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.
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.
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.