Daily Endocrinology Research Analysis

BACKGROUND: The cardiovascular safety of oral semaglutide, a glucagon-like peptide 1 receptor agonist, has been established in persons with type 2 diabetes and high cardiovascular risk. An assessment of the cardiovascular efficacy of oral semaglutide in persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both is needed. METHODS: In this double-blind, placebo-controlled, event-driven, superiority trial, we randomly assigned participants who were 50 years of age or older, had type 2 diabetes with a glycated hemoglobin level of 6.5 to 10.0%, and had known atherosclerotic cardiovascular disease, chronic kidney disease, or both to receive either once-daily oral semaglutide (maximal dose, 14 mg) or placebo, in addition to standard care. The primary outcome was major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), assessed in a time-to-first-event analysis. The confirmatory secondary outcomes included major kidney disease events (a five-point composite outcome). RESULTS: Among the 9650 participants who had undergone randomization, the mean (±SD) follow-up was 47.5±10.9 months, and the median follow-up was 49.5 months. A primary-outcome event occurred in 579 of the 4825 participants (12.0%; incidence, 3.1 events per 100 person-years) in the oral semaglutide group, as compared with 668 of the 4825 participants (13.8%; incidence, 3.7 events per 100 person-years) in the placebo group (hazard ratio, 0.86; 95% confidence interval, 0.77 to 0.96; P = 0.006). The results for the confirmatory secondary outcomes did not differ significantly between the two groups. The incidence of serious adverse events was 47.9% in the oral semaglutide group and 50.3% in the placebo group; the incidence of gastrointestinal disorders was 5.0% and 4.4%, respectively. CONCLUSIONS: Among persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both, the use of oral semaglutide was associated with a significantly lower risk of major adverse cardiovascular events than placebo, without an increase in the incidence of serious adverse events. (Funded by Novo Nordisk; SOUL ClinicalTrials.gov number, NCT03914326.).

Recent research has highlighted the significance of succinate and its receptor in gestational diabetes (GDM) pathogenesis. However, a clear interconnection between placenta metabolism, succinate levels, SUCNR1 signalling and pregnancy pathologies remains elusive. Here, we set out to investigate the potential role of succinate on labour and placental mechanisms by combining clinical and functional experimental data at the same time as exploring the specific SUCNR1-mediated effects of succinate on placenta vascularization, addressing its specific agonist actions. According to our data, succinate levels vary throughout pregnancy and postpartum, with a natural increase during the peripartum period. We also show that SUCNR1 activation in the umbilical cord endothelium promotes angiogenesis under normal conditions. However, in GDM, excessive succinate and impaired SUCNR1 function may weaken this angiogenic response. In conclusion, the present study underlines succinate as an emerging signalling molecule in the placenta, regulating labour and placental processes. The reduced sensitivity of the succinate/SUCNR1 pathway in the GDM environment may serve as a protective physiological mechanism or could have a pathogenic effect. KEY POINTS: Succinate levels increase at delivery in maternal and fetal circulation. Gestational diabetes (GDM) induces succinate accumulation and SUCNR1 downregulation in umbilical cords. GDM compromises angiogenic gene profile modulation by SUCNR1 in umbilical cord endothelium. SUCNR1 activation stimulates sprouting and tube-forming capacity of human umbilical vein endothelial cells from healthy, but not GDM pregnancies.

BACKGROUND: Primary aldosteronism (PA) is a distinct cause of low-renin hypertension (LRH), characterized by inappropriate aldosterone production. We investigated the distinction between LRH and PA by leveraging the physiological effects of angiotensin-converting enzyme inhibition. METHODS: We conducted a retrospective cohort study including 756 patients with LRH who underwent a captopril challenge test (CCT) for evaluation of PA. The distinction between PA and LRH was assessed using 4 CCT criteria: (1) Post-CCT plasma renin activity <1 ng/mL per hour and plasma aldosterone concentration decrease <30%; (2) Post-CCT aldosterone-to-renin ratio (ARR) >30 ng/dL per ng/mL per hour; (3) Post-CCT plasma renin activity <1 ng/mL per hour; and (4) Post-CCT plasma aldosterone concentration >11 ng/dL. Longitudinal outcomes following aldosterone-targeted therapy were assessed using the Primary Aldosteronism Surgery Outcome and Primary Aldosteronism Medical Outcome criteria. RESULTS: There was a continuous spectrum of nonsuppressible aldosterone production post-CCT. When interpreting CCT results based on both renin and aldosterone responses (criteria 1 or 2), 57.8% to 66.3% of patients were classified as having PA. In contrast, when based on aldosterone or renin responses alone (criteria 3 or 4), 82.5% to 95.1% of patients were classified as having PA. Complete or partial treatment response rates following aldosterone-targeted therapy were high, ranging from 86.5% to 91.7%, regardless of CCT interpretation. CONCLUSIONS: These findings highlight the blurred distinction between LRH and PA. Although persistently suppressed renin, or elevated aldosterone, following captopril facilitated the maximum capture of PA cases, the implementation of aldosterone-targeted therapy provided similar benefits to all patints, regardless of CCT interpretation. Empirical aldosterone-directed therapy for patients with LRH suspected of having PA may be an appropriate alternative to laborious diagnostics to confirm PA.