Rodolfo J. Galindo, MD

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 So far, we have been discussing how interesting a combination of basal insulin and GLP-1 [glucagon-like peptide-1] agents is. I applaud all the companies that decided to put effort into developing these new agents, and doing many studies, a really big portfolio of study with a lot of effort into that. And they were complementary. Then we discussed the validating studies for iGlarLixi [insulin glargine, lixisenatide] and for IDegLira [insulin degludec, liraglutide], the 2 agents that are available in the market. Then we discussed the studies that compare these agents in patients who are insulin naïve, not previously treated with insulin, and uncontrolled on oral agents. But then also we compared these agents to premixed insulin, which is commonly still used unfortunately, for many of our patients.

Now, I want to talk about something that is important to clinicians, of course, but I don’t think that patients see it as really important. I think it is actually a better metric for payers than for patients, which is adherence to therapy and persisting on X, Y therapy. The best treatment is not what will give you the better outcome, it is the treatment that the patient will use. And when you’re sitting in the office and you have a patient with type 2 diabetes, high blood pressure, a prior MI [myocardial infarction], kidney disease, and sleep apnea, or COPD [chronic obstructive pulmonary disease], and they’re taking 20 medications or 15, you need to face that patient and tell them that, “You need to take more medications now.” Remember, simplicity and agents that are complementary makes a lot of sense to us, but patients don’t see it, you need to explain that.

This was a very interesting poster that was presented at the Academy of Managed Care Pharmacy [AMCP], last year, 2021. The study observed the adherence and persistence of treatment with iGlarLixi versus its free combinations. This is very commonly seen. Insulin glargine has really good coverage, and we have been using it for a long time, so it tends to be an easy option for many clinicians. Then lixisenatide also, or other GLP-1s. But the point is that when you combine them, you get much better benefits. We can discuss that, an hour discussion, but more importantly, you are simplifying; you’re making simpler options for your patients. This study compares, again, iGlarLixi with the free-dose combination of basal insulin and lixisenatide, a GLP-1 receptor agonist, and it was presented by Lawrence Casalino, MD, et al, in 2021. The key point from this study is that a higher proportion of patients who were treated with iGlarLixi were persistent and adherent versus those treated with the free-dose combination.

If you ever wonder why your patient is not controlled, it is not your patient’s fault, it is never your patient’s fault. It is nobody’s fault, but you need to be more innovative and creative and try to find a way to have that patient be adherent and use their therapy as it is supposed to be used. It’s very hard for patients to do complex treatment regimes, even if they are really good at reducing A1C [glycated hemoglobin]. That’s very interesting to know. And we have many studies showing that patients treated with GLP-1 agents, they don’t tend to stick to it long term; 50% to 70%, some studies have suggested, of patients stop taking this medication. When you combine them, the adverse effects and the dose and everything is complemented by the basal insulin, so you have a better effect with lower doses sometimes. Some patients tend to be more adherent, and this study confirmed that, better adherence and better persistence. That was very interesting.

But then, you wonder why we need to know that. It is important for patients, and I keep saying that. But also, this study, which is very interesting, showed that it lowers costs, lowers pharmacy costs. Again, a fixed-ratio combination, simpler injection, once a day, complementary actions. You are always wondering, because it’s a new medication, is it going to be more expensive? The reality is that the pharmacy cost of this fixed-ratio combination, when you compare that to the individual components, was lower. It was very interesting to me to know that, and I think it’s important data for the payers. Also, you control the A1C, but that actually is not what is translated long term. It’s important to look at other stronger outcomes. For example, in this study, patients treated with iGlarLixi had fewer hospitalizations and fewer emergency department visits compared to those treated with the free-dose combination of these agents. It seems to be just simpler and common sense, when you combine them, they tend to work better.

I was very impressed by that, and I think it is very helpful for patients, but it’s important for payers to know that. Adherence has been shown to result in better care, fewer acute complications and fewer hospitalizations. When your patients are adherent to the treatment, you will have better outcomes long term. And it’s not that I’m telling our payer colleagues to do something and what they need to do, it is just showing evidence-based coverage modification. I don’t see a benefit, I don’t see a reason, and I don’t have any evidence to say that premixed insulin should have better coverage than fixed-ratio combinations. Nor do I see a reason why you have better coverage and lower out of pocket costs for the free-dose combination of these agents, basal insulin and GPL-1, and not for the fixed-ratio combination; it is just simpler. I think that these data are very helpful for those who make decisions, and we share this with patient advocacy groups as well. We’ll be sharing that with them.

