Longer Acting GLP-1 Receptor Agonists and the Potential for Improved Cardiovascular Outcomes

A Review of Current Literature

Courtney Aavang Tibble; Tricia Santos Cavaiola; Robert R Henry


Expert Rev Endocrinol Metab. 2013;8(3):247-259. 

In This Article

ITCA650 Subcutaneous Pump

ITCA650 is a unique formulation of exenatide currently in development, which delivers medication through an implantable subcutaneous pump delivery system. The osmotic mini pump provides a slow and continuous subcutaneous delivery of exenatide. This allows for the rapid achievement of steady-state drug delivery upon insertion and prompt absence within hours after removal of the device, if required. The pump is the size of a small matchstick, and can be inserted quickly in an in-office procedure.[102]

In 2011, preliminary data from a completed Phase II study were presented at the European Association for the study of Diabetes, which are also available on the Intarcia website. The study enrolled 155 subjects with T2D and a baseline A1c of 7–10% on metformin monotherapy, and randomized to receive varying dosages of exenatide via the pump system as well as exenatide subcutaneous injections b.i.d. for comparison. Efficacy and side-effect profile data collected suggest that treatment with ITCA650 at a starting dose of 20 µcg/day for 12 weeks provided effective glycemic control with the best tolerability profile, followed by a transition to ITCA650 at 60 µcg/day. This dose was then well tolerated and provided substantial incremental reductions in both HbA1c and bodyweight, with continued treatment to 48 weeks showing favorable patient satisfaction and sustained reductions in HbA1c, FPG and weight.[103] To date, there are no formally published studies on this device, but several Phase III trials are underway including the FREEDOM trials in patients with T2D.

FREEDOM-1 will compare ITCA650 in two different doses (40 and 60 µcg/day) to placebo to evaluate glycemic control in patients with uncontrolled T2D on 0–3 oral agents. The primary end point will be change in A1c after 39 weeks and should conclude in 2014. Similarly, a FREEDOM-1 HBL will evaluate patients with an A1c >10%. The combination of ICTA 20 µcg/day × 12 weeks escalated to 60 µcg/day will be initiated in upcoming Phase III trials.[104] Another 52-week trial will examine ITCA650 60 µcg/day versus sitagliptin as add-on therapy to metformin and is also set to conclude in 2014. Additional upcoming trials will include a randomized, parallel CV outcome trial of ITCA650 60 µcg/day versus placebo in patients >40 years old with T2D and A1c >6.5%. Inclusion criteria include a history of coronary, cerebrovascular or peripheral arterial disease. Primary outcome measure is major adverse CV events within 2 years. Further evaluation of ITCA 650 using longer duration devices for up to 1 year in T2D are planned. This novel delivery method has the potential advantage of improving compliance and consistency of delivery of GLP1-RA and the prompt normalization of circulating exenatide levels upon removal should serious side effects occur.