Importance Obstructive sleep apnea (OSA) is a common disorder characterized by repeated upper airway collapse during sleep that is associated with reduced quality of life and increased incidence of cardiometabolic disease. Objective To assess the effects of orforglipron on moderate to severe OSA in adults with obesity or overweight, compared with placebo. Design, Setting, and Participants Two 52-week, phase 3, multicenter, double-blind, placebo-controlled randomized clinical trials were conducted at 66 sites in the US, Argentina, Brazil, China, Czech Republic, Germany, Japan, Mexico, and Taiwan. Adults with moderate to severe OSA and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 27 or higher were enrolled between November 11, 2024, and July 23, 2025. Final follow-up occurred on July 30, 2026. Trial 1 included patients not receiving positive airway pressure treatment and trial 2 included patients receiving positive airway pressure treatment. Intervention Patients were randomized (1:1) to receive either once-daily orforglipron (maximum tolerated dose: equivalent to 9-, 14.5-, or 17.2-mg tablet dose) or placebo. Main Outcomes and Measures The primary end point was change in apnea-hypopnea index (AHI, events/h) from baseline to week 52. Seven key multiplicity-controlled secondary end points included change in sleep apnea–specific hypoxic burden, the Patient-Reported Outcomes Measurement Information System Short Form Sleep-Related Impairment T-score, and high-sensitivity C-reactive protein. Results A total of 363 patients were randomized in trial 1 (mean age, 48.4 years; BMI, 37.4; AHI, 50.7 events/h; 31.4% female) and 349 patients were randomized in trial 2 (mean age, 51.1 years; BMI, 38.6; AHI, 57.6 events/h; 26.9% female). For the treatment regimen estimand, in trial 1, the mean AHI change was −17.8 for orforglipron compared with −4.5 for placebo (difference, −13.2 [95% CI, −17.7 to −8.7]; P < .001) at 52 weeks. In trial 2, the mean AHI change was −17.3 for orforglipron and −5.3 for placebo (difference, −12.0 [95% CI, −17.1 to −6.9]; P < .001) at 52 weeks. Of 7 key secondary end points, 6 were statistically significant, favoring orforglipron. Gastrointestinal events were the most commonly reported adverse events, occurring in 123 (68.0%) participants randomized to receive orforglipron vs 68 (37.4%) randomized to receive placebo in trial 1 and in 125 (70.6%) participants randomized to receive orforglipron vs 63 (36.6%) randomized to receive placebo in trial 2. Conclusions and Relevance These results provide evidence for the potential use of oral orforglipron to improve sleep-disordered breathing in adults with moderate to severe OSA and obesity or overweight. Trial Registration ClinicalTrials.gov Identifier: NCT06649045
Importance Single-pill combination therapy improves medication adherence and hypertension control. However, limited evidence is available on its implementation in routine clinical practice. Objective To assess the long-term effectiveness, implementation, and sustainability of single-pill combination therapy through team-based care for blood pressure reduction among patients with uncontrolled hypertension in primary care settings in Colombia and Jamaica. Design, Setting, and Participants Multicountry, unblinded, pragmatic, cluster randomized clinical trial. Twenty primary care clinics in Jamaica and 20 in Colombia were randomly assigned to either the single-pill combination therapy group or the standard care group. A total of 1706 adults with uncontrolled hypertension were enrolled between February 23, 2023, and September 12, 2024. The final follow-up visit occurred on September 9, 2026. Interventions In the intervention group (n = 869), a team-based care approach that included physician and nurse training, health coaching, home blood pressure monitoring, and blood pressure audit and feedback was used to implement single-pill combination therapy. Single-pill combinations were purchased locally and provided to patients. In the standard care group (n = 837), patients received monotherapy or polytherapy with guideline-recommended medications covered by health insurance or government programs. The intervention lasted 18 months, with additional follow-up at 24 months. Main Outcomes and Measures The primary outcome was the