This study that was presented at the AMCP by Casalino, et al, in 2021, shows that the use of fixed-ratio combination, specifically the study was iGlarLixi, was a better option than either of these components alone. It was better than mixing insulin in another study published in 

 by Julio Rosenstock, MD, and it’s a really good option for patients not controlled on basal insulin and oral therapy. I would encourage clinicians to consider this and would also encourage our colleagues from pharmacy, and health care systems, and insurance to use this evidence to support their coverage decisions. Also, talking about what is going to be happening in the future and how these data are going to be impactful, I was very excited, because when you do a clinical trial, and I do many of them, it is not always what I see in my practice. We always need real-world data, and this study was real-world data. It’s always good to have data from the daily work and not just a clinical trial, which is a very monitored environment where patients are most of the time compliant.

These real-world data show that the fixed-ratio combination has better adherence or persistence of therapy. Very interesting, I think that patients with a hemoglobin A1C of more than 9%, up to 10%, had really good results. It needs to be validated, but we clinicians know that patients treated with multiple daily injections of basal plus bolus insulin, most of these patients have an A1C of more than 10%. And for years, we have been saying that this is the best therapy for them. I strongly believe that’s not the case. I think that a fixed-ratio combination is probably the best option for a patient with really high A1C. They will be more compliant. This is just a simple comparison, but consider 3 injections a day or 4 injections a day compared to 1 injection per day. It just make sense for patients and clinicians to use a fixed-ratio combination. I believe that multiple daily injections of basal, bolus insulin for type 2 diabetes will be dying soon. In the future, we have a better option for these patients. Not for everybody, some patients don’t make insulin at some point in their disease course, but not as many as we used to treat in the past. And this is recommended by the guidelines, actually.

Type 2 diabetes is a really complex disease with many different pathophysiological defects, the so-called ominous octet, so many different pathophysiological defects. Using 1 agent is very unlikely to solve the problem. You need to use an agent that has complementary actions. I don’t see a value in using insulin therapy with insulin secretagogues, because they work on the same action, they just increase insulin levels. From my thinking it doesn’t make sense, and we see it all the time in practice. Combining agents that have complementary actions is much better. And of course, agents that can counteract those potential adverse effects from medication. For example, for basal insulin, it is weight gain. If you use a GLP-1, you’re trying to decrease that. For insulin, it is hypoglycemia, and when you use a GLP-1, you decrease the amount of insulin needed and then you tend to have lower hypoglycemia. That was the data that we discussed.

The future of type 2 diabetes is going to be combining agents with complementary actions. If you combine them into 1, it is much better than if you need to take 2 or 3 individual doses. We discussed that the combination is much better than the use of these individual components. And I’m pretty sure that we’ll be using most of these combined therapies. I think that is really helpful for patients. We have strong data to support that it results in less complication, less hypoglycemia, weight loss, and more importantly, patient adherence. Patients tend to be more adherent with the fixed-ratio combination therapy than when they take both components individually.

Videos

An expert in endocrinology reviews updates from the AMCP Nexus 2021 conference on treatment persistence and adherence with iGlarLixi versus free-dose combinations of basal insulin and GLP-1 receptor agonists, and shares insight on future directions for disease management.

AMCP Nexus 2021 Updates on iGlarLixi in Type 2 Diabetes

 I would like to discuss with the audience a clinical scenario that we see very often in our practices, and it’s very interesting. Many of our patients with type 2 diabetes are treated with premixed insulin. Many years ago, in the 1990s, smart doctors who I have had the pleasure to know, such as Philip Raskin, MD, from UT [University of Texas] Southwestern, were working on combining 2 types of insulin—intermediate-acting insulin, so called NPH [neutral protamine hagedorn], and short-acting insulin, regular—because it makes sense. I discussed earlier the combination of basal plus GLP-1 [glucagon-like peptide-1]. Many years ago when we didn’t have GLP-1 with its wondrous actions, the thinking was, let’s combine intermediate insulin that would act as a basal insulin with a short-acting insulin that would treat the postprandial glucose excursion, which I mentioned happens and is not controlled by basal insulin. That was developed many years ago, and of course, when you combine it, it gives you good results but also many other undesired effects. Commonly, you get hypoglycemia, and it’s really hard to control that postprandial spike with the premixed insulin. It’s designed for that, but it actually does not achieve that goal as the combination of basal and GLP-1 does.

