Novel therapies for type 1 diabetes

Type 1 diabetes (T1D) is an idiopathic, autoimmune disease that results in the progressive loss of pancreatic β-cell function and eventual absolute insulin dependence.¹ Conventional therapy consists of lifelong insulin replacement. This approach does not address the underlying autoimmune destruction or restore endogenous insulin production. Recently, research has focused on developing novel therapies aimed at delaying the onset of disease, preserving residual β-cell function, and even restoring insulin independence through cellular replacement strategies.

The disease course of T1D is staged into 3 categories (Table 1).² Stage 1 is preclinical and defined by the presence of 2 or more diabetes-related autoantibodies, while glucose tolerance remains normal. In stage 2, β-cell dysfunction occurs, resulting in dysglycemia. Finally, stage 3 is defined by clinical onset of T1D, characterized by symptomatic hyperglycemia that meets diagnostic criteria.

The rate and extent of β-cell destruction vary among patients. In later stages of disease, there is β-cell destruction with little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide.¹ C-peptide, the cleavage product of insulin’s prohormone precursor, is often used as a marker of residual β-cell function. A C-peptide level of less than 0.2 nmol/L is commonly associated with established T1D, although levels vary at diagnosis, and a measurable C-peptide indicates ongoing insulin production.³

As β-cell function declines, C-peptide levels also decrease (Figure).² Patients with lower C-peptide levels have a higher incidence of severe hypoglycemia and require more exogenous insulin.

Novel therapeutic approaches for T1D are designed to delay disease onset in at-risk individuals, who are typically defined as relatives of patients with T1D with multiple diabetes-related autoantibodies and dysglycemia. These therapies also aim to preserve β-cell function in newly diagnosed patients and restore insulin production in those with established disease.

Teplizumab (Tzield; Sanofi) is one of the most recent novel medications for pediatric T1D on the market. Teplizumab is an anti-CD3 monoclonal antibody that partially inactivates T-cell function by binding to the CD3 receptor.⁴ In November 2022, the FDA approved teplizumab for delaying progression from stage 2 to stage 3 T1D in adults and children 8 years or older. In the phase 2 clinical trial of teplizumab, high-risk patients who received 2-week courses of teplizumab maintained significantly higher stimulated C-peptide levels than patients receiving a placebo.⁴ In the phase 3 trial, C-peptide levels were assessed after patients received two 12-day courses of teplizumab. This trial found that treatment with teplizumab resulted in maintenance of β-cell function. Important considerations for this medication include follow-up at 60 months post randomization, with transient lymphopenia being the most common adverse event, occurring in 73% of patients. Lymphocyte counts returned to normal range in 45 days in all patients except one, whose lymphopenia resolved on day 105.

Another immunomodulatory agent under investigation is baricitinib (Olumiant; Lilly), a Janus kinase (JAK) inhibitor. JAK inhibitors block the formation of immune synapses between β-cells and CD8+ T cells to help prevent the death of β-cell function.⁶ In the BANDIT phase 2 trial (NCT04774224), patients with new-onset T1D received daily baricitinib treatment or placebo over 48 weeks. Those in the baricitinib group had significantly higher mixed-meal–stimulated C-peptide levels compared with the placebo group, suggesting preserved β-cell function. Adverse events occurred at similar rates between groups (78% baricitinib vs 84% placebo), most commonly upper respiratory tract infections and dermatologic disorders.⁶ Various trials are ongoing to evaluate additional JAK inhibitors and their use in preserving β-cell function. One of these phase 2 trials is the JAKPOT trial (NCT05743244), which is evaluating abrocitinib and ritlecitinib in patients with recent-onset stage 3 T1D.⁷

Additional medications aimed at delaying the progression of T1D include verapamil (brand names: Calan SR, Verelan, Verelan PM) and ergocalciferol (Drisdol, Validus Pharmaceuticals; Calcidol, Patrin Pharma). Verapamil is a calcium channel blocker that is hypothesized to reduce β-cell apoptosis and glucotoxicity-induced β-cell death.⁸ In a randomized clinical trial of children newly diagnosed with T1D, verapamil had higher mixed-meal–stimulated C-peptide levels at 52 weeks as compared to placebo, suggesting improved β-cell function with few adverse events.⁸ Ergocalciferol is safe and has immunomodulatory functions that could protect residual β-cell function. In a secondary analysis of a randomized controlled trial, ergocalciferol significantly improved the proinsulin-to-C-peptide ratio (PI:C) compared with placebo, with fasting PI:C decreasing (mean [SE], −0.0009 [0.0008]) vs an increase with placebo (0.0011 [0.0003]; P = .01). Ergocalciferol also attenuated the decline in C-peptide over 12 months, with a 31% smaller reduction compared with placebo (−28.4% vs −41.5%).⁹

