Maturity-onset diabetes of the young (MODY) is a type of monogenic diabetes with an estimated prevalence of 1 of 10,000 in adults and 1 of 23,000 in children (1). HNF1A-MODY (52%) and HNF4A-MODY (10%), caused by pathogenic variants in the respective genes encoding β-cell transcription factors, are the most common treatment-requiring forms of MODY (2). Sulfonylurea is first-line treatment for HNF1A-MODY and HNF4A-MODY, and insulin is a second-line treatment. Insulin is problematic, as it often leads to hypoglycemia and weight gain. Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1) have been shown to potentiate sulfonylurea-induced insulin secretion in 10 HNF1A-MODY cases (3), but the clinical use of dual GIP/GLP-1 receptor agonist (RA) treatment has not been described. By focusing on the cases of two individuals with different disease pedigrees, we aim to describe the clinical use and efficacy of tirzepatide (a dual GIP/GLP-1 RA) treatment in HNF1A-MODY and HNF4A-MODY.
A 33-year-old Hispanic White woman presented for management of HNF4A-MODY [heterozygous variant NM_000457.6(HNF4A):c.418C>T(p.Arg140X)]. She was diagnosed with HNF4A-MODY at the age of 12 (by genetic testing for an established pedigree), and she was diagnosed with diabetes at age 20 at an outside hospital. At re-presentation in follow-up, she was on glipizide 2.5 mg twice daily, insulin glargine 65 units once daily (0.75 units/kg/day), and insulin lispro 5 units three times per day with meals (total daily dose 80 units/day [0.93 units/kg/day]). She gained 27.22 kg over 10 years (weight 86.2 kg, BMI 33.6 kg/m2) but had no microvascular or macrovascular complications. Her HbA1c was 7.3%. She did not report hypoglycemia but was interested in losing weight. Tirzepatide 2.5 mg once weekly was started (with discontinuation of glipizide and prandial insulin) and titrated by 2.5 mg every 4 weeks to 7.5 mg subcutaneously once weekly. She tolerated this well, except for mild nausea. After 10 months, her HbA1c decreased to 5.9% and her weight decreased by 19.9 kg (weight 67.1 kg, BMI 26.2 kg/m2, 23% body weight reduction) without a reported change in hypoglycemia. She did not experience significant postprandial hyperglycemia and significantly reduced her basal insulin to 35 units once daily (0.52 units/kg/day).
A 53-year-old non-Hispanic White woman presented for management of HNF1A-MODY [heterozygous variant NM_000545.5(HNF1A):c.955 + 1G>A]. She was diagnosed with diabetes at an outside hospital at age 24 (weight 52.1 kg, BMI 19.1 kg/m2) and was initiated on glipizide extended release (ER) 5 mg once daily. At presentation to our medical center, she was on glipizide ER 5 mg once daily, metformin ER 1,000 mg once daily, and insulin glargine 19 units daily (0.23 units/kg/day). She had no reported microvascular or macrovascular complications. Her HbA1c was 9.5% and she was overweight (weight 81.4 kg, BMI 29.8 kg/m2). An attempt was made to increase the glipizide dose, but she developed hypoglycemia (four hypoglycemic episodes, two severe, over a 30-day interval). Liraglutide was not tolerated due to nausea, and semaglutide was not tolerated due to nausea, vomiting, and diarrhea. Once-weekly subcutaneous tirzepatide was initiated and titrated to 5 mg once weekly (highest dose tolerated due to nausea) with discontinuation of glipizide. She reported no increase in postprandial hyperglycemia, a reduction in hypoglycemic events (no reported hypoglycemic events over 30 days), and a reduction in insulin glargine dose by 1 unit (0.30 units/kg/day). After 15 months of treatment, her HbA1c improved to 6.4% and her weight decreased by 21.3 kg (weight 60.1 kg, BMI 21.4 kg/m2, 26% body weight reduction).
