Two New Combination Injectable Drugs for Type 2 Diabetes

The US Food and Drug Administration (FDA) has approved two new combination injectable drugs that should be coming out on the market in the next few months. Both are combinations of insulin plus a GLP-1 receptor agonist. One is a combination of glargine and lixisenatide, which I am going to call LixiLan. The other is a combination of degludec and liraglutide, which I am going to call IDegLira. Those were the names that were used in the research studies for these two agents.^[1,2,3,4,5]

This may seem confusing, but the theory behind this is that type 2 diabetes is a disease of both insulin deficiency and insulin resistance—and a whole host of other issues. There is abnormal signaling in the gut and in the brain. Beta cells are not secreting normally. Glucagon levels are too high. We know about the ominous octet. Many issues are involved in the pathogenesis of type 2 diabetes. We know that giving insulin works, but we are not treating all of those issues. Giving a GLP-1 receptor agonist can be very helpful, but for patients with significant insulin deficiency, that might not be enough.

In the clinical trials^[1,2,3,4,5] where they combined the GLP-1 receptor agonist with a long-acting insulin and dosed it up slowly like they were dosing up basal insulin, they got very good reductions in A1c levels. Some of the trials saw the biggest A1c reductions that I have seen with a diabetes drug. They also got fewer gastrointestinal side effects and fewer side effects in general, because you are going up very slowly on these agents, so patients seemed to tolerate them fairly well. Many patients tolerate a slower titration better than a rapid one.

These two drugs will come out in different pens with slightly different ways of giving them. Let me start with their indications. Both of them are going to be indicated as a second injectable. What that means is that if a patient is on a basal insulin and they are not at target, you can stop the basal insulin and add one of these two agents. Or, if a patient is on a GLP-1 receptor agonist alone and is not at target, you can stop the GLP-1 receptor agonist and add this combination. Basically, it's stepping up the other injectable therapy. Say that we have uptitrated the basal insulin and we think about the next step. We think about adding in a premeal insulin dose or two. That is often a problem for patients. It's difficult in terms of lifestyle and risk for hypoglycemia. Now this is going to be the option. Instead of going to a more complex regimen, you are going to take one pen away and add this other pen that is a combination of the two agents.

The package inserts are available online and go through some of the subtle differences between the two pens. They are different drugs. The insulins are different and the GLP-1 receptor agonists are different. The key difference between them is that lixisenatide is a shorter-acting GLP-1 receptor agonist, so the combination of lixisenatide and glargine should be given in the morning before the biggest meal. The combination of liraglutide plus degludec can be given at any time of day because the two agents work individually.

As with most agents, I want patients to get into a habit, so I try to get patients to take whatever they are taking at the same time of day. The LixiLan combination will be given first thing in the morning and the IDegLira combination will be given at some point during the day when it seems most appropriate for the patient. You uptitrate these slowly. The recommended titration schedules are about 2 units every 3-4 days or every week, depending on which drug combination you are talking about. The side effects are basically the same side-effect profiles that you would see for the individual agents.

As I said, clinical trials using these combinations showed very nice A1c reductions. Remember that these are in patients who are sort of at the end of the line in terms of starting basal insulin and uptitrating or starting a GLP-1 receptor agonist. It combines two agents together, so you get the combination of both therapies and uptitrate the dose slowly in a way that your patients will tolerate.

Thank you. This has been Anne Peters for Medscape.

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