Published online Feb 15, 2024. doi: 10.4239/wjd.v15.i2.133
Peer-review started: November 3, 2023
First decision: December 6, 2023
Revised: December 17, 2023
Accepted: January 16, 2024
Article in press: January 16, 2024
Published online: February 15, 2024
Processing time: 93 Days and 0.8 Hours
Type 1 diabetes (T1D) is a chronic autoimmune condition that destroys insulin-producing beta cells in the pancreas, leading to insulin deficiency and hyper-glycemia. The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels. However, this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells. Recent research has explored the potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) as a novel intervention to modify the disease course and delay the onset of T1D. GLP-1RAs are medications initially developed for treating type 2 diabetes. They exert their effects by enhancing glucose-dependent insulin secretion, suppressing glucagon secretion, and slowing gastric emptying. Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D. This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D, possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells. This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification, which should open new avenues for preventing and treating T1D, improving the quality of life and long-term outcomes for individuals at risk of T1D.
Core Tip: New research suggests a novel approach to treating type 1 diabetes (T1D) by using glucagon-like peptide-1 receptor agonists, specifically semaglutide, to significantly improve blood glucose control and potentially slow the progression of the disease in newly diagnosed patients. This strategy, which leads to less insulin dependence and better metabolic markers, could change the way T1D is managed in a big way. At the same time, the study supports early T1D risk screening, especially in groups with high risk, so that early interventions can be made, evaluating the benefits against the possible emotional and financial effects. This dual approach shows that there are bright futures for improving the lives of patients with T1D.
- Citation: Nassar M, Chaudhuri A, Ghanim H, Dandona P. Glucagon-like peptide-1 receptor agonists as a possible intervention to delay the onset of type 1 diabetes: A new horizon. World J Diabetes 2024; 15(2): 133-136
- URL: https://www.wjgnet.com/1948-9358/full/v15/i2/133.htm
- DOI: https://dx.doi.org/10.4239/wjd.v15.i2.133
Type 1 diabetes (T1D) is a chronic disease that has long posed therapeutic challenges. This ailment, rooted in the autoimmune destruction of pancreatic β-cells by T-cells, results in a severe decline of β-cell activity and an eventual complete lack of insulin[1-3]. The only treatment for this disease is intensive insulin therapy, which requires multiple daily injections or continuous subcutaneous insulin infusion with frequent monitoring of blood glucose. Despite advances in closed-loop hybrid pumps and continuous glucose monitoring devices, 75% of subjects with T1D maintain an A1c above 7%. Moreover, there is a significant disease burden and emotional burden associated with the diagnosis and management of T1D. Even with modern medical breakthroughs, many T1D sufferers still grapple with maintaining optimal blood sugar levels. Intensive insulin therapies, though advantageous, can sometimes lead to hypoglycemia, presenting a therapeutic conundrum[4,5].
Researchers observed promising results in a study examining the potential benefits of Glucagon-like peptide-1 receptor agonists (GLP-1RAs) for T1D patients with positive C-peptide levels. Our recent exploration, as published in the New England Journal of Medicine, sheds light on a hopeful path. We delved into the impact of semaglutide, a GLP-1RA, within three months on ten newly diagnosed T1D patients. These individuals began with an average glycated hemoglobin of 11.7% ± 2.1% and a fasting C-peptide of 0.65% ± 0.33% ng/mL, all undergoing standard insulin treatments[6]. Introducing semaglutide and dietary modifications led to the discontinuation of prandial insulin for all participants within a quarter year. Impressively, by half a year, seven had ceased using basal insulin. A year later, the average glycated hemoglobin decreased to 5.7% ± 0.4%, while the fasting C-peptide surged to an average of 1.05 ± 0.40 ng/mL. Continuous glucose assessments revealed an 89% ± 3% time-in-range[6].
