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

Objective: To evaluate safety and efficacy of IONIS-PTP-1B, a second-generation 2'--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 Methods: In this phase II, double-blind, randomized, placebo-controlled, multicenter trial, overweight and obese patients (BMI ≥27 kg/m) with type 2 diabetes (HbA ≥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 200 mg ( = 62) or placebo ( = 30) once weekly for 26 weeks.

Results: Mean baseline HbA was 8.6% (70 mmol/mol) and 8.7% (72 mmol/mol) in placebo and active treatment, respectively. At week 27, IONIS-PTP-1B reduced mean HbA levels by -0.44% (-4.8 mmol/mol; = 0.074) from baseline and improved leptin (-4.4 ng/mL; = 0.007) and adiponectin (0.99 μg/mL; = 0.026) levels compared with placebo. By week 36, mean HbA was significantly reduced (-0.69% [-7.5 mmol/mol]; = 0.034) and accompanied by reductions in fructosamine (-33.2 μmol/L; = 0.005) and glycated albumin (-1.6%; = 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 versus placebo (-2.6 kg; = 0.002) independent of HbA reduction ( = 0.0020). No safety concerns were identified in the study.

Conclusions: Compared with placebo, IONIS-PTP-1B treatment for 26 weeks produced prolonged reductions in HbA, improved medium-term glycemic parameters, reduced leptin and increased adiponectin levels, and resulted in a distinct body weight-reducing effect.