Challenges of Accelerating Treatment to Get to Goal


Dr. Doron Schneider: Hi, I'm Dr. Doron Schneider. I'm a general internist at Abington Health Center right outside of Philadelphia. There I am the chief quality and safety officer for the health system and deputy program director for internal medicine. And with me I have Dr. Jack Leahy. Jack …
Dr. Jack Leahy: Great. I'm Jack Leahy. I'm the endocrine chief at the University of Vermont here in Burlington. I'm very interested in diabetes pathogenesis, but also clinical care.
Dr. Doron Schneider: Thanks, Jack. We are hoping in the next period of time to provide some reflections on current diabetes care. I'd like to get your perspective on the patient who's on two agents with an A1C greater than 8.5.
Dr. Jack Leahy: The answer to this is really important because this is a common, everyday scenario in so many doctors' offices. The standard starting drug is metformin. Many providers in this country or really around the world will then use a sulfonylurea for second choice. There used to be TZD usage that's reducing because of problems with that drug, and there certainly is more usage with the DPP-IV inhibitor. But still having said that let's assume a patient comes to you and if they're on two drugs we'll start with metformin and a sulfonylurea, and if their A1C is 8.5 percent and if the discussion with the patient is, "I would like another pill. Do not give me injection," then your choices are the following: you know, you could do a TZD, an insulin sensitizer. For some people it's magical. For some people it doesn't do much. There is a weight gain potential. It's an expensive drug. And, you know, we're all a little bit nervous about that class of drugs these days in part because of all this discussion about bladder issues, but also the bone fracture risk in woman. So, you know, it's probably not going to get you to goal if you're 8.5 down toall the way down to 7and it comes with some significant baggage so that would be a very limited choice, quite frankly. The other kind of oral agent that people love to talk about are the DPP-IV inhibitors because they're cool and they're new and there's a lot of discussion among the pharmaceutical companies in a lot of CME presentations, and they're just the new drugs on the block, but the problem is that their efficacy in terms of improving hemoglobin A1C is really pretty modest, as modest as our most modest drugs. And with the hemoglobin A1C of 8.5where people are on two oral agentsif it dropped another one percent when you added the DPP-IV that would be unusual. In most situations it's less than that so now you're going to have people on three oral agents, one of which, DPP-IV, is really expensive, and they're still not going to be to goal and you're going to be having ongoing discussions with your patient about "we need to do something in addition." So the real discussion for me when you're up at 8.5, is you want to chose a therapy that has a real chance, a very significant chance of that change, to get someone to goal. And the marketplace war right now is basal insulin, which I happen to love and have used, you know, for years. And I think it's incredibly powerful and comes with not a lot of baggage versus the injected incretin drugthe GLP-1 receptor agonist—and there are many, many head-to-head trials suggesting that at that chosen level of hemoglobin A1C of 8.5 percent both of those have a very significant chance of getting someone to goal, and they come with different clinical profiles. We all know the profile of insulin and the profile of the GLP-1 drugs. Positive is maybe some weight loss and some improvement in cardiovascular risk factors. Negative, cost and negative, some GI side effects. So sit down with the patient and say, "Well you know the best choice in that situation is insulin versus GLP-1. Let's talk about those two drugs, and then let's make a decision of what you want to do".
Dr. Doron Schneider: I think you're comments reflect very much what's going on in the primary care world. However, I think that the first half of your comments-where the patient not wanting to go to an injectableoccurs more often than not. There is an injection barrier.
Dr. Jack Leahy: That's of course true. And one of the things that interests me is I'll have conversations with our local primary doctors, and they'll tell me that and they'll tell me how that's an incredible barrier to intensifying therapy in their practice, and I understand that. But having said that, no one comes to my clinic who really wants to start injectables. It's not their favorite thing and so it very much becomes the conversation of balancing pluses and minuses and showing patients that the injection is not a big deal. So one of the things that fascinates me is I was recently in a meeting where someone showed data that about 95 percent of primary care doctors identify pain and/or discomfort from the injection as being a major barrier in starting injectables. That's what patients felt and that was a big issue. But then when you look at what percentage of those doctors were actually having patients injected with a needle during the office visit, it's very small. And that to me is a total disconnect because as soon as someone is given a needle injection or can look at the needles or look at pens and see how incredibly small and relatively easy the system is, it really diffuses a lot of the fear. So I understand the barrier, but I think what needs to be introduced in someone's practice are countermeasures against that barrier and it becomes less of a problem.
