PracticeUpdate Diabetes Best of 2018

EXPERT OPINION 16

An Overview of New Diabetes Treatments Interview with John (Jack) L. Leahy MD by Jason Sloane MD Dr. Leahy is Director of Endocrinology at the

University of Vermont Medical Center and a Professor at Larner College of Medicine at UVM in Burlington, Vermont.

Dr. Sloane: What do we know about the novel GLP-1 glucagon receptor dual agonists from preclinical and clinical trials in terms of mechanism of action, safety profile, and overall effects on weight and glycemic control? Dr. Leahy : We’re reasonably comfortable now with the GLP-1 receptor agonist world. We’ve learned a lot about it. We have clinical drugs and their pro- files are pretty spectacular. But it turns out in biology that when glucagon is broken down in the gut what comes out of part of the GI tract is not just GLP-1 but it’s something called oxyntomodulin. And what that is, is a combination of GLP-1, but also a combination of glucagon. And it actually turns out the glucagon, in addition to the GLP-1, serves an interesting role because what the glucagon seems to add to that is a better reduction in weight; a better energy utilization, a better satiety effect. So there’s been great interest based on preclinical data. Mostly to start with ani- mal models of creating these hybrid proteins, which you can do in a laboratory, and you get a GLP-1 and you get glucagon. You put it together and you start studying what hap- pens and the data in mice and even in nonhuman primates is pretty profound in that you get better reductions in weight than you would with GLP-1 alone. That you get no difference in hypoglycemia, that you get a reduction in hepatic glucose produc- tion, even improvement of insulin secretion, is kind of the standard data that’s seen. And so the hope is that that will translate into humans and there are beginning to be some human trials. In fact, some of these have actually progressed through pharma into phase II, and so we’ll start to see real human data in terms of testing all of the specifics. But at least what the human trials are starting to suggest is clearly an impact of these drugs to reduce weight, to improve insulin secretion, to have a low rate of hypoglycemia, relatively few side effects. And I think the important question that needs to be solved is whether the hybrid protein is measurably better than a GLP-1 ago- nist alone, and that’s where we’re really waiting to see where this class will evolve in the future.

Dr. Sloane: That’s very exciting. Some of the newer dia- betes medications, along the same line of thought, have been shown to significantly reduce diabetes related complications such as chronic kidney disease, heart disease, things like that. I was wondering if you could speak about the evidence regarding the impact of newer drugs on nonalcoholic fatty liver disease and whether or not there’s a benefit there of certain medications? Dr. Leahy: Well, this is a really important topic because, I think, everyone has come to the realization over the last 5 or more years that an enormous healthcare issue, which is exploding around us, is the evolution of nonalcoholic fatty liver disease into a very small proportion of patients to eventually cirrhosis, fibrosis, and end-stage liver disease. Anybody who talks to their local gastroenterologist will hear the story that the dominant effect they are now seeing, in terms of liver disease in many places, and the need for liver transplant, is related to this sequence. It’s a complicated sequence because about 70% of people with obesity with diabetes will have fat in the liver, but it ends up being a very, very small portion of those people who will eventually end up at the end stages with really clinical disease and that, in many ways, begins to address the question you’re ask- ing because what we know is that GLP-1 drugs and SGLT2 inhibitors, there’s data supporting that use of those drugs will lower liver fat. The same way data frommany years ago showing the thiazolidinediones are actually pretty potent drugs at lowering liver fat. The real issue will be with time, will it actually impact the number of people who go on to end stage liver disease and at what stage of the disease? If you have hepatitis, if you have fibrosis, can you use any

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