Management of Persistent Hyperglycemia in T2DM: Beyond Starting Doses of Basal Insulin

Transcript
Moderator: Aniket R. Sidhaye, MD
Faculty: Thomas Donner, MD, Armand Krikorian, MD
[SLIDE 1]
ANIKET SIDHAYE, MD: Hello and welcome to this Clinical Dialogue, Management of Persistent Hyperglycemia in Type 2 Diabetes: Beyond Starting Doses of Basal Insulin.
[SLIDE 2]
I'm Dr. Aniket Sidhaye, Assistant Professor of Medicine and Pediatrics in the Division of Endocrinology, Diabetes and Metabolism at the Johns Hopkins University School of Medicine here in Baltimore, Maryland.
Joining me today are two expert clinicians, Dr. Thomas Donner, Associate Professor of Medicine and Director of the Diabetes Center at Johns Hopkins University School of Medicine in the Division of Endocrinology, Diabetes and Metabolism. Also joining us is Dr. Armand Krikorian, Associate Professor of Clinical Medicine at the University of Illinois at Chicago, and Program Director Internal Medicine at the University of Illinois at Chicago's Advocate Christ Medical Center.  
I'd like to thank you both for joining me. Let's get started.
[SLIDE 3]
As we all know, 30 million Americans have diabetes mellitus. Most of them have type 2 diabetes, and insulin is an important part of their treatment regimen. Despite this, many patients do not reach the treatment targets that we all acknowledge are optimal, and even if they're on insulin sometimes they don't reach those targets. So today we're going to be discussing primarily the role of insulin, how it should be initiated and when, how it should be titrated, but also possible add-ons to insulin therapy when patients don't reach our targets. So I thought I would first get your thoughts about this issue, about patients not reaching the goals that we have set for them. Armand.  
ARMAND KRIKORIAN, MD: We all are guilty of doing too little too late. We know by now that by the time we diagnose patients with type 2 diabetes, at that point they have lost about 50% of their beta-cell mass. So we're already starting behind the ball, and going forward they continue to lose beta-cells, so their capacity to maintain their glucose within a desirable range gets progressively impaired. And that's one of the challenges we all face when we start them on medications. Is that what you see, Dr. Donner?
THOMAS DONNER, MD: I totally agree. Type 2 diabetes is not only a problem with insulin resistance, but a major problem with insulin deficiency, and this is progressive over time. And we see this clinically because patients who initially respond well to diet and exercise therapy or pill therapy for their diabetes or two-pill therapy for their diabetes are unable to be controlled, and that's because they've lost the capacity to make insulin, and without enough insulin, the diabetes can't be adequately controlled.
ANIKET SIDHAYE, MD: Yeah, and I think we all know that this information is not just anecdotal. It's been proven in studies again and again. The UKPDS showed that the rule really is monotherapy failure. Given that this is the case I think it's useful for us to review the indications for insulin treatment. Perhaps you could go over some of those indications.
[SLIDE 4]
ARMAND KRIKORIAN, MD: We usually tend to think of initiation of insulin on the outpatient side, really for our patients who are not well controlled, whether it's after monotherapy or when they present to us if they already are severely hyperglycemic or they have a high hemoglobin A1C to start with. This is usually an impetus for us to start them on insulin from the get-go.
Now on the inpatient side when we have a patient who comes to us with hyperglycemia, hyperosmolar hyperglycemia, diabetic ketoacidosis, we oftentimes think of glucotoxicity and we should start insulin for those patients from the get-go and then think of transitioning them maybe to orals down the line.
[SLIDE 5]
THOMAS DONNER, MD: When patients first see us and their glucose levels are quite high, we're not sure how insufficient-deficient they are, but we do know that adding one or two pills oftentimes -- especially if the A1C is well over 9% -- is not going to get them down to target. And so initiating, especially a basal insulin to start, to get them under control oftentimes with an oral agent to start would be a reasonable approach.
And so patients who are symptomatic with significant weight loss, very symptomatic from a polyuria, polydipsia standpoint, you're going to be much more effective at alleviating those symptoms by initiating insulin early on.
[SLIDE 6]
ANIKET SIDHAYE, MD: In the outpatient setting, do you have a number, an A1C number above which you start to say, "All right, we need to start insulin?"
