Jennifer Brigitte Green, MD

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: I always do look for opportunities to use combination therapies in patients with type 2 diabetes, and we have many such medications available now. We’ve had combinations of different kinds of oral agents from different classes for many years. And now, of course, we have combinations of both basal insulin and GLP-1 [glucagon-like peptide-1] receptor agonists available for prescription. If we think about the patients for whom that kind of combination therapy might be appropriate, I have to say that those could be considered appropriate interventions for just about anyone with type 2 diabetes.

If we look into that in a little greater detail or think a bit more carefully about that, naturally you would think of the person who is on basal insulin therapy, or for that matter a GLP-1 receptor agonist, who clearly needs additional intensification as the ideal candidate to switch to the injected combination of basal insulin plus a GLP-1 receptor agonist. Because that can be a very effective further intensification of their care, probably with the same number of injections per day and ideally no added injection or medication burden.

Thus, there are many different people who would be good candidates for that combination therapy. If we think about why those kinds of combinations are effective and good to think about in the treatment of type 2 diabetes, the rationale for using those medications together would be of course that the basal insulin works to control blood sugars overnight in the fasting state and in between meals. Then, the GLP-1 receptor agonist’s main role in glycemic control is to blunt the rise of blood sugar after meals. So they have a very complementary mechanism of action, and in general, those are combinations of very effective agents.

When we think about the Part D Senior Savings Model, which is known as the $35 insulin plan, first I have to say that any interventions or changes that can improve access to insulin, a drug many people need for survival, is a terrific step forward. This will hopefully result in fewer people rationing insulin in the future, which is unfortunately a practice that can be incredibly dangerous to the individual. Thus, I’m very happy to see this movement forward, and I think it will be of great benefit to many people with type 1 and type 2 diabetes.

However, I would love to see some consideration or expansion of access to other injectable therapies for people with type 2 diabetes moving forward. One of the reasons that this could be considered is shown in the most recent ADA [American Diabetes Association] standards of care for the management of type 2 diabetes, in which those guidelines or suggestions recommend that the first injectable agent used in someone with type 2 diabetes who requires intensification actually be a GLP-1 receptor agonist. And if we have improved access to care, that will be more likely accessible to the many people with type 2 diabetes in this country and can be implemented effectively.

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Dr Jennifer Brigitte Green considers the patient selection for fixed-ratio combinations of basal insulin and GLP-1 receptor agonists among patients with type 2 diabetes and provides insight around Medicare patient access to insulin and injectable medications.

Fixed-Ratio Combinations for Type 2 Diabetes

: There is quite a lot of clinical inertia in the management of type 2 diabetes, and I think that there are many reasons for that, and it’s an issue on the part of both the diabetes care provider and the person affected by type 2 diabetes. There tends to be always a desire to make additional lifestyle changes in order to improve glycemic control. That is not to say that lifestyle modification is not important in the management of type 2 diabetes, it’s really the foundation of care, but often lifestyle modification will not be adequate to manage type 2 diabetes. Thus, we do need to make sure that we move past what is kind of a natural desire on the part of everyone to minimize the number of medications that are taken and to rely on lifestyle changes to achieve glycemic goals. It just, unfortunately, doesn’t happen as often as we would like to see it. Now, the other thing that I think is often forgotten or not understood about type 2 diabetes is that the traditional stepped approach to glycemic management, the one that we’ve implemented really for decades in the management of type 2 diabetes, unfortunately, doesn’t seem to be very effective in either achieving or maintaining good glycemic control over time.

There are many studies of early type 2 diabetes management that have been published that have shown that combination therapy implemented right from the start of a diagnosis of type 2 diabetes is a much more effective approach, again, in achieving glycemic goals and maintaining good glycemic control for extended periods. Then, there is the approach where traditionally you start someone on a given medication, they essentially fail because they have inadequate glycemic control at some point on that medicine. And then at that point, perhaps a fairly long time after it’s clear that they failed that regimen, another medication is added. I think if we perhaps shift our thinking to the use of combinations of medicines that work in complementary physiologic ways very early in the lifetime of someone with type 2 diabetes, we may be able to change that trajectory, and inertia may become less of a problem.

Jennifer Brigitte Green, MD, discusses the reasoning behind clinical inertia in treating patients with type 2 diabetes and comments on achieving and maintaining glycemic control over an extended period.

Clinical Inertia in Treatment of Type 2 Diabetes

: Occasionally, patients will not respond to their oral regimen, and I think we need to make sure when we’re talking about response that we really define what we mean. Many people on oral medications for the management of hyperglycemia and type 2 diabetes will not be meeting their glycemic goals, but they still might be responding to the oral medications. It’s just not enough of an effect from those oral medications to control their blood sugars adequately. In the case where I’m seeing a person with a diagnosis of type 2 diabetes and they’re not responding at all to their oral medications, there are couple of big things that I need to keep in mind.

One would be are they actually taking the medications, because usually medicines for diabetes will do something. They might not do enough, but if it looks like somebody isn’t responding at all, I want to try to identify whether medicines are being filled and taken, and if they’re not, to determine why and see if we can figure out a regimen that’s going to be better suited to that person’s lifestyle. The other thing to keep in mind is that there will be the occasional cases where an adult with newly or recently diagnosed diabetes actually has a kind of diabetes that is autoimmune, or type 1, or related to very significant inability to product insulin. Thus, we need to be on the alert for that condition, and one of the signs would be that the oral medications for glycemic control simply don’t seem to be working.

