Daily Endocrinology Research Analysis
Three high-impact endocrinology-related studies stand out today: a phase 3 RCT shows the aldosterone synthase inhibitor baxdrostat significantly lowers systolic blood pressure in uncontrolled/resistant hypertension; a nationwide causal-inference cohort reveals that SGLT2 inhibitor cardiovascular benefits are heterogeneous and better predicted by individual traits rather than overall CVD risk; and a UK Biobank analysis uncovers that central obesity and diabetes elevate fracture risk despite highe
Summary
Three high-impact endocrinology-related studies stand out today: a phase 3 RCT shows the aldosterone synthase inhibitor baxdrostat significantly lowers systolic blood pressure in uncontrolled/resistant hypertension; a nationwide causal-inference cohort reveals that SGLT2 inhibitor cardiovascular benefits are heterogeneous and better predicted by individual traits rather than overall CVD risk; and a UK Biobank analysis uncovers that central obesity and diabetes elevate fracture risk despite higher BMI appearing protective.
Research Themes
- Aldosterone pathway inhibition for resistant hypertension
- Precision cardiometabolic therapy using heterogeneous treatment effect modeling
- Skeletal risk assessment beyond BMI: role of central adiposity and diabetes
Selected Articles
1. Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension.
In a phase 3, double-blind RCT of 794 patients with uncontrolled/resistant hypertension, baxdrostat 1 mg and 2 mg reduced seated systolic blood pressure by 8.7 and 9.8 mmHg more than placebo at 12 weeks. Hyperkalemia (>6.0 mmol/L) occurred infrequently (2.3%–3.0% vs 0.4% with placebo).
Impact: Introduces a first-in-class aldosterone synthase inhibitor demonstrating clinically meaningful BP reduction in hard-to-treat hypertension, potentially altering therapeutic algorithms.
Clinical Implications: Baxdrostat could become an add-on option for uncontrolled/resistant hypertension, especially in aldosterone-driven phenotypes, with routine potassium monitoring.
Key Findings
- Placebo-corrected seated SBP reduction at 12 weeks: −8.7 mmHg (1 mg) and −9.8 mmHg (2 mg), both P<0.001
- Hyperkalemia >6.0 mmol/L: 2.3% (1 mg), 3.0% (2 mg) vs 0.4% (placebo)
- Consistent BP lowering on top of multi-drug background therapy including a diuretic
Methodological Strengths
- Multinational, double-blind, randomized, placebo-controlled phase 3 design
- Adequate sample size with prespecified primary endpoint and consistent results across doses
Limitations
- Short duration (12 weeks) without cardiovascular outcome assessment
- Risk of hyperkalemia requires monitoring; applicability to severe CKD not established
Future Directions: Longer-term trials assessing cardiovascular outcomes, safety in CKD, and head-to-head comparisons with mineralocorticoid receptor antagonists.
2. Heterogeneous Cardiovascular Effects of SGLT2 Inhibitors in Type 2 Diabetes: A Causal Forest and Target Trial Emulation Study.
In 150,830 working-age adults with T2D, SGLT2 inhibitors reduced a 3-year composite of death/MI/stroke/HF compared with DPP4 inhibitors, with an absolute risk reduction of about 0.38 percentage points. Treatment benefit was heterogeneous and better predicted by individual BP, BMI, and fasting glucose than by overall CVD risk.
Impact: Combines target trial emulation with causal forests at national scale to reveal individualized benefit signals for SGLT2i, guiding precision prescribing beyond conventional risk scores.
Clinical Implications: Consider SGLT2 inhibitors for broader T2D populations, including those with lower aggregate CVD risk but with higher BP, BMI, or fasting glucose—prioritizing individualized profiles over composite risk categories.
Key Findings
- Nationwide cohort (n=150,830): SGLT2i associated with lower 3-year composite risk vs DPP4i (absolute risk reduction ≈0.38 percentage points; 95% CI 0.16–0.61)
- Heterogeneous treatment effects with weak correlation to overall CVD risk (r=0.287)
- In low CVD-risk stratum (n=107,425), 91% predicted to benefit; higher BP, BMI, and fasting glucose marked likely beneficiaries
Methodological Strengths
- Target trial emulation with active-comparator design (SGLT2i vs DPP4i)
- Machine-learning causal forest to quantify heterogeneous treatment effects at the individual level
Limitations
- Observational design susceptible to residual confounding and selection bias
- Limited generalizability (working-age cohort; 13.3% female); effect size (ARR ~0.38%) is modest at population level
Future Directions: Prospective pragmatic trials validating HTE-guided prescribing, integration of multi-omics and real-time EHR features to refine individual benefit prediction.
3. Beyond BMI: The role of diabetes and central obesity in fracture risk-Insights from the UK biobank.
In 446,219 UK Biobank participants, overweight and obesity were associated with lower overall fracture risk versus normal BMI. However, among overweight/obese individuals, greater waist circumference increased fracture risk, and diabetes independently elevated fracture risk across all BMI categories.
Impact: Challenges the simplistic notion of BMI-related protection by demonstrating that central adiposity and diabetes identify higher skeletal risk within overweight/obese populations.
Clinical Implications: Fracture risk assessment in overweight/obese adults should incorporate central adiposity metrics (waist circumference/WHtR) and diabetes status rather than relying on BMI alone.
Key Findings
- Overweight (aHR 0.79, 95% CI 0.76–0.82) and obesity (aHR 0.73, 95% CI 0.70–0.77) associated with lower fracture risk vs normal BMI
- Among overweight/obese, higher waist circumference increased fracture risk (aHR 1.12 overweight; 1.23 obese)
- Diabetes independently increased fracture risk across all BMI categories, amplified by central obesity
Methodological Strengths
- Very large prospective cohort (n=446,219) with multivariable Cox modeling
- Stratified analyses by BMI and central adiposity measures (WC, WHtR), clarifying effect modification
Limitations
- Observational design susceptible to residual confounding and healthy volunteer bias in UK Biobank
- Potential misclassification of fracture events and adiposity measures over time
Future Directions: Validate central adiposity thresholds for fracture risk stratification and test whether targeted interventions (e.g., diabetes control, visceral fat reduction) reduce fractures.