THOMAS DONNER, MD: So it depends on what therapy they're on at the time. I think many of us will use an A1C of over 9% as a strong motivator to initiate insulin therapy because, once again, adding another -- even one or even two oral agents -- would not be expected to get that person to goal.
If they're on multiple medications, their A1C may only be 8%. And at that point, since they failed standard multidrug therapy, then insulin therapy, would be started at a lower A1C.
ANIKET SIDHAYE, MD: Yeah, I agree. Maybe it's good to go over some of what the targets are. What A1C target do you use in most of your patients?
[SLIDE 7]
ARMAND KRIKORIAN, MD: So that's a great question. So the American Diabetes Association, as you know, recommends that we aim for the target of 7% for the hemoglobin A1C. Now that's a general statement that probably fits most of our patients, but there is room to individualize.
So, of course, if you have an elderly patient who is particularly literally at risk of hypoglycemia, then you may consider slightly more relaxed targets. On the other side, if you have a younger patient who has no end organ damage, and less risk of hypoglycemia, you may actually go for tighter hemoglobin A1C.
Now we know that the AACE, the American Association of Clinical Endocrinologists, advocates for a hemoglobin-A1C of 6.5, while the American Diabetes Association advocates for a hemoglobin-A1C of 7. I believe the truth is probably somewhere in between, and a lot of it goes, in my opinion, to the individualization. It's not one-size-fits-all, depending on what kind of patients we're treating.  
THOMAS DONNER, MD: It's as low as you can get without side effects of medications. We just have to be cautious with insulin use because the risk of hypoglycemia increases the lower the A1c falls with treatment, and so I think we just have to cautious as the A1c gets below 7% on insulin therapy that they're not having frequent or certainly severe hyperglycemia.  
ANIKET SIDHAYE, MD: Tom, could you review what the starting doses of basal insulin ought to be, because sometimes I wonder if people under dose their patients.
[SLIDE 8]
THOMAS DONNER, MD: Many of the studies, or early studies adding insulin to patient with type 2 diabetes started with 10 units of therapy, and we've recognized that that's oftentimes not enough insulin. If you have a 300-pound patient who has uncontrolled diabetes, 10 units will not adequately get them under control, certainly.  
And so more commonly we use a target of 0.2 units per kilogram, I think, is a reasonable dose to start. So it's somewhat of a weight-based dose. So that would be the initiation dose. And we use that dose because it is also one that would likely be safe for them. You're not going to be overexposing them to insulin. Oftentimes though, even that 0.2 units per kilogram starting dose may not be enough, and then titration, I think, is important thereafter, so you can reach your fasting glucose target.
ANIKET SIDHAYE, MD: That's great because I think it's useful to have that number in your mind because a 100-kilogram individual ought to start most likely with 20 units. Sometimes we adjust this weight-based calculation based on the A1C. Armand, do you do this in your practice?  
ARMAND KRIKORIAN, MD: I actually do, and I totally agree with 0.2, especially with weight considerations. However, sometimes when you do have a patient with a lower hemoglobin-A1C, so let's say less than 8, you may consider being a little bit more conservative and starting by at 0.1 unit per kilogram, and if the hemoglobin-A1C is more than 8, you may decide that you want to do a 0.2 or 0.3 [units], even especially if you have somebody whose weight is on the higher side.  
ANIKET SIDHAYE, MD: Those are great guidelines. So what -- do you have a favorite basal insulin you start with? Or maybe you could review for us sort of the range[s] of basal insulins that are out there.
[SLIDE 9]
ARMAND KRIKORIAN, MD: It's interesting how much far along we came because, you know, I remember when I trained it was really mostly NPH insulin as the basal insulin that was available. I know I'm dating myself now, but now we're very fortunate that we have actually more than one preparation of insulin.  
So we do have NPH insulin that's still around as the basal insulin, but we also have glargine, and glargine now comes in two different concentrations, the 100-unit concentration and the 300-unit/mL concentration. We also have insulin degludec that is on the market. That's another basal insulin that's out there. And we also do have combination insulin, so 75/25 or 70/30 insulins, which do contain basal components, and that is NPH, on top of a short-acting component that's premixed with it. That would be the 25% to 30% component, and that short-acting component can be either regular insulin or analog insulin.