The study entailed a retrospective analysis of 11 normal-weight T1D patients treated with GLP-1RA in conjunction with insulin. Notable findings included a significant reduction in HbA1c levels from 10.74% ± 0.96% to 7.4% ± 0.58% after 12 ± 1 wk of GLP-1RA therapy. Additionally, there was a noteworthy decline in total insulin dose by 64% and a minor weight reduction. Importantly, C-peptide concentrations, indicative of endogenous insulin production, surged significantly, enhancing pancreatic beta-cell function. Remarkably, 50% of the study participants achieved freedom from insulin therapy while on GLP-1RA therapy over the study duration[7].
In the Adjunct One Treat-To-Target Randomized Trial, the addition of liraglutide to insulin therapy in T1D was assessed over 52 wk in 1398 adults. Participants were administered liraglutide (at concentrations of 1.8, 1.2, or 0.6 mg) or a placebo in conjunction with insulin. The study found that HbA1c levels reduced by 0.34%–0.54% from an initial 8.2%, insulin doses diminished more with liraglutide compared to the placebo, and there was a notable weight reduction in the liraglutide cohorts. However, liraglutide recipients experienced elevated rates of symptomatic hypoglycemia, and the 1.8 mg liraglutide group saw a significant rise in hyperglycemia with ketosis. Consequently, despite its benefits, the increased adverse events suggest caution in the broader clinical application of liraglutide for T1D[8].
Various immunotherapies, including Teplizumab, Otelixizumab, and Abatacept, have displayed promise but are not without complications. For example, Otelixizumab users have reported headaches, fevers, and rashes, typical reactions to anti-CD3 antibodies[9,10]. Teplizumab has been linked to skin issues, leukopenia, respiratory infections, and lymphopenia[11-13]. Most issues with Abatacept were related to the infusion process[14,15].
The question of T1D risk screening remains contentious, especially for those without familial ties to the condition. A study by Ziegler et al[5] in Bavaria showcased the viability of screening children during standard pediatric appointments, pinpointing 280 children with multiple autoantibodies, 43 of whom later developed T1D[5,16]. The means of early identification and action are clear. Yet, the financial and emotional tolls of screening warrant consideration. Nevertheless, research indicates that psychosocial screenings can pinpoint vulnerable families[17]. Moreover, regions with a high prevalence of diabetic ketoacidosis could economically justify presymptomatic T1D screenings[18,19]. The timing and approach to screening are debated, focusing on the balance between cost and comprehensive detection[18,20,21].
Our findings suggest that early T1D screening, combined with interventions such as GLP-1RA, could significantly impede the progression of the disease, especially in high-risk obese individuals. Pediatric professionals should exercise heightened caution with patients prone to T1D due to genetic or autoimmune factors. As we venture further into this realm, the prospect of an enhanced quality of life for T1D patients becomes increasingly tangible.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Endocrinology and metabolism
Country/Territory of origin: United States
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B, B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Cai L, United States; Shalaby MN, Egypt S-Editor: Li L L-Editor: A P-Editor: Li L
1. | Araujo DB, Dantas JR, Silva KR, Souto DL, Pereira MFC, Moreira JP, Luiz RR, Claudio-Da-Silva CS, Gabbay MAL, Dib SA, Couri CEB, Maiolino A, Rebelatto CLK, Daga DR, Senegaglia AC, Brofman PRS, Baptista LS, Oliveira JEP, Zajdenverg L, Rodacki M. Allogenic Adipose Tissue-Derived Stromal/Stem Cells and Vitamin D Supplementation in Patients With Recent-Onset Type 1 Diabetes Mellitus: A 3-Month Follow-Up Pilot Study. Front Immunol. 2020;11:993. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 10] [Cited by in F6Publishing: 21] [Article Influence: 5.3] [Reference Citation Analysis (0)] |
