聚焦罕见遗传性肥胖综合征，双重激动剂替尔泊肽有望成为破局利器

Core Viewpoint - The article discusses the effectiveness of the dual GIP/GLP-1 agonist Tirzepatide in treating two cases of Alström syndrome, a rare obesity syndrome, highlighting its potential to provide significant metabolic benefits where previous GLP-1 receptor agonists had limited success [6][7][16]. Summary by Sections Introduction to Alström Syndrome - Alström syndrome is a rare genetic disorder caused by mutations in the ALMS1 gene, characterized by early-onset obesity, type 2 diabetes, significant insulin resistance, and uncontrollable appetite [9]. Case Reports - Two young male patients diagnosed with Alström syndrome previously showed limited response to GLP-1 receptor agonists and experienced weight regain after initial weight loss [10][11]. - Patient A (21 years old) had a baseline BMI of 42.2 kg/m² and was diagnosed with type 2 diabetes, fatty liver, and multiple endocrine deficiencies [11]. - Patient B (20 years old) had a baseline BMI of 46.3 kg/m², along with severe complications such as fatty liver and portal hypertension [12]. Treatment with Tirzepatide - Both patients switched from GLP-1 RA to Tirzepatide, with a gradual dosage adjustment to a stable dose of 15 mg per week, while continuing their hormone replacement therapy [14]. Metabolic Outcomes - Significant improvements were observed in key metabolic indicators: - Patient A lost 26.9% of body weight (from 113.6 kg to 83 kg) and reduced BMI to 30.9 kg/m² after 18 months [15]. - Patient B lost 7.2% of body weight (from 132 kg to 122.5 kg) and reduced BMI to 42.9 kg/m² after 9 months [15]. - Patient A's daily insulin dosage decreased by 83% (from 116 IU to 20 IU), with HbA1c levels maintained at ideal levels [15]. - MRI assessments indicated that Patient A's liver fat content decreased from 20% to <5%, while Patient B's liver fat content dropped from 21% to 11% [15]. Appetite Control and Safety - Both patients reported a significant reduction in previously uncontrollable appetite, and no severe drug-related adverse events were observed, indicating good tolerability [15]. Conclusion and Future Directions - The case report suggests that Tirzepatide may offer superior metabolic benefits for Alström syndrome patients who previously did not respond well to GLP-1 RA, including greater weight loss, improved insulin resistance, and reduced liver fat accumulation [16]. - Although the findings are based on only two cases, they open a promising avenue for treatment in this difficult-to-manage rare disease, warranting further research with larger sample sizes and longer follow-up [16].