Initial Combination Therapy in a Newly Diagnosed T2DM Patient

Doron Schneider, MD and Jack Leahy, MD discuss the pros and cons of combination therapy for as initial treatment. (17:40)


Dr. Doron Schneider (DS): Hello, my name is Doron Schneider, and I’m a practicing internist at Abington Memorial Hospital in Philadelphia, and today I’m joined by Dr. Jack Leahy [endocrinologist, University of Vermont] to discuss a case that is as follows:

38-year-old Caucasian male who presents to his primary care doctor, not having seen the doctor for over 10 years. He presents with fatigue, thirst and has had some recent weight loss. He has an elevated BMI of 36, his blood pressure’s found to be elevated, 150/96, and he reports a family history of cardiovascular disease, The initial exam is otherwise unrevealing, but blood work does show an A1C of 8.6, cholesterol level up at 130, triglycerides are at 350 and after that encounter we diagnosed him with Type 2 diabetes, hyperlipidemia, and hypertension. This patient does have insurance coverage and is started on hydrochlorothiazide and lisinopril for his blood pressure, atorvastatin for his hyperlipidemia, and now remains how to deal with his A1C which found at 8.6. First step was counseling and lifestyle modification and with a brief office-based counseling send him on his way to follow up in approximately 8 weeks.  Three months later he does show up, and his A1C is down to 8.2 and having had the trial of lifestyle therapy, the next step is to decide how best to manage his Type 2 diabetes.

We’re presented in this case with three possible options. One is monotherapy with metformin. The other is combination therapy, and number three is bariatric surgery. So why don’t we attack initial combination therapy first. So this is a broadly written option here, and I’d like to just point out that this patient does have health insurance, and I think we should really try to the extent that we can, consider that factor. Then we can have a small discussion around patients that don’t have health insurance as to whether that would change the treatment paradigm for those patients. So, from your prospective there are many different agents that are available now than there was in the world twenty years ago. So things have only become more complicated for us to reach into that toolbox and select the right combination. So for you, this patien--who’s 38, relatively healthy, does have risk factors for cardiovascular disease, does have insurance--what’s your favorite thought here if you were to pick the initial combination therapy having described that?

JL: Yeah, actually I like this case for this specific reason. What you're really look at is we've got one option which is to start with one drug and one option which is to start with more than one drug. This is actually a big discussion point in this diabetes world in part reflecting different kinds of guidelines. And so if people are familiar with guidelines they can actually see the battle that’s kind of going on between different groups in that the classic American Diabetes Association and European equivalent guidelines, which came to us toward the middle of last year, recommend starting with one drug, i.e., metformin, and then if you’re not controlled escalating as you need to through all the other drugs we have. The second kind of guidelines are from the American Association of Clinical Endocrinologists—the AACE guidelines—and they (actually, new ones just came out the last couple of weeks), they have very much focused on the feeling we should start therapy from the get-go that has a real chance of success, and try and avoid the inertia of one drug being started that’s not working, patients get lost or whatever it happens to be. So the concept of starting one and then going further may not always you know work, you know, the way we would like, so why not start a therapy from the get-go that has a real chance of working? And their [AACE] feeling is a hemoglobin A1C up to 7.5, you know, you can make a strong argument lifestyle plus metformin is a very reasonable approach. But 7.5 to 9 they more or less argue it’s probably preferable to think about lifestyle with two drugs, and the two drugs probably is easiest from many perspectives if it’s in a combination tablet, especially given that we have some pretty good combination tablets now. I actually like the second thought process, and when you raise the issue of “Well, it’s written, isn't that interesting it says he has insurance, isn’t that a curious statement?" Well, not so curious because our favorite combination potentially is metformin which clearly is inexpensive, but along with DPP-4 inhibitor, the oral incretin drug—those combinations are out there—they’ve been studied as monotherapy versus combination therapy head-to-head in patients with new onset Type 2 diabetes, and the reality is that the combination tablets are much more effective at improving levels of hemoglobin A1C than the individual drugs. I have a favorite study I love where the first author is Barry Goldstein, which is patients with new onset Type 2 diabetes, hemoglobin A1C of 8.8, and looking at DPP-4 inhibitor alone, metformin alone, or a combination product. And the combination product was much, much superior taking that A1C of 8.8 and getting it to goal when they used the combination product—the individual drugs didn’t. So that’s sort of the thought process, and our patient falls really into, exactly into, that window of argument. He started at 8.6, now he’s 8.3, and the real discussion is do you believe in your heart that 8.3 is going to get to your goal of less than 7, or, we said, less than 6.5 with metformin and lifestyle alone? And if the answer is no, then I think the people who favor combination therapy will say well, don’t dink around, then give him a drug that probably will, which has more than one drug in it.

