Antisense inhibition of protein tyrosine phosphatase 1B with IONIS-PTP-1BRx improves insulin sensitivity and reduces weight in overweight patients with type 2 diabetes

Abstract

OBJECTIVE To evaluate safety and efficacy of IONIS-PTP-1BRx, a second-generation 29-Omethoxyethyl 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 METHODS In this phase II, double-blind, randomized, placebo-controlled,multicenter trial, overweight and obese patients (BMI ≥27 kg/m2) with type 2 diabetes (HbA1c ≥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-1BRx 200 mg (n = 62) or placebo (n = 30) once weekly for 26 weeks. RESULTS Mean baseline HbA1c was 8.6% (70 mmol/mol) and 8.7% (72 mmol/mol) in placebo and active treatment, respectively. At week 27, IONIS-PTP-1BRx reducedmean HbA1c levels by 20.44% (24.8 mmol/mol; P = 0.074) from baseline and improved leptin (24.4 ng/mL; P = 0.007) and adiponectin (0.99 mg/mL; P = 0.026) levels compared with placebo. By week 36, mean HbA1c was significantly reduced (20.69% [27.5 mmol/mol]; P = 0.034) and accompanied by reductions in fructosamine (233.2 mmol/L; P = 0.005) and glycated albumin (21.6%; P = 0.031) versus placebo. Despite both treatment groups receiving similar lifestyle counseling, mean body weight significantly decreased frombaseline to week 27 with IONIS-PTP-1BRx versus placebo (22.6 kg; P = 0.002) independent of HbA1c reduction (R2 = 0.0020). No safety concerns were identified in the study. CONCLUSIONS Compared with placebo, IONIS-PTP-1BRx treatment for 26 weeks produced prolonged reductions in HbA1c, improved medium-term glycemic parameters, reduced leptin and increased adiponectin levels, and resulted in a distinct body weight-reducing effect.