A publication in Nature Medicine by RI-MUHC researchers describes an add-on treatment that could improve outcomes for people with type 1 diabetes.

People living with type 1 diabetes—an autoimmune disease that stops their body from producing insulin—require lifelong insulin replacement therapy to manage high glucose levels. They can use artificial pancreases to automatically adjust insulin delivery based on fluctuating glucose levels. However, on their own, these electronic devices called closed-loop systems do not allow all patients to reach desired glucose levels.

Recently published in Nature Medicine, the results of a placebo-controlled multisite clinical trial led by researchers at the Research Institute of the McGill University Health Centre (RI‑MUHC) and the Lunenfeld-Tanenbaum Research Institute in Toronto, Ontario, have shown that the addition of empagliflozin, a drug that promotes glucose excretion in the urine, to both closed-loop insulin delivery and standard pump therapy, improved blood glucose control for people living with type 1 diabetes. The greatest improvement was seen with the combined use of empagliflozin with closed-loop insulin delivery.

Left to right: First author of the study Ahmad Haidar, PhD, MUHC site clinical lead Jean-François Yale, MD, and study co-investigator Michael Tsoukas, MD, are members of the Metabolic Disorders and Complications Program at the Research Institute of the MUHC.

“We sought to combine the drug with closed-loop technology, two strategies known to effectively reduce blood glucose levels, in order to improve upon existing treatment options,” says Ahmad Haidar, a scientist in the Metabolic Disorders and Complications Program at the RI-MUHC and the first author of the study.

In their study, the researchers compared four weeks of each of closed-loop therapy plus empagliflozin, closed-loop therapy plus placebo, standard pump therapy plus empagliflozin and standard pump therapy plus placebo.

“This trial showed that empagliflozin can improve upon the performance of closed-loop systems,” says Dr. Jean-François Yale, clinical lead of the study at the MUHC site. “These results encourage further investigation into the benefits of adjunctive therapies for people with type 1 diabetes struggling to meet recommended targets with closed-loop systems alone.”

Potential benefits beyond glucose control

Approved for the treatment of type 2 diabetes, empagliflozin has been studied in several clinical trials for type 1 diabetes. It is part of a group of medications known as sodium glucose co-transporter 2 inhibitors (SGLT2i) that work independently from insulin to reduce blood glucose levels.

“SGLT2i provide cardiac and renal benefits in type 2 diabetes. Additionally, they have been shown to improve weight and blood pressure for people living with type 1 diabetes,” says Ahmad Haidar, who is also an assistant professor in the Department of Biomedical Engineering at McGill. “Given these benefits, this combination of therapies has the potential to provide wide benefits beyond even glucose control.”

Mitigating the risks of diabetic ketoacidosis

Diabetic ketoacidosis is a serious and potentially life-threatening complication of diabetes. It occurs when dangerous levels of acids, called ketones, are produced by the liver to compensate for the lack of insulin. People with type 1 diabetes are more at risk of diabetic ketoacidosis than those with type 2 diabetes.

The researchers report that, while no events of diabetic ketoacidosis occurred in the trial, ketosis rates increased with empagliflozin use, and were highest when on closed-loop therapy. Of note, rates of ketosis were lower in those participants with higher body mass index (BMI). Based on these findings, the researchers argue that mitigation strategies and continuous ketone monitoring devices are needed to better surveil and manage those at high risk of developing diabetic ketoacidosis.

About the study

The study Empagliflozin add-on therapy to closed-loop insulin delivery in type 1 diabetes: a 2 × 2 factorial randomized crossover trial was conducted by Ahmad Haidar, Leif Erik Lovblom, Nancy Cardinez, Nikita Gouchie-Provencher, Andrej Orszag, Michael A. Tsoukas, C. Marcelo Falappa, Adnan Jafar, Milad Ghanbari, Devrim Eldelekli, Joanna Rutkowski, Jean-François Yale and Bruce A. Perkins.

DOI : https://doi.org/10.1038/s41591-022-01805-3

The authors gratefully acknowledge support from the JDRF and by Diabetes Action Canada, a Canadian Institutes for Health Research (CIHR) Strategy for Patient-Oriented Research Network in Chronic Disease.