Differentiating Among Newer Combinations in Diabetes

Peter Salgo, MD: You talked about the degludec/liraglutide product studies, if you will. And the FDA did that. There was a DUAL phase III trial, right? So, that’s a different combination of drugs. Why is that different? What is the difference among all of these?

Julio Rosenstock, MD: The DUAL is the combination of degludec plus liraglutide. They have a greater development program than the LixiLan Trial. The LixiLan trial is interesting. They got approved with 2 studies. They did about 6 different studies, but there really was that comparable between the 2—the LixiLan-O with the DUAL-1, and the LixiLan-L with the DUAL-2—because they are testing the combination versus each individual component. And the DUAL-2 study is testing that the combination versus degludec plus liraglutide, versus degludec alone.

Peter Salgo, MD: Where are we with the DUAL trials compared to these?

Carol Wysham, MD: There was about a 0.7% difference when you added liraglutide to degludec versus degludec alone.

Julio Rosenstock, MD: Some vary. It could be 0.5%, and so on, and so forth.

Peter Salgo, MD: What I’m asking is if you’re going to take a look at the LixiLan trials versus the degludec trials, can you compare them?

Carol Wysham, MD: No, you can’t.

Peter Salgo, MD: That’s what I wanted to know.

Robert Henry, MD: Peter, it’s head-to-head. That’s unlikely going to happen. But, to me, they are both very effective. They’re both going to be valuable to the primary care provider who is using basal insulin and not getting the patient where they need to go with a simple, as Carol has said, transition—with a similar, titratable pen and very small needle.

Vivian Fonseca, MD: I think you’re asking, when would you choose this one versus that one? Let me spell it out my way, based on the current recommendations.

Peter Salgo, MD: Take a practitioner through this.

Vivian Fonseca, MD: The FDA says you’ve got to use the combination in somebody who is already on one of these. There are not that many people on lixisenatide since it’s new, but there are a lot of people on Lantus who are not controlled. To me, it means if I’ve got someone on Lantus who is poorly controlled and I need to add a GLP-1 (glucagon-like peptide 1), I would use LixiLan. On the other hand, there are not that many people on degludec because it’s new, but there are a lot of people on liraglutide and they need insulin. For them, I would use that combination that way I’m satisfying the FDA. I hope though, with time and with more trials, the FDA will say, “This is the way to use the first injectable. Choose whatever one you like and give it to people who are failing on oral agents.”

Robert Henry, MD: There is a conceptual difference, though. The conceptual difference is in the GLP-1, primarily. It’s also the insulin, but the GLP-1, with the insulin glargine/lixisenatide, is a rapidly acting GLP-1 that is mainly going to affect gastric emptying and postprandial glucose. The liraglutide component with degludec is going to affect the basal—the preprandial. So, it matters which is most abnormal in the patient. If the patient has good glucose control, except for an elevated postprandial after breakfast, which is very common, then it would be very ideal to use insulin glargine/lixisenatide. If the person is on liraglutide or on glargine and not doing well, you could easily add the combination of degludec and liraglutide to get the whole basal down.

Julio Rosenstock, MD: The rationale is spelled out. First of all, those are drugs that are given in the morning, which makes a lot of sense because you check your blood sugar in the morning and you make the changes right there. Before, we were using that drug at night (in the evening), and that’s probably not a great idea. But you give it in the morning. You know that with lixisenatide, you’re going to knock down the postprandial at breakfast, for sure, and a little bit at lunch. As Bob Henry said, with liraglutide, you have overall coverage. You lower the fasting and you have carryover effect. That’s why you see a difference on insulin. When you’re using LixiLan, you’re adjusting the basal insulin, LixiLan, according to the fasting. With the insulin glargine/liraglutide, you have a little bit of help with the basal insulin. That’s why you end up using much less. And then, you have the carryover. In the end, the bottom line is that both are effective. The major difference is the fact that one has the rule of the 30s. So, when you’re using 42 units and you do the switch, you go down to 30 units. It’s a little bit more of a comfort zone.

Carol Wysham, MD: It’s not as big of a change.

Julio Rosenstock, MD: It’s not going from 42 units to 16 units. And, despite the fact that you didn’t see a problem in the studies with that, in the real world, there may be some disenchantment there. Do you know who is going to decide, regardless of the head-to-head studies and whatever they’re going to show (there’s probably not much difference, regardless of all the smart rationale)? The formularies. Whatever is in the formulary is what the practicing physician is going to use.

Carol Wysham, MD: I really like Vivian’s approach though. I had a patient, yesterday, who I made the decision to change to the combination of insulin glargine/lixisenatide. She was on glargine insulin. Her fasting glucose looked better than her A1C. I knew she needed postprandial, and it was simple.

Peter Salgo, MD: Let’s fast-forward 5 years and assume that there is no new research, that these are the products that are out there, and that these are the products people are going to use. Someone comes in de novo type 2 diabetes. What are you going to start them on, right away, first line?

Robert Henry, MD: First thing I’m going to do is to sit down and talk with the patient about lifestyle modification with a new onset diabetic. Depending on his or her A1C, if he or she comes in with an A1C of 11%, it’s going to be very different than if they’re at 6.9%. My attitude is going to be totally different. All of them are still going to get the same kind of information on lifestyle modification, but obviously, my aggression toward treatment is going to be different. With someone with an A1C that’s less than 7%, or in the low 7%s, one has the opportunity to see some effects of lifestyle modification. But I still would probably start metformin right away.

Carol Wysham, MD: In the A1C that was in the lower range, I would probably agree with Julio and start on a combination metformin regimen.

Robert Henry, MD: Metformin and what?

Carol Wysham, MD: And an SGLT2 (sodium-glucose co-transporter-2) combination drug.

Vivian Fonseca, MD: But all their failures will then come to me, and I will add in one of the GLP-1 insulin combinations.

Carol Wysham, MD: I was just going to say that if my patient was at 11%, I would start them on metformin and one of these agents at the same time.

Transcript edited for clarity.