Is glucagon-like peptide-1 fully protected by dipeptidyl peptidase 4 inhibitor administration in patients with type 2 diabetes?

AIMS: Glucagon-like peptide-1 (GLP-1) is rapidly degraded by the enzyme dipeptidyl peptidase 4 (DPP-4), which exists in a soluble form in plasma and a membrane-bound form. Whether measurement of plasma DPP-4 activity reflects total DPP-4 activity, and whether this measurement correlates with protection of GLP-1 remains unclear. We used the DPP-4 inhibitor sitagliptin to evaluate the relationship between plasma DPP-4 activity and protection of GLP-1 infused intravenously to allow quantitative estimation of the degradation.

MATERIALS AND METHODS: On four separate study 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/m2 ; 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 body weight-1 × min-1 ) and double-blinded, single-dose oral administration of sitagliptin in different doses: 0 [placebo], 25, 100 and 200 mg, respectively.

RESULTS: Plasma DPP-4 activity decreased compared to baseline (placebo) with increasing doses of sitagliptin (P<0.01), 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 × (360min), (P<0.01)), but no further increase in intact GLP-1 levels was observed with 200 mg of sitagliptin (11.5 [17.6;23.4] nmol/l × (360min), (P=0.80).

CONCLUSIONS: Our findings suggest that the sitagliptin dose of 100 mg is sufficient to inhibit both plasma and membrane-bound DPP-4 activity presumably leading to a complete protection also of endogenous GLP-1 in patients with T2D.