James T. Kenney, RPh, MBA: They may. Clearly, within each of these classes we’ve talked about, most plans are going to have a preferred [1] or 2 choices within each category. So there are going to be lower-cost options available in the DPP-4s [dipeptidyl-peptidase-4 inhibitors], SGLT2s [sodium-glucose cotransporter 2 inhibitors], GLP-1s [glucagon-like peptide-1 receptor agonists], but not all are available, as we talked about earlier. So you’re going to have to—as a physician, you have to—work with the plan, or the formulary design, or the patient to try to figure out what the choices are that are going to be in the lower tiers and the lower cost. One comment about sulfonylureas: they’re old drugs, they’re all available generically, and they’re very inexpensive. If a patient is really money sensitive, you may have some primary care docs who are going to offer that as an alternative, which is not ideal, as Helena suggested. But because they’re inexpensive, we still see a fair amount of use of sulfonylureas. And the plans certainly aren’t promoting that. There’s no plan that’s saying use a sulfonylurea first typically. They’re saying metformin.

Peter Salgo, MD: We are in the 21st century, right? Those are old drugs. Not all old drugs are bad, but we have new drugs that are good, from what I heard over here. That’s surprising, I guess, and a bit depressing.

James T. Kenney, RPh, MBA: Well, it is, but a lot of your Medicare patients are very cost sensitive, so they’re looking for generics. If you look at the generic rates of use in that population, 90% of the drug use, or approaching 90%, is generic because [of] the co-pays. [In] some cases it’s 0 co-pay. If a drug falls in the first tier of a typical Medicare Part D benefit, there’s no co-pay. If it falls in the second tier as a generic, it may be a $10 co-pay. So it’s very aggressive for these patients to try to get that low-cost drug if they can get it.

Peter Salgo, MD: Other than money, are there some of these drugs which have better patient adherence than others? Do patients like them better?

Om P. Ganda, MD: Well, I think the adherence is not a major issue with the SGLT2 inhibitors. It’s 1 pill a day, so it’s not a big deal. And as we discussed, GLP-1 inhibitors, when we want to use them, [are] not only 1 injection a day, as [they] used to be, or 2 injections a day. Now it’s once a week. So the compliance is better, and then patients don’t mind taking injection once every week rather than once a day. So it’s easier.

Peter Salgo, MD: What about long-term safety data? We know about the good side. Are these drugs dangerous in any way? Are there [adverse] effects we need to know about? One drug class versus another that you’d rather prescribe?

Helena W. Rodbard, MD: Well, in terms of safety, the cardiovascular outcome trials have already shown that they’re safe with a few limitations.

Peter Salgo, MD: Like what?

Helena W. Rodbard, MD: The limitations are like the class of SGLT2 inhibitors. They tend to drop the blood pressure. They can also be associated with increased incidence of vaginal and genital infections, mycotic infections, [and] not necessarily urinary tract infections. So those are potential [adverse] effects [that are] relatively minor. They can be easily mitigated and avoided. The GLP-1 receptor agonists, typically it’s the GI [gastrointestinal] problems of nausea, vomiting, [and] diarrhea, which are also mitigated by gradual escalation of the dose. So there are lots of things we can do in terms of minimizing the potential [adverse] effects. But all in all they are safe drugs.

Om P. Ganda, MD: The only thing I would add to that is that there has been this concern about acute pancreatitis with incretin agents, both with the DPP-4 agents and the GLP-1 receptor. The FDA is still waiting for more data. We still don’t have a final answer on that, but if [a] patient has [a] history of acute pancreatitis, [it’s] probably wise not to use these agents. Similarly, with SGLT2 inhibitors, Helena mentioned the mycotic infections. That’s the main concern, more in women than in men, but still the incidence is less than 10%.

Peter Salgo, MD: But 10% is not 0.

Om P. Ganda, MD: No. That’s exactly right.

Helena W. Rodbard, MD: And then there is another concern, and that is [that] it [is] actually for amputations with 1 of the drugs of the class of the SGLT2 inhibitors—canagliflozin, specifically [for] lower-limb amputations. But that has not been seen in the study that was just published, the CREDENCE study. So they did not find that. So the drug has that warning in itself. And another 1, ertugliflozin—another drug of the SGLT2—also has that on [its] label. But this study, CREDENCE, did not find any increased incidence of amputation.

Peter Salgo, MD: [It’s] tricky, because a number of diabetics are going to get amputations no matter what, so you’ve got to parse all that out.

Helena W. Rodbard, MD: That’s the point. Yeah, that’s a good point.

Peter Salgo, MD: What about injectable versus oral. I’m going to ask the obvious question. What do patients like? Surprise me.

Helena W. Rodbard, MD: I’ll surprise you. They love injections—just kidding. No, they actually would rather pop a pill than take an injection. But what I do with the injectables is exactly what I do with insulin, [which] I alluded to at the beginning of our conversation today. I just give them the first shot in the office, and then the fear factor is over, so they don’t have to worry about it anymore. It’s not painful, and it is simple, especially if it’s a once-a-week, as Om said. It’s a once-a-week preparation. It’s a no-brainer. It’s very simple.

Peter Salgo, MD: But are there cost impacts of injectables that the orals don’t have?

