Skip to main content

Advertisement

SpringerLink
Log in

Antigen-based immunotherapies do not prevent progression of recent-onset autoimmune diabetes: a systematic review and meta-analysis

  • Meta-Analysis
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

We performed a systematic review and meta-analysis to assess the efficacy and safety of antigen-based immunotherapies in tertiary prevention of autoimmune diabetes. We searched for randomised controlled trials testing antigen-based immunotherapies in patients with recent-onset type 1 diabetes or latent autoimmune diabetes of adults in MEDLINE, COCHRANE and EMBASE databases, trial registries, conference proceedings and reference lists of pertinent records. Primary outcomes were fasting and stimulated C-peptide (after glucagon or mixed meal stimulation). Change in glycosylated haemoglobin (HbA1c), daily insulin needs and incidence of any or severe hypoglycaemic events or severe adverse events were secondary outcomes. Fifteen studies were included in the meta-analysis. Overall, there was no difference in fasting [weighted mean difference (WMD) 0.01 nmol/L; 95 % confidence interval (CI) −0.09, 0.11; I 2 = 73 %] or mixed meal stimulated C-peptide (WMD 0.02 nmol/L/min; 95 % CI −0.08, 0.12; I 2 = 50 %) compared with placebo. Glucagon stimulated C-peptide was maintained higher (WMD 0.13 nmol/L/min; 95 % CI 0.05, 0.21; I 2 = 0 %) in patients treated with Diapep277. Moreover, there was no change in daily insulin needs (WMD 0.02 IU/kg; 95 % CI −0.04, 0.09; I 2 = 51 %) or HbA1c (WMD −0.06 %; 95 % CI −0.35, 0.23; I 2 = 42 %) vs. placebo. Finally, there was no effect on the incidence of severe hypoglycaemic events or overall serious adverse events [risk ratio 0.94, 95 % CI 0.62, 1.41; I 2 = 0 % and 0.87; 95 % CI 0.53, 1.44; I 2 = 0 %, respectively). Antigen-based immunotherapies are not effective in preventing the progression of autoimmune diabetes in newly diagnosed patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. B. Brooks-Worrell, J.P. Palmer, Prevention versus intervention of type 1 diabetes. Clin. Immunol. 149(3), 332–338 (2013)

    Article  CAS  PubMed  Google Scholar 

  2. M. Rewers, P. Gottlieb, Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future. Diabetes Care 32(10), 1769–1782 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. S. Robert, H. Korf, C. Gysemans, C. Mathieu, Antigen-based vs. systemic immunomodulation in type 1 diabetes: the pros and cons. Islets 5(2), 53–66 (2013)

    Article  PubMed  PubMed Central  Google Scholar 

  4. L. Chaillous, H. Lefevre, C. Thivolet, C. Boitard, N. Lahlou, C. Atlan-Gepner, B. Bouhanick, A. Mogenet, M. Nicolino, J.C. Carel, P. Lecomte, R. Marechaud, P. Bougneres, B. Charbonnel, P. Sai, Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Lancet 356(9229), 545–549 (2000)

    Article  CAS  PubMed  Google Scholar 

  5. P. Pozzilli, D. Pitocco, N. Visalli, M.G. Cavallo, R. Buzzetti, A. Crino, S. Spera, C. Suraci, G. Multari, M. Cervoni, M.L. Manca Bitti, M.C. Matteoli, G. Marietti, F. Ferrazzoli, M.R. Cassone Faldetta, C. Giordano, M. Sbriglia, E. Sarugeri, G. Ghirlanda, No effect of oral insulin on residual beta-cell function in recent-onset type I diabetes (the IMDIAB VII). IMDIAB Group. Diabetologia 43(8), 1000–1004 (2000)

    Article  CAS  PubMed  Google Scholar 

  6. C.D. Agardh, C.M. Cilio, A. Lethagen, K. Lynch, R.D. Leslie, M. Palmer, R.A. Harris, J.A. Robertson, A. Lernmark, Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes. J. Diabetes Complications 19(4), 238–246 (2005)

