Daily Endocrinology Research Analysis
Across endocrinology and metabolism, three papers stood out today: a target-trial emulated cohort in Annals of Internal Medicine links GLP-1 receptor agonists to higher risks of GERD and complications versus SGLT2 inhibitors; a comprehensive systematic review supporting the Endocrine Society’s new primary aldosteronism guideline clarifies diagnostic pathways and treatment choices; and a PNAS global analysis indicates that increased dietary intake (not reduced energy expenditure) primarily drives
Summary
Across endocrinology and metabolism, three papers stood out today: a target-trial emulated cohort in Annals of Internal Medicine links GLP-1 receptor agonists to higher risks of GERD and complications versus SGLT2 inhibitors; a comprehensive systematic review supporting the Endocrine Society’s new primary aldosteronism guideline clarifies diagnostic pathways and treatment choices; and a PNAS global analysis indicates that increased dietary intake (not reduced energy expenditure) primarily drives obesity with economic development.
Research Themes
- Medication safety signals with GLP-1 receptor agonists
- Evidence synthesis guiding primary aldosteronism screening and therapy
- Global energetics: intake vs expenditure in obesity
Selected Articles
1. Glucagon-Like Peptide-1 Receptor Agonists and Risk for Gastroesophageal Reflux Disease in Patients With Type 2 Diabetes : A Population-Based Cohort Study.
In a large active-comparator new-user cohort emulating a target trial, GLP-1 receptor agonists were associated with higher risks of incident GERD (RR 1.27) and GERD complications (RR 1.55) compared with SGLT2 inhibitors over a median 3 years. Residual confounding by lifestyle is possible, but findings highlight a safety signal relevant to widespread GLP-1 RA use.
Impact: This study addresses an urgent pharmacovigilance question for GLP-1 RAs using rigorous target-trial emulation and an active comparator, providing actionable risk estimates for GERD and its complications.
Clinical Implications: For patients initiating GLP-1 RAs, clinicians should screen for and counsel about reflux symptoms, consider GERD prophylaxis in high-risk individuals, and weigh alternatives (e.g., SGLT2 inhibitors) if significant GERD is present.
Key Findings
- Among 24,708 GLP-1 RA and 89,096 SGLT2 inhibitor new users, GLP-1 RAs were associated with higher GERD risk: RR 1.27 (95% CI, 1.14–1.42); risk difference 0.7 per 100 patients at 3 years.
- GLP-1 RA use was associated with higher risk of GERD complications: RR 1.55 (95% CI, 1.12–2.29); risk difference 0.8 per 1000 patients.
- Target-trial emulation with propensity score fine stratification strengthens causal inference, though unmeasured lifestyle confounding remains possible.
Methodological Strengths
- Active-comparator new-user design emulating a target trial
- Propensity score fine stratification with large sample size and median 3-year follow-up
Limitations
- Residual confounding from unmeasured diet and lifestyle factors
- Observational data from primary care records may misclassify GERD outcomes
Future Directions: Prospective studies including granular dietary, lifestyle, and endoscopic data, and mechanistic work on GLP-1–mediated gastric motility and reflux physiology, could refine risk stratification and mitigation strategies.
2. A Systematic Review Supporting the Endocrine Society Clinical Practice Guideline on Management of Primary Aldosteronism.
Synthesizing 95 studies, this review supports PA guideline recommendations: consider broad screening; use adrenal venous sampling to guide surgery (with bleeding risk); prefer PA-specific therapy (surgical or medical) over nonspecific regimens; and favor spironolactone over eplerenone for hypokalemia control and medication minimization.
Impact: By consolidating heterogeneous evidence into practical recommendations, this review provides a strong foundation for an influential clinical guideline in a common but underdiagnosed endocrine hypertension.
Clinical Implications: Adopt systematic PA screening in hypertension clinics, use adrenal venous sampling to guide lateralization when indicated, and prioritize MRA therapy (often spironolactone) or unilateral adrenalectomy for lateralized disease to improve BP control and correct hypokalemia.
Key Findings
- Across 95 studies (7 RCTs, 88 observational), no trials evaluated outcomes of PA screening; one observational study linked screening to greater PA-specific therapy use and better BP control.
- Adrenal venous sampling (vs CT alone) was associated with improved post-adrenalectomy biochemical cure, albeit with increased adrenal hemorrhage risk.
- Small RCTs suggested surgery achieves superior BP control versus medical therapy; spironolactone may better correct hypokalemia and reduce antihypertensive burden versus eplerenone.
Methodological Strengths
- Comprehensive multi-database search and dual independent screening/data extraction
- GRADE-informed synthesis aligned with guideline questions
Limitations
- Lack of randomized trials evaluating screening outcomes limits causal inference for screening benefits
- Some conclusions rely on small RCTs or observational data with potential biases
Future Directions: Pragmatic trials or stepped-wedge designs testing PA screening strategies and randomized comparisons of surgical vs optimized medical therapy, including MRA titration guided by renin, are needed.
3. Energy expenditure and obesity across the economic spectrum.
Across 4,213 adults in 34 diverse populations, economic development increased body mass and fat yet also increased raw total, basal, and activity energy expenditure. After adjusting for body size, total/basal expenditure declined modestly with development and only weakly related to obesity, whereas higher energy intake and ultra-processed foods tracked more strongly with adiposity.
Impact: This global, multi-population analysis helps resolve a longstanding debate by quantifying that diet—particularly increased intake and ultra-processed foods—plays a larger role than reduced energy expenditure in development-associated obesity.
Clinical Implications: Public health and clinical strategies for obesity should prioritize dietary quality and reduction of ultra-processed foods, while recognizing that lower energy expenditure plays a smaller role than commonly assumed.
Key Findings
- Economic development was associated with higher body mass, BMI, and body fat, and also with greater unadjusted total, basal, and activity energy expenditure.
- After adjusting for body size, total and basal energy expenditure decreased by ~6–11% with development and varied widely, showing weak negative associations with obesity measures.
- Estimated energy intake and the percentage of ultra-processed foods were more strongly associated with body fat percentage than adjusted energy expenditure.
Methodological Strengths
- Large, diverse sample spanning 34 populations across six continents
- Use of body size–adjusted analyses and linkage with dietary composition (ultra-processed foods)
Limitations
- Observational design limits causal inference
- Dietary intake estimates and food processing classifications may vary across populations
Future Directions: Interventions reducing ultra-processed food intake across diverse settings, coupled with objective energy intake and expenditure measurements (e.g., doubly labeled water), are needed to test causal pathways.