Daily Endocrinology Research Analysis
Analyzed 101 papers and selected 3 impactful papers.
Summary
Analyzed 101 papers and selected 3 impactful articles.
Selected Articles
1. Effect of APOC3 Inhibition with Olezarsen on Coronary Atherosclerosis: Essence-TIMI 73b Imaging Study.
In a randomized, placebo-controlled CCTA study of 468 adults with predominantly moderate hypertriglyceridemia, olezarsen markedly lowered triglycerides and remnant cholesterol but did not reduce non-calcified coronary plaque volume over 12 months. LDL-C remained neutral and apoB decreased modestly.
Impact: This rigorous randomized imaging trial challenges assumptions that large triglyceride/remnant cholesterol lowering necessarily regresses non-calcified coronary plaque within a year, informing therapeutic expectations and development.
Clinical Implications: Clinicians should not assume short-term plaque regression with APOC3 inhibition despite robust triglyceride lowering; longer-term outcome data are needed to guide cardiovascular risk reduction strategies.
Key Findings
- Randomized, placebo-controlled CCTA study (n=468) in adults with moderate hypertriglyceridemia.
- Olezarsen substantially lowered triglycerides (~60%) and remnant cholesterol (~70%) with neutral LDL-C and ~15% apoB reduction.
- No reduction in non-calcified coronary plaque volume at 12 months versus placebo.
Methodological Strengths
- Randomized, placebo-controlled design with quantitative CCTA endpoint
- Large multicenter cohort with contemporary lipid-lowering background therapy
Limitations
- 12-month follow-up may be insufficient to observe plaque remodeling
- Imaging surrogate endpoint without clinical outcomes
Future Directions: Assess longer-term effects of APOC3 inhibition on plaque composition and clinical outcomes; explore combination strategies and subgroup responsiveness.
BACKGROUND: Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL cholesterol (LDL-C), and reduces apolipoprotein B (apoB) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. METHODS: We conducted a coronary computed tomography angiography (CCTA) study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen vs. placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence or high risk for cardiovascular disease, and non-calcified plaque on baseline CCTA. The primary endpoint was percent change from baseline to 12 months in non-calcified plaque volume (NCPV). RESULTS: Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (IQR 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (IQR 197-331), and remnant cholesterol was 53 mg/dL (IQR 38-76). Median baseline NCPV was 125.3 mm CONCLUSIONS: Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume.
2. Two-step clinical care pathway to predict MASLD-related advanced fibrosis and long-term outcomes in type 2 diabetes.
In 4,781 T2D patients with MASLD across biopsy-validated and international VCTE cohorts, a two-step FIB-4→LSM pathway accurately stratified advanced fibrosis and predicted 5-year liver-related events. Using LSM cut-offs of <10 and >15 kPa further reduced the indeterminate group while maintaining predictive performance.
Impact: Provides large-scale, pragmatic validation of a noninvasive, guideline-aligned pathway to triage T2D patients with MASLD by future liver risk, enabling targeted surveillance and referral.
Clinical Implications: Adopt FIB-4 followed by VCTE using refined LSM thresholds (e.g., <10 and >15 kPa) to reduce indeterminate cases, prioritize high-risk patients for hepatology referral, and optimize resource use in diabetes clinics.
Key Findings
- Biopsy cohort (n=352) with MASLD: FIB-4→LSM (<8, >12 kPa) achieved 71% correct classification of advanced fibrosis.
- International VCTE-Prognosis cohort (n=4429; median follow-up 51.3 months): 5-year LRE incidences were 0.7% (low), 0.9% (intermediate), and 11.8% (high).
- Refined LSM cut-offs (<10 and >15 kPa) reduced the intermediate-risk group to 5.6% while preserving predictive accuracy.
Methodological Strengths
- Large, multicenter cohorts with biopsy validation and longitudinal outcomes
- Predefined thresholds and external validation across continents
Limitations
- Observational design without randomized assignment
- Applicability to non-T2D MASLD populations requires confirmation
Future Directions: Integrate metabolic and genetic risk markers with FIB-4/LSM to refine individualized prognostication; evaluate algorithm-driven care pathways on clinical outcomes and cost-effectiveness.
