Daily Endocrinology Research Analysis
Analyzed 108 papers and selected 3 impactful papers.
Summary
Analyzed 108 papers and selected 3 impactful articles.
Selected Articles
1. Genetic Risk Factors for Kidney Function in Individuals with Type 1 Diabetes.
In DCCT/EDIC participants with type 1 diabetes (n=1,304; median 35 years of follow-up), an eGFR PRS was associated with higher eGFR and lower risk of incident eGFR <60 ml/min/1.73m2, while an albuminuria PRS predicted incident microalbuminuria. The COL4A3 variant rs55703767 was linked to lower macroalbuminuria risk, with treatment-group specific effects.
Impact: This study validates the portability of general-population polygenic risk scores to type 1 diabetes for distinct kidney outcomes, supporting genetically informed risk stratification.
Clinical Implications: Polygenic risk scores for eGFR and albuminuria may help tailor surveillance intensity and preventive strategies in T1D, complementing clinical risk factors.
Key Findings
- Each 1 SD higher eGFR PRS associated with 2.72 ml/min/1.73m2 higher eGFR and lower incident eGFR <60 ml/min/1.73m2 (HR 0.82, 95% CI 0.73–0.92).
- Albuminuria PRS predicted incident AER >30 mg/24h (HR 1.12, 95% CI 1.02–1.22) but not eGFR decline.
- COL4A3 rs55703767 associated with lower macroalbuminuria risk (HR 0.77 per minor allele, 95% CI 0.59–0.99), with protection confined to the conventional therapy group.
Methodological Strengths
- Prospective, well-characterized DCCT/EDIC cohort with long follow-up (~35 years).
- Genome-wide genotyping with predefined PRS and complementary candidate variant analysis (COL4A3).
Limitations
- PRS derived from general-population cohorts; ancestry transferability and calibration may be limited.
- Clinical utility thresholds and cost-effectiveness of PRS-guided care were not evaluated.
Future Directions: Validate PRS performance across ancestries, integrate with clinical predictors into actionable risk models, and test PRS-guided surveillance or intervention strategies.
BACKGROUND: Genetic risk factors underlying kidney disease in type 1 diabetes (T1D) remain poorly understood. We examined whether previously-established polygenic risk scores (PRS) for estimated glomerular filtration rate (eGFR) and albuminuria are associated with these measures in adults with T1D in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. METHODS: We applied eGFR and albuminuria PRS derived in general population cohorts to 1,304 DCCT/EDIC participants with genome-wide genotyping. We tested PRS associations with eGFR and urine albumin excretion rate (AER) as well as incident eGFR <60ml/min/1.73m2, AER >30mg/24h, and AER >300mg/24h. For consistency, PRS values were linearly transformed so higher scores corresponded to higher eGFR and AER. We also examined associations of kidney outcomes with rs55703767 in COL4A3, which has previously been associated with CKD in T1D.
2. Preventing post-denosumab bone loss with zoledronate: a 2-year randomized trial in post-menopausal women without and with pre-exposure to bisphosphonates.
Early (6-month) and, when needed, multiple zoledronate infusions better preserved lumbar spine BMD after denosumab discontinuation, especially in patients without prior bisphosphonate exposure who frequently required re-dosing. Prior bisphosphonate exposure reduced the need for multiple infusions under a biomarker-guided strategy.
Impact: Defines pragmatic, biomarker-informed timing and re-dosing of zoledronate to mitigate the denosumab rebound, addressing a pressing gap in osteoporosis care.
Clinical Implications: Plan zoledronate at 6 months after the last denosumab dose and anticipate the need for additional infusions—guided by CTX or ≥5% BMD loss—particularly in patients without prior bisphosphonate therapy.
Key Findings
- Most patients without prior bisphosphonate exposure required multiple zoledronate infusions over 2 years (median 2, range 1–5).
- Lumbar spine BMD declines measured 12 months after the last denosumab effect were numerically smaller with 6-month dosing and with prior BPs exposure than with 9-month or OBS strategies.
