Daily Endocrinology Research Analysis
Three studies advance endocrine and cardiometabolic care: an RCT in NEJM shows that initiating finerenone plus empagliflozin reduces albuminuria more than either drug alone in CKD with type 2 diabetes; a multicenter, double-blind RCT in BMJ demonstrates histologic improvement and fibrosis benefit with dapagliflozin in biopsy-proven MASH; and a first-in-human study introduces [18F]AldoView PET/CT for selective CYP11B2 imaging to noninvasively localize aldosterone-producing lesions.
Summary
Three studies advance endocrine and cardiometabolic care: an RCT in NEJM shows that initiating finerenone plus empagliflozin reduces albuminuria more than either drug alone in CKD with type 2 diabetes; a multicenter, double-blind RCT in BMJ demonstrates histologic improvement and fibrosis benefit with dapagliflozin in biopsy-proven MASH; and a first-in-human study introduces [18F]AldoView PET/CT for selective CYP11B2 imaging to noninvasively localize aldosterone-producing lesions.
Research Themes
- Combination reno-cardiometabolic therapy in diabetic kidney disease
- SGLT2 inhibition as disease-modifying therapy for MASH
- Molecular imaging for CYP11B2 to subtype primary aldosteronism
Selected Articles
1. Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes.
In adults with CKD and type 2 diabetes, initiating finerenone plus empagliflozin produced a 29–32% greater reduction in UACR at 180 days than either agent alone, with no unexpected safety signals. Symptomatic hypotension, AKI, and hyperkalemia leading to discontinuation were uncommon.
Impact: This well-powered RCT directly tests initial combination therapy, demonstrating additive renoprotection on a validated surrogate (albuminuria) with reassuring safety, informing therapeutic strategies in DKD.
Clinical Implications: For patients with CKD and type 2 diabetes with albuminuria, early co-initiation of finerenone and an SGLT2 inhibitor may provide superior antiproteinuric effects compared with monotherapy, pending confirmation on hard renal/cardiovascular outcomes.
Key Findings
- At day 180, UACR reduction was 29% greater versus finerenone alone (ratio 0.71; 95% CI 0.61–0.82; P<0.001).
- At day 180, UACR reduction was 32% greater versus empagliflozin alone (ratio 0.68; 95% CI 0.59–0.79; P<0.001).
- No unexpected adverse events; symptomatic hypotension, AKI, and hyperkalemia leading to discontinuation were uncommon.
- Baseline median UACR was 579 mg/g (IQR 292–1092) among those with available data.
Methodological Strengths
- Randomized, parallel-group trial with prespecified primary endpoint at 180 days
- Clinically relevant population with CKD and type 2 diabetes; trial registered (NCT05254002)
Limitations
- Primary outcome based on surrogate (albuminuria) over a short 180-day horizon
- Hard renal and cardiovascular outcomes not yet reported; details on blinding not specified in abstract
Future Directions: Longer-term trials should evaluate effects on eGFR slope, kidney failure, cardiovascular events, and mortality, and define which patient subgroups derive the greatest benefit from up-front combination therapy.
BACKGROUND: Limited evidence exists to support the simultaneous initiation of sodium-glucose cotransporter-2 inhibitors and finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in persons with chronic kidney disease and type 2 diabetes. METHODS: We randomly assigned participants with chronic kidney disease (estimated glomerular filtration rate [eGFR], 30 to 90 ml per minute per 1.73 m RESULTS: At baseline, the urinary albumin-to-creatinine ratio was similar among the participants in the three groups; the median value was 579 (interquartile range, 292 to 1092) among those with available data (265 in the combination-therapy group, 258 in the finerenone group, and 261 participants in the empagliflozin group). At day 180, the reduction in the urinary albumin-to-creatinine ratio with combination therapy was 29% greater than that with finerenone alone (least-squares mean ratio of the difference in the change from baseline, 0.71; 95% confidence interval [CI], 0.61 to 0.82; P<0.001) and 32% greater than that with empagliflozin alone (least-squares mean ratio of the difference in the change from baseline, 0.68; 95% CI, 0.59 to 0.79; P<0.001). Neither agent, alone or in combination, led to unexpected adverse events. Symptomatic hypotension, acute kidney injury, and hyperkalemia leading to drug discontinuation were uncommon. CONCLUSIONS: Among persons with both chronic kidney disease and type 2 diabetes, initial therapy with finerenone plus empagliflozin led to a greater reduction in the urinary albumin-to-creatinine ratio than either treatment alone. (Funded by Bayer; CONFIDENCE ClinicalTrials.gov number, NCT05254002.).