For many people with type 2 diabetes, they do progress to insulin therapy. I would love to be able to say that if a person were to add insulin to their treatment regimen, that they would be able to easily achieve adequate glycemic control, but we know that’s not true. And in fact, if you look across the landscape of people with type 2 diabetes in this country, unfortunately, people who are on insulin tend to have poorer glycemic control than individuals who aren’t using insulin. That’s probably because those people have longer standing diabetes that’s more difficult to manage, and they may have contraindications to the use of other medications.

Insulin though is a really powerful tool, and I don’t want to downplay its role in the management of type 2 diabetes. But insulin only addresses 1 of the physiologic abnormalities that contributes to hyperglycemia and type 2 diabetes. It only addresses inadequate insulin secretion. It doesn’t address all of the other disordered aspects of metabolism that we know are present in type 2 diabetes. Thus, it alone can often be inadequate to control blood sugars.

The other reason that insulin might not be enough to control blood sugars in someone with type 2 diabetes is that you often reach a point in the insulin dosing where you’re unable to uptitrate the dose because either the person is having hypoglycemia that can’t be alleviated by changes in the dose or timing of the insulin administration, or they’re experiencing an adverse effect such as weight gain that limits your ability to uptitrate further.

Dr Jennifer Brigitte Green addresses clinical considerations for patients with type 2 diabetes who are not responding to their oral antidiabetic agents and discusses her strategy for insufficient target glycemic control with insulin regimens.

Type 2 Diabetes: Considerations for Achieving Targeted Glycemic Control

: My approach to the treatment of people with type 2 diabetes relies fairly heavily upon the ADA [American Diabetes Association] standards of care, which are revised annually. Those care guidelines have become fairly sophisticated, and it is recommended that we make medication choices based upon, first, our individual patients’ personal level of risk for cardiovascular and kidney events or complications. Then, if a patient is not at particularly high risk for those complications or does not have cardiovascular or kidney disease yet, the guidelines recommend that we focus our medication choices on whether we have certain priorities for the care. And those would include issues such as reducing the risk of hypoglycemia, minimizing weight gain or promoting weight loss, or devising a treatment regimen that is low cost or accessible to the patient.

Of course, those are overlapping concerns, so we usually don’t just have 1 that applies to each individual. But that’s how I tend to think about my approach to care of the individual patient. Then, of course, we’re still worried about and want to make sure that our patients have individually appropriate glycemic control. That’s a separate but related issue, and we need to make sure that all of those goals of care are addressed simultaneously.

I think some of the major issues or major difficulties in the management of type 2 diabetes is simply the fact that a) Many people if they have diabetes for a number of years are going to need a number of medications to control their blood sugar adequately, and b) They often have many other related conditions, such as obesity, hypertension, hyperlipidemia, or even unrelated medical conditions that all need to be treated separately. The medication burden for the individual patient can become very significant. Thus, I like to look for opportunities to choose a pharmacotherapy or intervention that can address multiple of those issues at the same time. I also like to look for opportunities to make substitutions of potentially more effective medications for drugs that patients are already taking, again to minimize their medication or regimen burden and perhaps their cost as well.

If we’re talking about identifying patients who are not well controlled on oral agents, usually you would define that as having glycemic control that’s inadequate to meet their individual goals or individual targets. Usually, that’s pretty easy to identify based upon their hemoglobin A1c [glycated hemoglobin] being above the desired range. We’re also seeing, of course, many people use continuous glucose monitors or glucose sensors at home, and so we can easily identify the range in which their blood sugars fall. We can identify whether they’re having significant fluctuations in blood sugars at certain times of day. Thus, those are pretty good clues and can help us fairly readily identify when someone using oral glucose-lowering medications is not adequately controlled. There can be some rare circumstances in which a person’s hemoglobin A1c isn’t reliable, but that’s fairly uncommon. We do have other testing modalities such as measurement of fructosamine in those cases that can provide some insight into overall blood glucose control as well.

There are many goals of therapy in the management of type 2 diabetes, and there are really too many to list during this conversation. But I think personally, designing a regimen that both achieves the individually appropriate degree of glycemic control for the person I’m caring for but also addresses their excess risk of cardiovascular and kidney complications is really my goal. I want to do that using the regimen that is acceptable as well as accessible to the person who will be using it. To be honest, most of the people who are referred to endocrinologists are not meeting one or perhaps all of those goals, so there is an opportunity almost always to make meaningful changes.

Another goal of therapy is to make sure that the glycemic goal is reached, or we can get as close to that as possible with a minimum risk of hypoglycemia if at all possible. It’s sort of hard to describe or measure specifically, but my goal is for things not to happen. I want to keep people out of the hospital. I want to keep them from experiencing adverse cardiovascular or kidney outcomes. Thus, it’s really a matter of not letting bad things happen, which can be difficult to measure but is critically important.

Jennifer Brigitte Green, MD, reviews her treatment approach for managing patients with type 2 diabetes and shares insight on how to identify patients that are uncontrolled with oral antidiabetic agents.

Jennifer Brigitte Green, MD

Articles

Fixed-Ratio Combinations for Type 2 Diabetes

Clinical Inertia in Treatment of Type 2 Diabetes

Type 2 Diabetes: Considerations for Achieving Targeted Glycemic Control

Treatment Approach for Patients With Type 2 Diabetes