Daily Endocrinology Research Analysis
Three impactful endocrinology papers span mechanism, diagnostics, and comparative effectiveness. A mechanistic study reveals a reno-adipose autonomic neurocircuit whereby SGLT2 inhibitors raise renal adenosine to drive lipolysis and weight loss. Clinically, mass spectrometry–based aldosterone cut-offs strengthen saline infusion testing for primary aldosteronism, and target trial emulation shows higher 5-year cardiovascular risk with glipizide versus DPP4 inhibitors.
Summary
Three impactful endocrinology papers span mechanism, diagnostics, and comparative effectiveness. A mechanistic study reveals a reno-adipose autonomic neurocircuit whereby SGLT2 inhibitors raise renal adenosine to drive lipolysis and weight loss. Clinically, mass spectrometry–based aldosterone cut-offs strengthen saline infusion testing for primary aldosteronism, and target trial emulation shows higher 5-year cardiovascular risk with glipizide versus DPP4 inhibitors.
Research Themes
- Kidney-adipose neuroendocrine crosstalk in metabolic regulation
- Diagnostic standardization in hormonal hypertension
- Cardiovascular safety of antihyperglycemic therapies
Selected Articles
1. Sodium-glucose co-transporter 2 inhibitor-induced increase in adenosine promotes lipolysis and weight reduction by activating reno-adipose autonomic neurocircuitry.
Using renal denervation, β3-adrenergic blockade, and metabolomics in high-fat–fed mice, tofogliflozin increased renal adenosine, activated adipose sympathetic outflow (higher adipose norepinephrine), and drove lipolysis and weight loss. Disrupting renal sympathetic input or β3 signaling blunted these effects, revealing a reno-adipose autonomic neurocircuit.
Impact: This work uncovers a previously unrecognized neuroendocrine circuit linking renal energy sensing to adipose lipolysis, offering a mechanistic basis for the weight-reducing effects of SGLT2 inhibitors.
Clinical Implications: While preclinical, the findings suggest variability in SGLT2 inhibitor–induced weight loss may depend on renal sympathetic integrity and β3-adrenergic signaling. They highlight adenosine pathways and reno-adipose circuitry as potential therapeutic targets or biomarkers.
Key Findings
- Renal denervation attenuated tofogliflozin-induced lipolysis and weight loss in high-fat–fed mice.
- β3-adrenergic blockade reduced the lipolytic and weight-reducing effects of tofogliflozin.
- Metabolomics showed elevated renal adenosine after tofogliflozin; adipose tissue norepinephrine increased, indicating sympathetic activation.
- A reno-adipose autonomic neurocircuit was proposed linking renal energy depletion to systemic fatty acid oxidation.
Methodological Strengths
- Causal manipulations with renal denervation and β3-adrenergic blockade strengthen mechanistic inference.
- Untargeted metabolomics pinpointed adenosine as a mediator; tissue norepinephrine measurements confirmed sympathetic activation.
Limitations
- Findings are in mice; human validation is lacking.
- Specificity of denervation and systemic off-target effects of pharmacologic blockers may confound interpretation.
Future Directions: Validate the reno-adipose circuit and adenosine signaling in humans; test whether renal denervation, autonomic dysfunction, or β3 blockade modulate SGLT2 inhibitor weight effects; develop biomarkers of circuit engagement.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors promote weight loss in patients with type 2 diabetes mellitus; however, the underlying mechanisms remain unknown. This study investigated the role of renal autonomic nerves in SGLT2 inhibitor-induced lipolysis and body weight reduction by utilizing the renal denervation technique. The results indicated that renal autonomic nerves mediated lipolysis in mice fed a high-fat diet following treatment with tofogliflozin, an SGLT2 inhibitor. The effect was attenuated by renal denervation or β3-adrenergic blockade. Metabolomic analysis revealed that treatment with tofogliflozin elevated renal adenosine, which in turn activated adipose sympathetic nerves, as evidenced by increased norepinephrine concentrations in adipose tissue, thereby promoting lipolysis. These findings uncover a novel reno-adipose neurocircuitry linking renal energy depletion to systemic fatty acid oxidation, providing insights into the sustained weight-reducing effects of SGLT2 inhibitors. A scheme illustrating SGLT2 inhibitor-induced activation of reno-adipose autonomic neurocircuitry, which promotes lipolysis and weight reduction.