DS: I’d like to highlight one of the concepts that you said there which is a potential downside with starting with monotherapy is the lack of intensification of therapy after treatment failure. So, in my mind, the caveat, the only caveat, to what you have just described is that if you have built into your clinical system a way to ensure that these patients do get follow-up, that there is appropriate intensification after failure of monotherapy, and all of the systems requirements to ensure that, in fact, there is that dose escalation and then the further intensification with a second agent. Your point is well taken that most practices don’t have such robust systems to ensure that the patient does in fact follow up and then if they do follow up the protocols exist that really do push us to intensify. So that is a very well put point, and I just felt the need to reiterate that. Now the other question is around the tolerance and the tolerability and the side effects. When you begin with combination therapy, you have always this question of well, gee won’t they possibly not adhere to that combination? You’re starting two drugs and that increases the likelihood that they will either a) experience an intolerance to the medications or b) experience a hypoglycemic event which has been shown independently to be a risk factor for lack of adherence. So I wonder if you can comment a little bit about, you know, that aspect of that option, which is really one of the possible downsides I can see people thinking about regarding starting with any combination.

JL: So this is a great question though if you will I want to adjust sort of the theme of the question a little bit. Part of it is that you can actually use two drugs and run into a side effect from one or maybe both, and then all of a sudden your adherence to taking either of the drugs goes away. Absolutely. In terms of the combinations we have out there certainly if one of the combinations is sulfonylurea or one of them is a TZD, you know, we have very well-known issues with those medications. Risk of hypoglycemia with sulfonylureas, weight gain with TZD, maybe some other issues—that does pose a problem. But the other side to that question is I think [as] the drugs come to us—newer drugs in particular—we start to look at them from a profile of action that extends not only with the blood glucose lowering effect, but I think we’re trying to convince ourselves that to find drugs which come with some additional benefits: limitation of weight gain or maybe weight loss, certainly restriction or hopefully total lack of any risk of hypoglycemia, maybe some cardiovascular benefits or at least improvement in blood pressure or lipids or something like that. And actually the combination as we start to think about it you might not only have better improvements in blood glucose control, you might now have a combination that brings in additional benefit. So all of a sudden you get better blood pressure, or we start to lose some weight with our medicine, which we wouldn’t have with the one drug alone. So, you know, so far we’ve focused on DPP-4 and metformin kind of in our comment ‘cause that’s certainly a common combination. But one could easily do metformin with the injected incretin drug, the GLP-1 drug. Yes, it’s an injection. Yes, that would be quite expensive, but you would have, you know, theoretically spectacular blood glucose control along with some weight loss, some blood pressure improvement, some lipid improvement, the things we think about with that medicine. Or again, you might try a combination of the sulfonylurea with metformin. It should be super cheap. It should be better at lowering blood glucose values, and even though we worry about hypoglycemia with sulfonylureas, I mean the reality is that it’s not all that common if they’re used properly. So I think all and all we can worry about side effects, but we can also think about maybe we'll have added benefits that will improve adherence with the combination over a single drug.


