Pharmacokinetics and Pharmacodynamics of Vildagliptin in Healthy Chinese Volunteers

Hu, Pei; Yin, Qin; Deckert, Fabienne; Jiang, Ji; Liu, Dongyang; Kjems, Lise; Dole, William P.; He, Yan-Ling

doi:10.1177/0091270008325152

Cited by 56 publications

(44 citation statements)

References 25 publications

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“…The higher glucose infusion rates needed in the vagotomised subjects in order to achieve comparable glucose profiles, and thereby the lower GIGD, could be a consequence of the higher peak glucose levels probably caused by the accelerated gastric emptying. DPP4 inhibition reduced fasting PG in both groups, but had no effect on the glucose excursions, similar to previous observations in healthy subjects (41).…”

Section: Discussionsupporting

confidence: 91%

Characterisation of oral and i.v. glucose handling in truncally vagotomised subjects with pyloroplasty

Plamboeck

Veedfald

Deacon

et al. 2013

European Journal of Endocrinology

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ObjectiveGlucagon-like peptide 1 (GLP1) is rapidly inactivated by dipeptidyl peptidase 4 (DPP4), but may interact with vagal neurons at its site of secretion. We investigated the role of vagal innervation for handling of oral and i.v. glucose.Design and methodsTruncally vagotomised subjects (n=16) and matched controls (n=10) underwent 50 g-oral glucose tolerance test (OGTT)±vildagliptin, a DPP4 inhibitor (DPP4i) and isoglycaemic i.v. glucose infusion (IIGI), copying the OGTT without DPP4i.ResultsIsoglycaemia was obtained with 25±2 g glucose in vagotomised subjects and 18±2 g in controls (P<0.03); thus, gastrointestinal-mediated glucose disposal (GIGD) – a measure of glucose handling (100%×(glucoseOGTT−glucoseIIGI/glucoseOGTT)) – was reduced in the vagotomised compared with the control group. Peak intact GLP1 concentrations were higher in the vagotomised group. Gastric emptying was faster in vagotomised subjects after OGTT and was unaffected by DPP4i. The early glucose-dependent insulinotropic polypeptide response was higher in vagotomised subjects. Despite this, the incretin effect was equal in both groups. DPP4i enhanced insulin secretion in controls, but had no effect in the vagotomised subjects. Controls suppressed glucagon concentrations similarly, irrespective of the route of glucose administration, whereas vagotomised subjects showed suppression only during IIGI and exhibited hyperglucagonaemia following OGTT. DPP4i further suppressed glucagon secretion in controls and tended to normalise glucagon responses in vagotomised subjects.ConclusionsGIGD is diminished, but the incretin effect is unaffected in vagotomised subjects despite higher GLP1 levels. This, together with the small effect of DPP4i, is compatible with the notion that part of the physiological effects of GLP1 involves vagal transmission.

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Section: Discussionsupporting

confidence: 91%

Characterisation of oral and i.v. glucose handling in truncally vagotomised subjects with pyloroplasty

Plamboeck

Veedfald

Deacon

et al. 2013

European Journal of Endocrinology

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“…This result clearly demonstrates that sitagliptin is effective for improving postprandial hyperglycemia in non-diabetic subjects even though the action of incretin is glucosedependent. Although sitagliptin and vildagliptin were reported to have no effect on postprandial glucose level in subjects with NGT [13,15], we assume that the differences between this study and the previous (Fig. 1A, B), and the AUC of the plasma active GLP-1 level in the M+S group was greater than that in the M and S groups (Fig.…”

Section: Resultscontrasting

confidence: 54%

Effects of miglitol, sitagliptin or their combination on plasma glucose, insulin and incretin levels in non-diabetic men

et al. 2010

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α-Glucosidase inhibitors (αGIs) decrease plasma glucose and serum insulin levels in healthy subjects [1,2] and reduce the development of type 2 diabetes in subjects with impaired glucose tolerance (IGT) [3,4]. αGIs reportedly enhance active glucagon-like peptide-1 (GLP-1) responses and reduce total glucose-dependent insulinotropic polypeptide (GIP) responses [5][6][7]; however, their significance for protecting against the development of diabetes remains uncertain. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin, increase active GLP-1 and GIP by inhibiting DPP-4 enzymatic activity and improve hyperglycemia in a glucose-dependent fashion by increasing serum insulin and decreasing serum glucagon levels in diabetic patients [8] abstract. α-glucosidase inhibitors (αGIs) increase active glucagon-like peptide-1 (GLP-1) and reduce the total glucosedependent insulinotropic polypeptide (GIP) levels, but their ability to prevent diabetes remains uncertain. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin, increase active GLP-1 and GIP levels and improve hyperglycemia in a glucose-dependent fashion. However, the effectiveness of their combination in subjects with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) is uncertain. The present study evaluated the effect of miglitol, sitagliptin, and their combination on glucose, insulin and incretin levels in non-diabetic men. Miglitol and sitagliptin were administered according to four different intake schedules (C: no drug, M: miglitol; S: sitagliptin, M+S: miglitol and sitagliptin). The plasma glucose levels were significantly lower for M, S and M+S than for the control. The areas under the curve (AUCs) of the plasma active GLP-1 level in the M, S, and M+S groups were significantly greater than that in the control group. The AUC of the plasma active GLP-1 level was significantly greater for M+S group than for the M and S groups. The AUC of the plasma total GIP level was significantly smaller for M+S group than for the control and M and S groups. The results of our study suggest that miglitol, sitagliptin, or their combination contributes to the prevention of type 2 diabetes.

