Objective
The objective of the proposed work is to elucidate the conditions during sodium-glucose co-transporter 2 (SGLT2) inhibitors plus insulin therapy that increase the risk of diabetic ketoacidosis (DKA), and to adapt our existing glucose control algorithm and multivariable automated insulin delivery system to cooperate synergistically with the adjunctive therapy. This cooperative architecture is necessary for improved safety and efficacy of SGLT2 inhibitors as an adjunct to insulin in adults with type 1 diabetes mellitus (T1DM) inadequately controlled by insulin alone. SGLT2 inhibitors decrease glucose reabsorption in the kidneys and increase excretion of urinary glucose, thus reducing blood glucose levels independent of insulin. The antihyperglycemic effects of SGLT2 inhibitors reduce the required insulin dosage, and the relative lack of insulin leads the body to use other energy sources, such as fat, as an alternative to glucose, which produces acidic ketone bodies. The novel insulin therapy decisions rendered with cognizance of the adjunct SGLT2 inhibitor pharmacotherapy proposed in this work will leverage continuous glucose monitoring (CGM) measurements, estimates for plasma insulin concentration computed from CGM and insulin pump data, assessments of the concentration of ketone bodies in blood and the associated risk of DKA, estimates for plasma concentrations of SGLT2 inhibitors, and physical activity information to improve glycemic control and mitigate the predicted risk of DKA.
Background Rationale
Tight glycemic control is shown to reduce the risk of complications in people with type 1 diabetes mellitus (T1DM). However, many people with T1DM treated with intensive insulin therapy do not achieve the recommended glycemic targets for time in range and HbA1c levels. Barriers to achieving optimal glycemic control with insulin intensification include complexity of insulin regimens, uncertainties in insulin dosing parameters, insulin-associated weight gain, and risk of hypoglycemia. Adjunctive therapy options can improve glycemic control without increasing the risk of hypoglycemia, while also providing additional benefits such as weight loss. Recent studies have shown that for people with T1DM the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors, in addition to insulin, instigates therapeutic effects in regulating blood glucose concentrations. Double-blind randomized trials demonstrated the effectiveness of SGLT2 inhibitors as an adjunct to insulin in people with T1DM inadequately controlled by insulin alone. SGLT2 inhibitors plus insulin therapy exhibits clinically meaningful improvements in HbA1c, time in range, and weight, without an increase in hypoglycemia risk. However, SGLT2 inhibitors increase the incidence of DKA, a serious and life-threatening acute complication that occurs when the absolute or relative deficiency of insulin leads the body to use other energy sources, such as fat, as an alternative to glucose, which produces acidic ketone bodies. The U.S. Food and Drug Administration has rejected the use of SGLT2 inhibitors for people with T1DM due to concerns about an increased risk of diabetic ketoacidosis. The safety and efficacy of SGLT2 inhibitors as adjunctive therapy in T1DM requires understanding the conditions that increase the risk of DKA and adapting the insulin therapy decisions to accommodate the adjunct SGLT2 inhibitor pharmacotherapy.
Description of Project
Tight glycemic control is shown to reduce the risk of complications (eye disease, kidney disease, nerve damage, and cardiovascular disease) in people with type 1 diabetes mellitus (T1DM). Many people with T1DM treated with intensive insulin therapy struggle to achieve guideline-recommended targets for time in range and HbA1c levels. Barriers to achieving optimal glycemic control with insulin intensification include complexity of insulin regimens, uncertainties in insulin dosing parameters, insulin-associated weight gain, and risk of hypoglycemia. Adjunctive non-insulin therapies for T1DM can address some of the challenges that arise from insulin monotherapy. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a class of antidiabetic drugs that reduce blood glucose concentrations (BGC) independent of insulin. The ability of SGLT2 inhibitors to lower BGC without directly affecting insulin sensitivity can result in clinically meaningful improvements in glycemia, weight loss, and hypoglycemia risk. Compared to insulin monotherapy, SGLT2 inhibitors are associated with increased risk of diabetic ketoacidosis (DKA), which limits the use of SGLT2 inhibitors plus insulin therapy. The safety and efficacy of SGLT2 inhibitors as adjunctive therapy for the treatment of T1DM requires adapting the insulin therapy to accommodate the adjunct SGLT2 inhibitor pharmacotherapy. The objective of the proposed work is to elucidate the conditions during SGLT2 inhibitor plus insulin therapy that increase the risk of DKA, and to adapt our existing glucose control algorithms and automated insulin delivery system to cooperate synergistically with the adjunctive therapy. This cooperative architecture is necessary for improved safety and efficacy of SGLT2 inhibitors as an adjunct to insulin in adults with T1DM inadequately controlled by insulin alone.
