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Higher dose exploration (4.5mg trials) Rationale for testing 4.5mg: Investigate maximum tolerable dose Determine if higher = better weight loss Establish safety ceiling Results at 4.5mg weekly: Weight loss: ~12% (vs 10% at 2.4mg) Incremental benefit: Only 2% additional loss Side effects: Significantly worse nausea/vomiting Dropout rate: Higher than 2.4mg Clinical verdict: 4.5mg not recommended for routine use Risk-benefit ratio unfavorable 2.4mg remains optimal Some individuals may tolerate 3.0mg as compromise CagriSema combination dosing trials REDEFINE-1 protocol: Semaglutide: 2.4mg weekly (standard titration over 16 weeks) Cagrilintide: 2.4mg weekly (12-week titration) Both given as separate injections Started simultaneously from week 1 Semaglutide escalation (standard): Weeks 1-4: 0.25mg Weeks 5-8: 0.5mg Weeks 9-12: 1.0mg Weeks 13-16: 1.7mg Week 17+: 2.4mg Cagrilintide escalation (when combined): Weeks 1-4: 0.6mg Weeks 5-8: 1.2mg Weeks 9-12: 1.8mg Week 13+: 2.4mg Results: 15.6% average weight loss (68 weeks) Superior to either alone Side effects manageable with slow titration Combination well-tolerated See our cagrilintide and semaglutide combination guide and semaglutide dosage calculator

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N Engl J Med 369(4):330340 Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Gali N et al (2015) Selexipag for the Treatment of Pulmonary Arterial Hypertension

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