Sleep

There is an unmet need for effective and well-tolerated oral formulations of glucagon-like peptide 1 receptor agonists for the management of type 2 diabetes. Orforglipron and oral semaglutide are two oral glucagon-like peptide 1 receptor agonists evaluated in the ACHIEVE-3 clinical trial (NCT06045221). These novel treatments have the means to achieve clinically meaningful glycemic control and weight reduction, which may result in substantial positive changes in patients' daily lives. The objective of this study was to conduct exit interviews following the ACHIEVE-3 trial to characterize positive treatment experiences and outcomes, beyond glycated hemoglobin and weight reduction, reported by patients living with type 2 diabetes who received oral glucagon-like peptide 1 receptor agonist-based treatments. Qualitative interviews were conducted across ten clinical sites within the USA with patients who had enrolled in ACHIEVE-3 and completed at least 3 months of treatment. Interviews were conducted in English or Spanish, audio-recorded, and transcribed. Transcripts were analyzed to identify and categorize positive treatment benefits reported during the interviews. Descriptive statistics were used to characterize the sample. Sixty patients completed the qualitative exit interviews. Patients had a mean age of 59.1 years (standard deviation [SD] = 10.3), and almost half were female (n = 28, 46.7%). Patients had been diagnosed with type 2 diabetes for a mean of 8.5 years (SD = 5.7). By the end of the study, patients reduced their glycated hemoglobin by 1.6% (SD = 1.3) from a baseline of 8.3% and lost a mean of 4.7 kg (SD = 6.8) from a baseline of 96.0 kg. All patients reported being satisfied with the trial medication (n = 59/59), were likely to recommend the treatment to other patients, and all but one were willing to continue taking the medication. As expected, the two most important and most frequently reported positive changes were controlled glycated hemoglobin (n = 53, 88.3%) and weight reduction (n = 50, 83.3%). Other common spontaneously reported positive concepts included increased perceived energy (n = 28, 46.7%), reduced appetite and cravings (n = 23, 38.3%), improved exercise/movement (n = 18, 30.0%), and psychological improvements (n = 18, 30.0%). Additional positive changes included increased confidence/self-esteem, improved diet and eating habits, improved sleep, and improved or a lack of deterioration in vision. All reported positive changes were considered meaningful by patients. The current study explored the positive experiences of patients taking an oral glucagon-like peptide 1 receptor agonist in the ACHIEVE-3 trial beyond traditional clinical benefits, such as glycemic control and weight reduction. The positive changes identified may be suitable targets for future clinical trial clinical outcome assessment endpoint strategies to help differentiate treatments and in clinical practices to classify patients' experiences.

Emerging data has identified a potential association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and nonarteritic anterior ischemic optic neuropathy (NAION), a typically sudden, painless, and irreversible cause of optic nerve-mediated vision loss. This review synthesizes the current clinical, epidemiologic, and potential mechanism linking GLP-1RA-based therapies to NAION risk, informing balanced risk assessment and interdisciplinary clinical decision-making. A structured PubMed search was performed using terms including "GLP-1 receptor agonist," "semaglutide," "liraglutide," "tirzepatide," and "nonarteritic anterior ischemic optic neuropathy," in addition to NAION risk factors, including disc-at-risk anatomy, type 2 diabetes, obstructive sleep apnea, hypertension, hyperlipidemia, renal disease, and ischemic heart disease. A small cup-to-disc ratio ("disc-at-risk") was found to be the most robust anatomical predictor of NAION. Systemic microvascular disease (diabetes, hypertension, hyperlipidemia) and conditions such as obstructive sleep apnea and end-stage renal disease were also linked to increased susceptibility to optic nerve head ischemia. Although data across electronic health records, national registries, and pharmacovigilance analyses suggest a very low absolute incidence of NAION, the use of GLP-1RAs demonstrates a statistically significant association with NAION development, yielding relative risk estimates between 1.2 and 4.3. At this time, the potential association between GLP-1RA therapy and NAION should be interpreted as a safety signal rather than a contraindication. Screening for disc-at-risk anatomy, consideration of prior NAION history, and patient counseling regarding acute visual symptoms may be warranted prior to initiation of therapy. As evidence evolves, collaboration between endocrinologists and ophthalmologists will be essential to support safe and effective patient care.

