COMMENTARY

SGLT2 Inhibitors for T1D? Experts Debate at ENDO 2021

Dace Trence, MD

Disclosures

March 26, 2021

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Full disclosure: SGLT2 inhibitors are not FDA-approved for those with type 1 diabetes (T1D). But with the increased awareness of the benefits of SGLT2 inhibitors in type 2 diabetes (T2D), especially in patients with established cardiovascular and renal disease, there has been growing interest in their use in patients with T1D. The European Commission has already approved both dapagliflozin and sotagliflozin (a combined SGLT2 and SGLT1 inhibitor) — with some clear stipulations — for use in those with T1D. So, what should the considerations be in the United States?

This was the topic of an anticipated debate at the 2021 Endocrine Society annual meeting. What are the possible pros and cons of SGLT2 inhibitor use in T1DM? Dr Anne Peters, of the Keck School of Medicine at University of Southern California, presented the con view; while Dr Andrew Ahmann, of Oregon Health & Science University, presented the pro. And the discussion and following Q&A session were spirited.

Risk for Euglycemic Diabetic Ketoacidosis Is High

Peters opened by citing known concerns related to SGLT2 inhibitor use: increased risk for euglycemic diabetic ketoacidosis (DKA); relatively modest decreases in A1c as well as weight; no significant impact on decreasing hypoglycemia; and the need for significant patient education regarding safe use.

There was particular emphasis on the risk for euglycemic DKA, prevention of which included the advice to use low doses, target use to those with A1c of 9% or lower, test glucose levels whether by point in time or continuous glucose sensor, and have ready access to healthcare support. She added that, to date, clinical trials have not been helpful, as they have been limited by variable definitions of ketone presence and unclear ketosis mitigation strategies.

Peters spent considerable time reviewing her personal experience with a patient in whom improvement in glycemic control was very apparent with the addition of an SGLT2 inhibitor. But even though all possible risks associated with SGLT2 inhibitors had been reviewed and acknowledged by the patient, DKA happened — and recurred — despite repeated education.

Her recommendation for those with T1D needing intensification of glycemic control beyond basal-bolus insulin or an insulin pump is to instead consider a hybrid closed-loop system using an integrated continuous glucose sensor with insulin pump or to consider adding a GLP-1 receptor agonist.

The Benefits Are Many

Ahmann then came in fighting, well armed to present the pro side.

He began with data from published literature noting the pattern of weight gain in those with T1D and their relative lack of progress in renal function falloff prevention. He noted a recent review citing that by age 45 years, more than 70% of men and 50% of women with T1D have developed coronary artery calcification.

He reviewed the positive impact of SGLT2 inhibitors on decreasing A1c, weight, insulin dose needed, and glycemic variability, and improved quality of life and maybe renal function (at least in those with T2D). He reviewed a meta-analysis showing an overall decrease in A1c of 0.4%, weight decrease of 3.4%, and average insulin dose decrease of 10%.

Ahmann did acknowledge that the risk for DKA is concerning. He offered some guidelines for avoiding SGLT2 inhibitors in any patient with previous DKA, A1c levels over 9%, use of alcohol or other drugs that could cloud sensorium, psychiatric disease, female sex, and adolescent age. Factors that increase risks associated with SGLT2 inhibitors include the use of large doses of insulin, reduced dietary carbohydrate intake, dehydration, BMI < 25 kg/m2 (although he feels that 27 kg/m2, as recommended in the European stipulations, is a better cutoff), and insulin pump use.

He noted that patient education in the prevention of typical DKA has been shown to decrease the development of DKA, whereas DKA rates increased with the addition of SGLT2 inhibitors to insulin, despite patient education. This raises the question as to whether structured education has been helpful. He added that SGLT2 inhibitors should be particularly discouraged in high-risk situations (ie, acute illness; hospitalizations; or lack of caloric intake, especially carbohydrate intake).

More Studies Needed

In the post-debate discussion, both presenters acknowledged that although there are many potential safety concerns associated with SGLT2 inhibitors, we all know of the occasional patient in whom this class could be used cautiously with benefit. They reviewed the different approach to treatment of DKA in the setting of euglycemic DKA — the requirement for calories as well as hydration and insulin.

Both expressed the need for more studies in those with T1D in regard to safety and benefits. They also added that endocrinologists should be the specific clinicians to manage this medication class if prescribed for patients with T1D.

What's the Take-away Message?

SGLT2 inhibitors have shown unequivocal benefit in populations with T2D, especially in the setting of atherosclerotic disease as well as renal function falloff. We are seeing many individuals with T1D living longer, increasingly showing the vascular and renal function concerns that we are familiar with in people with T2D. Although we lack study data linking SGLT2 inhibitors with similar benefits in patients with T1D and the same complications, our cardiology colleagues have shown us the benefits of SGLT2 inhibitors in those without diabetes.

So, maybe the answer at this time is to choose the patient carefully and review, review, review "No drink, no food, no drug" — a catchy way to remind the patient of the risks — at each visit. And good luck with insurance coverage!

Dace Trence, MD, is a professor of medicine at the University of Washington in Seattle. She has published articles in JCEM, JAMA, and Endocrine Practice, and chapters in several texts. She is also co-author of the book Optimizing Diabetes Care for the Practitioner.

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