Endocrinology Research Analysis
November endocrinology was defined by outcome-changing lipid therapeutics and mechanistic advances. Two NEJM trials showed that APOC3 antisense therapy (olezarsen) not only lowers triglycerides but also reduces acute pancreatitis in severe hypertriglyceridemia. Another NEJM trial extended the benefit of PCSK9 inhibition (evolocumab) into primary prevention. Mechanistic work in Science revealed the adipogenin–seipin axis as a structural regulator of lipid droplet biogenesis, highlighting new targ
Summary
November endocrinology was defined by outcome-changing lipid therapeutics and mechanistic advances. Two NEJM trials showed that APOC3 antisense therapy (olezarsen) not only lowers triglycerides but also reduces acute pancreatitis in severe hypertriglyceridemia. Another NEJM trial extended the benefit of PCSK9 inhibition (evolocumab) into primary prevention. Mechanistic work in Science revealed the adipogenin–seipin axis as a structural regulator of lipid droplet biogenesis, highlighting new targets for lipid-storage disorders. Cross-cutting themes included precision risk stratification and the expanding cardio-renal-metabolic footprint of SGLT2/GLP-1 therapies.
Selected Articles
1. Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk.
Two double-blind RCTs (n=1,061) showed monthly olezarsen (50 or 80 mg) reduced triglycerides by ~49–72 percentage points vs placebo at 6 months and lowered acute pancreatitis incidence (rate ratio 0.15). Safety was similar overall, with more liver-enzyme elevations, thrombocytopenia, and dose-dependent hepatic fat increase at 80 mg.
Impact: First large randomized-trial evidence that APOC3 antisense therapy both powerfully lowers triglycerides and reduces a hard clinical outcome (acute pancreatitis) in severe hypertriglyceridemia.
Clinical Implications: Olezarsen is a potent option to reduce triglycerides and pancreatitis risk in severe hypertriglyceridemia; monitor liver enzymes, platelets, and hepatic fat, and weigh dose-dependent risks when selecting patients.
Key Findings
- Placebo-adjusted TG reductions at 6 months ranged from −49.2% to −72.2% (P<0.001).
- Acute pancreatitis incidence was significantly lower with olezarsen (mean rate ratio 0.15; 95% CI 0.05–0.40).
- Higher-dose (80 mg) regimen showed more enzyme elevations, thrombocytopenia, and hepatic fat increase.
2. Adipogenin promotes the development of lipid droplets by binding a dodecameric seipin complex.
Cryo-EM (~3.0 Å) and in vivo models show adipogenin (Adig) selectively binds dodecameric seipin, bridging and stabilizing subunits to promote lipid droplet biogenesis. Mouse gain- and loss-of-function data link Adig to adiposity and brown-fat triglyceride storage.
Impact: Provides a mechanistic, high-resolution structural basis for lipid droplet formation with in vivo validation, opening a novel druggable axis for disorders of lipid storage and obesity-related biology.
Clinical Implications: Translational target: Adig–seipin modulation could be pursued for lipodystrophy or obesity therapies, requiring human validation and safety profiling prior to clinical application.
Key Findings
- Cryo-EM revealed mammalian seipin forms undecamers and dodecamers; Adig selectively binds dodecamers.
- Adig bridges and stabilizes adjacent seipin subunits to promote lipid droplet development.
- Adipocyte-specific Adig overexpression increased fat mass, while Adig deletion impaired brown-fat triglyceride accumulation.
3. Evolocumab in Patients without a Previous Myocardial Infarction or Stroke.
An international double-blind RCT of 12,257 high-risk patients with atherosclerosis or diabetes and LDL-C ≥90 mg/dL but no prior MI/stroke showed evolocumab reduced 3-point and 4-point MACE over ~5 years, with no difference in safety events.
Impact: Extends robust evidence for PCSK9 inhibition to primary prevention of first major cardiovascular events in high-risk patients.
Clinical Implications: PCSK9 inhibitors can be considered for selected high-risk atherosclerotic or diabetic patients without prior events to reduce first MACE, with cost and LDL-C targets factored into decisions.
Key Findings
- 3-point MACE reduced (HR 0.75; 95% CI 0.65–0.86) over a median 4.6 years.
- 4-point MACE reduced (HR 0.81; 95% CI 0.73–0.89) with no between-group safety differences.
- Benefits were consistent across major clinical subgroups.