Anne L. Peters, MD; Kathleen M. Dungan, MD, MPH


June 20, 2014

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Weekly and Daily GLP-1 Drugs Go Head-to-Head

Anne L. Peters, MD: Hi. I am Dr. Anne Peters at the American Diabetes Association (ADA) meetings in San Francisco. I am here with Dr. Kathleen Dungan, Associate Professor of Medicine at Ohio State University and the director of their clinical endocrine trials unit.

Could you tell us about some of the exciting research that you are presenting here at the ADA meeting?

Kathleen M. Dungan, MD, MPH: This study[1] was part of the AWARD-6 trial investigating the clinical efficacy, safety, and tolerability of dulaglutide given once weekly.

Dr. Peters: What is dulaglutide?

Dr. Dungan: Dulaglutide is a glucagon-like peptide-1 (GLP-1)-based therapy. It consists of 2 GLP-1 analogs that are linked to an IgG fragment, which gives it a very large size and a prolonged life.

Dr. Peters: This is another once-weekly GLP-1 receptor agonist that is not yet on the market, correct?

Dr. Dungan: That is correct. It has been submitted to the US Food and Drug Administration. This trial was a randomized controlled trial comparing once-weekly dulaglutide with once-daily liraglutide in a noninferiority design. It was a 26-week study. Patients had type 2 diabetes and were on metformin monotherapy, and the primary endpoint was A1c level. At 26 weeks, the A1c had declined 1.42% in the dulaglutide group and 1.36% in the liraglutide group. That indicates a very small treatment difference that met the predefined endpoint of noninferiority.

Dr. Peters: What was the A1c level before treatment?

Dr. Dungan: The mean baseline A1c level was 8.1%, and 60% to 70% of patients achieved an A1c of less than 7% during this study.

Dr. Peters: The sample consisted of people who were overweight with type 2 diabetes and were in their mid-50s coming into the trial.

Dr. Dungan: Yes. Both groups had significant weight loss -- about 2.6 kg for liraglutide compared with 1.9 kg for dulaglutide. The difference was statistically significant, but we don't how clinically significant that would be.

Dr. Peters: Was this a placebo-controlled trial?

Dr. Dungan: No, this was an open-label study. At the beginning of the trial we wanted to make it completely blinded, but we were unable to acquire a liraglutide placebo device.

Dr. Peters: So this was truly an open-label study. Patients knew they were taking a once-daily or a once-weekly drug, but none of them had been on a GLP-1 receptor agonist in the past?

Dr. Dungan: That is correct.

Dulaglutide: Another Option

Dr. Peters: What does the study say? Were these the results that you expected? Does it make you feel comfortable using this new drug?

Dr. Dungan: From both a patient and physician prospective, having that robust A1c lowering with only a once-weekly therapy seems quite attractive. 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.

Dr. Peters: Did you do surveys of patient preferences? Do people like the weekly approach better than the daily approach?

Dr. Dungan: Some of that information is still being analyzed. From a high level, we didn't identify differences in composite scores, but we are still drilling down into the details. There is a poster here at ADA that looked at patient-reported outcomes.[2]

Dr. Peters: Do you uptitrate the dulaglutide or do you start with a certain dose and stay at that dose?

Dr. Dungan: Dulaglutide was started at 1.5 mg and continued for the 26-week treatment period. Liraglutide, on the other hand, was initiated according to labeling, so it was started at 0.6 mg and titrated up to 1.8 mg over a 2-week period.

Dr. Peters: Were the nausea rates the same from the start, or did they change with the uptitration of the liraglutide?

Dr. Dungan: Nausea peaked in both groups around 2 weeks and then declined to about 5% in both groups by 12 weeks. On our poster, we show a curve illustrating the prevalence of nausea in the 2 groups. The curves are almost superimposable.

Dr. Peters: That's interesting. Perhaps the once-weekly drug builds up slowly at the same rate that you are uptitrating the liraglutide.

Dr. Dungan: You reach a steady stay in 2 to 3 weeks.

Dr. Peters: How soon do you think this is going to be available?

Dr. Dungan: The review date is September.

Diabetes Treatment-Induced Hypoglycemia

Dr. Peters: I would like to change topics for a moment. Have you heard anything here at ADA that you think is particularly noteworthy that you would like to mention?

Dr. Dungan: I was in a symposium yesterday where they were discussing the effects of hypoglycemia on cardiovascular outcomes.[3] The results from ACCORD, the ORIGIN study, and the VA diabetes trial were all reported. The interesting conclusion from all of these studies was that the incidence of severe hypoglycemia increases with intensive treatment and intensive glucose targets. However, that didn't explain mortality differences in these clinical trials. There seems to be something different about treatment-induced hypoglycemia as opposed to the severe hyperglycemia that occurs during standard care.

Dr. Peters: This is a very complicated topic. I am only beginning to understand it. Not everyone is the same in terms of responding to treatments. I also read in passing, about the ORIGIN trial, that hypoglycemia might even be good for you. Do you have any comment on that?

Dr. Dungan: That was discussed at the symposium yesterday. Perhaps there might be some protective effect of mild hypoglycemia when it recurs.

Dr. Peters: Yes. I would argue that avoiding hypoglycemia truly remains a good goal -- not just because of the outcomes, per se, but because patients find it very uncomfortable. And I believe it leads to weight gain and serves as a negative reinforcement for lifestyle changes, whether it's exercise or reducing caloric intake. I'm not going to leap on the "hypoglycemia is good for you" bandwagon, but the data from those trials are fascinating.

Dr. Peters: A paradox that arose from these studies was that patients who were most hyperglycemic and did not improve in terms of A1c reduction were at higher risk for severe hypoglycemia. So there is this incredible paradox. The other conclusion that came from all of this is the importance of educating our patients about how to recognize hypoglycemia and how to treat it.

Dr. Peters: We have a lot of work to do. Thank you very much. This has been enjoyable. This has been Dr. Anne Peters from Medscape.


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