Somers, Virend K.

Abstract Aims Glucagon-like peptide-1 receptor agonists (GLP-1RA) reduce cardiovascular risk in patients with Type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease and are recommended in guidelines. We evaluated the real-world effectiveness of GLP-1RA therapy on cardiovascular outcomes in patients with T2D after myocardial infarction (MI) or ischaemic stroke and examined trends and disparities. Methods and results Using nationwide Czech registry data (2015–24), we identified patients with incident nonfatal MI or ischaemic stroke and confirmed T2D. GLP-1RA users—initiating therapy within 12 months post-event—were propensity score matched to non-users. The primary outcome was major adverse cardiovascular events (MACE: nonfatal MI, nonfatal stroke, cardiovascular death); secondary outcomes included individual components and all-cause mortality. GLP-1RA therapy was initiated in only ∼2% of MI and stroke survivors with T2D. Among 126 845 MI survivors, 28 206 had T2D; the matched cohort comprised 2271 patients (401 GLP-1RA; median follow-up 35 months). GLP-1RA use was associated with lower risk of MACE (HR 0.7; 95% CI, 0.52–0.93), all-cause (HR 0.61; 95% CI, 0.47–0.80), and cardiovascular death (HR 0.54; 95% CI, 0.36–0.80). Among 177 115 stroke survivors, 73 750 had T2D; the matched cohort comprised 2235 patients (385 GLP-1RA; median follow-up 27 months). GLP-1RA use was associated with lower risk of MACE (HR 0.71; 95% CI, 0.54–0.94), all-cause (HR 0.59; 95% CI, 0.46–0.76), and cardiovascular death (HR 0.55; 95% CI, 0.37–0.81). Conclusion GLP-1RA therapy after MI or stroke in T2D was associated with substantially lower risks of MACE, cardiovascular, and all-cause death in real-world practice. Utilization remained low, particularly among women and older adults, underscoring the need for broader and more equitable implementation in secondary prevention.

Abstract Study Objectives Respiratory events during sleep induce immediate cardiac alterations, including increased RR intervals during events and decreased RR intervals after events. However, the extent to which related desaturations and arousals modulate these responses remains underexplored. We hypothesized that desaturations and arousals are the main contributors to respiratory event-related cardiac response, with greatest cardiac alterations expected when both are present. Methods We analyzed RR, QT, and heart rate-corrected QT (QTc) intervals before, during, and after 4310 respiratory events from 129 obstructive sleep apnea patients. Mixed-effect statistical models were utilized to assess the influence of the presence and severity of desaturations and arousals on the cardiac electrical response to respiratory events. Results There were no significant differences between pre- and post-respiratory event RR and QTc intervals in the absence of desaturation or arousal. Arousal (RR estimate = −23.9 ms; QTc estimate = 5.7 ms) or simultaneous desaturation and arousal (RR estimate = −32.8 ms; QTc estimate = 8.4 ms) modulated significantly (p < .05) mean RR and QTc intervals after respiratory events. Desaturation alone affected only RR intervals (estimate = −9.3 ms, p<.05). Greater desaturation depth (RR estimate = −0.09 ms; QTc estimate = 0.56 ms) and longer arousal duration (RR estimate = −3.52 ms; QTc estimate = 0.84 ms) were significant (p < .05) predictors of RR and QTc magnitude alterations after respiratory events. Conclusions Not all respiratory events have the same effects on cardiac electrophysiology; they are associated with acute alterations after events if they cause desaturations and/or arousal, with longer arousal and deeper desaturations increasing the magnitude of cardiac responses. Statement of Significance This study provides a detailed analysis of the temporal dynamics of cardiac response to respiratory events in obstructive sleep apnea patients, with a focus on the potential modulators of this response. Our observations present that not all respiratory events have the same effects on cardiac electrophysiology; they are associated with significant cardiac response if they cause desaturations and/or arousals, with longer arousal and deeper desaturations increasing the magnitude of cardiac response. Our results present evidence of possible modulators of post-event cardiac function, providing a deeper understanding of obstructive sleep apnea’s impact on health as potential underlying mechanisms leading to adverse cardiovascular events.

