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.

Objective: To 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 Methods: In 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.
Results: Mean 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 μg/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 μmol/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.
Conclusions: Compared 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.
(© 2018 by the American Diabetes Association.)