2. Cardiovascular Events in Individuals Treated With Sulfonylureas or Dipeptidyl Peptidase 4 Inhibitors.
In a 48,165-person target trial emulation of second-line therapy after metformin, glipizide was associated with the highest 5-year MACE-4 risk compared with DPP4 inhibitors (risk ratio 1.13). Glimepiride and glyburide showed smaller or nonsignificant differences.
Impact: Large-scale, methodologically rigorous comparative effectiveness evidence informs agent selection when adding to metformin, highlighting differential cardiovascular risk within sulfonylureas.
Clinical Implications: When choosing a second-line agent for patients at moderate cardiovascular risk, prefer options with lower MACE risk; avoid or closely monitor glipizide if sulfonylureas are used. Individualize based on comorbidity and hypoglycemia risk.
Key Findings
- Target trial emulation including 48,165 metformin-treated adults initiating sulfonylureas or DPP4 inhibitors.
- 5-year MACE-4 risk was 9.1% for glipizide vs 8.1% for DPP4 inhibitors (risk ratio 1.13; 95% CI, 1.03-1.23).
- Glimepiride (RR 1.07; 95% CI, 0.96-1.16) and glyburide (RR 1.04; 95% CI, 0.83-1.24) showed smaller or nonsignificant differences vs DPP4 inhibitors.
Methodological Strengths
- Target trial emulation across multiple US health systems and insurers with large sample size and multiyear follow-up.
- Clinically meaningful composite outcome (MACE-4) with agent-specific comparisons.
Limitations
- Observational design susceptible to residual confounding and treatment selection bias despite emulation.
- Findings apply to moderate cardiovascular risk populations; generalizability to high-risk or diverse care settings may vary.
Future Directions: Assess subgroup heterogeneity (age, ASCVD, CKD), evaluate hypoglycemia-mediated pathways, and extend comparisons to newer agents (SGLT2i, GLP-1 RA) in similar emulations.
IMPORTANCE: Sulfonylureas are commonly used to treat type 2 diabetes (T2D). Research findings on cardiovascular risk associated with sulfonylureas have been inconsistent. OBJECTIVE: To emulate a target trial that compares the risk of cardiovascular events after initiation of treatment with individual sulfonylureas or dipeptidyl peptidase 4 inhibitors (DPP4is). DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness research study included individuals with T2D and moderate cardiovascular risk treated with metformin monotherapy who received care at 1 of 10 US health systems or were insured by 1 of 2 large health insurance plans between January 1, 2014, and January 1, 2023. Data were analyzed from July 2024 to March 2025. EXPOSURE: Initiation of treatment with a sulfonylurea (glimepiride, glipizide, or glyburide) or a DPP4i (reference category) as a second line therapy after metformin. MAIN OUTCOMES AND MEASUREMENTS: The primary outcome was a 4-point composite of major adverse cardiovascular events (MACE-4): myocardial infarction, ischemic stroke, heart failure hospitalization, or cardiovascular death (from any of these conditions). The 5-year risks of each outcome were estimated. RESULTS: Among 48 165 eligible individuals (median [IQR] age, 61 [52-69] years; 22 674 female [47.1%]; median [IQR] hemoglobin A1C, 7.8% [7.3%-8.5%]; median [IQR] low-density lipoprotein cholesterol, 89 mg/dL [70-112 mg/dL]), 18 147 started glipizide, 14 282 started glimepiride, 1887 started glyburide, and 13 849 started a DPP4i. Over the median (IQR) follow-up of 37 (20-64) months, 3158 individuals (6.6%) experienced a MACE-4. The estimated 5-year risks of MACE-4 were 8.1% (95% CI, 7.5%-8.7%) for DPP4i, 8.4% (95% CI, 6.8%-9.9%) for glyburide, 8.6% (95% CI, 7.9%-9.2%) for glimepiride, and 9.1% (95% CI, 8.7%-9.7%) for glipizide. Compared with DPP4is, the 5-year risk ratio of MACE-4 was 1.13 (95% CI, 1.03-1.23) for glipizide, 1.07 (95% CI, 0.96-1.16) for glimepiride, and 1.04 (95% CI, 0.83-1.24) for glyburide. CONCLUSIONS AND RELEVANCE: In this comparative effectiveness research study of sulfonylureas vs DPP4i in patients with T2D, the risk of MACE-4 events was highest for glipizide. These findings suggest that sulfonylureas, glipizide in particular, may not be the optimal agent in treatment of individuals with T2D at moderate cardiovascular risk.
