Daily Endocrinology Research Analysis
A negative, well-powered RCT in Nature Medicine found no additional reduction in visceral adipose tissue from time-restricted eating compared with Mediterranean diet counseling alone. A large new-user cohort in Diabetes Care linked SGLT2 inhibitors, but not GLP-1 receptor agonists, with lower cirrhosis risk in type 2 diabetes. A multicenter JCEM genetic study identified PDE11A as a phenotype modulator in PBMAH, associating damaging variants with attenuated hypercortisolism.
Summary
A negative, well-powered RCT in Nature Medicine found no additional reduction in visceral adipose tissue from time-restricted eating compared with Mediterranean diet counseling alone. A large new-user cohort in Diabetes Care linked SGLT2 inhibitors, but not GLP-1 receptor agonists, with lower cirrhosis risk in type 2 diabetes. A multicenter JCEM genetic study identified PDE11A as a phenotype modulator in PBMAH, associating damaging variants with attenuated hypercortisolism.
Research Themes
- Feeding window timing versus diet quality in obesity management
- Antidiabetic agents and liver outcomes in type 2 diabetes
- Genetic modifiers of adrenal hyperplasia and cortisol excess
Selected Articles
1. Effects of early, late and self-selected time-restricted eating on visceral adipose tissue and cardiometabolic health in participants with overweight or obesity: a randomized controlled trial.
In a four-arm RCT (n=197), adding early, late, or self-selected 8-hour TRE to Mediterranean diet counseling did not reduce visceral adipose tissue versus counseling alone over 12 weeks. TRE was safe, well tolerated, and highly adherent, but conferred no VAT advantage regardless of timing.
Impact: This trial challenges the prevailing narrative that TRE timing adds cardiometabolic benefit beyond diet quality, providing high-level evidence that Mediterranean diet counseling may suffice for VAT reduction targets.
Clinical Implications: Prioritize sustainable dietary quality (e.g., Mediterranean diet) over restricting eating windows when targeting visceral fat in overweight/obesity. TRE can be offered for behavioral fit, but clinicians should not expect VAT reduction beyond that achieved by diet counseling.
Key Findings
- No significant differences in MRI-assessed VAT change between TRE (early, late, self-selected) and usual care Mediterranean diet counseling over 12 weeks.
- High adherence to TRE (85–88%) with no serious adverse events; only five mild events reported.
- Timing of the 8-hour eating window did not influence outcomes; all pairwise comparisons among TRE schedules were nonsignificant.
Methodological Strengths
- Randomized, controlled, four-arm design with MRI-based VAT as a hard primary endpoint
- High adherence and systematic safety monitoring with explicit reporting of adverse events
Limitations
- 12-week duration may be insufficient to detect longer-term adipose or metabolic adaptations
- Generalizability to populations without Mediterranean diet counseling or with different cultural eating patterns is uncertain
Future Directions: Longer trials exploring TRE with and without structured diet quality interventions, mechanistic endpoints (e.g., energy expenditure, lipolysis flux), and patient-centered outcomes (sleep, adherence sustainability).
The optimal eating window for time-restricted eating (TRE) remains unclear, particularly its impact on visceral adipose tissue (VAT), which is associated with cardiometabolic morbidity and mortality. We investigated the effects of three TRE schedules (8 h windows in the early day, late day and participant-chosen times) combined with usual care (UC, based on education about the Mediterranean diet) versus UC alone over 12 weeks in adults with overweight or obesity. The primary outcome was VAT changes measured by magnetic resonance imaging. A total of 197 participants were randomized to UC (n = 49), early TRE (n = 49), late TRE (n = 52) or self-selected TRE (n = 47). No significant differences were found in VAT changes between early TRE (mean difference (MD): -4%; 95% confidence interval (CI), -12 to 4; P = 0.87), late TRE (MD: -6%; 95% CI, -13 to 2; P = 0.31) and self-selected TRE (MD: -3%; 95% CI, -11 to 5; P ≥ 0.99) compared with UC, nor among the TRE groups (all P ≥ 0.99). No serious adverse events occurred; five participants reported mild adverse events. Adherence was high (85-88%) across TRE groups. These findings suggest that adding TRE, irrespective of eating window timing, offers no additional benefit over a Mediterranean diet alone in reducing VAT. TRE appears to be a safe, well-tolerated and feasible dietary approach for adults with overweight or obesity. ClinicalTrials.gov registration: NCT05310721 .
2. Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors and the Prevention of Cirrhosis Among Patients With Type 2 Diabetes.
In an active-comparator, new-user UK cohort, SGLT2 inhibitors were associated with a lower incidence of cirrhosis (HR 0.64) and decompensated cirrhosis (HR 0.74) compared with DPP-4 inhibitors, while GLP-1 receptor agonists showed no cirrhosis risk reduction. No associations were observed for hepatocellular carcinoma or liver-related mortality.
Impact: Provides clinically actionable comparative effectiveness evidence suggesting SGLT2 inhibitors may confer hepatic benefits in T2D, informing drug selection for patients at risk of MASLD/MAFLD progression.
Clinical Implications: When choosing glucose-lowering therapy for T2D patients with steatotic liver disease risk, SGLT2 inhibitors may be favored to reduce incident cirrhosis; GLP-1RAs may not reduce cirrhosis risk. Continue routine HCC surveillance based on liver disease stage.
Key Findings
- SGLT2 inhibitors vs DPP-4 inhibitors: reduced incidence of cirrhosis (HR 0.64, 95% CI 0.46–0.90) and decompensated cirrhosis (HR 0.74, 95% CI 0.54–1.00).
- GLP-1 receptor agonists vs DPP-4 inhibitors: no significant association with cirrhosis risk (HR 0.90, 95% CI 0.68–1.19) or secondary liver outcomes.
- No reduction observed in hepatocellular carcinoma or liver-related mortality with either SGLT2 inhibitors or GLP-1 receptor agonists.
Methodological Strengths
- Active-comparator, new-user design minimizing confounding by indication
- Propensity score fine stratification weighting with linked primary care, hospital, and national statistics datasets
Limitations
- Observational design cannot fully eliminate residual confounding despite robust adjustment
- Follow-up duration and liver disease stage stratification details are not provided in the abstract
Future Directions: Prospective randomized trials or emulation studies in high-risk MASLD populations; mechanistic studies on SGLT2-mediated hepatic hemodynamics, steatosis, and fibrosis pathways.
OBJECTIVE: To determine whether glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, separately, compared with dipeptidyl peptidase 4 (DPP-4) inhibitors are associated with a reduced risk of cirrhosis and other adverse liver outcomes among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: With an active comparator, new-user approach, we conducted a cohort study using the U.K. Clinical Practice Research Datalink linked with hospital and national statistics databases. Cox proportional hazards models using propensity score fine stratification weighting were used to calculate hazard ratios (HRs) and 95% CIs for cirrhosis (primary outcome) and decompensated cirrhosis, hepatocellular carcinoma, and liver-related mortality (secondary outcomes). RESULTS: In the first cohort comparing 25,516 patients starting GLP-1RAs and 186,752 starting DPP-4 inhibitors, GLP-1RAs were not associated with the incidence of cirrhosis (HR 0.90, 95% CI 0.68-1.19) or the secondary outcomes. In a separate cohort comparing 33,161 patients starting SGLT-2 inhibitors and 124,431 starting DPP-4 inhibitors, SGLT-2 inhibitors were associated with a reduced incidence of cirrhosis (HR 0.64, 95% CI 0.46-0.90), as also decompensated cirrhosis (HR 0.74, 95% CI 0.54-1.00), but not with a lower risk of hepatocellular carcinoma or liver-related mortality. CONCLUSIONS: In patients with type 2 diabetes in the U.K., GLP-1RAs were not associated with a lower risk of cirrhosis compared with DPP-4 inhibitors in patients with type 2 diabetes. However, SGLT-2 inhibitors were associated with a lower risk of cirrhosis compared with DPP-4 inhibitors.
