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

Abstract and Introduction


With the rapidly rising incidence of Type 2 diabetes and an increasing variety of medications available for treatment, choosing the ideal regimen for patients can be challenging. Longer-acting glucagon-like peptide-1 (GLP-1) receptor agonists and devices have been recently developed and include once-weekly exenatide, dulaglutide, albiglutide, semaglutide and miniosmotic pump ITCA650. Some of the attractive qualities of the GLP-1 receptor agonist class include its association with weightloss and potential for cardiovascular benefits. The longer-acting forms have been shown in several studies to produce equal or greater reduction in A1c and weight compared with the standard twice-daily formulation of exenatide. They also result in lower reported incidence of nausea, in the setting of a less frequent injection schedule that would be desirable to many diabetic patients. There are emerging data to suggest patients treated with longer-acting GLP-1 receptor agonists have improved cardiac parameters, some of which are independent of weight and A1c reductions.


Each year, approximately 2 million individuals in the USA are newly diagnosed with Type 2 diabetes (T2D), and the disease affects approximately 300 million people worldwide.[1,101] In the next 20 years, this number has been estimated to increase to nearly 440 million, with a 69% increase in prevalence in developed countries.[1] In concert with the obesity epidemic, the incidence and prevalence of T2D has exponentially increased and includes more people being diagnosed at a younger age and ultimately requiring multiple medications to achieve adequate glycemic control.[2,3] Current guidelines support initial therapy that consists of lifestyle changes plus metformin.[4] However, for individuals who cannot tolerate metformin or who are unable to attain goal A1c on monotherapy, the next therapeutic agent to add is not clearly defined.

In the last 5 years, incretins such as glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl-peptidase 4 (DPP4) inhibitors have garnered much attention as novel classes of drugs for the treatment of T2D. GLP-1 is a gut-derived hormone secreted by intestinal L cells that is rapidly degraded by DPP4.[5] GLP-1 has many effects that regulate glucose levels and appetite, including enhancing insulin secretion in the setting of hyperglycemia, delaying gastric emptying, suppressing inappropriate glucagon secretion and acting on CNS centers of satiety.[6] Shorter-acting GLP1-RAs, including twice-daily (b.i.d.) exenatide and once-daily liraglutide, have demonstrated similar efficacy in reducing A1c compared with many other long-available therapeutic options, but with a lower incidence of severe hypoglycemia and weight gain (side effects that are commonly seen with other medications).[7–9] Longer-acting (LA) GLP1-RA approaches, such as once-weekly exenatide (EQW), albiglutide, dulaglutide, semaglutide and ITCA650, have shown similar results with even greater reductions in hemoglobin A1c (HbA1c).[10–19,102] Another LA GLP1-RA, taspoglutide, showed similar promising results; but investigation was halted after a high incidence of hypersensitivity reactions.

The three currently approved GLP1-RAs commonly used in the USA; exenatide b.i.d. injections (Byetta® [Amylin Pharmaceuticals, CA, California]), liraglutide once-daily injections (Victoza® [NovoNordisk, Denmark]), and exenatide once-weekly injections (Bydureon® [Amylin Pharmaceuticals, CA, USA]), have demonstrated an approximate A1c reduction of 1, 1.6 and 1.5–1.9%, respectively with most studies showing a mean 2–3 kg weightloss.[8–17] With the success of these medications, much research in the past few years has been focused on developing even LA GLP1 RAs that can be injected weekly rather than daily. The implanted osmotic mini pump ITCA 650 delivers exenatide continuously for up to a year. Studies have demonstrated that continuous intravenous infusion of GLP-1 over 24-h normalized blood glucose consistently.[20] This suggests that more constant exposure to the peptide could be preferable to the peak and valleys that occur with b.i.d. boluses. LA GLP1-RAs would also theoretically provide more continuous exposure to therapy while also allowing reduced frequency of injections, which may improve patient quality of life (QoL) perception and compliance.[21,22] This article reviews published studies looking at efficacy, benefits and potential beneficial cardiovascular (CV) effects of the LA GLP1-RAs currently on the market and in development, including EQW, albiglutide, dulaglutide, semaglutide and ITCA650 delivery system (Table 1).