ANIKET SIDHAYE, MD: In what circumstance would you use this glargine 300 unit per mL formulation or insulin degludec? Tom, do you have a lot of experience?
[SLIDE 10]
THOMAS DONNER, MD: Sure. Most of the experience is in the literature these days, but I've certainly placed some patients on these newer insulins. The primary side effect of insulin is hypoglycemia, and the reason today that the insulin analogs, such as glargine or detemir insulin, have become more favored than NPH is that there is a reduction in the risk of nocturnal hypoglycemia, especially compared to NPH. NPH is an intermediate-acting insulin with a peak, and it's less consistently absorbed. And so there's a higher rate of hypoglycemia. And I think many physicians appreciate that, and to reduce the risk of hypoglycemia they've gone to the newer insulin analogs.
The even-more-recent insulins, such as the U-300 glargine insulin, has an even smoother profile.
[SLIDE 11]
ANIKET SIDHAYE, MD: So just to review the list of the newer analogs that are available, we have insulin glargine now available in the two different preparations, degludec insulin, which has a slightly longer duration of action, and detemir insulin. Were there any points about any of these that you wanted to emphasize, either Armand or Tom?  
THOMAS DONNER, MD: If you compare detemir to glargine insulin, there seems to be a weight benefit with detemir that's not completely understood why that happens. But study after study has shown that the weight gain that we expect with the addition of insulin is less with the use of insulin detemir, so that might be a concern in patients who are overweight when you're starting a basal insulin.
ANIKET SIDHAYE, MD: Armand, are there things that you do or can advise patients to help when they start these basal insulins?  
[SLIDE 12]
ARMAND KRIKORIAN, MD: So I think we're very fortunate, again, that we have now different formulations as far as vials and pens. And I think this is great because different patients respond to them differently.  
The pens are extremely easier to use. They usually have very, very small needles, so the pain component is very minimal. The other beauty of the pens is a lot of them actually do have clicks, so give you an auditory signal when you use them, and that might be very useful for our patients who have diabetic eye disease, and then their vision may be impaired, and they may actually be relying on the clicks to determine how much insulin they are giving themselves.
ANIKET SIDHAYE, MD: Do you prescribe mostly the pen formulations for patients?
THOMAS DONNER, MD: I do. I think the studies have shown that there is -- patients prefer pens over vials head to head. They say that their quality of life is better with a pen. It's easier to carry around. That's mostly for short-acting insulins when they take it before the meal. The one time that I would sometimes suggest to a patient to use a vial instead of a pen is if they're using both long- and short-acting insulins. There are occasions where they might confuse which insulin they're giving, and so if they know their long-acting insulin is a vial and their short-acting insulin is a pen, they're less likely to confuse the two insulins.
ANIKET SIDHAYE, MD: Yeah, that's a great point. Another thing that I've experienced is many patients, although I know that they get education about this, they forget that they have to hold the pens in for about 10 seconds after depressing the button because if they don't they get substantially less insulin. Do you experience this at all in your practice, Armand?  
ARMAND KRIKORIAN, MD: I actually have. I vividly recall one of my patients who was on a very large dose of insulin via pen, and that dose was not commensurate with her weight. And then when we were demoing the use of the pen in clinic, she was not keeping it in long enough. And after what she thought she was done with the injection and we removed it, there was actually quite a bit of insulin that was still left to be dispensed but had not been dispensed.
ANIKET SIDHAYE, MD: Yeah, it happens every week, I think, in clinic. Let's move to titration of insulin. Tom, how do you approach this with patients?
[SLIDE 13]
THOMAS DONNER, MD: So I think titration is as important as starting insulin because if you've undershot (the dosage), especially, and you don't see the patient for another three or four months, their A1C is still going to be high. And this can be approached in one of two ways. If you have a patient who is reliable, I actually will give them algorithms to do self-titration of their dose.
And so depending on whether I've started the 0.1 unit or 0.2 units per kilogram (dose), I may have them increase by 1 to 2 units every several days, so three days, if the glucose levels are consistently above my target. And for a target glucose level, I typically pick under 130. I think in patients who have a lower risk of hypoglycemia, you could use a lower fasting glucose target, but I think under 130 is a reasonable target to shoot for. And if after three days they are over -- consistently over 130, have them increase by one 1 or 2 units.  
