PracticeUpdate Diabetes Best of 2018

CONFERENCE COVERAGE 22

Sequencing Injectable Therapies in Type 2 Diabetes Interview with John (Jack) L. Leahy MD by Jason Sloane MD

Dr. Sloane: I was wondering if you could tell me between basal insulin and GLP-1 agonist which agent should be used first in terms of treatment, and do you have a strategy in terms of when to use certain agents? Dr. Leahy: That is the perfect question because, in fact, we discuss all the time what should be the first injectable. If you approach it from a sort of clinical point of view and clinical trial point of view, I think the reality is that head-to-head would say basal insulin versus GLP-1 receptor ago- nists are pretty equivalent at improving levels of hemoglobin A1C even with rea- sonably high levels of A1C, but then there’s big differences. GLP-1 drugs come with a low rate of hypoglycemia, they come with weight reduction, they come with GI side

effects, and basal insulin come with really the opposite, which is no real GI side effects or risk of hypoglycemia potentially, and the risk of weight gain. So the real answer to the question is, when you know those facts to communicate those facts to a patient and then really understand from the patient what of those are important to them and what are not, and in many ways you can choose either. Now, if you take one step back and say what would the specialty world suggest would be the preferred sequence? I think there’s a lot of specialists who feel we would want to start with a GLP-1 receptor agonist. The whole profile of weight reduc- tion, low rate of hypoglycemia, and the new information supporting cardiovascular pro- tection and renal protection with some of these drugs that’s pretty nice compared to a basal insulin therapy. And then if that’s not enough you could add insulin later, so that’s kind of the sequence most people are talking about. Dr. Sloane: For patients who are already on basal insulin, and perhaps even on a prandial coverage of insulin, would you consider add- ing a GLP-1 and why? Dr. Leahy: Sure. I mean, if someone is not adequately controlled when you’re already

using insulin therapy, then you have to add something. And it turns out that adding a GLP-1 receptor agonist both conceptually and practically is a great choice, because if you think about what those drugs do is in some respects different than what insulin does. Now, if they’re on prandial insulin, of course, you’re having an effect on mealtime insulin. But the GLP-1s, they have weight protection, they have potentially cardiovas- cular protection, they’re insulin sensitizers, they come with a reduced rate of hypogly- cemia. And really one of the exciting kinds of research that’s been going on is to take people who are just on basal insulin and compare the next step. Do I add prandial insulin, do I add a GLP-1 receptor agonist? It turns out you can do as well with a GLP-1 receptor agonist even when you give once a week. So that’s a pretty common strat- egy we do in the specialty diabetes world. Dr. Sloane: Last but not least, there’s talk of combination therapy, so giving a little bit of basal insulin in combination with a GLP-1 agonist in the same treatment. Do you have any feelings about that, in terms of efficacy or safety? Dr. Leahy: Well, so those drugs exist. We cur- rently have two preparations available in the marketplace. One, a long-acting insulin dulaglutide along with a daily GLP-1 liraglu- tide, and one with a short-acting GLP-1 with lixisenatide in combination with glargine, Lantus, insulin. What I think about them is that clinical trials have shown the combi- nation is stunning. When you really look at the outcome of clinical trials on the background of almost starting therapy the attained levels of hemoglobin A1C are often in the mid-6s with some weight reduction as opposed to the standard kind of weight gain that one sees with insulin alone. A rel- atively low rate of GI side effects, which is kind of interesting because one of the ways we use these preparations is relatively slow titration, and I think the clinical trials are really persuasive. There’s one I really like for both of these drugs, people who are essentially injection-naïve comparing get- ting insulin alone, getting GLP-1 alone, or the combination product, and always the combination product does much better with attained levels of hemoglobin A1C, with a low rate of hypoglycemia and weight reduction, so they’re really pretty amazing products. www.practiceupdate.com/c/70069

" The whole profile of weight reduction, low rate of hypoglycemia, and the new

information supporting cardiovascular protection and renal protection with some of these drugs that’s pretty nice… " Enteroendocrine Function of the Intestine By Jason Sloane MD

W e were introduced to a relatively new concept in this lec- ture series about the fact that the intestine is the largest and one of the most important endocrine systems in the human body. We now know that most endocrine cells in the intes- tine have pluri-hormonal complexity and there are many hormones secreted by these cells aside from GLP-1 and GIP. In addition, we

now understand that GLP-1 has many mechanisms of action which go beyond glucose control, which regulate appetite, obesity, and even the immune system. L cells are located in the distal intestine and can secrete GLP-1. We know through experiments that GLP-1 agonists increase local protein synthesis but also can increase the exocrine pancreas secretions. There is also increased intestinal cell proliferation regulated by GLP-1. Perhaps most interestingly, GLP-1 has recently been found to attenuate the inflammatory response in the distal intestine to certain types of bacteria. It is important for clinicians to understand that GLP-1 agonists have actions beyond what they are prescribed for, and this may affect who these medications are pre- scribed for in the future and may even broaden their indications. www.practiceupdate.com/c/70309 

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