Study design and baseline profile for adults with type 2 diabetes in the once-weekly subcutaneous SEmaglutide randomized PRAgmatic (SEPRA) trial.

INTRODUCTION: Once-weekly subcutaneous semaglutide, a glucagon-like peptide-1 analog, is approved in the USA as an adjunct to diet and exercise for adults with inadequately controlled type 2 diabetes (T2D) to improve glycemic control and reduce the risk of major adverse cardiovascular events in people with T2D and established cardiovascular disease. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) phase III clinical trial program demonstrated the efficacy and safety of once-weekly subcutaneous semaglutide; however, determining its effectiveness in a real-world setting could support decision-making by clinicians, payers and policy makers in routine clinical practice. RESEARCH DESIGN AND METHODS: SEmaglutide PRAgmatic (SEPRA) is an ongoing open-label, randomized, pragmatic clinical trial designed to compare the effects of once-weekly subcutaneous semaglutide versus standard of care in US health-insured adults with T2D and physician-determined inadequate glycemic control. The primary end point is the proportion of participants achieving glycated hemoglobin (HbA1c) <7.0% at year 1; other key outcomes include glycemic control, weight loss, healthcare utilization, and patient-reported outcomes. Individual-level data will be collected from routine clinical practice and health insurance claims. The last patient last visit is expected by June 2023. RESULTS: Between July 2018 and March 2021, 1278 participants were enrolled from 138 study sites across the USA. At baseline, 54% were male with mean±SD age 57.4±11.1 years and body mass index 35.7±8.0 kg/m2. Mean diabetes duration was 7.4±6.0 years and mean HbA1c was 8.5±1.6%. At baseline, concomitant antidiabetes medications included metformin, sulfonylureas, sodium-glucose co-transporter-2 inhibitors, and dipeptidyl peptidase-4 inhibitors. The majority of participants had hypertension and dyslipidemia. The trial design was self-assessed using the PRagmatic Explanatory Continuum Indicator Summary-2 tool by the study steering group and was scored 4-5 in all domains suggesting a highly pragmatic study. CONCLUSIONS: SEPRA, a highly pragmatic ongoing study, will provide data on the effects of once-weekly subcutaneous semaglutide in a real-world setting when used during routine management of T2D. TRIAL REGISTRATION NUMBER: NCT03596450.

A new wearable diagnostic home sleep testing platform: comparison with available systems and benefits of multinight assessments.

STUDY OBJECTIVES: We assessed the real-world performance of the ANNE Sleep system against 2 Food and Drug Administration-cleared home sleep testing platforms and the intraindividual night-to-night variability of respiratory event index measured by ANNE Sleep. METHODS: We evaluated the home performance of the ANNE Sleep system compared with 2 Food and Drug Administration-cleared home sleep testing platforms (WatchPAT: n = 29 and Alice NightOne: n = 46) during a synchronous night with unsupervised patient application. Additionally, we evaluated night-to-night variability of respiratory event index and total sleep time using the ANNE Sleep system (n = 30). RESULTS: For the diagnosis of moderate and severe obstructive sleep apnea, the ANNE Sleep system had a positive percent agreement of 58% (95% confidence interval, 28-85%) and a negative percent agreement of 100% (95% confidence interval, 80-100%) compared to WatchPAT. The positive and negative percent agreement for ANNE Sleep vs Alice NightOne was 85% (95% confidence interval, 66-96%) and 95% (95% confidence interval, 74-100%). There were no differences in mean total sleep time or respiratory event index across multiple nights of monitoring with ANNE. There were no differences consistent with a first-night effect but testing multiple nights reclassified obstructive sleep apnea severity in 5 (17%) individuals and detected 3 additional cases of moderate disease, with only a 12% (standard deviation, 28%) mean fluctuation in respiratory event index from the first night of testing compared to a mean of multiple nights. Overall, 80% of users found ANNE comfortable and easy to use. CONCLUSIONS: ANNE Sleep exhibited stronger concordance with Alice NightOne compared to WatchPAT. While we illustrated low night-to-night variability for ANNE Sleep, the results suggest multiple nights increased detection of moderate or severe obstructive sleep apnea. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: ANNE Diagnostic Agreement With Home Sleep Testing; URL: https://clinicaltrials.gov/ct2/show/NCT05421754; Identifier: NCT05421754. CITATION: Walter J, Lee JY, Blake S, et al. A new wearable diagnostic home sleep testing platform: comparison with available systems and benefits of multinight assessments. J Clin Sleep Med. 2023;19(5):865-872.

A single-arm, open-label, multicenter, and comparative study of the ANNE sleep system vs polysomnography to diagnose obstructive sleep apnea.