GLP1 receptor agonists (GLP-1RAs) have transformed obesity treatment, but their impact on neuropsychiatric outcomes remains poorly understood. We conducted an observational study of 63,215 patients with preexisting neuropsychiatric conditions and evaluated 24 incident neuropsychiatric outcomes following treatment initiation. In propensity-matched analyses, semaglutide was associated with broadly lower neuropsychiatric event risk over two years compared with metformin, SGLT2 inhibitors, and DPP-4 inhibitors. Within the semaglutide-treated cohort, higher attained dose during the first two years after treatment initiation ("pre-landmark period") was associated with significantly lower incidence during the subsequent two years ("post-landmark period") of substance-related disorders (P < 0.001), mood disorders (P < 0.001), anxiety- and stress-related disorders (P < 0.001), central nervous system (CNS) atrophies (P < 0.001), neuromuscular disorders (P = 0.013), eating/sleep/behavioral disorders (P = 0.022), and personality/impulse-control disorders (P = 0.028). Consistent with prior clinical trials, the post-landmark incidence of dementia or CNS degenerative diseases was similar between the high-dose and low-dose semaglutide cohorts (P = 0.15). For most neuropsychiatric diagnoses, post-landmark incidence was strongly associated with the maximum attained dose. In contrast, incident cognitive symptoms and speech/language symptoms were more closely associated with weight loss (p < 0.001 and p < 0.003, respectively). Bulk and single-cell transcriptomic analyses identified low-level, regionally restricted GLP1R transcript signals in central and peripheral nervous system tissues, providing hypothesis-generating context for future experimental investigation. Together, these findings support an association between semaglutide exposure and multiple neuropsychiatric outcomes, and motivate prospective mechanistic and clinical studies.

This study aimed to evaluate short-term changes in depressive symptom burden and sleep quality and factors associated with clinical response in patients with obesity initiating GLP-1-based therapies. In this prospective observational study, patients with obesity initiating semaglutide or tirzepatide were enrolled. Depressive symptom burden and sleep quality were assessed at baseline and month 3 using the Patient Health Questionnaire-9 (PHQ-9) and Pittsburgh Sleep Quality Index (PSQI), respectively. Clinically significant depressive symptom burden was defined as PHQ-9 ≥ 10 and poor sleep quality as PSQI > 5; clinical response was defined as reductions of ≥ 5 PHQ-9 points and ≥ 3 PSQI points. Multivariable logistic regression models evaluated factors associated with each response. A total of 78 patients were included (tirzepatide n = 52; semaglutide n = 26). Median PHQ-9 decreased from 10.0 (7.0-14.0) to 6.0 (4.0-8.0), and the prevalence of PHQ-9 ≥ 10 declined from 55.1% to 11.5% (both p < 0.001). Median PSQI decreased from 6.0 (5.0-8.75) to 3.0 (2.0-4.0), and the prevalence of PSQI > 5 declined from 55.1% to 16.7% (both p < 0.001). In multivariable models, higher baseline PHQ-9 and younger age were associated with depressive symptom response, whereas higher baseline PSQI and greater improvement in depressive symptoms were associated with sleep response. Percentage weight loss and treatment type were not significantly associated with either response. In this prospective real-world cohort of patients with obesity, initiation of GLP-1-based therapy was followed by clinically meaningful short-term improvements in depressive symptom burden and sleep quality.