2. | Curtin F, Champion B, Davoren P, Duke S, Ekinci EI, Gilfillan C, Morbey C, Nathow T, O'Moore-Sullivan T, O'Neal D, Roberts A, Stranks S, Stuckey B, Vora P, Malpass S, Lloyd D, Maëstracci-Beard N, Buffet B, Kornmann G, Bernard C, Porchet H, Simpson R. A safety and pharmacodynamics study of temelimab, an antipathogenic human endogenous retrovirus type W envelope monoclonal antibody, in patients with type 1 diabetes. Diabetes Obes Metab. 2020;22:1111-1121. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 6] [Cited by in F6Publishing: 5] [Article Influence: 1.3] [Reference Citation Analysis (0)] |
3. | Ehlers MR. Strategies for clinical trials in type 1 diabetes. J Autoimmun. 2016;71:88-96. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 15] [Cited by in F6Publishing: 15] [Article Influence: 1.9] [Reference Citation Analysis (0)] |
4. | Cai J, Wu Z, Xu X, Liao L, Chen J, Huang L, Wu W, Luo F, Wu C, Pugliese A, Pileggi A, Ricordi C, Tan J. Umbilical Cord Mesenchymal Stromal Cell With Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion. Diabetes Care. 2016;39:149-157. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 109] [Cited by in F6Publishing: 124] [Article Influence: 15.5] [Reference Citation Analysis (0)] |
5. | Ziegler AG, Kick K, Bonifacio E, Haupt F, Hippich M, Dunstheimer D, Lang M, Laub O, Warncke K, Lange K, Assfalg R, Jolink M, Winkler C, Achenbach P; Fr1da Study Group. Yield of a Public Health Screening of Children for Islet Autoantibodies in Bavaria, Germany. JAMA. 2020;323:339-351. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 92] [Cited by in F6Publishing: 132] [Article Influence: 33.0] [Reference Citation Analysis (0)] |
6. | Dandona P, Chaudhuri A, Ghanim H. Semaglutide in Early Type 1 Diabetes. N Engl J Med. 2023;389:958-959. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 7] [Cited by in F6Publishing: 8] [Article Influence: 8.0] [Reference Citation Analysis (0)] |
7. | Kuhadiya ND, Prohaska B, Ghanim H, Dandona P. Addition of glucagon-like peptide-1 receptor agonist therapy to insulin in C-peptide-positive patients with type 1 diabetes. Diabetes Obes Metab. 2019;21:1054-1057. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 6] [Cited by in F6Publishing: 11] [Article Influence: 2.2] [Reference Citation Analysis (0)] |
8. | Mathieu C, Zinman B, Hemmingsson JU, Woo V, Colman P, Christiansen E, Linder M, Bode B; Adjunct One Investigators. Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The Adjunct One Treat-To-Target Randomized Trial. Diabetes Care. 2016;39:1702-1710. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 136] [Cited by in F6Publishing: 170] [Article Influence: 21.3] [Reference Citation Analysis (0)] |
9. | Aronson R, Gottlieb PA, Christiansen JS, Donner TW, Bosi E, Bode BW, Pozzilli P; Defend Investigator Group. Low-dose otelixizumab anti-CD3 monoclonal antibody Defend-1 study: results of the randomized phase III study in recent-onset human type 1 diabetes. Diabetes Care. 2014;37:2746-2754. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 91] [Cited by in F6Publishing: 91] [Article Influence: 9.1] [Reference Citation Analysis (0)] |
10. | Keymeulen B, van Maurik A, Inman D, Oliveira J, McLaughlin R, Gittelman RM, Roep BO, Gillard P, Hilbrands R, Gorus F, Mathieu C, Van de Velde U, Wisniacki N, Napolitano A. A randomised, single-blind, placebo-controlled, dose-finding safety and tolerability study of the anti-CD3 monoclonal antibody otelixizumab in new-onset type 1 diabetes. Diabetologia. 2021;64:313-324. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 14] [Cited by in F6Publishing: 23] [Article Influence: 7.7] [Reference Citation Analysis (0)] |
11. | Hagopian W, Ferry RJ Jr, Sherry N, Carlin D, Bonvini E, Johnson S, Stein KE, Koenig S, Daifotis AG, Herold KC, Ludvigsson J; Protégé Trial Investigators. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial. Diabetes. 2013;62:3901-3908. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 152] [Cited by in F6Publishing: 160] [Article Influence: 14.5] [Reference Citation Analysis (0)] |
