Effect of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, on C‐peptide kinetics

Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves indices of b-cell function estimated based on circulating C-peptide and glucose concentrations (e.g., Homeostasis Model Assessment [HOMA2-% B], meal tolerance test-based indices). However, use of these beta-cell function indices assumes C-peptide kinetics are not altered by canagliflozin. This 2-period crossover study assessed the effect of a single canagliflozin 300-mg dose on C-peptide kinetics in 10 healthy participants. Two hours after receiving canagliflozin or placebo, participants received intravenous somatostatin infusion to suppress endogenous C-peptide secretion and 1 hour later received a bolus injection of synthetic human C-peptide 150 mg. Serum C-peptide was measured over 3 hours and urinary glucose and C-peptide excretion were measured. C-peptide kinetic parameters, including total clearance (CLtotal) and renal clearance (CLrenal), were calculated. Serum C-peptide profiles were similar following canagliflozin or placebo treatment. C-peptide CLtotal was slightly lower with canagliflozin versus placebo (mean (SD) of 190 (37) vs. 197 (30) mL/min; canagliflozin/placebo ratio [90% CI] = 96.1% [ 93.0%; 99.3%]). Other kinetic parameters, including CLrenal, were generally similar between treatments. Results indicate canagliflozin 300 mg does not meaningfully alter C-peptide clearance or other kinetic parameters; therefore, C-peptide-based measurements of insulin secretion are appropriate for assessing beta-cell function in canagliflozin-treated participants.