Prevention of Type 1 Diabetes: Past Experiences and Future Opportunities
Abstract
:1. Introduction
2. Primary Prevention
3. Secondary Prevention
4. Tertiary Prevention
5. Discussion
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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DRB1 | DQB1 | DQA1 | Ethnic Backgrounds |
---|---|---|---|
High-risk haplotypes | |||
03:01 | 02:01 | 05:01 | Caucasians, Koreans |
04:01 | 03:02 | 03:01 | Caucasians |
04:02 | 04:02 | 04:01 | Caucasians |
04:05 | 03:02 | 03:01 | Caucasians |
04:01 | 03:03 | 04:05 | Japanese, Koreans |
03:02 | 03:01 | 08:02 | Japanese |
03:03 | 03:00 | 09:01 | Japanese, Koreans |
06:04 | 01:02 | 13:02 | Japanese |
Moderate risk haplotypes | |||
01 | 05:01 | 01:01 | Caucasians |
08:01 | 04:02 | 04:01 | Caucasians |
09:01 | 03:03 | 03:01 | Caucasians |
Study [Ref.] | Inclusion Criteria | Age | Intervention | Follow-Up/Primary Endpoint | Outcome | Status |
---|---|---|---|---|---|---|
TRIGR [14] | Newborns with risk-associated HLA genotypes | 0–7 days | Hydrolyzed infant formula | 10 years/T1D | Failed to delay or prevent the development of T1D | Completed |
FINDIA [15] | Newborns with high-risk HLA | Infants | Insulin-free whey-based formula | 2 years/islet autoantibodies, T1D | Reduced the incidence of autoantibodies by age 3 years | Completed |
BABYDIET [16] | First degree relatives with high-risk HLA | <3 months | Gluten-free diet | 3 years/islet autoantibodies | No evidence of reducing the risk for autoantibodies development | Completed |
NIP [17] | Pregnant mothers and newborns with genetic risk for T1D | >24 weeks gestation/ newborns | Docosahexaenoic acid (DHA) | 2 years/20% higher plasma levels of DHA | No effect on autoimmunity | Completed |
DAISY [18] | First-degree relatives of patients with T1D and newborns with genetic risk | <8 years/ newborns | Vitamin D | 2 years/islet autoantibodies, T1D | Failed to reduce the risk of islet autoantibodies/T1D development | Completed |
Pre-POINT [19] | Individuals with familial risk | 1.5–7 years | Oral insulin | 3–18 months/islet autoantibodies | A high dose of daily oral insulin is safe and appears to change the immune response to insulin. | Completed |
GPPAD-POInT [20] | Children with genetic risk for T1D | 4–7 months | Oral insulin | 7.5 years/islet autoantibodies, T1D | Not yet reported | Ongoing |
Study | Inclusion Criteria | Age | Intervention | Follow-Up/Primary Endpoint | Outcome | Status |
---|---|---|---|---|---|---|
DENIS [29] | First-degree relatives of patients with T1D | 3–12 year | Nicotinamide | 3.8 years/T1D | Failed to delay of T1D development | Completed |
ENDIT [30] | Family members with ICA positive but OGTT negative | <40 year | Nicotinamide | 5 years/T1D | No effect on halting or preventing T1D | Completed |
DPT-1 (first arm) [31] | ICA-positive T1D siblings with decreased first-phase insulin secretion | 3–45 year | Parenteral insulin | 5 years/T1D | The incidence of T1D in the intervention group was virtually the same as in the observation group | Completed |
DPT-1 (second arm) [32] | ICA-positive T1D siblings with normal first-phase insulin secretion | 3–45 year | Oral insulin | 5 years/T1D | Failed to delay or prevent T1D development | Completed |
TrialNet Oral Insulin [33] | Relatives with at least 2 autoantibodies | 1–45 year | Oral insulin | 7–8 years/T1D | No effect on reducing the risk of T1D onset | Completed |