    Article  PubMed  Google Scholar 

  7. S. Fourlanos, C. Perry, S.A. Gellert, E. Martinuzzi, R. Mallone, J. Butler, P.G. Colman, L.C. Harrison, Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. Diabetes 60(4), 1237–1245 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. T. Orban, K. Farkas, H. Jalahej, J. Kis, A. Treszl, B. Falk, H. Reijonen, J. Wolfsdorf, A. Ricker, J.B. Matthews, N. Tchao, P. Sayre, P. Bianchine, Autoantigen-specific regulatory T cells induced in patients with type 1 diabetes mellitus by insulin B-chain immunotherapy. J. Autoimmun. 34(4), 408–415 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. I. Raz, D. Elias, A. Avron, M. Tamir, M. Metzger, I.R. Cohen, Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet 358(9295), 1749–1753 (2001)

    Article  CAS  PubMed  Google Scholar 

  10. J.P. Palmer, G.A. Fleming, C.J. Greenbaum, K.C. Herold, L.D. Jansa, H. Kolb, J.M. Lachin, K.S. Polonsky, P. Pozzilli, J.S. Skyler, M.W. Steffes, C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes 53(1), 250–264 (2004)

    Article  CAS  PubMed  Google Scholar 

  11. U.S. Department of Health and Human Services Food and Drug Administration (2008) Guidance for Industry Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention. in., pp. 16–17

  12. JPT Higgins, S. Green (ed.). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.handbook.cochrane.org. Accessed 4 July 2016

  13. Type 1 Diabetes TrialNet Protocol Development Guidelines. in: TrialNet, T.D. (ed.). p. 8. (2011). https://www.diabetestrialnet.org/documents/protocol-dev-guiderev7-27-Secure.pdf. Accessed 4 July 2016

  14. C.J. Greenbaum, T. Mandrup-Poulsen, P.F. McGee, T. Battelino, B. Haastert, J. Ludvigsson, P. Pozzilli, J.M. Lachin, H. Kolb, Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care 31(10), 1966–1971 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  15. J. Higgins, S. Green, in: Cochrane Handbook for Systematic Reviews of Interventions, (2008), pp. 485-488

  16. S.P. Hozo, B. Djulbegovic, I. Hozo, Estimating the mean and variance from the median, range, and the size of a sample. BMC Med. Res. Methodol. 5, 13 (2005)

    Article  PubMed  PubMed Central  Google Scholar 

  17. J. Higgins, S. Green, in: Cochrane Handbook for Systematic Reviews of Interventions, (2008), pp. 553-555

  18. J. Higgins, S. Green, in: Cochrane Handbook for Systematic Reviews of Interventions, (2008), pp. 264-265

  19. J. Higgins, S. Green, in: Cochrane Handbook for Systematic Reviews of Interventions, (2008), p. 266

  20. T. Trikalinos, OpenMeta[Analyst]. Brown School of Public Health, http://www.cebm.brown.edu/openmeta/download.html. Accessed 4 July 2016

  21. J.P. Higgins, D.G. Altman, P.C. Gotzsche, P. Juni, D. Moher, A.D. Oxman, J. Savovic, K.F. Schulz, L. Weeks, J.A. Sterne; Cochrane Bias Methods, G., Cochrane Statistical Methods, G., The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343, d5928 (2011)

    Article  PubMed  PubMed Central  Google Scholar 

  22. G. Guyatt, A.D. Oxman, E.A. Akl, R. Kunz, G. Vist, J. Brozek, S. Norris, Y. Falck-Ytter, P. Glasziou, H. DeBeer, R. Jaeschke, D. Rind, J. Meerpohl, P. Dahm, H.J. Schunemann, GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J. Clin. Epidemiol. 64(4), 383–394 (2011)

    Article  PubMed  Google Scholar 

  23. B. Ergun-Longmire, J. Marker, A. Zeidler, R. Rapaport, P. Raskin, B. Bode, D. Schatz, A. Vargas, D. Rogers, S. Schwartz, J. Malone, J. Krischer, N.K. Maclaren, Oral insulin therapy to prevent progression of immune-mediated (type 1) diabetes. Ann. N. Y. Acad. Sci. (2004). doi:10.1196/annals.1309.057

