Tuesday, 15 September 2015
- New pooled data from direct comparative trials indicate upper gastrointestinal adverse events occur more frequently with shorter-acting glucagon-like peptide-1 receptor agonists (GLP-1RA), compared to exenatide once weekly
- Real-world evidence trial finds greater adherence to treatment with exenatide once weekly versus liraglutide once daily in patients in Germany initiating GLP-1RA therapy
- Combined analysis of DURATION-1, -2, -3 examines three-year efficacy and safety of exenatide once weekly compared to insulin glargine
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).1 These results were presented today at the 51st 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).1
“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.2
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).3 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.
About GLP-1 Receptor Agonists
GLP-1 receptor agonists (GLP-1RA) are a class of injectable anti-hyperglycaemic agents used in the treatment of type 2 diabetes and they mimic several actions of the naturally occurring hormone GLP-1, including lowering blood glucose levels.1 GLP-1RA work by stimulating insulin secretion from the pancreatic beta cells on a glucose-dependent basis, suppressing glucagon secretions and decreasing appetite which can lead to reduced food intake and the slowing of gastric emptying, reducing the rate at which glucose from meals appears in the blood.4
About Type 2 Diabetes
Type 2 diabetes is a chronic disease characterised by high blood glucose levels (or hyperglycaemia) resulting from the body’s ineffective use of insulin.5 It comprises 90% of people with diabetes around the world and increases the risk of cardiovascular disease and kidney failure.6 It is estimated to affect more than 382 million people worldwide and is projected to reach more than 592 million people by 2035.7 Approximately 77% of people with diabetes live in low- and middle-income countries and 179 million people with diabetes are undiagnosed.7 It is estimated that more than half of people living with type 2 diabetes are not achieving recommended HbA1c goals based on guidelines established by professional societies and advocacy organisations for diabetes management.6 The costs and consequences of diabetes are immense globally, resulting in at least USD 612 billion dollars in healthcare expenditures and causing 4.9 million deaths – one person every seven seconds – in 2014.9
About AstraZeneca in Diabetes
AstraZeneca is pushing the boundaries of science to create life-changing medicines that aim to reduce the global burden and complications of diabetes. Driven to redefine outcomes for diabetes patients, our current portfolio consists of the three newest classes of non-insulin, anti-diabetic treatments that support individualized treatment approaches: SGLT-2 inhibitors, GLP-1 receptor agonists and DPP-4 inhibitors. Our commitment to diabetes is exemplified by the depth and breadth of our global clinical research programme. This commitment is advancing understanding of the treatment effects of our diabetes medicines in broad patient populations, as well as exploring combination treatment approaches resulting in more patients achieving treatment success earlier in their disease progression. Our ambition is to reduce the long-term impact of diabetes. As a core strategic area for the company, we are focusing our research and development efforts in diverse populations and patients with significant co-morbidities, such as cardiovascular disease, heart failure, obesity, non-alcoholic steatohepatitis (NASH), and chronic kidney disease.
About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.
CONTACTS
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1 Horowitz, M., et al. “Upper and/or lower GI adverse events with long- vs short-acting GLP-1 receptor agonists: incidence, co-incidence, effects on HbA1c and weight.” 51st Annual Meeting of the European Association for the Study of Diabetes. Abstract #15
2 Qio, Q., S. Grandy, and K. Kostev. “Adherence with GLP-1RA therapy in Germany: exenatide once weekly vs liraglutide once daily”. 51st Annual Meeting of the European Association for the Study of Diabetes. Abstract #795
3 Trautmann, M., et al. “Three-year efficacy and safety of exenatide once weekly: a pooled analysis of three trials.” 51st Annual Meeting of the European Association for the Study of Diabetes. Abstract #770
4 Bydureon (prolonged-release exenatide) summary of product characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002020/WC500108241.pdf Last accessed September 2015.
5 Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Geneva, World Health Organization, 1999 (WHO/NCD/NCS/99.2).
6 Levitan B, Song Y, Ford ES, Liu S. Is nondiabetic hyperglycaemia a risk factor for cardiovascular
disease? A meta-analysis of prospective studies. Arch Intern Med. 2004;164:2147−55.
7 International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Poster Update 2014. Brussels, Belgium: International Diabetes Federation, 2014. http://www.idf.org/diabetesatlas/update-2014
8 Cook M.N., et al. “Initial monotherapy with either metformin or sulphonylureas often fails to achieve or maintain current glycaemic goals in patients with type 2 diabetes in UK primary care.” Diabetic Med 2007: 24; 350-358.
9 International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Poster Update 2014. Brussels, Belgium: International Diabetes Federation, 2014. http://www.idf.org/diabetesatlas/update-2014