If they're consistently over 160 or so, I may have them increase by 2 to 4 units, depending, again on how much insulin they're starting with.  
ANIKET SIDHAYE, MD: And when you say target of 130, you're referring to the fasting glucose. Is that correct?
THOMAS DONNER, MD: That's correct, a fasting glucose target of 130. I think studies have shown pretty well that if you're reaching a fasting target in many patients of under 130, then they're going to be much more likely to achieve an A1C of less than 7%.
ANIKET SIDHAYE, MD: Armand, do you have particular strategies for titration that you like to use?
ARMAND KRIKORIAN, MD: The strategy that Dr. Donner discussed is actually my favorite. It has been documented in several studies, so it is evidence-based, and it's amazing how much time you gain actually, as you mentioned, because now the patient comes back to you in three months and they're at a totally different dose than what you initiated them on, and you feel like you made a lot of gain as far as timing getting them to target, rather than waiting until their two-month/three-month followup and then you are the one who makes that titration after that.
ANIKET SIDHAYE, MD: Do you give them a ceiling, Armand?
ARMAND KRIKORIAN, MD: That's an interesting question. Sometimes you hit the ceiling by how much a syringe can take or how much the pen can dial up. As we know, the syringe actually will dial more than 100 units in one injection, and a lot of the pens actually stop at around 80.
Once you're injecting about 90 or 100 units under the skin, that's actually a larger volume that starts to be associated with pain and discomfort with patients. So usually when we're starting to hit those higher doses is where we need to reevaluate our approach.
THOMAS DONNER, MD: These long-acting insulins, such as glargine and detemir, will actually start peaking at larger dosages, so you'll see a little bit more of a peak effect when you're giving 50, 60, 70 units. And at that time, if the fasting glucose target has not been achieved yet, we'll actually consider splitting the dose to twice-daily to achieve a flatter insulin profile, once again.
ANIKET SIDHAYE, MD: That's great. So I think for our audience, both AACE and ADA actually have published titration guidelines that folks can refer to so that they can have it with them to prescribe to patients. The other thing I wanted to have everybody remember is both these major societies recommend the initiation of insulin at one year after diagnosis if targets have not been reached.
And I just bring that up because I just see -- and myself am guilty of -- not making this next step to insulin, despite a very clear guideline for insulin initiation just one year after diagnosis. And I think we're losing time in that regard as well.  
So we've gone over, you know, basal insulins and how to initiate how to titrate, and yet there's this vast amount of data that suggests that many, many patients do not reach these treatment target goals. What is your sense as to why this is?  Armand?
[SLIDE 14]
ARMAND KRIKORIAN, MD: Well, that's the million-dollar question. You're absolutely right. There is a lot of data that if we look at how many of our patients are at their A1C goals and their blood pressure goals and their lipid goals -- and it's "and" not "or", it's not a lot. I mean, we don't do a great job overall. And it's sometimes important for us to remember that our patients oftentimes don't have just one diagnosis, but unfortunately they have a lot of them, and that's a lot of medication, a lot of pills that they have to take. So compliance, of course, is an issue.
[SLIDE 15]
The real reason of why we don't do that well is probably multifactorial. There are physician reasons and there are patient reasons. Some of the physician reasons I can think of are inertia, clinical inertia. We like sometimes to just continue the same treatment. We also sometimes fear hypoglycemia as physicians, and we do not want our patients to go through hypoglycemic events, repeated hypoglycemic events. So that sometimes makes us be a little bit more conservative in our approach.
Part of it is unfamiliarity with the new medications, and as I mentioned earlier, although we're fortunate that there are so many new medications on the market now to control blood glucose, a lot of us are not very familiar with them all, and this lack of familiarity, of course, makes us not use them, or use them much more conservatively than they should be used. What do you think, Dr. Donner?
[SLIDE 16]
THOMAS DONNER, MD: To show how significant this problem is, upwards of 50% of patients who had diabetes for more than one year have not achieved an A1C of under 7%. And they've looked at case records of patients who have had diabetes for number of years uncontrolled, and it's upwards of seven years of clear indications for insulin initiation before a patient is typically started on insulin therapy.
