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Sam Engel on Clinical Inertia in Diabetes Treatment: DIC Interview

In this Exclusive Interview transcript, Sam Engel talks with Diabetes in Control Publisher Steve Freed during the ADA 2018 convention in Orlando about diabetes drugs in the pipeline at Merck; clinical trials on sitagliptin and ertugliflozin, including the CompoSIT and VERSIS studies; and the problem of “clinical inertia” in intensifying treatment.

View the video of this interview.


Steve Freed: I’m here with Diabetes in Control at the 78th Scientific Sessions from the American Diabetes Association, and today we have a special guest, Sam Engel, who is Associate Vice President, Cardiometabolic and Women’s Health at Merck Research Laboratories. That’s a pretty big title, must be a smart guy.

Sam Engel: I’m not so sure about that Steve. But thanks for inviting me.

Steve Freed: So I always like to ask people that are involved in the drugs and research, why you’re here, what are you looking forward to, either to tell other medical professionals or to learn, from some of the research that’s going on, what is the most exciting? What I found by the way for many people is that this year’s kind of a slow year. That compared to what’s been done in the past, that the excitement isn’t quite there. And your response?

Sam Engel: Well you know I think that there have been some landmark studies over the past several years that have been very exciting. So from that context there’s no large breaking mega trials, but I think there’s still some pretty important and interesting information that’s being disseminated both by us at Merck Research Labs, by other investigators and other pharmaceutical companies, other independent investigators. You know one of the challenges is obviously advancing the treatment of diabetes and better diabetes control and I think there’s still a ways to go.

Steve Freed: Maybe we’ll get started with the CompoSIT-I study, and the initiation of insulin therapy while using Januvia, and the results from that.

Sam Engel: Great. Well that’s one that I’m actually particularly excited about. CompoSIT-I was a study that was part of a program of several studies that we were doing with sitagliptin, really aimed at trying to better characterize some of the challenges and treatment paradigm choices that physicians have for which we felt there wasn’t sufficient evidence. So this is a study that really was based on the concept that when patients are on dual therapy and ready to initiate insulin the clinical question is, what do you do with the oral medications? Do you continue them, do you stop them? I think for the most part, clinicians continue metformin but for example in patients who are on a combination of a DPP4 inhibitor with metformin often the DPP4 inhibitor is discontinued, maybe up to 50 percent of the time. You know we had previously developed some data that suggests that that might not be the right thing to do. So in this study we took individuals who are on metformin and sitagliptin who required further intensification of therapy with insulin. And we randomized them to two groups either continuing sitagliptin with metformin, or discontinuing it. And everybody started taking insulin and it was a very intensive treat-to-target with insulin glargine. So it really was meant to provide evidence for, can we achieve better glycemic control, are there differences in hypoglycemia, because normally when we intensify insulin therapy we see increases in hypoglycemia; that’s been well established with all insulins.

And the remarkable observations from this study were one, in the group that continued with sitagliptin they achieved a much better glycemic control; the hemoglobin A1C on average dropped below 7 percent. But I think in some ways even more compelling was the fact that there was no increase in the risk of hypoglycemia compared to the group that was not continuing sitagliptin and that had worse glycemic control. That’s important. Because for me as a clinician it really answers the question, “What should I be doing with oral medications when I initiate it?”

Steve Freed: How many posters and abstracts or papers are you presenting this year?

Sam Engel:  Well I think from Merck Research Labs we have over 30; I actually don’t remember the exact number. You know we’ve got six from the sitagliptin program; I think we’ve got about six from the ertugliflozin program, so you know we’re well represented.

Steve Freed: Which ones do you feel most comfortable in discussing?

Sam Engel:  Well you know, obviously CompoSIT-I is one that I think highly of. There was another study for the CompoSIT program which was CompoSIT-R, and this was again a study that was thinking about individualization of patient therapy. Now, it’s probably not well recognized that about 40 percent of people with type 2 diabetes have mild renal insufficiency. That’s chronic kidney disease stage two, GFR is between 60 and 90. The question really is, for that population should there be any specific tailoring of treatment choices. And we typically think about people with stage 3 or stage 4. But this is to my knowledge the first study that specifically and prospectively looked at patients with stage 2 CKD, GFR to between 60 and 90. And so we took patients who were either on metformin, or metformin and a sulfonylurea, so dual; needed to be on advanced dual therapy or triple therapy. And we randomly assigned them to either sitagliptin or dapagliflozin, an SGLT-2 Inhibitor.

