Daily Endocrinology Research Analysis
Analyzed 29 papers and selected 3 impactful papers.
Summary
Three high-impact endocrinology papers stood out today: a blinded diagnostic trial shows the seated saline suppression test poorly anticipates adrenal vein sampling lateralization in primary aldosteronism; a randomized double-blind trial reveals empagliflozin suppresses hypoxia-related angiogenic factors in early diabetic kidney disease; and a 103,389-participant cohort links the number of abnormal pregnancy OGTT values to future cardiovascular disease risk. Together, they inform diagnostic pathways, mechanistic understanding of SGLT2 renoprotection, and postpartum cardiovascular prevention.
Research Themes
- Diagnostic accuracy and lateralization in primary aldosteronism
- Mechanistic renal protection by SGLT2 inhibition in early diabetic kidney disease
- Pregnancy glucose tolerance and long-term cardiovascular risk stratification
Selected Articles
1. Effect of empagliflozin on urinary albumin excretion and hypoxic biomarkers in early diabetic kidney disease: A randomised double-blind, placebo-controlled trial.
In a multicenter randomized double-blind trial of type 2 diabetes with microalbuminuria (n=79), empagliflozin did not significantly reduce ACR versus placebo at 24 weeks but significantly lowered serum VEGF and ANGPTL2. These findings support a mechanistic pathway whereby SGLT2 inhibition attenuates hypoxia-related angiogenic signaling in early diabetic kidney disease.
Impact: Provides randomized, blinded mechanistic evidence for SGLT2 renoprotection via suppression of hypoxia-induced angiogenic factors in early DKD, advancing understanding beyond albuminuria changes.
Clinical Implications: Supports continued use of SGLT2 inhibitors in early DKD for potential renoprotection even when short-term albuminuria changes are modest; biomarkers like VEGF and ANGPTL2 may serve as mechanistic readouts.
Key Findings
- At 24 weeks, ACR reduction with empagliflozin versus placebo was not statistically significant (difference −0.3643; 95% CI −0.7571 to 0.0285; p=0.0686).
- Serum VEGF and ANGPTL2 decreased significantly more with empagliflozin than placebo.
- No significant between-group differences were observed for urinary L-FABP, adrenomedullin, or ANGPTL4.
Methodological Strengths
- Randomized, double-blind, placebo-controlled multicenter design
- Predefined mechanistic biomarkers with clinically relevant endpoints
Limitations
- Modest sample size and 24-week duration may limit power for albuminuria outcomes
- Biomarker changes may not directly translate to long-term renal endpoints
Future Directions: Longer RCTs integrating serial hypoxia/angiogenesis biomarkers with hard renal outcomes to validate mechanistic surrogates and guide precision use of SGLT2 inhibitors.
AIMS: The precise mechanism of sodium glucose co-transporter 2 (SGLT2) inhibitor on reno-protective effect has been still unclear. In this study, we hypothesised that SGLT2 inhibitor prevents diabetic kidney disease via reduction of hypoxia-induced factors. MATERIALS AND METHODS: In this multicenter, prospective, randomised, double blinded clinical trial, people with type 2 diabetes and microalbuminuria were randomised equally to empagliflozin (10 mg/day) (n = 40) and placebo (n = 39) and followed 24 weeks. The primary endpoint was change in urinary albumin creatinine ratio (ACR) and urinary liver type fatty acid binding protein (L-FABP) excretion from baseline to 24 weeks. Major secondary outcome was change in serum vascular endothelial growth factor (VEGF), angiopoietin-like proteins 2 (ANGPTL2), angiopoietin-like proteins 4 (ANGPTL4), and adrenomedullin (AM) levels. RESULTS: Although the reduction of ACR was significantly greater in the empagliflozin group than the placebo group at 4 and 12 weeks, the difference of change at 24 weeks between the two groups was not statistically significant (Empagliflozin group-Placebo group: -0.3643, 95% CI: -0.7571 to 0.0285, p = 0.0686). There was no difference in urinary L-FABP excretion between the empagliflozin and placebo groups. Serum VEGF and ANGPTL2 decreased significantly more in the empagliflozin group, whereas there were no significant differences in AM and ANGPTL4. CONCLUSIONS: These results demonstrated that empagliflozin partially suppressed the hypoxia-induced angiogenic factors overproduction in addition to a declining trend in ACR in the early stage of diabetic kidney disease, which might contribute to the mechanisms of reno-protective effects of this agent (jRCTs051200147).
2. Seated Saline Suppression Test for Lateralizing Primary Aldosteronism.
In a blinded diagnostic-accuracy trial of 160 high-risk patients, the seated saline suppression test showed limited accuracy for identifying lateralizing primary aldosteronism relative to adrenal vein sampling. Positive likelihood ratios were weak across immunoassay cutoffs, indicating the SSST may misinform decisions about surgery versus medical therapy.
Impact: Directly challenges reliance on a widely used confirmatory test for lateralization in primary aldosteronism, favoring adrenal vein sampling to guide definitive therapy.
Clinical Implications: Clinicians should be cautious using SSST results to anticipate AVS lateralization; AVS remains essential for surgical decision-making in suspected unilateral PA.
Key Findings
- Overall diagnostic accuracy of SSST was 64.4% (cutoff ≥140 pmol/L) and 67.5% (cutoff ≥280 pmol/L).
- Positive likelihood ratios were weak: 1.1 at ≥140 pmol/L and 1.9 at ≥280 pmol/L.
- Negative likelihood ratios modestly reduced the probability of lateralization (0.3 and 0.5 for the two cutoffs).
- Results were consistent using LC-MS/MS thresholds.