Introduction: Excess sodium intake is strongly linked with hypertension and cardiovascular disease (CVD); people with narcolepsy (PwN) have increased CV risk. Hypothesis: Switching from high-sodium oxybate (SXB; Xyrem ® ; 6–9 g for ≥6 wks) to low-sodium oxybate (LXB; Xywav ® ; same regimen) reduces mean 24-hr ambulatory systolic blood pressure (ASBP) after ≈6 wks in PwN, regardless of antihypertensive (anti-HTN) use and site type. Methods: XYLO, an open-label, single-arm study (NCT05869773), assessed PwN aged 18−70 y with office SBPs of 130−155 mmHg. The primary and key secondary endpoints were changes from baseline (BL) to end-of treatment (EOT) in mean 24-hr ASBP and seated resting (“office”) SBP (OSBP), respectively; exploratory endpoints were diastolic BP (DBP) changes. Changes are baseline adjusted. Prespecified subgroup analyses explored BL anti-HTN use and participation site (ie, site-based [at study site] vs decentralized [at-home]). Results: In 43 PwN (mean age, 45 y; female, 65%; anti-HTN, 33%), mean±SD BL OSBP and DBP were 138.0±5.7 and 85.2±6.6 mmHg, respectively. Mean±SD total SXB vs LXB dosages were 8.0±1.1 vs 8.1±1.1 g/night, reflecting 1457±206 vs 118±16 mg sodium (difference: ≈1339 mg); median 24-hr urinary sodium was 4232 mg/d at BL and 2703 mg/d at EOT (median change: 1288 mg/d). Mean change in 24-hr ASBP (least squares mean [95% CI]) was −4.1 (−6.9, −1.4; 1-sided P =0.0019) mmHg (Fig 1) ; mean change in OSBP was −9.2 (−11.9, −6.5; 1-sided P <0.0001). Mean changes in 24-hr ambulatory and office DBP were −2.3 (−4.1, −0.5; 2-sided P =0.0118; nominal) and −3.8 (−6.0, −1.6; 2-sided P =0.0014; nominal) mmHg, respectively. In subgroups, mean change in 24-hr ASBP was −4.6 (−9.6, 0.3) mmHg with BL anti-HTN use and −3.9 (−7.3, −0.5) mmHg without BL anti-HTN use; changes in OSBP were −11.8 (−16.5, −7.1) and −7.9 (−11.1, −4.6) mmHg. Mean change in 24-hr ASBP was −3.6 (−8.0, 0.9) mmHg for site-based and −4.5 (−8.1, −1.0) mmHg for decentralized participation. Corresponding changes in OSBP were −9.0 (−13.3, −4.6; site-based) and −9.3 (−12.8, −5.8; decentralized) mmHg with a downward trend over 6 wks ( Fig 2 ). Treatment-emergent adverse events (all mild/moderate) occurred in 40% of PwN (N=67). Conclusions: Switching from SXB to LXB reduced daily medication-related sodium intake in PwN and was associated with clinically meaningful BP reductions overall and across subgroups, consistent with evidence on dietary and medication-related sodium effects.

Abstract Aims Retatrutide, a novel synthetic molecule, is a triple agonist activating the glucose‐dependent insulinotropic polypeptide, glucagon‐like peptide‐1 and glucagon receptors. The TRIUMPH clinical development program evaluates its safety and efficacy concurrently for the treatment of obesity and two related complications—obstructive sleep apnea (OSA) and knee osteoarthritis (OA). A novel basket trial design simultaneously evaluates retatrutide treatment across these multiple adiposity‐related disease states. Materials and methods TRIUMPH consists of four Phase 3, multicenter, randomized, double‐blind studies assessing weekly subcutaneous retatrutide compared to placebo, in conjunction with healthy diet and physical activity in over 5800 participants. The four trials consist of two weight management basket trials (TRIUMPH‐1 and TRIUMPH‐2) with OSA and/or OA protocols nested within the weight management trial; one weight management trial in a population with CVD (TRIUMPH‐3); and one stand‐alone OA trial (TRIUMPH‐4). The primary endpoint for weight management is percent change in body weight, for OSA is change in Apnea‐Hypopnea Index and for knee OA includes change in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score. The basket trial permits independent analysis of weight management, OSA and OA studies with type I error rate controlled at α = 0.05, split between the overarching weight management and each basket trial. Conclusions By recruiting participants with shared disease exposures, the TRIUMPH program will assess the safety and efficacy of retatrutide for the treatment of adults with obesity and two of its common complications—OSA and OA.

