Combinations in the Treatment of Type 2 Diabetes

Peter Salgo, MD: Let’s talk about something that you’ve alluded to, which is combinations of these products. Because I think it’s tempting to look at them as single entities, but you say that you can combine some.

Om P. Ganda, MD: Yeah. So we had actually this concept there for a long time. Believe it or not, it happened in the days of sulfonylurea and metformin. There used to be this combined drug Glucovance and things like that.

Helena W. Rodbard, MD: I remember.

Om P. Ganda, MD: They worked. And actually there is some science behind it too, because if you give 2 complementary drugs together, they actually seem to be a little bit better than each individual drug given separately. So that was the old concept. But now with the newer drugs, first of all, every drug that you can think about—[DPP-4s] [dipeptidyl-peptidase-4 inhibitors], or SGLT2s [sodium-glucose cotransporter 2 inhibitors], actually all the oral drugs—come in combination with metformin. So you don’t have to take a second drug in combination with metformin as a separate drug but as a fixed-dose combination. There are pluses and minuses of this approach, because you can’t change 1 drug without changing both of them at the same time, but they’re useful for some patients who are concerned with [the] number of pills they have to take.

Peter Salgo, MD: Cardiologists were kind of ahead of you guys too, with the antihypertensives, right?

Om P. Ganda, MD: Exactly, right. The hydrochlorothiazide and the ACE [angiotensin-converting enzyme] inhibitors.

Peter Salgo, MD: People, the argument they made was exactly yours. You can’t change 1 without changing the other. But at the end of the day, the combination products work.

Om P. Ganda, MD: Yeah. It was a little bit different there because they both seemed to be complementary from the blood pressure point of view, but here we’re talking about [how] maybe this combination may not work, [or] they may want to try a different combination. In any case, there are now drugs with the SGLT2 in combination with DPP-4 inhibitors.

Peter Salgo, MD: Right. First you were talking about DPP-4s and metformin. Now you’re upping your game. You’re going to DPP-4s and SGLT2 inhibitors. But they’re working on the same chemical here, right?

Om P. Ganda, MD: They are, and we think that the adherence might be better.

Peter Salgo, MD: Why?

Om P. Ganda, MD: Because again, [there’s a smaller] number of pills [and] hopefully less cost. That still remains to be determined, because as we discussed with SGLT2s, cost is the big driving factor [for why] co-pays are not trivial. And [it depends] on what your insurance plan is. So I’m hoping that some of these drugs will still be useful in primary care practice if not in endocrine practice. Because we might have a little bit [of a] different view about these fixed-drug combinations, but from a practicality point of view, they work.

Peter Salgo, MD: In your hands, what do you think it is?

Helena W. Rodbard, MD: Another combination that I like is insulin and GLP-1 receptor agonist.

Om P. Ganda, MD: Exactly.

Helena W. Rodbard, MD: I really think it’s a good combination. It’s 1 shot instead of 2 shots. It’s 1 co-pay, which patients really appreciate, and then it allows for the dose escalation of the GLP-1 receptor agonist very gradually. And ultimately the person needs less insulin than they would have needed and [is] achieving better glycemic control. So that’s another combination that I like a lot, and I think it would be particularly important for primary care physicians. It’s just easy. It’s simple.

Peter Salgo, MD: Wait, is that a commercial preparation that’s out there?

Helena W. Rodbard, MD: Oh yes, there are 2...

Peter Salgo, MD: You’re not brewing this up...

Helena W. Rodbard, MD: No, no. We have 2 such commercial preparations available that have been for a couple of years.

Peter Salgo, MD: So what are the practical implications of these combinations products? I hear it’s convenient. I hear that you can ramp them up a little bit and that they’re synergistic. But from the perspective of prescribing [and] monitoring, is this something that primary care [physicians] can do? Or is it something that you need to be an endocrinologist to do?

Helena W. Rodbard, MD: No, primary care physicians can do it, and they can do it very successfully. In fact, it’s just easier because, as Om said, it increases adherence, so they don’t have to worry about the patient not taking umpteen pills a day. Because let’s face it, people with diabetes have so many comorbidities in addition to having diabetes. They have blood pressure problems, they have lipids, they may have arthritis, they may have gout, they may have all kinds of other issues, so not uncommonly they are taking 6, 7, 8 different kind of medications. So if we can simplify a little bit, at least the diabetes regimen, that’s going to be very beneficial.

Om P. Ganda, MD: Yeah, and the other point about it is that we’ve been saying for a long time, when the older drugs don’t work or the noninsulin drugs don’t work, then GLP-1 receptor agonists along with basal insulin—which is the concept behind these injectable combinations—is a very good combination.

Peter Salgo, MD: What about safety? Is there an impact on safety, either plus or minus, compared [with] the individual drugs of putting these drugs together?

Om P. Ganda, MD: Well, the only safety issue—first of all, the hypoglycemia. With any insulin combination product, that still remains. But we think that the insulin load might go down, and there might be less hypoglycemia.

Peter Salgo, MD: Where do, in your view, these combination products fit into the plan? Do you like them?

James T. Kenney, RPh, MBA: It depends.

Peter Salgo, MD: Oh, thanks.

Om P. Ganda, MD: It always depends.

James T. Kenney, RPh, MBA: The first question you ask whenever you see a combination is what’s the cost of the combination compared [with] the individual components. That’s question No 1. Question No 2 is, are the individual components on formulary. So you often have a situation [in which] a combination is launched and maybe 1 of the 2 ingredients is on formulary but the second 1 is not. And then you have to figure out, can we add the second component? Is it going to blow up the rest of the formulary or blow up the preferred pool of drugs or not?

Peter Salgo, MD: But if it’s the same drug—in other words, the individual drug may not be in the formulary, but the combined drug can be in the formulary, even though 1 component is not.

James T. Kenney, RPh, MBA: Correct. But the formulary premise is if you’re going to cover a combination, you should be covering both ingredients as well, so the physician in theory could try both and then put them together, rather than just saying we only cover [part]. [If] you can’t get part of a drug combination because we don’t cover it, [that] really doesn’t provide a credible formulary to the physicians to work with. So you have to go back and figure out, are we going to change the original formulary and add the missing drug and add the combination? More often than not, these things flow as line extensions. If you have the DPP-4 and the SGLT2 already on formulary, the combination just gets added as a line extension. And most of the time, the cost is not a factor. In fact, it maybe costs substantially less than the actual 2 drugs individually, and then it’s a bonus. The plan saves money. The patient pays a single co-pay. Everybody wins.

Peter Salgo, MD: Now, we have 2 potential combinations here. You can have a branded drug with a generic or a branded drug with a branded drug. Does that make a difference?

James T. Kenney, RPh, MBA: Well, it only makes a difference just in terms of the formulary positioning. A generic is typically going to be on formulary across the board, unless for safety reasons or something it wasn’t covered. But brand to brand can create a challenge because, again, our view was always in the formulary committees I worked on—I did Medicaid, Medicare, commercial—was always you kind of needed both ingredients on formulary if you were going to put the combination on formulary.