  24. D.G. Alleva, R.A. Maki, A.L. Putnam, J.M. Robinson, M.S. Kipnes, P. Dandona, J.B. Marks, D.L. Simmons, C.J. Greenbaum, R.G. Jimenez, P.J. Conlon, P.A. Gottlieb, Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B epitope. Scand. J. Immunol. 63(1), 59–69 (2006)

    Article  CAS  PubMed  Google Scholar 

  25. V.A. Huurman, K. Decochez, C. Mathieu, I.R. Cohen, B.O. Roep, Therapy with the hsp60 peptide DiaPep277 in C-peptide positive type 1 diabetes patients. Diabetes Metab. Res. Rev. 23(4), 269–275 (2007)

    Article  CAS  PubMed  Google Scholar 

  26. L. Lazar, R. Ofan, N. Weintrob, A. Avron, M. Tamir, D. Elias, M. Phillip, Z. Josefsberg, Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: a randomised, double-blind phase II study. Diabetes Metab. Res. Rev. 23(4), 286–291 (2007)

    Article  CAS  PubMed  Google Scholar 

  27. N.C. Schloot, G. Meierhoff, C. Lengyel, G. Vándorfi, J. Takács, P. Pánczél, L. Barkai, L. Madácsy, T. Oroszlán, P. Kovács, G. Sütö, T. Battelino, N. Hosszufalusi, G. Jermendy, Effect of heat shock protein peptide DiaPep277 on beta-cell function in paediatric and adult patients with recent-onset diabetes mellitus type 1: two prospective, randomized, double-blind phase II trials. Diabetes Metab. Res. Rev. 23(4), 276–285 (2007)

    Article  CAS  PubMed  Google Scholar 

  28. J. Ludvigsson, M. Faresjö, M. Hjorth, S. Axelsson, M. Chéramy, M. Pihl, O. Vaarala, G. Forsander, S. Ivarsson, C. Johansson, A. Lindh, N.O. Nilsson, J. Aman, E. Ortqvist, P. Zerhouni, R. Casas, GAD treatment and insulin secretion in recent-onset type 1 diabetes. N. Engl. J. Med. (2008). doi:10.1056/NEJMoa0804328

  29. M. Walter, A. Philotheou, F. Bonnici, A.G. Ziegler, R. Jimenez, No effect of the altered peptide ligand NBI-6024 on beta-cell residual function and insulin needs in new-onset type 1 diabetes. Diabetes Care 32(11), 2036–2040 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. D.K. Wherrett, B. Bundy, D.J. Becker, L.A. DiMeglio, S.E. Gitelman, R. Goland, P.A. Gottlieb, C.J. Greenbaum, K.C. Herold, J.B. Marks, R. Monzavi, A. Moran, T. Orban, J.P. Palmer, P. Raskin, H. Rodriguez, D. Schatz, D.M. Wilson, J.P. Krischer, J.S. Skyler, Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 378(9788), 319–327 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. J. Ludvigsson, D. Krisky, R. Casas, T. Battelino, L. Castano, J. Greening, O. Kordonouri, T. Otonkoski, P. Pozzilli, J.J. Robert, H.J. Veeze, J. Palmer, U. Samuelsson, H. Elding Larsson, J. Aman, G. Kardell, J. Neiderud Helsingborg, G. Lundstrom, E. Albinsson, A. Carlsson, M. Nordvall, H. Fors, C.G. Arvidsson, S. Edvardson, R. Hanas, K. Larsson, B. Rathsman, H. Forsgren, H. Desaix, G. Forsander, N.O. Nilsson, C.G. Akesson, P. Keskinen, R. Veijola, T. Talvitie, K. Raile, T. Kapellen, W. Burger, A. Neu, I. Engelsberger, B. Heidtmann, S. Bechtold, D. Leslie, F. Chiarelli, A. Cicognani, G. Chiumello, F. Cerutti, G.V. Zuccotti, A. Gomez Gila, I. Rica, R. Barrio, M. Clemente, M.J. Lopez Garcia, M. Rodriguez, I. Gonzalez, J.P. Lopez, M. Oyarzabal, H.M. Reeser, R. Nuboer, P. Stouthart, N. Bratina, N. Bratanic, M. de Kerdanet, J. Weill, N. Ser, P. Barat, A.M. Bertrand, J.C. Carel, R. Reynaud, R. Coutant, S. Baron, GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N. Engl. J. Med. 366(5), 433–442 (2012)

