Objectives: Incretin mimetics (IMs) are highly efficient against cardiometabolic (CM) and neurodegenerative (ND, comorbid with CM) diseases, yet ~50% of users discontinue because of adverse events (AEs) and regain the lost weight. HPβCD is in randomized controlled trials (RCTs) against the NPC lysosomal (LY) storage (LS), the Alzheimer’s ND, and diabetic kidney diseases, but (1) its presumed MoA of “depleting cholesterol” (Chol) risks permanent hearing loss, and (2) it requires overnight infusion.
A secondary genetic data analysis discovered that phospholipids (PLs) rather than Chol impair the autophagic-LY pathway (ALP) via ABCA1, so that αCDs, too small to fit Chol but still more effective (unknown MoA) against several LS and aging-related diseases. Here, we present the first reliably absorbed αCD-based dietary component with a known MoA to maintain ND/CM benefits from IMs.
Methods: We draw on recently published crucial support for αCD’s MoA/effect and then present RCT data for a clathrate (two αCD rings aligned on a milk/coconut oil MCFA C10 string) taken orally at dinner with milk or non-dairy drinks.
Results: Dietary αCD consistently reduces hydrolysis of starch into sugar (Wittkowski 2022), a risk factor for diabetes (EU-authorized health claim), obesity, and reduced satiety, yet the MoA was unclear until a recent mouse study (Smits 2024-12) explained the RCT results. It triggers GLP-1 production in the gut, reducing food intake without causing GI AEs (nausea/vomiting). αCD also reduces lipotoxic long-chain fatty acids (LCFAs) and improves CNS (reducing fibrils, AlResaini 2024-11, activating ABCA1, Wang 2025-03) and athletic (Onishi 2025-01) performance, without causing HPβCD’s “acceptable” ototoxicity (Hastings 2025-03), while C10 is ketogenic (Neth 2025-01).
However, only < 5% of αCD is commonly believed to be absorbed from the intestine (see “overnight infusion”, above). The RCT shows (p < .05) that more αCD is absorbed (with dose-dependent excretion of PLs into urine) if the diet contains whole milk and even more (~50%) as a C10 clathrate. The other 50% feed commensal bacteria in the gut, which then produce pro-pancreatic SCFAs.
Conclusions: An αCD/C10 clathrate can be administered orally (as pills, sachets, or even wine, Liu 2025-03) without causing the IMs’ GI AEs and non-trivial clinical AEs with life-long use.