Methodological Strengths
- Blinded diagnostic-accuracy design with AVS as reference standard
- Pre-registered trial with predefined aldosterone cutoffs and dual assay platforms
Limitations
- Diagnostic study without long-term outcomes linking test performance to patient-centered endpoints
- Conducted in high-risk PA population; generalizability to broader screening populations may be limited
Future Directions: Evaluate streamlined diagnostic pathways that prioritize AVS and assess cost-effectiveness and outcomes; investigate alternative suppression or stimulation protocols with better lateralization performance.
BACKGROUND: Confirmatory testing to identify lateralizing primary aldosteronism (PA) is of uncertain benefit. METHODS: Blinded clinical trial where patients with high-risk features for PA underwent the seated saline suppression test (SSST). All patients received adrenal vein sampling, where lateralization was defined by an aldosterone/cortisol ratio ≥3:1 comparing the dominant versus the nondominant sides. The primary outcome was the overall diagnostic accuracy of the SSST in identifying lateralizing PA using postinfusion aldosterone concentrations of ≥140 pmol/L (5.0 ng/dL) and ≥280 pmol/L (10.1 ng/dL) with immunoassay, and ≥162 pmol/L (5.8 ng/dL) with liquid chromatography/tandem mass spectrometry. RESULTS: A total of 160 patients completed the trial. Lateralizing PA was diagnosed in 98 patients (61.3%). The overall diagnostic accuracy of the SSST using an aldosterone cutoff of ≥140 pmol/L (5.0 ng/dL) and ≥280 pmol/L (10.1 ng/dL) was 64.4% (95% CI, 56.4-71.8) and 67.5% (95% CI, 59.7-74.7), respectively. A positive result was equivocal at the lower cutoff of ≥140 pmol/L (5.0 ng/dL; positive likelihood ratio, 1.1 [95% CI, 1.0-1.3]) and minimally informative at the higher cutoff of ≥280 pmol/L (10.1 ng/dL; positive likelihood ratio, 1.9 [95% CI, 1.3-2.7]). Negative results modestly ruled against lateralization using cutoffs of ≥140 pmol/L (5.0 ng/dL) and ≥280 pmol/L (10.1 ng/dL; negative likelihood ratio, 0.3 [95% CI, 0.1-0.9]; and 0.5 [95% CI, 0.3-0.7], respectively). The SSST properties were similar with liquid chromatography/tandem mass spectrometry. CONCLUSIONS: Aldosterone suppression testing is unreliable for anticipating adrenal vein sampling outcomes. The SSST may misinform diagnostic-treatment decisions. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04422756.
3. An oral glucose tolerance test in pregnancy and its association with future cardiovascular diseases.
In 103,389 pregnancies with median 6.8-year follow-up, the risk of future cardiovascular disease rose with the number of abnormal values on the 100-g pregnancy OGTT, peaking at HR 2.41 for four abnormal values. Findings support early postpartum CVD risk identification and prevention among women with multiple OGTT abnormalities.
Impact: Large-scale evidence links pregnancy OGTT abnormalities with later-life CVD, refining postpartum risk stratification beyond diabetes risk alone.
Clinical Implications: Women with multiple abnormal pregnancy OGTT values should receive targeted postpartum CVD risk assessment and prevention (e.g., blood pressure, lipids, lifestyle, and follow-up screening).
Key Findings
- Among 103,389 women (median follow-up 6.8 years), 641 developed composite CVD (0.62%).
- Adjusted HR for CVD was 1.2 (95% CI 1.02–1.4) for 1–3 abnormal OGTT values versus normal.
- Adjusted HR rose to 2.41 (95% CI 1.44–4.05) for four abnormal OGTT values.
- Risk assessment used Cox models stratified by the number of abnormal OGTT values.
Methodological Strengths
- Very large cohort with nearly 887,000 person-years of follow-up
- Objective OGTT-based exposure and Cox modeling across graded abnormality levels
Limitations
- Retrospective design may be subject to residual confounding
- Outcome was a composite CVD endpoint; component-specific risks were not detailed in the abstract
Future Directions: Prospective validation with cause-specific CVD outcomes and integration into postpartum risk calculators to guide tailored prevention.
AIMS/HYPOTHESIS: Gestational diabetes and abnormal 100-g oral glucose tolerance test (OGTT) results in pregnancy are associated with type 2 diabetes, but their relationship with cardiovascular disease (CVD) is less clear. We evaluated the risk of CVD according to the number of abnormal OGTT values during pregnancy. METHODS: This retrospective cohort study used data from a major Israeli healthcare provider. Pregnant individuals aged 20-50 years without a prior diagnosis of type 2 diabetes and CVD who had a complete 100-g OGTT during their last pregnancy between January 2000 and December 2022 were included. The primary outcome was the development of a composite of CVD by September 2024. Risk was assessed using Cox proportional hazards models based on the number of abnormal OGTT values. RESULTS: The study included 103 389 individuals with a mean age of 34 ± 5.2 years. Overall, the median follow-up was 6.8 years (IQR, 3.4-12.9), totalling 886 955 person-years. A composite of CVD developed in 641 individuals (a cumulative incidence of 0.62%). When compared to individuals with all OGTT values normal, individuals with one to three abnormal values had an adjusted hazard ratio (HR) of 1.2 (95% CI: 1.02-1.4) for CVD, reaching 2.41 (95% CI 1.44-4.05) in those with four abnormal OGTT values. CONCLUSIONS: A history of abnormal 100-gram OGTT results during pregnancy, and specifically having four abnormal values, is associated with an elevated risk of CVD. These results underscore the need for early post-partum identification and prevention strategies in this high-risk population.