Weekly Endocrinology Research Analysis
This week produced high-impact advances across therapeutics, prevention trials, and mechanistic endocrinology. A pair of NEJM randomized trials showed that an APOC3 antisense (olezarsen) powerfully lowers triglycerides and reduces pancreatitis events, while genotype-stratified prevention signals emerged from a large POInT RCT for oral insulin. Mechanistic preclinical work (Cell Metabolism) revealed adipocyte-derived extracellular vesicles carrying leptin-sensitizing miRNAs as a reversible driver
Summary
This week produced high-impact advances across therapeutics, prevention trials, and mechanistic endocrinology. A pair of NEJM randomized trials showed that an APOC3 antisense (olezarsen) powerfully lowers triglycerides and reduces pancreatitis events, while genotype-stratified prevention signals emerged from a large POInT RCT for oral insulin. Mechanistic preclinical work (Cell Metabolism) revealed adipocyte-derived extracellular vesicles carrying leptin-sensitizing miRNAs as a reversible driver of central leptin resistance and a potential therapeutic delivery vector.
Selected Articles
1. Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk.
Two parallel double-blind randomized trials (CORE-TIMI 72a & CORE2-TIMI 72b; total n=1061) showed monthly olezarsen (50 or 80 mg) produced large triglyceride reductions (placebo-adjusted −49% to −72% at 6 months) and a significant reduction in acute pancreatitis incidence (rate ratio 0.15). Efficacy extended to reductions in APOC3, remnant cholesterol, and non-HDL cholesterol; higher dose was associated with more liver enzyme elevations, thrombocytopenia, and increased hepatic fat fraction.
Impact: First high-quality randomized evidence that APOC3 antisense therapy both markedly lowers triglycerides and reduces clinically meaningful pancreatitis events in severe hypertriglyceridemia, shifting therapeutic expectations for this high-risk group.
Clinical Implications: Olezarsen is a promising option to reduce triglycerides and pancreatitis risk in selected patients with severe hypertriglyceridemia; clinicians must monitor liver enzymes, platelets, and hepatic fat and weigh dose-dependent safety signals when selecting patients.
Key Findings
- Placebo-adjusted triglyceride reductions at 6 months ranged approximately −49% to −72% depending on dose and trial.
- Acute pancreatitis incidence was markedly lower with olezarsen (mean rate ratio 0.15; 95% CI 0.05–0.40).
- Higher (80 mg) dose was associated with increased liver enzyme elevations, thrombocytopenia, and dose-dependent hepatic fat increase.
2. Efficacy of once-daily, high-dose, oral insulin immunotherapy in children genetically at risk for type 1 diabetes (POInT): a European, randomised, placebo-controlled, primary prevention trial.
In a randomized, double-masked multicenter primary prevention RCT (n=1050) of daily escalating high-dose oral insulin in genetically at-risk infants, there was no overall reduction in development of multiple islet autoantibodies (primary outcome). A significant interaction by INS genotype was observed: susceptible INS genotypes showed protection against dysglycaemia/diabetes (HR 0.38), while non-susceptible genotypes had an unexpected increase in the primary outcome (HR 2.10). Safety was acceptable with rare hypoglycemia.
Impact: A definitive, multicenter RCT clarifying that non–genotype-selected oral insulin does not prevent islet autoimmunity overall, while revealing a clinically actionable genotype-specific signal that should direct future prevention trial designs.
Clinical Implications: Do not adopt oral insulin for routine primary prevention in unselected at-risk infants; future prevention strategies should consider INS genotype selection within trials and not in routine care until validated.
Key Findings
- Primary outcome (≥2 islet autoantibodies or diabetes) occurred in 10% (insulin) vs 9% (placebo); no overall prevention effect (HR 1.12; p=0.57).
- INS genotype interaction: protective effect in susceptible INS genotypes (HR 0.38) and increased events in non-susceptible genotypes (HR 2.10).
- Safety: hypoglycemia and adverse event rates were similar between groups.
3. Adipocyte-derived extracellular vesicles are key regulators of central leptin sensitivity and energy homeostasis.
Mechanistic preclinical work shows adipocyte-derived extracellular vesicles (Ad-EVs) carry leptin-sensitizing miRNAs that suppress negative regulators of leptin receptor signaling. Loss of these miRNAs in obesity contributes to central leptin resistance; engineered EVs targeted to the CNS delivering these miRNAs reversed leptin resistance and induced significant weight loss in obese mice.
Impact: Reframes leptin resistance as an EV-mediated, modifiable process and demonstrates a translational delivery strategy (engineered EVs) that reverses central leptin resistance in vivo—opening a new therapeutic avenue for obesity.
Clinical Implications: Preclinical but high-translational potential: engineered Ad-EVs or miRNA-mimetics could be developed to restore leptin sensitivity in selected obesity phenotypes. EV miRNA signatures may also serve as biomarkers of leptin sensitivity and treatment response.
Key Findings
- Adipocyte-derived EVs contain specific miRNAs that inhibit negative regulators of leptin receptor signaling, enhancing leptin sensitivity.
- Obesity is associated with loss of these leptin-sensitizing miRNAs in Ad-EVs, contributing to central leptin resistance.
- Engineered EVs targeted to the CNS delivering leptin-sensitizing miRNAs restored leptin responsiveness and produced significant weight loss in obese mice.