Weekly Endocrinology Research Analysis
This week saw major advances across obesity therapeutics, diabetes technology, and endocrine pathophysiology. Large phase‑3 trials and a landmark NEJM study showed robust efficacy for novel GLP‑1–based and oral GLP‑1 therapies (including dose escalation and an oral small molecule), while translational work revealed new targets (α‑cell FATP2) and adrenal signaling mechanisms (FGFR2). Diagnostic and precision‑medicine innovations — from CGM‑based postpartum diabetes detection to phenotype‑driven m
Summary
This week saw major advances across obesity therapeutics, diabetes technology, and endocrine pathophysiology. Large phase‑3 trials and a landmark NEJM study showed robust efficacy for novel GLP‑1–based and oral GLP‑1 therapies (including dose escalation and an oral small molecule), while translational work revealed new targets (α‑cell FATP2) and adrenal signaling mechanisms (FGFR2). Diagnostic and precision‑medicine innovations — from CGM‑based postpartum diabetes detection to phenotype‑driven mortality stratification and single‑RBC HbA1c imaging — promise to change screening, risk stratification, and individualized care.
Selected Articles
1. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment.
In a multinational phase 3 randomized, double‑blind trial (n=3127), once‑daily oral orforglipron produced dose‑dependent weight loss up to −11.2% at 36 mg versus −2.1% with placebo over 72 weeks, with improvements in waist circumference, systolic blood pressure, triglycerides, and non‑HDL cholesterol. Gastrointestinal adverse events were the most common reasons for discontinuation but were generally mild to moderate.
Impact: First large phase‑3 evidence that a nonpeptide, once‑daily oral GLP‑1 receptor agonist can deliver clinically meaningful, dose-dependent weight loss and cardiometabolic benefits, potentially widening access beyond injectables.
Clinical Implications: Oral GLP‑1RA may become a practical alternative or complement to injectable incretins for obesity management; clinicians should monitor GI tolerability and tailor dosing. Trials in people with diabetes and long‑term cardiovascular outcome studies are needed.
Key Findings
- Dose-dependent mean weight change at 72 weeks: −7.5% (6 mg), −8.4% (12 mg), −11.2% (36 mg) vs −2.1% placebo (P<0.001).
- At 36 mg, 54.6% achieved ≥10% weight loss and cardiometabolic markers (waist, SBP, TG, non‑HDL) improved.
- Gastrointestinal adverse events were common and led to discontinuation in 5.3–10.3% of orforglipron groups.
2. Efficacy and safety of tirzepatide in children and adolescents with type 2 diabetes (SURPASS-PEDS): a randomised, double-blind, placebo-controlled, phase 3 trial.
In a multinational phase‑3, double‑blind RCT (99 adolescents, 10 to <18 years) inadequately controlled on metformin and/or basal insulin, tirzepatide (5/10 mg) significantly improved HbA1c and reduced BMI versus placebo over a 30‑week double‑blind period with sustained effects through a 22‑week open‑label extension to one year.
Impact: First multinational phase‑3 RCT of tirzepatide in youth-onset type 2 diabetes, addressing a critical therapeutic gap with clinically meaningful glycemic and weight outcomes.
Clinical Implications: Tirzepatide could expand treatment options for adolescents with T2D unresponsive to metformin/basal insulin; growth and puberty effects require long‑term safety monitoring and real‑world effectiveness evaluation.
Key Findings
- Multinational, double‑blind phase 3 RCT across 39 sites in eight countries randomized 99 participants aged 10 to <18 years.
- Tirzepatide significantly improved HbA1c versus placebo at 30 weeks and reduced BMI; effects sustained through 1 year including extension.
- Demonstrated efficacy in a population with inadequate control on metformin and/or basal insulin.
3. Fatty acid transport protein 2 inhibition enhances glucose tolerance through α cell-mediated GLP-1 secretion.
Preclinical studies in db/db mice, α‑cell lines, and human islets show FATP2 is selectively expressed in α cells and suppresses α‑cell GLP‑1 secretion; genetic deletion or pharmacologic inhibition of FATP2 increases intra‑islet GLP‑1, enhances paracrine insulin release, and lowers glucose independently of intestinal GLP‑1.
Impact: Identifies a novel intra‑islet metabolic axis (α‑cell FATP2 → GLP‑1) that can be therapeutically targeted to augment endogenous insulin secretion, distinct from current incretin therapies.
Clinical Implications: Selective FATP2 inhibitors could complement incretin‑based therapies by increasing intra‑islet GLP‑1 and insulin secretion; human safety and efficacy trials are required before clinical adoption.
Key Findings
- Islet FATP2 expression is restricted to α cells and is functionally active.
- Genetic deletion or pharmacologic inhibition of FATP2 increases α‑cell GLP‑1 and enhances paracrine insulin release, lowering glucose in db/db mice.
- Mechanism validated in αTC1‑6 cells and human islets; effects are exendin(9‑39)–sensitive and independent of intestinal enteroendocrine GLP‑1.