Daily Endocrinology Research Analysis
A head-to-head randomized trial showed tirzepatide achieved greater weight and waist reduction than semaglutide in adults with obesity without diabetes over 72 weeks. Large cohort analyses suggest a practical lower prolactin threshold (~3 ng/mL) in women associates with adverse cardiometabolic outcomes, and mechanistic work identifies brain-derived uroguanylin as a regulator of postprandial brown fat activation with implications for glucose control.
Summary
A head-to-head randomized trial showed tirzepatide achieved greater weight and waist reduction than semaglutide in adults with obesity without diabetes over 72 weeks. Large cohort analyses suggest a practical lower prolactin threshold (~3 ng/mL) in women associates with adverse cardiometabolic outcomes, and mechanistic work identifies brain-derived uroguanylin as a regulator of postprandial brown fat activation with implications for glucose control.
Research Themes
- Comparative anti-obesity pharmacotherapy (incretin-based agents)
- Endocrine epidemiology and cardiometabolic risk thresholds
- Neuroendocrine regulation of brown adipose tissue and glucose homeostasis
Selected Articles
1. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity.
In a 72-week, open-label, randomized trial (n=751), tirzepatide achieved greater weight loss (−20.2% vs −13.7%) and waist reduction (−18.4 cm vs −13.0 cm) than semaglutide in adults with obesity without diabetes. Gastrointestinal adverse events were most common and mostly mild-to-moderate during dose escalation.
Impact: Provides definitive head-to-head comparative effectiveness between leading incretin-based anti-obesity agents with robust, clinically meaningful outcomes.
Clinical Implications: For adults with obesity without diabetes, tirzepatide may be preferred when maximizing weight and waist reduction is prioritized, with counseling on gastrointestinal tolerability during uptitration.
Key Findings
- At 72 weeks, mean weight change was −20.2% with tirzepatide vs −13.7% with semaglutide (P<0.001).
- Waist circumference decreased more with tirzepatide (−18.4 cm) than semaglutide (−13.0 cm) (P<0.001).
- Higher proportions achieved ≥10%, ≥15%, ≥20%, and ≥25% weight loss with tirzepatide; GI adverse events were common and mostly mild–moderate during dose escalation.
Methodological Strengths
- Randomized head-to-head design with prespecified clinically meaningful endpoints over 72 weeks.
- Adequate sample size (n=751) and consistent superiority across multiple weight-loss thresholds.
Limitations
- Open-label design may introduce expectation bias.
- Industry-sponsored trial; long-term safety beyond 72 weeks was not assessed.
Future Directions: Evaluate comparative cardiometabolic outcomes, quality of life, maintenance strategies, and long-term safety beyond 72 weeks, including cost-effectiveness analyses.
BACKGROUND: Tirzepatide and semaglutide are highly effective medications for obesity management. The efficacy and safety of tirzepatide as compared with semaglutide in adults with obesity but without type 2 diabetes is unknown. METHODS: In this phase 3b, open-label, controlled trial, adult participants with obesity but without type 2 diabetes were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly for 72 weeks. The primary end point was the percent change in weight from baseline to week 72. Key secondary end points included weight reductions of at least 10%, 15%, 20%, and 25% and a change in waist circumference from baseline to week 72. RESULTS: A total of 751 participants underwent randomization. The least-squares mean percent change in weight at week 72 was -20.2% (95% confidence interval [CI], -21.4 to -19.1) with tirzepatide and -13.7% (95% CI, -14.9 to -12.6) with semaglutide (P<0.001). The least-squares mean change in waist circumference was -18.4 cm (95% CI, -19.6 to -17.2) with tirzepatide and -13.0 cm (95% CI, -14.3 to -11.7) with semaglutide (P<0.001). Participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of at least 10%, 15%, 20%, and 25%. The most common adverse events in both treatment groups were gastrointestinal, and most were mild to moderate in severity and occurred primarily during dose escalation. CONCLUSIONS: Among participants with obesity but without diabetes, treatment with tirzepatide was superior to treatment with semaglutide with respect to reduction in body weight and waist circumference at week 72. (Funded by Eli Lilly; SURMOUNT-5 ClinicalTrials.gov number, NCT05822830.).
2. The relationship between hypoprolactinemia and cardiometabolic health in women.
Across two population cohorts, empirical lower limits for serum prolactin in women were derived, and low PRL was associated with type 2 diabetes, metabolic syndrome, and incident myocardial infarction over a median 12-year follow-up. A practical threshold near 3 ng/mL appears clinically informative across sexes.
Impact: Defines evidence-based lower PRL thresholds in women and links hypoprolactinemia to hard cardiovascular outcomes, informing risk stratification.
Clinical Implications: Consider low PRL (<~3 ng/mL) as a cardiometabolic risk marker in women, prompting evaluation for diabetes, metabolic syndrome, and aggressive risk factor management.
Key Findings
- Empirically derived low PRL thresholds: 2.60 ng/mL (premenopausal, SHIP-START), 2.29 ng/mL (all ages, SHIP-START), and 4.84 ng/mL (WENDY).
- Low PRL associated with higher prevalence of type 2 diabetes and metabolic syndrome at baseline.
- Over median 12 years, myocardial infarction risk increased with PRL <2.30 ng/mL (aHR 4.19) and PRL <3 ng/mL (aHR 2.74).
Methodological Strengths
- Discovery–validation approach across two independent population cohorts.