Beyond immunomodulation and other hypothesized medications, significant advances have been made in cell-based therapies designed to restore insulin production. In 2023, the FDA approved donislecel (Lantidra; CellTrans), the first allogeneic pancreatic islet cellular therapy derived from deceased donor pancreatic cells. It is indicated for adults with T1D who experience repeated episodes of severe hypoglycemia and are unable to reach glycemic targets with standard therapies.¹⁰ Zimislecel (VX-880; Vertex Pharmaceuticals) is an allogeneic stem cell–derived islet cell therapy currently in phase 3 trials. In a phase 1/2 study, 14 adult participants received a single infusion of zimislecel alongside glucocorticoid-free immunosuppression. After 12 months of follow-up, all patients demonstrated islet engraftment and measurable C-peptide levels, with no patients experiencing severe hypoglycemic events. Eighty-three percent of the participants had insulin independence and were not using exogenous insulin on day 365. These findings suggest that zimislecel may restore physiological insulin secretion and improve metabolic outcomes in patients with T1D.¹¹

eactive management of hyperglycemia toward disease modification and potential functional cure. Teplizumab has entered clinical use by delaying the onset of T1D in high-risk patients, whereas JAK inhibitors and other immunomodulatory agents may preserve β-cell function early in the disease course. Meanwhile, cellular therapies such as donislecel and zimislecel may potentially restore insulin independence in specific patients. Additional research will determine the long-term efficacy, safety, and accessibility of these therapies, specifically in the pediatric population. Table 2^12,13 presents a table summarizing FDA-approved and investigational therapies for T1D. The development of these novel therapies continues to advance the management of T1D and improve patient outcomes.

References

1. American Diabetes Association Professional Practice Committee. 2. Diagnosis and classification of diabetes: standards of care in diabetes—2024. Diabetes Care. 2024;47(suppl 1):S20-S42. doi:10.2337/dc24-S002

2. DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018;391(10138):2449-2462. doi:10.1016/S0140-6736(18)31320-5

3. Leighton E, Sainsbury CA, Jones GC. A practical review of C-peptide testing in diabetes. Diabetes Ther. 2017;8(3):475-487. doi:10.1007/s13300-017-0265-4

4. Ramos EL, Dayan CM, Chatenoud L, et al; PROTECT Study Investigators. Teplizumab and β-cell function in newly diagnosed type 1 diabetes. N Engl J Med. 2023;389(23):2151-2161. doi:10.1056/NEJMoa2308743

5. Herold KC, Bundy BN, Long SA, et al; Type 1 Diabetes TrialNet Study Group. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med. 2019;381(7):603-613. doi:10.1056/NEJMoa1902226

6. Waibel M, Wentworth JM, So M, et al; BANDIT Study Group. Baricitinib and β-cell function in patients with new-onset type 1 diabetes. N Engl J Med. 2023;389(23):2140-2150. doi:10.1056/NEJMoa2306691

7. Janus kinase (JAK) inhibitors to preserve C-peptide production in new onset type 1 diabetes (T1D). ClinicalTrials.gov. September 10, 2025. Accessed September 15, 2025. https://clinicaltrials.gov/study/NCT05743244

8. Forlenza GP, McVean J, Beck RW, et al; CLVer Study Group. Effect of verapamil on pancreatic beta cell function in newly diagnosed pediatric type 1 diabetes: a randomized clinical trial. JAMA. 2023;329(12):990–999. doi:10.1001/jama.2023.2064

9. Nwosu BU, Parajuli S, Sharma RB, Lee AF. Effect of ergocalciferol on β-cell function in new-onset type 1 diabetes: a secondary analysis of a randomized clinical trial. JAMA Netw Open. 2024;7(3):e241155. doi:10.1001/jamanetworkopen.2024.1155

10. Islet transplantation in type 1 diabetic patients using the University of Illinois at Chicago (UIC) protocol. ClinicalTrials.gov. Updated February 8, 2024. Accessed September 15, 2025. https://clinicaltrials.gov/study/NCT00679042

11. Reichman TW, Markmann JF, Odorico J, et al; VX-880-101 FORWARD Study Group. Stem cell-derived, fully differentiated islets for type 1 diabetes. N Engl J Med. 2025;393(9):858-868. doi:10.1056/NEJMoa2506549

12. Tzield. Prescribing information. Sanofi; 2022. Accessed September 15, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761183s000lbl.pdf 

13. Lantidra. Prescribing information. CellTrans; 2023. Accessed September 15, 2025. https://www.fda.gov/media/169920/download