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  • Review Article
  • Published:

Combination immunotherapies for type 1 diabetes mellitus

Nature Reviews Endocrinology volume 11, pages 289–297 (2015)Cite this article

Subjects

Key Points

  • As several mechanisms lead to β-cell failure in type 1 diabetes mellitus (T1DM), strategies combining different molecules could target different pathways involved in the pathogenesis of T1DM

  • Different combination therapies have been tested in preclinical studies with encouraging results, but results from clinical trials have not matched expectations

  • Heterogeneity in the age of patients with T1DM and the low rate of human β-cell regeneration are possible explanations for the negative results of clinical trials that should be addressed in future studies

  • Proton pump inhibitors and incretin-based agents can stimulate β-cell regeneration, so future trials in patients with T1DM should investigate their potential in combination with immunomodulatory compounds

  • The issue of patient heterogeneity can be addressed by designing trials evaluating the relative effectiveness of interventions in specific subgroups of patients

Abstract

Immunotherapies for type 1 diabetes mellitus (T1DM) have been the focus of intense basic and clinical research over the past few decades. Restoring β-cell function is the ultimate goal of intervention trials that target the immune system in T1DM. In an attempt to achieve this aim, different combination therapies have been proposed over the past few years that are based on treatments tackling the various mechanisms involved in the destruction of β cells. The results of clinical trials have not matched expectations based on the positive results from preclinical studies. The heterogeneity of T1DM might explain the negative results obtained, but previous trials have not addressed this issue. However, novel promising combination therapies are being developed, including those that couple immunomodulators with drugs that stimulate β-cell regeneration in order to restore normoglycaemia. This strategy is an encouraging one to pursue the goal of finding a cure for T1DM. This Review summarizes the available data about combination immunotherapies in T1DM, particularly addressing their clinical importance. The available data supporting the use of registered drugs, such as proton pump inhibitors and incretin-based agents, that have been shown to induce β-cell regeneration will also be discussed.

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Figure 1: DPP-4 inhibitors and PPIs could be combined with immunomodulators to cure type 1 diabetes mellitus.

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Acknowledgements

The authors acknowledge V. Greto, PhD student, for her invaluable help in searching PubMed for data for this Review.

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  1. Department of Endocrinology and Diabetes, University Campus Bio-Medico, Via Álvaro del Portillo 21, Rome, 00128, Italy

    Paolo Pozzilli & Ernesto Maddaloni

  2. Department of Experimental Medicine, “Sapienza” University, Viale Regina Elena 324, Rome, 00161, Italy

    Raffaella Buzzetti

Authors
  1. Paolo Pozzilli
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  2. Ernesto Maddaloni
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  3. Raffaella Buzzetti
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Contributions

P.P. and E.M. researched data and wrote the manuscript. R.B. contributed to the discussion, reviewed and edited the manuscript before submission.

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Correspondence to Paolo Pozzilli.

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Competing interests

P.P. has received honoraria and travel grants from Astra Zeneca, Eli Lilly, Merck Sharp & Dohme, Novartis, Takeda and Sanofi. R.B. has received honoraria from Astra Zeneca, Eli Lilly, Novartis, Novo Nordisk and Sanofi. E.M. declares no competing interests.

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Pozzilli, P., Maddaloni, E. & Buzzetti, R. Combination immunotherapies for type 1 diabetes mellitus. Nat Rev Endocrinol 11, 289–297 (2015). https://doi.org/10.1038/nrendo.2015.8

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