There are definitely patient and physician barriers to initiating insulin, and the physician barriers are, to some degree, the hope that adding one more oral agent will bring them down further. Again, when it's clearly indicated, I think we as practitioners need to say that it's warranted to start insulin and to dedicate the time to teach the patient how to initiate insulin therapy. I also have the patients (who) fear insulin because there is a stigma attached to insulin, as if they failed in some -- in some way.
So to overcome the patient barrier, one thing that I like to do is introduce the concept to patients early on that insulin deficiency is a part of the disease and I'm anticipating that down the road we may need to use insulin because their current therapy will no longer work when their body is not making enough insulin. I think if you plant that seed early on, then when the time comes it's clear that you need to start insulin, that patients will be much more accepting of insulin therapy.  
ANIKET SIDHAYE, MD: I like that. I think those are great pieces of advice. Armand, did you have something you wanted to say there?
ARMAND KRIKORIAN, MD: No, I cannot agree more with what you said, and it's amazing. Every time we think of starting insulin, we mention it sometimes. If we have not planted the seed early enough, like you said, we end up in this negotiation where the, you know, the patient would tell us, "Well, you give me another three months and I'll be good and my glucose will be normal.  I promise."
[SLIDE 17]
ANIKET SIDHAYE, MD: These are great pieces of advice. I think let's now move to the next phase, which is that we've started the basal insulin, and this is a scenario we frequently encounter. You may have titrated up. The fasting glucose is now less than 130, but the A1C is still 8% or 8.5%. How do you approach this and what do you start with, and how do you decide what to start with? Armand?  
ARMAND KRIKORIAN, MD: So once we hit that point, it's important for us remember actually, as you said, when the hemoglobin-A1C is about 8 and the fastings are controlled, that most of the contribution is coming from postprandial hyperglycemia. So that hemoglobin-A1C is elevated because of postprandial hyperglycemia that's happening.
So we have various ways of tackling that. In broad categories we could add prandial insulin. We could also use GLP-1 receptor agonists, DPP-4 inhibitors, or SGLT2-inhibitors. And the latter two are newer drugs that are on the market.
So the GLP-1 agonists are injectables and the DPP-4 inhibitors and the SGLT2-inhibitors are pills, and of course, the prandial insulins are injectables.
ANIKET SIDHAYE, MD: Tom, how do you approach this?
THOMAS DONNER, MD: So I think in terms of whether to start a prandial insulin versus an oral -- another oral agent the patient is not on or a GLP-1 agonist to some degree has to do with how poorly they're controlled and how severe their postprandial hyperglycemia.  
If the A1C is only mildly elevated, then a DPP-4 or SGLT2 inhibitor, I think would be a good option because the degree of glucose lowering (needed) after meals is not as dramatic.  
When the A1C is much higher and there is significantly more postprandial hyperglycemia, then you need to use an agent that has -- is more potent. And that would either be a prandial insulin or GLP-1 agonist. Those two agents are much more potent in terms of lowering postprandial hyperglycemia.  
ANIKET SIDHAYE, MD: Well, I think you've both outlined very well what the options are once patients have not reached target with basal insulin alone. And again, as a reminder to our audience, there are guidelines from both AACE and ADA. Maybe we should go over some of the data to convince people that these things work?
[SLIDE 18]
ARMAND KRIKORIAN, MD: Sure. So for GLP-1 receptor agonists used in combination with basal insulin, there is actually strong data in the form of meta-analysis that came out showing that they're actually as good. So combining a GLP-1 receptor agonist with basal insulin, as compared to basal bolus insulin therapy, they're actually as good as each other in terms of reaching hemoglobin-A1C targets with some advantage to the GLP-1 receptor agonist/basal insulin combo to less hypoglycemia events.  
And if you layer on top of that the fact that GLP-1 receptor agonists also in general have a weight-beneficial effect, that might be another advantage to their use.
ANIKET SIDHAYE, MD: How about for SGLT2-inhibitors? Are there particular things that make them attractive for you?
[SLIDE 19]
THOMAS DONNER, MD: So when compared to a prandial insulin, one bonus is also a weight benefit. Since the SGLT2s are acting by inhibiting glucose absorption in the kidney, and you get obligatory glucosuria, you're going to be experiencing a weight loss with it. And they are effective throughout the day, so you see good postprandial glucose reduction with some weight loss.  