3. PDE11A Is a Phenotype Modulator of Primary Bilateral Macronodular Adrenal Hyperplasia: Results of a 334-Patient Series.
In 334 phenotyped PBMAH patients, damaging PDE11A variants were associated with lower cortisol output and fewer adrenal nodules compared with PDE11A wild-type, while ARMC5 variants conferred more severe disease. Findings support PDE11A as a phenotype modulator with potential management implications.
Impact: Introduces a modulator gene concept in PBMAH that explains phenotypic heterogeneity and could refine risk stratification and surgical decision-making.
Clinical Implications: Genotyping for PDE11A (in addition to ARMC5) may inform disease severity, monitoring intensity, and timing of adrenalectomy in PBMAH; patients with damaging PDE11A variants may have attenuated hypercortisolism.
Key Findings
- Damaging PDE11A variants (11.4% prevalence) associated with lower urinary free cortisol (0.7 vs 1.25× ULN; P=0.0002) and lower midnight plasma cortisol (158 vs 222 nmol/L; P=0.016).
- PDE11A variant carriers had fewer adrenal nodules (3.46 vs 4.74; P=0.048) than wild-type.
- ARMC5 pathogenic variants (19.2%) linked to more severe phenotype, more comorbidities, and higher adrenalectomy rates (~60%).
Methodological Strengths
- Large multicenter cohort with NGS-based genotyping for ARMC5 and PDE11A
- Quantitative hormonal and morphological phenotyping enabling genotype–phenotype correlations
Limitations
- Cross-sectional phenotyping limits causal inference on disease trajectories
- In silico classification of variant pathogenicity requires functional validation
Future Directions: Functional studies of PDE11A variants; prospective validation of genotype-informed risk stratification; integration into surgical decision algorithms.
CONTEXT: Primary bilateral macronodular adrenal hyperplasia (PBMAH), the most common cause of Cushing syndrome due to bilateral nodules, is a heterogeneous disease at the clinical, hormonal, and morphological levels. ARMC5-inactivating pathogenic variants are causative of PBMAH, and rare variants of PDE11A have been associated with PBMAH. OBJECTIVE: The aim of this study, on a large cohort of individuals with PBMAH from Europe and America, was to study the ARMC5 and PDE11A genotype to determine the genotype/phenotype correlation and to investigate the hypothesis that PDE11A could be a modifying gene of the adrenal phenotype. METHODS: Leukocyte DNA of 354 PBMAH index cases was sequenced for ARMC5 and PDE11A genes by next-generation sequencing. Phenotypic characteristics of 334 of these patients were analyzed to study the genotype/phenotype correlations. RESULTS: Seven out of 16 PDE11A variants were considered damaging according to in silico predictions: 6 missense variants (p.Tyr727Cys, p.Met623Arg, p.Tyr658Cys, p.Ag867Trp, p.Asn298Ser, p.Glu840Lys) and 1 stop-gain variant (p.Arg307Ter). In the cohort, 11.4% of patients had one of these variants and 19.2% had ARMC5-pathogenic variants. There was no statistically significant difference in the distribution of PDE11A-damaging variants according to ARMC5 status (P = .83; OR = 0.79; 95% CI, 0.26-2.03) nor in the distribution of ARMC5 pathogenic variants according to PDE11A status (P = .83; OR = 0.81; 95% CI, 0.27-2.04). Patients with PDE11A-damaging variants had lower urinary free cortisol (0.7 vs 1.25 upper limit of normal; P = .0002), midnight plasma cortisol (157.81 vs 222.19 nmol/L, P = .016), and number of adrenal nodules (3.46 vs 4.74; P = .048) compared to PDE11A wild-type patients. Patients with ARMC5-pathogenic variants had a more severe phenotype with more frequent comorbidities and were more often treated by adrenalectomy (60%). CONCLUSION: PDE11A appears to be a modulator of PBMAH phenotype, damaging variants being associated with an attenuated form. This may contribute to the heterogeneity of PBMAH and could affect patient management.