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“…These results are thus in agreement with findings in experimental animals (22), where increased levels of active hormones seemed to inhibit incretin secretion in a negative feed-back loop. Migoya et al (23) reported approximately twofold higher levels of intact GLP1 and GIP after acute (2 days') administration of sitagliptin, with similar effects on GLP1 being reported by Hu et al (24) after a 10-day period with once daily ingestion of 100 mg vildagliptin in ten healthy subjects (GIP and incretin effect were not measured). In contrast to the relatively sparse data on the impact of DPP4 inhibition on glucose metabolism and incretin levels in healthy subjects, the 'acute' effect of DPP4 inhibition in type 2 diabetes has been studied in more detail.…”

Section: European Journal Of Endocrinologysupporting

confidence: 56%

The impact of dipeptidyl peptidase 4 inhibition on incretin effect, glucose tolerance, and gastrointestinal-mediated glucose disposal in healthy subjects

Rhee

Østoft

Holst

et al. 2014

European Journal of Endocrinology

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Objective: Inhibition of dipeptidyl peptidase 4 (DPP4) is thought to intensify the physiological effects of the incretin hormones. We investigated the effects of DPP4 inhibition on plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1), incretin effect, glucose tolerance, gastrointestinal-mediated glucose disposal (GIGD) and gastric emptying in healthy subjects. Design: A randomised, controlled and open-labelled study. Methods: Ten healthy subjects (six women; age, 40G5 years (meanGS.E.M.); BMI, 24G3 kg/m 2 ; fasting plasma glucose, 5.1G0.2 mmol/l and HbA1c, 34G1 mmol/mol (5.3G0.1%)) were randomised to two-paired study days comprising a 4-h 50 g oral glucose tolerance test (OGTT) with paracetamol (A) and an isoglycaemic intravenous (i.v.) glucose infusion (B), with (A 1 CB 1 ) and without (A 2 CB 2 ) preceding administration of the DPP4 inhibitor sitagliptin. Results: Isoglycaemia was obtained in all subjects on the paired study days. Significant increases in fasting levels and OGTT-induced responses of active GLP1 and GIP were seen after DPP4 inhibition. No significant impact of DPP4 inhibition on fasting plasma glucose (5.1G0.1 vs 4.9G0.1 mmol/l, PZ0.3), glucose tolerance (area under the curve (AUC) for plasma glucose, 151G35 vs 137G26 mmol/l!min, PZ0.7) or peak plasma glucose during OGTT (8.5G0.4 vs 8.1G0.3 mmol/l, PZ0.3) was observed. Neither incretin effect (40G9% (without DPP4 inhibitor) vs 40G7% (with DPP4 inhibitor), PZ1.0), glucagon responses (1395G165 vs 1223G195 pmol/l!min, PZ0.41), GIGD (52G4 vs 56G5%, PZ0.40) nor gastric emptying (T max for plasma paracetamol: 86G9 vs 80G12 min, PZ0.60) changed following DPP4 inhibition. Conclusions: These results suggest that acute increases in active incretin hormone levels do not affect glucose tolerance, GIGD, incretin effect, glucagon responses or gastric emptying in healthy subjects.

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Pharmacokinetics and Pharmacodynamics of Vildagliptin in Healthy Chinese Volunteers

Cited by 56 publications

References 25 publications

Characterisation of oral and i.v. glucose handling in truncally vagotomised subjects with pyloroplasty

Characterisation of oral and i.v. glucose handling in truncally vagotomised subjects with pyloroplasty

Effects of miglitol, sitagliptin or their combination on plasma glucose, insulin and incretin levels in non-diabetic men

The impact of dipeptidyl peptidase 4 inhibition on incretin effect, glucose tolerance, and gastrointestinal-mediated glucose disposal in healthy subjects

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