Pro‐inflammatory cytokine‐based treatments have proven to be safe and effective for treatment of various autoimmune diseases. Thus, inhibition of expression of those molecules can induce important changes in pancreatic β‐cells induce important changes in pancreatic β‐cells [51].
The aim of using the Anti‐Interleukin‐1 in newly diagnosed T1D subjects is to test the feasibility, safety/tolerability and potential efficacy of anti‐IL‐1 therapy in maintaining or enhancing β‐cell function in people with new onset T1D. Anti‐IL‐1 administration for rheumatoid arthritis has been proven to be well tolerated in patients [52, 53]. IL‐1 is also involved in T1D progression by activating T‐helper cells and improving the number of circulating memory T‐cells [54]. The active substance is interleukin‐1 receptor antagonist, a blocker of an immune‐signal molecule named interleukin‐1. Two randomized placebo‐controlled trials aimed to assess whether canakinumab, a human monoclonal anti‐interleukin‐1 antibody, or anakinra, a human interleukin‐1 receptor antagonist, improved β‐cell function in recent‐onset T1D, but their effectiveness was not demonstrated [54, 55].
More recently, the ongoing clinical trial EXTEND (Clinical trial NCT02293837; www.clinicaltrials.gov) is currently examining whether the blockade of IL‐6 signaling through tocilizumab, an anti‐IL‐6 receptor antibody, can induce a protection of β‐cell function in T1D patients (ages 6 to 17 years) (Table 2.3).
Interleukin‐8 appears to be another important mediator in the progression of T1D. Circulating levels of IL‐8 are elevated in children with T1D compared to non‐diabetic controls. Furthermore, levels of IL‐8 correlate with glycemic control, higher level being associated to poorer glucose control. As a result, the modulation or inhibition of IL8 activity may be a valid target for the development of novel treatments aimed to control the progression of T1D.
A multicenter, randomized, double‐blind, placebo‐controlled phase 2 trial of CXCR1/2 IL‐8 inhibitor (Ladarixin) has just presented its results at the American Diabetes Association's (ADA) 80th Scientific Sessions (Clinical trial NCT02814838; www.clinicaltrials.gov). The trial involved 76 patients with new‐onset T1D, randomly (2:1) assigned to receive either Ladarixin treatment (400 mg b.i.d. for 3 cycles of 14 days on/14 days off – treatment group) or placebo (control group). Although results indicated no statistically significant differences in stimulated C‐peptide at weeks 13 and 26, investigators noted 76.6% of patients receiving Ladarixin had an HbA1c below 7% and a daily insulin requirement of less than 0.50 IU/kg compared to just 45.8% of patients receiving placebo. Furthermore, in a prespecified subgroup analysis of patients with fasting C‐peptide below the median value of the trial population at baseline, MMTT AUC of C‐peptide trended at week 13 and reached statistical significance at week 26.
Incretin‐based Therapies
Recent knowledge regarding the heterogeneity in the extent of the β‐cell impairment and pancreatic lesions as well as the differences in circulating T‐cell and autoantibody immune signatures underscore the potential applications for incretin treatments, which improve capacity for insulin production by residual β‐cells and suppress glucagon secretion, as well as the need for therapeutics to reduce β‐cell stress co‐administered with immunomodulatory therapy to reverse autoimmunity in symptomatic T1D. Hence, therapies once considered only applicable to those with T2D may be of potential benefit for those with T1D. In this regard, ongoing T1D immunotherapy trials are investigating the potential benefits on β‐cell function in C‐peptide positive early diagnosed T1D patients.
In a post hoc analysis of pooled data from five randomized, placebo‐controlled studies, the dipeptidyl peptidase 4 (DPP‐4) inhibitor saxagliptin improved β‐cell function as assessed by HOMA2 of β‐cell function and post‐prandial C‐peptide from baseline in patients with Latent Autoimmune Diabetes in the Adult (LADA) [56]. Another small study found that sitagliptin, as an add‐on treatment to insulin, had a beneficial effect on C‐peptide decline compared with insulin alone. Moreover, a recent trial evaluated the effect of saxagliptin in combination with vitamin D3 in subjects with LADA with promising results [57]. As far as T1D is concerned, the effect of saxagliptin on immune regulation have been investigated in a phase IV trial (NCT02307695). Similarly, a phase III randomized controlled trial is evaluating the action of vildagliptin in the prevention of progressive β‐cell dysfunction in patients with newly diagnose of T1D (NCT01559025). In another ongoing study, researchers are testing the efficacy of 4 weeks rapamycin treatment and 4 weeks rapamycin treatment plus 3 months vildagliptin treatment versus placebo in increasing endogenous insulin production and correcting glycemic lability (NCT02803892). Glucagon‐like peptide (GLP‐1) analogues have been tested in large‐scale clinical trial to prove their various benefits for β‐cell and glucolipid metabolism in T2D and obesity patients. This has led to concerns regarding the potential applications in T1D patients. A small phase II randomized controlled trial (NCT02617654) is currently investigating the effect of 52 weeks of treatment with liraglutide 1.8 mg/day, compared to placebo, on stimulated C‐peptide concentrations in patients with long‐standing type 1 diabetes and residual insulin production (primary outcome: MMTT C‐peptide at 12 months).
Other studies on preservation of β‐cell function using incretin‐based therapies are currently active but not recruiting participants (NCT02443155; NCT02127047). Results from these studies are warranted to prove that incretin‐based therapy might preserve C‐peptide secretion (Table 2.3).
Conclusions
Today, one of the therapeutic goals in T1D is the preservation of the residual C‐peptide secretion that is detected in a significant percentage of patients at diagnosis and which potentially may influence the clinical course of the disease.
Several studies have been demonstrated that residual C‐peptide secretion, after T1D diagnosis, depends on genetic factors, the patient's age at the diabetes diagnosis, the number of anti‐islet antibodies, and the residual C‐peptide secretion. In the same way, intensive
