Efficacy of vildagliptin in combination with insulin in patients with type 2 diabetes and severe renal impairment.

BACKGROUND: The purpose of this study was to evaluate the efficacy of vildagliptin 50 mg once daily in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m(2)) and longstanding type 2 diabetes not adequately controlled with insulin therapy, which is a difficult-to-treat population, with limited therapeutic options and a high susceptibility to hypoglycemia. METHODS: This was a post hoc subanalysis of data obtained during a previously described randomized, double-blind, parallel-group, 24-week study comparing the efficacy and safety of vildagliptin 50 mg once daily versus placebo in patients with type 2 diabetes and moderate or severe renal impairment. The present data derive from 178 patients with severe renal impairment (baseline estimated glomerular filtration rate approximately 21 mL/min/1.73 m(2), 100 randomized to vildagliptin, 78 randomized to placebo), all of whom were receiving insulin therapy (alone or in combination with an oral antidiabetic agent) for longstanding type 2 diabetes (mean approximately 19 years). RESULTS: With vildagliptin in combination with insulin, the adjusted mean change (AMΔ) in HbA(1c) from baseline (7.7% ± 0.1%) was -0.9% ± 0.4% and the between-treatment difference (vildagliptin - placebo) was -0.6% ± 0.2% (P < 0.001). The percentage of patients achieving endpoint HbA(1c) < 7.0% was significantly higher with vildagliptin than placebo (45.2% versus 22.8%, P = 0.008). When added to insulin, vildagliptin and placebo had comparable hypoglycemic profiles and did not cause weight gain. Both treatments were similarly well tolerated, with comparable incidences of adverse events, serious adverse events, and deaths. CONCLUSION: When added to insulin therapy in patients with severe renal impairment and longstanding type 2 diabetes, vildagliptin 50 mg once daily was efficacious, eliciting HbA(1c) reductions consistent with those previously reported for a patient population with much more recent onset of type 2 diabetes and normal renal function, and had a hypoglycemic profile comparable with placebo. Accordingly, vildagliptin is a suitable treatment option for patients with advanced type 2 diabetes and impaired renal function who require insulin therapy and present a serious therapeutic challenge in clinical practice.

Efficacy and safety of nateglinide in type 2 diabetic patients with modest fasting hyperglycemia.

Nateglinide is a fast-acting insulin secretion agent that specifically targets postprandial hyperglycemia in patients with type 2 diabetes. The recent reduction in the diagnostic criteria for diabetes and improved understanding of the importance of early insulin secretion served as the rationale for this multicenter, double-blind, randomized, parallel-group, 24-wk study performed in 675 patients with type 2 diabetes but only moderately elevated fasting plasma glucose (FPG) (FPG = 7.0-8.3 mmol/liter) to assess the efficacy and safety of three fixed doses of nateglinide (30, 60, or 120 mg, with meals). A substudy of the effects on early insulin release and prandial glucose excursions following a standardized breakfast was performed in 127 subjects. Nateglinide was well tolerated and elicited a dose-dependent reduction of placebo-adjusted hemoglobin A(1c) (Delta = -0.26 to -0.39%) and FPG (Delta = -0.51 to -0.73 mmol/liter) accompanied by a dose-related increase in suspected hypoglycemic episodes. However, confirmed hypoglycemia occurred in only 5.3% of patients treated with the highest dose, compared with 1.2% in placebo-treated patients (P < 0.05). Nateglinide increased early insulin release and reduced prandial glucose excursions (P < 0.05 vs. placebo). In sum, nateglinide is a safe and effective therapeutic option for treatment of patients with mild to moderate fasting hyperglycemia.

Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) has been proposed as a new treatment modality for type 2 diabetes. To circumvent the drawback of the short half-life of GLP-1, inhibitors of the GLP-1-degrading enzyme dipeptidyl peptidase IV (DPP IV) have been examined. Such inhibitors improve glucose tolerance in insulin-resistant rats and mice. In this study, we examined the 4-week effect of 1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP DPP728), a selective, orally active inhibitor of DPP IV, in subjects with diet-controlled type 2 diabetes in a placebo-controlled double-blind multicenter study. RESEARCH DESIGN AND METHODS: A total of 93 patients (61 men and 32 women), aged 64 +/- 9 years (means +/- SD) and with BMI 27.3 +/- 2.7 kg/m(2), entered the study. Fasting blood glucose was 8.5 +/- 1.5 mmol/l, and HbA(1c) was 7.4 +/- 0.7%. Before and after treatment with NVP DPP728 at 100 mg x 3 (n = 31) or 150 mg x 5 (n = 32) or placebo (n = 30), subjects underwent a 24-h study with standardized meals (total 2,000 kcal). RESULTS: Compared with placebo, NVP DPP728 at 100 mg t.i.d. reduced fasting glucose by 1.0 mmol/l (mean), prandial glucose excursions by 1.2 mmol/l, and mean 24-h glucose levels by 1.0 mmol/l (all P < 0.001). Similar reductions were seen in the 150-mg b.i.d. treatment group. Mean 24-h insulin was reduced by 26 pmol/l in both groups (P = 0.017 and P = 0.023). Although not an efficacy parameter foreseen in the study protocol, HbA(1c) was reduced to 6.9 +/- 0.7% in the combined active treatment groups (P < 0.001). Laboratory safety and tolerability was good in all groups. CONCLUSIONS: We conclude that inhibition of DPP IV is a feasible approach to the treatment of type 2 diabetes in the early stage of the disease.