Many of our patients are treated with that combination of premixed insulin mainly because of cost, and I would say even more for access. Many of the insurance plans and the coverage are very friendly with premixed insulin and less friendly with the newer agents. The reality is that maybe cost is not the best factor to consider because you have a combination medication now that has a lower price, but long term you get patient complications, and you don’t achieve [the target] A1C [glycated hemoglobin]. In one or two years, you might not get that result and that lower cost that you’re seeing every month. You need to have a long-term perspective on that aspect. Many of our patients, unfortunately, are still treated with premixed insulin, mostly because of access and cost.

The iGlarLixi [insulin glargine, lixisenatide] team decided to do a study and compare iGlarLixi with premixed insulin. Again, combining glargine with lixisenatide was compared to premixed insulin, and I think it was really needed. For many years, I’ve been trying to use a more physiologic and more friendly approach to treating type 2 diabetes, combining agents with complementary actions. But I’m a specialist in diabetes, so I want everybody else to know that there are other ways to do it as well, not just for specialists. It was known to me that this combination of premixed insulin was not treating my patients well, but the data needed to come, and those were the data that were done. The study was published by Julio Rosenstock, MD, a good colleague from UT Southwestern and Dallas Diabetes Research Center. It was an international study and took patients who were not controlled on basal insulin therapy and oral agents. Basically, they were taking basal insulin and the oral agents were there to control this postprandial glucose excursion that I mentioned that we need to control, because the 2 components will lower the A1C. It was an open randomized trial, and they had an A1C inclusion of 7.5% to 10%, again, very uncontrolled patients.

One point that I want to make, always keep in mind what is important to your patients. Premixed insulin, you need to take it twice a day minimum, and the fixed-ratio combination is once a day, so at least you’re getting away from 1 injection, which is really important to our patients. Remember burden: burden of care, amount of work, amount of diabetes injections, number of finger sticks, and all of that. It’s important to decrease and minimize the burden. This study was published in 

 in 2021. When you compared iGlarLixi with premixed insulin in patients who were uncontrolled on basal insulin and oral therapy, there was a higher A1C reduction in the group with iGlarLixi. And more importantly, and I explained this before, patients lost more weight, approximately 1.9 kg. That’s about 5 lb of weight loss, and of course, some patients lost more, versus patients that were treated with premixed, who tended to gain weight. But more importantly, and I think this is also very important for patients and especially for me as a clinician, they had less hypoglycemia. Again, you can control the A1C, you can increase the insulin, but if you’re getting hypoglycemia, then you’re not really helping your patient. You’re putting them into treatment-related complications that don’t need to happen because there are newer agents with safer profiles. And of course, more patients achieved that composite A1C of less than 7%, with the weight targets.

It was very interesting to see this, that an old therapy that was conceived as a more accessible therapy was not better than this newer, simpler, once-a-day fixed-ratio combination of iGlarLixi. And we were very excited. I see many patients with managed care, and this is typically the case. Many of the managed care companies try to be very open to covering premixed insulin, and I guess it’s because of cost. The reality is that you may be getting better A1C reduction and lower cost, month to month, but when you put that on the long term, you may be getting more complications. Some patients are having more hypoglycemia and gaining weight. The adherence and the persistence and the continuation of therapy may not be the best. It’s very important that our patients know this, our clinicians, but also our colleagues from managed care, and health systems, and insurance companies, that they understand these points. Because it’s not just what happened this month, it is what will happen in the longer run.

Rodolfo J. Galindo, MD, comments on the benefits of fixed-ratio combination therapies for the management of type 2 diabetes compared with premixed insulin.

