Different effects of two dipeptidyl peptidase-4 inhibitors and glimepiride on β-cell function in a newly designed two-step hyperglycemic clamp.

BACKGROUND

Dipeptidyl peptidase (DPP)-4 inhibitors and sulfonylureas may have different effects on islet function. We designed a new two-step hyperglycemic clamp to further compare the effects of sitagliptin, saxagliptin, and glimepiride on β-cell function and the incretin effect.

METHODS

The present study was a four-way cross-over open label randomized study. Twelve healthy male subjects were administered a single dose of sitagliptin (100 mg), saxagliptin (5 mg), glimepiride (2 mg) or blank control 2 h before undergoing a two-step hyperglycemic clamp (Step 1: only intravenous glucose was administered; Step 2: i.v. glucose loading was combined with oral glucose consumption). Two-phase insulin secretion, glucagon secretion, and incretin levels were measured during the clamp.

RESULTS

In Step 1, with i.v. glucose only, there were no differences between the effects of the three drugs on insulin secretion, except that saxagliptin increased second-phase insulin secretion more than glimepiride (P = 0.007). In Step 2, oral glucose consumption led to an approximate two fold increase in insulin secretion and both gliptins significantly increased first-phase insulin secretion compared with glimepiride (P = 0.003 for both). Saxagliptin further increased second-phase insulin secretion compared with glimepiride (P = 0.005) and sitagliptin (P < 0.001). Both gliptins significantly decreased glucagon secretion and increased active glucagon-like peptide-1 (GLP-1) compared with glimepiride, especially in Step 2.

CONCLUSIONS

The two-step hyperglycemic clamp appears to be a precise method to assess β-cell function by taking the effect of incretins into consideration. The oral glucose consumption adds to the i.v. glucose infusion, amplifying the differences in the effects of DPP-4 inhibitors and glimepiride on insulin secretion.