Insulin plus incretin agent combination therapy in type 2 diabetes: a systematic review

Background: Insulin and incretin agents (dipeptidyl peptidase-4 inhibitors [DPP4is] and glucagon-like peptide-1 receptor agonists [GLP1 RAs]) are second-line treatment options in patients with type 2 diabetes (T2D) not achieving glycemic targets with metformin. Combinations of insulin with incretin agents have been explored in randomized controlled trials (RCTs) and retrospective studies. However, the optimal approach is still elusive; numerous combination regimens can be envisioned, differing in composition and in order of addition. Scope: A systematic survey was conducted of RCTs testing insulin/DPP4i or insulin/GLP1 RA regimens. PubMed and other online databases were queried using 'insulin' and the names of all incretin agents available in Canada, along with 'combination', 'concomitant', 'concurrent', and 'add-on'. Web of Science and clinicaltrials.gov were searched to identify unpublished trials. Findings: Fifteen placebo-controlled or active-comparator RCTs were identified, reporting outcomes for regimens combining insulins and incretin agents available in Canada. DPP4i add-on to insulin therapy (six trials) leads to modest A1c lowering, with weight neutrality. GLP1 RA and insulin combination therapy (GLP1 RA add-on, five trials; insulin add-on, two trials) is associated with significant A1c lowering, with beneficial effects on body weight. A single proof-of-concept trial compared GLP1 RA to DPP4i add-on to insulin, and only one RCT examined simultaneous introduction of an incretin agent with insulin. Adding an incretin agent to established basal insulin therapy may represent a useful alternative to insulin intensification with prandial or premixed insulin. Initial introduction of an incretin agent, with subsequent introduction of insulin, offers potential practical advantages. No study directly comparing order of addition has yet been reported. Conclusions: Insulin/incretin combination therapy comprises a variety of efficacious, weight-sparing regimens and may be considered for many patients who do not achieve glycemic targets when treated with insulin or an incretin agent.