12. | Herold KC, Gitelman SE, Willi SM, Gottlieb PA, Waldron-Lynch F, Devine L, Sherr J, Rosenthal SM, Adi S, Jalaludin MY, Michels AW, Dziura J, Bluestone JA. Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial. Diabetologia. 2013;56:391-400. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 89] [Cited by in F6Publishing: 98] [Article Influence: 8.9] [Reference Citation Analysis (0)] |
13. | Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, Gitelman SE, Gottlieb PA, Krischer JP, Linsley PS, Marks JB, Moore W, Moran A, Rodriguez H, Russell WE, Schatz D, Skyler JS, Tsalikian E, Wherrett DK, Ziegler AG, Greenbaum CJ; Type 1 Diabetes TrialNet Study Group. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019;381:603-613. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 388] [Cited by in F6Publishing: 556] [Article Influence: 111.2] [Reference Citation Analysis (0)] |
14. | Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Marks JB, Monzavi R, Moran A, Raskin P, Rodriguez H, Russell WE, Schatz D, Wherrett D, Wilson DM, Krischer JP, Skyler JS; Type 1 Diabetes TrialNet Abatacept Study Group. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;378:412-419. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 466] [Cited by in F6Publishing: 415] [Article Influence: 31.9] [Reference Citation Analysis (0)] |
15. | Russell WE, Bundy BN, Anderson MS, Cooney LA, Gitelman SE, Goland RS, Gottlieb PA, Greenbaum CJ, Haller MJ, Krischer JP, Libman IM, Linsley PS, Long SA, Lord SM, Moore DJ, Moore WV, Moran AM, Muir AB, Raskin P, Skyler JS, Wentworth JM, Wherrett DK, Wilson DM, Ziegler AG, Herold KC; Type 1 Diabetes TrialNet Study Group. Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial. Diabetes Care. 2023;46:1005-1013. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 16] [Cited by in F6Publishing: 16] [Article Influence: 16.0] [Reference Citation Analysis (0)] |
16. | Greenbaum CJ. A Key to T1D Prevention: Screening and Monitoring Relatives as Part of Clinical Care. Diabetes. 2021;70:1029-1037. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 13] [Cited by in F6Publishing: 12] [Article Influence: 4.0] [Reference Citation Analysis (0)] |
17. | Schwartz DD, Cline VD, Axelrad ME, Anderson BJ. Feasibility, acceptability, and predictive validity of a psychosocial screening program for children and youth newly diagnosed with type 1 diabetes. Diabetes Care. 2011;34:326-331. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 46] [Cited by in F6Publishing: 44] [Article Influence: 3.4] [Reference Citation Analysis (0)] |
18. | McQueen RB, Geno Rasmussen C, Waugh K, Frohnert BI, Steck AK, Yu L, Baxter J, Rewers M. Cost and Cost-effectiveness of Large-scale Screening for Type 1 Diabetes in Colorado. Diabetes Care. 2020;43:1496-1503. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 32] [Cited by in F6Publishing: 52] [Article Influence: 13.0] [Reference Citation Analysis (0)] |
19. | Sims EK, Besser REJ, Dayan C, Geno Rasmussen C, Greenbaum C, Griffin KJ, Hagopian W, Knip M, Long AE, Martin F, Mathieu C, Rewers M, Steck AK, Wentworth JM, Rich SS, Kordonouri O, Ziegler AG, Herold KC; NIDDK Type 1 Diabetes TrialNet Study Group. Screening for Type 1 Diabetes in the General Population: A Status Report and Perspective. Diabetes. 2022;71:610-623. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 50] [Cited by in F6Publishing: 64] [Article Influence: 32.0] [Reference Citation Analysis (0)] |
20. | Chmiel R, Giannopoulou EZ, Winkler C, Achenbach P, Ziegler AG, Bonifacio E. Progression from single to multiple islet autoantibodies often occurs soon after seroconversion: implications for early screening. Diabetologia. 2015;58:411-413. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in F6Publishing: 20] [Article Influence: 2.2] [Reference Citation Analysis (0)] |
21. | Parikka V, Näntö-Salonen K, Saarinen M, Simell T, Ilonen J, Hyöty H, Veijola R, Knip M, Simell O. Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. Diabetologia. 2012;55:1926-1936. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 161] [Cited by in F6Publishing: 159] [Article Influence: 13.3] [Reference Citation Analysis (0)] |