Combined Etanercept, GAD‐alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes

Ludvigsson, Johnny; Routray, Indusmita; Vigård, Tore; Hanås, Ragnar; Rathsman, Björn; Carlsson, Anders; Särnblad, Stefan; Albin, Anna Karin; Arvidsson, Carl Göran; Samuelsson, Ulf; Casas, Rosaura

doi:10.1002/dmrr.3440

Cited by 11 publications

(11 citation statements)

References 48 publications

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“…Approximately 70–95% of β-cells are usually lost at the onset of symptoms, resulting in a reduced pancreas size, although in some individuals a 40% reduction is adequate to elicit symptoms [ 2 , 16 , 27 ]. Efforts to preserve any residual β-cell function (measured by C-peptide production) using immune intervention therapies have had limited success [ 28 , 29 , 30 , 31 , 32 ]. Notably, only 15% of children displaying single IA positivity progress to T1D [ 33 ], and conversely, only 10% of individuals with T1D display single IA positivity [ 16 ].…”

Section: Islet Autoimmunitymentioning

confidence: 99%

Viruses and Type 1 Diabetes: From Enteroviruses to the Virome

et al. 2021

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For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in individuals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, as well as mechanistic studies of virus-infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here, we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses and summarise current unbiased efforts aimed at characterising the complete population of viruses (the “virome”) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.

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Section: Islet Autoimmunitymentioning

confidence: 99%

Viruses and Type 1 Diabetes: From Enteroviruses to the Virome

et al. 2021

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“…An open-label observational study of calciferol 2000 IU/d plus etanercept weekly during the first 3 months plus GAD-alum injections on days 30 and 60 was carried out in 20 T1D patients aged 12 years [63]. Pitocco et al conducted an open-label RCT of 70 newly diagnosed people who were given 0.25 µg 2nd-daily of 1,25D versus 25 mg/kg nicotinamide.…”

Section: Therapeutic Trials (Table 2)mentioning

confidence: 99%

Vitamin D and Beta Cells in Type 1 Diabetes: A Systematic Review

Sharma

Girgis

et al. 2022

IJMS

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The prevalence of type 1 diabetes (T1D) is rising steadily. A potential contributor to the rise is vitamin D. In this systematic review, we examined the literature around vitamin D and T1D. We identified 22 papers examining the role of vitamin D in cultured β-cell lines, islets, or perfused pancreas, and 28 papers examining vitamin D in humans or human islets. The literature reports strong associations between T1D and low circulating vitamin D. There is also high-level (systematic reviews, meta-analyses) evidence that adequate vitamin D status in early life reduces T1D risk. Several animal studies, particularly in NOD mice, show harm from D-deficiency and benefit in most studies from vitamin D treatment/supplementation. Short-term streptozotocin studies show a β-cell survival effect with supplementation. Human studies report associations between VDR polymorphisms and T1D risk and β-cell function, as assessed by C-peptide. In view of those outcomes, the variable results in human trials are generally disappointing. Most studies using 1,25D, the active form of vitamin D were ineffective. Similarly, studies using other forms of vitamin D were predominantly ineffective. However, it is interesting to note that all but one of the studies testing 25D reported benefit. Together, this suggests that maintenance of optimal circulating 25D levels may reduce the risk of T1D and that it may have potential for benefits in delaying the development of absolute or near-absolute C-peptide deficiency. Given the near-complete loss of β-cells by the time of clinical diagnosis, vitamin D is much less likely to be useful after disease-onset. However, given the very low toxicity of 25D, and the known benefits of preservation of C-peptide positivity for long-term complications risk, we recommend considering daily cholecalciferol supplementation in people with T1D and people at high risk of T1D, especially if they have vitamin D insufficiency.

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“…As this design show no benefit, we continued with the same design regarding 20 μg GAD-alum, given subcutaneously two times with 1-month interval parallel to oral vitamin D 2000 U/day but instead of Ibuprofen, we added TNF-alfa inhibition with Etanercept [77].…”

Section: Reviewmentioning

confidence: 99%

Glutamic acid decarboxylase immunotherapy for type 1 diabetes

Ludvigsson

2022

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of reviewTo describe recent development of an autoantigen (GAD) treatment towards well tolerated and efficacious precision medicine in type 1 diabetes. Recent findingsAlthough subcutaneous GAD-alum treatment failed to reach primary endpoint in a phase III trial, metanalyses showed a 97% probability of efficacy, and clear efficacy in patients carrying Hyman Leucoycte Antigen (HLA) DR3DQ2. Efforts have been made to improve efficacy by trying combination therapies with vitamin D þ Ibuprofen resp vitamin D þ Etanercept (TNF-a inhibition), without any breakthrough until the administration of GAD-alum was changed from subcutaneous to intralymphatic. With a very small dose of GAD-alum (4 mg) given into an inguinal lymph three times with 1 month interval, the efficacy in patients with HLADR3DQ2 has been impressive, with significantly better beta cell preservation than patients who got placebo in a double-blind randomized trial, and clinical efficacy with more patients in partial remission (IDAA1c < 9) and larger proportion of patients with CGM-measured blood glucose Time In Range (TIR), significantly correlated to the C-peptide values. The treatment has been easy for patients and healthcare without treatment-related risk or adverse events.

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Combined Etanercept, GAD‐alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes

Cited by 11 publications

References 48 publications

Viruses and Type 1 Diabetes: From Enteroviruses to the Virome

Viruses and Type 1 Diabetes: From Enteroviruses to the Virome

Vitamin D and Beta Cells in Type 1 Diabetes: A Systematic Review

Glutamic acid decarboxylase immunotherapy for type 1 diabetes

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