Daily Endocrinology Research Analysis
Three high-impact endocrinology studies stood out today: a large BMJ pharmacoepidemiologic analysis found no increased risk of suicidality with GLP-1 receptor agonists versus DPP-4 or SGLT-2 inhibitors; a network meta-analysis in PLoS One identified semaglutide and phentermine/topiramate as top-performing pharmacotherapies for pediatric obesity; and a Diabetologia mechanistic study showed brown adipose tissue–derived NRG4 protects podocytes in diabetic kidney disease via Akt–GSK-3β signaling.
Summary
Three high-impact endocrinology studies stood out today: a large BMJ pharmacoepidemiologic analysis found no increased risk of suicidality with GLP-1 receptor agonists versus DPP-4 or SGLT-2 inhibitors; a network meta-analysis in PLoS One identified semaglutide and phentermine/topiramate as top-performing pharmacotherapies for pediatric obesity; and a Diabetologia mechanistic study showed brown adipose tissue–derived NRG4 protects podocytes in diabetic kidney disease via Akt–GSK-3β signaling.
Research Themes
- Metabolic and obesity therapeutics across the lifespan
- Drug safety and pharmacoepidemiology of incretin-based therapies
- Adipose–renal endocrine crosstalk in diabetic complications
Selected Articles
1. Brown adipose tissue alleviates podocyte apoptosis through NRG4 in a male mouse model of diabetic kidney disease.
Using BAT-specific and global Nrg4 knockout mice, AAV-mediated NRG4 replenishment, BAT transplantation, and in vitro podocyte assays, the authors show that BAT-derived NRG4 reduces podocyte apoptosis and albuminuria in diabetic nephropathy. Mechanistically, protection is mediated via activation of the Akt–GSK-3β pathway.
Impact: This study identifies a novel endocrine axis from brown adipose tissue to the kidney, positioning NRG4 as a mechanistic mediator of renal protection in diabetes. It opens therapeutic avenues targeting BAT-derived factors to prevent or treat diabetic kidney disease.
Clinical Implications: While preclinical, the findings suggest that enhancing NRG4 signaling or BAT function could become a strategy to reduce albuminuria and podocyte injury in diabetic kidney disease. It also supports metabolic interventions that activate BAT as potentially renoprotective.
Key Findings
- BAT-specific Nrg4 knockout increased podocyte apoptosis by ~47% and raised urinary albumin/creatinine ratio by ~42%.
- AAV-mediated NRG4 replenishment and BAT transplantation reversed apoptosis and albuminuria phenotypes in knockout mice.
- Recombinant NRG4 and co-culture with WT brown adipocytes protected podocytes from high-glucose–induced apoptosis via Akt–GSK-3β signaling.
Methodological Strengths
- Multi-pronged design including loss- and gain-of-function in vivo models (BAT-specific and global KO, AAV rescue, BAT transplantation).
- Complementary in vitro validation with recombinant NRG4 and adipocyte–podocyte co-culture and pathway interrogation.
Limitations
- Findings are preclinical and based on male mouse models; human translatability remains to be established.
- The long-term systemic effects and safety of modulating NRG4/BAT activity were not assessed.
Future Directions: Define NRG4 receptor targets on podocytes, evaluate NRG4 analogs or BAT activators in large-animal models, and conduct biomarker-guided early phase trials in diabetic kidney disease.