Dr. Doron Schneider: I completely concur. I wonder if you can give us your thoughts or reflections on beta cell preservation. Our current state of the science is that we just don't know necessarily in humans especially how these drugs may or may not preserve beta cells over long periods of time.I wonder if you can reflect on that, and how should the primary care world be thinking about making a selection of agents based on beta cell preservation as a factor at all?
Dr. Jack Leahy: So this is a great question. I don't think we know enough in today's world to be making treatment choices based upon presumptions of how individual drugs may alter the natural history of the disease versus other drugs. Certainly we can go back five or eight years ago.  One of the disappointing, I think, eye openers in our world from the UKPDS and some of the later studies was a recognition that you can start any of our therapies that start out being reasonably effective, and with time their effectiveness wanes, and that seems to correlate in part with worsening beta cell function and certainly there is a lot of discussion and a lot of hope that we will identify ways—be they through specific agents or through some other mechanism—to change the loss of beta cell function, and therefore, change response to drugs and the natural history of the disease. So the real issue is do we have any of that with any individual drugs and I think probably the short answer is probably not. There was hope that the insulin sensitizers would do some of that, and I would say if you look at data on insulin sensitizers in a reasonably fair, balanced way, they may do better in terms of changing the natural history of the disease than some of our even prior agents to that of metformin and sulfonylurea. How long that lasts I'm not exactly sure and again we're a little bit afraid of those drugs and so that's probably not our future. So the other agents that we've thought a lot about are the incretin agents and the oral agents, the DPP-IV inhibitors and the injected drugs—the GLP-1 drugs. And there was just enormous excitement that they might actually improve beta cell biology in this disease and bring this goal of beta cell protection that's based a lot on both of these agents having been used in rodent models with Type 2 diabetes and in both of them they acted to build the beta cell mass—something that would be spectacularly useful if it had occurred in humans. And so we all waited with semi-bated breath to see if it looks like that occurred and we don't have full information yet, but I think prevailing opinion is probably not. So, when we look at those agents now, especially the injected GLP-1 drug, they seem to improve beta cell function over the long term. So if you're on the agent maybe four years out, beta cell function looks pretty good. So from a beta cell protection point of view it may turn out that they are more effective at improving beta cell function over the long term and then having a longer duration of action in terms of efficacy than our traditional agents. But we don't know that yet and, therefore, it's really premature to try and build that into a guideline. Now the last part of this conversation, and the one that's timely, is well, could insulin actually if used early and used aggressively-change beta cell function and be protective, and there's some information going back a few years that suggests that may be and in particular, a very exciting study that was done in China a few years ago used insulin as an initial therapy very aggressively and then stopped it and, in fact, people went into remission in the disease for more than a year in some people. And then we have the ORIGIN trial which was reported on just a month or two ago at the American Diabetes Association, which is using glargine Lantus insulin very early in the course of Type 2 diabetes—even in some patients in pre-diabetesand one of the findings of that study was the concept that people moving from pre-diabetes to actually Type 2 diabetes seem to be protected against better by an insulin injection as opposed to an oral agent like metformin. It was a fairly minor difference, but it was real. So, maybe insulin has a modest effect for beta cell protection, but when you put all this together I don't think any of this is so secure that this particular feature should be driving our treatment choices and be a prominent part of any treatment outlook.
Dr. Doron Schneider: Okay and just for clarity's sake, the idea of the incretins, you refer to their durability of action, their possible preservation of function over the long haul. Would you suggest that to take fullest advantage of that durability that there's any benefit to beginning incretins earlier in sort of in light of your insulin comment? Should that be how we think about incretins in general?
Dr. Jack Leahy: I don't think we know yet, but it is a really, really important question. There's a fascinating study from the United Kingdom that was published a few years ago of using liraglutide (Victoza) in patients with pre-diabetes, and they happen to use a very large dose—a dose that's more than what's clinically-approved right now. And they looked at weight reduction as one of the dominant clinical outcomes, and it showed that this very high dose of Victoza, 3 milligrams a day, there was just an enormous weight reduction over about 20 weeks of the study, but also the pre-diabetes basically disappeared. There was about a 90 percent reversal of pre-diabetes to normal glycemia. You might expect that because these people lost a lot of weight. So I don't think we know, but certainly one of the big discussions in the diabetes specialty world right now is we're interested in these GLP-1 drugs, and we're trying to figure out when best to use them and what clinical benefits will come with long-term usage of these drugs, and that's still very much an open issue.
Dr. Doron Schneider: Thank you for your wisdom. We look forward to the feedback of the readers and the listeners of Beta Cells in Diabetes and would like to hear your comments, suggestions, thoughts and reflections on what you've heard. Please submit those to betacellsanddiabetes.org. Thank you.