ANIKET SIDHAYE, MD: Let's go over some of the practicalities in terms of GLP-1 receptor agonists. What are the formulations that are available and how do you use them? Do you caution patients about any side effects? Armand.  
[SLIDE 20]
ARMAND KRIKORIAN, MD: Sure. So as we discussed earlier, GLP-1 receptor agonists are available in injection forms.
The once-a-day and twice-a-day injections are FDA approved to use with basal insulin. As far as I know, the once-a-week one has not yet been approved for use in combination with insulin. So these medications have, as we said, a favorable weight profile usually for our patients.  
Now their side effects really are -- at least from what I see in my patients, is nausea and vomiting, especially at the initiation of therapy, and most patients go through that and then it just goes away, which is great.  
So the weight loss that some of them may be experiencing is not really due because they're having nausea and vomiting every day and not keeping food down. Now what I caution my patients when they start on GLP-1 receptor agonist is really mainly two things. One, pancreatitis, and two the risk of medullary thyroid carcinoma.
But what I do is I tell my patients, "If you have a personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia, maybe we should consider an alternative therapy for you."
ANIKET SIDHAYE, MD: How about the other two categories we talked about, SGLT2-inhibitors and DPP-4 inhibitors? Could you comment about -- I mean, they're available as oral agents, but some side effects that you look out for?
[SLIDE 21]
THOMAS DONNER, MD: With the SGLT2-inhibitors, they have a diuretic effect, so just as we would be cautious in prescribing a diuretic to someone who's elderly, has orthostatic hypotension, you need to be cautious, but that side effect is pretty uncommon, especially in an otherwise healthy person.
Glucose is not supposed to be in the genitourinary tract, and so you do see an increased risk of yeast infections and also of urinary tract infections. They tend to be self-limited and easy to treat, but it's a -- it's a precaution that you need to warn patients about just so that if they develop symptoms suggestive of either of those infections, that they can contact you for the appropriate treatment.  
ANIKET SIDHAYE, MD: And I think there's been a report of normal glycemic ketoacidosis on the SGLT2-inhibitors.
THOMAS DONNER, MD: So reports came out not too long after these drugs were used, and what's concerning about that is there's ketoacidosis with glucose levels that are approaching the normal range.
[SLIDE 22]
ANIKET SIDHAYE, MD: How about the DPP-4 inhibitors? Armand, since you're on the incretin system, we'll keep you with that. How about any side effects?
ARMAND KRIKORIAN, MD: Sure, the DPP-4 inhibitors, we've been fortunate that they don't have actually that many side effects. The most common side effects that have been reported are really nasopharyngeal symptoms, some stuffiness, maybe some nasopharyngeal irritation, no nausea and vomiting like the GLP-1 receptor agonists, so overall, a much more favorable side effect profile that we've seen with those drugs.  
ANIKET SIDHAYE, MD: And do they induce weight loss or are they more weight neutral, would you say?
ARMAND KRIKORIAN, MD: That's a great point. Most of the data points that they are weight neutral.
THOMAS DONNER, MD: I want to comment on another benefit of these agents, is that they stimulate insulin secretion, but only in a glucose-dependent manner. So when glucose levels are in the normal range, you don't see hypoglycemia because insulin is no longer stimulated, as opposed to the sulfonylurea class where if glucose levels are normal, you continue to get stimulation of insulin secretion and the risk for hypoglycemia. So that is a benefit of the DPP-4 inhibitors versus the sulfonylureas.  
ANIKET SIDHAYE, MD: I think maybe we didn't touch on this is so much before, so we'll just take a step back to the initiation of insulin. Most of the time patients are on two or three oral hypoglycemics, perhaps the sulfonylurea. What do you do? Do you have them just stay on their previous treatment, or decrease it? What is the advice?
[SLIDE 23]
THOMAS DONNER, MD: So an excellent question. I think too often we see patients who are started on insulin, their other medications are discontinued. If you are adding a basal insulin alone, you're not getting any postprandial hyperglycemic control with basal insulin alone. The only thing you're doing is lowering the glucose level going into the meal. But then you no longer have an agent onboard that is controlling postprandial hyperglycemia.
So I will tend to continue all the other agents because most of the other agents are impacting postprandial hyperglycemia.