Anticipated Outcome
This project will provide valuable knowledge about the effects of adjunctive sodium-glucose co-transporter 2 (SGLT2) inhibitor pharmacotherapy on glucose, insulin, and ketone levels in people with type 1 diabetes mellitus. This work will result in a viable, multivariable artificial pancreas system that will work synergistically with the adjunctive SGLT2 inhibitor pharmacotherapy to better regulate glucose levels and mitigate the risks of diabetic ketoacidosis. The multivariable artificial pancreas system cognizant of adjunctive SGLT2 inhibitor therapy will perform better in regulating glucose levels without a significant increase in the risk of diabetic ketoacidosis compared to automated insulin dosing algorithms that do not take the adjunctive therapy into consideration. The proposed multivariable artificial pancreas system will cooperate synergistically with adjunctive SGLT2 inhibitor therapy to improve the safety and efficacy of the adjunctive SGLT2 inhibitor plus insulin therapy. The multivariable artificial pancreas system working synergistically with adjunctive SGLT2 inhibitor therapy will improve the time in range for concentration of ketone bodies in blood, reduce the risk of diabetic ketoacidosis, and increase the time spent in the desired glycemic range.
Relevance to T1D
Tight glycemic control is shown to reduce the risk of complications (eye disease, kidney disease, nerve damage, and cardiovascular disease) in people with type 1 diabetes mellitus (T1DM). However, many people with T1DM treated with intensive insulin therapy do not achieve the recommended glycemic targets for time in range and HbA1c levels. Barriers to achieving optimal glycemic control with insulin intensification include complexity of insulin regimens, uncertainties in insulin dosing parameters, insulin-associated weight gain, and risk of hypoglycemia. Adjunctive therapy options can improve glycemic control without increasing the risk of hypoglycemia, while also providing additional benefits such as weight loss. Recent studies have shown that for people with T1DM the use of adjunctive sodium-glucose co-transporter 2 (SGLT2) inhibitor pharmacotherapy, in addition to insulin, instigates therapeutic effects in regulating blood glucose concentrations. SGLT2 inhibitors plus insulin therapy exhibits clinically meaningful improvements in HbA1c, time in range, and weight, without an increase in hypoglycemia risk. However, SGLT2 inhibitors increase the risk of diabetic ketoacidosis, a serious and life-threatening acute complication that occurs when the absolute or relative deficiency of insulin leads the body to use other energy sources, such as fat, as an alternative to glucose, which produces acidic ketone bodies. The U.S. Food and Drug Administration has rejected the use of SGLT2 inhibitors for people with T1DM due to concerns about an increased risk of diabetic ketoacidosis. The safety and efficacy of SGLT2 inhibitors as adjunctive therapy in T1DM requires understanding the conditions that increase the risk of DKA and adapting the insulin therapy decisions to accommodate the adjunct SGLT2 inhibitor pharmacotherapy. This work will elucidate the conditions that increase the risk of diabetic ketoacidosis, develop predictive models to assess in real-time the risk of diabetic ketoacidosis, and adapt our existing glucose control algorithm and automated insulin delivery system to cooperate synergistically with adjunctive therapies. This cooperative multivariable automated insulin delivery system architecture is necessary for improved safety and efficacy of SGLT2 inhibitors as an adjunct to insulin in adults with T1DM inadequately controlled by insulin alone.