Dapagliflozin Plus Pioglitazone in T1DM
Dapagliflozin Plus Pioglitazone in T1DM
Purpose: To examine the effect of addition of combination therapy with dapagliflozin plus
 pioglitazone to insulin on glucose control and plasma ketone concentration in patients with
 type 1 diabetes (T1DM) Research Design: 120 patients with type 1 diabetes who otherwise are
 healthy constitute the study population. After screening, eligible subjects will start 4 week
 run in. At week 4, subjects will receive dapagliflozin for 12 weeks. At week 16, subjects
 will be randomized to receive in a double blind fashion pioglitazone or placebo for 16 weeks.

 Methods: the following techniques will be employed in the present study: (1) mixed meal
 tolerance test; (2) indirect calorimetry; (3) continuous glucose monitoring.

 Clinical Relevance: the results of the present study will demonstrate that the addition of
 pioglitazone to SGLT2 inhibitor in T1DM patients produces greater reduction in the HbA1c
 without increasing risk of ketoacidosis and hypoglycemia.
Insulin deficiency, due to autoimmune destruction of beta cells, is the primary factor
 responsible for the development of T1DM, and insulin replacement therapy is the mainstay for
 the management of hyperglycemia. However, insulin therapy often is associated with adverse
 events, including weight gain which promotes insulin resistance leading to an increase in
 insulin demand. This results in a self-perpetuating vicious cycle whereby the increase in
 insulin dose causes weight gain that worsens insulin sensitivity, and further enhances
 insulin requirement. Hyperinsulinemia per se also induces insulin resistance.

 To break this cycle, adjunctive therapies have been added to insulin in T1DM patients to
 lower the plasma glucose concentration. However, the addition of metformin, pioglitazone, and
 GLP-1 agonists to insulin in T1DM patients have not provided convincing evidence for a
 clinically meaningful reduction in the HbA1c or significant reduction in daily insulin dose.

 SGLT2 inhibitors (SGLT2i) are a novel class of antidiabetic agents which reduce the plasma
 glucose concentration by inhibiting renal glucose reuptake and producing glucosuria. Because
 of this unique mechanism of action, which is independent of insulin secretion and insulin
 action, SGLT2i have proven to be very effective in lowering the plasma glucose concentration
 in T1DM. Initial proof of concept studies have demonstrated that, compared to placebo, all
 members of this class (dapagliflozin, empagliflozin, canagliflozin and sotagliflozin)
 effectively lower the plasma glucose concentration, HbA1c and daily insulin dose in T1DM
 without increased risk of hypoglycemia. Further, SGLT2i improved cardiovascular risk factors
 in T1DM by promoting weight loss and decreasing blood pressure.

 Despite the promising potential for SGLT2i as adjunctive therapy to insulin in T1DM, recent
 large clinical trials have demonstrated two important limitations to this therapeutic
 strategy: First, although the decrease in HbA1c caused by SGLT2i in T1DM patients was
 statistically significant, the absolute decrease was relatively modest (0.30-0.45%). The
 investigators, previously have shown that SGLT2i stimulate an increase in the basal rate of
 hepatic glucose production (HGP) in T2DM patients. This SGLT2i-induced increase in HGP
 offsets by approximately one half the amount of glucose lost in the urine. Therefore, the
 investigators have hypothesize that, similar to what they have observed in T2DM patients, the
 addition of SGLT2i to insulin in T1DM patients stimulates HGP thereby attenuating the
 decrease in HbA1c. Further, the decrease in daily insulin dose after initiating therapy with
 SGLT2i in T1DM patients would be expected to enhance the increase in HGP and diminish the
 decrease in HbA1c. Thus, preventing the increase in HGP caused by SGLT2i in T1DM can be
 expected to markedly amplify the clinical efficacy of SGLT2i and enhance the reduction in
 HbA1c.