[SLIDE 24]
ANIKET SIDHAYE, MD: So that's great. So the guidelines from the major societies, I think it's important to emphasize, suggest that once basal insulin is not working they approve these alternatives that we've discussed.  
What are your guys' [sic] thoughts about this, and maybe you could go over in what specific circumstance you might pick each of these?
THOMAS DONNER, MD: Sure. We have luxury today of having a number of agents to pick from, and I think it's reasonable to consider a GLP-1 agonist as add-on to the failure of basal insulin.
ANIKET SIDHAYE, MD: Armand, how about you? Are there particular patients you pick one or the other of these agents for?
ARMAND KRIKORIAN, MD: So we're going to take into account patient preferences, whether they're, you know, open to taking more injections or not, cost, their side effect profile, where are they as far as their hemoglobin-A1C? And I believe Tom mentioned earlier, so if somebody has a hemoglobin-A1C of 7.6 or 7.5, I really would want a small nudge to bring their hemoglobin-A1C down to target, so I pick a different agent in this case. So maybe this will be an instance where I will pick a DPP-4 inhibitor to add on top. It is weight neutral. It has very little risk of hypoglycemia, and it is exactly -- it will bring the hemoglobin-A1C exactly as much as we want it to go down, not too much. Because we know that sometimes lowering the hemoglobin-A1c too much puts our patients at higher cardiovascular risk, or maybe at, you know hypoglycemia risk there.
So SGLT2-inhibitors, again, Tom mentioned it earlier, you can use them if you want some favorable impact on blood pressure, some favorable impact on weight. So again it's really starting with a patient and taking into account their weight, their hemoglobin-A1C, the cost, whether they're willing to do injections, and all those factors together and deciding on the therapy.
[SLIDE 25]
ANIKET SIDHAYE, MD: If there's anything you want our audience members to take away, I'll give you the opportunity to offer a nugget or a pearl. Armand.  
ARMAND KRIKORIAN, MD: Sure. I mean, my biggest message is doing nothing is not an option. We have to fight the clinical inertia that we all are guilty of, and doing something is better than doing nothing as far as controlling the blood glucose and the blood pressure and the lipids. So it's --what I tell my patients, it's like running the marathon, not the 100-meter dash.  
ANIKET SIDHAYE, MD: Tom
THOMAS DONNER, MD: And I agree. I think starting much earlier is the message that I would have practitioners consider, and also engaging the patients because if a patient is onboard, it's more likely to happen. And by talking to them a little bit about the pathophysiology of diabetes, that this is a disease of insulin deficiency, which we expect to continue to worsen over time, and that we’re expecting, despite their best efforts, that their current medications may fail and they may need insulin in the future, that acceptance to initiating insulin will be better among patients.  
ANIKET SIDHAYE, MD: And I think we all should remember that this -- that this particular condition, diabetes, is one where we expect so much more of patients. This is not like most other conditions where you prescribe an infusion or a medication and that's sort of the end of the story.
I would like to thank both of our expert faculty, Dr. Thomas Donner, Dr. Armand Krikorian, for their great insights and discussion, and I like to thank you, our audience, for participating in this Clinical Dialogue.  
Type 2 diabetes mellitus is a progressive disease that requires individualized therapy and appropriate titration of therapy. While there are many tools available in our medical toolbox to manage type 2 diabetes mellitus, patients can stagnate at high glucose levels for months to years when more aggressive therapy, including insulin therapy, is not utilized.
There is a risk where patients and providers are a step behind the disease, which can lead to poor outcomes. Practitioners must be comfortable with the current insulin options on the market, including the recent developments of newer basal insulins, including U-200 insulin degludec individually and in combination with aspart, and newer formulations of U-300 insulin glargine.  
Moreover, there are additional therapies that can be added as dual agents to these insulin therapies. These include GLP-1 receptor agonists, DPP-4 inhibitors and SGLT2-inhibitors. All of them are important tools that practitioners should feel comfortable utilizing when needed in the treatment of type 2 diabetes mellitus.
[SLIDE 26]
Before leaving, we invite you to participate in the eCase Challenge where you'll have the opportunity to apply what you've learned in this Clinical Dialogue in a real-world clinical situation and receive additional CME credits, too
I'm Dr. Aniket Sidhaye. We hope you enjoyed this Clinical Dialogue program. Thank you for joining us.
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