Daily Endocrinology Research Analysis
Analyzed 90 papers and selected 3 impactful papers.
Summary
Three impactful endocrinology studies stood out today: a large NEJM randomized trial showed tirzepatide is noninferior to dulaglutide for major cardiovascular outcomes in type 2 diabetes; a nationwide Veterans cohort linked both under- and over-replacement with thyroid hormone to higher incident heart failure; and integrated genomic-pathologic profiling established PRKACA constitutional duplication as a specific cause of PPNAD, clarifying adrenal disease nosology.
Research Themes
- Incretin-based therapies and cardiovascular outcomes in type 2 diabetes
- Thyroid hormone treatment intensity and heart failure risk
- Adrenal genetics clarifying the etiology of Cushing syndrome
Selected Articles
1. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes.
In SURPASS-CVOT, tirzepatide was noninferior to dulaglutide for the composite of cardiovascular death, myocardial infarction, or stroke (HR 0.92; 95.3% CI 0.83–1.01). Superiority was not demonstrated, and gastrointestinal adverse events were somewhat more frequent with tirzepatide.
Impact: This large, double-blind active-comparator CVOT provides definitive cardiovascular safety data for tirzepatide against a proven cardioprotective GLP-1 RA, informing drug selection in high-risk type 2 diabetes.
Clinical Implications: For patients with type 2 diabetes and established ASCVD, tirzepatide can be considered without excess cardiovascular risk versus dulaglutide, while anticipating somewhat higher gastrointestinal adverse events.
Key Findings
- Primary composite endpoint occurred in 12.2% (tirzepatide) vs 13.1% (dulaglutide); HR 0.92 (95.3% CI 0.83–1.01)
- Noninferiority was met (P=0.003), superiority was not (P=0.09)
- Gastrointestinal adverse events were more frequent with tirzepatide; overall adverse event profiles were otherwise similar
- Modified ITT population included 13,165 participants (6586 tirzepatide, 6579 dulaglutide)
Methodological Strengths
- Double-blind, active-comparator, noninferiority RCT with modified ITT analysis
- Large sample size of high-risk patients with established ASCVD
Limitations
- Did not achieve statistical superiority versus dulaglutide
- Higher gastrointestinal adverse events with tirzepatide; sponsor-funded trial
Future Directions: Head-to-head mechanistic and outcomes studies to elucidate whether specific subgroups may benefit more from tirzepatide; assessment of long-term renal and heart failure outcomes.
2. Association between Over- and Under-Replacement with Thyroid Hormone and Incident Heart Failure.
In a 641,504-patient VHA cohort, both thyroid hormone under-replacement (e.g., TSH >20 mIU/L; AOR 1.93) and over-replacement (e.g., FT4 >1.9 ng/dL; AOR 1.23) were associated with higher incident heart failure risk versus euthyroidism. Risk accumulated over time, with the strongest association seen for under-replacement.
Impact: This study quantifies a modifiable, dose–response relationship between thyroid hormone treatment intensity and incident heart failure at national scale, with direct implications for TSH/FT4 targets in clinical practice.
Clinical Implications: Avoid sustained TSH elevations and FT4 excess during levothyroxine therapy; implement tighter monitoring and dose adjustments, particularly in older adults and those with cardiovascular risk.
Key Findings
- Under-replacement: TSH >20 mIU/L associated with higher incident HF (AOR 1.93; 95% CI 1.84–2.02)
- Over-replacement: FT4 >1.9 ng/dL associated with higher incident HF (AOR 1.23; 95% CI 1.14–1.32); TSH <0.1 mIU/L AOR 1.06
- Risk accumulation over time; e.g., TSH >5.5 mIU/L linked to a 5.8-fold increase in incident HF over 5 years
- Large national cohort: 641,504 adults initiating thyroid hormone; 12.7% developed HF
Methodological Strengths
- Very large, real-world cohort with time-varying exposure modeling for TSH and FT4
- Adjusted for key cardiovascular risk factors; separate analyses for TSH and FT4 cohorts
Limitations
- Observational retrospective design with potential residual confounding and measurement bias
- Generalizability limited by male-predominant VHA population
Future Directions: Prospective studies to test TSH/FT4 target strategies on heart failure outcomes and to define safe therapeutic windows across age and comorbidity strata.
3. PRKACA constitutional duplication: a specific cause of Primary Pigmented Nodular Adrenocortical Disease (PPNAD).
Systematic genotyping of 781 BNAD index cases identified PRKACA constitutional duplications in 8 cases, all manifesting ACTH-independent hypercortisolism with histologic PPNAD. Immunohistochemistry (PRKACA/PRKAR1A) aided genetic attribution, and Hi-C demonstrated neo-domain formation, supporting a specific causal role for PRKACAdup in PPNAD.
Impact: Defines a precise genetic etiology and diagnostic workflow for PPNAD, integrating WGS/Hi-C and IHC, with implications for family screening and distinguishing from other BNAD forms.
Clinical Implications: Consider PRKACA duplication testing in suspected PPNAD (especially when PRKAR1A pathogenic variants are absent), and use PRKACA/PRKAR1A IHC to guide molecular diagnosis and family counseling.
Key Findings
- PRKACA duplications detected in 8/781 BNAD index cases; also in 8/12 screened relatives
- All PRKACAdup index cases had ACTH-independent hypercortisolism with PPNAD confirmed on pathology
- WGS showed no other pathogenic alterations within the duplicated region; IHC (PRKACA/PRKAR1A) facilitated attribution
- Tumor Hi-C revealed topologically associated neo-domains associated with PRKACAdup
Methodological Strengths
- Large BNAD cohort with systematic NGS/WGS screening
- Integrated molecular pathology including IHC and chromatin conformation (Hi-C)
Limitations
- Small number of PRKACA duplication cases limits precision of phenotype estimates
- Retrospective ascertainment; external validation and functional studies are needed
Future Directions: Prospective, multicenter validation of PRKACAdup screening algorithms in ACTH-independent hypercortisolism and mechanistic studies linking chromatin architecture changes to steroidogenesis.