Effects of Canagliflozin on Intravascular Volume and Hemodynamics

A Randomized, Double-Blind, Placebo-Controlled, Single-Center, Mechanistic Study to Evaluate the Effects of Canagliflozin on Intravascular Volume and Hemodynamics in Subjects With Type 2 Diabetes Mellitus and Heart Failure

RESEARCH HYPOTHESIS

• In subjects with T2DM and HF, effect of canagliflozin will be superior to placebo for the change from baseline in PCWP after a single dose (6 hours post-dose) and after 4 weeks.
• Treatment with canagliflozin will be well tolerated over 4 weeks.

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