Κυριακή 27 Ιουλίου 2014

ONCE WEEKLY GLP-1 AGONIST FOR DIABETES

The investigational once-weekly dulaglutide (Eli Lilly) is noninferior to once-daily liraglutide (Victoza, Novo Nordisk), providing similar glycated hemoglobin (HbA1c) reductions, in adults with type 2 diabetes poorly controlled with metformin, a new study finds. In addition, the glucagon-like peptide-1 receptor (GLP-1) agonists showed similar tolerability.
Kathleen M. Dungan, MD, MPH, associate professor of medicine and director of the clinical endocrine trials unit at Ohio State University, Columbus, and colleagues published the results from the phase 3, randomized, open-label, head-to-head AWARD-6 online July 11 in The Lancet.
In the 62-site, 9-country study, 269 patients in each group completed treatment with once-weekly dulaglutide or once-daily liraglutide. At 26 weeks, HbA1c dropped 1.42% with dulaglutide and 1.36% with liraglutide. The 0.06% difference met the prespecified 0.4% noninferiority margin.
"From both a patient and physician perspective, having that robust HbA1c lowering with only a once-weekly therapy seems quite attractive," Dr. Dungan told Medscape Medical News. "We do have to consider other potential issues, such as tolerability. About 20% of patients in both groups had some nausea. Ultimately, we are all going to be thinking about cost, and that remains to be seen. This presents another attractive option for treating hyperglycemia in patients with type 2 diabetes."
In an accompanying editorial, André J. Scheen, MD, of the University of Liège, Belgium, writes that the new findings may help inform the decision of which incretin-based drug is preferred as a second- or third-line agent when patients don't achieve target HbA1c with metformin alone or in combination with other agents, although questions remain.
With regard to the GLP-1 agonist class, Dr. Scheen writes, "The obvious advantage of a once-weekly versus a once-daily injection concerns patients' acceptance and possibly compliance. However, compliance might be different in clinical trials, in which it is strictly controlled and regularly reinforced, as compared with everyday practice. Therefore, prediction of how short-term differences in compliance, balanced by potential improvement in patients' acceptance and compliance with the once-weekly medication, would affect glycemic control in daily life is difficult and needs further study."
Adverse Event Rates Similar
At baseline, patients had an average HbA1c of 8.1%, even with metformin treatment. Dulaglutide was started at 1.5 mg once-weekly and continued at that dose for the 26-week treatment period. Liraglutide was initiated according to labeling, and started at 0.6 mg/day in Week 1 and titrated up to 1.8 mg/day in Week 3.
Despite the differences in dosing, gastrointestinal adverse-event rates were similar in the 2 groups. The most common were nausea (20% with dulaglutide and 18% with liraglutide), diarrhea (12% in both groups), dyspepsia (8% and 6%, respectively), and vomiting (7% and 8%, respectively).
"Nausea peaked in both groups around 2 weeks and then declined to about 5% in both groups by 12 weeks... The curves are almost superimposable. You reach a steady stay in 2 to 3 weeks," Dr. Dungan said.
Both groups experienced significant weight loss: 3.61 kg for liraglutide compared with 2.90 kg for dulaglutide (P = .011). "The difference was statistically significant, but we don't how clinically significant that would be," she noted.
Hypoglycemia rates were 0.34 and 0.52 events/patient/year, with no severe episodes reported.
The authors note that they had originally wanted the trial to be blinded, but had to conduct it open-label because they could not obtain a liraglutide placebo pen.
Which Incretin-Based Drug Is Best?
Incretin mimetics, such as GLP-1 agonists, and incretin enhancers, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, are increasingly being used as second-line treatment after failure of metformin monotherapy, or later in triple combinations, according to Dr. Scheen.
In comparing the drug classes, he notes that GLP-1 agonists are better at lowering glucose than DPP-4 inhibitors, and GLP-1 agonists promote weight loss. But they are expensive, cause nausea and vomiting, and must be injected. By comparison, DPP-4 inhibitors have the advantages of oral administration, lower cost, and better gastrointestinal tolerability. On the downside, they do not lower glucose levels as well and do not promote weight loss.
There are an increasing number of GLP-1 options from which to choose. Although they all share the same mechanism of action, data suggest that their effects differ, especially regarding gastric emptying, resulting in different effects on postprandial versus fasting plasma glucose, Dr. Scheen writes.
But most data about the differences among the agents come from indirect comparisons between short- and long-acting GLP-1 agonists rather than head-to-head trials, and that is also the case for several large, long-term prospective trials currently underway.
Dr. Scheen concludes, "Although none of these trials will provide head-to-head comparisons, the data they will offer to the medical community should help physicians in the best choice of incretin-based therapies for management of type 2 diabetes."
Dr. Dungan and colleagues presented the trial results earlier this year at the American Diabetes Association (ADA) 2014 Scientific Sessions.
This trial was sponsored by Eli Lilly . Dr. Dungan reports consulting and advisory board activities with Eli Lilly, and research support from Novo Nordisk. Her coauthors have also received honoraria, speaker fees, or advisory fees from Eli Lilly, and 3 coauthors are Eli Lilly employees. Dr. Scheen has received lecture, adviser’s, or investigator’s fees from AstraZeneca/Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, sanofi-aventis, and Takeda.
The Lancet. Published online July 11, 2014. Abstract Editorial extract

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