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Mechanistic Understanding Gaps Fundamental aspects of GLP2s mechanism require further clarification: Relative contributions of GIP versus GLP-1 receptor activation to overall efficacy remain incompletely characterized Whether imbalanced receptor engagement provides clinical advantages over balanced dual agonism unknown Tissue-specific effects and receptor distribution consequences not fully elucidated Long-term receptor desensitization or adaptation effects with chronic treatment unstudied Long-Term Safety Profile Critical safety questions persist beyond the typical 40-72 week trial durations: Chronic use effects extending beyond 2-3 years inadequately characterized Cardiovascular outcomes data pending from ongoing SURPASS-CVOT trial Long-term effects on thyroid function and potential thyroid tumor risk in humans remain under evaluation Optimal treatment duration and consequences of treatment discontinuation require further study Effects on bone health with sustained weight loss and extended treatment duration unclear Population-Specific Considerations Certain populations remain understudied: Limited data in older adults (over 75 years) and frail populations Insufficient evidence in patients with severe renal or hepatic impairment Pregnancy and lactation safety data absent (animal studies show potential risks) Pediatric safety and efficacy not established Long-term effects on growth and development in younger populations unknown Regulatory & Clinical Status FDA Approval Status GLP2 has received multiple approvals from the U.S

Mov Disord 24(7):979983

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