Daily Endocrinology Research Analysis
Three impactful studies shape endocrinology and metabolic care today: a multicohort algorithm flags individuals with G6PD p.Val68Met at risk for HbA1c underestimation and diabetes undertreatment; a randomized trial shows IL-17A inhibition with secukinumab is ineffective for active moderate-to-severe Graves’ orbitopathy; and a double-blind RCT demonstrates that adding gastric electrical stimulation to pyloroplasty improves symptoms and reduces hospitalizations in refractory gastroparesis.
Summary
Three impactful studies shape endocrinology and metabolic care today: a multicohort algorithm flags individuals with G6PD p.Val68Met at risk for HbA1c underestimation and diabetes undertreatment; a randomized trial shows IL-17A inhibition with secukinumab is ineffective for active moderate-to-severe Graves’ orbitopathy; and a double-blind RCT demonstrates that adding gastric electrical stimulation to pyloroplasty improves symptoms and reduces hospitalizations in refractory gastroparesis.
Research Themes
- Precision diagnostics and health equity in diabetes monitoring
- Negative RCT clarifying immunotherapy limits in Graves’ orbitopathy
- Device plus surgical synergy for refractory gastroparesis (often diabetic)
Selected Articles
1. A clinical algorithm to identify people with the glucose-6-phosphate dehydrogenase p.Val68Met variant at risk for diabetes undertreatment.
Using routine glucose, HbA1c, and RDW from a single draw, the authors trained and externally validated algorithms to flag individuals with the G6PD p.Val68Met variant whose HbA1c may be systematically underestimated. Among people with diabetes, those predicted as possibly deficient had 1.4-fold higher 20-year diabetic retinopathy rates, supporting the clinical relevance of identifying at-risk individuals for genotype testing and glucose-based monitoring.
Impact: This work operationalizes precision diagnostics using widely available labs to mitigate HbA1c bias, addressing an equity gap in diabetes care for populations with higher G6PD variant prevalence.
Clinical Implications: Health systems can deploy this algorithm to identify patients who may benefit from G6PD genotyping and a shift toward glucose-based monitoring and treatment targets, reducing the risk of undertreatment and complications such as retinopathy.
Key Findings
- Algorithm trained on 122,307 Black participants using concurrent glucose, HbA1c, and RDW predicted G6PD p.Val68Met deficiency risk.
- In hemizygous males, precision/recall were 31%/81% (possible) and 81%/10% (likely); in homozygous females, 6%/76% and 34%/13%, respectively.
- Predicted possible deficiency in diabetes was associated with a 1.4-fold higher 20-year retinopathy rate (14.3% vs 11.2%).
- External validation across All of Us, BioVU, and MVP supports generalizability.
Methodological Strengths
- Large multicohort development with external validation across multiple biobanks
- Uses routine laboratory data enabling scalable, real-world implementation
Limitations
- Lower precision in females and trade-offs between possible vs likely deficiency thresholds
- Focus on p.Val68Met and self-identified Black cohorts may limit ancestry generalizability; prospective clinical impact not yet tested
Future Directions: Prospective implementation trials should assess workflow integration, impact on treatment decisions and outcomes, and extension to other G6PD variants and ancestries.
PURPOSE: To develop an algorithm using routine clinical laboratory measurements to identify people at risk for systematic underestimation of glycated hemoglobin because of p.Val68Met glucose-6-phosphate dehydrogenase (G6PD) deficiency. METHODS: We analyzed 122,307 participants of self-identified Black race across 4 large cohorts with blood glucose, glycated hemoglobin, and red cell distribution width measurements from a single blood draw. In UK Biobank, we used recursive partitioning to train 2 models to predict possible and likely G6PD deficiency. We validated the algorithm in NIH AllofUs, Vanderbilt BioVU, and the Million Veterans Program. In the Vanderbilt Synthetic Derivative with clinical but no genetic data, we created a cohort of 48,031 participants with type 2 diabetes and no genetic data to test whether predicted risk for G6PD deficiency was associated with incident diabetic retinopathy. RESULTS: G6PD deficiency predictions in hemizygous males showed precision/recall of 31%/81% for possible and 81%/10% for likely deficiency. In homozygous females, precision/recall was 6%/76% for possible and 34%/13% for likely deficiency. Patients with diabetes having predicted possible deficiency demonstrated 1.4-fold higher 20-year retinopathy rates (14.3% vs 11.2%, CONCLUSION: We report a simple clinical algorithm that enables health care systems to identify people who may benefit from G6PD genotyping and glucose-based diabetes monitoring.
