Acute Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor on Bone Metabolism in Healthy Volunteers
Acute Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor on Bone Metabolism in Healthy Volunteers
Background:

 - Canagliflozin (sold as InvokanaTM) is a new medicine for diabetes. But it might increase
 the bone fracture risk in people with diabetes.

 Objective:

 - To see if Invokana has negative side effects on bone health.

 Eligibility:

 - Healthy men ages 18 45.

 Design:

 -  Participants will be screened with a medical history, physical exam, and blood tests. A
 nutritionist will discuss their dietary history and the study dietary requirements.
 Participants will get a food diary to record what they eat and drink on 3 separate days.

 -  Participants will have a DEXA scan x-ray test of bone health. Participants will lie
 still on a table while a small camera passes over the body.

 -  Participants will have 2 stays in the clinic. They will be 1 week apart and each last 6
 overnights starting on a Sunday.

 -  Before each stay, participants will:

 -  Pick up food each day for 7 days. They will get breakfast, lunch, dinner, and snacks.
 They must eat only the food provided during these times.

 -  Collect their urine twice.

 -  During the stays, participants will:

 -  Be evaluated by a doctor and have blood drawn.

 -  On each Monday, participants will:

 -  Skip breakfast

 -  At about 8 a.m. take a placebo pill in one stay, the study drug in the other stay.

 -  Drink 6 ounces of water every 2 hours for 4 hours.

 -  An intravenous (IV) catheter will be inserted into an arm. Blood will be drawn every 2
 hours from 8 a.m. until noon.

 -  Get lunch.

 -  Have blood testing again at 8pm and midnight.

 -  Repeat the testing days 2 5.

 -  Have urine collected.
Background

 Canagliflozin is a new oral drug for the treatment of type 2 diabetes mellitus (T2DM), and is
 one of four recently FDA approved sodium glucose co-transporter 2 (SGLT2) inhibitors, which
 target renal glucose reabsorption and offer promising improvement in HbA1c. In the approval
 process, the FDA Advisory Committee reviewed data suggesting that canagliflozin increased the
 incidence of fractures. In addition, the drug induced changes in phosphate, bone resorption
 markers, parathyroid hormone (PTH) and vitamin D metabolism which might mediate the adverse
 changes in bone homeostasis. For a variety of reasons, the data on bone fracture risk are
 relatively limited. First, the drug s development program was focused primarily on
 demonstrating efficacy, and bone fractures were only one of many safety end-points which were
 monitored. Second, only a minority of patients (approximately 1%) experienced bone fractures
 in the course of the development program. Finally, there appears to be a lag time prior to
 the time increased bone resorption translates into a significant increase in the rate of bone
 fractures. We hypothesize that this class of drugs causes a cascade of hormonal changes
 induced by increased phosphorus reabsorption that leads to significant changes in fibroblast
 growth factor 23 (FGF23), PTH, and vitamin D metabolism which ultimately increase fracture
 risk.

 Aim

 The primary endpoint is to determine the effects of canagliflozin on bone health by
 evaluating changes in the area under the curve (AUC) of FGF23 during the first 24-72 hours.
 Secondary endpoints include the evaluation of canagliflozin on other biochemical parameters
 in the early phase (1 week) of drug administration during which we hypothesize a new steady
 state will be reached related to bone metabolism including PTH, 1,25 vitamin D, tubular
 reabsorption of phosphate (TRP), and carboxy-terminal telopeptide (CTX).

 Methods

 A randomized, blinded, placebo-controlled cross-over pilot study of healthy volunteers age 18
 years and older with a BMI of 20 - 30 kg/m2.

 Patients will be randomized to canagliflozin (300mg once daily) or placebo for 5 days and
 will be studied as inpatients (NIH Clinical Center metabolic unit). Serial blood and urine
 testing for 4 hours after daily drug administration and at 12 and 24 hours thereafter will be
 used to assess changes in the pre-specified endpoints. Each subject will be provided a diet
 containing fixed contents of phosphate, sodium, and calcium throughout the study, beginning 7
 days prior to the administration of drug (or placebo).
-  INCLUSION CRITERIA:

 We are targeting healthy men and women greater than or equal to 18 years old, inclusive of
 all races and ethnicity within a BMI of 20 30 kg/m(2). Specifically, we have defined
 healthy to mean: normal fasting glucose and hemoglobin A1c less than or equal to 6%, normal
 Hb, no glucosuria, normal renal function (based on normal serum creatinine + Cystatin C),
 urine albumin:creatinine ratio, protein:creatinine ratio, and GFR > 80 as calculated by the
 CKD-Epi equation and normal lab urinalysis.

 EXCLUSION CRITERIA:

 If you have any of the following health issues, you cannot participate in the study:

 -  Presence of heart disease, untreated high blood pressure (>140/90 mm Hg), orthostatic
 hypotension or symptomatic hypotension, cancer, diabetes, recurrent symptomatic
 hypoglycemia and /or history of recurrent genital or urinary tract infection, thyroid
 disease, or any other condition that affects bone health

 -  Past history of eating disorder or psychiatric disorders, including severe depression,
 anxiety, or psychosis or presently on treatment with medications for any of these
 conditions

 -  Taking certain medications, especially those that affect bone metabolism (e.g., high
 dose vitamin D [>1000 units daily] or calcium supplements [>800mg daily], high dose
 vitamin A [>20,000 units daily], phosphate binding antacids, calcitonin, calcitriol,
 growth hormone, or any anti-seizure medications for any reason including valproic
 acid, lamotrigine), certain medications for high blood pressure (diuretics), steroids
 including inhalers, diet/weight loss medications, or any other medications at the
 discretion of the principal investigator and/or study team

 -  Have started, increased or decreased calcium [>400mg daily] or vitamin D [>1000 units
 daily] supplements within 2 weeks of the study

 -  Dependence or regular use of alcohol (>2 drinks per day), tobacco (smoking or
 chewing), amphetamines, cocaine, heroin or marijuana over the past 6 months

 -  Volunteers will be excluded if they have abnormal blood concentrations of

 -  inorganic phosphate level (less than or equal to 2.5 mg/dl or greater than or
 equal to 4.8 mg/dl),

 -  parathyroid hormone (PTH) (less than or equal to 60 pg/ml),

 -  creatinine (less than or equal to 1.5 mg/dl) or eGFR (< 80 ml/min/1.73sq.m),

 -  fasting glucose (greater than or equal to 100 mg/dl),

 -  hemoglobin (less than or equal to 11 g/dl),

 -  liver function tests (more than twice normal),

 -  testosterone (less than or equal to 260 ng/dl)

 -  Participation in a vigorous exercise program (>3h/day of vigorous activity)

 -  Consume more than 300 mg/day of caffeine (about two to three 8 fluid ounce servings)

 -  Have strict dietary concerns (e.g., vegan or kosher diet, multiple food allergies)

 -  Cannot commit to the research experience at the Clinical Research Center as required
 by the study timeline

 -  Have previous hypersensitivity reaction to canagliflozin (including but not limited to
 rash, raised red patches on your skin (hives), swelling of the face, lips, tongue, and
 throat that may cause difficulty in breathing or swallowing).

 -  Positive urine pregnancy test and/or planning to become pregnant during the course of
 the study.

 -  You are unwilling to use effective contraceptive methods for duration of study
 (hormonal or barrier.

 -  Irregular menstrual cycles