Diabetes In Control Publisher Steve Freed interviewed Dr. David D’Alessio, Associate Professor of Medicine, Division of Endocrinology, University of Cincinnati, and the Albert Vontz chair in Diabetes Research. Dr. D’Alessio helps us understand some of the newest research on GLP-1’s, how he uses these therapies in his own practice and what he’s looking forward to in the pipeline….
Steve Freed: As far as the positive effect the GLP-1s have on postprandial blood glucose, is that primarily due to the restoration of the first phase insulin response?
Dr. D’Alessio: I think that in humans eating a meal, having early insulin secretion is important, and people have shown that with GLP-1 or exendin-4 you do left-shift the insulin response; it tends to be faster. And this, I think, is part of a whole, you make the beta cell more sensitive to glucose, and I think that’s a big thing. I think that’s an important aspect of the GLP-1 actions. I think suppressing glucagon probably plays a pretty good role, too, and I think especially with exendin-4, with Byetta, the glucose regulation in the short term, there is a contribution from delaying gastric emptying, that is having a meal just sit in the stomach for longer such that what gets metered out to the intestine and absorbed into the blood happens at a slower pace.
One way to look at people with diabetes is that their storage, their assimilation of glucose is much slower because of their insulin resistance and decreased insulin secretion. So if it’s slower and you give them glucose slower, I think that can be an advantage. So I think the GLP-1s, to a certain extent, have this really broad range of actions, and I think that is one of the things that makes them such an appealing drug. Part of me wonders why, with all these great actions, you don’t get reductions in A1C of 2 or 2.5. Mechanistically, they seem like fantastic drugs, and I think in a lot of people they are fantastic drugs. But on average they lower blood sugar about the same as everything else.
SF: What do we actually know, in the GLP-1 compounds, about the extra islet effect on the heart?
Dr. D’Alessio: That’s a great question, and since that’s really at the core of what are trying to do with diabetes, I’m a little surprised that that field hasn’t moved as fast. I mean, there is data going back six or seven years that GLP-1 might have some effect on the heart. Dan Drucker gave a nice review of this at the ADA, and his group has done a lot of the animal work. I still think we’re lacking for a lot of good human data. I think it seems likely that GLP-1 binds to cardiomyocytes and to vascular endothelial cells, and you can show effects in humans, diabetic and non-diabetic humans, that GLP-1 promotes vasodilation. I think everybody thinks that a good thing.
There was an abstract or a presentation at the ADA that you could use GLP-1 in the ICU to lower blood sugar and that it was nearly as effective as using insulin with maybe less hypoglycemia. I think that actually is a plausible use of GLP-1 going forward. I think what we lack now, though, are studies, and I think there’s some information that will come out in the next few years about what happens if you treat a diabetic patient with heart disease with a GLP-1 versus a conventional drug. Do you affect the cardiac outcomes? And that’s the kind of thing that would really drive the field.
I think that as part of the FDA’s new mandate, that new diabetes drugs have a cardiovascular safety study, I think a lot of companies have safety studies ongoing with their GLP drug or their DPP-4 inhibitor. These aren’t powered to show positive effects. They’re powered to show no negative effect, and that’s a smaller sample. But, if they showed positive effects, I think that would change the game entirely. That would really drive the usage of these drugs. If you could show that a type 2 diabetic patient who had had a recent stent or myocardial infarction or something, if you put them on a GLP versus anything else, that their cardiac disease would be better, I think the push would be to really use these drugs a lot. But again, I think that is all presumptive right now.
We don’t have enough data to make that as a recommendation. But I agree. To me that’s ultimately, maybe, the most important aspect of this class of drugs is, Is there a cardiac effect in humans? How potent is it? What exactly is it? It’s funny. It’s one of those sort of cross-cutting areas of research where you’re talking about outcomes that the cardiologists usually focus on, and treatments that the diabetologist usually use, and nobody has put together a team to go after this in a multidisciplinary way. But I think there will be information coming forward in the next couple of years.
SF: Is the GLP-1’s major effect from the glucagon reduction in the alpha cells, or is the effect on insulin secretion?
