12 & 52 Week Efficacy of Dipeptidyl PeptidaseIV Inhibitor LAF237
12 & 52 Week Efficacy of Dipeptidyl PeptidaseIV Inhibitor LAF237
Objective: To assess the 12- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 versus placebo in patients with type 2 diabetes continuing metformin treatment.
Research Design and Methods: We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 107 patients with type 2 diabetes with a 40-week extension in those completing the core study and agreeing, together with the investigator, to extend treatment to 1 year. Placebo (n = 51) or LAF237 (50 mg once daily, n = 56) was added to ongoing metformin treatment (1,500-3,000 mg/day). HbA1c and fasting plasma glucose (FPG) were measured periodically, and standardized meal tests were performed at baseline, week 12, and week 52.
Results: In patients randomized to LAF237, baseline HbA1c averaged 7.7 ± 0.1% and decreased at week 12 (Δ = -0.6 ± 0.1%), whereas HbA1c did not change from a baseline of 7.9 ± 0.1% in patients given placebo (between-group difference in ΔHbA1c = -0.7 ± 0.1%, P < 0.0001). Mean prandial glucose and FPG were significantly reduced in patients receiving LAF237 versus placebo by 2.2 ± 0.4 mmol/l (P < 0.0001) and 1.2 ± 0.4 mmol/l (P = 0.0057), respectively, but plasma insulin levels were not affected. At end point of the extension, the between-group differences in change in mean prandial glucose, insulin, and FPG were -2.4 ± 0.6 mmol/l (P = 0.0001), 40 ± 16 pmol/l (P = 0.0153), and -1.1 ± 0.5 mmol/l (P = 0.0312), respectively. HbA1c did not change from week 12 to week 52 in LAF237-treated patients (n = 42) but increased in participants given placebo (n = 29). The between-group difference in ΔHbA1c after 1 year was -1.1 ± 0.2% (P < 0.0001).
Conclusions: Data from this study demonstrate that LAF237 effectively prevents deterioration of glycemic control when added to metformin monotherapy in type 2 diabetes.
The compound LAF237 is an agent that potentiates the effects of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) by inhibiting the enzyme responsible for their degradation (dipeptidyl peptidase IV [DPP-4]). In short-term studies, LAF237 inhibited plasma DPP-4 activity, increased circulating levels of intact GLP-1, and improved glucose tolerance in animal models of type 2 diabetes and in diabetic patients. Similar findings were reported for a related compound NVP DPP728, suggesting that DPP-4 inhibitors will be effective as monotherapy.
Given the documented therapeutic effects of GLP-1 agonists, both alone and in combination with metformin, we hypothesized that LAF237 would also be effective in metformin-treated patients. In view of the potential disease-modifying effects of the incretins, we further hypothesized that the efficacy of LAF237 would be maintained with long-term treatment. The present study tested these hypotheses by assessing the effects of LAF237 added to an ongoing stable dosage of metformin in patients with type 2 diabetes. In addition to providing "proof of concept" regarding the efficacy of a DPP-4 inhibitor combined with metformin, this study offers the first 52-week data on the efficacy and tolerability of a DPP-4 inhibitor.
Objective: To assess the 12- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 versus placebo in patients with type 2 diabetes continuing metformin treatment.
Research Design and Methods: We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 107 patients with type 2 diabetes with a 40-week extension in those completing the core study and agreeing, together with the investigator, to extend treatment to 1 year. Placebo (n = 51) or LAF237 (50 mg once daily, n = 56) was added to ongoing metformin treatment (1,500-3,000 mg/day). HbA1c and fasting plasma glucose (FPG) were measured periodically, and standardized meal tests were performed at baseline, week 12, and week 52.
Results: In patients randomized to LAF237, baseline HbA1c averaged 7.7 ± 0.1% and decreased at week 12 (Δ = -0.6 ± 0.1%), whereas HbA1c did not change from a baseline of 7.9 ± 0.1% in patients given placebo (between-group difference in ΔHbA1c = -0.7 ± 0.1%, P < 0.0001). Mean prandial glucose and FPG were significantly reduced in patients receiving LAF237 versus placebo by 2.2 ± 0.4 mmol/l (P < 0.0001) and 1.2 ± 0.4 mmol/l (P = 0.0057), respectively, but plasma insulin levels were not affected. At end point of the extension, the between-group differences in change in mean prandial glucose, insulin, and FPG were -2.4 ± 0.6 mmol/l (P = 0.0001), 40 ± 16 pmol/l (P = 0.0153), and -1.1 ± 0.5 mmol/l (P = 0.0312), respectively. HbA1c did not change from week 12 to week 52 in LAF237-treated patients (n = 42) but increased in participants given placebo (n = 29). The between-group difference in ΔHbA1c after 1 year was -1.1 ± 0.2% (P < 0.0001).
Conclusions: Data from this study demonstrate that LAF237 effectively prevents deterioration of glycemic control when added to metformin monotherapy in type 2 diabetes.
The compound LAF237 is an agent that potentiates the effects of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) by inhibiting the enzyme responsible for their degradation (dipeptidyl peptidase IV [DPP-4]). In short-term studies, LAF237 inhibited plasma DPP-4 activity, increased circulating levels of intact GLP-1, and improved glucose tolerance in animal models of type 2 diabetes and in diabetic patients. Similar findings were reported for a related compound NVP DPP728, suggesting that DPP-4 inhibitors will be effective as monotherapy.
Given the documented therapeutic effects of GLP-1 agonists, both alone and in combination with metformin, we hypothesized that LAF237 would also be effective in metformin-treated patients. In view of the potential disease-modifying effects of the incretins, we further hypothesized that the efficacy of LAF237 would be maintained with long-term treatment. The present study tested these hypotheses by assessing the effects of LAF237 added to an ongoing stable dosage of metformin in patients with type 2 diabetes. In addition to providing "proof of concept" regarding the efficacy of a DPP-4 inhibitor combined with metformin, this study offers the first 52-week data on the efficacy and tolerability of a DPP-4 inhibitor.
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