6989 Novel Use of Dual GIP/GLP-1 Receptor Agonist in HNF4A-MODY

Abstract Disclosure: A. Mehdi: None. M.C. Foss de Freitas: Advisory Board Member; Self; PTC Pharmaceuticals. Other; Self; Scientific presenter in a symposium funded by Amryt Pharmaceuticals. C.L. Martin: None. B.E. Gregg: None. N. Nachawi: None. E. Frontera: None. E.A. Oral: Consulting Fee; Self; Amryt Pharmaceuticals, Akcea Therapeutics, Ionis Pharmaceuticals Inc., Regeneron Pharmaceuticals. Grant Recipient; Self; Amryt Pharmaceuticals (now part of Cheisi, manufacturer of metreleptin), Akcea Therapeutics, Ionis Pharmaceuticals Inc., Regeneron Pharmaceuticals, Novo Nordisk, Rhythm Pharmaceuticals, Fractyl Laboratories, GI Dynamics (now Morfic Medical. Other; Self; Royalty rights from the use of Metreleptin in lipodystrophy. W.H. Herman: Advisory Board Member; Self; Member of the Data Safety and Monitoring Board for Merck Sharp Self; Chair for the National Committee for Quality Assurance (NCQA) Healthcare Effectiveness Data and Information Set (HEDIS) Workgroup. D.T. Broome: Consulting Fee; Self; Tayco, Inc. Research Investigator; Self; Novo Nordisk, Fractyl Laboratories, Rhythm Pharmaceuticals, Inc. HNF4A-MODY (formerly MODY-1) is an autosomal dominant form of diabetes caused by a mutation in the transcription factor HNF4A1,2. Affected patients are initially very sensitive to the anti-hyperglycemic effect of sulfonylureas, but become unresponsive to sulfonylureas at a rate of 1-4% per year3. Recently, the efficacy of glucagon-like peptide-1 receptor agonists has been demonstrated in HNF4A-MODY2, but there have been no reports on the use of dual gastric inhibitory polypeptide/glucagon-like peptide-1 receptor agonists (dual GIP/GLP-1 RA) in HNF4A-MODY. This report describes a patient with HNF4A-MODY who was treated with a dual GIP/GLP-1 RA. A 42-year-old White male with a pathogenic heterozygous mutation in Q268X was diagnosed with HNF4A-MODY at the age of 10 years (part of the RW pedigree)3. He was diagnosed with diabetes at age 20, treated with metformin from age 20 to age 30, and had glipizide extended release added at age 30. His dose of glipizide was titrated over 9-years to the maximum therapeutic dose. At the age of 40, when his HbA1c was no longer controlled, dulaglutide 1.5 mg once weekly was added. Thereafter, his HbA1c was well controlled between 5.5-7.0%, until it increased to 7.7%. He was then transitioned from dulaglutide to tirzepatide 5 mg once weekly for 4 weeks, 7.5 mg once weekly for 4 weeks, then 10 mg once weekly. He has been maintained on tirzepatide 10 mg once weekly, glipizide extended release 10 mg once daily, and metformin 1,000 mg twice daily without significant side effects. His HbA1c improved from 7.7% to 5.8% and he lost 7 lbs since transitioning from dulaglutide to tirzepatide (while on tirzepatide for 4 months in total). During his recent visit, he was without significant hyper- or hypoglycemia and his BMI was 31.2 kg/m2. (down from 32.32 kg/m2). To our knowledge, this is the first case report demonstrating preliminary efficacy of dual GIP/GLP-1 receptor agonist in HNF4A-MODY. While it is known that GIP and GLP-1 can cause glucose stimulated insulin secretion, and the mechanism of GLP-1 was previously described in MODY4, the differential effects and/or predominance of GIP or GLP-1 in MODY requires further investigation. References: 1. Pihoker C, Gilliam LK, Ellard S, et al. SEARCH for Diabetes in Youth Study Group. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. J Clin Endocrinol Metab. 2013;98(10):4055-4062.2. Broome DT, Pantalone KM, Kashyap SR, et al. Approach to the Patient with MODY-Monogenic Diabetes. J Clin Endocrinol Metab. 2021;106(1): 237-250. 3. Fajans SS, Bell GI. MODY: History, genetics, pathophysiology, and clinical decision making. Diabetes Care. 2011;34(8):1878-1884. 4. Broome DT, Tekin Z, Pantalone KM, et al. Novel Use of GLP-1 Receptor Agonist Therapy in HNF4A-MODY. Diabetes Care. 2020;43(6):e65. Presentation: 6/2/2024