An Investigation Into the Effect of Dapagliflozin on Ketogenesis in Type 1 Diabetes

Study Overview
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Brief Summary
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The study investigations include evaluation of the acute effects of a single dose of dapagliflozin (10mg), exenatide (5µg), a combination of exenatide and dapagliflozin or placebo under insulinopenic condition and the long term effect under basal conditions before and after 12 weeks treatment with dapagliflozin, Exenatide extended release, a combination of Exenatide extended release and dapagliflozin or placebo on ketogenesis, glucagon and lipolysis.

Detailed Description
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The study investigations include evaluation of the acute effects of a single dose of dapagliflozin (10mg), exenatide (5µg), a combination of exenatide and dapagliflozin or placebo under insulinopenic condition and the long term effect under basal conditions before and after 12 weeks treatment with dapagliflozin, Exenatide extended release, a combination of Exenatide extended release and dapagliflozin or placebo on ketogenesis, glucagon and lipolysis. In the acute effects study, qualified patients will come fasting to the research center. Review of study procedures and vitals will be performed. Insulin infusion (pump) will be stopped and basal blood, urine and adipose tissue biopsy samples will be obtained. Placebos, exenatide (5µg) or dapagliflozin (10mg) (with appropriate placebos) or combination of exenatide and dapagliflozin will be administered, according to a randomized fashion, and blood samples will be collected every 30 min for up to 8 hours after starting the treatment. Urine will be collected every hour up to 8 hours and a second adipose tissue biopsy will be collected at 6 hours after the start of the treatment. Additional blood samples will be collected at 1, 2, 4 and 6 and 8 hour marks for MNC isolation. Plasma and mononuclear cell (MNC) fractions will be prepared from the blood samples. The patient will then come back at the 24 hour mark for a fasting blood and urine collection. The long term study will then commence. Exenatide extended release or dapagliflozin (along with appropriate placebos) or a combination of both drugs will be started and continued for 12 weeks according to original randomization of day 0. In the long term study, dapagliflozin (or the appropriate placebo) will be started at 5mg dose and will be titrated to 10mg/day after 5 days. Fasting blood and 24hr urine samples will be collected at 1, 4 and 8 weeks. At 12 weeks, the 2nd acute effects testing study will be repeated as described above. Measurements of beta-hydroxybutyrate, acetoacetic acid, glucose, FFA and glucagon, will be measured from all blood samples collected. HSL, GLP-1, glycerol, electrolytes, serum bicarbonate, cortisol and catecholamines will be measured at 0, 60, 120, 240, 360, 480 min and at 24hr following single dose studies at 0 and 12 weeks visits and at baseline on the 1, 4 and 8 weeks visits. Ketone bodies will be measured in all urine samples. All MNC and adipose tissue samples will be tested for HSL and SGLT2 expression.

Official Title
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An Investigation Into the Effect of Dapagliflozin on Ketogenesis in Type 1 Diabetes

Conditions
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Evaluate Ketogenic Stress

