Insulin Can't Solve Everything: Adjunctive Therapies in T1D

Jeremy Pettus, MD; Mark Harmel, MPH


June 23, 2020

This transcript has been edited for clarity.

There's still a huge need for exploring adjunctive therapies in type 1 diabetes. This area of research is absolutely critical, and we're at an important juncture in this space where we're trying to figure out our way forward.

What do we really want from adjunctive therapy in type 1 diabetes? We need to stop and pause, and think about the problems we're trying to solve. What metabolic consequences are we trying to deal with? As for me, I think we should take a page from the type 2 diabetes playbook.

When we talk about type 2 diabetes, we talk about the "ominous octet," and when we see somebody with type 2 diabetes, we are always thinking combination therapies. It's been hammered home that you use this medication to address this metabolic pathway and this medication to address this metabolic pathway. And in doing so, we get better clinical results; we get lower A1c and reduction in cardiovascular disease.

But when we think about type 1 diabetes, it's insulin, insulin, insulin — and that's all we think about. We need to realize that all of the same abnormal pathways that occur in type 2 diabetes are basically present in type 1 diabetes. Certainly, we don't have insulin secretion in type 1 diabetes, but we know that the alpha cell is extremely dysregulated. Glucagon is not secreted in response to hypoglycemia and it's excreted in excess in hyperglycemia, so it's not there when we need it and it's there when we don't need it.

We know that there is complete amylin deficiency. We know that there's insulin resistance at the level of the muscle, the adipose tissue at the liver. And we know there's abnormal glucose reabsorption at the kidneys. So all of these pathways that are well founded in science, we are ignoring completely in type 1 diabetes.

If we can develop therapies that address some of these pathways, they might be able to do things that insulin cannot. What I mean by that is, if we had the perfect artificial pancreas system that got me time-in-range 90%-100% of the time, well, great. My glucose would be awesome. I would be stoked about that. I would have probably zero microvascular disease. But I'd still be at very high risk for cardiovascular disease. We know that even people with well-controlled type 1 diabetes with an A1c of 7 or less still have a two- to fourfold higher risk for cardiovascular disease, so this is a problem that is not being solved by insulin.

Personally, I think this is a result of insulin resistance that comes from high levels of insulin itself in type 1 diabetes. Addressing hyperinsulinemia, improving insulin resistance, maybe restoring glucagon physiology — these are areas where we can really intervene to get better outcomes in type 1 diabetes.

When I see patients now, of course I'm looking at their CGM and their pump data and all these things. But I do have a bullet point there that says "adjunctive therapy." Is this a person who is struggling with high A1c, and is weight a major issue for this person? Is cardiovascular disease a concern? These are people for whom we might already be considering adjunctive therapies: GLP-1 inhibitors, SGLT2 inhibitors.

I'm hoping that as the data build, we'll have other alternatives that we can use in this space. I have to say that there has been some disappointment. GLP-1 inhibitors are not currently approved. However, I do use them off-label on the right patient. SGLT2 inhibitors are now approved in Europe but not here because of the risk for diabetic ketoacidosis.

I think we're learning from some of these "failures" from trying to push these drugs into these type 2 diabetes protocols, where we put the patients on it and see what happens with their A1c, and we say, "Oh, it's only improved by 0.3%, so forget about these drugs." We have to open our minds that, yes, we want better glycemic control, but it's really these other things that we're looking for that insulin cannot do. We need to really think carefully about what we're looking for in this space, and when we redefine that, I think we'll have success moving forward.

Jeremy Pettus, MD, is an endocrinologist in La Jolla, California, who specializes in treating diabetes. He was himself diagnosed with type 1 diabetes at the age of 15, and he conducts clinical research into new approaches to managing the disease.

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