INIT [34] | Individuals with one or more T1D-related autoantibodies | 4–33 year | Nasal insulin | 1 year/T1D | Improved immune tolerance, but no significant effects on beta-cell function | Completed |
INIT-II [35] | Relatives with at least 2 autoantibodies, HLA | 4–30 year | Nasal insulin | 5 years/T1D | Intranasal insulin-induced immune response, but has no effect on the prevention of T1D | Active, not recruiting |
Fr1da Insulin Intervention [36] | General population with at least two islet autoantibodies | 2–12 year | Oral insulin | 1–7 years/T1D | Not yet reported | Ongoing |
DIPP [37] | General population with high-risk genotypes for T1D | Newborn | Nasal insulin | 10 years/T1D | Failed to find an effect of nasal insulin administration on T1D progression | Completed |
DiAPREV-IT [38] | Individuals with multiple islet autoantibodies | 4–18 year | GAD-Alum | 5 years/T1D | Failed to halt the progression of the autoimmune process | Completed |
DiAPREV-IT2 [39] | Individuals with multiple islet autoantibodies | 10–18 year | GAD-Alum and Vitamin D | 5 years/T1D | Not yet reported | Ongoing |
TrialNet Teplizumab [40] | Relatives with at least 2 autoantibodies, with impaired OGTT | 8–45 year | Anti-CD3 (teplizumab) | 4–6 years/T1D | Teplizumab can delay T1D diagnosis a median of 2 years | Completed |
TrialNet Abatacept [41] | Relatives with at least 2 autoantibodies | 6–45 year | Anti–CTLA-4 (abatacept) | 5–6 years/AGT, T1D | Not yet reported | Ongoing |
TrialNet HCQ [42] | Individuals with multiple islet autoantibodies | 3–18 year | HCQ | 5–6 years/AGT, T1D | Not yet reported | Ongoing |
SIMPONI [43] | Individuals with at least 2 autoantibodies, with impaired OGTT | 6–21 year | TNF-a (golimumab) | 5–6years/AEs | Not yet reported | Ongoing |
Study | Time from Diagnosis/ Eligibility | Age | Intervention | Follow-Up/Primary End Point | Outcome | Status |
---|---|---|---|---|---|---|
Silverstein et al. [52] | <2 weeks | 4–32 year | Azathioprine and Prednisone | 2.5 years/MMTT C-peptide | Short-lived remission in the treatment group | Completed |
Bougneres et al. [53] | Newly diagnosed | 7–15 year | Cyclosporine A | 2 years/glucagon stimulation test C-peptide | Cyclosporin A transiently maintained a residual insulin secretion | Completed |
Keymeulen et al. [54,55] | <4 weeks/> C-peptide 0.2 pmol/mL | 12–39 year | Anti-CD3 (otelixizumab) | 48 months/glucagon stimulation test C-peptide | Anti-CD3 maintained a residual beta-cell function | Completed |
DEFEND-1 and -2 [56] | ≤12 weeks/C-peptide 0.2–3.5 pmol/mL | 12–45 year | Anti-CD3 (otelixizumab) | 1 year/MMTT C-peptide | No preservation of beta-cell function | Completed |
Protégé study [57] | ≤12 weeks/C-peptide detectable | 8–35 year | Anti-CD3 (teplizumab) | 2 years/insulin dose + HbA1c MMTT C-peptide | Improved C-peptide responses in the 14-day high dose subgroup | Completed |
AbATE [58] | <8 weeks | 8–30 year | Anti-CD3 (teplizumab) | 2 years/MMTT C-peptide | Lower insulin requirement in the treatment group | Completed |
Orban et al. [59] | <14 weeks/> C-peptide 0.2 pmol/mL | 6–36 year | CTLA4-Ig (abatacept) | 2 years/MMTT C-peptide | Abatacept slowed the decline of beta-cell function over two years. | Completed |
TIDAL [60] | <14 weeks/> C-peptide 0.2 pmol/mL * | 12–35 year | Alafacept | 2 years/MMTT C-peptide | C-peptide in the treatment group was significantly higher compared to placebo | Completed |
