Effectiveness of the Dual GLP-1R/GCGR Agonist Mazdutide in GSD IXc: A Case Report

Background: Glycogen storage disease type IXc (GSD IXc), caused by pathogenic PHKG2 variants leading to phosphorylase kinase deficiency, is associated with the most unfavorable prognosis among GSD IX subtypes. Patients are at markedly increased risk of progressive hepatic fibrosis and cirrhosis, for which no established disease-modifying therapies exist. Mazdutide, a dual glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonist approved for type 2 diabetes and obesity, has demonstrated beneficial effects on hepatic metabolism, steatosis, and fibrosis in preclinical studies. Objectives: To explore the efficacy of mazdutide for weight management, hepatic function, and glycemic control in an overweight patient with GSD IXc. Methods: We describe a 24-year-old woman with a 20-year history of GSD who presented with chronically elevated liver enzymes, dyslipidemia, and progressive weight gain (BMI 27.4 kg/m²). Genetic testing identified a homozygous PHKG2 c.765del variant, confirming the diagnosis of GSD IXc. Clinical data were collected throughout the mazdutide treatment course and follow-up, including body weight, liver stiffness, serum transaminases, lipid profiles, and glycemic parameters. Written informed consent was obtained. Results: After 4 months of treatment, the patient achieved a 20.6% reduction in body weight (from 85.0 to 67.5 kg). Compared with the most recent assessment performed 4 years prior, liver stiffness measurement (LSM) by transient elastography was 55% lower (29.3 to 13.1 kPa), and controlled attenuation parameter (CAP) was 18% lower (309 to 254 dB/m). Improvements in liver enzymes and partial lipid profiles were observed. Notably, the patient discontinued uncooked cornstarch (UCCS) for one month during maintenance therapy and short-term continuous glucose monitoring showed no level 2 hypoglycemia. Conclusions: Mazdutide may represent a promising therapeutic strategy for patients with GSD IXc accompanied by metabolic abnormalities, obesity, and hepatic fibrosis. Validation through larger cohorts and mechanistic studies is warranted.