DS: I like the way you frame that. And the issue of the injectable and you bring that up as being a possible combination—I’d like to just explore just for a moment the notion that the injectables include the GLP-1 agonist, but also include insulin as, you know, possible thinking about as a possible combination. So, is there any role for insulin here? Is there a threshold whereby you think about an injectable GLP-1? And then I’m talking threshold A1C, that isa threshold A1C that you think really should deserve an injectable as part of the initial thinking regarding the combination that you’re going to be using, either at the GLP side or the insulin level side. Again adjusting the case because we are presenting with an A1C of 8.2, but I’m just trying to isolate that variable out for our listeners to think about going forward.  Any threshold for you that suggests that initial approach should be different based on the A1C value?


JL: Yes, so this is a very important question for me because I live in a world where I’m prescribing injectables daily to patients almost on a daily basis and so I view them as having many, many more positives than negatives. Certainly people come in with fears, but once we get through those fears, they end up being hugely important therapies with relatively few downsides in terms of just the injection. But having said that we sort of have talked in part about this case based on guidelines, so the ADA guidelines, the AACE guidelines, and each of them integrate statements about people who newly present, who are very hyperglycemic—typically a hemoglobin A1C of 9 or 9.5 percent or above—along with symptoms that suggest that they are very significantly hyperglycemic, i.e., catabolic symptoms, people are losing weight, they’re peeing multiple times a night so they can barely sleep, women are having yeast infections which are recurrent and hard to treat. Sort of on and on people feel terrible, profound fatigue, and I think most of the guidelines integrate that that kind of patient would the kind of patient that should be started on insulin, maybe along with metformin, whether it’s permanent or transient sort of depends on individual patients, but that would be the sort of the kick off to use insulin. I don’t disagree with that. I’ve certainly seen many patients who present with very high levels of hemoglobin A1C who are not started on insulin. They make some lifestyle change, and they have an incredible reversal of glucose toxicity, and they do well on the oral agent. So I’m okay with the concept. I’m not sure it’s an absolute. But I could now take your question the other way because if we get away from that classic patient, who presents pretty sick and losing weight and really symptomatic, and go to a little more typical patient like our man right here, is the implication, "oh my god he’s not an insulin patient because he’s A1C is not that high and, you know, he’s not sick, and we’re going to use a bunch of drugs before we get to insulin"—I’m not sure that that’s accurate. The Origin Trial, which is a trial that came out last year published in the New England Journal, used basal insulin very, very early in the course of Type 2 diabetes, some pre-diabetes or in patients who had not seen more than one drug—metformin—some were on no drugs, the average hemoglobin A1C was 6.4, and it worked incredibly well. Their blood sugars were well controlled, mostly on one injection a day for multiple years; they really didn’t gain any weight; they really didn’t have any problem with hypoglycemia. It’s an option. I’m not advocating we do it, but I’m saying that we present to patients all of the options that are out there, and there might be an occasional person who would rather take an injection and get on with their life as opposed to pop a bunch of pills and worry about the side effects of the pills. They’re pretty good drugs in that regard. But also blood pressure reduces a little bit. Lipids improve a little bit. Certainly, there are groups of patients that really lose weight, and we’re waiting with bated breath to know if that comes with cardiac protection. I mean, all of the studies are being done now to see if we finally have a class of medicines that might actually bring not only the metabolic improvements we’d like in terms of risk factors, but translate down the way with true reductions in cardiovascular outcomes. And if they do, then I think if we were doing this case again, then we’d probably have four options: one drug, two drugs, surgery, and/or incretin therapy from the get-go, and that latter one could rise quickly to the top of the list. So, you know, I think the theme of the ADA/EASD guidelines is talk to the patient, provide them all the different options and then make your choice, and I could certainly make an argument in this patient that an incretin drug would be not an inappropriate choice, either with metformin or maybe even in some patients as their first therapy although that’s still fairly atypical.


DS: So it really is a nice overview of all the different treatment approaches here that are possible. Clearly that would be constrained should a patient not have health insurance, and I just do want again to make that point that clearly cost issues do prohibit some of the options that you do describe. So with that I would like to extend my sincere gratitude to you, Dr. Leahy, for joining me in a discussion of this fascinating case, and we look forward to the next opportunity to get together. Thank you.


JL: Thanks a lot.