    Article  CAS  PubMed  Google Scholar 

  32. I. Raz, A.G. Ziegler, T. Linn, G. Schernthaner, F. Bonnici, L.A. Distiller, C. Giordano, F. Giorgino, L. de Vries, D. Mauricio, V. Prochazka, J. Wainstein, D. Elias, A. Avron, M. Tamir, R. Eren, D. Peled, S. Dagan, I.R. Cohen, P. Pozzilli, Treatment of recent-onset type 1 diabetic patients with DiaPep277: results of a double-blind, placebo-controlled, randomized phase 3 trial. Diabetes Care 37(5), 1392–1400 (2014)

    Article  CAS  PubMed  Google Scholar 

  33. J. Ludvigsson, M. Hjorth, M. Cheramy, S. Axelsson, M. Pihl, G. Forsander, N.O. Nilsson, B.O. Samuelsson, T. Wood, J. Aman, E. Ortqvist, R. Casas, Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial. Diabetologia 54(3), 634–640 (2011)

    Article  CAS  PubMed  Google Scholar 

  34. DIAPREVENT - A Phase III Study to Investigate the Impact of Diamyd in Patients Newly Diagnosed With Type 1 Diabetes (USA). https://clinicaltrials.gov/ct2/show/study/NCT00751842?term=NCT00751842&rank=1. Accessed 17 March 2016

  35. DIABGAD - Trial to Preserve Insulin Secretion in Type 1 Diabetes Using GAD-Alum (Diamyd) in Combination With Vitamin D and Ibuprofen. https://clinicaltrials.gov/ct2/show/NCT01785108?term=NCT01785108&rank=1. Accessed 17 March 2016

  36. Diabetes Virus Detection Project, Intervention With GAD-alum (DiViD). https://clinicaltrials.gov/ct2/show/NCT01129232?term=NCT01129232&rank=1. Accessed 17 March 2016

  37. Safety, Tolerability, Immunological and Clinical Efficacy of Multiple Subcutaneous Doses of DiaPep277 in Latent Autoimmune Diabetes in Adults (LADA). https://clinicaltrials.gov/ct2/show/NCT00058981?term=NCT00058981&rank=1. Accessed 17 March 2016

  38. Efficacy and Safety Study of DiaPep277 in Newly Diagnosed Type 1 Diabetes Adults (DIA-AID2). https://clinicaltrials.gov/ct2/show/NCT01103284?term=NCT01103284&rank=1. Accessed 17 March 2016

  39. C.D. Agardh, K. Lynch, J.A. Robertson, Safety of GAD65 Immunomodulation. During One Year Follow-Up in GAD65 Autoantibody Positive Type 2 Diabetes Patients. Diabetes 56. Suppl. 1, 1240-P. (2007)

  40. C.D. Agardh, K.F. Lynch, M. Palmer, K. Link, A. Lernmark, GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes. Diabetologia 52(7), 1363–1368 (2009)

    Article  CAS  PubMed  Google Scholar 

  41. D. Elias, A. Avron, M. Tamir, I. Raz, DiaPep277 preserves endogenous insulin production by immunomodulation in type 1 diabetes. Ann. N. Y. Acad. Sci. 1079, 340–344 (2006)

