Is glucagon‐like peptide‐1 fully protected by the dipeptidyl peptidase 4 inhibitor sitagliptin when administered to patients with type 2 diabetes?

Aim To evaluate the relationship between plasma dipeptidyl‐peptidase 4 (DPP‐4) activity and its protection of glucagon‐like peptide‐1 (GLP‐1) using the DPP‐4 inhibitor sitagliptin. Methods On four separate days, patients with type 2 diabetes (T2D) (n = 8; age: 59.9 ±10.8 [mean ±SD] years; body mass index [BMI]: 28.8 ±4.6 kg/m 2 ; glycated haemoglobin A1c [HbA1c]: 43.1 ±0.5 mmol/mol [6.6% ±1.7%]) received a 380‐minute continuous intravenous infusion of GLP‐1 (1.0 pmol × kg bodyweight −1 × minutes −1 ) and a double‐blind, single‐dose oral administration of sitagliptin in doses of 0 (placebo), 25, 100 and 200 mg. Results Plasma DPP‐4 activity decreased compared to baseline (placebo) with increasing doses of sitagliptin ( P < .01), reaching a maximal inhibition with the 100 mg dose. Levels of intact GLP‐1 increased with increasing doses of sitagliptin from placebo to 100 mg (area under curve [AUC] 7.2 [95%, CI; 12.1, 16.4] [placebo], 10.7 [16.1, 21.4] [25 mg], 11.7 [17.8, 23.6] [100 mg] nmol/L × 360 minutes [ P < .01]), but no further increase in intact GLP‐1 levels was observed with 200 mg of sitagliptin (11.5 [17.6, 23.4] nmol/L × 360 minutes) ( P = .80). Conclusion Our findings suggest that the sitagliptin dose of 100 mg is sufficient to inhibit both plasma and membrane‐bound DPP‐4 activity, presumably also leading to complete protection of endogenous GLP‐1 in patients with T2D.