AIMS/HYPOTHESIS: Brown adipose tissue (BAT) consumes excess energy through heat production by uncoupling protein 1 (UCP1) to regulate the metabolic profile, but the UCP1-independent mechanisms of BAT, such as in endocrine function, are largely unknown. Our previous study showed that BAT-derived neuregulin 4 (NRG4) displays anti-atherosclerotic properties. Thus, we hypothesised that BAT could regulate diabetic nephropathy, a diabetic microvascular complication, via NRG4. METHODS: To investigate the influence of NRG4 from BAT on podocyte apoptosis, both loss- and gain-of-function approaches were used in in vivo experiments. Diabetic nephropathy models were created using BAT-specific Nrg4-knockout (BKO) mice, global Nrg4-knockout (KO) mice and wild-type (WT) mice. In in vitro studies, podocytes (MPC5) were exposed to glucose and recombinant NRG4 (rNrg4). Additionally, brown adipocytes were co-cultured with MPC5 podocytes using a transwell system. The expression levels of proteins associated with podocyte apoptosis and signalling pathways were measured. RESULTS: BAT-specific NRG4 deficiency aggravated podocyte apoptosis (increased by 47.46%) and increased the urinary albumin/creatinine ratio (increased by 41.71%), decreased nephrin expression and increased desmin expression. As expected, these changes were reversed by NRG4 replenishment using adeno-associated virus-NRG4 interscapular BAT injection and BAT transplantation assays in KO mice. Additionally, co-culture experiments demonstrated that brown adipocytes from WT mice could alleviate high-glucose-induced podocyte apoptosis. In in vitro experiments, recombinant NRG4 inhibited high-glucose-induced podocyte apoptosis. Mechanistically, the Akt-glycogen synthase kinase 3 β (GSK-3β) pathway is crucial for the protection that BAT-derived NRG4 provides to podocytes in diabetic nephropathy. CONCLUSIONS/INTERPRETATION: Our data show that BAT had a protective effect on podocyte apoptosis in diabetic nephropathy through BAT-derived NRG4, and the Akt-GSK‑3β signalling pathway may mediate the inhibition of BAT-derived NRG4 on podocyte apoptosis in diabetic nephropathy.
2. Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study.
Using two active-comparator new-user cohorts from linked UK primary care and hospital/death records, GLP-1 receptor agonist use was not associated with higher risk of suicidality (suicidal ideation, self-harm, or suicide) versus DPP-4 inhibitors or SGLT-2 inhibitors. Median follow-up was 1.3–1.7 years in the first cohort with >270,000 participants.
Impact: Addresses widespread regulatory and public concerns about suicidality with GLP-1 therapies using rigorous comparative designs, informing benefit–risk assessments and prescribing confidence.
Clinical Implications: Clinicians can reassure patients that GLP-1 receptor agonists are not associated with increased suicidality relative to DPP-4 or SGLT-2 inhibitors, while still screening for mental health risks as part of routine care.
Key Findings
- Two active-comparator new-user cohorts compared GLP-1 RAs to DPP-4 inhibitors and SGLT-2 inhibitors using propensity score fine stratification weighted Cox models.
- In the DPP-4 comparator cohort, 36,082 GLP-1 RA users and 234,028 DPP-4 users were included (median follow-up 1.3 vs 1.7 years).
- GLP-1 RA use was not associated with increased risk of suicidality versus either comparator class.
Methodological Strengths
- Active-comparator, new-user design minimizes confounding by indication and time-related biases.
- Linked primary care, hospital admissions, and death registries with propensity score fine stratification weighting.
Limitations
- Observational design cannot fully exclude residual confounding and outcome misclassification.
- Median follow-up was relatively short for rare outcomes like suicide; under-ascertainment is possible.
Future Directions: Extend analyses to longer follow-up, psychiatric subgroups, weight-loss indications, and international datasets; integrate patient-reported outcomes to improve suicidality ascertainment.
OBJECTIVE: To determine whether the use of glucagon-like peptide-1 (GLP-1) receptor agonists is associated with an increased risk of suicidal ideation, self-harm, and suicide among patients with type 2 diabetes compared with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter-2 (SGLT-2) inhibitors. DESIGN: Active comparator, new user cohort study. SETTING: Primary care practices contributing data to the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics Admitted Patient Care and Office for National Statistics Death Registration databases. PARTICIPANTS: Patients with type 2 diabetes. EXPOSURES: Two cohorts were assembled, with the first composed of patients who started and continued on GLP-1 receptor agonists or DPP-4 inhibitors between 1 January 2007 and 31 December 2020 and the second composed of patients who started and continued on GLP-1 receptor agonists or SGLT-2 inhibitors between 1 January 1 2013 and 31 December 2020. Both cohorts were followed until 29 March 2021. MAIN OUTCOME MEASURES: The primary outcome was suicidality, defined as a composite of suicidal ideation, self-harm, and suicide. Secondary outcomes were each of these events considered separately. Propensity score fine stratification weighted Cox proportional hazards models were fitted to estimate hazard ratios and 95% confidence intervals (CIs) to estimate the average treatment effect among the treated patients. RESULTS: The first cohort included 36 082 GLP-1 receptor agonist users (median follow-up 1.3 years) and 234 028 DPP-4 inhibitor users (median follow-up 1.7 years). In crude analyses, GLP-1 receptor agonist use was associated with an increased incidence of suicidality compared with DPP-4 inhibitors (crude incidence rates 3.9 CONCLUSIONS: In this large cohort study, the use of GLP-1 receptor agonists was not associated with an increased risk of suicidality compared with the use of DPP-4 inhibitors or SGLT-2 inhibitors in patients with type 2 diabetes.
