Effect of Single Oral Doses of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on Incretin and Plasma Glucose Levels after an Oral Glucose Tolerance Test in Patients with Type 2 Diabetes

Herman, Gary; Bergman, Arthur; Stevens, C. Melinda; Kotey, Paul; Yi, Bingming; Zhao, Peng; Dietrich, Bruno; Golor, George; Schrodter, Andreas; Keymeulen, Bart; Lasseter, Kenneth C.; Kipnes, Mark; Snyder, Karen; Hilliard, Deborah; Tanen, Michael; Cilissen, Caroline; Smet, M. De; Lepeleire, Inge De; Dyck, Kristien Van; Wang, Amy Q.; Zeng, Wei; Davies, Michael J.; Tanaka, Wesley; Holst, Jens J.; Deacon, Carolyn F.; Gottesdiener, Keith; Wagner, John A.

doi:10.1210/jc.2006-1009

Cited by 476 publications

(500 citation statements)

References 23 publications

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“…This increase in the halflife of liraglutide is most likely to be mediated via a lower susceptibility to metabolism by DPP-IV [20] and a high degree of albumin binding of liraglutide (as has been shown for other fatty acid derivatives [21,22]); moreover, after subcutaneous administration, an additional prolongation of the half-life is mediated by slow absorption of liraglutide from the injection site, as evidenced by the further increase in half-life observed with subcutaneous vs intravenous administration. Thus, liraglutide treatment probably induces much higher plasma levels compared with native GLP-1 concentration in plasma [19,23,24]. Therefore, the concentration of liraglutide required to produce beneficial effects in HUVECs (0.1 μg/ml=26.6 nmol/l) might be achievable with the therapeutic doses used to treat patients with type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

et al. 2010

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Aims/hypothesis Glucagon-like peptide-1 (GLP-1), a member of the proglucagon-derived peptide family, was seen to exert favourable actions on cardiovascular function in preclinical and clinical studies. The mechanisms through which GLP-1 modulates cardiovascular function are complex and incompletely understood. We thus investigated whether the GLP-1 analogue, liraglutide, which is an acylated GLP-1, has protective effects on vascular endothelial cells. Methods Nitrite and nitrate were measured in medium with an automated nitric oxide detector. Endothelial nitric oxide synthase (eNOS) activation was assessed by evaluating the phosphorylation status of the enzyme and evaluating eNOS activity by citrulline synthesis. Nuclear factor κB (NF-κB) activation was assessed by reporter gene assay. Results Liraglutide dose-dependently increased nitric oxide production in HUVECs. It also caused eNOS phosphorylation, potentiated eNOS activity and restored the cytokineinduced downregulation of eNOS (also known as NOS3) mRNA levels, which is dependent on NF-κB activation. We therefore examined the effect of liraglutide on TNFα-induced NF-κB activation and NF-κB-dependent expression of proinflammatory genes. Liraglutide dose-dependently inhibited NF-κB activation and TNFα-induced IκB degradation. It also reduced TNFα-induced MCP-1 (also known as CCL2), VCAM1, ICAM1 and E-selectin mRNA expression. Liraglutide-induced enhancement of nitric oxide production and suppression of NF-κB activation were attenuated by the AMP-activated protein kinase (AMPK) inhibitor compound C or AMPK (also known as PRKAA1) small interfering RNA. Indeed, liraglutide induced phosphorylation of AMPK, which occurs through a signalling pathway independent of cyclic AMP. Conclusions/interpretation Liraglutide exerts an antiinflammatory effect on vascular endothelial cells by increasing nitric oxide production and suppressing NF-κB activation, partly at least through AMPK activation. These effects may explain some of the observed vasoprotective properties of liraglutide, as well as its beneficial effects on the cardiovascular system.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

et al. 2010

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“…Thus, it was shown that good glycemic control could be achieved with lower sulfonylurea doses by administering sitagliptin. These results suggest that β‐cell function is actually well activated with combined use of sulfonylurea drugs and DPP‐4 inhibitors, although the effect of sitagliptin to lower glucagon 4 might also contribute to the reduced sulfonylurea doses. It is coming to be understood that incretin not only promotes the insulin release reaction in β‐cells 5,23 , but it also stimulates the insulin secretion response through multiple actions 24 , such as promoting adenosine triphosphate generation in mitochondria 25 , and both sulfonylurea and incretin act on exchange protein directly activated by cyclic adenosine monophosphate 2A in β‐cells 26,27 .…”