2. Effect of dapagliflozin on metabolic dysfunction-associated steatohepatitis: multicentre, double blind, randomised, placebo controlled trial.
In biopsy-proven MASH, dapagliflozin significantly increased the proportion achieving MASH improvement without fibrosis worsening (53% vs 30%; RR 1.73) and showed benefits on MASH resolution and fibrosis improvement over 48 weeks. Discontinuations due to adverse events were rare and comparable to placebo.
Impact: This double-blind RCT provides histologic evidence that SGLT2 inhibition can modify disease activity and fibrosis in MASH, addressing a major unmet therapeutic need.
Clinical Implications: Dapagliflozin may be considered in patients with MASH (with or without T2D) to improve steatohepatitis activity and fibrosis, with attention to regulatory guidance and individual risk–benefit; confirms rationale for larger, longer outcome trials.
Key Findings
- MASH improvement without fibrosis worsening: 53% with dapagliflozin vs 30% with placebo (RR 1.73; P=0.006).
- MASH resolution without fibrosis worsening: 23% vs 8% (RR 2.91; P=0.01).
- Fibrosis improvement without MASH worsening: 45% vs 20% (RR 2.25; P=0.001).
- Mean NAS decreased more with dapagliflozin (Δ −1.39; P<0.001); discontinuations due to AEs were low (1% vs 3%).
Methodological Strengths
- Multicenter, double-blind, randomized, placebo-controlled design with biopsy-confirmed MASH
- Intention-to-treat analysis with prespecified histologic endpoints
Limitations
- Moderate sample size (n=154) and 48-week duration; long-term clinical outcomes not assessed
- Single-country study (China) may limit generalizability; mechanistic biomarkers not deeply explored
Future Directions: Confirm efficacy across diverse populations and longer horizons, evaluate effects on decompensation, cirrhosis progression, and mortality, and explore combinatorial regimens and mechanistic correlates.
OBJECTIVE: To assess the efficacy and safety of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in participants with metabolic dysfunction-associated steatohepatitis (MASH). DESIGN: Multicentre, double blind, randomised, placebo controlled trial. SETTING: Six tertiary hospitals in China from 23 November 2018 to 28 March 2023. PARTICIPANTS: 154 adults with biopsy diagnosed MASH, with or without type 2 diabetes. INTERVENTIONS: All participants were randomly assigned to receive 10 mg orally of dapagliflozin or matching placebo once daily for 48 weeks. MAIN OUTCOME MEASURES: The primary endpoint was MASH improvement (defined as a decrease of at least 2 points in non-alcoholic fatty liver disease activity score (NAS) or a NAS of ≤3 points) without worsening of liver fibrosis (defined as without increase of fibrosis stage) at 48 weeks. The secondary endpoints included the MASH resolution without worsening of fibrosis and fibrosis improvement without worsening of MASH. Analyses used the intention-to-treat dataset. RESULTS: MASH improvement without worsening of fibrosis was reported in 53% (41/78) of participants in the dapagliflozin group and 30% (23/76) in the placebo group (risk ratio 1.73 (95% confidence interval (CI) 1.16 to 2.58); P=0.006). Mean difference of NAS was -1.39 (95% CI -1.99 to -0.79); P<0.001). MASH resolution without worsening of fibrosis occurred in 23% (18/78) of participants in the dapagliflozin group and 8% (6/76) in the placebo group (risk ratio 2.91 (95% CI 1.22 to 6.97); P=0.01). Fibrosis improvement without worsening of MASH was reported in 45% (35/78) of participants in the dapagliflozin group, as compared with 20% (15/76) in the placebo group (risk ratio 2.25 (95% CI 1.35 to 3.75); P=0.001). The percentage of individuals who discontinued treatment because of adverse events was 1% (1/78) in the dapagliflozin group and 3% (2/76) in the placebo group. CONCLUSION: Treatment with dapagliflozin resulted in a higher proportion of participants with MASH improvement without worsening of fibrosis, as well as MASH resolution without worsening of fibrosis and fibrosis improvement without worsening of MASH, than with placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT03723252.
