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

• Status: Unknown status
• Trial end date: 2018-10-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University at Buffalo
• Collaborator: AstraZeneca
• Treatments: Dapagliflozin; Exenatide

Criteria

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:

1. Aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN

2. Total bilirubin >2.0 mg/dL (34.2 µmol/L)

3. Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C virus antibody

4. 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