Daily Endocrinology Research Analysis
Three impactful endocrinology papers advance precision care and risk stratification: a Diabetologia cohort study validates a model to target SGLT2 inhibitors for kidney protection beyond albuminuria thresholds; a JCEM inpatient experiment shows estradiol suppression and sleep fragmentation independently worsen cardiometabolic health, highlighting sleep as a modifiable target; a JACC Advances analysis demonstrates that mortality risks from both obesity and underweight are strongest in younger adu
Summary
Three impactful endocrinology papers advance precision care and risk stratification: a Diabetologia cohort study validates a model to target SGLT2 inhibitors for kidney protection beyond albuminuria thresholds; a JCEM inpatient experiment shows estradiol suppression and sleep fragmentation independently worsen cardiometabolic health, highlighting sleep as a modifiable target; a JACC Advances analysis demonstrates that mortality risks from both obesity and underweight are strongest in younger adults, underscoring age-tailored interventions.
Research Themes
- Precision therapeutics in type 2 diabetes and kidney protection
- Menopause biology: estradiol, sleep fragmentation, and cardiometabolic risk
- Age-modified associations between adiposity and mortality
Selected Articles
1. Precision medicine in type 2 diabetes: targeting SGLT2 inhibitor treatment for kidney protection.
Using UK primary care EHR data, the authors validated a CKD-PC–adapted model that predicts individual absolute kidney benefit from SGLT2 inhibitors, outperforming the conventional albuminuria (uACR ≥3 mg/mmol) threshold in targeting therapy. SGLT2 initiation was associated with a 42% lower relative risk of kidney disease progression, and model-guided targeting could prevent >10% more events over 3 years, including in a subgroup with uACR <3 mg/mmol.
Impact: Provides a clinically actionable precision tool to allocate SGLT2 inhibitors for kidney protection beyond albuminuria thresholds, potentially improving population-level outcomes.
Clinical Implications: Clinicians can use a validated risk-prediction approach to identify individuals— including some with uACR <3 mg/mmol— who derive greater absolute kidney benefit from SGLT2 inhibitors, enabling more efficient, equitable prescribing than current guideline thresholds.
Key Findings
- Initiation of SGLT2 inhibitors was associated with a 42% lower relative risk of kidney disease progression vs DPP4i/sulfonylurea (HR 0.58; 95% CI 0.48–0.69).
- The adapted CKD-PC model showed strong calibration (slope ~1.05–1.10) and predicted a median absolute risk reduction of 0.37% at 3 years.
- Model-guided targeting prevented >10% more kidney events over 3 years than the uACR ≥3 mg/mmol threshold, identifying a 6.7% subgroup with uACR <3 mg/mmol with higher absolute benefit (3.2% vs 1.2% over 5 years; p=0.05).
Methodological Strengths
- Large real-world comparative cohort with robust EHR data and externalized risk score (CKD-PC) calibration.
- Clear clinical utility demonstration via event prevention estimates under model-guided targeting.
Limitations
- Observational design with potential residual confounding and treatment selection bias.
- Generalizability beyond UK primary care and to diverse ethnicities requires further validation.
Future Directions: Prospective pragmatic trials to test model-guided SGLT2i allocation, integration into electronic prescribing systems, and external validation across healthcare systems and ancestries.
2. Adverse cardiometabolic impacts of sleep fragmentation and estradiol suppression: An experimental model of menopause.
In a controlled inpatient crossover experiment with 38 healthy women, estradiol suppression reduced leptin and worsened lipid profiles, while sleep fragmentation raised heart rate and tended to increase fasting glucose. Combined, these core menopausal components worsened cardiometabolic measures, with sleep fragmentation adding a 103% deterioration over estradiol suppression alone, highlighting sleep as a modifiable risk factor.
Impact: Provides mechanistic human evidence that sleep fragmentation independently contributes to cardiometabolic risk during menopausal transition beyond estradiol decline.
Clinical Implications: Menopausal care should address sleep fragmentation (eg, hot flash management, behavioral sleep interventions) alongside hormonal changes to mitigate cardiometabolic risk; monitoring of lipids, heart rate, and possibly leptin may be warranted.
Key Findings
- Estradiol suppression significantly decreased leptin and worsened lipid profiles (FDR-adjusted p≤0.05).
- Sleep fragmentation significantly increased heart rate (FDR-adjusted p=0.002) and trended toward higher fasting glucose (FDR-adjusted p=0.08).
- Sleep fragmentation worsened a composite cardiometabolic index by an additional 103% over estradiol suppression alone; combined exposures worsened individual outcomes by a median of 4.0% from baseline.
Methodological Strengths
- Within-subject, tightly controlled inpatient protocol under eucaloric conditions minimizing confounding.
- Objective multi-domain outcomes with FDR-adjusted analyses across lipid, autonomic, and glycemic measures.
Limitations
- Modest sample size and short-term exposures limit generalizability and long-term inference.
- Induced hypoestrogenism and laboratory sleep fragmentation may not fully recapitulate natural menopausal transition.
Future Directions: Randomized trials testing sleep interventions for cardiometabolic risk reduction in peri/postmenopausal women; mechanistic profiling (autonomic, inflammatory) to map causal pathways and identify biomarkers.
3. Age-Specific Associations Between Adiposity and Mortality in U.S. Adults, 1999-2018.
In 44,041 U.S. adults with median 10.1-year follow-up, age significantly modified adiposity–mortality associations across BMI, waist circumference, weight, and waist-to-height ratio. Risks from both severe obesity and underweight were greatest in younger adults, emphasizing the importance of earlier, age-tailored prevention and treatment strategies.
Impact: Quantifies how age modifies the mortality risks of both high and low adiposity using nationally representative data, informing targeted public health and clinical strategies.
Clinical Implications: Prioritize aggressive obesity prevention and treatment in younger adults while also addressing risks of underweight; use multiple adiposity metrics for risk stratification and age-tailored counseling.
Key Findings
- Significant interactions between age and all four adiposity measures for all-cause and cardiovascular mortality (P < 0.05).
- Per 1-SD higher BMI, cardiovascular mortality HR was 1.49 (95% CI 1.27–1.77) in ages 18–49 vs 1.15 (95% CI 0.99–1.32) in ages 70–79.
- Class 3 obesity had HR 4.37 (95% CI 2.01–9.50) for cardiovascular mortality in younger adults; underweight was linked with higher all-cause mortality in younger individuals (HR 2.04; 95% CI 1.24–3.36).
Methodological Strengths
- Nationally representative sample with long follow-up and linkage to mortality outcomes.
- Assessment across multiple adiposity measures with multivariable adjustment and formal age-interaction testing.
Limitations
- Observational design with potential residual confounding and measurement error in anthropometrics.
- Attenuation in older adults may reflect survivor bias or competing risks not fully captured.
Future Directions: Investigate causal pathways and life-course interventions targeting early adulthood; evaluate whether intensive obesity treatment in younger adults reduces long-term mortality.