3. First-in-Human Evaluation of [ 18 F]AldoView: A Highly Selective PET Tracer for Aldosterone Synthase Imaging in Primary Aldosteronism.
[18F]AldoView PET/CT was safe, low-dose, and selectively localized CYP11B2-positive aldosterone-producing lesions, with strong concordance to pathology. No off-target uptake was seen in Cushing’s or nonfunctional adenomas, supporting noninvasive subtyping of primary aldosteronism.
Impact: This first-in-human, target-selective imaging approach could transform diagnostic pathways by reducing reliance on invasive adrenal venous sampling for PA subtyping.
Clinical Implications: If validated, [18F]AldoView may enable accurate, noninvasive localization of aldosterone-producing adenomas/nodules to guide surgery and personalize therapy, potentially reducing invasive testing.
Key Findings
- No adverse events; effective dose 0.012±0.0022 mSv/MBq indicating a favorable dosimetry profile.
- All 10 PA patients with positive scans had high uptake (mean SUVmax 15.73; LAR 8.02; LLR 10.24) and strong CYP11B2 staining confirming APA/APN.
- No positive uptake in idiopathic hyperaldosteronism, Cushing’s syndrome, or nonfunctional adenomas, suggesting high target specificity.
Methodological Strengths
- Prospective first-in-human feasibility with predefined positivity criteria and quantitative SUV metrics
- Pathology correlation of resected lesions confirming CYP11B2 expression; inclusion of healthy volunteers for dosimetry
Limitations
- Small sample size and ongoing study; limited external validation and no head-to-head comparison with adrenal venous sampling
- Potential selection and verification biases; short imaging time point (60 minutes) without dynamic characterization
Future Directions: Conduct larger, multicenter diagnostic accuracy studies against adrenal venous sampling, assess interreader reliability, and evaluate impact on clinical decision-making and outcomes.
OBJECTIVES: Aldosterone synthase (CYP11B2) is overexpressed in primary aldosteronism (PA), making it a promising target for imaging. This first-in-human study evaluates the safety and feasibility of [ 18 F]AldoView, a highly selective PET tracer targeting CYP11B2, for PA subtyping. METHODS: Biodistribution and dosimetry of [ 18 F]AldoView were assessed in 3 healthy volunteers using whole-body PET/CT. Fifteen patients with adrenal lesions (13 with PA, 1 with Cushing's syndrome, and 1 with a nonfunctional adenoma) were enrolled. PET/CT scans were performed 60 minutes postinjection. Lesions were considered positive if tracer uptake exceeded normal adrenal tissue. Semi-quantitative analyses included maximum standardized uptake value (SUVmax), lesion-to-liver ratio (LLR), and lesion-to-adrenal ratio (LAR). Ten PA patients with positive imaging findings and 1 with Cushing's syndrome underwent adrenalectomy, and resected specimens were analyzed for CYP11B2 expression. This ongoing study is registered with the Chinese Clinical Trial Registry (ChiCTR2400093214). RESULTS: [ 18 F]AldoView was well-tolerated, with no adverse events. The effective dose was 0.012±0.0022 mSv/MBq. PET/CT identified positive lesions in all 10 PA patients, with a mean SUVmax of 15.73±8.57, LAR of 8.02±4.06, and LLR of 10.24±1.48. No positive lesions were observed in patients with idiopathic hyperaldosteronism, Cushing's syndrome, or nonfunctional adenomas. Positive lesions showed strong CYP11B2 staining on pathology, confirming aldosterone-producing adenomas (APA) or nodules (APN). CONCLUSIONS: [ 18 F]AldoView PET/CT is safe and feasible for the imaging of APAs and APNs in PA patients. These results highlight its potential for noninvasive in vivo detection of CYP11B2, supporting its use in PA subtyping.