Dr. D’Alessio: That’s really hard to say. There was nice paper in Diabetes last fall by Jens Holst that said it was 50-50, and I wrote an editorial to that paper that said that’s a good estimate but I think it’s really hard to tell. One of the problems is, when you put people on a GLP-1 drug, glucose goes down, glucagon goes down, insulin goes up, and to carefully sort out which of those is the major player is really hard. So the way I think of it is, probably the glucagon effect is at least 20 percent, the beta cell effect is probably at least 50 percent, and the truth is somewhere in between there.
The other thing I’d say is that in some diabetic patients high glucagon and a big drive to deliver glucose production is probably a very prominent part of their disease. In other people, the glucagon level is not so high and maybe it doesn’t have such a big effect. Beta cell deficiency is a big part of their disease. So in those two different patients, GLP-1 might have different relative actions. The guy with high glucagon might really benefit a lot from inhibiting glucagon. The guy with bad beta cells may be the opposite. To me that’s an interesting question, scientifically, but it also is one that we’re going to have really limited tools to answer in humans, and ultimately in the clinic it may not matter that much.
SF: How comfortable do you feel with the safety of the GLP-1 compounds?
Dr. D’Alessio: I think so far we have a few years of data and a few million patients, and that makes me moderately comfortable. A drug like metformin, where it’s been around for decades and tens of millions of patients, you have a little more surety. There is this sort of background buzz now about, is GLP-1 going to cause GLP-1 receptor activation? Is it going to cause thyroid C-cell hyperplasia? Is it going to cause exocrine pancreas hypertrophy and potentially neoplasms?
Those, again, are studies that are driven by animal models, and there don’t seem to be a lot of them, and you can find counterbalancing evidence across the board. But that’s the way with any new drug. If it’s only been on the market for five years, you don’t know what the toxicity is going to be in ten-year exposures. But I’m moderately happy with the safety, tolerability for sure, of those drugs right now. The nausea has been less of a problem than I thought it was going to be. The DPP-4 inhibitors have been way more tolerable even than I imagined that they’d be. Ultimately, safety just takes a lot of time to really iron out.
SF: You said nausea isn’t a really major problem for most of your patients, but when it is, how do you normally deal with it?
Dr. D’Alessio: Well, again, when I start to worry usually is when you start somebody on a low dose of either liraglutide or exenatide and the nausea persists for 10 to 14 days. Almost everybody will say they feel something at the beginning, and half the people actually say, “I feel queasy,” but it gets better over time. And in a minority of patients it doesn’t, and it becomes impossible for them to advance the dose. Some of them start to tolerate a low dose and you just keep them on a low dose for awhile. But yeah, there are some people but it’s a small percentage that just never get over that.
SF: Have you seen in your patients, that if they take the dose closer to the meal, then you won’t get as much nauseousness.
Dr. D’Alessio: That’s a good tip, although I’ve had patients say, “I take my second dose right before bed because if I’m asleep I’m not nauseated.” So it goes both ways, but yeah, there are ways to mitigate it, although the best way to mitigate it is to just stay on it and develop a bit of a tolerance to it, is what seems to happen for most people. But when they first came out I thought, “Man, you’re talking about 40 percent of people being nauseated with the first dose? You’re going to have nobody take the second dose.” But people do, and the clinical trial experience and the clinic experience aren’t that far off in terms of number of people you can get on the drug.
SF: I always thought that because the DPP-4s prevent destruction of GLP-1 that maybe a combination product, where you can lower the dose of the GLP-1 and make it more effective, but I haven’t really heard anything about that.
Dr. D’Alessio: I think, in general, most of the injectable agonists – certainly liraglutide and exenatide just aren’t that susceptible to DPP-4, period. They’re metabolized by other systems that DPP-4 doesn’t affect. And then the native GLP-1 that DPP-4s protect, it doesn’t go up a lot compared to, say, what you get when you give an injectable. Now, I think nobody’s tried it in a trial. I bet there are docs out there that are using the combination and it may work to good effect. Not all combination therapy has to make sense on paper, but so far nobody’s taken that up as a proposed combination to really test hard.
SF: What are some of the new therapies in the pipeline that you’re most excited about?
Dr. D’Alessio: The things I’ve been watching the hardest is the SGLT-2 inhibitors. I really thought that was going to go nowhere, so when you’re wrong you’re always more interested, because it’s actually gone somewhere. It’s gotten pretty close. I mean, there are still a lot of questions. It seems like getting from Phase 3 to market can be a big leap sometimes. I would be curious as to how those do. If they end up being safe and tolerable, I can see them having a broad role because they could complement almost any other therapy.
