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 β‐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 β‐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 µg. 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 β‐cell function in canagliflozin‐treated participants.