Advantages of Using Fixed-Ratio Combinations in Type 2 Diabetes

The first study I’d like to explain is the LixiLan-O, which was 1 of the first studies done. It was published by Dr Melanie Davies, et al. The study question was simple: to compare this new agent, iGlarLixi, the combination of insulin glargine and lixisenatide, with its individual components, glargine and lixisenatide. The study was designed to include patients who were insulin naïve-patients who weren’t treated with insulin before. They were uncontrolled, meaning they had an A1C [glycated hemoglobin] at entry between 7.5% and 10%, which is a high level for many patients. Patients who have been taking metformin alone could have been taking metformin and another second oral agent. This is a common in our practice: many patients struggle to get their A1C under control on metformin or metformin and a second oral therapy. Insulin can do that, but what we’ve learned is that it will do that at the expense of weight gain and increasing hypoglycemia, which is the main limitation of insulin therapy.

This study compared these 3 arms. The hypothesis was proven because iGlarLixi [insulin glargine, lixisenatide] had a greater reduction in hemoglobin A1C. More subjects in that group reached the target hemoglobin A1C of less than 7%. Another important metric that we have, that is important not only to us scientists and clinicians but also to patients and payers, is the combination of a hemoglobin A1C less than 7% and no weight gain. If you have a patient who has type 2 diabetes—80% to 90% of them are overweight or obese—and you put them on a therapy that made them gain weight, they’ll have other complications later. That’s why it’s important for payers to understand that some therapies that improve A1C at the expense of other complications may not be the perfect therapy. You need to have more complementary reactions.

It was very interesting to see that that composite outcome of A1C less than 7% and no weight gain was achieved in more patients on the iGlarLixi [insulin glargine, lixisenatide] group compared with the glargine and the lixisenatide. As I explained earlier, the group with iGlarLixi [insulin glargine, lixisenatide] had a better postprandial glucose control, meaning it had a better control of the spike on the glucose after eating compared with the group with glargine. Glargine focuses only on endogenous glucose production, resulting in a better-fasting glucose. You need the second component, and that’s where lixisenatide comes in.

Patients are really happy when you talk about these and when they see the results: patients treated with iGlarLixi [insulin glargine, lixisenatide] had a mean body weight decrease. They had decreased body weight and lixisenatide, compared with glargine, which increased body weight. When you treat a patient and they know they’re going to be losing weight, they feel much better. They try to take the medication because they feel it’s really important. Patient-reported outcomes are important. We try to focus on A1C because of the scientific value, but sometimes patients don’t understand that. Patients want to see their own outcomes. It’s very important to understand what your patient needs.

In a post hoc analysis for LixiLan-O for patients with hemoglobin A1C more than 9%—remember, patients could have an A1C of up to 10%; this is a high-risk population with high glucose and very uncontrolled diabetes that needs insulin therapy—there was also a greater reduction in A1C when you treat them with iGlarLixi [insulin glargine, lixisenatide] compared with glargine and lixisenatide. It was a good development in our therapeutic for type 2 diabetes, and it was proven to be much better than the 2 individual components.

The other study I want to discuss is DUAL-I and the other fixed-ratio combination available, which is degludec and liraglutide. DUAL-I included patients [with an A1C of] 7% to 10% and a BMI [body mass index] less than 40 on metformin, with or without pioglitazone, a second oral agent. They saw higher A1C reduction, with more patients achieving an A1C target of less than 7% and less weight gain compared with degludec. It’s interesting because they didn’t see a difference in fasting plasma glucose, and it has to do with liraglutide, which is long acting. Lixisenatide is considered short acting, and it has a bigger effect on delaying gastric emptying, which is important for the postprandial glucose spike. In summary, years ago we were excited about this development in therapeutics. Used as a complementary action of basal insulin with GLP1 and many other studies, this proves that when you combine basal insulin with GLP1, you have better patient-related outcomes: greater A1C reduction, less weight gain and in some studies weight loss, less hypoglycemia, and better postprandial glucose control.

A key opinion leader reviews clinical data for newly approved injectable medications, iGlarLixi and iDegLira, for the management of type 2 diabetes as seen in the LixiLan-O and DUAL studies.

LixiLan-O and DUAL Studies in Type 2 Diabetes

This topic is very interesting, and I was really involved and interested since the beginning from a scientific perspective. Our population of patients with type 2 is expanding. We have many patients, and unfortunately many don’t achieve like glycemic targets. We’ve known for many years that if you improve glycemic targets—in this case, hemoglobin A1C [glycated hemoglobin]—you can prevent diabetes-related complications. One important measure is to improve diabetes and prevent diabetes complications by reducing hemoglobin A1C, and we have proof that we can reduce it.

