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Introduction Neurons in the pre-Bötzinger complex are critical for the generation of inspiratory rhythm and regulation of activity of phrenic motoneurons, which control the activity of the diaphragm. Dysregulation of this neuronal network and resulting dysfunction of the diaphragm is associated with central sleep apnea (CSA). Orexins by stimulating both orexin 1 receptor (OX1R) and/or orexin 2 receptor (OX2R) can activate these neurons and the diaphragm. In this study, we assessed effects of OX2R-selective agonists on the activity of neurons in the pre-Bötzinger complex, phrenic motoneurons, and the diaphragm. Methods OX2R-selective agonists danavorexton (TAK-925) and OX-201 (a tool compound with longer plasma half-life than danavorexton in rodents) were used. OX2R and OX1R agonistic activities were examined by calcium mobilization assay in hOX2R/CHO-K1 cells and hOX1R/CHO-K1 cells, respectively. Activity of neurons in the pre-Bötzinger complex and phrenic motoneurons was investigated by electrophysiological recording in rat tissues. Activity of the diaphragm was evaluated by electromyogram recording in anesthetized rats. Respiratory activity was evaluated by whole-body plethysmography recording in mice. Results Danavorexton and OX-201 showed potent OX2R agonistic activity with 50% effective concentration (EC50) values of 5.5 nM and 8.0 nM, respectively. Danavorexton and OX-201 had >5,000-fold and 1,000-fold OX2R selectivity over OX1R, respectively. In in vitro electrophysiological analyses, danavorexton and OX-201 increased the burst frequency of neurons in the pre-Bötzinger complex (EC50: 300 nM and 760 nM, respectively) and phrenic motoneurons (EC50: 1.6 µM and not determined, respectively). Intravenous administration of OX-201 at 1 and 3 mg/kg increased burst frequency of the diaphragm in anesthetized rats and oral administration at 3 mg/kg increased respiratory activity in conscious mice. Conclusion OX2R-selective agonists may enhance respiratory function via activation of the diaphragm through stimulation of neurons in the pre-Bötzinger complex and phrenic motoneurons. OX2R agonists may have therapeutic potential in patients with CSA if enhancement of respiratory function by OX2R agonists can be observed at non-arousal concentrations. Further preclinical and clinical studies are worth conducting in patients with CSA. Support (if any) This work was conducted by Takeda Pharmaceutical Company Limited.

In a trial in patients with cardiovascular disease and overweight or obesity but no diabetes, semaglutide was superior to placebo in lowering the risk of major adverse cardiovascular events at a mean follow-up of 39.8 months.

Peripheral artery disease is a highly morbid type of atherosclerotic vascular disease involving the legs and is estimated to affect over 230 million individuals globally. Few therapies improve functional capacity and health-related quality of life in people with lower limb peripheral artery disease. We aimed to evaluate whether semaglutide improves function as measured by walking ability as well as symptoms, quality of life, and outcomes in people with peripheral artery disease and type 2 diabetes. STRIDE was a double-blind, randomised, placebo-controlled trial done at 112 outpatient clinical trial sites in 20 countries in North America, Asia, and Europe. Participants were aged 18 years and older, with type 2 diabetes and peripheral artery disease with intermittent claudication (Fontaine stage IIa, able to walk >200 m) and an ankle–brachial index of less than or equal to 0·90 or toe–brachial index of less than or equal to 0·70. Participants were randomly assigned (1:1) using an interactive web response system to receive subcutaneous semaglutide 1·0 mg once per week for 52 weeks or placebo. The primary endpoint was the ratio to baseline of the maximum walking distance at week 52 measured on a constant load treadmill in the full analysis set. Safety was evaluated in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT04560998 and is now completed. From Oct 1, 2020, to July 12, 2024, 1363 patients were screened for eligibility, of whom 792 were randomly assigned to semaglutide (n=396) or placebo (n=396). 195 (25%) participants were female and 597 (75%) were male. Median age was 68·0 years (IQR 61·0–73·0). The estimated median ratio to baseline in maximum walking distance at week 52 was significantly greater in the semaglutide group than the placebo group (1·21 [IQR 0·95–1·55] vs 1·08 [0·86–1·36]; estimated treatment ratio 1·13 [95% CI 1·06–1·21]; p=0·0004). Six serious adverse events in five (1%) participants in the semaglutide group and nine serious adverse events in six (2%) participants in the placebo group were possibly or probably treatment related, with the most frequent being serious gastrointestinal events (two events reports by two [1%] in the semaglutide group and five events reported by three [1%] in the placebo group). There were no treatment-related deaths. Semaglutide increased walking distance in patients with symptomatic peripheral artery disease and type 2 diabetes. Research implications include the need for future studies to further elucidate mechanisms of benefit and to assess the efficacy and safety in patients with peripheral artery disease who do not have type 2 diabetes. Novo Nordisk.

Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose-response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known. We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed. We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was -7.2% in the 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, and -17.5% in the 12-mg group, as compared with -1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter. In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04881760.).

In patients with type 2 diabetes and chronic kidney disease, weekly semaglutide significantly reduced risks of major kidney events, cardiovascular events, and death from any cause while slowing loss of kidney function.

Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide produced greater reductions in symptoms, physical limitations, and body weight than placebo at 1 year.

This large trial involving children with asthma examined whether the addition of a long-acting beta-agonist to current therapy with inhaled glucocorticoids affected asthma control in children. The primary safety end point was within the prespecified noninferiority margin. The safety of inhaled beta-agonists in patients with asthma has been debated since the 1960s. 1 – 5 After the introduction of long-acting beta-agonists (LABAs) in the 1990s and the findings of two studies involving adults, attention focused on a potential association of LABAs with an increased risk of asthma-related death. 6 , 7 A 2008 meta-analysis conducted by the Food and Drug Administration (FDA) showed a higher risk of asthma-related events (death, intubation, or hospitalization) among patients receiving LABAs than among patients not receiving these medications. 8 In a subsequent meta-analysis, a higher risk of serious asthma-related events was observed with salmeterol than with . . .