Antisense Inhibition of Protein Tyrosine Phosphatase 1B With IONIS-PTP-1B(Rx) Improves Insulin Sensitivity and Reduces Weight in Overweight Patients With Type 2 Diabetes

摘要

OBJECTIVETo evaluate safety and efficacy of IONIS-PTP-1B(Rx), a second-generation 2-O-methoxyethyl antisense inhibitor of protein tyrosine phosphatase 1B, as add-on therapy in overweight patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea therapy.RESEARCH DESIGN AND METHODSIn this phase II, double-blind, randomized, placebo-controlled, multicenter trial, overweight and obese patients (BMI 27 kg/m(2)) with type 2 diabetes (HbA(1c) 7.5% [58 mmol/mol] and 10.5% [91 mmol/mol]) on a stable dose of metformin alone or with sulfonylurea were randomized 2:1 to IONIS-PTP-1B(Rx) 200 mg (n = 62) or placebo (n = 30) once weekly for 26 weeks.RESULTSMean baseline HbA(1c) was 8.6% (70 mmol/mol) and 8.7% (72 mmol/mol) in placebo and active treatment, respectively. At week 27, IONIS-PTP-1B(Rx) reduced mean HbA(1c) levels by -0.44% (-4.8 mmol/mol; P = 0.074) from baseline and improved leptin (-4.4 ng/mL; P = 0.007) and adiponectin (0.99 g/mL; P = 0.026) levels compared with placebo. By week 36, mean HbA(1c) was significantly reduced (-0.69% [-7.5 mmol/mol]; P = 0.034) and accompanied by reductions in fructosamine (-33.2 mol/L; P = 0.005) and glycated albumin (-1.6%; P = 0.031) versus placebo. Despite both treatment groups receiving similar lifestyle counseling, mean body weight significantly decreased from baseline to week 27 with IONIS-PTP-1B(Rx) versus placebo (-2.6 kg; P = 0.002) independent of HbA(1c) reduction (R-2 = 0.0020). No safety concerns were identified in the study.CONCLUSIONSCompared with placebo, IONIS-PTP-1B(Rx) treatment for 26 weeks produced prolonged reductions in HbA(1c), improved medium-term glycemic parameters, reduced leptin and increased adiponectin levels, and resulted in a distinct body weight-reducing effect.