Objective
The main objective of the present study is to examine the ability of pioglitazone to amplify the decrease in HbA1c caused by SGLT2i in T1DM patients. Because SGLT2i stimulate hepatic glucose production, a large amount of glucose is added to the blood stream and this antagonizes the decrease in HbA1c caused by SGLT2i. Since pioglitazone is a powerful inhibitor of glucose production by the liver, we hypothesize that pioglitazone will prevent the increase in hepatic glucose production caused by SGLT2i and amplify the decrease in HbA1c caused by SGLT2i in T1DM patients.
Secondary objectives of the present study are to examine whether pioglitazone prevents the adverse events caused by SGLT2i in T1DM patients, in particular the increased risk of ketoacidosis and hypoglycemia. The use of SGLT2i in T1DM is associated with increased risk of ketoacidosis (~5%). We previously have shown that SGLT2i increase plasma FFA concentration, augment fat oxidation and stimulate ketone production. Because pioglitazone is a strong inhibitor of lipolysis and markedly decreases plasma FFA and fat oxidation, we hypothesize that it will prevent the increase in plasma FFA and ketone production caused by SGLT2i and, therefore, reduce the risk of ketoacidosis. Further, because pioglitazone inhibits hepatic glucose production and lowers the plasma FFA concentration independent of plasma insulin concentration, it allows a reduction in the daily insulin dose as needed to avoid the risk of hypoglycemia.
Background Rationale
Poor glycemic control is the principal risk factor responsible for diabetic damage to the eye, kidney and nerves. Further, many studies have unequivocally documented that lowering the plasma glucose concentration reduces the risk of eye, kidney and nerve damage. Because of the destruction of insulin secreting beta cells in T1DM patients, exogenous injection of insulin is the only effective therapy for glucose control. However, insulin therapy is associated with significant adverse events that often pose an obstacle for achieving the desired goal of glycemic control. Insulin causes weight gain which impairs insulin action (i.e. it causes insulin resistance) and results in increased need for insulin for glucose control. This, produces a vicious cycle whereby insulin therapy causes weight gain which worsens insulin action and increases the demand for insulin leading to more weight gain. Further, escalating the insulin dose increases the risk of hypoglycemia. Thus, identification of an adjunctive therapy to insulin that effectively lowers the plasma glucose concentration, independent of insulin, will have important role in improving glucose control in T1DM patients.
Sodium glucose co-transport inhibitors (SGLT2i) are a novel class of drugs utilized to treat type 2 diabetes. Members of this class of drugs lower the plasma glucose concentration by inhibiting renal glucose uptake and causing urinary glucose loss. Because of this unique mechanism of action, SGLT2i also effectively lower the plasma glucose concentration in T1DM patients. However, large clinical trials that have assessed the efficacy of SGLT2i in T1DM have revealed 2 limitations of SLGT2i therapy: (1) the magnitude of decrease in HbA1c caused by SGLT2i in T1DM patients was modest (0.3-.45%), and (2) the use of SGLT2i in T1DM was associated with increased risk of ketoacidosis.
We previously have shown that SGLT2i exert multiple metabolic actions in T2DM patients including increased glucose production by the liver, increased plasma free fatty acid concentration and increased ketone production. Similar metabolic actions of SGLT2i in T1DM patients can explain the modest reduction in HbA1c in T1DM and increased risk of ketoacidosis. Pioglitazone is a generic drug used in the treatment of T2DM individuals. Pioglitazone strongly inhibits glucose production in the liver and suppresses the plasma free fatty acid concentration in T2DM patients. Further, because pioglitazone inhibits hepatic glucose production and suppresses plasma free fatty acid concentration, independent of plasma insulin concentration, it allows the daily insulin dose to be reduced to avoid the risk of hypoglycemia. We hypothesize that the addition of pioglitazone to T1DM patients treated with SGLT2i will amplify the decrease in HbA1c caused by SGLT2i and prevent the increase in plasma FFA and risk of ketoacidosis without increased risk of hypoglycemia.
Description of Project
Controlling blood sugar levels in patients with type 1 diabetes (T1DM) is important to prevent damage to the eye, kidney and nerves (microvascular complications). Because of the loss of insulin secreting beta cells in T1DM patients, exogenous injection of insulin is the only effective therapy for glucose control. However, insulin therapy is associated with significant adverse events. Insulin causes weight gain, which impairs insulin action (insulin resistance), and results in the need for an increase in insulin dose to maintain glucose control. This produces a vicious cycle whereby weight gain worsens insulin action which results in an increase in insulin dose and more weight gain. The increase in insulin dose also increases the risk of hypoglycemia, which often times becomes a major obstacle for further increase in insulin dose.
