Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Added to Ongoing Metformin Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Alone

Charbonnel B, Karasik A, Lu J, Wu M, Meininger G; Sitagliptin Study 020 Group. Diabetes Care. 2006;29:2638-2643.

Patients with type 2 diabetes mellitus (T2DM) often fail to achieve or maintain glycemic control while receiving monotherapy with antihyperglycemic agents, and many require combinations of therapies. The biguanide metformin (MET) is one of the most commonly used treatments for T2DM and that antihyperglycemic can lower hepatic glucose production and improve insulin resistance. Incretin hormones are gut-derived peptides released into circulation following the ingestion of a meal, and glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are peptides that account for the majority of incretin actions that occur during elevated glucose concentrations, including increased insulin release among patients with T2DM. GLP-1 also lowers glucagon secretion, causing reductions of fasting and post-meal glucose concentrations. Inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4) that inactivates both GLP-1 and GIP could increase the amount of incretin hormones that are active among patients with T2DM. DPP-4 inhibitors have been shown to improve glucose control by increasing levels of incretin hormones, therefore providing benefits for patients who have not achieved adequate glycemic control with MET alone.

The efficacy and safety of the DPP-4 inhibitor sitagliptin (SITA) were assessed among patients with T2DM who were receiving a stable dose of MET ≥1,500 mg/day as a monotherapy but had inadequate control of glycosylated hemoglobin A_1c (A1C), defined as ≥7% and ≤10%. Patients who were not taking an oral antihyperglycemic agent (OHA), were taking any OHA other than MET as monotherapy, or taking a combination of MET and another OHA were placed on MET alone for up to 19 weeks until their A1C met the criteria of ≥7% and ≤10%. A total of 1,464 patients were screened and 701 met inclusion criteria, after which they immediately entered a 2-week, single-blind, placebo run-in period followed by randomization to placebo or SITA 100 mg once daily in a 1:2 ratio for 24 weeks. Patients were administered rescue therapy with pioglitazone (PIO) that was continued until the end of the study if they exceeded the following fasting plasma glucose (FPG) limits: >15.0 mmol/L (270 mg/dL) from baseline through Week 6, >13.3 mmol/L (240 mg/dL) from Weeks 7 through 12, and >11.1 mmol/L (200 mg/dL) from Weeks 13 to 24.

A greater percentage of patients that received placebo than SITA withdrew from the study (19% vs 10%), and the most common reasons for discontinuation were lack of efficacy (5.5% vs 1.5%), withdrawal of consent (4.2% vs 2.2%), clinical adverse experiences (2.1% vs 2.4%), and lost to follow-up (2.1% vs 0.9%). At the conclusion of the study patients treated with SITA had significant reductions in the primary endpoint, which was change from baseline to Week 24 in A1C (-0.67% [-0.77 to -0.57] vs -0.02 [-0.15 to -0.10]; P <.001). A significantly greater proportion of patients treated with SITA than placebo achieved A1C <7% (47.0% vs 18.3%; P <0.001), and that group had a significant reduction in FPG (P <.001). Other significant improvements from baseline in the SITA compared to placebo group included fasting insulin (P <.050), fasting C-peptide (P <.010), homeostasis model assessment of β-cell function (HOMA-β) (P <.001), quantitative insulin sensitivity check index (P <.050), fasting proinsulin-to-insulin ratio at Week 24 (P <.010), decrease in 2-h post-meal glucose (P <.001), increase in 2-hour post-meal insulin (P <.050), 2-hour post-meal C-peptide (P <.001), 2-hour post-meal glucose total areas under the curve (AUC) (P <.001), 2-hour post-meal insulin total AUC (P <.010), 2-hour post-meal C-peptide AUC (P <.001), and 2-hour post-meal insulin-to-glucose AUC ratio (P <.001). A significantly smaller proportion of SITA-treated patients required glycemic rescue therapy (4.5% vs 13.5%; P <.001), and the time to initiation of rescue therapy was significantly longer for that group (P <.001). Patients treated with SITA also had significant decreases in total cholesterol, triglycerides, non-HDL cholesterol, and triglyceride-to-HDL cholesterol ratio, along with significant increases in HDL cholesterol; however, there were no significant between-group differences in LDL cholesterol, total cholesterol, triglycerides, HDL cholesterol, non-HDL cholesterol, triglyceride-to-HDL cholesterol ratio, or LDL cholesterol. The SITA group had no significant improvements in fasting proinsulin levels or homeostasis model assessment of insulin resistance.

The incidence of discontinuation due to adverse experiences was similar throughout the study among the placebo- and SITA-treated groups. The overall incidence of clinical adverse experiences, drug-related clinical adverse experiences, serious clinical adverse experiences, and drug-related serious clinical adverse experiences did not differ significantly between the two treatment groups, and there were no significant differences in the incidence of hypoglycemia or predefined gastrointestinal adverse experiences. Small but statistically significant (P <.05) decreases in body weight, ranging from -0.6 to -0.7 kg, were observed in both treatment groups but there was no significant between-group difference.

The results of this study demonstrate that the addition of SITA 100 mg once-daily to ongoing MET therapy is efficacious and well tolerated among patients with T2DM who have not achieved adequate glycemic control with MET monotherapy. Although none of the patients had reached the American Diabetes Association glycemic goal of A1C <7% while receiving MET monotherapy prior to this trial, nearly half of them did so while treated with SITA, compared to less than one-fifth of those receiving placebo during this study. Treatment with SITA also led to significant increases in measurements of β-cell function, including HOMA-β, an indicator of the ability of pancreatic β cells to secrete insulin under fasting conditions. Treatment with SITA also significantly increased the fasting proinsulin-to-insulin ratio, an indicator of improvements in β-cell function, along with improvements in postmeal glucose, insulin, C-peptide concentrations, and the insulin-to-glucose ratio. These results indicate that patients with T2DM who have inadequate glycemic control with MET alone can achieve multiple benefits from SITA 100 mg once daily, and that it is well tolerated while causing no significant changes in body weight.