Insulin-Based Combinations in Type 2 Diabetes

Peter Salgo, MD: We’ve got all kinds of new therapies out there. What is the clinical rationale for combining insulin with a GLP-1 (glucagon-like peptide 1) receptor antagonist, for example?

Robert Henry, MD: Complementary mechanisms. The insulin is obviously mandatory at that stage of the disease, but the GLP-1 adds an extra therapy, which is complementary in terms of enhancing insulin secretion. And for some of the GLP-1s, delaying gastric emptying has a marked effect, and postprandial glucose levels can come down pretty dramatically, as well as preprandials or fasting glucose. So, it’s a concept of using the one-two punch. And generally, we tend to use it more after the oral agents. But that’s starting to move up. I think that we’re starting to see a greater move after failure of 2 or more oral agents. Starting a GLP-1 insulin combination therapy either separately or, I believe, together, is the way to go.

Vivian Fonseca, MD: Most of what we said earlier about insulin was around basal insulin, which addresses fasting glucose very well, but does not use the physiological replacement, which involves prandial control—insulin secretion during a meal. You would either have to do that, which is complex, or give something else. You mentioned GLP-1. This is a good combination whereby the basal insulin controls the fasting glucose. Instead of prandial insulin, we’re using GLP-1 receptor antagonists—often 1 injection a day, or once a week, that will stimulate insulin secretion at the time of a meal and suppress glucagon at that time, slow gastric emptying, and control the weight gain. So, there are lots of reasons for using these 2 together.

Carol Wysham, MD: The studies that have been done are remarkable in that they show that doing twice-a-day or once-a-day, or once-weekly GLP-1 on top of basal insulin, is as good as, in terms of A1C reduction, 3-times-a-day prandial insulin—with less hypoglycemia and, of course, a favorable weight outcome. It’s a no-brainer.

Peter Salgo, MD: So, we’re all in agreement?

Vivian Fonseca, MD: Now we are moving toward combining the 2 into 1 injection, and that’s really the key.

Julio Rosenstock, MD: Except that GLP-1 receptor agonists are costly and GLP-1 receptor agonists have an issue of gastrointestinal adverse events. For the most part, they have 25% or 30% nausea and around 8% of vomiting that eventually subsides over time. But many people in the real world stop the medication.

Peter Salgo, MD: I heard a little gasp over here.

Carol Wysham, MD: Yes, because it’s not 20% to 25%. In some cases, it’s 9% or 10%.

Julio Rosenstock, MD: No.

Carol Wysham, MD: Yes. That’s what the data show.

Julio Rosenstock, MD: No.

Carol Wysham, MD: And I think that it’s important to point out that up to 25% of people on metformin have side effects and stop taking it. So, yes, you have an agent that is highly effective. Yes, there’s a percentage of patients that won’t respond and may have side effects. The medications are highly effective. If you look at persistence, it depends upon what you look at. If you compare to oral medications, yes, it’s not going to be as persistent as you get with oral medications.

Julio Rosenstock, MD: But for the most part, the cumulative incidence of nausea is around 25% to 30%. Some people may not have it, but the cumulative incidence is 25% to 35% and vomiting is 8% to 10%. And in an individual in the real world, they’re going to stop this.

The other issue is that the GLP-1 receptor agonists have been prescribed many times, with the expectations of having great weight loss. And when they don’t have the weight loss, they tend to stop it. There’s no question, they do work very well. But it has a reality of gastrointestinal side effects that has been a problem for many patients.

Vivian Fonseca, MD: These side effects are somewhat dose-dependent.

Julio Rosenstock, MD: Of course.

Vivian Fonseca, MD: And titration-dependent.

Julio Rosenstock, MD: Of course.

Vivian Fonseca, MD: We can use lower doses and titrate slowly in order to get that. Now, with the pens it’s not always easy, but it’s possible.

Julio Rosenstock, MD: The only way to titrate slowly is what I conceive as the real game changer, because I like to use game changers. I think that the metformin, when it came in in 1995, was a game changer. Glargine, when it came in in 2000, was a game changer. I think SGLT2s (sodium-glucose co-transporter-2s) are a game changer. And now, putting the 2 together (the basal insulin with the GLP-1) in the same formulation is a major game changer because you start very slowly and as you adjust slowly, the basal insulin, you are giving the GLP-1 very slowly also. And then, instead of having a cumulative of 25% or 30% of nausea, you have 9%. And that becomes highly effective and very tolerable.

Peter Salgo, MD: Did I miss something or did he just agree with you?

Carol Wysham, MD: You know, I think he would agree with me if he used them the way I used them.

Robert Henry, MD: That’s what I was saying earlier: that these drugs are becoming additive, in terms of efficacy, and they’re limiting the side effect profile. Less weight gain or, in fact, weight loss in combination, greater A1C reductions, and the added value of the other benefits that go along with these agents together makes them an ideal combination. And with efficacy, at this stage when they’re used, you can design them to not only lower, as we said, the preprandial or the fasting, but the postprandial as well.

Peter Salgo, MD: You were talking about titrating up. We’ve been talking about fixed-dose combinations. What’s the rationale for the fixed-dose combination then?

Vivian Fonseca, MD: One injection. You’re giving 2 drugs. That injectable with 1 injection.

Robert Henry, MD: Slow titration.

Vivian Fonseca, MD: And slow titration is another. But really, the key for the patient is 1 injection.

Julio Rosenstock, MD: Yes. Let’s be careful with the semantics. You said fixed-dose. Fixed-dose refers to a combination of metformin and a DPP-4 (dipeptidyl peptidase-4) in 1 pill or an SGLT2 and metformin in 1 pill. Here you have a fixed dose. Here, with the basal insulin and GLP-1, you have a fixed ratio that is titrated—so, then you can adjust. People say, “Oh, I’m going to give you something fixed dose.” No, you need to adjust the thing. No, it is fixed ratio between the ratio of the insulin and the ratio of the GLP-1, and as you adjust, you adjust both at the same time and it’s titratable.

Peter Salgo, MD: I get it. That actually does make more physiologic sense, doesn’t it?

Julio Rosenstock, MD: Yes.

Peter Salgo, MD: It’s not just, “Here’s your dose, see you next year.”

Julio Rosenstock, MD: No.

Peter Salgo, MD: The ratio is where we’re at. The FDA has been looking at all of this, right?

Robert Henry, MD: I think it’s going to be much safer, too.

Peter Salgo, MD: How so?

Robert Henry, MD: The algorithms generally go up 2 to 4 units, depending on these fixed ratios. But, in fact, you can do 1 unit per day. And it’s slow, and steady, and safe. I think it’s the way to go—not to be in a terrible rush. This is more to get it done.

Carol Wysham, MD: You know, that fast titration is something that I found, over time, is so much more effective because people get excited at the beginning and they’re really working hard. If you take too long to get to goal, there’s 2 things that are going to happen: they think, “Oh, insulin doesn’t work because my sugars aren’t looking better.” Or they get tired of titrating and they quit testing and quit titrating. So, I like that 1 unit every day. I think it really has improved the patients getting to goal.

Julio Rosenstock, MD: The Canadians did a study and showed that 1 little unit a day in the blood sugars above 100 is totally nonthreatening.

Transcript edited for clarity.