Effects of Canagliflozin on Intravascular Volume and Hemodynamics

This is a randomized, double-blind, placebo-controlled, parallel-group, single-center study
(Figure 1). Thirty subjects will be randomized in a 3:2 randomization ratio to canagliflozin
300 mg once daily (QD) or placebo. The study will include a 3-week pretreatment screening
phase and a 4-week double-blind treatment phase.

Inclusion Criteria:

- on stable doses (more than 3 months) of antihyperglycemic agents (except for an SGLT2
inhibitor and insulin)

- have an A1c ≥7% and ≤11%

- Estimated glomerular filtration rate (eGFR) must be ≥45 ml/min•1.73 m2

- have an NT-proBNP ≥500 pg/mL

- be on a stable dose of guideline-directed HF medication (i.e., angiotensin converting
enzyme [ACE] inhibitor, angiotensin II receptor blocker [ARB], or angiotensin receptor
neprilysin inhibitor [ARNI], β-blocker, diuretics, and/or mineralcorticoid receptor
antagonist) for at least 4 weeks

- be on stable antihypertensive therapy for at least 2 months

Exclusion Criteria:

- T1DM

- repeated fasting plasma glucose (FPG) or fasting self-monitored blood glucose
measurements ≥240 mg/dL or both

- during the pretreatment phase, NYHA Class IV HF status, uncontrolled hypertension as
defined as systolic blood pressure (SBP) >160 or diastolic blood pressure (DBP) >100
mmHg

- liver disease (ALT or AST >3 x ULN)

- anemia Hb<10

- anticipated cardiac surgery or coronary intervention within the next 3 months

- severe unremediated valvular heart disease

- major CV event (e.g., MI, cerebrovascular accident) within 3 months prior to screening
visit

- hospitalization for HF within 2 months prior to screening visit

- documented atrial fibrillation

- history of atraumatic amputation within past 12 months of screening or critical
ischemia of the lower extremity within 6 months of screening

- an active skin ulcer, osteomyelitis, or gangrene

- have an allergy to iodocyanine green and inulin