STUDY OBJECTIVES: Evaluate per-patient diagnostic performance of a wireless dual-sensor system (ANNE sleep) compared with reference standard polysomnography (PSG) for the diagnosis of moderate and severe obstructive sleep apnea (OSA) with a minimum prespecified threshold of 80% for both sensitivity and specificity. METHODS: A multicenter clinical trial was conducted to evaluate ANNE sleep vs PSG to diagnose moderate and severe OSA in individuals 22 years or older. For each testing approach, apnea-hypopnea index (AHI) was manually scored and averaged by 3 registered sleep technologists blinded to the other system. Average variations > 15% were adjudicated by a sleep medicine physician. RESULTS: In a total of n = 225 participants (mean age 53 years, range 22-88 years), PSG diagnosed 30% (n = 68) of participants with moderate or severe OSA (AHI ≥ 15 events/h) compared to 29% (n = 65) diagnosed by ANNE sleep (P = .55). The sensitivity and specificity for ANNE sleep were 90% (95% confidence interval: 80-96%) and 98% (95% confidence interval: 94-99%), respectively. Strong correlation was shown in terms of final AHI (r = .93), with an average AHI bias of 0.5 (95% limits of agreement: -12.8 to 11.8). The majority of users noted comfort with using the ANNE sleep in the home setting. No adverse events were noted. CONCLUSIONS: Using PSG as the gold standard, ANNE sleep demonstrated high sensitivity and specificity for the diagnosis of moderate or severe OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Comparative Study of the ANNE™ One System to Diagnose Obstructive Sleep Apnea; URL: https://clinicaltrials.gov/ct2/show/NCT04643782; Identifier: NCT04643782. CITATION: Davies C, Lee JY, Walter J et al. A single-arm, open-label, multicenter, and comparative study of the ANNE sleep system vs polysomnography to diagnose obstructive sleep apnea. J Clin Sleep Med. 2022;18(12):2703-2712.

Effectiveness of Combining Antiobesity Medication With an Employer-Based Weight Management Program for Treatment of Obesity: A Randomized Clinical Trial.

Importance: The clinical efficacy of antiobesity medications (AOMs) as adjuncts to lifestyle intervention is well characterized, but data regarding their use in conjunction with workplace wellness plans are lacking, and coverage of AOMs by US private employers is limited. Objective: To determine the effect of combining AOMs with a comprehensive, interdisciplinary, employer-based weight management program (WMP) compared with the WMP alone on weight loss, treatment adherence, and work productivity and limitations. Design, Setting, and Participants: This 1-year, single-center, open-label, parallel-group, real-world, randomized clinical trial was conducted at the Cleveland Clinic's Endocrinology and Metabolism Institute in Cleveland, Ohio, from January 7, 2019, to May 22, 2020. Participants were adults with obesity (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared] ≥30) enrolled in the Cleveland Clinic Employee Health Plan. Interventions: In total, 200 participants were randomized 1:1, 100 participants to WMP combined with an AOM (WMP+Rx), and 100 participants to WMP alone. The WMP was the Cleveland Clinic Endocrinology and Metabolism Institute's employer-based integrated medical WMP implemented through monthly multidisciplinary shared medical appointments. Participants in the WMP+Rx group initiated treatment with 1 of 5 US Food and Drug Administration-approved medications for chronic weight management (orlistat, lorcaserin, phentermine/topiramate, naltrexone/bupropion, and liraglutide, 3.0 mg) according to standard clinical practice. Main Outcomes and Measures: The primary end point was the percentage change in body weight from baseline to month 12. Results: The 200 participants were predominately (177 of 200 [88.5%]) women, had a mean (SD) age of 50.0 (10.3) years, and a mean (SD) baseline weight of 105.0 (19.0) kg. For the primary intention-to-treat estimand, the estimated mean (SE) weight loss was -7.7% (0.7%) for the WMP+Rx group vs -4.2% (0.7%) for the WMP group, with an estimated treatment difference of -3.5% (95% CI, -5.5% to -1.5%) (P < .001). The estimated percentage of participants achieving at least 5% weight loss was 62.5% for WMP+Rx vs 44.8% for WMP (P = .02). The rate of attendance at shared medical appointments was higher for the WMP+Rx group than for the WMP group. No meaningful differences in patient-reported work productivity or limitation measures were observed. Conclusions and Relevance: Clinically meaningful superior mean weight loss was achieved when access to AOMs was provided in the real-world setting of an employer-based WMP, compared with the WMP alone. Such results may inform employer decisions regarding AOM coverage and guide best practices for comprehensive, interdisciplinary employer-based WMPs. Trial Registration: ClinicalTrials.gov Identifier: NCT03799198.

