Being an autoimmune disease, type 1 diabetes (T1D) is characterized by the infiltration of immune cells into the pancreas that causes the destruction of insulin-producing β-cells in the pancreatic islets of Langerhans.¹ While it has been the mainstay therapy for patients with T1D since its discovery over a century ago, exogenous insulin is a lifelong regimen and many patients still bear a high risk of severe complications such as cardiovascular mortality.^1,2 Recent research focus has thus shifted to preventive management strategies, such as immunomodulation and suppression, which are integral to T1D pathogenesis, as well as β-cells protection for the preservation of their insulin-producing capacity.² One such example is the combination therapy of anti-interleukin (IL)-21 and liraglutide which could preserve the β-cell function in patients recently diagnosed with T1D, as demonstrated by a recent phase 2 trial.³

"This is the first large trial for a combination therapy, and the data suggest it has value for patients," commented Dr. Matthias von Herrath, the lead author of the trial and Professor at the La Jolla Institute for Immunology (LJI). "The groundwork for choosing a combination therapy was laid through preclinical work at LJI."

Early preclinical studies have hypothesized that the combination of liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist initially approved for type 2 diabetes, and an antibody against IL-21, a multi-functional cytokine pivotal to the pathogenic cascade in autoimmune diseases, could enhance or protect residual functional β-cells as well as thwarting their further destruction, respectively.¹ Subsequent to these findings, clinical studies have been conducted and the results of a phase 2 trial were recently published in The Lancet Diabetes & Endocrinology.³

In this phase 2, randomized, placebo-controlled, double-blind, parallel-group, double-dummy, proof-of-principle trial, 308 participants aged 18-45 with recently diagnosed T1D and residual β-cell function were randomized to receive either the anti-IL-21 and liraglutide combination, anti-IL-21 monotherapy, liraglutide monotherapy or placebo, all in tandem with insulin.³

The primary endpoint, a measurement of the mixed-meal tolerance test (MMTT)-stimulated C-peptide concentration changes from baseline at week 54 by the area under the concentration-time curve (AUC) over 4 hours, shows that the anti-IL-21/liraglutide combination achieved a significantly smaller decrease in MMTT-stimulated C-peptide concentration from baseline than placebo (ratio to baseline=0.90 vs. 0.61; ETR=1.48; 95% CI: 1.16-1.89; p=0.0017), while not having statistical significance when compared to anti-IL-21 monotherapy (estimated treatment ratio [ETR]=1.23; 95% CI: 0.97-1.57; p=0.093) or liraglutide alone (ETR=1.12; 95% CI: 0.87-1.42; p=0.38).³

In terms of the change in hemoglobin A1c (HbA1c) level at week 54, a key secondary outcome, even though more insulin was used in the placebo group, the decrease in HbA1c with all active treatments was numerically greater than that of placebo (percentage points=-0.50 vs. -0.10) but was not statistically significant.³

Aside from assessing these key outcomes during therapy, the investigators continued to follow up on the participants for an additional 26 weeks after the treatment period was over.³ They discovered that the therapeutic effects diminished on treatment cessation, for which they attributed to the possible resumption of the ongoing autoimmune process.³

For safety, the adverse event (AE) profiles of anti-IL-21/liraglutide combination were generally consistent with that reported previously for anti-IL-21 monotherapy and the established safety profile of GLP-1R agonists. The most common adverse events of the combination therapy were nasopharyngitis (26.0%) and nausea (24.7%).^3,4

While more phase 3 trials are needed to further evaluate and consolidate the efficacy and safety of this combination therapy, the present phase 2 study has nonetheless established its preliminary clinical significance in preserving β-cell function among the T1D population.³ Professor Thomas R Pieber, M.D., another study investigator, and his team thus concluded, “This combination has the potential to offer a novel and valuable disease-modifying therapy for patients with recently diagnosed type 1 diabetes.”