2. Secukinumab in Moderate-to-Severe Graves' Orbitopathy: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study.
In a multicenter randomized, double-blind trial of 28 adults with active moderate-to-severe Graves’ orbitopathy, secukinumab 300 mg did not improve a stringent composite endpoint (CAS and proptosis reduction) versus placebo at 16 weeks, nor after open-label extension to 32 weeks. Ophthalmic metrics and thyroid-related biomarkers showed no meaningful changes, while safety was acceptable.
Impact: A negative, well-controlled RCT provides decisive evidence that IL-17A blockade with secukinumab is not effective for active moderate-to-severe GO, redirecting therapeutic strategies and avoiding ineffective treatment.
Clinical Implications: Secukinumab should not be used for active, moderate-to-severe GO outside clinical trials. Focus should remain on established therapies and alternative pathways (e.g., IGF-1R inhibition) while refining patient selection and endpoints in future trials.
Key Findings
- No participants met the composite primary endpoint at 16 weeks; results remained negative after open-label secukinumab to 32 weeks.
- No clinically meaningful changes in proptosis, lid aperture, motility, CAS, or quality of life.
- No meaningful effects on thyroid hormones or autoantibodies; safety profile was acceptable with mostly mild adverse events.
Methodological Strengths
- Randomized, double-blind, placebo-controlled multicenter design
- Predefined composite clinical endpoint and systematic safety assessment
Limitations
- Small sample size (n=28) and limited power for subgroup analyses
- Treatment duration may be insufficient to detect delayed structural changes
Future Directions: Investigate alternative immune pathways and targets; optimize inclusion criteria, timing, and endpoints; and compare against standard-of-care and newer agents in adequately powered trials.
CONTEXT: Interleukin (IL) 17, a key pro-inflammatory cytokine, drives inflammation and fibrosis in Graves' orbitopathy (GO), and elevated IL-17 and Th17 cells correlate with disease activity and severity. OBJECTIVE: The ORBIT study aimed to evaluate the efficacy and safety of secukinumab, an IL-17A inhibitor, in subjects with active, moderate-to-severe GO. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. PATIENTS AND METHODS: Adults with active, moderate-to-severe, non-sight-threatening GO randomly (1:1) received secukinumab 300 mg or placebo subcutaneously over a 16-week double-blind treatment period, followed by an additional 16-week open-label treatment phase for proptosis non-responders. Safety parameters, thyroid-related hormones, and autoantibodies were also assessed. PRIMARY ENDPOINT: Overall response of reduced clinical activity score (CAS) of ≥2 points and reduction of ≥2 mm in proptosis from baseline without worsening in the fellow eye at Week 16. RESULTS: Twenty-eight adult GO patients with a CAS ≥4 were enrolled (secukinumab, n=14; placebo, n=14). None in either the secukinumab or placebo group achieved an overall response at Weeks 16 and 32, respectively, when all patients received open-label secukinumab. No clinically meaningful changes were observed in ophthalmic symptoms and signs, proptosis, lid aperture, eye muscle motility, CAS, and health-related quality of life either at Week 16 or Week 32. No meaningful impact on serum levels of thyroid-related hormones and antibodies was observed. Secukinumab was well tolerated, with mostly mild adverse events. Neither treatment-induced study discontinuation nor new safety signals were registered. CONCLUSION: Secukinumab did not show clinical efficacy versus placebo when treating patients with active, moderate-to-severe GO.
3. Combined Gastric Electrical Stimulation and Pyloroplasty in Gastroparesis: A Randomized Clinical Trial.
In a double-blind randomized trial of medication-refractory gastroparesis (mostly diabetic), turning GES on after pyloroplasty led to significantly greater symptom improvements at 3 months versus device-off. After crossover activation, both groups achieved comparable benefits at 6 months, alongside reduced hospital length of stay and favorable safety.
Impact: Demonstrates that combining GES with pyloroplasty yields superior short-term symptom control and lowers hospitalization in refractory gastroparesis, informing surgical/device decision-making in a population heavily affected by diabetes.
