Daily Endocrinology Research Analysis

The burden of cardiovascular disease is rising in the Asia-Pacific region, in contrast to falling cardiovascular disease mortality rates in Europe and North America. Here we perform quantification of 883 metabolites by untargeted mass spectroscopy in 8,124 Asian adults and investigate their relationships with carotid intima media thickness, a marker of atherosclerosis. Plasma concentrations of 3beta-hydroxy-5-cholestenoate (3BH5C), a cholesterol metabolite, were inversely associated with carotid intima media thickness, and Mendelian randomization studies supported a causal relationship between 3BH5C and coronary artery disease. The observed effect size was 5- to 6-fold higher in Asians than Europeans. Colocalization analyses indicated the presence of a shared causal variant between 3BH5C plasma levels and messenger RNA and protein expression of ferredoxin-1 (FDX1), a protein that is essential for sterol and bile acid synthesis. We validated FDX1 as a regulator of 3BH5C synthesis in hepatocytes and macrophages and demonstrated its role in cholesterol efflux in macrophages and aortic smooth muscle cells, using knockout and overexpression models.

IMPORTANCE: People with obesity and diabetes have poorer psychiatric and cognitive outcomes and lower quality of life (QOL) compared with those without. Glucagon-like peptide 1 receptor agonists (GLP1-RAs) are treatments for diabetes and obesity that may also influence psychiatric outcomes. OBJECTIVE: To conduct a meta-analysis of randomized placebo-controlled trials to evaluate psychiatric, cognitive, and QOL outcomes with GLP1-RA treatment. DATA SOURCES: MEDLINE, Embase, PsycINFO, and CENTRAL databases were searched from inception through June 24, 2024. STUDY SELECTION: Double-blind placebo-controlled trials comparing GLP1-RA to placebo in adults with overweight/obesity and/or diabetes, reporting on psychiatric, cognition, or QOL outcomes, were included. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed in parallel by 2 reviewers. Random-effects meta-analysis was performed. Effect size measures were log risk ratios (log[RR]) and standardized mean differences (Hedges g). The quality of studies was appraised using the Cochrane risk-of-bias tool (RoB2). Certainty of evidence was assessed via GRADEpro. MAIN OUTCOMES AND MEASURES: Main outcomes were risk of psychiatric adverse events (serious and nonserious) and change in mental health symptom severity, health-related quality of life, and cognition. RESULTS: Eighty randomized clinical trials involving 107 860 patients were included in the meta-analysis. The mean (SD) age of participants across studies in the meta-analysis was 60.1 (7.1) years; 43 251 were female (40.1%) and 64 608 male (59.9%). GLP1-RA treatment was not associated with a significant difference in risk of serious psychiatric adverse events (log[RR] = -0.02; 95% CI, -0.20 to 0.17; P = .87) and nonserious psychiatric adverse events (log[RR] = -0.03; 95% CI, -0.21 to 0.16], P = .76), or depressive symptom change (g = 0.02; 95% CI, -0.51 to 0.55; P = .94), compared with placebo. GLP1-RA treatment was associated with improvements in restrained eating (g = 0.35; 95% CI, 0.13 to 0.57; P = .002) and emotional eating behavior (g = 0.32; 95% CI, 0.11 to 0.54; P = .003) and in mental health-related QOL (g = 0.15; 95% CI, 0.07 to 0.22; P < .001), physical health-related QOL (g = 0.20; 95% CI, 0.14 to 0.26; P < .001), diabetes-related QOL (g = 0.23; 95% CI, 0.15 to 0.32; P < .001), and weight-related QOL (g = 0.27; 95% CI, 0.18 to 0.35; P < .001) compared with placebo. CONCLUSIONS AND RELEVANCE: In patients with overweight/obesity and/or diabetes , GLP1-RA treatment is not associated with increased risk of psychiatric adverse events or worsening depressive symptoms relative to placebo and is associated with improvements in QOL, restrained eating, and emotional eating behavior. These findings provide reassurance regarding the psychiatric safety profile of GLP1-RAs and suggest that GLP1-RA treatment contributes to both physical and emotional well-being.

BACKGROUND AND AIMS: The prognosis of adult-onset type 1 diabetes (T1D) and prognostic factors are sparsely investigated. This study assessed mortality, major adverse cardiovascular events (MACE), and prognostic factors in adult-onset T1D, particularly focusing on those diagnosed at age ≥40. METHODS: Participants were people diagnosed with adult-onset T1D (n = 10 184) or type 2 diabetes (T2D, n = 375 523) in 2001-20 from the Swedish National Diabetes Register and 509 172 population controls from the Total Population Register, followed until 2022. Hazard ratios (HR) and population attributable risk fraction (PAR%) were estimated. RESULTS: People with T1D had higher incidence of MACE (HR 1.30 [95% confidence interval 1.17, 1.45]), all-cause mortality (1.71 [1.60, 1.84]), and mortality from cardiovascular or non-cardiovascular diseases, cancer, or infection than population controls. They had lower MACE incidence (0.67 [0.60, 0.75]) and higher mortality from diabetic coma or ketoacidosis (7.04 [4.54, 10.9]) than people with T2D. Smoking (PAR% 10.7%) and glycated haemoglobin (HbA1c) ≥ 53 mmol/mol (10.4%) accounted for most deaths while overweight/obesity (19.8%), smoking (8.4%), and high HbA1c (8.8%) accounted for most MACE events in T1D. Results were similar for T1D diagnosed at age ≥40, although they had lower insulin pump use and higher HbA1c than people diagnosed earlier. CONCLUSIONS: Adult-onset T1D carries excess risk of death and MACE compared with population controls but less MACE risk than T2D. Individuals diagnosed after age 40 had similar excess risk and poorer glycaemic control than those diagnosed earlier, underscoring the need for improved management. Key prognostic factors were smoking, poor glycaemic control, and overweight/obesity.