Type 1 diabetes (T1D) is a disease of multiple hormonal and metabolic impairments. In addition to deficient insulin secretion from the pancreas, T1D patients experience insulin resistance, increased risk of cardiovascular disease, increased glucose reabsorption by the kidneys, and other abnormalities that are not directly addressed by current treatments. There is a clear need for medications that can be used alongside insulin to simultaneously improve glycemic control and target other metabolic abnormalities. This clinical trial, conducted at the University of California – San Diego, will test combining two non-insulin therapies with insulin therapy to improve glucose control (measured by continuous glucose monitoring), reduce insulin needs, and improve markers of cardiovascular disease (blood tests and noninvasive measures of vascular function).
The first medication included in this trial is a sodium-glucose cotransporter-2 (SGLT2) inhibitor. This class of medications is FDA-approved for people with type 2 diabetes. In this population, the SGLT2 inhibitors improve blood glucose, lead to weight loss, and help protect the heart and kidneys. We hypothesize that SGLT2 inhibitors may provide the same benefits to people with T1D, however these medications increase the risk of diabetic ketoacidosis (DKA), a dangerous acute complication of diabetes that occurs when there is insufficient insulin in the body.
The second medication included in this trial is a glucagon receptor antagonist (GRA), which blocks the action of the glucagon hormone. In T1D, glucagon levels are abnormally elevated after meals, which worsens blood glucose and increases the amount of insulin needed to maintain glucose control. By blocking glucagon, the GRA lowers blood glucose levels and decreases insulin dosing needs. Our preliminary data suggest that the GRA also decreases ketone body formation and therefore may help prevent DKA. The central hypothesis of this trial is that combination therapy with both the SGLT2 inhibitor and the GRA medication will lead to significant metabolic benefits including: better glucose control, reduced insulin use, weight loss, and potentially improved markers of cardiovascular function, while concurrently lowering the risk of DKA.
Despite advances in insulin treatments and diabetes technologies, there remains a significant need for add-on non-insulin therapies for use in T1D. We believe this study is likely to be successful and will open up an entirely new avenue of combined metabolic therapies for patients living with T1D.