BACKGROUND: Current guidelines recommend a two-step approach for risk stratification of metabolic dysfunction-associated steatotic liver disease (MASLD), starting with Fibrosis-4 index (FIB-4) followed by liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE). OBJECTIVE: To evaluate this approach for predicting advanced fibrosis and liver-related events (LREs) in patients with type 2 diabetes (T2D). DESIGN: A prospective liver biopsy cohort of T2D patients with histologically confirmed MASLD from seven centres in China was used to assess diagnostic performance for advanced fibrosis. The international VCTE-Prognosis cohort, including T2D patients with MASLD who underwent VCTE at 16 centres in the USA, Europe and Asia, with longitudinal follow-up, was used to assess LREs, defined as hepatic decompensation or hepatocellular carcinoma. RESULTS: 4781 participants were included. In the liver biopsy cohort (n=352; 22.2% with advanced fibrosis), applying LSM thresholds of <8 kPa and >12 kPa after FIB-4 classified patients into 63.4% low-risk, 9.4% intermediate-risk and 27.3% high-risk, with a correct classification rate of 71%. In the VCTE-Prognosis cohort (n=4429; median follow-up 51.3 (IQR 27.4-70.7) months), 140 (3.2%) patients developed LREs (110 (2.5%) with hepatic decompensation and 59 (1.3%) with hepatocellular carcinoma). The two-step approach classified 72.6%, 6.8% and 20.6% of patients into low-risk, intermediate-risk and high-risk groups, with corresponding 5-year cumulative LRE incidences of 0.7%, 0.9% and 11.8%. Refining classification of intermediate FIB-4 patients using LSM <10 kPa (low-risk) and >15 kPa (high-risk) reduced the intermediate-risk group to 5.6% while preserving predictive accuracy. CONCLUSION: The non-invasive two-step approach of FIB-4 followed by LSM effectively stratifies MASLD-related advanced fibrosis and LREs risk in T2D. Applying LSM cut-offs of 10 and 15 kPa further optimises risk stratification for future LREs.
3. Screening for Diabetes and Prediabetes in Cystic Fibrosis Using a Nonfasting 50-Gram 1-Hour Oral Glucose Challenge Test.
In 185 individuals with CF without known diabetes, a nonfasting 50-g, 1-hour glucose challenge (GCT) outperformed opportunistic tests for detecting pre-CFRD/CFRD (AUC 0.73) and CFRD (AUC 0.75). A 1-hour plasma glucose of 147 mg/dL achieved 90% sensitivity and 58% specificity, potentially reducing OGTT volume by 56%.
Impact: Offers a pragmatic, high-sensitivity, in-clinic screening pathway that can raise CFRD detection while reducing burdensome OGTT use.
Clinical Implications: Implement a 1-hour 50-g GCT as first-line screening in CF clinics; refer individuals above 147 mg/dL for confirmatory OGTT while sparing low-risk patients.
Key Findings
- GCT 1-hour plasma glucose had ROC-AUC 0.73 for pre-CFRD/CFRD and 0.75 for CFRD, outperforming RPG, RCG, and HbA1c.
- A 147 mg/dL cutoff yielded 90% sensitivity and 58% specificity for CFRD detection.
- Using GCT could reduce OGTTs by 56% while maintaining high sensitivity.
Methodological Strengths
- Prospective in-clinic assessment with head-to-head comparison against multiple tests
- ROC-based threshold optimization with clear sensitivity/specificity reporting
Limitations
- Small number of CFRD cases (n=10) limits precision of estimates
- Single time-point screening without longitudinal outcome assessment
Future Directions: Validate GCT thresholds in larger, diverse CF populations; assess integration with CGM and evaluate impact on clinical outcomes and screening adherence.
OBJECTIVE: Cystic fibrosis (CF)-related diabetes (CFRD) affects nearly half of adults with CF, but screening rates with the recommended oral glucose tolerance test (OGTT) are low. We evaluated the utility of a nonfasting, 50-g, 1-h oral glucose challenge test (GCT) as first-line screening for CFRD and pre-CFRD. The objectives were to define a cutoff that provides high sensitivity and reasonable specificity, and to determine how GCT compares with other opportunistic tests. RESEARCH DESIGN AND METHODS: Participants with CF ≥10 years old, without known diabetes, had baseline random plasma and capillary glucose (RPG and RCG), then underwent an in-clinic GCT for collection of 1-h plasma glucose (GCTpl). This was followed by hemoglobin A1C (HbA1c) and OGTT on a separate day. Receiver operating characteristic (ROC) curves were generated for identifying CFRD and pre-CFRD. RESULTS: Of 185 participants, 94 had normal glucose tolerance, 81 had pre-CFRD, and 10 had CFRD. For detecting pre-CFRD or CFRD, GCTpl had an area under the ROC curve (ROC-AUC) of 0.73 (95% CI 0.65-0.80), higher than ROC-AUCs for RPG of 0.56 (0.48-0.65, P = 0.003), RCG of 0.55 (0.46 = 0.63, P = 0.002), and HbA1c of 0.62 (0.53-0.67, P = 0.02). The ROC-AUC for detecting CFRD was 0.75 (0.64-0.86) for GCTpl, 0.64 (0.42-0.87) for RPG, and 0.56 (0.39-0.73) for HbA1c. A GCTpl of 147 mg/dL provides 90% sensitivity and 58% specificity for detecting CFRD and could reduce the OGTTs needed by 56%. CONCLUSIONS: GCT offers a practical, in-clinic method for CFRD screening. This spares low-risk individuals from OGTT, while maintaining high sensitivity for CFRD.