AstraZeneca presents safety and efficacy data for ExQW at 51st Annual Meeting of EASD

Sep 16 2015

AstraZeneca today announced new analyses of exenatide once weekly (ExQW)  demonstrating a favorable gastrointestinal (GI) tolerability profile, including less frequent upper and lower GI adverse events (AE), compared to shorter-acting glucagon-like peptide-1 receptor agonists (GLP-1RA), exenatide twice daily (ExBID) and liraglutide once daily (LiraQD). These results were presented today at the 51^st Annual Meeting of the European Association for the Study of Diabetes (EASD) in Stockholm, Sweden.

To evaluate differences in GI tolerability with short- and long-acting GLP-1RAs, intent-to-treat (ITT) analyses were conducted, using pooled data from three studies comparing ExQW (n=617) to ExBID (n=606) and, separately, data from DURATION-6, which compared ExQW (n=461) to LiraQD (n=450). Investigators also explored whether GI AEs were associated with differences in HbA1c or weight reductions.

In the pooled analysis of three Bydureon clinical  trials, ExQW was associated with lower rates of upper GI AEs such as nausea and vomiting (24%) compared to ExBID (37%). Separate analysis of DURATION-6 also demonstrated that ExQW was associated with lower rates of upper GI AEs at 17% compared to 33% for LiraQD (P<0.001 vs longer-acting). Similarly, the percentage of patients treated with ExQW who experienced a combination of upper and lower AEs was less (7%) compared to LiraQD (14%), P<0.001 vs longer-acting. While few patients stopped treatment because of a GI AE, discontinuation was more frequent with the shorter-acting ExBID (6%) and LiraQD (4%), respectively compared to ExQW (1%) in both analyses (P<0.05).   

“The availability of GLP-1RA agonists is an important addition to treatment options for patients with type 2 diabetes. However, some patients may be unable to tolerate them because of  adverse gastrointestinal effects,” said Michael Horowitz, MD, lead study investigator and Director of the Endocrine and Metabolic Unit at the Royal Adelaide Hospital, Australia. “Our analysis of the adverse event profiles of short- and long-acting GLP-1 agonists demonstrated that exenatide once weekly has a favorable GI tolerability profile and lower rates of discontinuation compared to daily agents, which may support patients in remaining adherent to achieve clinically meaningful treatment benefits.”

Data was also presented from a real-world evidence study assessing German health insurance claims and adherence rates for patients initiating GLP-1RA therapy with ExQW (n=5,449) and LiraQD (n=24,648). Adherence was measured over a six-month period by calculating the ‘proportion of days covered’ (PDC) and demonstrated that the median PDC was 0.88 for ExQW and 0.77 for LiraQD (P<0.001). Overall, 53.4% of patients receiving ExQW, and 47.7% of those receiving LiraQD had an adherence rate of at least 80% (P<0.001) during the six months post-initiation of treatment.

A separate post-hoc analysis of pooled data (n=329) from extensions (2.5-3 years) of three trials (DURATION-1, -2, -3) showed that after three years, patients receiving ExQW experienced significant reductions in mean HbA1c (-1.06%) and fasting glucose (1.7 mmol/L) from baseline. These patients also achieved reductions in body weight (-2.4 kg). The effect on weight is not currently an approved indication for treatment with ExQW.

“Given variations in dosing frequency across GLP-1 agents, it is important that physicians understand the differences between daily and weekly options,” said Elisabeth Björk, Vice President, Head of Cardiovascular and Metabolic Diseases, Global Medicines Development, AstraZeneca. “These data strengthen support behind exenatide once weekly on key factors that can potentially impact patient outcomes and quality of life.”

Additional Study Details

Upper and/or lower GI adverse events with long- vs short-acting GLP-1RA receptor agonists: Incidence, co-incidence, effects on HbA1C and weight (Abstract #15)

This study, a pooled analysis of DURATION 1, 5, and a study in Asian Type 2 diabetes patients, was designed to evaluate differences in GI tolerability with longer- versus shorter-acting GLP-1RA (specifically ExQW, ExBID and LiraQD) according to location (upper, lower) and co-incidence. In this study, the most common upper GI AEs were nausea or vomiting, while the most common lower GI AEs were diarrhoea or constipation. Incidences of upper GI AEs occurred less for ExQW than shorter-acting GLP-1RA, while lower GI AEs appeared comparable across GLP-1RA. Changes in HbA1c and body weight from baseline were assessed according to occurrence of GI AEs, with HbA1c reductions similar for patients with no GI AEs and those with upper, lower or combined GI AEs.

HbA1c reductions from baseline were similar for patients with no GI AEs and those with upper, lower or combined GI AEs for shorter or longer-acting GLP-1RA. Reductions in body weight from baseline were observed in patients without GI AEs (-2.0 for both ExQW and ExBID; -2.4 vs -3.5 kg for ExQW and LiraQD, respectively); however, greater body weight reductions were achieved among patients treated with ExBID who experienced upper and lower GI AEs compared to patients who did not experience GI AEs (-3.5 kg vs -2.0 kg, respectively). In DURATION-6, patients treated with ExQW experiencing upper GI AEs achieved greater reductions in body weight than those without any GI AEs (-3.9 kg vs -2.4 kg, respectively). Based on these observations, the presence or absence of GI AEs did not affect HbA1c reductions but may influence weight reductions in some patients.

Adherence with GLP-1RA therapy in Germany: exenatide once weekly vs liraglutide once daily (Abstract #795)

To estimate the adherence of primary care patients initiating GLP-1RA therapy, data documented in statutory health insurance from 5,449 patients [mean age: 59.7] initiating ExQW and 24,648 patients [mean age: 59.4] initiating LiraQD therapy between January 1, 2011 and September 30, 2014 were analysed. Adherence was measured using the ‘proportion of days covered’ (PDC) with index GLP-1RA during a six-month period.

Overall, the median PDC was 0.88 for ExQW and 0.77 for LiraQD (P<0.001). 53.4% of the patients receiving ExQW, and 47.7% of those receiving LiraQD had an adherence of at least 80% (P<0.001) during the six months after initiating the drugs. Over a six-month period after initiation of GLP-1RA therapy, patients treated with ExQW had significantly better adherence compared with patients on LiraQD, particularly among patients aged 50 years or older.

Three-year efficacy and safety of exenatide once weekly: A pooled analysis of three trials (Abstract #770)

This post hoc analysis examined the efficacy and safety of ExQW in pooled completer data (n=329) from extensions (2.5-3 years) of three trials (DURATION-1, -2, -3); three-year data for insulin glargine (IG) was included for reference (n=158), as IG was a long-term comparator in one trial (DURATION-3). At three years, patients receiving ExQW had improvements from baseline in HbA1c, fasting glucose, body weight and some cardiovascular risk markers. A total of 30.7% of ExQW-treated patients and 16.5% IG-treated patients achieved goal of HbA1c ≤ 6.5%, while 28.9% and 7.0% of patients, respectively, achieved the composite goal of HbA1c < 7% without hypoglycaemia or weight gain. Patients receiving ExQW did experience a higher incidence of GI and injection-site events, most commonly diarrhoea, nausea, vomiting, and injection-site pruritus.