As noted earlier, the proteolytic action of DPP-IV rapidly degrades GLP-1 in the circulation, and inhibitors of DPP-IV suppress this degradation of endogenous GLP-1, thereby increasing the half-life and actions of the hormone.37 A number of orally available DPP-IV inhibitors are currently in clinical development and they seem to reduce the activity of DPP-IV by 75% or more, thereby increasing endogenous GLP-1 hormone concentrations.94 Early clinical studies in drug naïve patients report that DPP-IV inhibitors improve glycemic control by increasing basal and postprandial GLP-1 concentrations and reducing postprandial glucagon secretion, leading to reduced postprandial and fasting glucose concentrations. An interesting aspect of this pharmacological approach is the ubiquitous effect of the DPP-IV enzyme, which cleaves an array of circulating peptides and hormones, and as such, it is not yet known whether this approach presents unanticipated safety issues. Some researchers have speculated that the glycemic effect of the DPP-IV inhibitors may be mediated through some non-GLP-1 related pathway.94 The preliminary results of investigations with DPP-IV inhibitors in patients with diabetes have demonstrated reductions in A1C and reasonable tolerability, with no effects on body weight.95 Among all the DPP-IV inhibitors being studied, two compounds, sitagliptin (MK-0431, Merck and Co., Inc, Whitehouse Station, NJ) and vildagliptin (LAF237, Novartis International AG, Basel, Switzerland), have advanced the furthest in clinical development, with US New Drug Applications filed for both in 2006.
Sitagliptin (MK-0431, Merck and Co., Inc. Whitehouse Station, NJ), is a β-amino acid derived DPP-IV inhibitor, currently in late-stage clinical development. In a small number of patients, sitagliptin has been reported to reduce plasma glucose concentrations with concomitant increase in plasma concentrations of insulin, C-peptide, as well as active GLP-1, and reduction in plasma glucagon concentrations.96 No significant effects on changes in body weight have been reported with sitagliptin in patients with type 2 diabetes. Sitagliptin has also been shown to inhibit DPP-IV activity by 80%, resulting in a 2-fold increase in postprandial plasma GLP-1 concentration.97 Clinical adverse events associated with sitagliptin were qualitatively similar to those seen with placebo, and were generally mild and transient.97
Vildagliptin (LAF237, Novartis International AG, Basel, Switzerland), a cyanopyrrolidide-based DPP-IV inhibitor, also in late stage clinical development, has been reported to reduce fasting and postprandial glucose concentrations.98 Furthermore, it also increased basal and postprandial GLP-1 concentrations.98,98 In a 12-week clinical trial in patients with type 2 diabetes, not treated with other oral antidiabetic agents, treatment with vildagliptin (50 mg/day and 100 mg/day) showed an reduction in A1C of -0.53 and -0.56%, at doses of 100 mg/day and 50 mg/day respectively , with improvements in fasting plasma glucose, 4-hour postprandial plasma glucose, 4-hour postprandial insulin, without significant changes in body weight.100 Similar improvements in glycemic control were reported in a 52-week clinical trial of patients with type 2 diabetes treated with stable doses of metformin and 50 mg/day vildagliptin.101 The most frequently reported adverse events in these trials were consistent with mild hypoglycemia.100,101
Table 1. Summary of Randomized clinical trials with GLP-1
|
Authors |
Number of Patients |
Duration of treatment |
Treatment groups |
Primary Endpoint |
Summary of Results |
|---|---|---|---|---|---|
|
Juntti-Berggren et al.62 |
12 |
1 week |
GLP-1 (IV infusion) +regular insulin and NPH insulin vs. regular insulin and NPH insulin |
Glucose |
Addition of GLP-1 significantly lowered blood glucose concentrations. Improvement in lipid profile with GLP-1 when added to intensive insulin therapy. |
|
Larsen et al.63 |
40 |
1 week |
GLP-1 (SC infusion) for 16h or. 24h vs. placebo |
24-h plasma glucose |
Dose-dependent reduction in mean plasma glucose. Optimal control seen with 24-h infusion only. Dose related increase in nausea, headache and vomiting with GLP-1 infusion. |
|
Meneilly et al.64 |
16 |
12 weeks |
GLP-1 (SC infusion) vs. conventional oral therapy |
A1C and mean plasma glucose |
No significant change in A1C. Enhanced glucose dependent insulin secretion and enhanced insulin-mediated glucose disposal in the group infused with GLP-1. Hypoglycaemia more frequent in conventional therapy patients than in GLP-1 treated patients. |
|
Zander et al.65 |
8 |
2 days |
GLP-1 (SC infusion) ± pioglitazone (30 mg, qd) vs. pioglitazone (30 mg, qd) vs. saline |
Fasting and 24-h mean plasma glucose |
Additive and significant reduction in mean plasma glucose with addition of GLP-1 to pioglitazone. Reduction in appetite sensation with GLP-1 infusion. |