I’m a clinician, so I see patients. For my clinical practice, I’m always interested in finding simpler ways to manage diabetes because our patient has a big burden of care. It’s not just diabetes. They have other conditions, other chronic diseases, and diabetes itself imposes a big burden on our patients. From a scientific perspective, I was very interested in the medication itself because it combined 2 agents that are complementary. But from a clinician standpoint and as a patient advocate—I also work a lot on patient advocacy—it was very interesting because a patient was going to have a simpler option to control the diabetes.

What does a fixed-ratio combination of basal insulin and GLP1 agonist mean? It’s a combination of basal insulin and 1 of the GLP1 agonists. One is iGlarLixi [insulin glargine, lixisenatide], which combines insulin glargine, which is well known and has been used for many years. It has a lot of data supporting their efficacy and safety. The short-acting GLP1 lixisenatide also has a strong safety and efficacy validating data. The second agent is called IDegLira [insulin degludec, liraglutide], which combines insulin degludec and a GLP1 agonist, liraglutide. Both agents have strong supporting programs in which the studies prove their safety and efficacy.

Why combine basal insulin and GLP1? Basal insulin acts primarily by reducing fasting plasma glucose. It suppresses that endogenous glucose production, which happens uncontrolled in patients with type 2 diabetes. You get that result early in the morning—when the patient wakes up fasting—that you have a reduction in the fasting plasma glucose. However, it doesn’t control the second portion of the A1C, which has the baseline hyperglycemia postprandial, so the glucose is elevated after a meal. Those 2 components elevate the A1C value. Basal insulin works only on the fasting plasma glucose. We usually need another agent to control meal-related hyperglycemic spikes. The spike in glucose after the patient eats usually happens 3 times a day, sometimes 4.

When the development of this medication was in place, they said, “This is great. You combine basal with GLP1 in 1 injection, simplify the treatment, and use in these 2 complementary actions.” One would suppress fasting plasma glucose, and the other would suppress postprandial glucose exposures or spikes. The short-acting lixisenatide works through that, but most of them delay gastric emptying, which is actually lixisenatide.

GLP1 agents also increase endogenously the insulin production that the pancreas can make. It helps the patient need less insulin because it’s acting in a way that the patient will produce insulin. More important, something that’s important in type 2 diabetes is suppression. The GLP1 agent decreases glucagon. Glucagon is the opposite of insulin; it raises glucose. It’s higher in patients with type 2 diabetes than in patients with no diabetes. It’s important that we control that, and we didn’t have that agent before. In summary, this combination of basal insulin and GLP1 suppresses fasting plasma glucose, stimulates the uptake—the use of this glucose that is circulating in the blood by the tissues—increases the insulin production by the pancreas, and decreases glucagon. It’s acting in many areas, but it also delays gastric emptying, which is very important in patients.

About 80% to 90% of our patients with type 2 diabetes have obesity or are overweight. They need to lose weight and it’s really hard. When your gastric emptying is delayed, you feel fullness early. That also sends a signal to the brain to suppress cravings and hunger. Also, it decreases the spike of the glucose after eating. It’s a really strong action. GLP1 works really well on that. By doing that, patients tend to lose weight. Insulin, on the other hand, makes patients gain weight.

These 2 agents provide many actions that you won’t get with 1 agent—some really important actions. Patient with type 2 diabetes are deficient. Many of our patients with type 2 diabetes have lung disease, so they need insulin at some point. That was interesting for us as scientists but also as clinicians, because our patients are asking for simplicity all the time. The simpler the regimen, the better their adherence on the therapy. GLP1s are really good, but we have strong data suggesting that 50% to 70% of patients have stopped taking their GLP1. When you combine with this agent, the thinking was that it will improve adherence. We’ll probably talk about that more later.

Rodolfo J. Galindo, MD, provides insight on the benefit of fixed-ratio combinations of basal insulin and GLP1 agonists for the optimal management of type 2 diabetes.

Rodolfo J. Galindo, MD

Articles

AMCP Nexus 2021 Updates on iGlarLixi in Type 2 Diabetes

Advantages of Using Fixed-Ratio Combinations in Type 2 Diabetes

LixiLan-O and DUAL Studies in Type 2 Diabetes

Managing Type 2 Diabetes With Fixed-Ratio Combinations