Intervention / Treatment
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* Drug: Exenatide/Exenatide extended release
* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 Diabetes for at least 1 year on continuous subcutaneous insulin infusion (CSII; also known as insulin pump) HbA1c of 7-10% (inclusive) Ages 18-65 years (inclusive of ages 18 and 65) BMI 20-30 kg/m2 Exclusion Criteria: Inability to give informed consent Inability or refusal to comply with protocol Use of GLP-1 Receptor Agonists in the last 3 months or DPP-IV and SGLT-2 inhibitors therapy in the last 1 month. Risk for pancreatitis (e.g., history of gallstones, alcohol abuse, and hypertriglyceridemia) History of pancreatitis and or chronic pancreatitis Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty) or stroke in the previous 3 months. Congestive Heart Failure class III or IV or tachyarrhythmia. Hepatic disease: Severe hepatic insufficiency and/or significant abnormal liver function defined as: Aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN Total bilirubin >2.0 mg/dL (34.2 µmol/L) Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C virus antibody Liver function tests more than 3 times the upper limit of normal Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women, or eGFR <60 mL/min/1.73 m2) or history of unstable or rapidly progressing renal disease or end stage renal disease. History of unexplained microscopic or gross hematuria, or microscopic hematuria at visit 1, confirmed by a follow-up sample at next scheduled visit. HIV positive History of gastroparesis History of medullary thyroid carcinoma or MEN 2 syndrome History of recurring UTI Uncontrolled thyroid disease (documented normal TSH), Cushing's syndrome, congenital adrenal hyperplasia or hyperprolactinemia. Prior history of a malignant disease requiring chemotherapy or patients with a prior history of bladder cancer regardless of treatment Alcoholism or drug addiction. Hypertriglyceridemia (>400 mg/dl). Any other life-threatening, non-cardiac disease Uncontrolled hypertension (BP > 160/95 mm of Hg) Patients with hypotension or at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics or recently donated >500ml of blood should have careful monitoring of their volume status Pregnant or breastfeeding patients or patient not willing to use two barrier method contraception during study period (unless sterilized or have an IUD) Use of hormonal medications, anti-obesity drugs or weight loss medications (prescription or OTC) and medications known to exacerbate glucose tolerance (such as isotretinoin, GnRH agonists, glucocorticoids, anabolic steroids, C-19 progestins) stopped for at least 8 weeks. Use of anti-androgens that act peripherally to reduce hirsutism such as 5-alpha reductase inhibitors (finesteride, spironolactone, flutamide) stopped for at least 4 weeks Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions Known hypersensitivity or contraindications to use GLP1 receptor agonists (exenatide, liraglutide) Known hypersensitivity to heparin/ IV catheter equipment. Eating disorders (anorexia, bulimia) or gastrointestinal disorders Having a history of bariatric surgery Debilitating psychiatric disorder such as psychosis or neurological condition that might confound outcome variables Use of an investigational agent or therapeutic regimen within 30 days of study Participation in any other concurrent clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dapagliflozin Arm:<br>dapagliflozin 10mg (oral tablet) and exenatide (5µg acutely)/Exenatide extended release (long term) placebo (subcutaneous injection) | Drug: Dapagliflozin<br>* Eighty (80) patients with T1D will be enrolled and randomized into 4 groups(20 each) to receive placebo, or dapagliflozin, or exenatide (5µg acutely)/Exenatide extended release (long term), or exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin treatments acutely and for 12 weeks<br>* Other names: Farxiga;|
| Active Comparator: Exenatide extended release Arm:<br>subcutaneous injection of Exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin placebo | Drug: Exenatide/Exenatide extended release<br>* Eighty (80) patients with T1D will be enrolled and randomized into 4 groups(20 each) to receive placebo, or dapagliflozin, or exenatide (5µg acutely)/Exenatide extended release (long term), or exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin treatments acutely and for 12 weeks<br>* Other names: Bydureon;|
| Placebo Comparator: Placebo Arm:<br>dapagliflozin placebo (oral tablet) and exenatide (5µg acutely)/Exenatide extended release (long term) placebo (subcutaneous injection) | Drug: Placebo<br>* Eighty (80) patients with T1D will be enrolled and randomized into 4 groups(20 each) to receive placebo, or dapagliflozin, or exenatide (5µg acutely)/Exenatide extended release (long term), or exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin treatments acutely and for 12 weeks<br>|
| Active Comparator: Exenatide extended release & dapagliflozin Arm:<br>Exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin 10mg | Drug: Exenatide/Exenatide extended release<br>* Eighty (80) patients with T1D will be enrolled and randomized into 4 groups(20 each) to receive placebo, or dapagliflozin, or exenatide (5µg acutely)/Exenatide extended release (long term), or exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin treatments acutely and for 12 weeks<br>* Other names: Bydureon;Drug: Dapagliflozin<br>* Eighty (80) patients with T1D will be enrolled and randomized into 4 groups(20 each) to receive placebo, or dapagliflozin, or exenatide (5µg acutely)/Exenatide extended release (long term), or exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin treatments acutely and for 12 weeks<br>* Other names: Farxiga;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in beta-hydroxybutyrate in the plasma samples from baseline |  | following 6 hr and 12 weeks of treatment | 
| change in acetoacetic acid in the plasma samples from baseline |  | following 6 hr and 12 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in urinary ketone bodies changes after 12 weeks of dapagliflozin and Bydureon or combination of both treatments compared to baseline |  | following 6 hr and 12 weeks of treatment | 
| change in basal plasma glucagon after 12 weeks of dapagliflozin and Bydureon or combination of both treatments compared to baseline |  | following 6 hr and 12 weeks of treatment | 
| change in FFA ( free fatty acids) after 12 weeks of dapagliflozin and Bydureon or combination of both treatments compared to baseline |  | following 6 hr and 12 weeks of treatment | 
| changes in AUC0hr-6hr of ketone bodies (plasma and urine), FFA and glucagon between dapagliflozin, exenatide, combination of both and placebo from baseline |  | following 6 hr and 12 weeks of treatment | 
| Changes in lipolysis mediator (HSL) in plasma and expression of HSL and SGLT-2 in adipose tissue and MNC will be compared to baseline |  | following 6 hr and 12 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dapagliflozin, Ketogenesis, Type 1 Diabetes, DKA, ketones, exenatide/Bydureon