Steve Freed: So you’re looking at ertugliflozin; what have we learned from that drug as far as its ability to combine with other drugs, and see the positive results?

Sam Engel:  So ertugliflozin is our SGLT-2 Inhibitor and it’s been studied across the spectrum; I think that’s what you’re referring to. It’s been looked at as monotherapy, as a second line therapy, as triple therapy and really across the spectrum of disease we’ve seen very consistent results in terms of A1C reduction, weight reduction, blood pressure reduction.

Steve Freed: What about with Januvia?

Sam Engel:  So we have done a number of studies combining ertugliflozin with Januvia, sitagliptin; there are actually three studies in the VERTIS program (VERTIS is the name of the clinical trial program for ertugliflozin). So we looked at it as a third line add on therapy in getting ertugliflozin to patients on metformin and sitagliptin. And we also looked at the combination of ertugliflozin and sitagliptin initiated at the same time, both in patients who were drug naïve but also in patients who were on a background of metformin. So again across the treatment spectrum. And we found very nice additive effects on glycemic efficacy with the combination compared to the single components.

Steve Freed: With all the drugs that Merck has in the field of diabetes in the past and what’s in the pipeline — let’s start with the pipeline and what’s in the pipeline from Merck when it comes to diabetes, because the drugs are coming out so fast it’s hard to keep track.

Sam Engel:  Right. Well what I what I can tell you — there are things I can’t tell you, but what I can tell you is we’re currently investigating glucagon/GLP1 co-agonist and I think this is an area of intense interest by a number of pharmaceutical companies looking to what I call build a better GLP1; leverage the additional potential benefits of a glucagon stimulus and its effects on weight loss to the profile of GLP1s. We’re also interested in developing insulins, novel insulins that have an improved therapeutic index that potentially could reduce the risk of hypoglycemia. So I think those are probably the two areas where we’re most focused on right now.

Steve Freed: So in the time that Merck has been involved in diabetes, what do you feel is probably one of the most successful drugs in reducing A1c? Because we have so many now. It’s difficult for a physician, a family practitioner, to know which one is working best for which patient. I mean, if you go back a few years we have one drug for diabetes. Now we’ve got six million combinations of drugs. I mean I don’t know how you go from one to six million. But we have it available, so it’s more difficult for the family practitioner to decide. What are your thought processes along those lines?

Sam Engel:  Well I think you hit on it that when you said, a given drug for a given patient. And I think it really is about individualization of treatment choices. So we look at the obvious things such as the patients A1c; do they need one drug or should they be started on two drugs at the same time? And for patients who are you know very far from glycemic goal, you know it’s pretty clear that one oral agent won’t be sufficient for many of them. And so rather than deal with the issues of clinical inertia, delaying glycemic control for a long time, you know that’s a patient who you would start on a combination of drugs that were complementary. It’s about looking at patients’ renal function; that’s why we did the study in mild renal insufficiency. It’s about looking at side effect profiles. It’s about looking at comorbidities; so, they have cardiovascular disease, what’s their lipid status, are they overweight? So there’s no one answer. I mean it makes it more complicated in fact, because there isn’t a single drug that for every patient is appropriate. But I think we generally look at the profile. And you know it’s what keeps us thinking a little bit I guess.

Steve Freed: Let’s change a topic a little bit and talk about real world data. What is clinical inertia, and what are the ramifications for patients?

Sam Engel: Well so clinical inertia is a term that’s used to define the failure to appropriately intensify therapy in a timely way. You know the traditional approach in diabetes, in my view, is far out of sync with what many other diseases have as their treatment paradigm. If you don’t mind if I digress: if we think about hypertension, if we think about various types of heart disease, we’ll start people on combination therapies from the beginning because we realize that there are different mechanisms or defects at play and so we need to tailor the therapy to attack all of those at the same time. For diabetes, in many ways we’re still stuck in the 1970s period that you were referring to before, right? Well we only had one drug so you start one drug and then you wait and then you add a second drug and then you add a third drug. But in thinking about it we can pretty much predict how effective a single drug will be. And for those people who are not at goal, it takes a long time to have that second drug started, whether it’s because of physician factors, patient factors, health system factors. I mean there’s a lot of things that play into the clinical inertia problem. But the result of it is that many patients remain significantly hypoglycemic and they’re exposed to a glucose burden of hypoglycemic burden that can increase their risk for the long term complications of diabetes. So I think clinical inertia is something that we really need to address much more aggressively from a I guess a treatment paradigm perspective.

