Double-blind, randomized study evaluating the glycemic and anti-inflammatory effects of subcutaneous LY2189102, a neutralizing IL-1β antibody, in patients with type 2 diabetes

Abstract

Objective: Inflammation is associated with pancreatic β-cell apoptosis and reduced insulin sensitivity. Literature suggests that interleukin (IL)-1β may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed to determine the efficacy, safety, and tolerability of LY2189102, a neutralizing IL-1β antibody, in T2DM patients.

Research design and methods: Phase II, randomized, double-blind, parallel, placebo-controlled study of subcutaneous LY2189102 (0.6, 18, and 180 mg) administered weekly for 12 weeks in T2DM patients on diet and exercise, with or without approved antidiabetic medications.

Results: LY2189102 reduced HbA1c at 12 weeks (adjusted mean differences versus placebo: -0.27, -0.38 and -0.25% for 0.6, 18 and 180 mg doses, respectively), and fasting glucose at multiple time points compared with placebo. LY2189102 also reduced postprandial glycemia, and inflammatory biomarkers, including hs-CRP and IL-6. LY2189102 was generally well tolerated.

Conclusions: Weekly subcutaneous LY2189102 for 12 weeks was well tolerated, modestly reduced HbA1c and fasting glucose, and demonstrated significant anti-inflammatory effects in T2DM patients. Neutralizing IL-1β holds promise as a convenient adjuvant treatment for T2DM.

Figure 1

Glucose and inflammatory biomarker changes from baseline by treatment. Symbols indicate actual mean change from baseline. A: Fasting glucose. *P ≤ 0.05 versus placebo per ANCOVA in the compliant set with treatment, site, and baseline fasting glucose as covariates. Baseline means (SD) were 9.3 (1.7), 8.2 (1.8), 9.1 (2.2), and 10.3 (2.1) mmol/L for placebo and 0.6, 18, and 180 mg LY, respectively. B: Plasma hs-CRP. All LY values, except at week 8, were P ≤ 0.05 versus placebo per ANCOVA in the compliant set with treatment, site, and baseline hs-CRP as covariates. Baseline means (SD) were 6.1 (4.5), 6.2 (6.2), 6.0 (4.5), and 7.2 (7.0) mg/L for placebo and 0.6, 18, and 180 mg LY, respectively. C: IL-6. *P < 0.05 versus placebo per ANCOVA in the compliant set with treatment, site, and baseline IL-6 as covariates. Baseline means (SD) were 3.1 (1.9), 3.0 (2.0), 5.9 (12.6), and 4.1 (5.0) pg/mL for placebo and 0.6, 18, and 180 mg LY, respectively. D: PAI-1. Baseline means (SD) were 249.0 (71.9), 222.7 (51.0), 215.3 (63.8), and 219.4 (61.7) ng/mL for placebo and 0.6, 18, and 180 mg LY, respectively.

Figure 2

Mean change from baseline to end of dosing from MMTT analysis, by treatment group. ANCOVA main treatment effect P value shown. A: Plasma glucose (mmol/L) at 2 h after meal ingestion. B: Ratio of AUC of insulin to AUC of glucose (AUC_ins/gluc). C: Index of whole-body insulin sensitivity: ISI (composite) = 10,000/√(FPG ⋅ FPI) ⋅ (MMG ⋅ MMI), where FPG is fasting plasma glucose, FPI is fasting plasma insulin, MMG is mean MMTT glucose, and MMI is mean MMTT insulin (20). D: Plasma insulin (μIU/L) at 2 h after meal ingestion.