Objective
Type 1 diabetes (T1D) is a disease of multiple hormonal and metabolic impairments. In addition to deficient insulin secretion from the pancreas, people living with T1D experience high levels of ketones, increased glucose reabsorption at the kidneys, and other abnormalities that are not addressed by current treatments. Thus, there is a clear need for new medications that can be used along with insulin to simultaneously improve glycemic control and target other metabolic abnormalities. The goal of this project is to test the ability of two medications to improve glucose control (measured by HbA1c and continuous glucose monitoring), to reduce insulin needs, and to reduce ketones and the risk of diabetic ketoacidosis.
Background Rationale
We will study two medications (individually and in combination) to be used with insulin. 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 whom the SGLT2 inhibitors improve blood glucose, lead to weight loss, and help protect the heart and kidneys. The SGLT2 inhibitors likely provide the same benefits to people with T1D, however these medications are not approved for use in T1D because they 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 inappropriately 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.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disorder that destroys the insulin-producing beta-cells of the pancreas, leading to high blood glucose levels. Intensive insulin therapy is required for glucose control, but this therapy is burdensome, and most people do not achieve blood glucose goals. When insulin levels are low or absent, individuals with T1D are at risk of developing very high levels of ketones, which can lead to a life-threatening high-acid state called diabetic ketoacidosis (DKA). One class of medication, the sodium-glucose cotransporter-2 (SGLT2) inhibitors, helps with glucose control and may protect the heart and kidneys, but also increases the risk of DKA. Another type of medication, a glucagon receptor antagonist (GRA), may reduce the risk of DKA by decreasing ketone production. The goal of the present study is to examine the ability of the GRA to protect against ketoacidosis in people with T1D who are also taking an SGLT2 inhibitor medication. In addition, we will study the safety and tolerability of these two medications when taken together and examine the ability of the combination therapy to improve blood glucose control and reduce insulin needs.
Anticipated Outcome
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, namely increasing glucose control, reducing the amount of insulin needed, and lowering the risk of DKA. We also anticipate that the combination therapy with SGLT2 inhibitor and GRA will increase treatment satisfaction, decrease diabetes-related distress, and improved quality of life in participants with type 1 diabetes.
Relevance to T1D
Despite advances in insulin treatments and diabetes technologies, there is a significant unmet need for non-insulin therapies to help improve blood glucose control and other metabolic imbalances, such as high ketone levels. Combined therapy with an SGLT2 inhibitor and a glucagon receptor antagonist has the potential to improve glucose control, reduce insulin needs, reduce the risk of diabetic ketoacidosis, and improve quality of life. We believe this study is likely to be successful and will open up an entirely new avenue of therapies for people living with T1D.