Obesity-related obstructive sleep apnea (OSA) is common, clinically heterogeneous, and tightly linked to cardiometabolic dysfunction, impaired daytime function, and reduced quality of life. Positive airway pressure (PAP) remains the standard device-based treatment for moderate-to-severe disease because it immediately stabilizes the upper airway, but it does not directly reverse the obesity that drives disease in many patients and its long-term effectiveness is often constrained by adherence. This narrative, non-systematic review synthesizes direct OSA-specific randomized evidence, indirect obesity-trial evidence, and mechanistic literature to clarify what is established, what is inferred, and what remains hypothetical. The clinical evidence for incretin therapy in OSA is promising but uneven. Direct OSA-specific randomized evidence is concentrated in liraglutide and tirzepatide: SCALE Sleep Apnea established proof of concept that pharmacologic weight loss can improve the primary apnea-hypopnea index (AHI) outcome, whereas in SURMOUNT-OSA change in AHI was the primary endpoint. Reductions in body weight, sleep apnea-specific hypoxic burden, selected patient-reported sleep outcomes, hsCRP, and systolic blood pressure were reported as key secondary or additional secondary findings, supporting a broader disease-burden signal but not proving long-term cardiovascular event reduction. Discordant vascular-imaging evidence further cautions that GLP-1-mediated weight loss should not be assumed to reproduce all vascular effects of PAP or to prove cardiovascular event reduction. Semaglutide provides important indirect obesity and cardiometabolic evidence, but direct OSA-specific outcome data remain limited; evidence from other incretin agents also remains largely indirect because most trials were designed for obesity or cardiometabolic endpoints rather than sleep outcomes. The most parsimonious mechanistic interpretation is weight-loss-mediated anatomical unloading. This interpretation is supported by non-incretin weight-loss imaging studies and upper-airway physiology, but it has not yet been directly confirmed by serial upper-airway imaging, Pcrit measurement, or physiological endotyping within incretin-treated OSA cohorts. This narrative review organizes the field into three evidence tiers: direct OSA-specific randomized trials, indirect obesity-trial evidence relevant to OSA, and mechanistic extrapolation. We argue that the current evidence is strong enough to position incretin therapy as a disease-modifying adjunct for selected patients with obesity-driven, anatomically dominant OSA, but not yet strong enough to support class-wide claims, routine PAP replacement, or confident attribution of benefit to direct modulation of non-anatomical endotypes. Many people with obstructive sleep apnea also live with obesity. In these patients, extra fat around the tongue, throat, chest, and abdomen can make the airway more likely to narrow or collapse during sleep. PAP treatment can keep the airway open each night, but it does not treat the obesity that often helps drive the problem. Newer medicines such as liraglutide and tirzepatide were developed for obesity and diabetes care, and they can produce meaningful weight loss. The best direct sleep-apnea evidence currently comes from only two drugs: liraglutide and tirzepatide. For other incretin medicines, the evidence is still mostly indirect because many studies measured weight and metabolic outcomes rather than sleep-apnea outcomes. Right now, the most likely explanation is still inferred from weight-loss studies: losing weight reduces the mechanical load on the upper airway. Incretin trials have not yet directly confirmed this mechanism with repeated airway imaging or detailed breathing-physiology testing. These medicines may also influence breathing control or airway muscle function, but that has not yet been proven in people with sleep apnea. One small trial also suggested that PAP may improve some early vascular markers when GLP-1-mediated weight loss alone did not, so weight loss or AHI improvement should not automatically be treated as cardiovascular protection. For most patients, incretin therapy should be viewed as part of a combined treatment plan - not as an automatic replacement for PAP. If weight loss is substantial, treatment settings and overall management may need reassessment, but PAP should not be stopped without repeat objective sleep testing.

Incretin-based therapies have changed the management of type 2 diabetes and obesity. Semaglutide acts through the glucagon-like peptide-1 receptor, while tirzepatide combines glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonism. These therapies were initially used mainly for glycaemic control and weight reduction, but recent evidence suggests that their role now extends into obesity-related organ disease, including atherosclerotic cardiovascular disease, hear

Sleep disturbances affect up to half of older adults with type 2 diabetes mellitus (T2DM) and represent a clinically meaningful but under addressed dimension of diabetes care. Metformin, the universally recommended first-line agent for T2DM, exerts multiple pleiotropic effects, including modulation of AMPK signaling, circadian clock gene expression, neuroinflammation, and neuropathic pain, that are each mechanistically relevant to sleep regulation. Although metformin may influence pathways relev

Obesity plays a central role in the pathomechanism of obstructive sleep apnea and is strongly associated with the severity of sleep-disordered breathing. Weight reduction in obese patients has been shown to decrease the apnea-hypopnea index (AHI), improve sleep architecture, and reduce cardiometabolic risk. However, traditional, specialty-specific models of care do not address sleep and metabolic disorders in an integrated manner, and weight management often receives less emphasis in obstructive

Obstructive sleep apnea syndrome (OSAS) is a potentially life-threatening condition that is increasingly prevalent in developed countries. OSAS treatment involves multiple components, including general lifestyle modifications and specific interventions such as intraoral fixation devices and continuous positive airway pressure (CPAP). Surgical treatments, including correction of nasopharyngeal and oropharyngeal structures, orthognathic operations, and bariatric surgery, are used under strict indi