- Longitudinal analysis with Cox modeling and median 12-year follow-up supporting temporality.
Limitations
- Heterogeneity in derived thresholds between cohorts (e.g., WENDY vs SHIP-START).
- Observational design cannot establish causality; residual confounding possible.
Future Directions: Prospective interventional studies to test whether modifying PRL (or addressing underlying causes) improves cardiometabolic outcomes; refine sex- and age-specific reference limits.
BACKGROUND: An evidence-based definition for the lower reference limit of serum prolactin (PRL) is lacking. We recently examined the European Male Ageing Study (EMAS) data and derive a threshold set at 3.0 ng/mL for hypoprolactinemia in men. Here, we identified the lower reference limit for PRL in women. METHODS: We used data from the Study of Health of Pomerania (SHIP-START, Germany, discovery cohort), and the Women's Health Study (WENDY, Finland, validation cohort). The two-sigma empirical rule was applied to obtain a threshold at 2.5% of the log10 PRL distribution. Logistic and Cox regressions were used to examine the association between PRL and cardiometabolic outcomes at baseline and follow-up, respectively. RESULTS: There were 2048 women aged 20-81 year from SHIP-START and 1730 women aged 33-37 year from WENDY. The low serum PRL threshold was derived at 2.60 ng/mL for premenopausal women and 2.29 ng/mL in women of all ages from SHIP-START, and 4.84 ng/mL in WENDY. These thresholds were not far off from that previously identified in men (3 ng/mL). In SHIP-START, we further found that compared to PRL levels of 5.0-34.9 ng/mL, lower PRL level were more commonly associated with type-2 diabetes and metabolic syndrome at baseline. Moreover, after a median of 12 year of follow-up (IQR = 6.9-15.8 year), the risk of developing myocardial infarction was greater in women with PRL < 2.30 ng/mL (SHIP-START criteria): adjusted hazard ratio = 4.19 (95% CI: 1.74-10.12), and in women with PRL < 3 ng/mL (EMAS criteria): hazard ratio = 2.74 (95% CI: 1.44-5.21). CONCLUSIONS: Our data suggests that a serum PRL level lower than 3 ng/mL could be adopted for identifying PRL-associated cardiometabolic disease in both sexes.
3. Brain-derived uroguanylin as a regulator of postprandial brown adipose tissue activation: a potential therapeutic approach for metabolic disorders.
UGN is expressed in mouse and human brain and is feeding-regulated. Central UGN (and linaclotide) activates brown adipose tissue and lowers glucose in mice; obesity associates with reduced hypothalamic proUGN in humans. GLP-1 therapy modulates proUGN and BAT activity, suggesting a brain–BAT axis for postprandial glucose control.
Impact: Reveals a previously underappreciated brain-derived UGN pathway that links feeding to BAT activation and glucose lowering, bridging human and animal data.
Clinical Implications: Modulating the brain–UGN–BAT axis (e.g., via central GUanylate cyclase pathways or leveraging GLP-1 interactions) could complement current therapies to improve postprandial glucose in obesity/T2D.
Key Findings
- UGN is expressed in mouse and human brain interneurons and is feeding-regulated; obesity disrupts proUGN regulation in human BA10 and reduces hypothalamic proUGN.
- Central UGN and linaclotide activate BAT acutely and chronically in mice, lowering plasma glucose.
- GLP-1 (liraglutide) modulates proUGN expression and associates with altered BAT activation postprandially in T2D patients.
Methodological Strengths
- Cross-species evidence integrating human brain expression mapping with murine interventional experiments.
- Use of central administration and functional readouts (BAT activation, plasma glucose) to establish mechanistic links.
Limitations
- Human data are observational with limited sample characterization; causality in humans is not established.
- Central administration in mice may not directly translate to feasible clinical routes.
Future Directions: Quantify brain–UGN–BAT axis in larger human cohorts (imaging, CSF/plasma markers), and test peripheral agonists with central actions for metabolic benefits in early-phase trials.
BACKGROUND: Preclinical and clinical research of insulin resistance and glucose homeostasis in metabolic disorders are essential. In this study, we aim to determine the expression of uroguanylin (UGN) in the mouse and human brain, its regulatory mechanisms, and its significance to patients with obesity and type 2 diabetes (T2D). METHODS: UGN expression, regulation, and its correlation with feeding status and obesity in the mouse and human brain were analyzed at the mRNA level using RT-PCR, qPCR, and RESULTS: UGN was expressed in both the mouse and human brain, and its expression was regulated by feeding. In the human prefrontal cortex, UGN was expressed in several interneuron subpopulations across all cortical layers. In Brodmann area (BA) 10, prouroguanylin (proUGN) expression was not regulated by feeding in obesity, whereas this regulation still persisted in BA9. In mice, centrally applied UGN and its analog linaclotide, affecting the hypothalamus, induced both acute and chronic activation of BAT, which decreases the plasma glucose concentration. However, in obesity, proUGN expression was reduced in the human hypothalamus, suggesting reduced postprandial glucose consumption in BAT. Similarly, centrally applied analog of glucagon-like peptide 1 (GLP-1-liraglutide) affected proUGN expression and was associated with increased basal BAT activity but reduced BAT activation after a meal in patients with T2D receiving GLP-1 therapy. CONCLUSION: Postprandial BAT activation is regulated by brain-derived UGN, which could serve as a novel therapeutic approach to enhance BAT activity in patients with obesity and T2D to improve postprandial glucose regulation.