BACKGROUND: People with narcolepsy are at increased risk for hypertension and cardiovascular disease; excessive sodium intake is linked to both. METHODS: We studied patients with narcolepsy and office systolic blood pressures (BPs) of 130 to 155 mm Hg taking twice-nightly high-sodium oxybate for ≥6 weeks who switched to low-sodium oxybate at the same dosage. The primary end point was the change from baseline in mean 24-hour ambulatory systolic BP at the end of treatment (≈6 weeks after switching). Secondary and exploratory end points included changes in diastolic BP, office BP, and 24-hour sodium excretion. RESULTS: Patients (n=43) had a mean age of 45 years, were 65% female, 33% on antihypertensives, with baseline mean (SD) office BP of 138.0/85.2 (5.7/6.6). Mean (SD) total high- and low-sodium oxybate dosages of 8.0 (1.1) and 8.1 (1.1) g/night, respectively, represented 1456.5 (206.2) and 117.8 (16.3) mg of sodium. The median 24-hour urinary sodium was 4278 mg/d at baseline and 2703 mg/d at the end of treatment (median change, 1288 mg/d). Mean (SE) 24-hour ambulatory systolic BPs at baseline and study end were 132.3 (1.8) and 128.2 (1.8) mm Hg (least-squares mean change, −4.1 [95% CI, −6.9 to −1.4] mm Hg; 1-sided P =0.0019). BP changes by narcolepsy subtype, sex, body mass index, baseline office BP, and baseline antihypertensive use were consistent with the overall effect size. CONCLUSIONS: People with narcolepsy switching from high- to low-sodium oxybate showed substantially reduced daily medication-related sodium intake and significant 24-hour BP reductions. These results demonstrate the importance of reducing pharmaceutical sodium content in this elevated cardiovascular risk patient population. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05869773.

Abstract Background Obstructive sleep apnea (OSA) is a risk factor for hypertension and some evidence suggests this risk may not be mitigated with positive airway pressure. Low-intensity statin therapy can modestly reduce blood pressure (BP). In this exploratory analysis, we examined if six months of high-intensity statin therapy could lower resting or ambulatory BP in patients with OSA. Methods 39 patients with OSA (13F, age = 49 ± 9yrs, body mass index = 32.9 ± 4.2kg/m2, apnea-hypopnea index = 22.2 ± 12.4 events/hour) were randomized to high-intensity atorvastatin or placebo. BP was assessed using seated, “office” measurements and in 20-minute intervals over 24 consecutive hours at three timepoints (baseline, three- and six-months post-randomization). Participants maintained a diary denoting sleep and wake times for analysis. Changes (Δ) in BP from baseline were assessed and adjusted for adherence to participants’ intervention (atorvastatin or placebo) as well as to their treatment for OSA (yes or no). Results There were no between-group differences in baseline BP variables (P = .09-.96). At three months, the changes in resting (P = .74-.87), 24 hour mean (P = .54-.96), daytime (P = .70-.96), nor nighttime (P = .74-.96) BP did not differ between groups. Similarly, the changes in resting (P = .23-.92), 24 hour mean (P = .51-.82), daytime (P = .17-.78), and nighttime (P = .51-1.00) BP did not differ between groups following six months of their respective intervention. Conclusions Our data suggest that high-intensity atorvastatin does not lower resting or ambulatory BP in patients with OSA relative to a placebo. Thus, it does not appear that atorvastatin is a viable adjunct intervention for BP reduction in patients with OSA. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03308578.

Restless legs syndrome (RLS) is a frequent sleep-related sensorimotor disorder defined by an urge to move the legs in the evening while resting. Severe RLS symptoms can negatively impact sleep, mood, and quality of life. Periodic leg movements during sleep and wakefulness are found in 60% to 80% of patients with RLS. The pathophysiology of RLS and periodic leg movement is still poorly understood and involves brain iron deficiency, dopamine dysregulation, and genetic predisposition. Over the past decades, several cross-sectional and longitudinal studies have reported an association between RLS, cardiovascular disease, and hypertension although the magnitude, direction, and underlying mechanisms of these associations remain inconclusive. Periodic leg movements during sleep are concomitant with an increase in blood pressure and heart rate, which may affect the physiological nocturnal blood pressure dip and, therefore, lead to an increased incidence of cardiovascular disease. Insomnia and sleep deprivation linked to sensory discomfort could also increase the sympathetic tone and contribute to an increase in cardiovascular risk. Comorbidities and associated sleep disorders may also synergically increase cardiovascular risk. This narrative review details the current knowledge of RLS, a still underdiagnosed and poorly recognized disorder, and examines the epidemiological relationship between RLS, cardiovascular disease and hypertension, potential mechanisms underlying this association, and strategies to reduce the risk of cardiovascular disease in patients with moderate-to-severe RLS. Greater multidisciplinary collaborations between cardiologists and sleep specialists are needed to better identify, understand, and manage patients with sleep disorders, including those with RLS.