like to include caregivers in the evaluation. Finally, because caregiving is best addressed from a team approach, the authors plan to pilot the project at other health professions programs.

Neoplasms Reported With Liraglutide or Placebo in People With Type 2 Diabetes: Results From the LEADER Randomized Trial.

OBJECTIVE: This study explored neoplasm risk with liraglutide versus placebo in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) cohort. RESEARCH DESIGN AND METHODS: LEADER (NCT01179048) was an international, phase 3b, randomized, double-blind, controlled trial. Participants aged ≥50 years with type 2 diabetes and high cardiovascular risk were assigned 1:1 to receive liraglutide (≤1.8 mg daily; n = 4,668) or placebo (n = 4,672) in addition to standard care and monitored for 3.5-5 years (median follow-up 3.8 years). The occurrence of neoplasms was a prespecified, exploratory secondary end point. Post hoc analyses of the time to the first confirmed neoplasms were conducted using a Cox regression model. RESULTS: Neoplasm was confirmed in 10.1% of patients with liraglutide versus 9.0% with placebo (hazard ratio [HR] 1.12 [95% CI 0.99; 1.28]). The HR (95% CI) for liraglutide versus placebo was 1.06 (0.90; 1.25) for malignant neoplasms and 1.16 (0.93; 1.44) for benign neoplasms. Sensitivity analyses excluding neoplasms occurring <1 year or <2 years after randomization and analyses by sex provided similar results. In our main analyses, the 95% CI for the HR included one for all malignant neoplasms evaluated (including pancreatic and thyroid neoplasms) except for prostate neoplasms, which occurred in fewer liraglutide-treated patients. CONCLUSIONS: LEADER was not primarily designed to assess neoplasm risk. Firm conclusions cannot be made regarding numeric imbalances observed for individual neoplasm types (e.g., pancreatic cancer) that occurred infrequently. LEADER data do, however, exclude a major increase in the risk of total malignant neoplasms with liraglutide versus placebo. Additional studies are needed to assess longer-term exposure.

Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes: The ADJUNCT TWO Randomized Trial.

OBJECTIVE: To investigate the efficacy and safety of liraglutide added to capped insulin doses in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A 26-week, placebo-controlled, double-blind, parallel-group trial enrolling 835 subjects randomized 3:1 receiving once-daily subcutaneous liraglutide (1.8, 1.2, and 0.6 mg) or placebo added to an individually capped total daily dose of insulin. RESULTS: Mean baseline glycated hemoglobin (HbA1c) (8.1% [65.0 mmol/mol]) was significantly decreased with liraglutide versus placebo at week 26 (1.8 mg: -0.33% [3.6 mmol/mol]; 1.2 mg: -0.22% [2.4 mmol/mol]; 0.6 mg: -0.23% [2.5 mmol/mol]; placebo: 0.01% [0.1 mmol/mol]). Liraglutide significantly reduced mean body weight (-5.1, -4.0, and -2.5 kg for 1.8, 1.2, and 0.6 mg, respectively) versus placebo (-0.2 kg). Significant reductions in daily insulin dose and increases in quality of life were seen with liraglutide versus placebo. There were higher rates of symptomatic hypoglycemia (21.3 vs. 16.6 events/patient/year; P = 0.03) with liraglutide 1.2 mg vs. placebo and of hyperglycemia with ketosis >1.5 mmol/L with liraglutide 1.8 mg vs. placebo (0.5 vs. 0.1 events/patient/year; P = 0.01). CONCLUSIONS: In a broad population of subjects with long-standing type 1 diabetes, liraglutide added to capped insulin reduced HbA1c, body weight, and insulin requirements but with higher rates of hypoglycemia for liraglutide 1.2 mg and hyperglycemia with ketosis for liraglutide 1.8 mg.

Safety and tolerability of as-needed nalmefene in the treatment of alcohol dependence: results from the Phase III clinical programme.

