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This effect is likely driven by the prolonged circulating half-lives of long-acting and ultra-long-acting GLP-1RAs, such as semaglutide (via fatty acid acylation) and dulaglutide (via Fc fragment fusion), which maintain sustained GLP-1 receptor stimulation and enhance intestinal motility, thereby increasing diarrhea risk

Phase 2 trials investigated once-weekly subcutaneous doses of 1 mg to 12 mg with gradual escalation, but no regulatory authority has yet approved the medicine

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How this cardiac protective effect of stimulating the brain leptin-melanocortin pathway is transmitted to the heart (Fig