Section: Discussionmentioning

confidence: 93%

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

Kubota

Maeda

Kanamori

et al. 2012

J of Diabetes Invest

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(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00221.x, 2012) Aims/Introduction: To determine the efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients after 3 months’ therapy.Materials and Methods: A retrospective, observational study of 741 type 2 diabetes patients was carried out; 110 received sitagliptin monotherapy, and 631 received combination therapy with sitagliptin when other oral medications were insufficient. The primary outcome measure was glycated hemoglobin (HbA1c) measured at 0, 4 and 12 weeks of sitagliptin therapy.Results: In the monotherapy and combination therapy groups, HbA1c decreased significantly after 12 weeks. Target HbA1c (<7%) was achieved in 39.1% overall. On logistic regression analysis, baseline HbA1c was the strongest contributing factor for achieving target HbA1c; baseline body mass index and duration of diabetes were also significant factors. A total of 82 patients (11%) were unresponsive to sitagliptin. These patients’ baseline body mass index was significantly higher and their baseline HbA1c was significantly lower than those of patients who responded to sitagliptin. The most commonly co‐administered drugs were sulfonylureas (508 patients). In these patients, the dose of sulfonylurea decreased with time. In 66 patients whose sulfonylurea dosage was reduced when sitagliptin was started, HbA1c and bodyweight decreased significantly after 12 weeks. A total of 24 patients receiving sulfonylureas had mild hypoglycemia, but none discontinued sitagliptin.Conclusions: Sitagliptin was effective and safe as both monotherapy and combination therapy in Japanese type 2 diabetes patients. When sulfonylureas were ineffective, sitagliptin improved glycemic control. In patients whose sulfonylurea dose was reduced at the start of sitagliptin, blood glucose improved and bodyweight decreased after 12 weeks.

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“…In patients with type 2 diabetes, Ն80% inhibition of plasma DPP-4 activity with single doses of sitagliptin produced twoto threefold increases in active GLP-1 and GIP levels, increased insulin and Cpeptide levels, reduced plasma glucagon levels, and reduced glycemic excursion following an oral glucose tolerance test (9). Two 12-week studies in patients with type 2 diabetes demonstrated that sitagliptin dose-dependently reduced HbA 1c (A1C) and fasting plasma glucose (FPG), with a neutral effect on body weight and incidences of hypoglycemia and gastrointestinal adverse experiences similar to placebo (16,17).…”

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confidence: 99%

Effect of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin as Monotherapy on Glycemic Control in Patients With Type 2 Diabetes

et al. 2006

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FOR THE SITAGLIPTIN STUDY 021 GROUP*OBJECTIVE -To examine the efficacy and safety of once-daily oral sitagliptin as monotherapy in patients with type 2 diabetes. RESULTS -Sitagliptin 100 and 200 mg produced significant (P Ͻ 0.001) placebosubtracted reductions in A1C (Ϫ0.79 and Ϫ0.94%, respectively) and fasting plasma glucose (Ϫ1.0 mmol/l [Ϫ17.1 mg/dl] and Ϫ1.2 mmol/l [Ϫ21.3 mg/dl], respectively). Patients with baseline A1C Ն9% had greater reductions in placebo-subtracted A1C with sitagliptin 100 and 200 mg (Ϫ1.52 and Ϫ1.50%, respectively) than those with baseline A1C Ͻ8% (Ϫ0.57 and Ϫ0.65%) or Ն8 to Ͻ9.0% (Ϫ0.80 and Ϫ1.13%, respectively). In a meal tolerance test, sitagliptin 100 and 200 mg significantly decreased 2-h postprandial glucose (PPG) (placebo-subtracted PPG Ϫ2.6 mmol/l [Ϫ46.7 mg/dl] and Ϫ3.0 mmol/l [Ϫ54.1 mg/dl], respectively). Results for the above key efficacy parameters were not significantly different between sitagliptin doses. Homeostasis model assessment of ␤-cell function and proinsulin-to-insulin ratio improved with sitagliptin. The incidence of hypoglycemia was similar, and overall gastrointestinal adverse experiences were slightly higher with sitagliptin. No meaningful body weight changes from baseline were observed with sitagliptin 100 (Ϫ0.2 kg) or 200 mg (Ϫ0.1 kg). The body weight change with placebo (Ϫ1.1 kg) was significantly (P Ͻ 0.01) different from that observed with sitagliptin. RESEARCH DESIGN AND METHODSCONCLUSIONS -In this 24-week study, once-daily sitagliptin monotherapy improved glycemic control in the fasting and postprandial states, improved measures of ␤-cell function, and was well tolerated in patients with type 2 diabetes.

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Effect of Single Oral Doses of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on Incretin and Plasma Glucose Levels after an Oral Glucose Tolerance Test in Patients with Type 2 Diabetes

Cited by 476 publications

References 23 publications

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

Effect of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin as Monotherapy on Glycemic Control in Patients With Type 2 Diabetes

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