    Article  CAS  PubMed  Google Scholar 

  42. I. Raz, A.G. Ziegler, T. Linn, G. Schernthaner, F. Bonnici, L.A. Distiller, C. Giordano, F. Giorgino, L. de Vries, D. Mauricio, V. Prochazka, J. Wainstein, D. Elias, A. Avron, M. Tamir, R. Eren, D. Peled, S. Dagan, I.R. Cohen, P. Pozzilli, Treatment of recent-onset type 1 diabetic patients with DiaPep277: results of a double-blind, placebo-controlled, randomized phase 3 trial. Diabetes Care 37, 1392–1400 (2014). doi:10.2337/dc13-1391 Diabetes Care 38(1), 178 (2015)

    Article  CAS  PubMed  Google Scholar 

  43. G.Y. Gandhi, M.H. Murad, D.N. Flynn, M.B. Elamin, P.J. Erwin, V.M. Montori, Y.C. Kudva, Immunotherapeutic agents in type 1 diabetes: a systematic review and meta-analysis of randomized trials. Clin. Endocrinol. 69(2), 244–252 (2008)

    Article  CAS  Google Scholar 

  44. J. Ludvigsson, M. Cheramy, S. Axelsson, M. Pihl, L. Akerman, R. Casas, GAD-treatment of children and adolescents with recent-onset type 1 diabetes preserves residual insulin secretion after 30 months. Diabetes Metab. Res. Rev. 30(5), 405–414 (2014)

    Article  CAS  PubMed  Google Scholar 

  45. M. Cokol, F. Ozbay, R. Rodriguez-Esteban, Retraction rates are on the rise. EMBO Rep. 9(1), 2 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. F.C. Fang, R.G. Steen, A. Casadevall, Misconduct accounts for the majority of retracted scientific publications. Proc. Natl. Acad. Sci. USA 109(42), 17028–17033 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. R.G. Steen, Retractions in the medical literature: how can patients be protected from risk? J. Med. Ethics 38(4), 228–232 (2012)

    Article  PubMed  Google Scholar 

  48. P. Perel, I. Roberts, Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst. Rev. Cd000567 (2011)

  49. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. in: CHMP (ed.). European Medicines Agency (2012). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf. Accessed 4 July 2016

  50. C.A. Beam, S.E. Gitelman, J.P. Palmer, Recommendations for the definition of clinical responder in insulin preservation studies. Diabetes 63(9), 3120–3127 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

CR and AT conceived the study. CR, AGT and AT designed the study. CR and EB searched the scientific literature. CR and MR did data extraction. CR and MS did risk of bias assessment and grading of recommendations. CR and AL conducted the statistical analysis and ABH contributed to the analysis. CR, AL and AT drafted the paper. EB, MR and AGT contributed to the interpretation of the findings. All authors edited and approved the final version of the manuscript to be published. AT had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Author information

Authors and Affiliations

  1. Clinical Research and Evidence-Based Medicine Unit, Aristotle University Thessaloniki, Thessaloniki, Greece

    Chrysoula Rizava, Eleni Bekiari, Aris Liakos, Maria Sarigianni & Apostolos Tsapas

  2. Diabetes Centre, Second Medical Department, Aristotle University Thessaloniki, Thessaloniki, Greece

    Eleni Bekiari, Maria Rika & Apostolos Tsapas

  3. Department of Hygiene and Epidemiology, School of Health Sciences, Department of Medicine, Aristotle University Thessaloniki, Thessaloniki, 54124, Greece

    Anna Bettina Haidich

  4. Fourth Paediatric Department, Aristotle University Thessaloniki, Thessaloniki, Greece

    Asimina Galli-Tsinopoulou

  5. Harris Manchester College, University of Oxford, Oxford, UK

    Apostolos Tsapas

Authors
  1. Chrysoula Rizava
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eleni Bekiari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aris Liakos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Sarigianni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Rika
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anna Bettina Haidich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Asimina Galli-Tsinopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Apostolos Tsapas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Apostolos Tsapas.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rizava, C., Bekiari, E., Liakos, A. et al. Antigen-based immunotherapies do not prevent progression of recent-onset autoimmune diabetes: a systematic review and meta-analysis. Endocrine 54, 620–633 (2016). https://doi.org/10.1007/s12020-016-1033-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-016-1033-3

Keywords

Search

Navigation