OBJECTIVE: To investigate safety and tolerability of nalmefene for reduction of alcohol consumption in alcohol-dependent patients. METHODS: Pooled data from three randomized, placebo-controlled studies (two 6-month; one 12-month) of 18 mg nalmefene (as-needed use) in alcohol-dependent patients looking at the total population (placebo n = 824, nalmefene n = 1123) and patients with high/very high drinking risk levels at screening and randomization (target population: placebo n = 374, nalmefene n = 450). RESULTS: In the study, 62.7% of patients on placebo and 74.7% on nalmefene in the total population had treatment-emergent adverse events (TEAEs). Fourty-seven (5.9%) on placebo and 149 (13.0%) on nalmefene dropped out due to TEAEs. Thirty-five (4.4%) on placebo and 57 (5.0%) on nalmefene had serious adverse events. Tolerability and safety were similar in the target population and total population. Most frequent TEAEs were transient, mainly occurring at treatment initiation. There was no difference in tolerability and safety if nalmefene was taken daily or intermittently; no signal of increased risk of suicide-related behavior with nalmefene. The higher incidence of psychiatric events in the nalmefene group was mainly due to the TEAE of confusional state. CONCLUSIONS: Although there was a higher incidence of TEAEs and TEAEs leading to dropout, nalmefene was well-tolerated and no major safety issues were identified.

[The effect of tesofensine on body weight and body composition in obese subjects--secondary publication]. / Effekt af tesofensine på kropsvaegt og kropssammensaetning hos svaert overvaegtige--sekundaerpublikation.

Results from a phase II trial with Tesofensine for treatment of obesity are presented. In total 203 obese persons were randomised to treatment with Tesofensine 0.25, 0.5, or 1.0 mg, or placebo daily for 24 weeks. Treatment with Tesofensine resulted in a mean weight reduction of 4.5, 9.2 and 10.6% higher than that of placebo for 0.25, 0.5 and 1.0 mg, respectively. Tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved anti-obesity drugs. Findings of safety and efficacy of 0.5 mg Tesofensine need confirmation in phase III trials.

3-[Substituted]-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitriles: identification of highly potent and selective metabotropic glutamate subtype 5 receptor antagonists.

Structure-activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery that small, non-hydrogen bond donor substituents at the 3-position led to a substantial increase in in vitro potency. In particular, 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (7) is a highly potent and selective mGlu5 receptor antagonist with good rat pharmacokinetics, brain penetration, and in vivo receptor occupancy.

Phase 2 reentry in man.

BACKGROUND: Ventricular extrasystoles are characterized by a fixed coupling interval to the last QRST complex preceding it. OBJECTIVES: We hypothesized that this QRST complex differed from QRST complexes of other sinus beats not followed by ventricular extrasystoles. Further, we investigated whether phase 2 reentry, demonstrated in animal experiments to initiate ventricular extrasystoles, ventricular tachycardia, and ventricular fibrillation, also plays a role in humans. METHODS: We examined 18 patients with ventricular extrasystoles and/or ventricular tachycardia by signal averaging of the ECG (group A) or by single-beat analysis of intracardiac electrograms (group B). Group A consisted of six patients without structural heart disease and one patient with the Brugada syndrome. Six of the seven patients had right ventricular outflow tract ventricular extrasystoles. Group B consisted of 11 patients undergoing radiofrequency ablation. Eight of the 11 patients had right ventricular outflow tract extrasystoles. RESULTS: In six of the seven patients in group A, we demonstrated significant ST-elevation and/or T-wave changes in the sinus beat preceding ventricular extrasystoles compared with the second last sinus beat in one or more of the three orthogonal leads X, Y, and Z. In 9 of the 11 patients in group B, single-beat analysis of unipolar and bipolar electrograms recorded close to successful ablation sites demonstrated similar changes, that is, ST-elevation (median peak voltage gradient 150 muV, range 0-1,700) and T-wave changes in the sinus beat prior to ventricular ectopy. In addition, J-point elevation was demonstrated in several cases. In total, significant changes were demonstrated in 15 of the 18 patients studied (83%). CONCLUSION: J-point elevation, ST-elevation, and T-wave changes documented in the last sinus beat prior to ventricular extrasystoles are in agreement with phase 2 reentry, suggesting that this may be the responsible mechanism for ventricular extrasystoles and ventricular tachycardia/fibrillation. The phenomenon has been demonstrated in only animal experiments to date.