Achieving Remission of Type 1 Diabetes Advances

Early introduction of a specialized antibody agent may preserve β-cell function to sufficiently improve HbA1c in new-onset type 1 diabetes.

With Michael Haller, MD, and Lauren Golden, MD

Until recently, nearly all attempts to stop the chronic autoimmune process underlying type 1 diabetes (T1D) have focused on monotherapy with immunosuppressive or immunomodulatory agents. 

While several of these agents that target T and B lymphocytes produced promising results,1,2 they have not afforded success over the long-term towards preserving pancreatic beta cell function (as measured by C-peptide) and reducing Hemoglobin (Hb) A1c. This has led the T1D TrialNet study group to postulate whether combination therapy including an immunosuppressive agent might provide synergy to preserve residual beta cell function.3

Use of a specialized antibody appears to preserve beta cell function in T1D.

Anti-thymocyte globulin (ATG) is a specialized antibody against human T cells used to treat aplastic anemia, in the treatment of graft-versus-host disease in patients having a stem cell transplant, and in the prevention and treatment of acute rejection in organ transplantation. Similarly, type 1 diabetes represents a T-cell mediated process in which the beta cells are destroyed.

Seeking Evidence of Beta Cell Preservation 

An early 12-month phase 2 clinical trial was initiated to assess whether ATG (6.5 mg/kg) might be efficacious in reducing this autoimmune response.4 Individuals with recent-onset T1D were randomized to ATG (n=38) or placebo (n=20) but after 12 months, ATG did not demonstrate favorable action in the preservation of beta-cell function. Also, there was no significant difference in C-peptide levels between the two groups.

Nearly all of the participants receiving ATG had both cytokine release syndrome and serum sickness, which when combined with lack of efficacy, led the investigators to conclude this approach was an ineffective treatment for type 1 diabetes.4

More recently, investigators focused on low-dose ATG (2.5 mg/kg),3 based on results from prior studies suggesting that low-dose ATG combined with pegylated granulocyte colony-stimulating factor (G-CSF) preserved C-peptide in patients with established T1D.4,5

In the original randomized, placebo-controlled trial evaluated a combined low-dose ATG (2.5 mg/kg) with pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) in patients diagnosed with T1D within the previous 4 months to 2 years.4

“This study found that low-dose ATG, with or without G-CSF, did not alter insulin requirements significantly,” lead author Michael Haller, MD, MS-CI, professor and chief of pediatric endocrinology at the University of Florida at Gainesville, told EndocrineWeb.

Results of this study offered favorable indications that a combination preserved C-peptide in subjects treated with these dual agents resulted in a relative increase of circulating regulatory T cells (Treg).4 While this initial study was placebo-controlled, there was no arm with patients receiving low-dose ATG monotherapy; an acknowledged limitation.

Drawing Closer to Remission in Type 1 Diabetes

Undeterred, the study team design a three-arm, randomized, double-masked, placebo-controlled multicenter trial involving 89 patients (12-45 years) with new-onset T1D (diagnosed within the prior 100 days).3 All participants had at least one T1D-related autoantibody.

Patients randomized to the first group received low-dose ATG with GCSF (ATG/GCSF); those randomized to the second arm received low-dose ATG monotherapy (ATG/placebo [PBO]), and participants randomized to the third arm received only placebo (PBO/PBO).3 All participants also received intensive diabetes management aimed to achieve recommended intensive glycemic control. There were no significant differences in clinical or demographic variables between the treatment groups.

At one year, subjects who received low-dose ATG had higher levels of C-peptide versus those receiving placebo (P = 0.0003), indicating preservation of insulin production. According to the authors, the C-peptide levels were not significantly different among participants who received the combination of ATG + GCSF versus placebo (P = 0.031, with statistical significance set at P < 0.025). In contrast, HbA1c was significantly lower at the 12-month mark in both groups of participants who received low-dose ATG versus placebo.

According to Dr. Haller, it is possible that in time, individuals whose screening tests indicate multiple antibodies that put them at risk of T1D may be treated to prevent or at least delay the initiation or progression of their type 1 diabetes.

Preserving Beta Cell Function in T1D Appears Feasible   

Lauren Golden, MD, director of the Center for Diabetes & Metabolic Health at NYU Langone Health in New York City, told EndocrineWeb, this is an “interesting next step in the quest to identify therapies that may slow insulin loss and preserve beta-cell function in people with new-onset T1D.” Dr. Golden who was not involved in the study agreed to review the findings at our request.

She noted that earlier clinical studies using GCSF or higher dose ATG as monotherapy failed to show preservation of c-peptide; yet, this study examined whether lower dose-ATG monotherapy or combination therapy with these agents might be effective.

“Taken together,” she said, “these data suggest that treatment with low-dose ATG early after the diagnosis of type 1 diabetes may support the preservation of insulin production. The addition of GCSF did not appear to add further therapeutic benefit in terms of insulin production but added some adverse side effects.”

Both Drs. Haller and Golden noted that although low-dose ATG might be something to consider in some patients with newly-diagnosed T1D, it is premature to consider integrating it into current clinical care, and additional studies are needed before low-dose ATG can be considered as a preventive therapeutic intervention for those at risk. Additional research is needed before this type of immunotherapy may be applicable to all patients.

While these side effects are manageable, Dr. Golden said, “future studies would need to demonstrate efficacy in prevention of T1D before exposing asymptomatic/healthy people with stage 1 diabetes to this therapy.”

Dr. Haller noted that 2-year data will be out soon, and hopefully will help inform a better understanding of the role of low-dose ATG in new-onset T1D. In conclusion, he reiterated (1) the importance of supporting clinical trials and (2) the importance of screening all family members to potentially prevent/delay the onset of type 1 diabetes.

There were no reported conficts of interest with regard to this article.

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