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The Dipeptidyl Peptidase-4 Inhibitor Vildagliptin Improves ß-cell Function and Insulin Sensitivity in Subjects with Impaired Fasting Glucose

¹Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System and University of Washington, Seattle, WA
²Northwest Lipid Metabolism and Diabetes Research Laboratories,; University of Washington, Seattle, WA
³ Novartis Institute of Biomedical Research, Cambridge, MA
⁴Novartis Pharmaceuticals, East Hanover, NJ
⁵ Biomedical Sciences, Panum Institute, University of Copenhagen, ; Copenhagen, Denmark

kutzschn{at}u.washington.edu

ABSTRACT

Objective: To evaluate the effect of treatment with the DPP-4 inhibitor vildagliptin on insulin sensitivity and ß-cell function in subjects with impaired fasting glucose (IFG).

Research Design and Methods: Twenty-two subjects with IFG (11F/11M, age 59.6±11.5 years, mean±SD) were treated with vildagliptin 100 mg po daily in a single-blind study. Subjects received placebo for 2 weeks (run-in) followed by vildagliptin for 6 weeks (treatment) and then placebo for 2 weeks (washout). A frequently sampled intravenous glucose tolerance test (FSIGT) followed by a 2-hour meal tolerance test (MTT) was performed at 2, 8 and 10 weeks. From the FSIGT the acute insulin response to glucose (AIRg) and insulin sensitivity (S_I) were determined and used to compute the disposition index (AIRg x S_I) as a measure of ß-cell function.

Results: Fasting plasma glucose did not change after 6 weeks of vildagliptin treatment. With treatment AIRg increased from 224±44 to 286±52 pM (mean±SEM; p<0.05) and S_I improved from 2.8±0.5 to 3.5±0.5 x 10^–5 min^–1/pM (p<0.01), resulting in an increase in the disposition index from 688±180 to 1164±318 x10^–5/min (p<0.05). These effects were not sustained after washout. During the MTT the incremental area under the curve glucose was significantly decreased after treatment (240±15 vs. 191±14 mM.min; mean±SEM, p=0.002) but this effect was not sustained after washout.

Conclusions: The DPP-4 inhibitor vildagliptin improves insulin sensitivity and ß-cell function leading to improved post-prandial glycemia in subjects with IFG, who are known to have ß-cell dysfunction. Thus, vildagliptin may prevent progression to diabetes in high-risk subjects.

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