Daily Endocrinology Research Analysis
Analyzed 38 papers and selected 3 impactful papers.
Summary
Among 38 endocrinology-related papers, three stood out for clinical and translational impact: a 1.8-million–patient multinational cohort clarifying comparative safety of second-line antihyperglycemics in older adults; an integrated cohort/RCT analysis revealing distinct fasting vs postprandial metabolomic signatures associated with liver fat and their dietary modulation; and a phase II trial suggesting dual PD-L1/CTLA-4 blockade benefits in anaplastic thyroid carcinoma.
Research Themes
- Comparative safety of antihyperglycemic agents in older adults with T2D
- Liver fat and postprandial metabolomics in cardiometabolic risk
- Dual immune checkpoint blockade in advanced thyroid carcinoma
Selected Articles
1. Real-world evidence for comparative safety of second-line antihyperglycemic agents in older adults with type 2 diabetes.
In 1.8 million older adults with type 2 diabetes across nine databases, GLP-1 receptor agonists and SGLT2 inhibitors had lower risks of hypoglycemia and hyperkalemia than sulfonylureas, while GLP-1 receptor agonists also reduced peripheral edema versus DPP-4 inhibitors. SGLT2 inhibitors carried a higher risk of diabetic ketoacidosis compared with GLP-1 receptor agonists and sulfonylureas.
Impact: This is a large, rigorously analyzed multinational cohort addressing a critical evidence gap in older adults underrepresented in RCTs, directly informing safer antihyperglycemic selection.
Clinical Implications: Prefer GLP-1 receptor agonists or SGLT2 inhibitors over sulfonylureas to reduce hypoglycemia in older adults, monitor for DKA with SGLT2 inhibitors, and consider GLP-1 receptor agonists when peripheral edema is a concern.
Key Findings
- GLP-1 receptor agonists and SGLT2 inhibitors were associated with significantly lower hypoglycemia risk than sulfonylureas in adults ≥65.
- GLP-1 receptor agonists showed lower peripheral edema risk compared with DPP-4 inhibitors.
- SGLT2 inhibitors were linked to higher diabetic ketoacidosis risk than GLP-1 receptor agonists and sulfonylureas.
- Propensity score adjustment and empirical calibration were used across nine U.S. and European databases (N≈1.8 million).
Methodological Strengths
- Very large, multinational multi-database cohort with harmonized analyses
- Robust bias control using propensity score adjustment, empirical calibration, and prespecified diagnostics
Limitations
- Observational design with potential residual confounding and outcome misclassification
- Class-level comparisons may not capture molecule-specific safety differences
Future Directions: Pragmatic head-to-head trials and risk-stratified prescribing algorithms in very old and frail populations; exploration of molecule-specific safety signals.
As prescribing of newer antihyperglycemic agents expands, there remains limited comparative safety data for older adults-a population particularly vulnerable to adverse drug events and underrepresented in clinical trials. We conduct a multinational cohort study using nine databases from the U.S. and Europe. Among adults aged ≥65, we compare eighteen safety outcomes across four classes of second-line antihyperglycemic agents. We use propensity score adjustment, empirical calibration, and prespecified diagnostics and estimated hazard ratios. In a cohort of 1.8 million, both GLP-1 receptor agonists and SGLT2 inhibitors are linked to significantly lower risks of hypoglycemia and hyperkalemia than sulfonylureas. GLP-1 receptor agonists show lower risks of peripheral edema than DPP-4 inhibitors. However, SGLT2 inhibitors are associated with a higher risk of diabetic ketoacidosis compared to GLP-1 receptor agonists and sulfonylureas. These results support informed, safety-conscious prescribing in the older adults underrepresented in clinical trials yet highly susceptible to adverse events.
2. The association between liver fat content and plasma metabolite profiles in fasting and postprandial states: an integration of a cohort study and a randomized controlled trial.
Higher liver fat content was associated with adverse fasting and postprandial metabolomic signatures, including elevated triglycerides, VLDL, small LDL/HDL, ApoB, fatty acids, GlycA, and BCAAs, and reduced medium/large HDL and acetate. Dietary reduction of liver fat improved 40 fasting metabolites but did not normalize postprandial responses.
Impact: By integrating a large MRS-based cohort with a randomized dietary intervention, this study delineates fasting versus postprandial metabolomic correlates of liver fat, informing mechanistic understanding and intervention targets.
Clinical Implications: Lifestyle interventions that reduce liver fat may yield broad improvements in fasting lipid and amino acid risk markers, but clinicians should be aware that postprandial metabolic dysregulation may persist and require targeted strategies.
Key Findings
- High liver fat was linked to higher fasting and postprandial triglycerides, all VLDL, small LDL/HDL, ApoB, fatty acids, GlycA, and BCAAs, and to lower medium/larger HDL and acetate.
- Postprandial responses of cholesterol in S-LDL, IDL, and S-HDL, as well as glutamine, histidine, omega-3%, and DHA% were blunted in high vs low liver fat.
- Diet-induced liver fat reduction over 12 weeks was associated with favorable changes in 40 fasting metabolites (e.g., VLDL-TG, tyrosine, isoleucine, fatty acid ratios), but not in postprandial responses.
Methodological Strengths
- MRS-quantified liver fat in a large cohort combined with an RCT
- NMR-based fasting and postprandial metabolomics enabling pathway-level insights
Limitations
- Heterogeneity in postprandial assessment protocols; harmonization is needed
- The dietary RCT sample size was modest (n=80) and short duration (12 weeks)
Future Directions: Standardize postprandial testing, test targeted interventions to correct postprandial dysmetabolism, and link metabolomic changes to clinical endpoints.