3. Pharmacological interventions for addressing pediatric and adolescent obesity: A systematic review and network meta-analysis.
Across 30 randomized trials (n=3,822), semaglutide consistently outperformed other anti-obesity medications for BMI, weight, and waist circumference reductions in youths, with phentermine/topiramate showing broadly comparable efficacy. Effect estimates favored semaglutide versus exenatide (BMI% change MD −12.43) and against multiple comparators for weight and waist.
Impact: Provides the most comprehensive comparative efficacy evidence to date for pediatric obesity pharmacotherapy, informing guideline development and payer decisions as use of GLP-1 agonists expands in adolescents.
Clinical Implications: For adolescents with obesity requiring pharmacotherapy, semaglutide and phentermine/topiramate should be prioritized based on superior weight-related outcomes, balancing efficacy with safety, access, and long-term adherence considerations.
Key Findings
- Semaglutide reduced BMI more than most comparators, including exenatide and liraglutide (MD range −8.28 to −1.24), and exceeded exenatide in BMI% change (MD −12.43).
- Both semaglutide and phentermine/topiramate produced greater weight loss than seven other agents; each was the top performer except against each other.
- Semaglutide lowered waist circumference more than other AOMs except phentermine/topiramate; certainty of evidence ranged from very low to moderate.
Methodological Strengths
- Network meta-analysis synthesizing direct and indirect evidence across multiple active agents from randomized trials.
- Comprehensive evaluation of BMI, weight, BMI-SDS, waist circumference, and metabolic/safety outcomes.
Limitations
- Certainty of evidence varied from very low to moderate; heterogeneity and small pediatric samples may limit precision.
- Long-term durability, safety, and real-world adherence in youths remain insufficiently characterized.
Future Directions: Head-to-head pediatric RCTs of semaglutide versus phentermine/topiramate, longer-term safety and maintenance trials, and health-economic analyses to guide equitable access.
BACKGROUND: Obesity significantly impacts the health outcomes of children and adolescents, necessitating a comprehensive study to evaluate the effects of various anti-obesity medications (AOMs) on weight-related and metabolic outcomes. METHODS: PubMed, EMBASE, and CENTRAL were searched for studies published up to January 3, 2024. We performed a network meta-analysis on randomized clinical trials that compared various treatments for pediatric and adolescent obesity, such as phentermine/topiramate, semaglutide, exenatide, liraglutide, topiramate, metformin, fluoxetine, metformin/fluoxetine, sibutramine, and orlistat. The study evaluated body mass index (BMI), BMI percentage change, weight, BMI-SDS, waist circumference, metabolic, anthropometric, and safety outcomes. RESULTS: The study gathered 2733 studies, including 30 articles that involved 3822 participants. The results of our research showed that PHEN/TPM was better at lowering BMI than exenatide, liraglutide, metformin, fluoxetine, Met/Flu, topiramate, orlistat, and sibutramine, with mean differences (MD) ranging from -10.29 to -1.28. Additionally, semaglutide demonstrated superior efficacy over other AOMs (MD ranged from -8.28 to -1.24). Various levels of certainty, ranging from very low to moderate, supported the findings. Furthermore, semaglutide demonstrated superior efficacy over exenatide (MD-12.43, 95% CI -23.95 to -0.30) regarding percentage change in BMI. Semaglutide also showed enhanced weight reduction effectiveness compared to seven other AOMs except for PHEN/TPM (MD ranging from -15.56 to -12.65). Similarly, PHEN/TPM displayed greater weight reduction effectiveness than seven other AOMs, except for semaglutide (MD ranged from -12.17 to -9.27). Moreover, semaglutide proved more effective in decreasing waist circumference when compared with other AOMs apart from PHEN/TPM (MD ranged from -11.61 to -6.07). Similarly, we found that PHEN/TPM, excluding semaglutide and sibutramine, was more effective in reducing waist circumference (MD ranged from -8.64 to -5.51). CONCLUSIONS: The study found that semaglutide outperformed other AOMs in reducing BMI and additional weight-related outcomes in children and adolescents with obesity, while PHEN/TPM showed comparable efficacy.