Clinical Implications: For patients failing medical therapy, consider PP with GES implantation; activation provides additional symptomatic benefit beyond pyloroplasty alone, with potential reductions in hospital utilization.
Key Findings
- At 3 months, PP+GES-ON showed larger improvements in GCSI (median difference −1.33; P=.01) and TSS (median difference −12.00; P=.005) versus PP+GES-OFF.
- Gastric emptying improved similarly in both groups, suggesting symptom gains with GES beyond pyloroplasty-driven emptying changes.
- After activation in the OFF group at 3 months, both groups showed comparable symptom improvement at 6 months with reduced hospital length of stay.
Methodological Strengths
- Double-blind randomized design with device ON/OFF crossover
- Intention-to-treat analysis and preregistration (NCT03123809)
Limitations
- Modest sample size (n=38) and 6-month follow-up limit long-term inference
- Single academic setting may affect generalizability
Future Directions: Larger, longer-term RCTs comparing PP alone vs PP+GES across etiologies (diabetic vs idiopathic), incorporating cost-effectiveness and patient-reported outcomes.
IMPORTANCE: Patients with gastroparesis who do not respond to medical therapy may require surgical intervention, typically involving pyloroplasty (PP) alone or with implantation of a gastric electrical stimulation (GES) device. OBJECTIVE: To investigate the outcomes of combining PP with GES in medication-refractory gastroparesis. DESIGN, SETTING, AND PARTICIPANTS: This double-blind randomized clinical trial included patients who had diabetic or idiopathic gastroparesis. Patients from a US academic gastrointestinal motility clinic, who failed medical therapy, were included from January 10, 2017, to September 20, 2023. Patients were followed up for 6 months. INTERVENTIONS: Patients with refractory gastroparesis underwent simultaneous implantation of GES with PP and were randomized into PP + GES-ON and PP + GES-OFF groups. In the PP + GES-ON group, the GES was turned on after surgery. In the PP + GES-OFF group, the device was kept off for 3 months and then was turned on for the following 3 months. MAIN OUTCOMES AND MEASURES: Symptom scores measured with the Gastroparesis Cardinal Symptom Index (GCSI) and the total symptom score (TSS), gastric emptying, and hospitalization length of stay were recorded and compared at baseline and at 3-month and 6-month follow-up visits. Between-group comparisons at 3 months were performed using the Wilcoxon rank sum test following the intention-to-treat procedure. RESULTS: The study included 38 patients with gastroparesis (24 females [63.2%]; mean [SD] age, 46.7 [13.2] years), of whom 31 (81.6%) had diabetic gastroparesis, and 7 (18.4%) had idiopathic gastroparesis. Patients were randomized to the PP + GES-ON (n = 19) or the PP + GES-OFF (n = 19) group. At 3 months, the improvement from baseline in the GCSI (median [IQR] ON: -2.2 [-2.6 to -1.5] vs median [IQR] OFF: -0.9 [-1.8 to -0.4]; median difference, -1.33 [95% CI, -2.34 to -0.33]; P = .01) and the TSS (median [IQR] ON: -15.0 [-16.0 to -8.0] vs median [IQR] OFF: -3.0 [-10.0 to -1.0]; median difference, -12.00 [95% CI, -17.49 to -6.51]; P = .005) was significantly greater in the PP + GES-ON compared with the PP + GES-OFF group. Both groups exhibited significantly faster and similar gastric emptying results compared with the baseline. When the PP + GES-OFF group had GES activated at 3 months, symptoms improved significantly by 6 months (median [IQR] GCSI at 6 months: 1.2 [0.4-2.5] vs at baseline: 3.3 [2.8-4.1]; median [IQR] TSS at 6 months: 8.0 [2.0-10.0] vs at baseline: 18 [14.0-21.0]), achieving results comparable with those patients who had their GES device on for the full 6 months. These results at 6 months were accompanied by a significant reduction in hospital length of stay (median [IQR] at 6 months: 0 [0-2.0] vs at baseline: 4.1 [0-10.1]) and an excellent safety profile. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the combination of GES and PP yielded superior outcomes compared with PP alone, resulting in greater alleviation of gastroparesis symptoms and a reduction in hospitalization, which may enhance patient profiling and optimize decision-making for treatments. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03123809.