GLP-1 agonists and DPP-4 inhibitors in combination with agents other than metformin
The addition of liraglutide 0.6 mg, 1.2 mg, or 1.8 mg; rosiglitazone 4 mg; or placebo to glimepiride 2 mg to 4 mg was compared in patients with inadequately controlled blood glucose on monotherapy or combination therapy, excluding insulin (N=1041).49 After 26 weeks, the mean A1C level decreased 1.1% with either liraglutide 1.2 mg or 1.8 mg once daily and 0.4% with rosiglitazone 4 mg daily but increased 0.2% with placebo (all, P<.0001). Similarly, the decrease in FPG was significantly greater with liraglutide 1.2 mg and 1.8 mg compared with placebo (treatment difference, 47 mg/dL; P<.0001) and rosiglitazone 4 mg (treatment difference, 13 mg/dL; P<.006). Reductions in PPG were also significantly greater with liraglutide 1.2 mg and 1.8 mg (45 and 49 mg/dL, respectively) than with rosiglitazone 4 mg (32 mg/dL; P≤.043 vs liraglutide 1.2 mg; P=.0022 vs liraglutide 1.8 mg) and placebo (7 mg/dL; P<.0001 for both liraglutide doses).
Two trials have investigated treatment with a DPP-4 inhibitor in combination with a thiazolidinedione. In 1 trial, patients (N=353) were randomized to receive sitagliptin 100 mg once daily or placebo in combination with pioglitazone 30 mg to 45 mg daily.50 After 24 weeks, the mean A1C level decreased 0.9% with the addition of sitagliptin and 0.2% with placebo (P<.001). The FPG level decreased 17 mg/dL in the sitagliptin group and increased 1 mg/dL in the placebo group (P<.001). Similar changes in A1C and FPG levels were observed in another trial involving the addition of saxagliptin 2.5 mg or 5 mg once daily to pioglitazone 30 mg to 45 mg or rosiglitazone 4 mg to 8 mg once daily.51 Reduction in the PPG area under the curve was greater with either dose of saxagliptin than with placebo.
The addition of saxagliptin to a submaximal dose of glyburide was compared with uptitration of glyburide in 768 patients with T2DM.52 Patients were randomized to receive saxagliptin 2.5 mg or 5 mg once daily in combination with glyburide 7.5 mg once daily, or glyburide 10 mg to 15 mg once daily for 24 weeks. The mean A1C level decreased 0.5% and 0.6% in the saxagliptin 2.5 mg and 5 mg groups, respectively, and increased 0.1% in the glyburide uptitration group (P<.0001 vs both saxagliptin groups). The FPG level decreased 7 and 10 mg/dL in the saxagliptin 2.5 mg and 5 mg groups, respectively, and increased 1 mg/dL in the glyburide uptitration group (P=.0218 and P=.002, respectively). Similar changes were observed in PPG (P<.0001).
These trials demonstrate that the efficacy of GLP-1 agonists and DPP-4 inhibitors extend to combined use with agents other than metformin.
Extensive experience from randomized clinical trials demonstrates the efficacy of GLP-1 agonists and DPP-4 inhibitors as monotherapy and in combination with metformin and other agents, although reductions in FPG and PPG, and consequently A1C, are greater with GLP-1 agonists than with DPP-4 inhibitors. This difference may result from the pharmacologic levels of GLP-1 activity that are achieved with the GLP-1 agonists and their direct action on the GLP-1 receptor. The GLP-1 agonists have attributes that would make either of them an appropriate choice in the management of all 3 patients in our case studies, while either DPP-4 inhibitor would be an appropriate choice for Case 1. Differences in dosing, administration, safety, and tolerability should be considered.