3. The saline infusion test with mass spectrometric measurements of aldosterone to confirm primary aldosteronism.
In a prospective multicenter cohort, mass spectrometry–based aldosterone after seated saline infusion achieved AUC 0.964. A 169 pmol/L cut-off yielded 97% sensitivity and 89% specificity, while 255 pmol/L increased specificity to 95% at 75% sensitivity. Adherence to standard procedures (minimizing ambulation) markedly improved reproducibility.
Impact: Provides actionable, assay-specific cut-offs for a widely used confirmatory test in primary aldosteronism and emphasizes SOPs to ensure reproducibility.
Clinical Implications: Implement seated saline infusion testing with LC-MS/MS aldosterone using 169 pmol/L as a high-sensitivity cut-off and 255 pmol/L for high specificity, ensuring minimized ambulation during infusion. Consider repeat testing if results conflict with clinical probability.
Key Findings
- AUC 0.964 for post-saline aldosterone measured by mass spectrometry; 169 pmol/L cut-off yielded 97% sensitivity and 89% specificity.
- A 255 pmol/L cut-off improved specificity to 95% at 75% sensitivity.
- Intra-patient discordance (26%) was largely center-related; adherence to minimized ambulation improved AUC to 0.985 with 96% sensitivity/specificity.
Methodological Strengths
- Prospective, multicenter design with LC-MS/MS measurement and ROC-derived cut-offs.
- Assessment of intra-patient variability and identification of procedural sources of discordance.
Limitations
- Non-randomized diagnostic cohort; reliance on alternative confirmatory criteria as reference.
- Procedural heterogeneity across centers affected reproducibility before SOP enforcement.
Future Directions: Standardize and validate protocol across diverse centers and populations; integrate cut-offs with pretest probability models; assess cost-effectiveness of LC-MS/MS-based confirmation.
OBJECTIVE: Confirmation of primary aldosteronism with the saline infusion test requires accurate measurements of plasma aldosterone, which is best achieved by mass spectrometry. Diagnostic performance, appropriate cut-offs and intra-patient variability of the test remain inadequately defined. The objective of this prospective multicenter cohort study was to address these limitations. METHODS: Primary aldosteronism was confirmed and excluded using alternative criteria to confirmatory tests in 138 and 282 respective patients with suspected disease. Those criteria were not satisfied in 89 patients. Diagnostic performance of the saline infusion test and optimal cut-offs were determined from receiver operating characteristic curves. Intra-patient variability was determined in 57 patients. RESULTS: Analysis of receiver operating characteristic curves indicated an area under the curve of 0.964 and a cut-off of 169 pmol/l for posttest aldosterone concentrations that provided 97% sensitivity and 89% specificity. A cut-off of 255 pmol/l enabled improved specificity of 95% at a sensitivity of 75%. Among the 57 patients in whom the saline infusion test was repeated, 15 (26%) had posttest aldosterone concentrations that were discordant using the 169 pmol/l cut-off. Eighty percent of the discordant results were from a single center. With exclusion of that center, which did not minimize ambulation during saline infusion, the area under the curve increased to 0.985 and an optimal cut-off of 169 pmol/l provided 96% specificity and sensitivity. CONCLUSION: The seated saline infusion test with mass spectrometric measurements of aldosterone and the cut-offs documented here provides a useful confirmatory test, although this requires adherence to standard-operating procedures.