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.
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), medications used to treat type 2 diabetes and obesity, are associated with delayed gastric emptying, which is a risk factor for gastroesophageal reflux disease (GERD). However, evidence linking these drugs to GERD is limited. OBJECTIVE: To estimate the effect of GLP-1 RAs compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors on the risk for GERD and its complications among patients with type 2 diabetes. DESIGN: Active-comparator new-user cohort study emulating a target trial. SETTING: U.K. Clinical Practice Research Datalink. PARTICIPANTS: Adults aged 18 years or older with type 2 diabetes initiating GLP-1 RAs or SGLT-2 inhibitors between 1 January 2013 and 31 December 2021, with follow-up until 31 March 2022. MEASUREMENTS: The primary outcome was incident GERD, and the secondary outcome was its complications. Three-year risk differences (RDs) and risk ratios (RRs) were estimated and weighted using propensity score fine stratification. RESULTS: The study included 24 708 new users of GLP-1 RAs and 89 096 new users of SGLT-2 inhibitors. Over a median follow-up of 3.0 years, the RRs were 1.27 (95% CI, 1.14 to 1.42) for GERD, with an RD of 0.7 per 100 patients, and 1.55 (95% CI, 1.12 to 2.29) for its complications, with an RD of 0.8 per 1000 patients, among GLP-1 RA users compared with SGLT-2 inhibitor users. LIMITATION: Residual confounding due to lack of information on dietary or lifestyle factors. CONCLUSION: The estimated effect of GLP-1 RAs compared with SGLT-2 inhibitors suggested a higher risk for GERD and its complications in patients with type 2 diabetes. Clinicians should be aware of this potential adverse effect to provide timely prevention and treatment strategies. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.
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.
CONTEXT: Primary aldosteronism (PA) is a leading endocrine cause of secondary hypertension. OBJECTIVE: To support the development of the Endocrine Society Clinical Practice Guideline on managing PA. DATA SOURCE: MEDLINE, Embase, Scopus, and others were searched on October 4, 2024. STUDY SELECTION: Studies were selected by pairs of independent reviewers. DATA EXTRACTION: Data were extracted and appraised by pairs of independent reviewers. DATA SYNTHESIS: We included 95 studies (7 randomized trials and 88 observational studies). We did not identify trials that evaluated the outcomes of PA screening. One observational study suggested that screening was associated with higher rates of using PA-specific medical therapies and better blood pressure control. Patients managed with adrenal venous sampling (vs computed tomography alone) may have a better post-adrenalectomy biochemical cure rate, but with an increased risk of adrenal hemorrhage. Two small observational studies suggested that PA-specific medical or surgical therapy was likely associated with better blood pressure control than nonspecific therapy. Small randomized trials suggested that surgical therapy may be associated with better blood pressure control than medical therapy, with a lower number and dosage of antihypertensive medications. Compared to eplerenone, spironolactone may be associated with better control of hypokalemia and a lower number and dosage of antihypertensive agents. Unsuppressed plasma renin activity was associated with better control of hypokalemia, while suppression was associated with higher risk of mortality, atrial fibrillation, and stroke (very low certainty). CONCLUSION: This systematic review addresses various aspects of managing PA and will support the development of the Endocrine Society guidelines.
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.
Global economic development has been associated with an increased prevalence of obesity and related health problems. Increased caloric intake and reduced energy expenditure are both cited as development-related contributors to the obesity crisis, but their relative importance remains unresolved. Here, we examine energy expenditure and two measures of obesity (body fat percentage and body mass index, BMI) for 4,213 adults from 34 populations across six continents and a wide range of lifestyles and economies, including hunter-gatherer, pastoralist, farming, and industrialized populations. Economic development was positively associated with greater body mass, BMI, and body fat, but also with greater total, basal, and activity energy expenditure. Body size-adjusted total and basal energy expenditures both decreased approximately 6 to 11% with increasing economic development, but were highly variable among populations and did not correspond closely with lifestyle. Body size-adjusted total energy expenditure was negatively, but weakly, associated with measures of obesity, accounting for roughly one-tenth of the elevated body fat percentage and BMI associated with economic development. In contrast, estimated energy intake was greater in economically developed populations, and in populations with available data (n = 25), the percentage of ultraprocessed food in the diet was associated with body fat percentage, suggesting that dietary intake plays a far greater role than reduced energy expenditure in obesity related to economic development.