Daily Endocrinology Research Analysis
Analyzed 21 papers and selected 3 impactful papers.
Summary
Three papers stand out today in endocrinology: a Nature Medicine multi-omics study defines a metabolite-informed obesity metric (metBMI) linked to adipose dysfunction and the gut microbiome; a randomized withdrawal trial shows diazoxide choline ER reduces hyperphagia in Prader–Willi syndrome; and a large real-world analysis associates GLP-1 receptor agonists with lower mortality and hospitalization in patients with diabetes undergoing cancer therapy.
Research Themes
- Precision phenotyping of metabolic obesity via multi-omics and microbiome integration
- Therapeutics for rare endocrine obesity (Prader–Willi syndrome) targeting hyperphagia
- Onco-endocrinology: GLP-1 receptor agonists and survival in patients with cancer and diabetes
Selected Articles
1. Multi-omic definition of metabolic obesity through adipose tissue-microbiome interactions.
Using multi-omics in 1,408 individuals with external validation, the authors introduce metBMI, a metabolite-informed obesity metric that captures adipose dysfunction and links to microbiome features. Higher-than-expected metBMI stratified elevated cardiometabolic risk and predicted less weight loss after bariatric surgery; a 66-metabolite panel retained substantial explanatory power and mediated host–microbiome interactions.
Impact: This work provides a mechanistically anchored, clinically relevant alternative to BMI that integrates adipose biology and the microbiome, enabling precision risk stratification. It advances the field by quantifying a bidirectional host–microbiome metabolic axis.
Clinical Implications: metBMI could refine identification of high-risk individuals for fatty liver disease, insulin resistance, and poor post-bariatric outcomes, guiding targeted prevention and tailored interventions beyond BMI.
Key Findings
- metBMI explained 52% of BMI variance in an external cohort (n=466) and better reflected adiposity than other omics models.
- Individuals with higher-than-expected metBMI had 2–5-fold higher odds of fatty liver disease, diabetes, visceral adiposity, insulin resistance, hyperinsulinemia, and inflammation.
- In bariatric surgery patients (n=75), higher obesogenic metBMI signature predicted 30% less weight loss.
- A 66-metabolite panel retained 38.6% explanatory power, with 90% covarying with the microbiome; mediation analysis showed a bidirectional, metabolite-centered host–microbiome axis.
Methodological Strengths
- Deep multi-omics phenotyping with external validation and a bariatric surgery subset.
- Systems-level integration linking metabolomics to microbiome features with mediation analysis.
Limitations
- Observational design limits causal inference; potential residual confounding.
- Clinical implementation requires standardization and validation across diverse populations and platforms.
Future Directions: Prospective studies to test metBMI-guided interventions, standardization of the 66-metabolite panel, and interventional trials targeting the host–microbiome axis.
Obesity's metabolic heterogeneity is not fully captured by body mass index (BMI). Here we show that deep multi-omics phenotyping of 1,408 individuals defines a metabolome-informed obesity metric (metBMI) that captures adipose tissue-related dysfunction across organ systems. In an external cohort (n = 466), metBMI explained 52% of BMI variance and more accurately reflected adiposity than other omics models. Individuals with higher-than-expected metBMI had 2-5-fold higher odds of fatty liver disease, diabetes, severe visceral fat accumulation and attenuation, insulin resistance, hyperinsulinemia and inflammation and, in bariatric surgery (n = 75), achieved 30% less weight loss. This obesogenic signature aligned with reduced microbiome richness, altered ecology and functional potential. A 66-metabolite panel retained 38.6% explanatory power, with 90% covarying with the microbiome. Mediation analysis revealed a bidirectional, metabolite-centered host-microbiome axis, mediated by lipids, amino acids and diet-derived metabolites. These findings define an adipose-linked, microbiome-connected metabolic signature that outperforms BMI in stratifying cardiometabolic risk and guiding precision interventions.
2. Diazoxide Choline Extended-Release Tablets in Prader-Willi Syndrome: A Randomized, Double-Blind, Withdrawal Period Study.
In a 16-week randomized, double-blind withdrawal study (n=77), continued diazoxide choline ER significantly mitigated hyperphagia progression (HQ-CT LS mean change 2.6 vs 7.6; P=0.0022) versus placebo and favored weight and BMI z-score changes, with similar adverse events and no serious events on DCCR.
Impact: This RCT provides controlled evidence supporting DCCR as a therapy for hyperphagia in Prader–Willi syndrome, addressing a critical unmet need in a rare endocrine/metabolic disorder.
Clinical Implications: DCCR can be considered to sustain hyperphagia control and potentially attenuate weight gain in Prader–Willi syndrome, supporting continued therapy with monitoring for tolerability.
Key Findings
- Primary endpoint: HQ-CT total score increased less with DCCR vs placebo (LS mean change 2.6 vs 7.6; P=0.0022).
- Exploratory endpoints favored DCCR: placebo gained more weight and had higher BMI z-score (LS mean weight difference −1.6 kg; BMI z-score difference −0.09).
- Safety: adverse event rates similar between arms; no serious adverse events in the DCCR arm.
Methodological Strengths
- Randomized, double-blind withdrawal design with validated patient-reported outcome (HQ-CT).
- Inclusion of participants with long-term prior exposure allows assessment of continued benefit.
Limitations
- Modest sample size (n=77) and prior DCCR exposure may limit generalizability.
- CGI measures favored DCCR but did not reach statistical significance.