Several attempts have been made to identify adjunctive therapies to insulin that can safely and effectively lower the plasma glucose level in T1DM, however, no such therapy has yet to be identified.
Sodium glucose co-transport inhibitors (SGLT2i) are a novel class of drugs utilized to treat individuals with type 2 diabetes. Members of this class lower the plasma glucose concentration by inhibiting renal glucose uptake and causing urinary glucose loss. Because of this unique mechanism of action, SGLT2i also effectively lower the plasma glucose concentration in T1DM patients. However, large clinical trials that have assessed the efficacy of SGLT2i in T1DM have exposed 2 limitations of SLGT2i in T1DM: (1) the magnitude of decrease in HbA1c in T1DM patients is modest (0.29-.45%), and (2) the use of SGLT2i in T1DM is associated with an increased risk of ketoacidosis.
We previously have shown that SGL2i exert multiple metabolic actions in T2DM patients including an increase in glucose production by the liver, an increase in plasma free fatty acid concentration, and an increase in ketone production. Similar metabolic actions of SGLT2i in T1DM patients can explain the modest reduction in HbA1c in T1DM and increased risk of ketoacidosis. Pioglitazone is a generic drug used in the treatment of T2DM. Pioglitazone strongly inhibits glucose production in the liver and suppresses plasma free fatty acid concentration. Therefore, we hypothesize that the addition of pioglitazone to T1DM patients treated with SGLT2i will amplify the decrease in HbA1c caused by SGLT2i and prevent the increase in plasma FFA and risk of ketoacidosis. We will test this hypothesis in the present study.
To test this hypothesis, we will recruit 120 poorly controlled T1DM patients who require >60 units of insulin per day. After a 4-week run in period in which patient compliance, glucose control and hypoglycemic rate assessed, subjects will start treatment with 10 mg/day dapagliflozin until the end of the study (week 32). At 16 weeks, subjects will be randomized to receive, in a double blind fashion, pioglitazone (45 mg) or placebo for additional 16 weeks.
Fasting plasma glucose, HbA1c, insulin, glucagon, GLP-1, GIP, FFA, lactate, and ketones will be measured monthly.
Indirect calorimetry will be measured at weeks 4, 16 and 32. During the follow-up down titration of insulin dose will be allowed to avoid hypoglycemia.
The primary outcome of the study is the decrease in HbA1c from week 16 to week 32 in pioglitazone-treated versus placebo-treated T1DM subjects who receive dapagliflozin. Secondary outcomes include: (i) change in plasma FFA and ketone concentration from week 16 to week 32; (ii) decrease in daily insulin dose; (iii) incidence of hypoglycemia.
We believe that the results of the present study will establish the combination therapy with pioglitazone plus dapagliflozin as a safe and effective adjunctive therapy to insulin in T1DM patients.
Anticipated Outcome
We anticipate that dapagliflozin will cause a small but significant (0.4-0.5%) reduction in the HbA1c (from week 4 to week 16) with significant increase in plasma FFA concentration, increase in fat oxidation rate and increase in plasma ketone concentration.
We anticipate that subjects receiving pioglitazone will experience a robust reduction in the HbA1c (from week 16 to week 32) with significant reduction in plasma FFA concentration and plasma ketones concentration compared to placebo. We also anticipate a significant reduction in daily insulin dose in subjects receiving pioglitazone compared to placebo-treated subjects. Further, despite a robust reduction in HbA1c in pioglitazone-treated subjects, we do not anticipate increase in the rate of hypoglycemic events. Thus, the results of the present study will show that, pioglitazone causes a robust reduction in HbA1c and daily insulin dose in T1DM patients receiving dapagliflozin with reduced risk of ketoacidosis and without increased risk of hypoglycemia
Relevance to T1D
The results of the present study will identify pioglitazone plus SGLT2i as a very effective adjunctive therapy to insulin in T1DM patients that safely (no hypoglycemia and reduced risk of ketoacidosis) and effectively lowers the plasma glucose concentration and HbA1c. This novel therapeutic strategy will have an important impact on the management of T1DM patients. This therapeutic strategy (pioglitzone plus SGLT2i) will represent the first safe and effective adjunctive therapy to insulin that improves glycemic control and minimizing side effects in T1DM patients.
Because of the adverse side effects associated with insulin therapy, the majority of T1DM patients (~75%) fail to achieve the desired goal of glycemic control (i.e. HbA1c <7.0%) and, therefore, remain at increased risk of diabetic microvascular complications. A novel adjunctive therapy that safely and effectively reduces the plasma glucose concentration in T1DM patients will allow more T1DM patients to achieve optimal glycemic control thereby reducing their risk of microvascular complications