James T. Kenney, RPh, MBA: Well, I think the question of oral versus injectable does come back to cost from the plan perspective. So you might have a situation [in which] the injectable is less expensive than the oral, and a plan might say we want you to use the injectable before you can use the oral. Now, we’re going to have potentially an oral GLP-1 that’s coming to market. We don’t know where the price is going to be. If it was priced at a premium to the injection, I suspect that plans would require injection first because there’s no reason not to say you can take a once-a-week injection. These devices are great: the pens are very easy to use, [and] the needles are small. It makes it very easy. So it’s not always the most convenient or easiest dose that the plans are in favor of because cost can play a big role.

Peter Salgo, MD: But I can hear the patient saying right now, got injectable, got a pill. I’m taking the pill, no?

Om P. Ganda, MD: You might have them take both.

Peter Salgo, MD: Or both.

Helena W. Rodbard, MD: That’s right.

Om P. Ganda, MD: There is a reason to use them both together because they complement each other’s actions.

Helena W. Rodbard, MD: That’s right.

James T. Kenney, RPh, MBA: And adherence is a funny thing. There [are] a lot of issues related to adherences. There’s cost driven. Patient can’t afford it, so they’re nonadherent. But there [are] lots of other reasons to be nonadherent, and there’s no guarantee that somebody [who] gets a once-a-week injection is going to be any more adherent than somebody [who] has a once-a-day pill because they still have to remember every week to take the injection.

Peter Salgo, MD: Unless you bring them back to your office once a week.

James T. Kenney, RPh, MBA: Correct.

Peter Salgo, MD: And then you actually have a real hard follow-up.

James T. Kenney, RPh, MBA: But then the health plan doesn’t want to pay for the office visit.

Helena W. Rodbard, MD: It’s not feasible.

Peter Salgo, MD: They won’t pay for the office visit. When you compare primary care physicians versus endocrinologists, do they tend to choose 1 agent more than another?

Helena W. Rodbard, MD: Yeah. Typically, as Jim said, they tend to use more sulfonylureas. They seem to like sulfonylureas because they’re inexpensive. There are no calls for preauthorization. It’s just easy. However.

Peter Salgo, MD: But it’s also inertia, right?

Helena W. Rodbard, MD: It’s inertia. It is the inertia. But they don’t want to handle all the—in general, all the strings attached to the newer drugs.

Peter Salgo, MD: If you had a message for them, what would it be?

Helena W. Rodbard, MD: My message would be please think about the patients first. I know it’s inconvenient. I do pre-authorizations. I don’t like them. But if I’m worried about my patient, I don’t want them to have hypoglycemia. I don’t want them to be gaining weight in general.

Om P. Ganda, MD: Yeah, I think these drugs are not going to go away because they can be useful in certain people who are not financially well off [and] can’t afford to pay the co-pay. And look at it globally, where these drugs are either not available or they’re very, very expensive because people have no insurance. We are fortunate in this country that the majority of the people have some kind of coverage. So it comes down to only a small co-pay. Or the co-pay can be higher until these drugs go generic.

Peter Salgo, MD: Let’s just put the 900-pound elephant on the table. What tier do these new drugs fall into?

James T. Kenney, RPh, MBA: Well, I think the newer drugs that launch typically are in a noncovered position, and then the formulary committee has to take a look at it, figure out where it’s going to be placed, [and] do a full analysis of the science. And we look at all the same things the physicians look at—efficacy, safety, [and] tolerability are paramount first. If it passes those as being favorable, then we look at cost and then compare it [with] what’s already on formulary, what’s already in the basket. And I think what you see is a mixed bag. Most of the time, you’re going to see a preferred agent or 2 in each of these categories on a preferred tier. And the numbering doesn’t make sense. People say, “I want to be tier 3. I want to be tier 2.” The numbers are all over the place. The bottom line is you’re looking to have drugs in a preferred branded tier from each of the classes—DPP-4, SGLT2, GLP-1s. But others are going to either be not covered at all because the plans are trying to drive to the preferred products on the formulary or they’re going to be in a higher tier. Now with co-pay assistance programming, you can certainly work around that, but you might have to fail 1 or 2 preferred drugs within 1 of those therapeutic classes first before you can get 1 of the nonpreferreds.

Peter Salgo, MD: And where does Medicare [and] Medicaid reimbursement fall in all this?

James T. Kenney, RPh, MBA: Well, Medicare and Medicaid are similar. I think the Medicaid plans are also driven by formulary process. They’re driven by price. They’re driven by mandatory rebates that are paid on the Medicaid products—[that] drives a lot of that choice. And Medicare similarly. There’s contracting in the Medicare space. There’s also a limit as to how many drugs a plan wants to put on a formulary. Plans also worry about adverse selection if you think about that. If your formulary has every drug imaginable on it, you’re going to get [them]—all the diabetics are going to join your plan. So you have to have some available, and they’re also evaluated by the local carrier units for Medicare. They look at them and say, “Yeah, your formulary has enough choices, so we’re going to accept that.” We also have that for the state health [insurance marketplace] exchanges. Those formularies have required numbers of drugs within the categories. So at a minimum, you might need 10 drugs in the diabetes category on formulary. [That] doesn’t necessarily [mean] 10 from each category but 10 across all the categories. It’s a bit of a juggling act to try to build the formularies, and that’s why some of them are very different.