 A second limitation of the use of SGLT2i an adjunct therapy to insulin in T1DM patients is
 the increase in diabetic ketoacidosis (DKA) risk. In three large clinical trials , the
 addition of SGLT2i to insulin in T1DM patients was associated with a 3-6% increase in DKA
 risk (see Table 1 below). Because of the significant morbidity and mortality associated with
 DKA, the increased DKA risk in T1DM has raised concerns about the use of SGLT2i as an adjunct
 therapy to insulin in T1DM patients despite their multiple metabolic benefits.

 The Investigators previously have demonstrated that SGLT2i cause a significant increase in
 plasma FFA concentration, fat oxidation and subsequent increase in plasma ketone
 concentration in T2DM patients (27). Therefore, they hypothesize that in T1DM, SGLT2i cause a
 similar increase in plasma FFA concentration, fat oxidation and plasma ketone concentration
 which in certain clinical conditions (e.g. acute illness) can increase the production of
 ketones and result in the development of DKA. Further, prevention of the increase in plasma
 FFA concentration will inhibit the increase in plasma ketone concentration and reduce DKA
 risk associated with SGLT2i use in T1DM patients.

 Pioglitazone inhibits lipolysis and markedly decreases the plasma FFA concentration. Further,
 pioglitazone is a potent inhibitor of HGP. These actions of pioglitazone are due to direct
 actions of the drug on adipocytes and liver, respectively, are mediated by PPAR gama, and are
 independent of the plasma insulin and glucagon concentrations. In fact, pioglitazone inhibits
 lipolysis and HGP in type 2 diabetic patients despite a decrease in plasma insulin
 concentration. Therefore, the investigators hypothesize that the addition of pioglitazone to
 SGLT2i in T1DM patients will prevent the rise in HGP caused by SGLT2i and, thereby, augment
 the decrease in HbA1c. Further, combination therapy with pioglitazone plus SGLT2i will
 prevent the increase in plasma FFA concentration and subsequent increase in plasma ketone
 concentration, thus reducing the risk of DKA.
Inclusion Criteria:

 -  Age >18 years

 -  T1DM

 -  Good general health

 -  Fasting C-peptide concentration <0.7 ng/ml

 -  Poor glycemic control (HbA1c=7.0-11.0%)

 -  Treatment with multiple daily insulin injections or insulin pump

 -  Total daily insulin dose ≥0.6 U/kg per day

 -  Stable insulin dose (±4 units) in the preceding three months.

 -  eGFR≥60 ml/min

 -  Weight stable over the preceding 3 months (± 3 pounds)

 -  Do not participate in an excessively heavy exercise program

 Exclusion Criteria:

 -  T2DM

 -  Daily insulin dose <0.6 U/kg per day

 -  Fasting C-peptide >0.7 ng/ml

 -  HbA1c <7.0% or >11.0%

 -  eGFR<60 ml/min

 -  Hematuria in urine analysis

 -  Pregnancy, lactating, positive pregnancy test or planning to become pregnant in the
 following year.

 -  Women of child-bearing potential will be requested to use at least two barrier methods
 before being enrolled in the study.

 -  Major organ system disease which includes: (i) malignancy or history of malignancy
 including bladder cancer; (ii) Congestive heart failure or history of coronary heart
 disease or any other cardiac disease; (iii) chronic liver disease or LFT >3 times the
 upper normal level; (iv) History of alcohol or drug abuse; (v) History of chronic lung
 disease (e.g., COPD, asthma); (vi) history of rheumatic disease; (vii) History of
 chronic pancreatitis or pancreatic surgery; (viii) History of CVA or TIA (ix) Planned
 surgery during the study; (x) history of HIV infection or other immune compromised
 disease; and history of organ transplantation; (xi) patients who take medications,
 other than insulin, known to affect glucose metabolism, e.g., prednisone.

 -  Evidence of proliferative diabetic retinopathy

 -  Patients enrolled in a heavy exercise program

 -  Patients on ketogenic diet

 -  History of hospitalization for DKA, hypoglycemia or uncontrolled hyperglycemia in the
 preceding 6 month.

 -  Presence of symptoms of poor glycemic control, e.g. polydipsia or polyurea

 -  History of hypersensitivity to dapagliflozin or pioglitazone