TrialNet Rituximab [61] | ≤12 weeks/C-peptide 0.2 pmol/mL * | 8–45 year | Anti-CD20 (rituximab) | 2 years/MMTT C-peptide | C-peptide levels were significantly higher in the rituximab versus the placebo group | Completed |
START [62,63] | 6 weeks/C-peptide * 0.4 pmol/mL | 12–35 year | ATG | 2 years/MMTT C-peptide | Failed to show that ATG preserves beta-cell function in new-onset T1D | Completed |
TrialNet ATG-GCSF [64,65] | <14 weeks/C-peptide 0.2 pmol/mL * | 12–45 year | ATG/GCSF or ATG alone | 2 year/MMTT C-peptide | Low-dose ATG preserved beta-cell function and improved insulin production | Completed |
Ludvigsson et al. [66] | <12 weeks/C-peptide 0.1 pmol/mL, GAD autoantibody positive | 10–20 year | rhGAD65-alum | 15 months/MMTT C-peptide | No difference in C-peptide concentrations or insulin requirements | Completed |
TrialNet GAD Study [67] | <12 weeks/C-peptide 0.2 pmol/mL, GAD autoantibody positive | 3–45 year | rhGAD65-alum | 2 years/MMTT C-peptide | No change in the course of loss of insulin secretion | Completed |
Marek-Trzonkowska et al. [68] | <8 weeks/C-peptide 0.1 pmol/mL | 5–18 year | Infusion of ex vivo expanded Tregs | 2 years/MMTT C-peptide | An increase in Tregs number in peripheral blood and c-peptide levels | Completed |
Bluestone et al. [69] | >3 weeks and <24 months/C-peptide 0.1 pmol/mL * | 18–45 year | Infusion of expanded polyclonal Tregs | 2.5 years/MMTT C-peptide | C-peptide levels persisted out to 2+ years after transfer in several individuals | Completed |
Hartemann et al. [70] | ≤ 2 years | 18–50 year | Aldesleukin (IL-2) | Kinetic parameters of Treg proportions variation within CD4+ T cells in peripheral blood | IL-2 induced a dose-dependent increase in the proportion of Treg cells | Completed |
ITAD [71] | <6 weeks/C-peptide 0.2 pmol/mL | 6–18 year | Aldesleukin (IL-2) | Differences in C-peptide over the 6 month-treatment periods between the active and placebo groups | Not yet available | Recruiting |
Gottlieb et al. [72] | ≤12 weeks/C-peptide 0.2 pmol/mL * | 8–45 year | Mycophenolate mofetil alone or plus daclizumab | 2 years/MMTT C-peptide | No effect on residual beta-cell function | Completed |
DiViDInt [73] | <3 weeks | 6–15 year | Pleconaril and ribavirin | 3 years/MMTT C-peptide | Not yet available | Ongoing |
REPAIR-T1D [74] | <6 months | 11–36 year | Sitagliptin plus lansoprazole | 1 year/MMTT C-peptide | No effect on residual beta-cell function | Completed |
DPP-IV LADA [75] | <3 years/diagnosed with LADA | 25–70 year | Sitagliptin | 2 years/MMTT C-peptide | Beneficial effect on beta-cell function | Completed |
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Beik, P.; Ciesielska, M.; Kucza, M.; Kurczewska, A.; Kuźmińska, J.; Maćkowiak, B.; Niechciał, E. Prevention of Type 1 Diabetes: Past Experiences and Future Opportunities. J. Clin. Med. 2020, 9, 2805. https://doi.org/10.3390/jcm9092805
Beik P, Ciesielska M, Kucza M, Kurczewska A, Kuźmińska J, Maćkowiak B, Niechciał E. Prevention of Type 1 Diabetes: Past Experiences and Future Opportunities. Journal of Clinical Medicine. 2020; 9(9):2805. https://doi.org/10.3390/jcm9092805
Chicago/Turabian StyleBeik, Przemysław, Martyna Ciesielska, Maria Kucza, Alicja Kurczewska, Joanna Kuźmińska, Bartosz Maćkowiak, and Elżbieta Niechciał. 2020. "Prevention of Type 1 Diabetes: Past Experiences and Future Opportunities" Journal of Clinical Medicine 9, no. 9: 2805. https://doi.org/10.3390/jcm9092805