between-group difference in change in systolic blood pressure from baseline to 18 months. Three blood pressure measurements were obtained at each of 2 visits at each time point using a standard protocol. Results Among the 1706 enrolled participants, at baseline, the mean age was 61.4 years, 69.9% of participants were female, and 98.2% were taking antihypertensive medications. Among the 1574 participants included in the primary analysis, systolic blood pressure decreased by 19.1 mm Hg, from 145.9 mm Hg at baseline to 126.8 mm Hg at 18 months, in the intervention group and by 9.0 mm Hg, from 145.0 mm Hg to 136.1 mm Hg, in the standard care group, with a between-group difference of −10.1 mm Hg (95% CI, −13.3 to −6.9 mm Hg; P < .001). At 18 months, 69.5% of patients in the intervention group and 29.2% in the standard care group achieved systolic blood pressure less than 130 and diastolic blood pressure less than 80 mm Hg. Serious adverse events (death and hospitalization) occurred at similar frequencies in the intervention (7.9%) and standard care (9.9%) groups. Conclusions and Relevance Implementing single-pill combination therapy through team-based care significantly reduced blood pressure over 18 months among adults with uncontrolled hypertension in Colombia and Jamaica. This comprehensive strategy integrating single-pill combination therapy with team-based care could be widely adopted and scaled up for hypertension control, particularly in resource-constrained settings. Trial Registration ClinicalTrials.gov Identifier: NCT05405920
Importance Pulmonary vein isolation (PVI) for persistent atrial fibrillation (AF) has demonstrated modest success rates. Ablation of atrial low-voltage areas (LVA) has shown potential results, but more data are required. Objective To determine whether PVI plus LVA ablation is superior to PVI alone in reducing atrial arrhythmia recurrence in patients with AF. Design, Setting, and Participants Single-blind randomized clinical trial in 14 AF ablation centers in Canada. Adults with persistent AF of more than 3 months were enrolled between August 2018 and September 2024 and followed up for 18 to 36 months through April 2026. Intervention Patients were randomized to PVI plus LVA ablation or PVI alone. Main Outcomes and Measures The primary outcome was atrial arrhythmia recurrence beyond 90 days after a single catheter ablation procedure. Secondary outcomes included repeat ablation for AF, atrial flutter, or atrial tachycardia, emergency visits or hospitalization, arrhythmia recurrence over 18 months, procedure duration, total ablation delivery time, AF burden, and safety outcomes. The primary efficacy analysis was based on the modified intention-to-treat principle for patients who received the intervention. Results Among 508 enrolled patients, 253 were randomized to PVI plus LVA ablation and 255 to PVI alone. Mean (SD) age was 65.2 (9.0) years, 386 (76%) were male and 268 (54%) had LVA. After a mean (SD) follow-up of 21 (15) months, 124 (49.4%) randomized to PVI plus LVA and 146 (57.5%) randomized to PVI reached the primary outcome (hazard ratio [HR], 0.82; 95% CI, 0.65-1.04; P = .11). In the prespecified principal subgroup analysis of 268 patients with LVA, arrhythmia recurrence occurred in 68 of 138 patients (49.3%) following PVI plus LVA ablation compared with 90 of 130 patients (69.2%) following PVI alone (HR, 0.77; 95% CI, 0.66-0.91; P = .002). Arrhythmia recurrence over 18 months (37.0% vs 56.2%; HR, 0.77; 95% CI, 0.64-0.92) and AF burden were lower after PVI plus LVA ablation in this group. Among patients without LVA, recurrence was similar between ablation groups (56 of 113 [49.6%] vs 51 of 113 [45.1%]; HR, 1.09; 95% CI, 0.90-1.32). Procedure duration and ablation delivery time were longer in the PVI plus LVA ablation group. Safety outcomes were similar between groups. Conclusions and Relevance In this study, among patients with persistent AF, adjunctive LVA ablation did not significantly reduce atrial arrhythmia recurrence in the overall population over a mean 21-month follow-up. A prespecified principal subgroup analysis of patients with LVA suggested that adjunctive LVA ablation was consistent with reduced recurrence of atrial arrhythmias in this group. Trial Registration ClinicalTrials.gov, Identifier: NCT03347227
