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

Disclosures

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

In This Article

Albiglutide Weekly Injection

Another LA GLP1-RA under clinical investigation is albiglutide, which has a novel molecular formulation. This macromolecule is made of two copies of a 30 amino acid sequence of DPP4-resistant human GLP-1, fused to recombinant human albumin. The tandem structure increases potency compared with having only one GLP-1 molecule bound to albumin, and the average plasma half-life is 5–8 days.[30] One other notable difference between albiglutide and EQW is its relative impermeability to the CNS which, based upon speculation, may partially decrease GI side effects of nausea/vomiting.[31]

A Phase II trial evaluated the safety, efficacy and side-effect profile of three different dosing regimens of the albiglutide. This was a randomized, double-blind trial enrolling 356 subjects with T2D. Patients were randomized to receive exenatide b.i.d. (open label), albiglutide weekly dosing (4, 15 or 30 mg), biweekly dosing (15, 30 or 50 mg), monthly dosing (50 or 100 mg) or placebo dosing matched to one of the albiglutide schedules. All injections were administered under supervision in a physician's office, with the exception of the open-label exenatide group. All groups had similar baseline characteristics including an average A1c of 8% and were either drug naive or on metformin monotherapy. Subjects received 16 weeks of active therapy and were then monitored for an 11-week washout period.[18]

At the end of a 16-week treatment period, albiglutide significantly reduced A1c in a dose-dependent fashion across all groups receiving the drug. The greatest mean A1c reductions were similar in the highest dosing schedule with each albiglutide frequency tested; -0.87% in 30 mg weekly, -0.79% in 50 mg biweekly and -0.87% in 100 mg monthly. These reductions were greater than those seen in the exenatide b.i.d. group (-0.54%, no statistical comparisons made) and the placebo group (-0.17%; p ≤ 0.003). The percentage of study subjects reaching A1c <7% was 52% in the 30-mg albiglutide weekly group, 53% in the 50-mg albiglutide biweekly group and 48% in the albiglutide 100-mg monthly group, as compared with 35% in exenatide group and 20% in placebo group.[18]

There was no significant difference in weight change between any of the albiglutide dosings, with average weightloss being -1.1 to -1.7 kg (less than that observed in the exenatide group of -2.4 kg). Neither albiglutide nor exenatide therapy resulted in significant change of lipid profile. The most commonly reported side effects with albiglutide were nausea (12–54% across groups) and vomiting (0–41% across groups). The proportion of subjects experiencing nausea and/or vomiting was significantly less with lower-dose albiglutide (<30 mg per injection) and correlated with peak levels of the drug in serum, especially at higher doses (i.e., 100 mg monthly). In patients receiving 30 mg weekly, nausea was reported by a total of only 29% of subjects (on average <10% incidence reported per week), versus nausea reported by 54% of subjects in the 50 mg biweekly and 55.9% in the 100 mg monthly arms, with peak nausea occurring within the first week after injection. In all groups, the incidence of nausea reports declined over time, with subjects taking 30 mg weekly reporting no nausea after the first 8 weeks of therapy.[18]

Based on dose–response and dose–timing studies, as well as safety and tolerability profiles, albiglutide 30 mg weekly was chosen for study in a comprehensive Phase III program known as HARMONY. This program will include trials with albiglutide as monotherapy, add-on to metformin ± sulfonylurea, pioglitazone and insulin, and head-to-head versus glargine and liraglutide. One study will also evaluate albiglutide versus sitagliptin in patients with renal impairment. The HARMONY program is aimed to fulfill the recent FDA guidelines regarding CV safety, and will therefore enroll patients with more advanced diabetes and with known CV disease.[32]

Early results from the head-to-head trial of once-weekly albiglutide and once-daily liraglutide were presented at the American Diabetes Association in 2012. Approximately 400 patients with T2D, mean A1c of 8.16%, on any combination of metformin, thiazolidinedione or sulfonylurea were randomized each to albiglutide 30 mg weekly (titrated to 50 mg at week 6) or liraglutide 0.6 mg (titrated to 1.2 mg at week 2 and 1.8 mg at week 3). While albiglutide significantly reduced A1c -0.78% (p < 0.001), it did not meet noninferiority criteria to liraglutide (A1c -0.99%). Liraglutide showed larger reductions in weight compared with albiglutide (-2.19 and -0.64 kg, respectively), but albiglutide was associated with less nausea/vomiting (9.9/5 vs 29.2/9.3%) and less hypoglycemia (16.3 vs 20.8%.) Statistical significance for adverse events is unknown.[33]

In 2012, additional early HARMONY data were presented at the European Association for the study of Diabetes annual meeting (1–5 October, Berlin, Germany) in a study evaluating patients with T2D and a mean A1c of 8.45% on oral agents (no sulfonylurea) and basal insulin. After an initial run-in standardization to basal glargine, subjects were randomized to albiglutide 30 mg weekly or lispro or continued on oral medications and basal insulin. Albiglutide could be titrated up to 50 mg weekly based on A1c targets while lispro was adjusted based on a prespecified algorithm. Albiglutide was noninferior to lispro with A1c reductions of -0.82 and -0.66%, respectively. However, albiglutide was associated with weightloss compared with weight gain with lispro (-0.96 vs +1.66 kg) and less hypoglycemia compared with lispro (33 vs 50%).[34]

Therefore, albuglutide may be comparable with current GLP1-RA in terms of glycemic control, but may also have some benefits in terms of side-effect profiles. In addition, different dose formulations of albiglutide (i.e., 50 mg every other week) will continue to be studied in the Harmony program.[32]

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