At some point you knew the DPP-4s were going to get to market because they just had very little toxicity, and I’m not as comfortable saying that about the SGLT-2s, but I am interested in that class of drug. In terms of other stuff that may be coming down the line, of course I’m very interested in long-acting GLP-1s, mostly how they may different in their effects from short-acting GLP-1s. That is sort of a physiologically and scientifically interesting question to me.
The other kinds of drugs that are out there, things like glucokinase activators, the G-protein-coupled receptor for GP-40 and GP-119 – those, again, are sort of chalkboard therapies right now. I just don’t think there’s enough information to say yay or nay about them. I mean, I’m happy that there’s stuff in the pipeline. I’m always interested in what ends up being a potential therapy. But at some point you have to see some Phase 2 data before you really get on the bandwagon.
SF: I know you’ve got to get back to the clinic, so the last question is, what do you think is the key to physicians’ acceptance of GLP-1 therapy, because I still see a lot of patients where doctors are just reluctant to prescribe the GLP-1 drugs because it’s only been on the market five years, and many physicians would like to have it on the market for 20 years before they feel safe in prescribing.
Dr. D’Alessio: To a certain extent I like to have the bulk of the physician population be sort of conservative with what they are prescribing. I think it’s like anything, is that once you get one or two good experiences with a drug – and oftentimes it’s in patients who come in and ask for it. They say, “I want this one. I read about this and I want to try this,” and you say, “You know, it’s new, blah-blah-blah,” and they say, “No, I don’t care. I’ll try it.” And if you do and you get a couple of good experiences, I think that always has a really big impact in practice.
Unfortunately, our practice patterns are shaped a lot more by anecdote – which oftentimes is very unsystematic – but I think that’s the reality is that you believe what your experience tells you, to a certain extent. And again, it’s like the bariatric surgeons always ask me, “The primary cares don’t believe in this,” and I say, “All it takes is one good outcome. They’re all struggling with obese patients and all is takes is for them to see one guy get a bypass and lose 100 pounds, and they’ll start to believe.” I think that’s probably how it goes with new drugs, too, is that you sort of jump in there, or are pushed in there, or you get a good outcome. But I agree with you completely. It is a glacial process. It takes time.
SF: Thank you very much for taking the time from your busy schedule to answer our questions
Dr. D’Alessio: Great talking to you.
Dr. David D’Alessio is an Associate Professor of Medicine, in the Division of Endocrinology, and holds the Albert Vontz chair in Diabetes Research. He joined the faculty at University of Cincinnati in 1999. Dr. D’Alessio has received national recognition for research on gastrointestinal hormones and the regulation of insulin secretion. He has published widely in this area, as well as in related aspects of energy metabolism and nutrition. Dr. D’Alessio is ABIM certified in Internal Medicine and Endocrinology and attends the Diabetes and Endocrine clinics at University Hospital and the Cincinnati VA hospital. He is a member of the Endocrine Society, American Diabetes Association, American Heart Association, and serves on the national council for the American Federation for Medical Research.
The primary focus of Dr. D’Alessio’s research is the regulation of insulin secretion and glucose tolerance in type 2 diabetes, and specifically the influence of intestinal hormones on these processes. In addition, he has additional projects to investigate the actions of GI peptides to control food intake and body weight. Central themes that are common to all of this research is the interaction of ingested nutrients with endocrine signaling systems, and the interface between hormones and the nervous system. The overall goal of this work is to better understand the physiologic mechanisms underlying nutrient metabolism and apply this knowledge to the treatment of diabetes and obesity.
Dr. D’Alessio joined the faculty at the University of Cincinnati in 1999. He has published widely in gastrointestinal hormones and the regulation of insulin secretion as well as in related aspects of energy metabolism and nutrition. He is ABIM certified in Internal Medicine and Endocrinology and serves as an attending in the Diabetes and Endocrine subspecialty clinics at the Cincinnati VA Hospital. He is a member of the Endocrine Society, the American Diabetes Association, and the American Federation for Medical Research. Dr. D’Alessio is also a faculty member in the Pathobiology and Neuroscience programs at the University of Cincinnati.
See more SGLT-2 Resources