In these individuals, treatment with tirzepatide for HNF4A-MODY and HNF1A-MODY led to a 3.1% and 1.4% HbA1c reduction, 23% and 26% body weight reduction (compared with average of 14.7% reduction in patients with obesity and type 2 diabetes [4]), 45 units and 1 unit total daily insulin dose reduction, and sulfonylurea discontinuation, respectively. These cases highlight dual GIP/GLP-1 RA as adjuvant treatment and highlight a potential use of dual GIP/GLP-1 RA as monotherapy. Although it is known that GLP-1 receptor activation on β-cells leads to downstream stimulation of β-cells distal to the genetic defect (5), the mechanism of action of GIP and dual GIP/GLP-1 RA in HNF1A-MODY and HNF4A-MODY is not known. Patients with MODY may develop obesity and/or insulin resistance, which may be environmental, genetic, or a combination of the complex interplay of these risk factors. It is likely that the pleiotropic effects of tirzepatide will play a future role in the treatment of individuals with HNF1A-MODY and HNF4A-MODY who are overweight or obese. Given these preliminary findings, the effect of dual GIP/GLP-1 RA in HNF1A-MODY and HNF4A-MODY warrants further investigation.
Article Information
Acknowledgments. We are grateful to the many patients who participate in the University of Michigan MODY registry and who have given us permission to use and publish their data. We are grateful to the late Stefan S. Fajans, MD, and Graeme Bell, PhD, for laying the groundwork for this registry through their early description of MODY. We are grateful to Louis H. Philipson, MD, PhD, Siri Greeley, MD, PhD, and Rochelle Naylor, MD, for their ongoing discussions and collaborations through the Data 4 The Common Good (D4CG) registry and the Rare and Atypical Diabetes Network (RADIANT).
Funding. D.T.B., M.F.d.F., E.A.O., and B.E.G. receive grant support from the Caswell Diabetes Institute and from the National Institutes of Health (grant U54DK118612-04). E.A.O. and M.F.d.F. are funded by National Institutes of Health grant R01DK125513.
Duality of Interest. D.T.B. is a research investigator for Fractyl Health Laboratories and Rhythm Pharmaceuticals. M.F.d.F. is an advisory board member for PTC Pharmaceuticals and was a scientific presenter in a symposium funded by Amryt Pharmaceuticals. E.A.O. has received grant support from Aegerion Pharmaceuticals (manufacturer of metreleptin), Akcea Therapeutics, Ionis Pharmaceuticals, Gemphire Therapeutics, Novo Nordisk, Rhythm Pharmaceuticals, Fractyl Health Laboratories, and GI Dynamics. E.A.O. has served as an advisor and/or a consultant to Aegerion Pharmaceuticals, Akcea Therapeutics, Ionis Pharmaceuticals, and Regeneron. E.A.O. has royalty rights from the use of metreleptin in lipodystrophy. W.H.H. is on data safety and monitoring boards for Merck Sharp & Dohme and Rivus Pharmaceuticals. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. D.T.B. wrote the manuscript. A.M., M.F.d.F., B.E.G., E.A.O., and W.H.H. edited and revised the manuscript. D.T.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Handling Editors. The journal editors responsible for overseeing the review of the manuscript were John B. Buse and M. Sue Kirkman.
Funding Statement
D.T.B., M.F.d.F., E.A.O., and B.E.G. receive grant support from the Caswell Diabetes Institute and from the National Institutes of Health (grant U54DK118612-04). E.A.O. and M.F.d.F. are funded by National Institutes of Health grant R01DK125513.
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;98:4055–4062 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Shields BM, Hicks S, Shepherd MH, et al. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetalogia 2010;53:2504–2508 [DOI] [PubMed] [Google Scholar]
- 3. Østoft SH, Bagger JI, Hansen T, et al. Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes Care 2014;37:1797–1805 [DOI] [PubMed] [Google Scholar]
- 4. Christensen AS, Hædersdal S, Storgaard H, et al. GIP and GLP-1 potentiate sulfonylurea-induced insulin secretion in hepatocyte nuclear factor 1α mutation carriers. Diabetes 2020;69:1989–2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Garvey WT, Frias JP, Jastreboff AM, et al.; SURMOUNT-2 Investigators . Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2023;402:613–626 [DOI] [PubMed] [Google Scholar]