Comparison of Outcomes in Patients With Diabetes Mellitus Treated With Versus Without Insulin + Heart Failure With Preserved Left Ventricular Ejection Fraction (from the TOPCAT Study).

We aimed to evaluate the impact of diabetes mellitus (DM) and insulin treatment on clinical outcomes in patients with heart failure and preserved left ventricular ejection fraction enrolled in the TOPCAT study. We investigated the influence of DM status (insulin-treated [ITDM], non-insulin treated [NITDM], and no diabetes [non-DM]) at baseline on time to development of the primary end point, a composite of cardiovascular (CV) mortality, heart failure hospitalization, and aborted cardiac arrest. Secondary end points included the individual components of the primary end point, myocardial infarction, stroke, all-cause mortality, hyperkalemia, and worsened renal function. Due to marked regional differences in characteristics and outcomes of the TOPCAT patients, with much lower events in patients enrolled in Russia/Georgia, we restricted our analyses on findings from patients enrolled from the Americas. Compared to patients without DM, patients with ITDM had approximately 2-fold increased risk for the primary end point, heart failure hospitalization, and myocardial infarction (hazard ratios: 1.80, 1.97, and 2.27, respectively) and approximately 50% increases in all-cause and CV mortality. The risks for these outcomes were also increased in patients with ITDM in comparison to patients with NITDM as well (hazard ratios: 1.63, 1.65, and 2.73, respectively, and approximately 40% increases in all-cause and CV mortality). Patients with NITDM had similar risks for the primary end point and all secondary end points as patients without DM. In conclusion, the apparent increased risk of adverse outcomes in patients with heart failure and preserved left ventricular ejection fraction and ITDM merits future research to improve the prognosis of these high-risk patients.

Overall Postneonatal Mortality and Rates of SIDS.

BACKGROUND: Reductions in sudden infant death syndrome (SIDS) are commonly attributed to modifications in infant sleep environments. Approaches to diagnosis in sudden infant death, death scene investigations, the prevalence of intrinsic risk factors for SIDS, and the potential influence of treatment-related factors on infant vulnerability have also changed. Understanding all contributory factors may help reduce residual SIDS rates. METHODS: We analyzed US Mortality Multiple Causes Records for 1983 to 2012 to compare SIDS postneonatal mortality rates with a projection applying non-SIDS mortality changes, using those changes as a proxy measure for alterations in intrinsic risk. Composites of neglect-related, unknown, and circumstantial respiratory diagnoses were measured, as was a cumulative composite of unexplained infant death diagnoses. Cluster analysis with leading causes of postneonatal mortality and SIDS mortality rates for low birth weight infants were also examined. RESULTS: SIDS and non-SIDS postneonatal mortality rates were concordant over time. Important variance was seen 1994 to 1996, coinciding with Back-to-Sleep initiation. Other variance, eliminated in the cumulative composite, appeared related to differences in diagnostic practices. Changes in SIDS rates resembled changes in mortality from congenital malformations, respiratory distress of the newborn, and diseases of the circulatory system. SIDS rates for low birth weight infants followed broader postneonatal trends. CONCLUSIONS: SIDS mortality followed trends in overall postneonatal mortality, including effects of changes in the infant sleep environment and diagnostic classification. Preventing asphyxia risk in the sleep environment must be coupled with efforts to understand intrinsic biological pathways, some potentially associated with other categories of infant and perinatal mortality.

Serotonin metabolites in the cerebrospinal fluid in sudden infant death syndrome.

Forensic biomarkers are needed in sudden infant death syndrome (SIDS) to help identify this group among other sudden unexpected deaths in infancy. Previously, we reported multiple serotonergic (5-HT) abnormalities in nuclei of the medulla oblongata that help mediate protective responses to homeostatic stressors. As a first step toward their assessment as forensic biomarkers of medullary pathology, here we test the hypothesis that 5-HT-related measures are abnormal in the cerebrospinal fluid (CSF) of SIDS infants compared with those of autopsy controls. Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the degradative products of 5-HT and dopamine, respectively, were measured by high-performance liquid chromatography in 52 SIDS and 29 non-SIDS autopsy cases. Tryptophan (Trp) and tyrosine (Tyr), the substrates of 5-HT and dopamine, respectively, were also measured. There were no significant differences in 5-HIAA, Trp, HVA, or Tyr levels between the SIDS and non-SIDS groups. These data preclude the use of 5-HIAA, HVA, Trp, or Tyr measurements as CSF autopsy biomarkers of 5-HT medullary pathology in infants who have died suddenly and unexpectedly. They do, however, provide important information about monoaminergic measurements in human CSF at autopsy and their developmental profile in infancy that is applicable to multiple pediatric disorders beyond SIDS.