FDA Response to Sotagliflozin 'Disappointing'

Anne L. Peters, MD


April 02, 2019

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This transcript has been edited for clarity.

Today I'm going to discuss sotagliflozin and how it recently received a complete response letter from the US Food and Drug Administration (FDA). Basically, sotagliflozin is not going to be approved for use in the US market anytime soon. I don't have the results of what the FDA is thinking, but I'd like to comment on the basis of my own experience, having been at the FDA for the hearing, and talk about the future of SGLT inhibitor therapy in patients with type 1 diabetes.

What I'm about to discuss is all off-label use. I have been using SGLT2 inhibitors off-label for the management of my patients with type 1 diabetes, pretty much since the drugs came out. I'm well aware of the risk for diabetic ketoacidosis, having published about this risk[1] early on.

The reason I believe in using SGLT inhibitors in patients with type 1 diabetes is because of how much better my patients feel. They really feel like these drugs help them control their diabetes and reduce some of the variability that they live with as they go through their days. So, my entire reason for supporting the FDA approval of sotagliflozin in patients with type 1 diabetes is based on what my patients say about how well these drugs work.

The nonnumeric, hard-to-quantitate impact of SGLT inhibitors may have gotten lost in translation.

When I was at the FDA hearing, it seemed to me that the panel was not fully understanding people's experiences living with type 1 diabetes. Although a number of people spoke about this, it wasn't as impactful as some of the things that biostatisticians look at, such as changes in A1c, hypoglycemia, or anything that's numeric. Half of the panel was endocrinologists and a patient voice. And then there were cardiologists and others on the panel.

One of the things that might have gotten lost in translation is the nonnumeric, hard-to-quantitate impact of SGLT inhibitors. Obviously, the other side to it is the risk. These drugs in clinical trials have increased the risk for diabetic ketoacidosis in patients with type 1 diabetes. It also happens in people with type 2 diabetes, but much more rarely. However, none of the clinical trials were done with a careful risk-mitigation plan.

I have very specific things that I do to help reduce the risk in my patients, and frankly, it's worked very well for me. I'd love to see it as part of a larger ongoing study. I truly believe that the FDA could create a pathway whereby we restrict initial use of sotagliflozin in patients with type 1 diabetes to endocrinologists and patients who fit certain criteria.

What I Do in My Practice

So, what are my criteria? First is that the patient is doing reasonably well on insulin. I don't use these agents in patients whose A1c is > 9.

Then I have patients monitor their ketones, whether it's fingerstick or urine ketones. I tend to use fingerstick ketones because I'm used to it. I have patients do this for a week or two before they actually start on the active drug, to make sure that they aren't ketotic when starting on an SGLT inhibitor and to help patients get used to ketone testing.

My patients give me baseline ketone levels. I think patients should be required to have normal or very minimally elevated ketone levels before starting on an agent, because that shows you that they are on enough insulin to inhibit ketosis at baseline.

I tend to start with a low dose of the SGLT inhibitor. It may be half a tablet; I'm very conservative. I don't have my patients reduce their insulin by much early on, and I have them continue daily ketone monitoring until I get them to where I want, with a stable dose of insulin and a stable dose of the SGLT inhibitor.

I speak with my patients every week and I follow their ketones. After they've uptitrated the SGLT inhibitor and, in many cases, reduced their insulin to some degree, I make sure that they're stable, without a marked increase in ketone levels.

Let's say that somebody's baseline ketones on fingerstick are 0 to 0.1 or 0.2. You'll see a little bit of an increase, to 0.2 or 0.3. But my threshold is that my patients have to be at a serum ketone level of < 0.6 for me to start the agent. If they go above 0.6 after starting on the agent, I may need to further intensify their insulin therapy, making sure that I'm giving them enough carbohydrates and insulin.

Lots of Education

Then I give them a handout and lots of lessons on when to stop the SGLT2 inhibitor—for any sickness, procedure, dehydration, or intense exercise. We really work on that. At every 3-month follow-up visit, I ensure that they have ketone testing supplies available, that they know how to use them, and that they know what would happen if they develop ketones—specifically, that they'd stop the SGLT inhibitor and take more insulin and carbohydrate.

At annual visits, I again make absolutely certain that they're prepared and know when to stop the agents. Over time, people get very used to being on the agent—I have patients now who've been on an SGLT2 inhibitor for 3 or 4 years, and they've done really well. But I want to make sure that they remember to stop taking it if they get sick, so I reinforce that. I try to do it at every visit, but I make sure at an annual visit that they're prepared.

If we have a stepwise approach and a way of monitoring patients as SGLT inhibitors become available for patients with type 1 diabetes, we can make sure that patients do this safely. I was disappointed that sotagliflozin didn't get approved this time around, but I'm optimistic that this therapy would be a very useful tool in the management of type 1 diabetes.

I really hope that there's ongoing development for the adjunctive use of sotagliflozin in the management of type 1 diabetes. Thank you.

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