Steve Freed: Can you quantify the benefits of avoiding clinical inertia?

Sam Engel: Well it’s really hard to quantify; it depends in large part on how long patients remain uncontrolled, how uncontrolled they are. So it really would be difficult to answer your questions in a quantitative way.

Steve Freed: And what are some of the barriers to earlier intensification, in the real world, and what can physicians do about it? Because like you said we started out with one, wait three to six months, we add a second one, three to six months. But most of the people that are involved with diabetes, the medical professionals that understand it, are certainly more aggressive in starting on two or three drugs immediately to get their A1c down. So what are your thought processes, should we do it slowly, or should we, from your experience, speed it up a little bit.

Sam Engel: I think primarily it relates to how far from goal somebody is. I think if patients are close to goal — let’s say if the goal is 7 percent; now of course we have different goals now for different patients, but let’s assume a goal of 7 percent — if we’re starting at an A1c above 8 percent it’s unlikely that a single agent will get patients to goal. We know that the American Diabetes Association has a recommendation that above 9 percent two drugs get started. The American Association of Clinical Endocrinologists uses seven point five as that threshold. But I think there are data sets. There’s analyses that can and have been done that help quantify how successful will you be with monotherapy or dual therapy, if you’re starting at a certain A1c, and if a certain A1c is your goal. So I would say as clinicians we need to start using those evidence bases to really make those rational decisions, and that’s what I would call glycemic profiling. I think that would go a long way towards helping to cut down the problem with clinical inertia, but we also need to understand better, what are the factors that slow down decision making? What are the factors that impact on the long lag in the time to intensification? And as I said earlier it’s really a combination of patient, physician and health system factors.

Steve Freed: Have you seen that the CGM has helped Merck, as far as increasing the use of some of the pharmaceuticals, basically having physicians be more aggressive because of the use of CGM?

Sam Engel: Well continuous glucose monitoring obviously has changed the landscape for type 1 diabetes. You know when you say from Merck’s perspective, certainly we support, applaud that. We’re happy about it. The therapies that we currently have developed are for type 2 diabetes. So there hasn’t been really a direct impact of CGM on I think type 2 diabetes the same way it has on type 1.

Steve Freed: Well if you look at it the CGM I personally think is going to replace blood glucose monitors for everybody, because why would you want to stick yourself ten times a day if you’re really involved in your care, or even three times a day, when you know you can put something on your arm and check it whenever you want. So I’m saying I think the demise of blood glucose monitors is in the future.

Sam Engel: Well I think you’re right for type 1. I think you’re right for insulin treated type 2 diabetic patients. But for the patients with type 2 diabetes who are on what are called  the modern drugs where the risk of hypoglycemia is very low, you’re not really seeing that same need for such intensive glucose monitoring. So for those people glucose monitoring may be much less frequent than 10 times a day or three times a day, that you think about when you think of somebody who’s on drugs that can cause hypoglycemia.

Steve Freed: I’d like to debate you on that because, if as a non diabetic, I’m checking my blood sugars after eating some of the wrong foods, and I see my blood and I’m at risk for diabetes, if I see my blood sugars go up, I’m not going to eat that same food again; this is going to be stuck on my mind, you can’t eat if it’s a certain food. So it’s going to help with reducing weight, preventing diabetes and prediabetes, preventing you from going on to diabetes; that I can foresee for CGM and pre diabetics.

Sam Engel: Well on that point I think you could be right, that if somebody were testing after eating and if they were modifying their eating behaviors it could be a positive impact.

Steve Freed: So I would be curious and eventually it will happen where they do a study for weight loss for people even without diabetes using CGMs, to see if it motivates them to cut back on some of the fattier foods.

Sam Engel: That would be an interesting study.

Steve Freed: So I’m hoping Merck wil finance that! Well I want to thank you for your time. Always good to hear from you and see what’s happening with Merck. Been around for a long time and certainly involved in the diabetes arena. So thanks and enjoy the rest of your stay here.



SamuelEngel2017Dr. Sam Engel is the Associate Vice President, Cardiometabolic and Women’s Health at Merck Research Laboratories. He graduated from New York University School of Medicine. Prior to joining Merck’s team, he was a Clinical Professor at Albert Einstein College of Medicine.