Future Directions: Larger, longer-duration RCTs to assess durability of hyperphagia control, functional outcomes, and metabolic endpoints; head-to-head comparisons with emerging therapies.
CONTEXT: The hallmark condition of Prader-Willi syndrome, a rare, genetic neurobehavioral/metabolic disorder is life-threatening hyperphagia. OBJECTIVE: We assessed the efficacy and safety of recently FDA-approved diazoxide choline extended-release (DCCR) tablets for the treatment of hyperphagia in adults and children four years of age and older with Prader-Willi syndrome. METHODS: We conducted a 16-week, randomized withdrawal study in children and adults with Prader-Willi syndrome and hyperphagia. Participants who previously completed randomized (13-week DCCR or placebo) and open-label (2.5-4.5 years DCCR) studies were randomized one:one to receive once-daily DCCR or placebo. The primary endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total score change from baseline to 16 weeks. Secondary endpoints included Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I); exploratory endpoints included weight and body mass index (BMI) z-score. RESULTS: Seventy-seven participants were randomized (DCCR:38; placebo:39). Statistically significant increases in HQ-CT from baseline to week 16 were observed with placebo versus DCCR (least square [LS] mean [standard error] change 7.6 [1.09] with placebo and 2.6 [1.12] with DCCR; P=0.0022). CGI scores favored DCCR but were not significantly changed. Consistent with the hyperphagia response, the placebo cohort gained more weight and increased their BMI z-score more than the DCCR cohort (LS mean weight difference (95% confidence interval) -1.6 kg (-3.1, -0.1); LS mean z-score difference -0.09 (-0.17, -0.01). Adverse events were similar with both treatments, with no serious adverse events in the DCCR arm. CONCLUSIONS: Continued DCCR treatment was superior to placebo for hyperphagia. DCCR appears to offer meaningful therapeutic benefits for people with Prader-Willi syndrome.
3. GLP- 1 Receptor Agonists in Patients with Cancer are Associated with Reduced All-Cause Mortality and Hospitalization.
In a large TriNetX cohort, type 2 diabetes patients starting cancer therapy who received GLP-1 receptor agonists had lower all-cause mortality (HR 0.875 overall; HR 0.786 in new starts) and fewer hospitalizations and complications compared with metformin controls. Benefits were consistent across subgroups, though BMI/A1c-stratified sub-analyses were not statistically significant.
Impact: This real-world analysis suggests GLP-1 RAs may confer survival and morbidity benefits in patients with diabetes undergoing cancer therapy, informing onco-endocrine management and prioritizing agents beyond glycemic control.
Clinical Implications: When selecting glucose-lowering therapy for patients with active cancer, GLP-1 RAs may be preferred given associations with lower mortality and hospitalization; prospective trials should validate this strategy.
Key Findings
- All-cause mortality was lower with GLP-1 RA use: HR 0.875 (95% CI 0.778–0.985) overall and HR 0.786 (95% CI 0.662–0.934) in new starters.
- Secondary outcomes favored GLP-1 RAs: reduced all-cause hospitalization, sepsis, MACE, pulmonary embolism, and pneumonia.
- BMI- and A1c-stratified sub-analyses did not achieve statistical significance; findings support need for prospective trials.
Methodological Strengths
- Large, multi-institutional real-world database (TriNetX) with sizable comparator cohorts.
- Multiple clinically relevant secondary outcomes analyzed consistently with primary findings.
Limitations
- Observational design with potential residual confounding and confounding by indication.
- Cancer type, stage, therapy regimens, and duration of exposure not fully detailed; reliance on EHR coding.
Future Directions: Prospective, cancer-specific randomized or pragmatic trials to test GLP-1 RA effects on survival and treatment tolerance; mechanistic studies of anti-tumor pathways vs glycemic effects.
BACKGROUND: GLP- 1 RA have been reported to decrease cancer incidence, but less is known about their potential in patients with active cancer. Preclinical studies have demonstrated that GLP-1 RA inhibit progression of solid tumor malignancies via downregulation of cellular proliferation pathways and improved glycemic control. Despite these promising findings, studies characterizing the effects of GLP-1 RA in patients with active cancer are limited. METHODS: Using TriNetX, a global database comprising over 120 million patients, we identified an overall cohort of 3747 patients with type 2 diabetes who received GLP-1 RA within 3 months of starting systemic therapy and identified 52,061 patients receiving metformin in the same timeframe as a control cohort. Additional sub-analyses stratified patients by hemoglobin A1c range, obesity, and by participants "newly started" on their first instance of GLP-1 RA within 3 months of starting cancer treatment. RESULTS: Patients receiving GLP-1 RA had significantly reduced mortality in both the overall monotherapy setting (HR: 0.875, 95% CI: (0.778-0.985), p=0.0268) and the new start setting (HR: 0.786 , 95% CI: (0.662-0.934), p= 0.0062) cohorts. Secondary analyses found lower rates of all-cause hospitalization, sepsis, major adverse cardiovascular events, pulmonary embolism, and pneumonia in patients on GLP-1 RA. Sub-analyses stratified by BMI and A1c did not meet statistical significance. CONCLUSIONS: Patients with diabetes and cancer who received GLP-1 RA experienced superior survival outcomes and reduced rates of hospitalization compared to patients receiving metformin. Additionally, patients already on metformin and newly started on GLP-1 RA demonstrated superior survival outcomes compared to patients newly started on insulin. Further prospective, well-controlled studies are needed to evaluate the benefits of GLP-1 RA in patients with diabetes and cancer.