- Re-dosing criteria (CTX >644 ng/L or ≥5% BMD loss) operationalized a biomarker-guided approach to preserve BMD.
Methodological Strengths
- Randomized allocation to timing strategies with a 2-year follow-up.
- Objective monitoring using DXA BMD and CTX thresholds; multicentric design.
Limitations
- Small sample size (n=44) and open-label design; fracture outcomes were not assessed.
- Some comparisons were descriptive with numerically rather than statistically significant differences.
Future Directions: Larger, blinded trials powered for fracture endpoints and health-economic analyses of biomarker-guided re-dosing strategies.
UNLABELLED: This study investigated the timing and effects of zoledronate infusions in long-term denosumab users having reached T-score targets (BMD > -2.0 T-score). Findings support that early and multiple zoledronate injections are needed to preserve as much BMD as possible after stopping denosumab. PURPOSE: This study evaluated the effects of zoledronate (Zol) administration and the need for multiple infusions to prevent bone loss after stopping denosumab (Dmab) in long-term users, and the influence of previous bisphosphonates (BPs) exposure. METHODS: This was a multicentric, randomized, open-label study, including 44 post-menopausal women treated with Dmab > 2 years and reaching BMD T-scores > -2.0. Patients without pre-Dmab BPs were randomized into 3 groups receiving Zol at 6 months (6 M, n = 12) or 9 months (9 M, n = 11) after the last Dmab, or to a group receiving Zol if CTX > 644 ng/l or BMD decreased ≥ 5% (OBS, n = 11).
3. Real-World Associations of KidneyIntelX Risk Stratification With Guideline-Directed Therapy, Kidney Outcomes, and Metabolic Trajectories in Early Diabetic Kidney Disease.
In 2,470 adults with T2D and CKD stages G1–G3b, KidneyIntelX risk categories were associated with targeted uptake of guideline-directed therapies and favorable shifts in kidney and metabolic measures. Baseline risk strata discriminated the probability of sustained ≥40% eGFR decline or kidney failure, and repeat testing at ~12 months tracked risk reduction with therapy initiation.
Impact: Provides real-world evidence that prognostic biomarker testing can steer therapy uptake and improve risk trajectories in early DKD, supporting implementation of precision nephrology.
Clinical Implications: KidneyIntelX can help prioritize SGLT2 inhibitors, RAAS blockade, and other guideline-directed therapies for high-risk patients and support risk re-assessment at ~12 months.
Key Findings
- Among 2,470 T2D+CKD patients, higher KidneyIntelX risk aligned with greater use of guideline-directed therapies and favorable kidney/metabolic trajectory changes after testing.
- Baseline risk strata discriminated the probability of the composite kidney outcome (sustained ≥40% eGFR decline or kidney failure).
- Repeat testing at ~12 months showed lower predicted risk among those initiating guideline-directed therapies and biomarker improvements.
Methodological Strengths
- Large, multi-center real-world cohort with integration of process (therapy uptake) and outcome measures.
- Assessment of dynamic risk re-stratification with repeat testing.
Limitations
- Observational design with potential residual confounding and indication bias.
- Heterogeneous follow-up intervals; detailed adjudication of hard outcomes not described.
Future Directions: Pragmatic trials to test biomarker-guided initiation/intensification of therapies and cost-effectiveness analyses of testing plus care pathways.
BACKGROUND: KidneyIntelX is a prognostic blood test for the progression of diabetic kidney disease (DKD) within 5 years. Long-term utility is important. MATERIALS AND METHODS: Adults with type 2 diabetes (T2D) and CKD (G1-G3b) from two medical centres were assessed for the following: (1) baseline KidneyIntelX risk levels and their association with GDMT usage; (2) changes in temporal kidney and metabolic trajectories after testing; (3) probability for a kidney composite outcome of sustained eGFR decline of 40% or kidney failure by baseline KidneyIntelX risk strata; and (4) risk at 12-month for repeat-tested participants. RESULTS: 2470 patients with T2D and CKD (median baseline eGFR 63 mL/min/1.73 m