Safety and efficacy of albiglutide —results from two trials

1. Safety and efficacy of albiglutide—results from two trials Nat Rev Endocrinol. 2014 Sep;10(9):514-6.

2. Introduction • Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by worsening function of the pancreatic islet cells and increasing insulin resistance, which lead to disease progression and cause glycaemic control to worsen over time • Initial antihyperglycaemic monotherapy often does not achieve adequate glycaemic control in patients with T2DM • Despite advances in the available treatments, nearly 50% of patients with this condition do not meet their glycaemic target

3. Introduction • Incretin-based therapies have been developed in the past few years and are now widely used in clinical practice. This class of drugs includes both the dipeptidyl peptidase‑4 (DPP‑4) inhibitors (sitagliptin, vildagliptin, saxagliptin and linagliptin) and the glucagon-like peptide 1 (GLP‑1) receptor agonists (exenatide, exenatide long acting release, liraglutide and lixisenatide)

4. Introduction • Given the efficacy and safety of these drugs new molecules have been developed, such as alogliptin (a new DPP‑4 inhibitor) and albiglutide (a long-acting GLP‑1 receptor agonist). Albiglutide is of particular interest • The HARMONY program has been designed to adequately evaluate this new drug • This program includes eight pivotal phase III studies designed to evaluate the efficacy, tolerability and safety (including cardiovascular safety) of albiglutide as monotherapy and add-on therapy, compared with placebo, oral antidiabetic medications, insulin glargine, insulin lispro and once daily liraglutide in a typical population of patients with T2DM

5. HARMONY 3 • The HARMONY 3 trial compared the efficacy and safety of weekly albiglutide (30 mg titrated to 50 mg based on predefined hyperglycaemia criteria) with daily sitagliptin (100 mg), daily glimepiride (2 mg titrated to 4 mg based on predefined hyperglycaemia criteria) and placebo for 104 weeks • At week 104, albiglutide significantly reduced levels of HbA1c compared with placebo (–0.9%, P <0.0001), sitagliptin (–0.4%, P = 0.0001) and glimepiride (–0.3%, P = 0.0033)

6. HARMONY 3 • Rates of serious adverse events in the group who received albiglutide were similar to those in the comparison groups • This study suggests that albiglutide, when added to metformin, produces a clinically and statistically superior reduction in levels of HbA1c at week 104 compared with placebo, sitagliptin and glimepiride that is sustained • Moreover, albiglutide resulted in a weight decrease and was generally well tolerated

7. HARMONY 6 • The HARMONY 6 trial compared onceweekly albiglutide with thrice-daily prandial insulin lispro as an add-on to titrated once daily insulin glargine • Patients taking basal insulin (with HbA1c levels of 7.0–10.5%) entered an insulin glargine standardization period, followed by randomization to albiglutide (30 mg weekly, which was subsequently up-titrated to 50 mg if necessary) or thrice-daily prandial insulin lispro, while continuing metformin and/or pioglitazone treatment for 26 weeks • At week 26, HbA1c had decreased from baseline by 0.82% with albiglutide and 0.66% with insulin lispro

8. HARMONY 6 • The treatment difference was –0.16% (P <0.0001), which meets the noninferiority end point • Body weight decreased with albiglutide, but increased with insulin lispro (–0.73 kg versus +0.81 kg) • The HARMONY 6 study suggests that once-weekly albiglutide might be a reasonable option and a simpler approach to therapy intensification in patients treated with basal insulin in situations where health-care support and/or patient willingness to perform the necessary self-management tasks for basal bolus insulin therapy are limited

9. Discussion • The data reported about albiglutide seem to suggest that it is efficacious and safe: in addition to effectively reducing levels of HbA1c, albiglutide decreases body weight compared with glimepiride6 and with insulin • A decrease in body weight contributes to a reduction in insulin resistance, which increases the efficacy of antidiabetic drugs Moreover, compared with insulin, albiglutide is associated with a low rate of hypoglycaemia, which is a common, unpredictable and potentially dangerous adverse effect of antidiabetic treatment

10. Conclusion • Albiglutide is the second once-weekly GLP‑1 receptor agonist to be made available for patients with T2DM, and might be preferred over daily GLP‑1 receptor agonists, because of its mild adverse effect profile, convenient once-weekly dosing and efficacy • For the future, it would be interesting to see if albiglutide also has some positive effects on cardiovascular end points