BACKGROUND: Postprandial metabolic impairments play a key role in the pathophysiology of cardiometabolic diseases. While liver fat content has been linked to distinct fasting metabolite profiles, its relationship with postprandial metabolite profiles remains unexplored. In this study, we aimed to (1) examine to what extent liver fat content is associated with the postprandial metabolomic profile beyond fasting metabolites; and (2) investigate whether diet-induced changes in liver fat content are associated with changes in plasma metabolites identified in objective 1. METHODS: In a subpopulation (n = 1986) of an existing cohort study and a 12-week dietary intervention study (n = 80), liver fat content was measured by proton magnetic resonance spectroscopy and categorized as low (< 2.5%), middle (2.5-5.5%), or high (> 5.5%). In the cohort study, plasma metabolomic profiles were quantified by NMR spectroscopy at fasting (T RESULTS: High liver fat group was characterized by higher fasting and postprandial levels of triglycerides, all VLDL and the small LDL/HDL subclasses, ApoB, fatty acids, glycoprotein acetyls, and BCAAs, and lower medium/larger HDL subclasses, and acetate compared to the low liver fat group. In the high vs. low liver fat group, postprandial responses of cholesterol content of S-LDL, IDL, and S-HDL, glutamine and histidine, omega-3% and DHA % were lower. Diet-induced reductions in liver fat were associated with reductions in 40 fasting plasma metabolites, including VLDL-TG, tyrosine, isoleucine, fatty acid ratios, and most of the VLDL subclasses. CONCLUSIONS: Postprandial metabolomic profiling revealed additional associations between liver fat content and plasma metabolites beyond fasting measures, particularly in lipoprotein cholesterol and fatty acid composition. Diet-induced reductions in liver fat were associated with favorable changes in fasting metabolites, but not postprandial metabolite responses. Future studies with harmonized postprandial assessment are needed to further elucidate the postprandial observations and the underlying mechanisms. TRIAL REGISTRATION: The trials in this study were registered at clinicaltrials.gov as NL21981.058.08/P08.109 and NCT02194504.
3. Durvalumab plus tremelimumab for the treatment of patients with progressive, refractory advanced thyroid carcinoma: the phase II GETNE-DUTHY trial.
In a prospective phase II, single-arm trial, durvalumab plus tremelimumab achieved a 6-month overall survival of 65.6% and an objective response rate of 33% in anaplastic thyroid carcinoma, meeting the prespecified primary endpoint. Differentiated and medullary thyroid carcinoma cohorts showed modest activity with 6-month PFS of 32.4% and 40.8% and ORR of 8% and 10%, respectively, without new safety concerns.
Impact: This trial suggests clinically meaningful activity of dual checkpoint blockade in anaplastic thyroid carcinoma, a disease with dire prognosis and limited options, warranting confirmatory randomized studies.
Clinical Implications: For refractory anaplastic thyroid carcinoma, dual PD-L1/CTLA-4 blockade may be considered in clinical trials or selected cases; limited benefit was observed in differentiated and medullary thyroid carcinoma.
Key Findings
- In anaplastic thyroid carcinoma (n=12), 6-month overall survival was 65.6% and objective response rate was 33%, meeting the cohort’s primary endpoint.
- Differentiated (n=37) and medullary (n=30) thyroid carcinoma cohorts had 6-month PFS of 32.4% and 40.8%, and ORR of 8% and 10%, respectively.
- No additional safety signals were observed with durvalumab plus tremelimumab.
Methodological Strengths
- Prospective, preregistered, multi-cohort phase II design with clearly defined endpoints
- Systematic assessment of efficacy and safety across histologic subtypes
Limitations
- Single-arm design without randomized comparator limits causal inference
- Small sample size in the anaplastic cohort (n=12) may limit precision and generalizability
Future Directions: Randomized trials versus standard care, biomarker-driven enrichment, and rational combinations (e.g., with targeted therapies or radiation) in anaplastic thyroid carcinoma.
Single-agent PD-1 blockade demonstrated promising efficacy in advanced thyroid cancer. The phase II, single-arm, multi-cohort GETNE-DUTHY trial (clinicaltrials.gov NCT03753919, EudraCT 2018-001066-42) aimed to determine whether dual anti-PD-L1/CTLA-4 inhibition using durvalumab and tremelimumab can improve the clinical outcomes in advanced thyroid cancer. Three parallel cohorts including patients with differentiated thyroid carcinoma (Cohort 1, n = 37), medullary thyroid carcinoma (Cohort 2, n = 30), and anaplastic thyroid carcinoma (Cohort 3, n = 12) were recruited. Cohort 1 and 2 included patients following progression to previous standard systemic therapy and in Cohort 3 were recruited regardless of previous therapy. The primary endpoint was 6-month progression-free survival rate for Cohort 1 and 2 and 6-month overall survival rate for Cohort 3. Secondary endpoints included objective response rate, progression-free survival, overall survival, and safety. The 6-month progression-free survival rates were 32.4% (95% confidence interval [CI]: 20.4-51.6) (Cohort 1) and 40.8% (95% CI: 26.3-63.6) (Cohort 2); 6-month overall survival rate was 65.6% (95% CI: 43.2-99.8) (Cohort 3). The objective response rates were 8%, 10%, and 33% for Cohort 1, 2, and 3, respectively. No additional safety signals observed. Durvalumab plus tremelimumab treatment in patients with anaplastic thyroid carcinoma met the primary endpoint of this study, showing encouraging survival outcomes.