Highlights
- The ATTAIN-2 phase 3 trial demonstrates that orforglipron, a daily oral small-molecule GLP-1 receptor agonist, significantly reduces body weight by up to 9.6% in adults with type 2 diabetes.
- The GATEWAY phase 2 trial shows zodasiran (RNAi targeting ANGPTL3) reduces LDL cholesterol by approximately 40% in patients with homozygous familial hypercholesterolaemia (HoFH).
- A nationwide cohort study identifies delayed puberty in male adolescents as a significant, BMI-independent risk factor for early-adult-onset type 2 diabetes.
- International consensus now strongly endorses the use of Continuous Glucose Monitoring (CGM) and Automated Insulin Delivery (AID) for pregnant women with type 1 diabetes to optimize perinatal outcomes.
Background
Cardiometabolic diseases, including obesity, type 2 diabetes (T2D), and severe dyslipidemias, represent a global health crisis. Despite the success of injectable GLP-1 receptor agonists (GLP-1 RAs), there remains a clinical need for potent, oral non-peptide alternatives to improve accessibility and patient adherence. Simultaneously, rare genetic conditions like homozygous familial hypercholesterolaemia (HoFH) require novel therapeutic mechanisms independent of the LDL receptor. Furthermore, understanding the life-course epidemiology of T2D, from adolescent development to pregnancy management, is essential for preventive medicine and precision care.
Key Content
Oral Small-Molecule GLP-1 Receptor Agonists: The ATTAIN-2 Trial
The ATTAIN-2 trial (NCT05872620) evaluated orforglipron, a first-in-class oral non-peptide GLP-1 RA. Unlike current peptide-based oral options that require strict fasting, orforglipron offers simplified dosing. In this 72-week, phase 3 study of 1,613 participants with BMI ≥27 kg/m² and T2D, orforglipron (36 mg) achieved a mean weight reduction of -9.6% compared to -2.5% for placebo (p<0.0001). Beyond weight loss, significant improvements were noted in HbA1c and cardiometabolic markers. The safety profile was consistent with the GLP-1 RA class, primarily involving mild-to-moderate gastrointestinal events during dose escalation.
RNA Interference (RNAi) in HoFH: The GATEWAY Trial
For patients with HoFH, traditional LDL receptor-dependent therapies often fail. The GATEWAY trial investigated zodasiran, an RNAi therapeutic targeting Angiopoietin-like 3 (ANGPTL3). This liver-targeted approach inhibits ANGPTL3 expression, promoting the clearance of atherogenic lipoproteins via mechanisms independent of the LDL receptor. At 6 months, patients receiving 200 mg or 300 mg quarterly doses showed fasting LDL cholesterol reductions of 35.7% and 39.9%, respectively. These effects were even more pronounced in patients already on PCSK9 inhibitors, suggesting a synergistic potential for multimodal lipid-lowering therapy.
Metabolic Risk Trajectories and Adolescence
New evidence highlights the importance of early-life developmental markers. A nationwide retrospective cohort study of 964,108 Israeli male adolescents found that those diagnosed with delayed puberty had a significantly higher risk of developing T2D in early adulthood (HR 2.47). Interestingly, this risk remained elevated (HR 1.37) even after adjusting for baseline BMI, suggesting that delayed puberty may be a marker of underlying metabolic vulnerability.
Additionally, the Teen-LABS study followed adolescents for five years post-metabolic-bariatric surgery (MBS). While highly effective for weight loss, the study noted that healthcare utilization remains high, particularly for those who experienced complications within 30 days of the initial procedure. Interestingly, vertical sleeve gastrectomy was associated with higher rates of unrelated healthcare events compared to Roux-en-Y gastric bypass in patients without baseline diabetes.
Advancing Diabetes Technology in Pregnancy
A recent international consensus statement highlights a paradigm shift in managing diabetes during pregnancy. For women with type 1 diabetes, the use of CGM is now recommended throughout preconception and pregnancy to reduce neonatal complications like large-for-gestational-age births. Furthermore, the statement supports the use of AID systems to manage the complex insulin resistance shifts that occur across trimesters, providing a level of glycemic control previously difficult to achieve with manual insulin therapy.
Expert Commentary
The evolution of GLP-1 therapy from injectables to small-molecule orals like orforglipron marks a turning point in making metabolic surgery-like weight loss accessible to a broader population. However, clinical implementation must balance efficacy with the gastrointestinal tolerability seen during titration. In the realm of lipidology, ANGPTL3 inhibition via RNAi (zodasiran) offers hope for HoFH patients who were previously considered refractory to treatment.
From a physiological standpoint, researchers are now looking into the interaction between amylin-based therapies and the renin-angiotensin system (RAS). There is a hypothesis that dual amylin and calcitonin-receptor agonists (like cagrilintide) might activate the RAS, and concurrent use of ACE inhibitors or ARBs could redirect this activation toward protective pathways, potentially enhancing cardiorenal benefits. This warrants further prospective investigation to optimize combination therapies in high-risk patients.
Conclusion
Recent clinical data underscore a move toward more convenient, potent, and targeted cardiometabolic interventions. Orforglipron and zodasiran represent the next generation of pharmacotherapy for obesity and HoFH. Concurrently, identifying early risk markers such as delayed puberty and implementing advanced technologies like CGM/AID in pregnancy reflect a more nuanced, life-cycle approach to diabetes care. Future research must focus on the long-term sustainability of these interventions and the integration of surveillance systems to ensure equitable access to these life-saving innovations.
References
- Pratley R, et al. Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial. Lancet. 2026;406(10522):2927-2944. PMID: 41275875
- Raal FJ, et al. Zodasiran, an RNAi therapeutic targeting ANGPTL3, for treating patients with homozygous familial hypercholesterolaemia (GATEWAY): an open-label, randomised, phase 2 trial. Lancet Diabetes Endocrinol. 2026;14(2):123-136. PMID: 41422812
- Zucker I, et al. Delayed puberty and early-onset type 2 diabetes risk: a nationwide cohort study of male adolescents in Israel. Lancet Child Adolesc Health. 2026;10(2):103-110. PMID: 41513398
- Battelino T, et al. Application of continuous glucose monitoring and automated insulin delivery technologies for pregnant women with type 1, type 2, or gestational diabetes: an international consensus statement. Lancet Diabetes Endocrinol. 2026;14(2):157-177. PMID: 41421368
- Inge TH, et al. Healthcare utilisation across five years among adolescents following metabolic-bariatric surgery; a prospective observational study. Lancet Reg Health Am. 2025;54:101332. PMID: 41536501