Double-Blind , Randomized Study Evaluating the Glycemic and Anti-in fl ammatory Effects of Subcutaneous LY 2189102 , a Neutralizing IL-1 b Antibody , in PatientsWith Type 2 Diabetes
Type 2 diabetes occurs when pancreatic b-cell function fails to compensate for insulin resistance (1,2). As the duration of diabetes increases, b-cell function progressively deteriorates, partly as a result of apoptotic cell death (3–5). Inflammation is associated with pancreatic b-cell apoptosis and reduced insulin sensitivity, supporting the notion that inflammation plays a key role in aggravating or even causing type 2 diabetes specifically or the metabolic syndrome generally (6). Interleukin (IL)-1b is an inflammatory mediator that may contribute to this pathophysiology. IL-1b expression has been observed in b-cells of patients with type 2 diabetes (7). Moreover, production and secretion of IL-1b from b-cells is induced by high glucose levels and inhibits the function and promotes the apoptosis of b-cells (7–10). The IL-1 receptor antagonist (IL-1ra) protects human b-cells from glucose-induced functional impairment (7) and apoptosis, and its expression is decreased in patients with type 2 diabetes (11). The hypothesis that blocking IL-1b activity could be therapeutic in type 2 diabetes was tested clinically with anakinra, a recombinant IL-1ra (12,13). Results from a proof-of-concept study indicated that anakinra modestly improved hemoglobin A1c (HbA1c) relative to placebo, reduced circulating inflammatory cytokines, and showed signs of improved b-cell secretory function after 13 weeks of daily subcutaneousdosing (13).Ninemonths after treatment completion, anakinratreated patients continued to have improved proinsulin/insulin ratios and reduced inflammatory cytokines; anakinra responders required less exogenous insulin than did nonresponders (14). Clinical evaluation of a neutralizing IL-1b monoclonal antibody (XOMA 052) in type 2 diabetic patients showed similar results. XOMA 052 improved HbA1c relative to placebo after a single intravenous infusion and after repeated subcutaneous dosing; improvements in fasting blood glucose and insulin sensitivity after subcutaneous dosing were also noted (15). Typically only a small percentage of cytokine receptors require engagement to activate downstream signaling pathways, and cytokines are typically labile proteins expressed at low concentrations. Because anakinra binds to the IL-1 receptor and has a short half-life (4–6 h) (16), it is unclear whether the modest nature of the response in type 2 diabetes was related to compound-specific properties or a reflection of the role of this cytokine pathway in the disease pathogenesis. Although XOMA 052 binds and neutralizes IL-1b directly and has a longer half-life, it was dosed in a limited number of subjects and for short duration. Further evaluation c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c